Elementary school girls with particular emotional and behavioral symptoms, including irritability, were significantly more likely to experience anxiety disorders in adolescence and young adulthood, based on data from a network analysis of 932 girls.

Data from previous studies suggest that targeting emotional problems in early childhood might prevent mental health disorders in young adults, wrote Alexandra Rouquette, MD, PhD, of Paris-Saclay University, Paris, and her colleagues. “However, these interventions are challenging to implement because we lack knowledge on which specific childhood symptoms have predictive associations with adult psychopathologic disorders,” they said.

In the study, published in JAMA Psychiatry, the researchers used data from an ongoing longitudinal prospective analysis of kindergarten children in the Canadian province of Quebec to assess potential “bridge symptoms,” defined as those that might affect the development of anxiety later in life. The study population included 932 girls whose parents completed the Social Behavior Questionnaire (SBQ) at baseline when the girls were 6 years old, and again at ages 8 and 10 years. Of these, 780 participants underwent screening for mental health disorders at age 15 and/or 22 years.

Of the 780 participants assessed at follow-up, 270 (35%) had developed at least one anxiety disorder, and 128 (16%) had developed at least one diagnosis of major depression or another depressive disorder.

The researchers used a network analysis technique to review 33 items in the SBQ and how they related to future anxiety disorders. They identified five bridge symptoms – irritability, blaming others, not being liked by others, frequent crying, and solitary behavior – as having “a distinctive position in the network because most of the direct relationships between the disruptive and internalized communities transited through them.”

In addition, children who were disobedient, irritable, and not liked by others had the strongest and earliest association with anxiety disorders over time, the researchers said. By contrast, the kicks disruptive symptom in early childhood was a negative predictor of anxiety disorders at follow-up.

The study findings were limited by several factors, including the relatively small study population, the number of statistical tests performed, and the challenges of identifying anxiety disorders at follow-up. However, the results support the potential role of childhood bridge symptoms in later life anxiety, the researchers said. “Clinicians may wish to focus on these bridge symptoms when assessing patients,” they noted, because those symptoms could be “early targets in disease-prevention and health-promotion interventions.”

The researchers had no financial conflicts to disclose. The study was funded by a grant to Dr. Rouquette from the OpenHealth Institute.

SOURCE: Rouquette A et al. JAMA Psychiatry. 2018 Aug 15. doi: 10.1001/jamapsychiatry.2018.2119.

Elementary school girls with particular emotional and behavioral symptoms, including irritability, were significantly more likely to experience anxiety disorders in adolescence and young adulthood, based on data from a network analysis of 932 girls.

Data from previous studies suggest that targeting emotional problems in early childhood might prevent mental health disorders in young adults, wrote Alexandra Rouquette, MD, PhD, of Paris-Saclay University, Paris, and her colleagues. “However, these interventions are challenging to implement because we lack knowledge on which specific childhood symptoms have predictive associations with adult psychopathologic disorders,” they said.

In the study, published in JAMA Psychiatry, the researchers used data from an ongoing longitudinal prospective analysis of kindergarten children in the Canadian province of Quebec to assess potential “bridge symptoms,” defined as those that might affect the development of anxiety later in life. The study population included 932 girls whose parents completed the Social Behavior Questionnaire (SBQ) at baseline when the girls were 6 years old, and again at ages 8 and 10 years. Of these, 780 participants underwent screening for mental health disorders at age 15 and/or 22 years.

Of the 780 participants assessed at follow-up, 270 (35%) had developed at least one anxiety disorder, and 128 (16%) had developed at least one diagnosis of major depression or another depressive disorder.

The researchers used a network analysis technique to review 33 items in the SBQ and how they related to future anxiety disorders. They identified five bridge symptoms – irritability, blaming others, not being liked by others, frequent crying, and solitary behavior – as having “a distinctive position in the network because most of the direct relationships between the disruptive and internalized communities transited through them.”

In addition, children who were disobedient, irritable, and not liked by others had the strongest and earliest association with anxiety disorders over time, the researchers said. By contrast, the kicks disruptive symptom in early childhood was a negative predictor of anxiety disorders at follow-up.

The study findings were limited by several factors, including the relatively small study population, the number of statistical tests performed, and the challenges of identifying anxiety disorders at follow-up. However, the results support the potential role of childhood bridge symptoms in later life anxiety, the researchers said. “Clinicians may wish to focus on these bridge symptoms when assessing patients,” they noted, because those symptoms could be “early targets in disease-prevention and health-promotion interventions.”

The researchers had no financial conflicts to disclose. The study was funded by a grant to Dr. Rouquette from the OpenHealth Institute.

SOURCE: Rouquette A et al. JAMA Psychiatry. 2018 Aug 15. doi: 10.1001/jamapsychiatry.2018.2119.

Elementary school girls with particular emotional and behavioral symptoms, including irritability, were significantly more likely to experience anxiety disorders in adolescence and young adulthood, based on data from a network analysis of 932 girls.

Data from previous studies suggest that targeting emotional problems in early childhood might prevent mental health disorders in young adults, wrote Alexandra Rouquette, MD, PhD, of Paris-Saclay University, Paris, and her colleagues. “However, these interventions are challenging to implement because we lack knowledge on which specific childhood symptoms have predictive associations with adult psychopathologic disorders,” they said.

In the study, published in JAMA Psychiatry, the researchers used data from an ongoing longitudinal prospective analysis of kindergarten children in the Canadian province of Quebec to assess potential “bridge symptoms,” defined as those that might affect the development of anxiety later in life. The study population included 932 girls whose parents completed the Social Behavior Questionnaire (SBQ) at baseline when the girls were 6 years old, and again at ages 8 and 10 years. Of these, 780 participants underwent screening for mental health disorders at age 15 and/or 22 years.

Of the 780 participants assessed at follow-up, 270 (35%) had developed at least one anxiety disorder, and 128 (16%) had developed at least one diagnosis of major depression or another depressive disorder.

The researchers used a network analysis technique to review 33 items in the SBQ and how they related to future anxiety disorders. They identified five bridge symptoms – irritability, blaming others, not being liked by others, frequent crying, and solitary behavior – as having “a distinctive position in the network because most of the direct relationships between the disruptive and internalized communities transited through them.”

In addition, children who were disobedient, irritable, and not liked by others had the strongest and earliest association with anxiety disorders over time, the researchers said. By contrast, the kicks disruptive symptom in early childhood was a negative predictor of anxiety disorders at follow-up.

The study findings were limited by several factors, including the relatively small study population, the number of statistical tests performed, and the challenges of identifying anxiety disorders at follow-up. However, the results support the potential role of childhood bridge symptoms in later life anxiety, the researchers said. “Clinicians may wish to focus on these bridge symptoms when assessing patients,” they noted, because those symptoms could be “early targets in disease-prevention and health-promotion interventions.”

The researchers had no financial conflicts to disclose. The study was funded by a grant to Dr. Rouquette from the OpenHealth Institute.

SOURCE: Rouquette A et al. JAMA Psychiatry. 2018 Aug 15. doi: 10.1001/jamapsychiatry.2018.2119.

The relationship between the immune system and tumors is complex and dynamic, and for immunotherapy to reach its full potential it will likely need to attack on multiple fronts. Here, we discuss some of the latest and most promising developments in the immuno-oncology field designed to build on the successes and address limitations.

The anti-tumor immune response

Cancer is a disease of genomic instability, whereby genetic alterations ranging from a single nucleotide to the whole chromosome level frequently occur. Although cancers derive from a patient’s own tissues, these genetic differences can mark the cancer cell as non-self, triggering an immune response to eliminate these cells.

The first hints of this anti-tumor immunity date back more than a century and a half and sparked the concept of mobilizing the immune system to treat patients.^1-3 Although early pioneers achieved little progress in this regard, their efforts provided invaluable insights into the complex and dynamic relationship between a tumor and the immune system that are now translating into real clinical successes.

We now understand that the immune system has a dual role in both restraining and promoting cancer development and have translated this understanding into the theory of cancer immunoediting. Immunoediting has three stages: elimination, wherein the tumor is seemingly destroyed by the innate and adaptive immune response; equilibrium, in which cancer cells that were able to escape elimination are selected for growth; and escape, whereby these resistant cancer cells overwhelm the immune system and develop into a symptomatic lesion.^4,5

Immuno-oncologists have also described the cancer immunity cycle to capture the steps that are required for an effective anti-tumor immune response and defects in this cycle form the basis of the most common mechanisms used by cancer cells to subvert the anti-tumor immune response. Much like the cancer hallmarks did for molecularly targeted cancer drugs, the cancer immunity cycle serves as the intellectual framework for cancer immunotherapy.^6,7

Exploiting nature’s weapon of mass destruction

Initially, attempts at immunotherapy focused on boosting the immune response using adjuvants and cytokines. The characterization of subtle differences between tumor cells and normal cells led to the development of vaccines and cell-based therapies that exploited these tumor-associated antigens (TAAs).^1-6

Despite the approval of a therapeutic vaccine, sipuleucel-T, in 2010 for the treatment of metastatic prostate cancer, in general the success of vaccines has been limited. Marketing authorization for sipuleucel-T was recently withdrawn in Europe, and although it is still available in the United States, it is not widely used because of issues with production and administration. Other vaccines, such as GVAX, which looked particularly promising in early-stage clinical trials, failed to show clinical efficacy in subsequent testing.^8,9

Cell-based therapies, such as adoptive cellular therapy (ACT), in which immune cells are removed from the host, primed to attack cancer cells, and then reinfused back into the patient, have focused on T cells because they are the major effectors of the adaptive immune response. Clinical success with the most common approach, tumor-infiltrating lymphocyte (TIL) therapy, has so far been limited to only one type of cancer – metastatic melanoma – but ACT may be inching closer to the mainstream with the development of techniques that allow genetic manipulation of the T cells before they are infused back into the patient.

Two key techniques have been developed (Figure 1). T-cell receptor (TCR) therapy involves genetically modifying the receptor on the surface of T cells that is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs). The TCR can be altered to recognize a specific TAA or modified to improve its antigen recognition and binding capabilities. This type of therapy is limited by the fact that the TCRs need to be genetically matched to the patient’s immune type.

Releasing the brakes

To ensure that it is only activated at the appropriate time and not in response to the antigens expressed on the surface of the host’s own tissues or harmless materials, the immune system has developed numerous mechanisms for immunological tolerance. Cancer cells are able to exploit these mechanisms to allow them to evade the anti-tumor immune response. One of the main ways in which they do this is by manipulating the signaling pathways involved in T-cell activation, which play a vital role in tolerance.¹²

To become fully activated, T cells require a primary signal generated by an interaction between the TCR and the antigen-MHC complex on the surface of an APC, followed by secondary costimulatory signals generated by a range of different receptors present on the T-cell surface binding to their ligands on the APC.

If the second signal is inhibitory rather than stimulatory, then the T cell is deactivated instead of becoming activated. Two key coinhibitory receptors are programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) and tumor cells are able to overcome the anti-tumor immune response in part by expressing the ligands that bind these receptors to dampen the activity of tumor-infiltrating T cells and induce tolerance.¹³

The development of inhibitors of CTLA-4 and PD-1 and their respective ligands has driven some of the most dramatic successes with cancer immunotherapy, particularly with PD-1-targeting drugs which have fewer side effects. Targeting of this pathway has resulted in durable responses, revolutionizing the treatment of metastatic melanoma, with recently published long-term survival data for pembrolizumab showing that 40% of patients were alive 3 years after initiating treatment and, in a separate study, 34% of nivolumab-treated patients were still alive after 5 years.^14,15 More recently, PD-1 inhibitors have been slowly expanding into a range of other cancer types and 4 immune checkpoint inhibitors are now approved by the United States Food and Drug Administration (FDA): ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda) and atezolizumab (Tecentriq).

Six years on from the first approval in this drug class and an extensive network of coinhibitory receptors has been uncovered – so-called immune checkpoints – many of which are now also serving as therapeutic targets (Table, Figure 2).¹⁶ Lymphocyte activation gene 3 (LAG-3) is a member of the immunoglobulin superfamily of receptors that is expressed on a number of different types of immune cell. In addition to negatively regulating cytotoxic T-cell activation like PD-1 and CTLA-4, it is also thought to regulate the immunosuppressive functions of regulatory T cells and the maturation and activation of dendritic cells. T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) is found on the surface of helper and cytotoxic T cells and regulates T-cell inhibition as well as macrophage activation. Inhibitors of both proteins have been developed that are being evaluated in phase 1 or 2 clinical trials in a variety of tumor types.17

Indeed, although T cells have commanded the most attention, there is growing appreciation of the potential for targeting other types of immune cell that play a role in the anti-tumor immune response or in fostering an immunosuppressive microenvironment. NK cells have been a particular focus, since they represent the body’s first line of immune defense and they appear to have analogous inhibitory and activating receptors expressed on their surface that regulate their cytotoxic activity.

The best-defined NK cell receptors are the killer cell immunoglobulin-like receptors (KIRs) that bind to the MHC class I proteins found on the surface of all cells that distinguish them as ‘self’ or ‘non-self’. KIRs can be either activating or inhibitory, depending upon their structure and the ligands to which they bind.¹⁹ To date, 2 antibodies targeting inhibitory KIRs have been developed. Though there has been some disappointment with these drugs, most recently a phase 2 trial of lirilumab in elderly patients with acute myeloid leukemia, which missed its primary endpoint, they continue to be evaluated in clinical trials.²⁰

The inhibitory immune checkpoint field has also expanded to include molecules that regulate T-cell activity in other ways. Most prominently, this includes enzymes like indoleamine-2,3 dioxygenase (IDO), which is involved in the metabolism of the essential amino acid tryptophan. IDO-induced depletion of tryptophan and generation of tryptophan metabolites is toxic to cytotoxic T cells, and IDO is also thought to directly activate regulatory T cells, thus the net effect of IDO is immunosuppression. Two IDO inhibitors are currently being developed.²¹

Stepping on the gas

Despite their unprecedented success, immune checkpoint inhibitors are not effective in all patients or in all tumor types. Their efficacy is limited in large part by the requirement for a pre-existing anti-tumor immune response. If there are no T cells within the tumor microenvironment then releasing the brakes on the immune system won’t help.

More recently, researchers have returned to the idea of stimulating an anti-tumor immune response, this time by targeting the other side of the immune checkpoint coin, the costimulatory molecules. These drugs could prove more effective as they aren’t reliant on a pre-existing anti-tumor immune response. A number of agonist antibodies designed to target these receptors have now been developed and are undergoing clinical evaluation.²²

Furthest along in development are those targeting OX40, a costimulatory molecule that is upregulated on the surface of T cells once they have been fully activated by the TCR signal and an initial costimulatory signal. OX40 is thought to be involved in a more long-term immune response and in the formation of a memory response. A mouse monoclonal antibody had a potent immune-stimulating effect accompanied by the regression of at least 1 metastatic lesion in 30% of patients treated in a phase 1 clinical trial, but was limited by the generation of anti-mouse antibodies. 7 OX40 agonists are now in clinical development, 6 fully human monoclonal antibodies and 1 OX40 ligand-Fc fusion protein, MEDI-6383.²³

Combinations are key

Many researchers are now reaching the conclusion that combination therapy is likely to be key in expanding the scope of immunotherapy into currently unresponsive patient populations. Investigating rational combinations is already becoming a burgeoning area of the immuno-oncology field, with a variety of different strategies being tested.

Now the question becomes what are the optimal combinations and the timing and sequencing of combination therapy is likely to be a paramount consideration. Developing combinations that have distinct mechanisms of action or target multiple steps in the cancer immunity cycle offers the greatest potential for therapeutic synergy since this is most likely to address potential mechanisms of resistance by blocking other paths to immune evasion for cancer cells (Figure 3).

Given the expanding network of immune-checkpoint inhibitors and agonists, the focal point of combination therapy has been combining immune checkpoint-targeting drugs with different mechanisms of action, including those that would simultaneously release the brakes and step on the gas pedal. The vast majority of ongoing clinical trials of approved checkpoint inhibitors and the drugs in development listed in the table are combination trials.

These efforts yielded the first FDA-approved combination immunotherapy regimen in 2015; nivolumab and ipilimumab for the treatment of metastatic melanoma. Approval was based on the demonstration of improved ORR, prolonged response duration, and improved progression-free survival among 142 patients treated with the combination, compared to either drug alone.²⁴

The results of a phase 1/2 trial evaluating the combination of a 4-1BB receptor agonist urelumab with nivolumab in hematologic malignancies and solid tumors found the combination to be safe and particularly effective in patients with advanced/metastatic melanoma, with an ORR of 50%.²⁵ Nivolumab was also combined with the CD27 agonist varlilumab in a phase 1/2 clinical trial of patients with solid tumors, for which data was also recently released. Among 46 patients enrolled, primarily those with colorectal and ovarian cancer the combination had an acceptable safety profile and favorable changes in intratumoral immune biomarkers were observed. The phase 2 portion of the trial is ongoing.²⁶

Meanwhile, Incyte’s IDO inhibitor epacadostat has recently been making waves in combination with pembrolizumab in patients with advanced solid tumors. It demonstrated particularly promising clinical activity in patients with metastatic melanoma, with an overall response rate (ORR) of 57%, including 2 complete responses (CRs), prompting initiation of a phase 3 trial of this combination (NCT02752074).²⁷

The relationship between the immune system and tumors is complex and dynamic, and for immunotherapy to reach its full potential it will likely need to attack on multiple fronts. Here, we discuss some of the latest and most promising developments in the immuno-oncology field designed to build on the successes and address limitations.

The anti-tumor immune response

Cancer is a disease of genomic instability, whereby genetic alterations ranging from a single nucleotide to the whole chromosome level frequently occur. Although cancers derive from a patient’s own tissues, these genetic differences can mark the cancer cell as non-self, triggering an immune response to eliminate these cells.

The first hints of this anti-tumor immunity date back more than a century and a half and sparked the concept of mobilizing the immune system to treat patients.^1-3 Although early pioneers achieved little progress in this regard, their efforts provided invaluable insights into the complex and dynamic relationship between a tumor and the immune system that are now translating into real clinical successes.

We now understand that the immune system has a dual role in both restraining and promoting cancer development and have translated this understanding into the theory of cancer immunoediting. Immunoediting has three stages: elimination, wherein the tumor is seemingly destroyed by the innate and adaptive immune response; equilibrium, in which cancer cells that were able to escape elimination are selected for growth; and escape, whereby these resistant cancer cells overwhelm the immune system and develop into a symptomatic lesion.^4,5

Immuno-oncologists have also described the cancer immunity cycle to capture the steps that are required for an effective anti-tumor immune response and defects in this cycle form the basis of the most common mechanisms used by cancer cells to subvert the anti-tumor immune response. Much like the cancer hallmarks did for molecularly targeted cancer drugs, the cancer immunity cycle serves as the intellectual framework for cancer immunotherapy.^6,7

Exploiting nature’s weapon of mass destruction

Initially, attempts at immunotherapy focused on boosting the immune response using adjuvants and cytokines. The characterization of subtle differences between tumor cells and normal cells led to the development of vaccines and cell-based therapies that exploited these tumor-associated antigens (TAAs).^1-6

Despite the approval of a therapeutic vaccine, sipuleucel-T, in 2010 for the treatment of metastatic prostate cancer, in general the success of vaccines has been limited. Marketing authorization for sipuleucel-T was recently withdrawn in Europe, and although it is still available in the United States, it is not widely used because of issues with production and administration. Other vaccines, such as GVAX, which looked particularly promising in early-stage clinical trials, failed to show clinical efficacy in subsequent testing.^8,9

Cell-based therapies, such as adoptive cellular therapy (ACT), in which immune cells are removed from the host, primed to attack cancer cells, and then reinfused back into the patient, have focused on T cells because they are the major effectors of the adaptive immune response. Clinical success with the most common approach, tumor-infiltrating lymphocyte (TIL) therapy, has so far been limited to only one type of cancer – metastatic melanoma – but ACT may be inching closer to the mainstream with the development of techniques that allow genetic manipulation of the T cells before they are infused back into the patient.

Two key techniques have been developed (Figure 1). T-cell receptor (TCR) therapy involves genetically modifying the receptor on the surface of T cells that is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs). The TCR can be altered to recognize a specific TAA or modified to improve its antigen recognition and binding capabilities. This type of therapy is limited by the fact that the TCRs need to be genetically matched to the patient’s immune type.

Releasing the brakes

To ensure that it is only activated at the appropriate time and not in response to the antigens expressed on the surface of the host’s own tissues or harmless materials, the immune system has developed numerous mechanisms for immunological tolerance. Cancer cells are able to exploit these mechanisms to allow them to evade the anti-tumor immune response. One of the main ways in which they do this is by manipulating the signaling pathways involved in T-cell activation, which play a vital role in tolerance.¹²

To become fully activated, T cells require a primary signal generated by an interaction between the TCR and the antigen-MHC complex on the surface of an APC, followed by secondary costimulatory signals generated by a range of different receptors present on the T-cell surface binding to their ligands on the APC.

If the second signal is inhibitory rather than stimulatory, then the T cell is deactivated instead of becoming activated. Two key coinhibitory receptors are programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) and tumor cells are able to overcome the anti-tumor immune response in part by expressing the ligands that bind these receptors to dampen the activity of tumor-infiltrating T cells and induce tolerance.¹³

The development of inhibitors of CTLA-4 and PD-1 and their respective ligands has driven some of the most dramatic successes with cancer immunotherapy, particularly with PD-1-targeting drugs which have fewer side effects. Targeting of this pathway has resulted in durable responses, revolutionizing the treatment of metastatic melanoma, with recently published long-term survival data for pembrolizumab showing that 40% of patients were alive 3 years after initiating treatment and, in a separate study, 34% of nivolumab-treated patients were still alive after 5 years.^14,15 More recently, PD-1 inhibitors have been slowly expanding into a range of other cancer types and 4 immune checkpoint inhibitors are now approved by the United States Food and Drug Administration (FDA): ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda) and atezolizumab (Tecentriq).

Six years on from the first approval in this drug class and an extensive network of coinhibitory receptors has been uncovered – so-called immune checkpoints – many of which are now also serving as therapeutic targets (Table, Figure 2).¹⁶ Lymphocyte activation gene 3 (LAG-3) is a member of the immunoglobulin superfamily of receptors that is expressed on a number of different types of immune cell. In addition to negatively regulating cytotoxic T-cell activation like PD-1 and CTLA-4, it is also thought to regulate the immunosuppressive functions of regulatory T cells and the maturation and activation of dendritic cells. T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) is found on the surface of helper and cytotoxic T cells and regulates T-cell inhibition as well as macrophage activation. Inhibitors of both proteins have been developed that are being evaluated in phase 1 or 2 clinical trials in a variety of tumor types.17

Indeed, although T cells have commanded the most attention, there is growing appreciation of the potential for targeting other types of immune cell that play a role in the anti-tumor immune response or in fostering an immunosuppressive microenvironment. NK cells have been a particular focus, since they represent the body’s first line of immune defense and they appear to have analogous inhibitory and activating receptors expressed on their surface that regulate their cytotoxic activity.

The best-defined NK cell receptors are the killer cell immunoglobulin-like receptors (KIRs) that bind to the MHC class I proteins found on the surface of all cells that distinguish them as ‘self’ or ‘non-self’. KIRs can be either activating or inhibitory, depending upon their structure and the ligands to which they bind.¹⁹ To date, 2 antibodies targeting inhibitory KIRs have been developed. Though there has been some disappointment with these drugs, most recently a phase 2 trial of lirilumab in elderly patients with acute myeloid leukemia, which missed its primary endpoint, they continue to be evaluated in clinical trials.²⁰

The inhibitory immune checkpoint field has also expanded to include molecules that regulate T-cell activity in other ways. Most prominently, this includes enzymes like indoleamine-2,3 dioxygenase (IDO), which is involved in the metabolism of the essential amino acid tryptophan. IDO-induced depletion of tryptophan and generation of tryptophan metabolites is toxic to cytotoxic T cells, and IDO is also thought to directly activate regulatory T cells, thus the net effect of IDO is immunosuppression. Two IDO inhibitors are currently being developed.²¹

Stepping on the gas

Despite their unprecedented success, immune checkpoint inhibitors are not effective in all patients or in all tumor types. Their efficacy is limited in large part by the requirement for a pre-existing anti-tumor immune response. If there are no T cells within the tumor microenvironment then releasing the brakes on the immune system won’t help.

More recently, researchers have returned to the idea of stimulating an anti-tumor immune response, this time by targeting the other side of the immune checkpoint coin, the costimulatory molecules. These drugs could prove more effective as they aren’t reliant on a pre-existing anti-tumor immune response. A number of agonist antibodies designed to target these receptors have now been developed and are undergoing clinical evaluation.²²

Furthest along in development are those targeting OX40, a costimulatory molecule that is upregulated on the surface of T cells once they have been fully activated by the TCR signal and an initial costimulatory signal. OX40 is thought to be involved in a more long-term immune response and in the formation of a memory response. A mouse monoclonal antibody had a potent immune-stimulating effect accompanied by the regression of at least 1 metastatic lesion in 30% of patients treated in a phase 1 clinical trial, but was limited by the generation of anti-mouse antibodies. 7 OX40 agonists are now in clinical development, 6 fully human monoclonal antibodies and 1 OX40 ligand-Fc fusion protein, MEDI-6383.²³

Combinations are key

Many researchers are now reaching the conclusion that combination therapy is likely to be key in expanding the scope of immunotherapy into currently unresponsive patient populations. Investigating rational combinations is already becoming a burgeoning area of the immuno-oncology field, with a variety of different strategies being tested.

Now the question becomes what are the optimal combinations and the timing and sequencing of combination therapy is likely to be a paramount consideration. Developing combinations that have distinct mechanisms of action or target multiple steps in the cancer immunity cycle offers the greatest potential for therapeutic synergy since this is most likely to address potential mechanisms of resistance by blocking other paths to immune evasion for cancer cells (Figure 3).

Given the expanding network of immune-checkpoint inhibitors and agonists, the focal point of combination therapy has been combining immune checkpoint-targeting drugs with different mechanisms of action, including those that would simultaneously release the brakes and step on the gas pedal. The vast majority of ongoing clinical trials of approved checkpoint inhibitors and the drugs in development listed in the table are combination trials.

These efforts yielded the first FDA-approved combination immunotherapy regimen in 2015; nivolumab and ipilimumab for the treatment of metastatic melanoma. Approval was based on the demonstration of improved ORR, prolonged response duration, and improved progression-free survival among 142 patients treated with the combination, compared to either drug alone.²⁴

The results of a phase 1/2 trial evaluating the combination of a 4-1BB receptor agonist urelumab with nivolumab in hematologic malignancies and solid tumors found the combination to be safe and particularly effective in patients with advanced/metastatic melanoma, with an ORR of 50%.²⁵ Nivolumab was also combined with the CD27 agonist varlilumab in a phase 1/2 clinical trial of patients with solid tumors, for which data was also recently released. Among 46 patients enrolled, primarily those with colorectal and ovarian cancer the combination had an acceptable safety profile and favorable changes in intratumoral immune biomarkers were observed. The phase 2 portion of the trial is ongoing.²⁶

Meanwhile, Incyte’s IDO inhibitor epacadostat has recently been making waves in combination with pembrolizumab in patients with advanced solid tumors. It demonstrated particularly promising clinical activity in patients with metastatic melanoma, with an overall response rate (ORR) of 57%, including 2 complete responses (CRs), prompting initiation of a phase 3 trial of this combination (NCT02752074).²⁷

The relationship between the immune system and tumors is complex and dynamic, and for immunotherapy to reach its full potential it will likely need to attack on multiple fronts. Here, we discuss some of the latest and most promising developments in the immuno-oncology field designed to build on the successes and address limitations.

The anti-tumor immune response

Cancer is a disease of genomic instability, whereby genetic alterations ranging from a single nucleotide to the whole chromosome level frequently occur. Although cancers derive from a patient’s own tissues, these genetic differences can mark the cancer cell as non-self, triggering an immune response to eliminate these cells.

The first hints of this anti-tumor immunity date back more than a century and a half and sparked the concept of mobilizing the immune system to treat patients.^1-3 Although early pioneers achieved little progress in this regard, their efforts provided invaluable insights into the complex and dynamic relationship between a tumor and the immune system that are now translating into real clinical successes.

We now understand that the immune system has a dual role in both restraining and promoting cancer development and have translated this understanding into the theory of cancer immunoediting. Immunoediting has three stages: elimination, wherein the tumor is seemingly destroyed by the innate and adaptive immune response; equilibrium, in which cancer cells that were able to escape elimination are selected for growth; and escape, whereby these resistant cancer cells overwhelm the immune system and develop into a symptomatic lesion.^4,5

Immuno-oncologists have also described the cancer immunity cycle to capture the steps that are required for an effective anti-tumor immune response and defects in this cycle form the basis of the most common mechanisms used by cancer cells to subvert the anti-tumor immune response. Much like the cancer hallmarks did for molecularly targeted cancer drugs, the cancer immunity cycle serves as the intellectual framework for cancer immunotherapy.^6,7

Exploiting nature’s weapon of mass destruction

Initially, attempts at immunotherapy focused on boosting the immune response using adjuvants and cytokines. The characterization of subtle differences between tumor cells and normal cells led to the development of vaccines and cell-based therapies that exploited these tumor-associated antigens (TAAs).^1-6

Despite the approval of a therapeutic vaccine, sipuleucel-T, in 2010 for the treatment of metastatic prostate cancer, in general the success of vaccines has been limited. Marketing authorization for sipuleucel-T was recently withdrawn in Europe, and although it is still available in the United States, it is not widely used because of issues with production and administration. Other vaccines, such as GVAX, which looked particularly promising in early-stage clinical trials, failed to show clinical efficacy in subsequent testing.^8,9

Cell-based therapies, such as adoptive cellular therapy (ACT), in which immune cells are removed from the host, primed to attack cancer cells, and then reinfused back into the patient, have focused on T cells because they are the major effectors of the adaptive immune response. Clinical success with the most common approach, tumor-infiltrating lymphocyte (TIL) therapy, has so far been limited to only one type of cancer – metastatic melanoma – but ACT may be inching closer to the mainstream with the development of techniques that allow genetic manipulation of the T cells before they are infused back into the patient.

Two key techniques have been developed (Figure 1). T-cell receptor (TCR) therapy involves genetically modifying the receptor on the surface of T cells that is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs). The TCR can be altered to recognize a specific TAA or modified to improve its antigen recognition and binding capabilities. This type of therapy is limited by the fact that the TCRs need to be genetically matched to the patient’s immune type.

Releasing the brakes

To ensure that it is only activated at the appropriate time and not in response to the antigens expressed on the surface of the host’s own tissues or harmless materials, the immune system has developed numerous mechanisms for immunological tolerance. Cancer cells are able to exploit these mechanisms to allow them to evade the anti-tumor immune response. One of the main ways in which they do this is by manipulating the signaling pathways involved in T-cell activation, which play a vital role in tolerance.¹²

To become fully activated, T cells require a primary signal generated by an interaction between the TCR and the antigen-MHC complex on the surface of an APC, followed by secondary costimulatory signals generated by a range of different receptors present on the T-cell surface binding to their ligands on the APC.

If the second signal is inhibitory rather than stimulatory, then the T cell is deactivated instead of becoming activated. Two key coinhibitory receptors are programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) and tumor cells are able to overcome the anti-tumor immune response in part by expressing the ligands that bind these receptors to dampen the activity of tumor-infiltrating T cells and induce tolerance.¹³

The development of inhibitors of CTLA-4 and PD-1 and their respective ligands has driven some of the most dramatic successes with cancer immunotherapy, particularly with PD-1-targeting drugs which have fewer side effects. Targeting of this pathway has resulted in durable responses, revolutionizing the treatment of metastatic melanoma, with recently published long-term survival data for pembrolizumab showing that 40% of patients were alive 3 years after initiating treatment and, in a separate study, 34% of nivolumab-treated patients were still alive after 5 years.^14,15 More recently, PD-1 inhibitors have been slowly expanding into a range of other cancer types and 4 immune checkpoint inhibitors are now approved by the United States Food and Drug Administration (FDA): ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda) and atezolizumab (Tecentriq).

Six years on from the first approval in this drug class and an extensive network of coinhibitory receptors has been uncovered – so-called immune checkpoints – many of which are now also serving as therapeutic targets (Table, Figure 2).¹⁶ Lymphocyte activation gene 3 (LAG-3) is a member of the immunoglobulin superfamily of receptors that is expressed on a number of different types of immune cell. In addition to negatively regulating cytotoxic T-cell activation like PD-1 and CTLA-4, it is also thought to regulate the immunosuppressive functions of regulatory T cells and the maturation and activation of dendritic cells. T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) is found on the surface of helper and cytotoxic T cells and regulates T-cell inhibition as well as macrophage activation. Inhibitors of both proteins have been developed that are being evaluated in phase 1 or 2 clinical trials in a variety of tumor types.17

Indeed, although T cells have commanded the most attention, there is growing appreciation of the potential for targeting other types of immune cell that play a role in the anti-tumor immune response or in fostering an immunosuppressive microenvironment. NK cells have been a particular focus, since they represent the body’s first line of immune defense and they appear to have analogous inhibitory and activating receptors expressed on their surface that regulate their cytotoxic activity.

The best-defined NK cell receptors are the killer cell immunoglobulin-like receptors (KIRs) that bind to the MHC class I proteins found on the surface of all cells that distinguish them as ‘self’ or ‘non-self’. KIRs can be either activating or inhibitory, depending upon their structure and the ligands to which they bind.¹⁹ To date, 2 antibodies targeting inhibitory KIRs have been developed. Though there has been some disappointment with these drugs, most recently a phase 2 trial of lirilumab in elderly patients with acute myeloid leukemia, which missed its primary endpoint, they continue to be evaluated in clinical trials.²⁰

The inhibitory immune checkpoint field has also expanded to include molecules that regulate T-cell activity in other ways. Most prominently, this includes enzymes like indoleamine-2,3 dioxygenase (IDO), which is involved in the metabolism of the essential amino acid tryptophan. IDO-induced depletion of tryptophan and generation of tryptophan metabolites is toxic to cytotoxic T cells, and IDO is also thought to directly activate regulatory T cells, thus the net effect of IDO is immunosuppression. Two IDO inhibitors are currently being developed.²¹

Stepping on the gas

Despite their unprecedented success, immune checkpoint inhibitors are not effective in all patients or in all tumor types. Their efficacy is limited in large part by the requirement for a pre-existing anti-tumor immune response. If there are no T cells within the tumor microenvironment then releasing the brakes on the immune system won’t help.

More recently, researchers have returned to the idea of stimulating an anti-tumor immune response, this time by targeting the other side of the immune checkpoint coin, the costimulatory molecules. These drugs could prove more effective as they aren’t reliant on a pre-existing anti-tumor immune response. A number of agonist antibodies designed to target these receptors have now been developed and are undergoing clinical evaluation.²²

Furthest along in development are those targeting OX40, a costimulatory molecule that is upregulated on the surface of T cells once they have been fully activated by the TCR signal and an initial costimulatory signal. OX40 is thought to be involved in a more long-term immune response and in the formation of a memory response. A mouse monoclonal antibody had a potent immune-stimulating effect accompanied by the regression of at least 1 metastatic lesion in 30% of patients treated in a phase 1 clinical trial, but was limited by the generation of anti-mouse antibodies. 7 OX40 agonists are now in clinical development, 6 fully human monoclonal antibodies and 1 OX40 ligand-Fc fusion protein, MEDI-6383.²³

Combinations are key

Many researchers are now reaching the conclusion that combination therapy is likely to be key in expanding the scope of immunotherapy into currently unresponsive patient populations. Investigating rational combinations is already becoming a burgeoning area of the immuno-oncology field, with a variety of different strategies being tested.

Now the question becomes what are the optimal combinations and the timing and sequencing of combination therapy is likely to be a paramount consideration. Developing combinations that have distinct mechanisms of action or target multiple steps in the cancer immunity cycle offers the greatest potential for therapeutic synergy since this is most likely to address potential mechanisms of resistance by blocking other paths to immune evasion for cancer cells (Figure 3).

Given the expanding network of immune-checkpoint inhibitors and agonists, the focal point of combination therapy has been combining immune checkpoint-targeting drugs with different mechanisms of action, including those that would simultaneously release the brakes and step on the gas pedal. The vast majority of ongoing clinical trials of approved checkpoint inhibitors and the drugs in development listed in the table are combination trials.

These efforts yielded the first FDA-approved combination immunotherapy regimen in 2015; nivolumab and ipilimumab for the treatment of metastatic melanoma. Approval was based on the demonstration of improved ORR, prolonged response duration, and improved progression-free survival among 142 patients treated with the combination, compared to either drug alone.²⁴

The results of a phase 1/2 trial evaluating the combination of a 4-1BB receptor agonist urelumab with nivolumab in hematologic malignancies and solid tumors found the combination to be safe and particularly effective in patients with advanced/metastatic melanoma, with an ORR of 50%.²⁵ Nivolumab was also combined with the CD27 agonist varlilumab in a phase 1/2 clinical trial of patients with solid tumors, for which data was also recently released. Among 46 patients enrolled, primarily those with colorectal and ovarian cancer the combination had an acceptable safety profile and favorable changes in intratumoral immune biomarkers were observed. The phase 2 portion of the trial is ongoing.²⁶

Meanwhile, Incyte’s IDO inhibitor epacadostat has recently been making waves in combination with pembrolizumab in patients with advanced solid tumors. It demonstrated particularly promising clinical activity in patients with metastatic melanoma, with an overall response rate (ORR) of 57%, including 2 complete responses (CRs), prompting initiation of a phase 3 trial of this combination (NCT02752074).²⁷

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T- and natural killer-cell neoplasms that comprise about 10%-15% of all non-Hodgkin lymphomas in the United States.^1,2 The development of effective therapies for PTCL has been challenging because of the rare nature and heterogeneity of these lymphomas. Most therapies are a derivative of aggressive B-cell lymphoma therapies, including CHOP (cyclophosphamide, hydroxydaunorubicin, vinicristine, prednisone) and CHOEP (cyclophosphamide, hydroxydaunorubicin, vinicristine, etoposide, prednisone).¹ Many centers use autologous or allogeneic stem cell transplant in this setting,¹ but outcomes remain poor and progress in developing effective treatments has been slow.

Pralatrexate is the first drug to have been approved by the US Food and Drug Administration specifically for treating patients with relapsed or refractory PTCL.³ As a folate analog metabolic inhibitor, pralatrexate competitively inhibits dihydrofolate reductase and reduces cellular levels of thymidine monophosphate, which prevents the cell from synthesizing genetic material and triggers it to undergo apoptosis.⁴ The agency’s approval of pralatrexate was based on results from the PROPEL study, which is possibly the largest prospective study conducted in patients with relapsed or refractory PTCL (109 evaluable patients).² Findings from the study showed an overall response rate (ORR) of 29%, and a median duration of response (DoR) of 10 months.²

Pralatrexate is administered intravenously at 30 mg/m2 once weekly for 6 weeks of a 7-week treatment cycle. It is generally continued until disease progression or an unacceptable level of toxicity.² Alternative dosing schedules have been described, including 15 mg/m2 once weekly for 3 weeks of a 4-week treatment cycle for cutaneous T-cell lymphomas.⁵

In this case series, we examine the outcomes of 2 patients with particularly aggressive subtypes of PTCL who were treated with pralatrexate. The significance of this report is in describing the long duration of response and reporting on a PTCL subtype – subcutaneous panniculitis-like T-cell lymphoma, alpha/beta type – that was underrepresented in the PROPEL study and is underreported in the literature.
 

Case presentations and summaries

Case 1

A 23-year-old Asian American man with a medical history of osteogenesis imperfecta presented to Emergency Department at the Hospital of University of Pennsylvania with bilateral lower extremity edema, low-grade fevers, a weight loss of 25 lb, and flat hyperpigmented scaly skin patches across his torso. Symptoms had started manifesting around five months prior to the visit. A punch biopsy of a skin lesion revealed skin tissue with focal infiltrate of small- to medium-sized, atypical lymphocytes infiltrating subcutaneous adipose tissue (panniculitis-like) and adnexa. Immunohistochemical stains showed that the abnormal lymphocytes were positive for CD3, CD8, perforin, granzyme B, TIA-1 (minor subset), and TCR beta; and negative for CD4, CD56, and CD30. Proliferation index (Ki67) was 70%. The findings were consistent with primary subcutaneous panniculitis-like T-cell lymphoma, alpha/beta type (Figure 1). A staging positron-emission tomography–computed tomography (PET–CT) scan demonstrated stage IVB lymphoma with subcutaneous involvement without nodal disease.

He was initially treated with aggressive combination regimens including EPOCH (etoposide, prednisolone, vincristine, cyclophosphamide, hydroxydaunorubicin) and ICE (ifosfamide, carboplatin, etoposide), but he had no response and his disease was primary refractory. Because of his osteogenesis imperfecta, he was not a candidate for allogenic stem cell transplant.

He responded to hyperCVAD B combination therapy (methotrexate and cytarabine), but the course was complicated by cytarabine-induced ataxia and dysarthia. He was then treated with 3 months of intravenous alemtuzumab without response. Intravenous methotrexate (2,000 mg/m²) was then used for 3 cycles, but this exacerbated his previous cytarabine-induced neurological symptoms and resulted in only partial response with persistent fluorine-18-deoxyglucose (FDG) avid lesions on a subsequent PET–CT scan.

At that point, the patient was started on pralatrexate at 15 mg/m² weekly for 3 weeks on a 4-week cycle schedule. This was his fifth line of therapy and at 16 months from his initial diagnosis. This dosage was continued for 6 months, and he tolerated the therapy well. He reported no exacerbations of his dysarthia, and by the second month, he had achieved clinical and radiographic remission with complete resolution of B symptoms (fevers, night sweats, and weight loss). The dosing was modified to 15 mg/m² every 2 weeks for 3 months. A whole body PET–CT scan showed resolution of previously FDG avid lesions.

The patient was then continued on 15 mg/m² pralatrexate every 3 weeks for 1 year and he has been maintained on once-a-month dosing for a second and now third year of therapy. He continues to tolerate the therapy and remains disease free at nearly 2 years since starting pralatrexate.
 

Case 2

A 64-year-old white man with a medical history of myasthenia gravis (in remission) and invasive thymoma (after thymectomy) presented with diffuse bulky lymphadenopathy and lung lesions to outpatient clinic at the Abramson Cancer Center at the University of Pennsylvania. His LDH was elevated (278 U/L, reference range 98-192 U/L). Excisional biopsy of a left inguinal lymph node revealed sheets of mitotically active large cells with oval to irregular nuclei, clumped chromatin, conspicuous and sometimes multiple nucleoli, and ample eosinophilic cytoplasm. Immunohistochemical staining showed that the neoplastic cells were positive for CD3, CD4, CD30, BCL2 (variable), and MUM1; and negative for ALK 1, CD5, CD8, CD15, CD43, and CD56. Proliferation index (Ki67) was 90% (Figure 2). PET-CT scan showed widespread hypermetabolic lymphoma in the chest, neck, abdomen, and pelvis with pulmonary metastases. Imaging also demonstrated FDG-avid lesions in the gastric and sinus area. The findings were consistent with ALK-negative, anaplastic large cell lymphoma. He was stage IVA; had gastric, lung, and sinus involvement; and disease above and below the diaphragm.

The patient was initially treated with 6 cycles of CHOP and intrathecal methotrexate injections. His post-treatment PET–CT scan showed persistent FDG-avid disease and his LDH level remained elevated. He underwent 1 cycle of ICE and then BCV (busulfan, cyclophosphamide, etoposide) autologous stem cell transplant. Post-transplant PET–CT scan showed improvement from previous 2 scans but still showed several hypermetabolic lymph nodes consistent with persistent disease.

The patient was started on a pralatrexate regimen of 30 mg/m² once weekly for 6 weeks of a 7-week treatment cycle. After 5 doses, he developed thrombocytopenia and mucositis, which were deemed pralatrexate related. The dosage was reduced to 20 mg/m² once weekly with variable frequency depending on tolerability. His response assessment with PET–CT scan demonstrated radiographic complete response with resolution of hypermetabolic lesions (Figure 3B).

Discussion

PTCL is a rare and heterogeneous lymphoma with poor prognosis. Only 3 agents – pralatrexate, belinostat, and romidespin – have been approved specifically for the treatment of PTCL and all of them have an ORR of less than 30%, based on findings from phase 2 studies.^2,6,7 In the PROPEL study, pralatrexate showed an ORR of 29% and a median DoR of 10 months.² Those results could be considered discouraging, but some PTCL patients may have durable response to pralatrexate monotherapy.

In this case series, each of the patients presented with a particularly aggressive subtype of PTCL, and 1 suffered from a notably rare subtype for which there was scant clinical data to guide treatment. Both patients went through several lines of aggressive treatment that were ineffective and resulted in minimal response. However, both were able to achieve complete resolution of their disease and maintained remission for a significant duration of time after treatment with pralatrexate. In addition, each patient has maintained his remission – one for 6 years after the last dose. These are noteworthy results, and give both patients and clinicians hope that this therapy can be highly effective in some settings.

A better understanding at the molecular level of the oncogenic mechanisms in PTCL patients will be necessary to guide our therapy choices. In these 2 cases, it is likely that the tumor demonstrated superior sensitivity to dihydrofolate reductase inhibition by pralatrexate. In the future, we hope that analysis of the tumor tissue from PTCL patients will allow us to better categorize the tumor sensitivities to particular therapeutic agents. We believe that individualized treatment will lead to better overall outcomes in this challenging group of lymphomas.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T- and natural killer-cell neoplasms that comprise about 10%-15% of all non-Hodgkin lymphomas in the United States.^1,2 The development of effective therapies for PTCL has been challenging because of the rare nature and heterogeneity of these lymphomas. Most therapies are a derivative of aggressive B-cell lymphoma therapies, including CHOP (cyclophosphamide, hydroxydaunorubicin, vinicristine, prednisone) and CHOEP (cyclophosphamide, hydroxydaunorubicin, vinicristine, etoposide, prednisone).¹ Many centers use autologous or allogeneic stem cell transplant in this setting,¹ but outcomes remain poor and progress in developing effective treatments has been slow.

Pralatrexate is the first drug to have been approved by the US Food and Drug Administration specifically for treating patients with relapsed or refractory PTCL.³ As a folate analog metabolic inhibitor, pralatrexate competitively inhibits dihydrofolate reductase and reduces cellular levels of thymidine monophosphate, which prevents the cell from synthesizing genetic material and triggers it to undergo apoptosis.⁴ The agency’s approval of pralatrexate was based on results from the PROPEL study, which is possibly the largest prospective study conducted in patients with relapsed or refractory PTCL (109 evaluable patients).² Findings from the study showed an overall response rate (ORR) of 29%, and a median duration of response (DoR) of 10 months.²

Pralatrexate is administered intravenously at 30 mg/m2 once weekly for 6 weeks of a 7-week treatment cycle. It is generally continued until disease progression or an unacceptable level of toxicity.² Alternative dosing schedules have been described, including 15 mg/m2 once weekly for 3 weeks of a 4-week treatment cycle for cutaneous T-cell lymphomas.⁵

In this case series, we examine the outcomes of 2 patients with particularly aggressive subtypes of PTCL who were treated with pralatrexate. The significance of this report is in describing the long duration of response and reporting on a PTCL subtype – subcutaneous panniculitis-like T-cell lymphoma, alpha/beta type – that was underrepresented in the PROPEL study and is underreported in the literature.
 

Case presentations and summaries

Case 1

A 23-year-old Asian American man with a medical history of osteogenesis imperfecta presented to Emergency Department at the Hospital of University of Pennsylvania with bilateral lower extremity edema, low-grade fevers, a weight loss of 25 lb, and flat hyperpigmented scaly skin patches across his torso. Symptoms had started manifesting around five months prior to the visit. A punch biopsy of a skin lesion revealed skin tissue with focal infiltrate of small- to medium-sized, atypical lymphocytes infiltrating subcutaneous adipose tissue (panniculitis-like) and adnexa. Immunohistochemical stains showed that the abnormal lymphocytes were positive for CD3, CD8, perforin, granzyme B, TIA-1 (minor subset), and TCR beta; and negative for CD4, CD56, and CD30. Proliferation index (Ki67) was 70%. The findings were consistent with primary subcutaneous panniculitis-like T-cell lymphoma, alpha/beta type (Figure 1). A staging positron-emission tomography–computed tomography (PET–CT) scan demonstrated stage IVB lymphoma with subcutaneous involvement without nodal disease.

He was initially treated with aggressive combination regimens including EPOCH (etoposide, prednisolone, vincristine, cyclophosphamide, hydroxydaunorubicin) and ICE (ifosfamide, carboplatin, etoposide), but he had no response and his disease was primary refractory. Because of his osteogenesis imperfecta, he was not a candidate for allogenic stem cell transplant.

He responded to hyperCVAD B combination therapy (methotrexate and cytarabine), but the course was complicated by cytarabine-induced ataxia and dysarthia. He was then treated with 3 months of intravenous alemtuzumab without response. Intravenous methotrexate (2,000 mg/m²) was then used for 3 cycles, but this exacerbated his previous cytarabine-induced neurological symptoms and resulted in only partial response with persistent fluorine-18-deoxyglucose (FDG) avid lesions on a subsequent PET–CT scan.

At that point, the patient was started on pralatrexate at 15 mg/m² weekly for 3 weeks on a 4-week cycle schedule. This was his fifth line of therapy and at 16 months from his initial diagnosis. This dosage was continued for 6 months, and he tolerated the therapy well. He reported no exacerbations of his dysarthia, and by the second month, he had achieved clinical and radiographic remission with complete resolution of B symptoms (fevers, night sweats, and weight loss). The dosing was modified to 15 mg/m² every 2 weeks for 3 months. A whole body PET–CT scan showed resolution of previously FDG avid lesions.

The patient was then continued on 15 mg/m² pralatrexate every 3 weeks for 1 year and he has been maintained on once-a-month dosing for a second and now third year of therapy. He continues to tolerate the therapy and remains disease free at nearly 2 years since starting pralatrexate.
 

Case 2

A 64-year-old white man with a medical history of myasthenia gravis (in remission) and invasive thymoma (after thymectomy) presented with diffuse bulky lymphadenopathy and lung lesions to outpatient clinic at the Abramson Cancer Center at the University of Pennsylvania. His LDH was elevated (278 U/L, reference range 98-192 U/L). Excisional biopsy of a left inguinal lymph node revealed sheets of mitotically active large cells with oval to irregular nuclei, clumped chromatin, conspicuous and sometimes multiple nucleoli, and ample eosinophilic cytoplasm. Immunohistochemical staining showed that the neoplastic cells were positive for CD3, CD4, CD30, BCL2 (variable), and MUM1; and negative for ALK 1, CD5, CD8, CD15, CD43, and CD56. Proliferation index (Ki67) was 90% (Figure 2). PET-CT scan showed widespread hypermetabolic lymphoma in the chest, neck, abdomen, and pelvis with pulmonary metastases. Imaging also demonstrated FDG-avid lesions in the gastric and sinus area. The findings were consistent with ALK-negative, anaplastic large cell lymphoma. He was stage IVA; had gastric, lung, and sinus involvement; and disease above and below the diaphragm.

The patient was initially treated with 6 cycles of CHOP and intrathecal methotrexate injections. His post-treatment PET–CT scan showed persistent FDG-avid disease and his LDH level remained elevated. He underwent 1 cycle of ICE and then BCV (busulfan, cyclophosphamide, etoposide) autologous stem cell transplant. Post-transplant PET–CT scan showed improvement from previous 2 scans but still showed several hypermetabolic lymph nodes consistent with persistent disease.

The patient was started on a pralatrexate regimen of 30 mg/m² once weekly for 6 weeks of a 7-week treatment cycle. After 5 doses, he developed thrombocytopenia and mucositis, which were deemed pralatrexate related. The dosage was reduced to 20 mg/m² once weekly with variable frequency depending on tolerability. His response assessment with PET–CT scan demonstrated radiographic complete response with resolution of hypermetabolic lesions (Figure 3B).

Discussion

PTCL is a rare and heterogeneous lymphoma with poor prognosis. Only 3 agents – pralatrexate, belinostat, and romidespin – have been approved specifically for the treatment of PTCL and all of them have an ORR of less than 30%, based on findings from phase 2 studies.^2,6,7 In the PROPEL study, pralatrexate showed an ORR of 29% and a median DoR of 10 months.² Those results could be considered discouraging, but some PTCL patients may have durable response to pralatrexate monotherapy.

In this case series, each of the patients presented with a particularly aggressive subtype of PTCL, and 1 suffered from a notably rare subtype for which there was scant clinical data to guide treatment. Both patients went through several lines of aggressive treatment that were ineffective and resulted in minimal response. However, both were able to achieve complete resolution of their disease and maintained remission for a significant duration of time after treatment with pralatrexate. In addition, each patient has maintained his remission – one for 6 years after the last dose. These are noteworthy results, and give both patients and clinicians hope that this therapy can be highly effective in some settings.

A better understanding at the molecular level of the oncogenic mechanisms in PTCL patients will be necessary to guide our therapy choices. In these 2 cases, it is likely that the tumor demonstrated superior sensitivity to dihydrofolate reductase inhibition by pralatrexate. In the future, we hope that analysis of the tumor tissue from PTCL patients will allow us to better categorize the tumor sensitivities to particular therapeutic agents. We believe that individualized treatment will lead to better overall outcomes in this challenging group of lymphomas.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T- and natural killer-cell neoplasms that comprise about 10%-15% of all non-Hodgkin lymphomas in the United States.^1,2 The development of effective therapies for PTCL has been challenging because of the rare nature and heterogeneity of these lymphomas. Most therapies are a derivative of aggressive B-cell lymphoma therapies, including CHOP (cyclophosphamide, hydroxydaunorubicin, vinicristine, prednisone) and CHOEP (cyclophosphamide, hydroxydaunorubicin, vinicristine, etoposide, prednisone).¹ Many centers use autologous or allogeneic stem cell transplant in this setting,¹ but outcomes remain poor and progress in developing effective treatments has been slow.

Pralatrexate is the first drug to have been approved by the US Food and Drug Administration specifically for treating patients with relapsed or refractory PTCL.³ As a folate analog metabolic inhibitor, pralatrexate competitively inhibits dihydrofolate reductase and reduces cellular levels of thymidine monophosphate, which prevents the cell from synthesizing genetic material and triggers it to undergo apoptosis.⁴ The agency’s approval of pralatrexate was based on results from the PROPEL study, which is possibly the largest prospective study conducted in patients with relapsed or refractory PTCL (109 evaluable patients).² Findings from the study showed an overall response rate (ORR) of 29%, and a median duration of response (DoR) of 10 months.²

Pralatrexate is administered intravenously at 30 mg/m2 once weekly for 6 weeks of a 7-week treatment cycle. It is generally continued until disease progression or an unacceptable level of toxicity.² Alternative dosing schedules have been described, including 15 mg/m2 once weekly for 3 weeks of a 4-week treatment cycle for cutaneous T-cell lymphomas.⁵

In this case series, we examine the outcomes of 2 patients with particularly aggressive subtypes of PTCL who were treated with pralatrexate. The significance of this report is in describing the long duration of response and reporting on a PTCL subtype – subcutaneous panniculitis-like T-cell lymphoma, alpha/beta type – that was underrepresented in the PROPEL study and is underreported in the literature.
 

Case presentations and summaries

Case 1

A 23-year-old Asian American man with a medical history of osteogenesis imperfecta presented to Emergency Department at the Hospital of University of Pennsylvania with bilateral lower extremity edema, low-grade fevers, a weight loss of 25 lb, and flat hyperpigmented scaly skin patches across his torso. Symptoms had started manifesting around five months prior to the visit. A punch biopsy of a skin lesion revealed skin tissue with focal infiltrate of small- to medium-sized, atypical lymphocytes infiltrating subcutaneous adipose tissue (panniculitis-like) and adnexa. Immunohistochemical stains showed that the abnormal lymphocytes were positive for CD3, CD8, perforin, granzyme B, TIA-1 (minor subset), and TCR beta; and negative for CD4, CD56, and CD30. Proliferation index (Ki67) was 70%. The findings were consistent with primary subcutaneous panniculitis-like T-cell lymphoma, alpha/beta type (Figure 1). A staging positron-emission tomography–computed tomography (PET–CT) scan demonstrated stage IVB lymphoma with subcutaneous involvement without nodal disease.

He was initially treated with aggressive combination regimens including EPOCH (etoposide, prednisolone, vincristine, cyclophosphamide, hydroxydaunorubicin) and ICE (ifosfamide, carboplatin, etoposide), but he had no response and his disease was primary refractory. Because of his osteogenesis imperfecta, he was not a candidate for allogenic stem cell transplant.

He responded to hyperCVAD B combination therapy (methotrexate and cytarabine), but the course was complicated by cytarabine-induced ataxia and dysarthia. He was then treated with 3 months of intravenous alemtuzumab without response. Intravenous methotrexate (2,000 mg/m²) was then used for 3 cycles, but this exacerbated his previous cytarabine-induced neurological symptoms and resulted in only partial response with persistent fluorine-18-deoxyglucose (FDG) avid lesions on a subsequent PET–CT scan.

At that point, the patient was started on pralatrexate at 15 mg/m² weekly for 3 weeks on a 4-week cycle schedule. This was his fifth line of therapy and at 16 months from his initial diagnosis. This dosage was continued for 6 months, and he tolerated the therapy well. He reported no exacerbations of his dysarthia, and by the second month, he had achieved clinical and radiographic remission with complete resolution of B symptoms (fevers, night sweats, and weight loss). The dosing was modified to 15 mg/m² every 2 weeks for 3 months. A whole body PET–CT scan showed resolution of previously FDG avid lesions.

The patient was then continued on 15 mg/m² pralatrexate every 3 weeks for 1 year and he has been maintained on once-a-month dosing for a second and now third year of therapy. He continues to tolerate the therapy and remains disease free at nearly 2 years since starting pralatrexate.
 

Case 2

A 64-year-old white man with a medical history of myasthenia gravis (in remission) and invasive thymoma (after thymectomy) presented with diffuse bulky lymphadenopathy and lung lesions to outpatient clinic at the Abramson Cancer Center at the University of Pennsylvania. His LDH was elevated (278 U/L, reference range 98-192 U/L). Excisional biopsy of a left inguinal lymph node revealed sheets of mitotically active large cells with oval to irregular nuclei, clumped chromatin, conspicuous and sometimes multiple nucleoli, and ample eosinophilic cytoplasm. Immunohistochemical staining showed that the neoplastic cells were positive for CD3, CD4, CD30, BCL2 (variable), and MUM1; and negative for ALK 1, CD5, CD8, CD15, CD43, and CD56. Proliferation index (Ki67) was 90% (Figure 2). PET-CT scan showed widespread hypermetabolic lymphoma in the chest, neck, abdomen, and pelvis with pulmonary metastases. Imaging also demonstrated FDG-avid lesions in the gastric and sinus area. The findings were consistent with ALK-negative, anaplastic large cell lymphoma. He was stage IVA; had gastric, lung, and sinus involvement; and disease above and below the diaphragm.

The patient was initially treated with 6 cycles of CHOP and intrathecal methotrexate injections. His post-treatment PET–CT scan showed persistent FDG-avid disease and his LDH level remained elevated. He underwent 1 cycle of ICE and then BCV (busulfan, cyclophosphamide, etoposide) autologous stem cell transplant. Post-transplant PET–CT scan showed improvement from previous 2 scans but still showed several hypermetabolic lymph nodes consistent with persistent disease.

The patient was started on a pralatrexate regimen of 30 mg/m² once weekly for 6 weeks of a 7-week treatment cycle. After 5 doses, he developed thrombocytopenia and mucositis, which were deemed pralatrexate related. The dosage was reduced to 20 mg/m² once weekly with variable frequency depending on tolerability. His response assessment with PET–CT scan demonstrated radiographic complete response with resolution of hypermetabolic lesions (Figure 3B).

Discussion

PTCL is a rare and heterogeneous lymphoma with poor prognosis. Only 3 agents – pralatrexate, belinostat, and romidespin – have been approved specifically for the treatment of PTCL and all of them have an ORR of less than 30%, based on findings from phase 2 studies.^2,6,7 In the PROPEL study, pralatrexate showed an ORR of 29% and a median DoR of 10 months.² Those results could be considered discouraging, but some PTCL patients may have durable response to pralatrexate monotherapy.

In this case series, each of the patients presented with a particularly aggressive subtype of PTCL, and 1 suffered from a notably rare subtype for which there was scant clinical data to guide treatment. Both patients went through several lines of aggressive treatment that were ineffective and resulted in minimal response. However, both were able to achieve complete resolution of their disease and maintained remission for a significant duration of time after treatment with pralatrexate. In addition, each patient has maintained his remission – one for 6 years after the last dose. These are noteworthy results, and give both patients and clinicians hope that this therapy can be highly effective in some settings.

A better understanding at the molecular level of the oncogenic mechanisms in PTCL patients will be necessary to guide our therapy choices. In these 2 cases, it is likely that the tumor demonstrated superior sensitivity to dihydrofolate reductase inhibition by pralatrexate. In the future, we hope that analysis of the tumor tissue from PTCL patients will allow us to better categorize the tumor sensitivities to particular therapeutic agents. We believe that individualized treatment will lead to better overall outcomes in this challenging group of lymphomas.

In this edition of the MDedge Psychcast Laura Marsh, MD, returns to discuss Parkinson’s disease. And later, Dr. RK gives Part 2 on her talk on HIPAA.

In this edition of the MDedge Psychcast Laura Marsh, MD, returns to discuss Parkinson’s disease. And later, Dr. RK gives Part 2 on her talk on HIPAA.

In this edition of the MDedge Psychcast Laura Marsh, MD, returns to discuss Parkinson’s disease. And later, Dr. RK gives Part 2 on her talk on HIPAA.

Lenalidomide may be the best maintenance treatment option for patients with newly diagnosed multiple myeloma, say the authors of a systematic review and meta-analysis.

Francesca M. Gay, MD, from the division of hematology at the University of Torino (Italy), and her coauthors wrote that despite the well-recognized importance of novel agent–based maintenance therapy for multiple myeloma, there is a lack of direct or indirect comparisons between the available regimens.

In a paper published online in JAMA Oncology, the researchers reported the results of the systematic review and meta-analysis of 11 prospective, phase 3 randomized, controlled trials of eight varieties of maintenance therapy, in 5,073 participants with newly diagnosed multiple myeloma.

Their analysis found that lenalidomide-based regimens showed the best progression-free survival rates (hazard ratio, 0.39 for lenalidomide plus prednisone; HR, 0.47 for lenalidomide alone), compared with placebo, and in 74% of the network meta-analysis simulations, they were the most effective options.

Four other maintenance treatment options - thalidomide-interferon, thalidomide-bortezomib, bortezomib-prednisone, and thalidomide alone – also showed progression-free survival gains – but interferon therapy failed to show any benefit.

However, for overall survival, lenalidomide alone was the best option, followed by thalidomide-bortezomib and bortezomib-prednisone. None of the other regimens considered showed benefits for overall survival.

“Long-term use of lenalidomide undoubtedly has advantages, owing to the lack of neuropathy, which is the main factor limiting the long-term use of both thalidomide and bortezomib,” the authors wrote.

When the authors restricted their analysis to trials conducted in the setting of autologous stem cell transplantation they found similar results, with lenalidomide-based regimens having the best progression-free and overall survival.

Patients with a good prognosis and standard-risk chromosomal abnormalities also did best with lenalidomide-based maintenance, while those with a poor prognosis – for example, with ISS stage III disease – benefited more from bortezomib-based maintenance. However patients with high-risk chromosomal abnormalities gained no advantage from any regimen, which the authors suggested may relate to small sample size, different cut-off points or their extremely poor prognosis.

The authors noted that their analysis did not take into account adverse events, drug discontinuations, or quality of life but focused solely on progression-free survival and overall survival.

“An increase in second primary malignant disease with prolonged lenalidomide therapy has been reported, but the survival benefit overcame the risk in all the trials,” they wrote.

They also commented that better treatment options are needed for patients with aggressive disease, and there are ongoing trials looking at second-generation proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies for maintenance therapy.

Most authors declared research funding, advisory board positions, fees and honoraria from the pharmaceutical industry, including lenalidomide manufacturer Celgene.

SOURCE: Gay F et al. 2018 Aug 9. doi:10.1001/jamaoncol.2018.2961.

Lenalidomide may be the best maintenance treatment option for patients with newly diagnosed multiple myeloma, say the authors of a systematic review and meta-analysis.

Francesca M. Gay, MD, from the division of hematology at the University of Torino (Italy), and her coauthors wrote that despite the well-recognized importance of novel agent–based maintenance therapy for multiple myeloma, there is a lack of direct or indirect comparisons between the available regimens.

In a paper published online in JAMA Oncology, the researchers reported the results of the systematic review and meta-analysis of 11 prospective, phase 3 randomized, controlled trials of eight varieties of maintenance therapy, in 5,073 participants with newly diagnosed multiple myeloma.

Their analysis found that lenalidomide-based regimens showed the best progression-free survival rates (hazard ratio, 0.39 for lenalidomide plus prednisone; HR, 0.47 for lenalidomide alone), compared with placebo, and in 74% of the network meta-analysis simulations, they were the most effective options.

Four other maintenance treatment options - thalidomide-interferon, thalidomide-bortezomib, bortezomib-prednisone, and thalidomide alone – also showed progression-free survival gains – but interferon therapy failed to show any benefit.

However, for overall survival, lenalidomide alone was the best option, followed by thalidomide-bortezomib and bortezomib-prednisone. None of the other regimens considered showed benefits for overall survival.

“Long-term use of lenalidomide undoubtedly has advantages, owing to the lack of neuropathy, which is the main factor limiting the long-term use of both thalidomide and bortezomib,” the authors wrote.

When the authors restricted their analysis to trials conducted in the setting of autologous stem cell transplantation they found similar results, with lenalidomide-based regimens having the best progression-free and overall survival.

Patients with a good prognosis and standard-risk chromosomal abnormalities also did best with lenalidomide-based maintenance, while those with a poor prognosis – for example, with ISS stage III disease – benefited more from bortezomib-based maintenance. However patients with high-risk chromosomal abnormalities gained no advantage from any regimen, which the authors suggested may relate to small sample size, different cut-off points or their extremely poor prognosis.

The authors noted that their analysis did not take into account adverse events, drug discontinuations, or quality of life but focused solely on progression-free survival and overall survival.

“An increase in second primary malignant disease with prolonged lenalidomide therapy has been reported, but the survival benefit overcame the risk in all the trials,” they wrote.

They also commented that better treatment options are needed for patients with aggressive disease, and there are ongoing trials looking at second-generation proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies for maintenance therapy.

Most authors declared research funding, advisory board positions, fees and honoraria from the pharmaceutical industry, including lenalidomide manufacturer Celgene.

SOURCE: Gay F et al. 2018 Aug 9. doi:10.1001/jamaoncol.2018.2961.

Lenalidomide may be the best maintenance treatment option for patients with newly diagnosed multiple myeloma, say the authors of a systematic review and meta-analysis.

Francesca M. Gay, MD, from the division of hematology at the University of Torino (Italy), and her coauthors wrote that despite the well-recognized importance of novel agent–based maintenance therapy for multiple myeloma, there is a lack of direct or indirect comparisons between the available regimens.

In a paper published online in JAMA Oncology, the researchers reported the results of the systematic review and meta-analysis of 11 prospective, phase 3 randomized, controlled trials of eight varieties of maintenance therapy, in 5,073 participants with newly diagnosed multiple myeloma.

Their analysis found that lenalidomide-based regimens showed the best progression-free survival rates (hazard ratio, 0.39 for lenalidomide plus prednisone; HR, 0.47 for lenalidomide alone), compared with placebo, and in 74% of the network meta-analysis simulations, they were the most effective options.

Four other maintenance treatment options - thalidomide-interferon, thalidomide-bortezomib, bortezomib-prednisone, and thalidomide alone – also showed progression-free survival gains – but interferon therapy failed to show any benefit.

However, for overall survival, lenalidomide alone was the best option, followed by thalidomide-bortezomib and bortezomib-prednisone. None of the other regimens considered showed benefits for overall survival.

“Long-term use of lenalidomide undoubtedly has advantages, owing to the lack of neuropathy, which is the main factor limiting the long-term use of both thalidomide and bortezomib,” the authors wrote.

When the authors restricted their analysis to trials conducted in the setting of autologous stem cell transplantation they found similar results, with lenalidomide-based regimens having the best progression-free and overall survival.

Patients with a good prognosis and standard-risk chromosomal abnormalities also did best with lenalidomide-based maintenance, while those with a poor prognosis – for example, with ISS stage III disease – benefited more from bortezomib-based maintenance. However patients with high-risk chromosomal abnormalities gained no advantage from any regimen, which the authors suggested may relate to small sample size, different cut-off points or their extremely poor prognosis.

The authors noted that their analysis did not take into account adverse events, drug discontinuations, or quality of life but focused solely on progression-free survival and overall survival.

“An increase in second primary malignant disease with prolonged lenalidomide therapy has been reported, but the survival benefit overcame the risk in all the trials,” they wrote.

They also commented that better treatment options are needed for patients with aggressive disease, and there are ongoing trials looking at second-generation proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies for maintenance therapy.

Most authors declared research funding, advisory board positions, fees and honoraria from the pharmaceutical industry, including lenalidomide manufacturer Celgene.

SOURCE: Gay F et al. 2018 Aug 9. doi:10.1001/jamaoncol.2018.2961.

PARIS – The so-called hybrid strategy is now the preferred approach to percutaneous coronary intervention (PCI) for chronic total occlusions (CTO), 12-month outcomes of the multicenter observational CONSISTENT CTO trial suggest, according to Simon J. Walsh, MD, an interventional cardiologist at Belfast Health and Social Care Trust.

Bruce Jancin/MDedge News

The hybrid algorithm-based PCI strategy utilizes an individual’s CTO anatomy to dictate the initial choice of approach. The goal is to pick the strategy that is most likely to achieve successful outcome efficiently, with minimal contrast and radiation doses for that particular type of CTO. The hybrid algorithm begins with dual-catheter injection and intravascular ultrasound aimed at determining whether four key anatomic features are present: an ambiguous proximal cap, a poor distal target, good interventional collaterals, and a major side branch at the distal cap.

If those four features are absent and the CTO lesion is less than 20-mm long, the algorithm dictates that the initial approach is antegrade wire escalation; if the lesion is 20 mm or more, the first approach is antegrade dissection reentry. However, if those anatomic features are present, the initial strategy is retrograde wire escalation if the lesion is less than 20 mm, and retrograde dissection reentry for longer lesions. When the initial approach fails, structured protocols dictate the selection of second and third approaches (JACC Cardiovasc Interv. 2012 Apr;5[4]:367-79).

The right coronary artery was the site of the CTO in 70% of study participants. Dual-catheter access was utilized in 79% of patients; only 10% had exclusively radial access. An average of 2.8 Synergy stents were deployed, with a whopping mean total stent length of 96.6 mm in the 48% of patients with dissection and 75.4 mm in those without. Mean procedure time was 122 minutes, with a fluoroscopy time of 44.6 minutes.

The primary efficacy endpoint was the rate of target vessel failure (TVF) at 12 months, defined as cardiac death, MI related to the target vessel, or any ischemia-driven revascularization of the target vessel. The rate was 5.24%.

“We were pleasantly surprised by that,” Dr. Walsh admitted.

Indeed, based upon studies of PCI for CTO published by other investigators, he and his colleagues had initially projected a 13% TVF rate, then bumped it up to 15% because of the high degree of lesion complexity.

Diabetes was the main predictor of target vessel revascularization.

At the time of the index PCI, 19% of patients were scheduled to return for an early optimization procedure within 3 months. This was arranged when operators anticipated significant positive remodeling would occur as the target vessel readjusted to blood flow or distal disease of borderline severity was noted beyond the CTO segment. These were not counted as adverse events. Half of the returnees underwent angiography and no further action was undertaken. The others underwent postdilation of their Synergy stents or new stenting of distal disease.

Complete revascularization of the target territory was achieved in 98.6% of patients. Key complications consisted of 5 perforations, 10 hematomas at vascular access sites, 2 cases of pericardiocentesis, and 4 instances of bleeding requiring transfusion.

The final successful CTO revascularization strategy was antegrade dissection reentry in 18% of patients, retrograde dissection reentry in 30%, antegrade wire escalation in 34%, and retrograde wire escalation in 18%. A switch from the initial algorithm-based strategy to a second strategy occurred in 41% of patients, and a third strategy was employed in 9%.

“I think the key message is you need to have more than one option to treat complicated disease. Half of patients had a switch in strategy,” Dr. Walsh observed.

Intravascular ultrasound (IVUS) adjudication in the central core lab showed a humbling rate of discordance between the operators’ impression of how their procedures were proceeding and what was really going on.

“There’s a bit of a mantra [that says] if you’re wiring stuff you’re always in the lumen, and if you’re using dissection techniques you’re always not in the lumen. In fact, that’s nonsense. You get it wrong one in six times. When you use IVUS adjudication to see if you’re outside the lumen or not, with wire-based retrograde escalation you’re out of the lumen and in the subintimal space 27% of the time. And with dissection strategies you’re wrong in about 15%,” according to the cardiologist.

He described the study participants as “extremely limited” at baseline as evidenced by their scores on the Seattle Angina Questionnaire Physical Limitation, Angina Stability, and Angina Frequency domains. At 12 months of follow-up, patients averaged 20- to 40-point improvements across all three domains.

One member of the discussion panel expressed a wish that the study had included a sham PCI arm. He raised the possibility that PCI had exerted an enormous placebo effect that could conceivably account for the substantial quality of life benefits documented in the study. But another panelist scoffed at this notion. This wasn’t a modest improvement in quality of life, nor was it measured after a mere 6 weeks, as was the case in the sham-controlled ORBITA trial.

“It’s really difficult to imagine a sham effect that persists out to a year,” he argued.

Dr. Walsh reported receiving research grants from and serving as a consultant to Boston Scientific, which funded the CONSISTENT CTO Study.

[email protected]

PARIS – The so-called hybrid strategy is now the preferred approach to percutaneous coronary intervention (PCI) for chronic total occlusions (CTO), 12-month outcomes of the multicenter observational CONSISTENT CTO trial suggest, according to Simon J. Walsh, MD, an interventional cardiologist at Belfast Health and Social Care Trust.

Bruce Jancin/MDedge News

The hybrid algorithm-based PCI strategy utilizes an individual’s CTO anatomy to dictate the initial choice of approach. The goal is to pick the strategy that is most likely to achieve successful outcome efficiently, with minimal contrast and radiation doses for that particular type of CTO. The hybrid algorithm begins with dual-catheter injection and intravascular ultrasound aimed at determining whether four key anatomic features are present: an ambiguous proximal cap, a poor distal target, good interventional collaterals, and a major side branch at the distal cap.

If those four features are absent and the CTO lesion is less than 20-mm long, the algorithm dictates that the initial approach is antegrade wire escalation; if the lesion is 20 mm or more, the first approach is antegrade dissection reentry. However, if those anatomic features are present, the initial strategy is retrograde wire escalation if the lesion is less than 20 mm, and retrograde dissection reentry for longer lesions. When the initial approach fails, structured protocols dictate the selection of second and third approaches (JACC Cardiovasc Interv. 2012 Apr;5[4]:367-79).

The right coronary artery was the site of the CTO in 70% of study participants. Dual-catheter access was utilized in 79% of patients; only 10% had exclusively radial access. An average of 2.8 Synergy stents were deployed, with a whopping mean total stent length of 96.6 mm in the 48% of patients with dissection and 75.4 mm in those without. Mean procedure time was 122 minutes, with a fluoroscopy time of 44.6 minutes.

The primary efficacy endpoint was the rate of target vessel failure (TVF) at 12 months, defined as cardiac death, MI related to the target vessel, or any ischemia-driven revascularization of the target vessel. The rate was 5.24%.

“We were pleasantly surprised by that,” Dr. Walsh admitted.

Indeed, based upon studies of PCI for CTO published by other investigators, he and his colleagues had initially projected a 13% TVF rate, then bumped it up to 15% because of the high degree of lesion complexity.

Diabetes was the main predictor of target vessel revascularization.

At the time of the index PCI, 19% of patients were scheduled to return for an early optimization procedure within 3 months. This was arranged when operators anticipated significant positive remodeling would occur as the target vessel readjusted to blood flow or distal disease of borderline severity was noted beyond the CTO segment. These were not counted as adverse events. Half of the returnees underwent angiography and no further action was undertaken. The others underwent postdilation of their Synergy stents or new stenting of distal disease.

Complete revascularization of the target territory was achieved in 98.6% of patients. Key complications consisted of 5 perforations, 10 hematomas at vascular access sites, 2 cases of pericardiocentesis, and 4 instances of bleeding requiring transfusion.

The final successful CTO revascularization strategy was antegrade dissection reentry in 18% of patients, retrograde dissection reentry in 30%, antegrade wire escalation in 34%, and retrograde wire escalation in 18%. A switch from the initial algorithm-based strategy to a second strategy occurred in 41% of patients, and a third strategy was employed in 9%.

“I think the key message is you need to have more than one option to treat complicated disease. Half of patients had a switch in strategy,” Dr. Walsh observed.

Intravascular ultrasound (IVUS) adjudication in the central core lab showed a humbling rate of discordance between the operators’ impression of how their procedures were proceeding and what was really going on.

“There’s a bit of a mantra [that says] if you’re wiring stuff you’re always in the lumen, and if you’re using dissection techniques you’re always not in the lumen. In fact, that’s nonsense. You get it wrong one in six times. When you use IVUS adjudication to see if you’re outside the lumen or not, with wire-based retrograde escalation you’re out of the lumen and in the subintimal space 27% of the time. And with dissection strategies you’re wrong in about 15%,” according to the cardiologist.

He described the study participants as “extremely limited” at baseline as evidenced by their scores on the Seattle Angina Questionnaire Physical Limitation, Angina Stability, and Angina Frequency domains. At 12 months of follow-up, patients averaged 20- to 40-point improvements across all three domains.

One member of the discussion panel expressed a wish that the study had included a sham PCI arm. He raised the possibility that PCI had exerted an enormous placebo effect that could conceivably account for the substantial quality of life benefits documented in the study. But another panelist scoffed at this notion. This wasn’t a modest improvement in quality of life, nor was it measured after a mere 6 weeks, as was the case in the sham-controlled ORBITA trial.

“It’s really difficult to imagine a sham effect that persists out to a year,” he argued.

Dr. Walsh reported receiving research grants from and serving as a consultant to Boston Scientific, which funded the CONSISTENT CTO Study.

[email protected]

PARIS – The so-called hybrid strategy is now the preferred approach to percutaneous coronary intervention (PCI) for chronic total occlusions (CTO), 12-month outcomes of the multicenter observational CONSISTENT CTO trial suggest, according to Simon J. Walsh, MD, an interventional cardiologist at Belfast Health and Social Care Trust.

Bruce Jancin/MDedge News

The hybrid algorithm-based PCI strategy utilizes an individual’s CTO anatomy to dictate the initial choice of approach. The goal is to pick the strategy that is most likely to achieve successful outcome efficiently, with minimal contrast and radiation doses for that particular type of CTO. The hybrid algorithm begins with dual-catheter injection and intravascular ultrasound aimed at determining whether four key anatomic features are present: an ambiguous proximal cap, a poor distal target, good interventional collaterals, and a major side branch at the distal cap.

If those four features are absent and the CTO lesion is less than 20-mm long, the algorithm dictates that the initial approach is antegrade wire escalation; if the lesion is 20 mm or more, the first approach is antegrade dissection reentry. However, if those anatomic features are present, the initial strategy is retrograde wire escalation if the lesion is less than 20 mm, and retrograde dissection reentry for longer lesions. When the initial approach fails, structured protocols dictate the selection of second and third approaches (JACC Cardiovasc Interv. 2012 Apr;5[4]:367-79).

The right coronary artery was the site of the CTO in 70% of study participants. Dual-catheter access was utilized in 79% of patients; only 10% had exclusively radial access. An average of 2.8 Synergy stents were deployed, with a whopping mean total stent length of 96.6 mm in the 48% of patients with dissection and 75.4 mm in those without. Mean procedure time was 122 minutes, with a fluoroscopy time of 44.6 minutes.

The primary efficacy endpoint was the rate of target vessel failure (TVF) at 12 months, defined as cardiac death, MI related to the target vessel, or any ischemia-driven revascularization of the target vessel. The rate was 5.24%.

“We were pleasantly surprised by that,” Dr. Walsh admitted.

Indeed, based upon studies of PCI for CTO published by other investigators, he and his colleagues had initially projected a 13% TVF rate, then bumped it up to 15% because of the high degree of lesion complexity.

Diabetes was the main predictor of target vessel revascularization.

At the time of the index PCI, 19% of patients were scheduled to return for an early optimization procedure within 3 months. This was arranged when operators anticipated significant positive remodeling would occur as the target vessel readjusted to blood flow or distal disease of borderline severity was noted beyond the CTO segment. These were not counted as adverse events. Half of the returnees underwent angiography and no further action was undertaken. The others underwent postdilation of their Synergy stents or new stenting of distal disease.

Complete revascularization of the target territory was achieved in 98.6% of patients. Key complications consisted of 5 perforations, 10 hematomas at vascular access sites, 2 cases of pericardiocentesis, and 4 instances of bleeding requiring transfusion.

The final successful CTO revascularization strategy was antegrade dissection reentry in 18% of patients, retrograde dissection reentry in 30%, antegrade wire escalation in 34%, and retrograde wire escalation in 18%. A switch from the initial algorithm-based strategy to a second strategy occurred in 41% of patients, and a third strategy was employed in 9%.

“I think the key message is you need to have more than one option to treat complicated disease. Half of patients had a switch in strategy,” Dr. Walsh observed.

Intravascular ultrasound (IVUS) adjudication in the central core lab showed a humbling rate of discordance between the operators’ impression of how their procedures were proceeding and what was really going on.

“There’s a bit of a mantra [that says] if you’re wiring stuff you’re always in the lumen, and if you’re using dissection techniques you’re always not in the lumen. In fact, that’s nonsense. You get it wrong one in six times. When you use IVUS adjudication to see if you’re outside the lumen or not, with wire-based retrograde escalation you’re out of the lumen and in the subintimal space 27% of the time. And with dissection strategies you’re wrong in about 15%,” according to the cardiologist.

He described the study participants as “extremely limited” at baseline as evidenced by their scores on the Seattle Angina Questionnaire Physical Limitation, Angina Stability, and Angina Frequency domains. At 12 months of follow-up, patients averaged 20- to 40-point improvements across all three domains.

One member of the discussion panel expressed a wish that the study had included a sham PCI arm. He raised the possibility that PCI had exerted an enormous placebo effect that could conceivably account for the substantial quality of life benefits documented in the study. But another panelist scoffed at this notion. This wasn’t a modest improvement in quality of life, nor was it measured after a mere 6 weeks, as was the case in the sham-controlled ORBITA trial.

“It’s really difficult to imagine a sham effect that persists out to a year,” he argued.

Dr. Walsh reported receiving research grants from and serving as a consultant to Boston Scientific, which funded the CONSISTENT CTO Study.

[email protected]

Hundreds of reports since the 1980s have associated Alzheimer disease with bacteria and viruses. But researchers could not explain the connection. Now new research suggests that viral species, particularly herpes viruses, play a role in Alzheimer disease biology.

The hypotheses that link viruses to brain disease are not new, Richard Hodes, MD, director of the National Institute on Aging, says, but this is the first study to provide “strong evidence” based on unbiased approaches and large datasets.

The study, which was funded by National Institute of Aging (NIA) , originally was intended to find out whether drugs used to treat other diseases can be repurposed for treating Alzheimer. Researchers analyzed large datasets from postmortem brain samples to map and compare biological networks underlying Alzheimer disease. They found that the disease biology is impacted by a “complex constellation” of factors, including the ways the interrelated systems of DNA, RNA, proteins, and metabolites interact with molecular, genetic, and clinical aspects of Alzheimer disease.

Among the key findings: Human herpes virus 6A and 7 were more abundant in Alzheimer disease samples than in non-Alzheimer samples. Researchers also found multiple points of overlap between virus-host interactions and genes associated with Alzheimer risk.

The research “reinforces the complexity of Alzheimer disease,” Hode says, and “highlights the importance of sharing data freely and widely with the research community.”

Hundreds of reports since the 1980s have associated Alzheimer disease with bacteria and viruses. But researchers could not explain the connection. Now new research suggests that viral species, particularly herpes viruses, play a role in Alzheimer disease biology.

The hypotheses that link viruses to brain disease are not new, Richard Hodes, MD, director of the National Institute on Aging, says, but this is the first study to provide “strong evidence” based on unbiased approaches and large datasets.

The study, which was funded by National Institute of Aging (NIA) , originally was intended to find out whether drugs used to treat other diseases can be repurposed for treating Alzheimer. Researchers analyzed large datasets from postmortem brain samples to map and compare biological networks underlying Alzheimer disease. They found that the disease biology is impacted by a “complex constellation” of factors, including the ways the interrelated systems of DNA, RNA, proteins, and metabolites interact with molecular, genetic, and clinical aspects of Alzheimer disease.

Among the key findings: Human herpes virus 6A and 7 were more abundant in Alzheimer disease samples than in non-Alzheimer samples. Researchers also found multiple points of overlap between virus-host interactions and genes associated with Alzheimer risk.

The research “reinforces the complexity of Alzheimer disease,” Hode says, and “highlights the importance of sharing data freely and widely with the research community.”

Hundreds of reports since the 1980s have associated Alzheimer disease with bacteria and viruses. But researchers could not explain the connection. Now new research suggests that viral species, particularly herpes viruses, play a role in Alzheimer disease biology.

The hypotheses that link viruses to brain disease are not new, Richard Hodes, MD, director of the National Institute on Aging, says, but this is the first study to provide “strong evidence” based on unbiased approaches and large datasets.

The study, which was funded by National Institute of Aging (NIA) , originally was intended to find out whether drugs used to treat other diseases can be repurposed for treating Alzheimer. Researchers analyzed large datasets from postmortem brain samples to map and compare biological networks underlying Alzheimer disease. They found that the disease biology is impacted by a “complex constellation” of factors, including the ways the interrelated systems of DNA, RNA, proteins, and metabolites interact with molecular, genetic, and clinical aspects of Alzheimer disease.

Among the key findings: Human herpes virus 6A and 7 were more abundant in Alzheimer disease samples than in non-Alzheimer samples. Researchers also found multiple points of overlap between virus-host interactions and genes associated with Alzheimer risk.

The research “reinforces the complexity of Alzheimer disease,” Hode says, and “highlights the importance of sharing data freely and widely with the research community.”

Platelet-transmitted bacterial infections persist as a cause of transfusion-associated morbidity and mortality, according to researchers writing in Mortality and Morbidity Weekly Report. They describe 2 separate clusters of platelet transfusion-associated bacterial sepsis reported in Utah and California, in which 3 patients died.

Contamination of blood products most commonly happens when skin microbiota is introduced during needle insertion. Because most platelets are stored at room temperature, bacteria can proliferate to clinically important levels by the time the unit is transfused, the CDC says. About 1 in 5,000 platelet collections are contaminated; 1 in 100,000 platelet transfusions results in bacterial sepsis.

In Utah, 2 patients received contaminated apheresis platelet units. One developed rigors 30 minutes after infusion, but transfusion-transmitted bacterial infection was not considered because of the patient’s complex medical history. He died 4 days later.

Less than a day after the first patient’s infusion, the second patient received the other platelet unit. No immediate symptoms of sepsis followed but later that day routine laboratory testing revealed new intravascular hemolysis. She died 11 hours after transfusion.

In California, a patient developed vomiting, tachycardia, and hypotension within 15 minutes of an infusion that came from an apheresis blood donation. Although the transfusion was stopped, he died within 5 hours. A second patient developed septic shock approximately 9 hours after infusion but recovered.

Subsequent investigation found that both the Utah and California collection facilities followed current practices. However, the CDC report highlights that even when procedures are followed appropriately, the risk remains. The CDC says evidence-based strategies such as pathogen inactivation, rapid detection devices, and modified screen of bacterial culture protocols can help mitigate that risk.

Platelet-transmitted bacterial infections persist as a cause of transfusion-associated morbidity and mortality, according to researchers writing in Mortality and Morbidity Weekly Report. They describe 2 separate clusters of platelet transfusion-associated bacterial sepsis reported in Utah and California, in which 3 patients died.

Contamination of blood products most commonly happens when skin microbiota is introduced during needle insertion. Because most platelets are stored at room temperature, bacteria can proliferate to clinically important levels by the time the unit is transfused, the CDC says. About 1 in 5,000 platelet collections are contaminated; 1 in 100,000 platelet transfusions results in bacterial sepsis.

In Utah, 2 patients received contaminated apheresis platelet units. One developed rigors 30 minutes after infusion, but transfusion-transmitted bacterial infection was not considered because of the patient’s complex medical history. He died 4 days later.

Less than a day after the first patient’s infusion, the second patient received the other platelet unit. No immediate symptoms of sepsis followed but later that day routine laboratory testing revealed new intravascular hemolysis. She died 11 hours after transfusion.

In California, a patient developed vomiting, tachycardia, and hypotension within 15 minutes of an infusion that came from an apheresis blood donation. Although the transfusion was stopped, he died within 5 hours. A second patient developed septic shock approximately 9 hours after infusion but recovered.

Subsequent investigation found that both the Utah and California collection facilities followed current practices. However, the CDC report highlights that even when procedures are followed appropriately, the risk remains. The CDC says evidence-based strategies such as pathogen inactivation, rapid detection devices, and modified screen of bacterial culture protocols can help mitigate that risk.

Platelet-transmitted bacterial infections persist as a cause of transfusion-associated morbidity and mortality, according to researchers writing in Mortality and Morbidity Weekly Report. They describe 2 separate clusters of platelet transfusion-associated bacterial sepsis reported in Utah and California, in which 3 patients died.

Contamination of blood products most commonly happens when skin microbiota is introduced during needle insertion. Because most platelets are stored at room temperature, bacteria can proliferate to clinically important levels by the time the unit is transfused, the CDC says. About 1 in 5,000 platelet collections are contaminated; 1 in 100,000 platelet transfusions results in bacterial sepsis.

In Utah, 2 patients received contaminated apheresis platelet units. One developed rigors 30 minutes after infusion, but transfusion-transmitted bacterial infection was not considered because of the patient’s complex medical history. He died 4 days later.

Less than a day after the first patient’s infusion, the second patient received the other platelet unit. No immediate symptoms of sepsis followed but later that day routine laboratory testing revealed new intravascular hemolysis. She died 11 hours after transfusion.

In California, a patient developed vomiting, tachycardia, and hypotension within 15 minutes of an infusion that came from an apheresis blood donation. Although the transfusion was stopped, he died within 5 hours. A second patient developed septic shock approximately 9 hours after infusion but recovered.

Subsequent investigation found that both the Utah and California collection facilities followed current practices. However, the CDC report highlights that even when procedures are followed appropriately, the risk remains. The CDC says evidence-based strategies such as pathogen inactivation, rapid detection devices, and modified screen of bacterial culture protocols can help mitigate that risk.

DR HENRY I thought we might discuss some cases of patients with myeloma, starting with a relatively simple case and ending with one that is a little more complicated. For the first case, we have a 56-year-old healthy man with IgG kappa myeloma whose work-up shows he has multiple lytic bone lesions. He has normal renal function, normal calcium, and he’s transplant-eligible by other health issues. I’ll leave the cytogenetics up to you if that changes your approach. How would you develop or pose some options for this man’s treatment to begin with?

DR ANDERSON It’s important to start out by saying that we, in myeloma, have many new classes of drugs and many new opportunities to choose from to treat this patient.¹ As you know, we have proteasome inhibitors, the first-generation bortezomib, then carfilzomib and ixazomib. We have the immunomodulatory drugs (IMiDs), thalidomide, and now lenalidomide and pomalidomide. We have a histone deacetylase (HDAC) inhibitor approved called panobinostat, and we have 2 monoclonal antibodies approved, elotuzumab and daratumumab. These classes of medicine have made it possible for 20 different Food and Drug Administration (FDA) approvals in the last 10-15 years. These agents, having been tested in advanced myeloma, have moved toward initial management.

This person is 50 years old. He has adequate liver, heart, lung, and kidney function, so he would be eligible for high-dose therapy and stem-cell transplantation. In terms of initial management, there are many options (Figure 1). We strongly recommend that triplet therapy be used initially. The most common triplets would be lenalidomide, bortezomib, and dexamethasone (RVD)^2,3 or cyclophosphamide, bortezomib, and dexamethasone (CyBorD).⁴ If this man had neuropathy, perhaps carfilzomib, the second-generation proteasome inhibitor, with lenalidomide and dexamethasone could have been used. Why do we use these? The extent and frequency of response with these triplets is nearly universal overall response rate, with three-quarters very good partial and half-complete responses, including minimal residual disease negative responses. In this patient, we would therefore recommend treatment with either RVD or CyBorD for several cycles to maximal response.

DR HENRY In summary then, this would be, in 2017, off-protocol while the data is pending: it’s reasonable to get a deep induction response, collect stem cells, have a discussion with the patient, and then consider high-dose therapy or not.

DR ANDERSON Yes. I think it’s reasonable to discuss it. We need to be open and honest with patients that the standard of care remains transplant, that you incorporate novel treatments before the transplant and novel treatments as maintenance after the transplant. The happy news is that the outcome, especially for patients who have standard-risk myeloma, is at least a decade or longer progression-free survival. It’s an optimistic picture. The data in terms of transplant being needed or not, will come within the next several years.

For now, it is a standard of care to use 1 high-dose melphalan and stem-cell transplant in this setting. I will add into our discussion with patients – besides the opportunity to harvest stem cells and think about whether one needs to do a transplant early on or not – is the issue of toxicity. High-dose melphalan by itself has a small but real secondary incidence of cancer, myelodysplasia, or leukemia. If one uses lenalidomide maintenance after melphalan transplantation treatment, that risk of secondary cancer is slightly increased.

In my experience, if patients have achieved a complete response with induction therapy only, it’s not unreasonable to offer early transplant and be clear that’s the standard of care. The alternative is maintenance with lenalidomide, knowing once the stem cells have been harvested, that transplantation can be an option to treat relapsed myeloma. We have many other options available as well. Time will tell in terms of the ongoing randomized trials as to whether transplant remains central to our treatment paradigm.

DR HENRY This leads us to our second patient. Here we have an older man of 74 years. He’s a professional piano player, so we want to try to avoid peripheral neuropathy in him. He has some mild renal insufficiency and some coronary artery disease, so he’s deemed transplant-ineligible. He has IgG kappa myeloma, and he’s brand new. What would you consider to be options for him for treatment?

DR ANDERSON This brings up the issue of a transplant-ineligible patient. He has significant comorbidity that would make transplantation an increased risk. What we would recommend in such a patient is still triplet induction therapy incorporating novel agents (Figure 1). Lenalidomide, the immunomodulatory drug, can safely be given in the context of neuropathy because it does not cause significant neuropathy. It would need to be dose modified, depending on the degree of renal insufficiency. We would recommend also including proteasome inhibitors. Bortezomib, the first-generation proteasome inhibitor, would be contraindicated because it does have a small but real attendant neuropathy. If, however, it is given weekly and subcutaneously, the risk of attendant neuropathy is quite low. In this patient, therefore, one could start with lenalidomide and bortezomib weekly and subcutaneously,^1,2 with a very early and vigilant follow-up for the earliest signs of neuropathy, so as not to allow it to develop and compromise his career.

Alternatively, one could use a proteasome inhibitor that does not have attendant neuropathy. Carfilzomib, the second-generation proteasome inhibitor, does not have neuropathy.⁹ But we would need to have caution here, because this patient has a history of coronary artery disease, and carfilzomib has a very small, but real, incidence of cardiac toxicity so would need to be used judiciously in this setting. The third proteasome inhibitor, ixazomib, is the next-generation bortezomib-class proteasome inhibitor, and it’s oral.¹⁰ It has less neuropathy than does bortezomib, so in my view is a very realistic option for him together with lenalidomide. It does have a small incidence of neuropathy, so close monitoring for neuropathy would be indicated. We could use lenalidomide–dexamethasone as a doublet and avoid neuropathy,¹¹ but usually doublets are reserved only for frail patients.

My recommendation, therefore, would be RVD with the bortezomib weekly or subcutaneously, or alternatively, lenalidomide, ixazomib, dexamethasone as an all-oral regimen as induction therapy. In my view, this 74-year-old patient with comorbidity is not a transplant candidate. However, one can be very optimistic with this patient. The likelihood that he could have myeloma as a chronic illness and die from something else is quite high. Initial induction triplet therapy would achieve a very high response extent and frequency. The durability would be long, especially with lenalidomide maintenance if it’s standard-risk myeloma or lenalidomide and a proteasome inhibitor, probably ixazomib in this setting, if he were to have high-risk myeloma.

If myeloma relapses, then there are many options that could be used in this patient and achieve years of progression-free and overall survival. Indeed, he is 74 years old and will respond very well to induction triplet therapy, with many years’ duration of response due to continuous lenalidomide or lenalidomide and proteasome inhibitor maintenance. Then there are many effective options to treat relapsed therapy using triplet novel agents. Therefore, his lifespan is unlikely to be shortened by multiple myeloma.

DR HENRY It’s so incredible compared with what it was when I trained. The next patient, a 45-year-old woman with IgG lambda myeloma, has had RVD induction and responded. She had lenalidomide maintenance, but then she progressed, and she got her stem-cell transplant, and she’s progressing after that. I guess we’re looking here to fold in some of the newer agents. How you would you do that in this patient?DR ANDERSON Yes. I think one of the most remarkable and exciting developments with myeloma is the rapid approval of the novel classes of agents that I mentioned earlier – the proteasome inhibitors, the immunomodulatory drugs, the HDAC inhibitor, and the monoclonal antibodies.¹ They’re particularly relevant in a patient such as this one, whose myeloma has relapsed after what would be considered standard therapy for a young person with standard-risk myeloma. This patient had RVD and maintenance therapy, and then progressed. The transplant was given for relapsed myeloma. The opportunity to use stem-cell transplant in patients when myeloma becomes active after maintenance should not be forgotten as it can be very effective. In all the trials done to date in which early versus late transplant are compared, there have been similar outcomes. Therefore, if the transplant isn’t done early, don’t forget that it’s an option at the time the myeloma progresses. I do want to mention, that there are lots of options for relapsed myeloma (Figures 3 and 4). I mentioned RVD or CyBorD as initial triplet therapies.^2-4 In North America, those are the 2 most common regimens. If myeloma then relapses and is resistant to RVD or to CyBorD, then we need to identify alternatives.

We also need to think about the comorbidities in the patient – issues such as age, neuropathy, presence of renal dysfunction, and other clinical factors. And we need to think about what treatment they’ve had in the past. This patient has had RVD, maintenance with lenalidomide, and a stem-cell transplant. We can offer patients a variety of therapies, but in the context of resistance to the first-generation proteasome inhibitor bortezomib and the first-generation immunomodulatory drug lenalidomide, we would strongly recommend the second-generation immunomodulatory drug pomalidomide¹² together with a second-generation proteasome inhibitor, be that carfilzomib¹³ or ixazomib.¹⁴ When one uses the second-generation IMiDs and proteasome inhibitors together, there’s a very high frequency of response in the order of 70%-80%, which lasts years.

Besides carfilzomib and ixazomib proteasome inhibitors, we also have elotuzumab and daratumumab, the monoclonal antibodies.^15-17 These agents have been FDA approved to treat patients such as this one who has had 1-3 previous therapies for their myeloma. All of them have been approved in randomized phase 3 trials compared with lenalidomide-dexamethasone in the control arm.^13-15,17 They’ve all been found to be superior. Although lenalidomide-dexamethasone combined with daratumumab, ixazomib, elotuzumab, or carfilzomib is superior to lenalidomide in relapsed myeloma, the situation in North America, as in this patient, is usually that patients have had lenalidomide-dexamethasone as part of their initial treatment and their myeloma is refractory to lenalidomide.

Hence, we recommend, that we go to the second-generation pomalidomide and second-generation proteasome inhibitors, either carfilzomib or ixazomib. Having said that, the treatment paradigm is evolving. For example, the monoclonal antibody daratumumab was initially approved by the FDA in multiply relapsed disease as a single agent because it achieves a 30% response rate.¹⁶ It now has been moved earlier into the first relapse of multiple myeloma, where it achieves much higher response rates when combined with lenalidomide–dexamethasone or combined with bortezomib–dexamethasone.^17,18 Response rates of 70%-80% can be achieved, including minimal residual disease negative complete responses.

Today, in a patient who has had RVD transplant and myeloma has returned, we would recommend second-generation IMiDs, pomalidomide, and second-generation proteasome inhibitors, either carfilzomib or ixazomib. Data for daratumumab combined with lenalidomide-dexamethasone or with bortezomib-dexamethasone, look very promising. We need, however, to see more experience of daratumumab together with lenalidomide-dexamethasone or daratumumab together with bortezomib-dexamethasone in patients whose myeloma is refractory to RVD, that is, patients whose myeloma has returned after RVD induction treatment. Of note, pomalidomide, dexamethasone, and daratumumab have just been approved by the FDA and may also be active even in myeloma recurring after RVD treatment.¹⁹

Daratumumab in combination will be moving earlier and earlier and may be appropriate to treat the first relapse. I do want to stress, however, that at present I save daratumumab for the second or greater relapse. Daratumumab is active even when relapse occurs after treatment with second-generation IMiDs and proteasome inhibitors.

DR HENRY Before we close, I have a couple practical questions with these antibodies. Daratumumab has the track record of first-treatment severe reactions and long infusion times. How long are you anticipating the first daratumumab treatment takes? There has been some talk that maybe splitting it in half and going over 2 days is easier on the patient and the infusion center. Have you done that?

DR ANDERSON Yes, I think that’s a very important point. We need to be thinking – first and foremost – about efficacy of our therapy. Equally important, however, are the safety profile and the user-friendliness for the patient. Daratumumab infusions are quite long – on the order of 8 hours or longer on day 1 of infusion. And to date, all the clinical trials have used daratumumab infusions weekly for 8 treatments, followed by 8 treatments given every 2 weeks. Then monthly daratumumab is given as a maintenance therapy. Thus, there is a requirement for multiple outpatient clinic visits that can be prolonged.

One of the opportunities that’s being tested is to give daratumumab subcutaneously. While this is being evaluated in protocols now, the results that have been reported at our national meetings look to be quite promising in terms of efficacy, similar to results with the intravenous administration. Obviously, this would allow for a much more convenient clinic visit and shorter time for the patients being treated.

I should mention that the other antibody, elotuzumab, has been approved in combination with lenalidomide and dexamethasone.¹⁵ The infusions with lenalidomide, dexamethasone, and the antibody elotuzumab are much shorter, on the order of 2- or 3-hour visits. The place for elotuzumab in the management of relapsed myeloma is yet to be totally defined. We tend to use it now in the setting of more indolent relapses, where patients might have a slowly rising monoclonal protein. Elotuzumab-lenalidomide-dexamethasone has maintained an overall survival advantage at 4 years compared with lenalidomide-dexamethasone when used in relapsed myeloma.

We are quite excited about both antibodies. Daratumumab tends to get most of the activity, as it achieves responses as a single agent,¹⁶ and the depth of the responses are markedly increased when it’s combined with lenalidomide-dexamethasone or bortezomib-dexamethasone.^17,18 However, one shouldn’t forget elotuzumab¹⁵ based on its tolerability and the survival advantage I mentioned at 4 years.

The final point is that we think about myeloma genetically at the time of diagnosis and relapse in terms of standard or high-risk disease. One of the hallmarks of high-risk disease has been 17P deletion or P53 dysfunction. One of the most exciting outcomes of the development of monoclonal antibodies has been the responses observed even in the context of P53 deletion. Clearly, antibody-mediated cellular cytotoxicity, complement-mediated cytotoxicity, and other mechanisms of action of these antibodies do not require normal P53 function. The important point, therefore, is that what has previously been thought of as high-risk disease can nowadays be effectively treated with these new immune treatments, correlating with the marked improvement in survival and overall outcome.

DR HENRY We have outlined 3 kinds of myeloma patients we see, and especially interesting is the last patient, who has relapsed and then progressed, and in whom newer drugs have a role. Thank you for such a complete and thorough discussion, Dr Anderson.

DR HENRY I thought we might discuss some cases of patients with myeloma, starting with a relatively simple case and ending with one that is a little more complicated. For the first case, we have a 56-year-old healthy man with IgG kappa myeloma whose work-up shows he has multiple lytic bone lesions. He has normal renal function, normal calcium, and he’s transplant-eligible by other health issues. I’ll leave the cytogenetics up to you if that changes your approach. How would you develop or pose some options for this man’s treatment to begin with?

DR ANDERSON It’s important to start out by saying that we, in myeloma, have many new classes of drugs and many new opportunities to choose from to treat this patient.¹ As you know, we have proteasome inhibitors, the first-generation bortezomib, then carfilzomib and ixazomib. We have the immunomodulatory drugs (IMiDs), thalidomide, and now lenalidomide and pomalidomide. We have a histone deacetylase (HDAC) inhibitor approved called panobinostat, and we have 2 monoclonal antibodies approved, elotuzumab and daratumumab. These classes of medicine have made it possible for 20 different Food and Drug Administration (FDA) approvals in the last 10-15 years. These agents, having been tested in advanced myeloma, have moved toward initial management.

This person is 50 years old. He has adequate liver, heart, lung, and kidney function, so he would be eligible for high-dose therapy and stem-cell transplantation. In terms of initial management, there are many options (Figure 1). We strongly recommend that triplet therapy be used initially. The most common triplets would be lenalidomide, bortezomib, and dexamethasone (RVD)^2,3 or cyclophosphamide, bortezomib, and dexamethasone (CyBorD).⁴ If this man had neuropathy, perhaps carfilzomib, the second-generation proteasome inhibitor, with lenalidomide and dexamethasone could have been used. Why do we use these? The extent and frequency of response with these triplets is nearly universal overall response rate, with three-quarters very good partial and half-complete responses, including minimal residual disease negative responses. In this patient, we would therefore recommend treatment with either RVD or CyBorD for several cycles to maximal response.

DR HENRY In summary then, this would be, in 2017, off-protocol while the data is pending: it’s reasonable to get a deep induction response, collect stem cells, have a discussion with the patient, and then consider high-dose therapy or not.

DR ANDERSON Yes. I think it’s reasonable to discuss it. We need to be open and honest with patients that the standard of care remains transplant, that you incorporate novel treatments before the transplant and novel treatments as maintenance after the transplant. The happy news is that the outcome, especially for patients who have standard-risk myeloma, is at least a decade or longer progression-free survival. It’s an optimistic picture. The data in terms of transplant being needed or not, will come within the next several years.

For now, it is a standard of care to use 1 high-dose melphalan and stem-cell transplant in this setting. I will add into our discussion with patients – besides the opportunity to harvest stem cells and think about whether one needs to do a transplant early on or not – is the issue of toxicity. High-dose melphalan by itself has a small but real secondary incidence of cancer, myelodysplasia, or leukemia. If one uses lenalidomide maintenance after melphalan transplantation treatment, that risk of secondary cancer is slightly increased.

In my experience, if patients have achieved a complete response with induction therapy only, it’s not unreasonable to offer early transplant and be clear that’s the standard of care. The alternative is maintenance with lenalidomide, knowing once the stem cells have been harvested, that transplantation can be an option to treat relapsed myeloma. We have many other options available as well. Time will tell in terms of the ongoing randomized trials as to whether transplant remains central to our treatment paradigm.

DR HENRY This leads us to our second patient. Here we have an older man of 74 years. He’s a professional piano player, so we want to try to avoid peripheral neuropathy in him. He has some mild renal insufficiency and some coronary artery disease, so he’s deemed transplant-ineligible. He has IgG kappa myeloma, and he’s brand new. What would you consider to be options for him for treatment?

DR ANDERSON This brings up the issue of a transplant-ineligible patient. He has significant comorbidity that would make transplantation an increased risk. What we would recommend in such a patient is still triplet induction therapy incorporating novel agents (Figure 1). Lenalidomide, the immunomodulatory drug, can safely be given in the context of neuropathy because it does not cause significant neuropathy. It would need to be dose modified, depending on the degree of renal insufficiency. We would recommend also including proteasome inhibitors. Bortezomib, the first-generation proteasome inhibitor, would be contraindicated because it does have a small but real attendant neuropathy. If, however, it is given weekly and subcutaneously, the risk of attendant neuropathy is quite low. In this patient, therefore, one could start with lenalidomide and bortezomib weekly and subcutaneously,^1,2 with a very early and vigilant follow-up for the earliest signs of neuropathy, so as not to allow it to develop and compromise his career.

Alternatively, one could use a proteasome inhibitor that does not have attendant neuropathy. Carfilzomib, the second-generation proteasome inhibitor, does not have neuropathy.⁹ But we would need to have caution here, because this patient has a history of coronary artery disease, and carfilzomib has a very small, but real, incidence of cardiac toxicity so would need to be used judiciously in this setting. The third proteasome inhibitor, ixazomib, is the next-generation bortezomib-class proteasome inhibitor, and it’s oral.¹⁰ It has less neuropathy than does bortezomib, so in my view is a very realistic option for him together with lenalidomide. It does have a small incidence of neuropathy, so close monitoring for neuropathy would be indicated. We could use lenalidomide–dexamethasone as a doublet and avoid neuropathy,¹¹ but usually doublets are reserved only for frail patients.

My recommendation, therefore, would be RVD with the bortezomib weekly or subcutaneously, or alternatively, lenalidomide, ixazomib, dexamethasone as an all-oral regimen as induction therapy. In my view, this 74-year-old patient with comorbidity is not a transplant candidate. However, one can be very optimistic with this patient. The likelihood that he could have myeloma as a chronic illness and die from something else is quite high. Initial induction triplet therapy would achieve a very high response extent and frequency. The durability would be long, especially with lenalidomide maintenance if it’s standard-risk myeloma or lenalidomide and a proteasome inhibitor, probably ixazomib in this setting, if he were to have high-risk myeloma.

If myeloma relapses, then there are many options that could be used in this patient and achieve years of progression-free and overall survival. Indeed, he is 74 years old and will respond very well to induction triplet therapy, with many years’ duration of response due to continuous lenalidomide or lenalidomide and proteasome inhibitor maintenance. Then there are many effective options to treat relapsed therapy using triplet novel agents. Therefore, his lifespan is unlikely to be shortened by multiple myeloma.

DR HENRY It’s so incredible compared with what it was when I trained. The next patient, a 45-year-old woman with IgG lambda myeloma, has had RVD induction and responded. She had lenalidomide maintenance, but then she progressed, and she got her stem-cell transplant, and she’s progressing after that. I guess we’re looking here to fold in some of the newer agents. How you would you do that in this patient?DR ANDERSON Yes. I think one of the most remarkable and exciting developments with myeloma is the rapid approval of the novel classes of agents that I mentioned earlier – the proteasome inhibitors, the immunomodulatory drugs, the HDAC inhibitor, and the monoclonal antibodies.¹ They’re particularly relevant in a patient such as this one, whose myeloma has relapsed after what would be considered standard therapy for a young person with standard-risk myeloma. This patient had RVD and maintenance therapy, and then progressed. The transplant was given for relapsed myeloma. The opportunity to use stem-cell transplant in patients when myeloma becomes active after maintenance should not be forgotten as it can be very effective. In all the trials done to date in which early versus late transplant are compared, there have been similar outcomes. Therefore, if the transplant isn’t done early, don’t forget that it’s an option at the time the myeloma progresses. I do want to mention, that there are lots of options for relapsed myeloma (Figures 3 and 4). I mentioned RVD or CyBorD as initial triplet therapies.^2-4 In North America, those are the 2 most common regimens. If myeloma then relapses and is resistant to RVD or to CyBorD, then we need to identify alternatives.

We also need to think about the comorbidities in the patient – issues such as age, neuropathy, presence of renal dysfunction, and other clinical factors. And we need to think about what treatment they’ve had in the past. This patient has had RVD, maintenance with lenalidomide, and a stem-cell transplant. We can offer patients a variety of therapies, but in the context of resistance to the first-generation proteasome inhibitor bortezomib and the first-generation immunomodulatory drug lenalidomide, we would strongly recommend the second-generation immunomodulatory drug pomalidomide¹² together with a second-generation proteasome inhibitor, be that carfilzomib¹³ or ixazomib.¹⁴ When one uses the second-generation IMiDs and proteasome inhibitors together, there’s a very high frequency of response in the order of 70%-80%, which lasts years.

Besides carfilzomib and ixazomib proteasome inhibitors, we also have elotuzumab and daratumumab, the monoclonal antibodies.^15-17 These agents have been FDA approved to treat patients such as this one who has had 1-3 previous therapies for their myeloma. All of them have been approved in randomized phase 3 trials compared with lenalidomide-dexamethasone in the control arm.^13-15,17 They’ve all been found to be superior. Although lenalidomide-dexamethasone combined with daratumumab, ixazomib, elotuzumab, or carfilzomib is superior to lenalidomide in relapsed myeloma, the situation in North America, as in this patient, is usually that patients have had lenalidomide-dexamethasone as part of their initial treatment and their myeloma is refractory to lenalidomide.

Hence, we recommend, that we go to the second-generation pomalidomide and second-generation proteasome inhibitors, either carfilzomib or ixazomib. Having said that, the treatment paradigm is evolving. For example, the monoclonal antibody daratumumab was initially approved by the FDA in multiply relapsed disease as a single agent because it achieves a 30% response rate.¹⁶ It now has been moved earlier into the first relapse of multiple myeloma, where it achieves much higher response rates when combined with lenalidomide–dexamethasone or combined with bortezomib–dexamethasone.^17,18 Response rates of 70%-80% can be achieved, including minimal residual disease negative complete responses.

Today, in a patient who has had RVD transplant and myeloma has returned, we would recommend second-generation IMiDs, pomalidomide, and second-generation proteasome inhibitors, either carfilzomib or ixazomib. Data for daratumumab combined with lenalidomide-dexamethasone or with bortezomib-dexamethasone, look very promising. We need, however, to see more experience of daratumumab together with lenalidomide-dexamethasone or daratumumab together with bortezomib-dexamethasone in patients whose myeloma is refractory to RVD, that is, patients whose myeloma has returned after RVD induction treatment. Of note, pomalidomide, dexamethasone, and daratumumab have just been approved by the FDA and may also be active even in myeloma recurring after RVD treatment.¹⁹

Daratumumab in combination will be moving earlier and earlier and may be appropriate to treat the first relapse. I do want to stress, however, that at present I save daratumumab for the second or greater relapse. Daratumumab is active even when relapse occurs after treatment with second-generation IMiDs and proteasome inhibitors.

DR HENRY Before we close, I have a couple practical questions with these antibodies. Daratumumab has the track record of first-treatment severe reactions and long infusion times. How long are you anticipating the first daratumumab treatment takes? There has been some talk that maybe splitting it in half and going over 2 days is easier on the patient and the infusion center. Have you done that?

DR ANDERSON Yes, I think that’s a very important point. We need to be thinking – first and foremost – about efficacy of our therapy. Equally important, however, are the safety profile and the user-friendliness for the patient. Daratumumab infusions are quite long – on the order of 8 hours or longer on day 1 of infusion. And to date, all the clinical trials have used daratumumab infusions weekly for 8 treatments, followed by 8 treatments given every 2 weeks. Then monthly daratumumab is given as a maintenance therapy. Thus, there is a requirement for multiple outpatient clinic visits that can be prolonged.

One of the opportunities that’s being tested is to give daratumumab subcutaneously. While this is being evaluated in protocols now, the results that have been reported at our national meetings look to be quite promising in terms of efficacy, similar to results with the intravenous administration. Obviously, this would allow for a much more convenient clinic visit and shorter time for the patients being treated.

I should mention that the other antibody, elotuzumab, has been approved in combination with lenalidomide and dexamethasone.¹⁵ The infusions with lenalidomide, dexamethasone, and the antibody elotuzumab are much shorter, on the order of 2- or 3-hour visits. The place for elotuzumab in the management of relapsed myeloma is yet to be totally defined. We tend to use it now in the setting of more indolent relapses, where patients might have a slowly rising monoclonal protein. Elotuzumab-lenalidomide-dexamethasone has maintained an overall survival advantage at 4 years compared with lenalidomide-dexamethasone when used in relapsed myeloma.

We are quite excited about both antibodies. Daratumumab tends to get most of the activity, as it achieves responses as a single agent,¹⁶ and the depth of the responses are markedly increased when it’s combined with lenalidomide-dexamethasone or bortezomib-dexamethasone.^17,18 However, one shouldn’t forget elotuzumab¹⁵ based on its tolerability and the survival advantage I mentioned at 4 years.

The final point is that we think about myeloma genetically at the time of diagnosis and relapse in terms of standard or high-risk disease. One of the hallmarks of high-risk disease has been 17P deletion or P53 dysfunction. One of the most exciting outcomes of the development of monoclonal antibodies has been the responses observed even in the context of P53 deletion. Clearly, antibody-mediated cellular cytotoxicity, complement-mediated cytotoxicity, and other mechanisms of action of these antibodies do not require normal P53 function. The important point, therefore, is that what has previously been thought of as high-risk disease can nowadays be effectively treated with these new immune treatments, correlating with the marked improvement in survival and overall outcome.

DR HENRY We have outlined 3 kinds of myeloma patients we see, and especially interesting is the last patient, who has relapsed and then progressed, and in whom newer drugs have a role. Thank you for such a complete and thorough discussion, Dr Anderson.

DR HENRY I thought we might discuss some cases of patients with myeloma, starting with a relatively simple case and ending with one that is a little more complicated. For the first case, we have a 56-year-old healthy man with IgG kappa myeloma whose work-up shows he has multiple lytic bone lesions. He has normal renal function, normal calcium, and he’s transplant-eligible by other health issues. I’ll leave the cytogenetics up to you if that changes your approach. How would you develop or pose some options for this man’s treatment to begin with?

DR ANDERSON It’s important to start out by saying that we, in myeloma, have many new classes of drugs and many new opportunities to choose from to treat this patient.¹ As you know, we have proteasome inhibitors, the first-generation bortezomib, then carfilzomib and ixazomib. We have the immunomodulatory drugs (IMiDs), thalidomide, and now lenalidomide and pomalidomide. We have a histone deacetylase (HDAC) inhibitor approved called panobinostat, and we have 2 monoclonal antibodies approved, elotuzumab and daratumumab. These classes of medicine have made it possible for 20 different Food and Drug Administration (FDA) approvals in the last 10-15 years. These agents, having been tested in advanced myeloma, have moved toward initial management.

This person is 50 years old. He has adequate liver, heart, lung, and kidney function, so he would be eligible for high-dose therapy and stem-cell transplantation. In terms of initial management, there are many options (Figure 1). We strongly recommend that triplet therapy be used initially. The most common triplets would be lenalidomide, bortezomib, and dexamethasone (RVD)^2,3 or cyclophosphamide, bortezomib, and dexamethasone (CyBorD).⁴ If this man had neuropathy, perhaps carfilzomib, the second-generation proteasome inhibitor, with lenalidomide and dexamethasone could have been used. Why do we use these? The extent and frequency of response with these triplets is nearly universal overall response rate, with three-quarters very good partial and half-complete responses, including minimal residual disease negative responses. In this patient, we would therefore recommend treatment with either RVD or CyBorD for several cycles to maximal response.

DR HENRY In summary then, this would be, in 2017, off-protocol while the data is pending: it’s reasonable to get a deep induction response, collect stem cells, have a discussion with the patient, and then consider high-dose therapy or not.

DR ANDERSON Yes. I think it’s reasonable to discuss it. We need to be open and honest with patients that the standard of care remains transplant, that you incorporate novel treatments before the transplant and novel treatments as maintenance after the transplant. The happy news is that the outcome, especially for patients who have standard-risk myeloma, is at least a decade or longer progression-free survival. It’s an optimistic picture. The data in terms of transplant being needed or not, will come within the next several years.

For now, it is a standard of care to use 1 high-dose melphalan and stem-cell transplant in this setting. I will add into our discussion with patients – besides the opportunity to harvest stem cells and think about whether one needs to do a transplant early on or not – is the issue of toxicity. High-dose melphalan by itself has a small but real secondary incidence of cancer, myelodysplasia, or leukemia. If one uses lenalidomide maintenance after melphalan transplantation treatment, that risk of secondary cancer is slightly increased.

In my experience, if patients have achieved a complete response with induction therapy only, it’s not unreasonable to offer early transplant and be clear that’s the standard of care. The alternative is maintenance with lenalidomide, knowing once the stem cells have been harvested, that transplantation can be an option to treat relapsed myeloma. We have many other options available as well. Time will tell in terms of the ongoing randomized trials as to whether transplant remains central to our treatment paradigm.

DR HENRY This leads us to our second patient. Here we have an older man of 74 years. He’s a professional piano player, so we want to try to avoid peripheral neuropathy in him. He has some mild renal insufficiency and some coronary artery disease, so he’s deemed transplant-ineligible. He has IgG kappa myeloma, and he’s brand new. What would you consider to be options for him for treatment?

DR ANDERSON This brings up the issue of a transplant-ineligible patient. He has significant comorbidity that would make transplantation an increased risk. What we would recommend in such a patient is still triplet induction therapy incorporating novel agents (Figure 1). Lenalidomide, the immunomodulatory drug, can safely be given in the context of neuropathy because it does not cause significant neuropathy. It would need to be dose modified, depending on the degree of renal insufficiency. We would recommend also including proteasome inhibitors. Bortezomib, the first-generation proteasome inhibitor, would be contraindicated because it does have a small but real attendant neuropathy. If, however, it is given weekly and subcutaneously, the risk of attendant neuropathy is quite low. In this patient, therefore, one could start with lenalidomide and bortezomib weekly and subcutaneously,^1,2 with a very early and vigilant follow-up for the earliest signs of neuropathy, so as not to allow it to develop and compromise his career.

Alternatively, one could use a proteasome inhibitor that does not have attendant neuropathy. Carfilzomib, the second-generation proteasome inhibitor, does not have neuropathy.⁹ But we would need to have caution here, because this patient has a history of coronary artery disease, and carfilzomib has a very small, but real, incidence of cardiac toxicity so would need to be used judiciously in this setting. The third proteasome inhibitor, ixazomib, is the next-generation bortezomib-class proteasome inhibitor, and it’s oral.¹⁰ It has less neuropathy than does bortezomib, so in my view is a very realistic option for him together with lenalidomide. It does have a small incidence of neuropathy, so close monitoring for neuropathy would be indicated. We could use lenalidomide–dexamethasone as a doublet and avoid neuropathy,¹¹ but usually doublets are reserved only for frail patients.

My recommendation, therefore, would be RVD with the bortezomib weekly or subcutaneously, or alternatively, lenalidomide, ixazomib, dexamethasone as an all-oral regimen as induction therapy. In my view, this 74-year-old patient with comorbidity is not a transplant candidate. However, one can be very optimistic with this patient. The likelihood that he could have myeloma as a chronic illness and die from something else is quite high. Initial induction triplet therapy would achieve a very high response extent and frequency. The durability would be long, especially with lenalidomide maintenance if it’s standard-risk myeloma or lenalidomide and a proteasome inhibitor, probably ixazomib in this setting, if he were to have high-risk myeloma.

If myeloma relapses, then there are many options that could be used in this patient and achieve years of progression-free and overall survival. Indeed, he is 74 years old and will respond very well to induction triplet therapy, with many years’ duration of response due to continuous lenalidomide or lenalidomide and proteasome inhibitor maintenance. Then there are many effective options to treat relapsed therapy using triplet novel agents. Therefore, his lifespan is unlikely to be shortened by multiple myeloma.

DR HENRY It’s so incredible compared with what it was when I trained. The next patient, a 45-year-old woman with IgG lambda myeloma, has had RVD induction and responded. She had lenalidomide maintenance, but then she progressed, and she got her stem-cell transplant, and she’s progressing after that. I guess we’re looking here to fold in some of the newer agents. How you would you do that in this patient?DR ANDERSON Yes. I think one of the most remarkable and exciting developments with myeloma is the rapid approval of the novel classes of agents that I mentioned earlier – the proteasome inhibitors, the immunomodulatory drugs, the HDAC inhibitor, and the monoclonal antibodies.¹ They’re particularly relevant in a patient such as this one, whose myeloma has relapsed after what would be considered standard therapy for a young person with standard-risk myeloma. This patient had RVD and maintenance therapy, and then progressed. The transplant was given for relapsed myeloma. The opportunity to use stem-cell transplant in patients when myeloma becomes active after maintenance should not be forgotten as it can be very effective. In all the trials done to date in which early versus late transplant are compared, there have been similar outcomes. Therefore, if the transplant isn’t done early, don’t forget that it’s an option at the time the myeloma progresses. I do want to mention, that there are lots of options for relapsed myeloma (Figures 3 and 4). I mentioned RVD or CyBorD as initial triplet therapies.^2-4 In North America, those are the 2 most common regimens. If myeloma then relapses and is resistant to RVD or to CyBorD, then we need to identify alternatives.

We also need to think about the comorbidities in the patient – issues such as age, neuropathy, presence of renal dysfunction, and other clinical factors. And we need to think about what treatment they’ve had in the past. This patient has had RVD, maintenance with lenalidomide, and a stem-cell transplant. We can offer patients a variety of therapies, but in the context of resistance to the first-generation proteasome inhibitor bortezomib and the first-generation immunomodulatory drug lenalidomide, we would strongly recommend the second-generation immunomodulatory drug pomalidomide¹² together with a second-generation proteasome inhibitor, be that carfilzomib¹³ or ixazomib.¹⁴ When one uses the second-generation IMiDs and proteasome inhibitors together, there’s a very high frequency of response in the order of 70%-80%, which lasts years.

Besides carfilzomib and ixazomib proteasome inhibitors, we also have elotuzumab and daratumumab, the monoclonal antibodies.^15-17 These agents have been FDA approved to treat patients such as this one who has had 1-3 previous therapies for their myeloma. All of them have been approved in randomized phase 3 trials compared with lenalidomide-dexamethasone in the control arm.^13-15,17 They’ve all been found to be superior. Although lenalidomide-dexamethasone combined with daratumumab, ixazomib, elotuzumab, or carfilzomib is superior to lenalidomide in relapsed myeloma, the situation in North America, as in this patient, is usually that patients have had lenalidomide-dexamethasone as part of their initial treatment and their myeloma is refractory to lenalidomide.

Hence, we recommend, that we go to the second-generation pomalidomide and second-generation proteasome inhibitors, either carfilzomib or ixazomib. Having said that, the treatment paradigm is evolving. For example, the monoclonal antibody daratumumab was initially approved by the FDA in multiply relapsed disease as a single agent because it achieves a 30% response rate.¹⁶ It now has been moved earlier into the first relapse of multiple myeloma, where it achieves much higher response rates when combined with lenalidomide–dexamethasone or combined with bortezomib–dexamethasone.^17,18 Response rates of 70%-80% can be achieved, including minimal residual disease negative complete responses.

Today, in a patient who has had RVD transplant and myeloma has returned, we would recommend second-generation IMiDs, pomalidomide, and second-generation proteasome inhibitors, either carfilzomib or ixazomib. Data for daratumumab combined with lenalidomide-dexamethasone or with bortezomib-dexamethasone, look very promising. We need, however, to see more experience of daratumumab together with lenalidomide-dexamethasone or daratumumab together with bortezomib-dexamethasone in patients whose myeloma is refractory to RVD, that is, patients whose myeloma has returned after RVD induction treatment. Of note, pomalidomide, dexamethasone, and daratumumab have just been approved by the FDA and may also be active even in myeloma recurring after RVD treatment.¹⁹

Daratumumab in combination will be moving earlier and earlier and may be appropriate to treat the first relapse. I do want to stress, however, that at present I save daratumumab for the second or greater relapse. Daratumumab is active even when relapse occurs after treatment with second-generation IMiDs and proteasome inhibitors.

DR HENRY Before we close, I have a couple practical questions with these antibodies. Daratumumab has the track record of first-treatment severe reactions and long infusion times. How long are you anticipating the first daratumumab treatment takes? There has been some talk that maybe splitting it in half and going over 2 days is easier on the patient and the infusion center. Have you done that?

DR ANDERSON Yes, I think that’s a very important point. We need to be thinking – first and foremost – about efficacy of our therapy. Equally important, however, are the safety profile and the user-friendliness for the patient. Daratumumab infusions are quite long – on the order of 8 hours or longer on day 1 of infusion. And to date, all the clinical trials have used daratumumab infusions weekly for 8 treatments, followed by 8 treatments given every 2 weeks. Then monthly daratumumab is given as a maintenance therapy. Thus, there is a requirement for multiple outpatient clinic visits that can be prolonged.

One of the opportunities that’s being tested is to give daratumumab subcutaneously. While this is being evaluated in protocols now, the results that have been reported at our national meetings look to be quite promising in terms of efficacy, similar to results with the intravenous administration. Obviously, this would allow for a much more convenient clinic visit and shorter time for the patients being treated.

I should mention that the other antibody, elotuzumab, has been approved in combination with lenalidomide and dexamethasone.¹⁵ The infusions with lenalidomide, dexamethasone, and the antibody elotuzumab are much shorter, on the order of 2- or 3-hour visits. The place for elotuzumab in the management of relapsed myeloma is yet to be totally defined. We tend to use it now in the setting of more indolent relapses, where patients might have a slowly rising monoclonal protein. Elotuzumab-lenalidomide-dexamethasone has maintained an overall survival advantage at 4 years compared with lenalidomide-dexamethasone when used in relapsed myeloma.

We are quite excited about both antibodies. Daratumumab tends to get most of the activity, as it achieves responses as a single agent,¹⁶ and the depth of the responses are markedly increased when it’s combined with lenalidomide-dexamethasone or bortezomib-dexamethasone.^17,18 However, one shouldn’t forget elotuzumab¹⁵ based on its tolerability and the survival advantage I mentioned at 4 years.

The final point is that we think about myeloma genetically at the time of diagnosis and relapse in terms of standard or high-risk disease. One of the hallmarks of high-risk disease has been 17P deletion or P53 dysfunction. One of the most exciting outcomes of the development of monoclonal antibodies has been the responses observed even in the context of P53 deletion. Clearly, antibody-mediated cellular cytotoxicity, complement-mediated cytotoxicity, and other mechanisms of action of these antibodies do not require normal P53 function. The important point, therefore, is that what has previously been thought of as high-risk disease can nowadays be effectively treated with these new immune treatments, correlating with the marked improvement in survival and overall outcome.

DR HENRY We have outlined 3 kinds of myeloma patients we see, and especially interesting is the last patient, who has relapsed and then progressed, and in whom newer drugs have a role. Thank you for such a complete and thorough discussion, Dr Anderson.

The treatment landscape for hematologic malignancies is evolving faster than ever before, with a range of available therapeutic options that is now almost as diverse as this group of tumors. Immunotherapy in particular is front and center in the battle to control these diseases. Here, we describe the latest promising developments.

Exploiting T cells

The treatment landscape for hematologic malignancies is diverse, but one particular type of therapy has led the charge in improving patient outcomes. Several features of hematologic malignancies may make them particularly amenable to immunotherapy, including the fact that they are derived from corrupt immune cells and come into constant contact with other immune cells within the hematopoietic environment in which they reside. One of the oldest forms of immunotherapy, hematopoietic stem-cell transplantation (HSCT), remains the only curative option for many patients with hematologic malignancies.^1,2

Given the central role of T lymphocytes in antitumor immunity, research efforts have focused on harnessing their activity for cancer treatment. One example of this is adoptive cellular therapy (ACT), in which T cells are collected from a patient, grown outside the body to increase their number and then reinfused back to the patient. Allogeneic HSCT, in which the stem cells are collected from a matching donor and transplanted into the patient, is a crude example of ACT. The graft-versus-tumor effect is driven by donor cells present in the transplant, but is limited by the development of graft-versus-host disease (GvHD), whereby the donor T cells attack healthy host tissue.

Other types of ACT have been developed in an effort to capitalize on the anti-tumor effects of the patients own T cells and thus avoid the potentially fatal complication of GvHD. Tumor-infiltrating lymphocyte (TIL) therapy was developed to exploit the presence of tumor-specific T cells in the tumor microenvironment. To date, the efficacy of TIL therapy has been predominantly limited to melanoma.^1,3,4

Most recently, there has been a substantial buzz around the idea of genetically engineering T cells before they are reintroduced into the patient, to increase their anti-tumor efficacy and minimize damage to healthy tissue. This is achieved either by manipulating the antigen binding portion of the T-cell receptor to alter its specificity (TCR T cells) or by generating artificial fusion receptors known as chimeric antigen receptors (CAR T cells; Figure 1). The former is limited by the need for the TCR to be genetically matched to the patient’s immune type, whereas the latter is more flexible in this regard and has proved most successful.

Headlining advancements with CAR T cells

CAR T cells directed against the CD19 antigen, found on the surface of many hematologic malignancies, are the most clinically advanced in this rapidly evolving field (Table 1). Durable remissions have been demonstrated in patients with relapsed and refractory hematologic malignancies, including non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and acute lymphoblastic lymphoma (ALL), with efficacy in both the pre- and posttransplant setting and in patients with chemotherapy-refractory disease.^4,5

CTL019, a CD19-targeted CAR-T cell therapy, also known as tisagenlecleucel-T, has received breakthrough therapy designation from the US Food and Drug Administration (FDA) for the treatment of pediatric and adult patients with relapsed/refractory B-cell ALL and, more recently, for the treatment of adult patients with relapsed/refractory diffuse large B cell lymphoma.⁶

It is edging closer to FDA approval for the ALL indication, having been granted priority review in March on the basis of the phase 2 ELIANA trial, in which 50 patients received a single infusion of CTL019. Data presented at the American Society of Hematology annual meeting in December 2016 showed that 82% of patients achieved either complete remission (CR) or CR with incomplete blood count recovery (CRi) 3 months after treatment.⁷

Meanwhile, Kite Pharma has a rolling submission with the FDA for KTE-C19 (axicabtagene ciloleucel) for the treatment of patients with relapsed/refractory B-cell NHL who are ineligible for HSCT. In the ZUMA-1 trial, this therapy demonstrated an overall response rate (ORR) of 71%.⁸ Juno Therapeutics is developing several CAR T-cell therapies, including JCAR017, which elicited CR in 60% of patients with relapsed/refractory NHL.⁹

Target antigens other than CD19 are being explored, but these are mostly in the early stages of clinical development. While the focus has predominantly been on the treatment of lymphoma and leukemia, a presentation at the American Society for Clinical Oncology annual meeting in June reported the efficacy of a CAR-T cell therapy targeting the B-cell maturation antigen in patients with multiple myeloma. Results from 19 patients enrolled in an ongoing phase 1 trial in China showed that 14 had achieved stringent CR, 1 partial remission (PR) and 4 very good partial remission (VGPR).¹⁰

Antibodies evolve

Another type of immunotherapy that has revolutionized the treatment of hematologic malignancies is monoclonal antibodies (mAbs), targeting antigens on the surface of malignant B and T cells, in particular CD20. The approval of CD20-targeting mAb rituximab in 1997 was the first coup for the development of immunotherapy for the treatment of hematologic malignancies. It has become part of the standard treatment regimen for B-cell malignancies, including NHL and CLL, in combination with various types of chemotherapy.

Several other CD20-targeting antibodies have been developed (Table 2), some of which work in the same way as rituximab (eg, ofatumumab) and some that have a slightly different mechanism of action (eg, obinutuzumab).¹¹ Both types of antibody have proved highly effective; ofatumumab is FDA approved for the treatment of advanced CLL and is being evaluated in phase 3 trials in other hematologic malignancies, while obinutuzumab has received regulatory approval for the first-line treatment of CLL, replacing the standard rituximab-containing regimen.¹²

Innovative design

Newer drug designs, which have sought to take mAb therapy to the next level, have also shown significant efficacy in hematologic malignancies. Antibody-drug conjugates (ADCs) combine the cytotoxic efficacy of chemotherapeutic agents with the specificity of a mAb targeting a tumor-specific antigen. This essentially creates a targeted payload that improves upon the efficacy of mAb monotherapy but mitigates some of the side effects of chemotherapy related to their indiscriminate killing of both cancerous and healthy cells.

The development of ADCs has been somewhat of a rollercoaster ride, with the approval and subsequent withdrawal of the first-in-class drug gemtuzumab ozogamicin in 2010, but the field was reinvigorated with the successful development of brentuximab vedotin, which targets the CD30 antigen and is approved for the treatment of multiple different hematologic malignancies, including, most recently, for posttransplant consolidation therapy in patients with Hodgkin lymphoma at high risk of relapse or progression.¹⁸

Brentuximab vedotin may soon be joined by another FDA-approved ADC, this one targeting CD22. Inotuzumab ozogamicin was recently granted priority review for the treatment of relapsed/refractory ALL. The FDA is reviewing data from the phase 3 INO-VATE study in which inotuzumab ozogamicin reduced the risk of disease progression or death by 55% compared with standard therapy, and a decision is expected by August.¹⁹ Other ADC targets being investigated in clinical trials include CD138, CD19, and CD33 (Table 3). Meanwhile, a meta-analysis of randomized trials suggested that the withdrawal of gemtuzumab ozogamicin may have been premature, indicating that it does improve long-term overall survival (OS) and reduces the risk of relapse.²⁰

21

B-cell signaling a ripe target

Beyond immunotherapy, molecularly targeted drugs directed against key drivers of hematologic malignancies are also showing great promise. In particular, the B-cell receptor (BCR) signaling pathway, a central regulator of B-cell function, and its constituent kinases that are frequently dysregulated in B cell malignancies, has emerged as an exciting therapeutic avenue.

A variety of small molecule inhibitors targeting different nodes of the BCR pathway have been developed (Table 4), but the greatest success to date has been achieved with drugs targeting Bruton’s tyrosine kinase (BTK). Their clinical development culminated in the approval of ibrutinib for the treatment of patients with mantle cell lymphoma in 2013 and subsequently for patients with CLL, Waldenström macroglobulinemia, and most recently for patients with marginal zone lymphoma.

The treatment landscape for hematologic malignancies is evolving faster than ever before, with a range of available therapeutic options that is now almost as diverse as this group of tumors. Immunotherapy in particular is front and center in the battle to control these diseases. Here, we describe the latest promising developments.

Exploiting T cells

The treatment landscape for hematologic malignancies is diverse, but one particular type of therapy has led the charge in improving patient outcomes. Several features of hematologic malignancies may make them particularly amenable to immunotherapy, including the fact that they are derived from corrupt immune cells and come into constant contact with other immune cells within the hematopoietic environment in which they reside. One of the oldest forms of immunotherapy, hematopoietic stem-cell transplantation (HSCT), remains the only curative option for many patients with hematologic malignancies.^1,2

Given the central role of T lymphocytes in antitumor immunity, research efforts have focused on harnessing their activity for cancer treatment. One example of this is adoptive cellular therapy (ACT), in which T cells are collected from a patient, grown outside the body to increase their number and then reinfused back to the patient. Allogeneic HSCT, in which the stem cells are collected from a matching donor and transplanted into the patient, is a crude example of ACT. The graft-versus-tumor effect is driven by donor cells present in the transplant, but is limited by the development of graft-versus-host disease (GvHD), whereby the donor T cells attack healthy host tissue.

Other types of ACT have been developed in an effort to capitalize on the anti-tumor effects of the patients own T cells and thus avoid the potentially fatal complication of GvHD. Tumor-infiltrating lymphocyte (TIL) therapy was developed to exploit the presence of tumor-specific T cells in the tumor microenvironment. To date, the efficacy of TIL therapy has been predominantly limited to melanoma.^1,3,4

Most recently, there has been a substantial buzz around the idea of genetically engineering T cells before they are reintroduced into the patient, to increase their anti-tumor efficacy and minimize damage to healthy tissue. This is achieved either by manipulating the antigen binding portion of the T-cell receptor to alter its specificity (TCR T cells) or by generating artificial fusion receptors known as chimeric antigen receptors (CAR T cells; Figure 1). The former is limited by the need for the TCR to be genetically matched to the patient’s immune type, whereas the latter is more flexible in this regard and has proved most successful.

Headlining advancements with CAR T cells

CAR T cells directed against the CD19 antigen, found on the surface of many hematologic malignancies, are the most clinically advanced in this rapidly evolving field (Table 1). Durable remissions have been demonstrated in patients with relapsed and refractory hematologic malignancies, including non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and acute lymphoblastic lymphoma (ALL), with efficacy in both the pre- and posttransplant setting and in patients with chemotherapy-refractory disease.^4,5

CTL019, a CD19-targeted CAR-T cell therapy, also known as tisagenlecleucel-T, has received breakthrough therapy designation from the US Food and Drug Administration (FDA) for the treatment of pediatric and adult patients with relapsed/refractory B-cell ALL and, more recently, for the treatment of adult patients with relapsed/refractory diffuse large B cell lymphoma.⁶

It is edging closer to FDA approval for the ALL indication, having been granted priority review in March on the basis of the phase 2 ELIANA trial, in which 50 patients received a single infusion of CTL019. Data presented at the American Society of Hematology annual meeting in December 2016 showed that 82% of patients achieved either complete remission (CR) or CR with incomplete blood count recovery (CRi) 3 months after treatment.⁷

Meanwhile, Kite Pharma has a rolling submission with the FDA for KTE-C19 (axicabtagene ciloleucel) for the treatment of patients with relapsed/refractory B-cell NHL who are ineligible for HSCT. In the ZUMA-1 trial, this therapy demonstrated an overall response rate (ORR) of 71%.⁸ Juno Therapeutics is developing several CAR T-cell therapies, including JCAR017, which elicited CR in 60% of patients with relapsed/refractory NHL.⁹

Target antigens other than CD19 are being explored, but these are mostly in the early stages of clinical development. While the focus has predominantly been on the treatment of lymphoma and leukemia, a presentation at the American Society for Clinical Oncology annual meeting in June reported the efficacy of a CAR-T cell therapy targeting the B-cell maturation antigen in patients with multiple myeloma. Results from 19 patients enrolled in an ongoing phase 1 trial in China showed that 14 had achieved stringent CR, 1 partial remission (PR) and 4 very good partial remission (VGPR).¹⁰

Antibodies evolve

Another type of immunotherapy that has revolutionized the treatment of hematologic malignancies is monoclonal antibodies (mAbs), targeting antigens on the surface of malignant B and T cells, in particular CD20. The approval of CD20-targeting mAb rituximab in 1997 was the first coup for the development of immunotherapy for the treatment of hematologic malignancies. It has become part of the standard treatment regimen for B-cell malignancies, including NHL and CLL, in combination with various types of chemotherapy.

Several other CD20-targeting antibodies have been developed (Table 2), some of which work in the same way as rituximab (eg, ofatumumab) and some that have a slightly different mechanism of action (eg, obinutuzumab).¹¹ Both types of antibody have proved highly effective; ofatumumab is FDA approved for the treatment of advanced CLL and is being evaluated in phase 3 trials in other hematologic malignancies, while obinutuzumab has received regulatory approval for the first-line treatment of CLL, replacing the standard rituximab-containing regimen.¹²

Innovative design

Newer drug designs, which have sought to take mAb therapy to the next level, have also shown significant efficacy in hematologic malignancies. Antibody-drug conjugates (ADCs) combine the cytotoxic efficacy of chemotherapeutic agents with the specificity of a mAb targeting a tumor-specific antigen. This essentially creates a targeted payload that improves upon the efficacy of mAb monotherapy but mitigates some of the side effects of chemotherapy related to their indiscriminate killing of both cancerous and healthy cells.

The development of ADCs has been somewhat of a rollercoaster ride, with the approval and subsequent withdrawal of the first-in-class drug gemtuzumab ozogamicin in 2010, but the field was reinvigorated with the successful development of brentuximab vedotin, which targets the CD30 antigen and is approved for the treatment of multiple different hematologic malignancies, including, most recently, for posttransplant consolidation therapy in patients with Hodgkin lymphoma at high risk of relapse or progression.¹⁸

Brentuximab vedotin may soon be joined by another FDA-approved ADC, this one targeting CD22. Inotuzumab ozogamicin was recently granted priority review for the treatment of relapsed/refractory ALL. The FDA is reviewing data from the phase 3 INO-VATE study in which inotuzumab ozogamicin reduced the risk of disease progression or death by 55% compared with standard therapy, and a decision is expected by August.¹⁹ Other ADC targets being investigated in clinical trials include CD138, CD19, and CD33 (Table 3). Meanwhile, a meta-analysis of randomized trials suggested that the withdrawal of gemtuzumab ozogamicin may have been premature, indicating that it does improve long-term overall survival (OS) and reduces the risk of relapse.²⁰

21

B-cell signaling a ripe target

Beyond immunotherapy, molecularly targeted drugs directed against key drivers of hematologic malignancies are also showing great promise. In particular, the B-cell receptor (BCR) signaling pathway, a central regulator of B-cell function, and its constituent kinases that are frequently dysregulated in B cell malignancies, has emerged as an exciting therapeutic avenue.

A variety of small molecule inhibitors targeting different nodes of the BCR pathway have been developed (Table 4), but the greatest success to date has been achieved with drugs targeting Bruton’s tyrosine kinase (BTK). Their clinical development culminated in the approval of ibrutinib for the treatment of patients with mantle cell lymphoma in 2013 and subsequently for patients with CLL, Waldenström macroglobulinemia, and most recently for patients with marginal zone lymphoma.

The treatment landscape for hematologic malignancies is evolving faster than ever before, with a range of available therapeutic options that is now almost as diverse as this group of tumors. Immunotherapy in particular is front and center in the battle to control these diseases. Here, we describe the latest promising developments.

Exploiting T cells

The treatment landscape for hematologic malignancies is diverse, but one particular type of therapy has led the charge in improving patient outcomes. Several features of hematologic malignancies may make them particularly amenable to immunotherapy, including the fact that they are derived from corrupt immune cells and come into constant contact with other immune cells within the hematopoietic environment in which they reside. One of the oldest forms of immunotherapy, hematopoietic stem-cell transplantation (HSCT), remains the only curative option for many patients with hematologic malignancies.^1,2

Given the central role of T lymphocytes in antitumor immunity, research efforts have focused on harnessing their activity for cancer treatment. One example of this is adoptive cellular therapy (ACT), in which T cells are collected from a patient, grown outside the body to increase their number and then reinfused back to the patient. Allogeneic HSCT, in which the stem cells are collected from a matching donor and transplanted into the patient, is a crude example of ACT. The graft-versus-tumor effect is driven by donor cells present in the transplant, but is limited by the development of graft-versus-host disease (GvHD), whereby the donor T cells attack healthy host tissue.

Other types of ACT have been developed in an effort to capitalize on the anti-tumor effects of the patients own T cells and thus avoid the potentially fatal complication of GvHD. Tumor-infiltrating lymphocyte (TIL) therapy was developed to exploit the presence of tumor-specific T cells in the tumor microenvironment. To date, the efficacy of TIL therapy has been predominantly limited to melanoma.^1,3,4

Most recently, there has been a substantial buzz around the idea of genetically engineering T cells before they are reintroduced into the patient, to increase their anti-tumor efficacy and minimize damage to healthy tissue. This is achieved either by manipulating the antigen binding portion of the T-cell receptor to alter its specificity (TCR T cells) or by generating artificial fusion receptors known as chimeric antigen receptors (CAR T cells; Figure 1). The former is limited by the need for the TCR to be genetically matched to the patient’s immune type, whereas the latter is more flexible in this regard and has proved most successful.

Headlining advancements with CAR T cells

CAR T cells directed against the CD19 antigen, found on the surface of many hematologic malignancies, are the most clinically advanced in this rapidly evolving field (Table 1). Durable remissions have been demonstrated in patients with relapsed and refractory hematologic malignancies, including non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and acute lymphoblastic lymphoma (ALL), with efficacy in both the pre- and posttransplant setting and in patients with chemotherapy-refractory disease.^4,5

CTL019, a CD19-targeted CAR-T cell therapy, also known as tisagenlecleucel-T, has received breakthrough therapy designation from the US Food and Drug Administration (FDA) for the treatment of pediatric and adult patients with relapsed/refractory B-cell ALL and, more recently, for the treatment of adult patients with relapsed/refractory diffuse large B cell lymphoma.⁶

It is edging closer to FDA approval for the ALL indication, having been granted priority review in March on the basis of the phase 2 ELIANA trial, in which 50 patients received a single infusion of CTL019. Data presented at the American Society of Hematology annual meeting in December 2016 showed that 82% of patients achieved either complete remission (CR) or CR with incomplete blood count recovery (CRi) 3 months after treatment.⁷

Meanwhile, Kite Pharma has a rolling submission with the FDA for KTE-C19 (axicabtagene ciloleucel) for the treatment of patients with relapsed/refractory B-cell NHL who are ineligible for HSCT. In the ZUMA-1 trial, this therapy demonstrated an overall response rate (ORR) of 71%.⁸ Juno Therapeutics is developing several CAR T-cell therapies, including JCAR017, which elicited CR in 60% of patients with relapsed/refractory NHL.⁹

Target antigens other than CD19 are being explored, but these are mostly in the early stages of clinical development. While the focus has predominantly been on the treatment of lymphoma and leukemia, a presentation at the American Society for Clinical Oncology annual meeting in June reported the efficacy of a CAR-T cell therapy targeting the B-cell maturation antigen in patients with multiple myeloma. Results from 19 patients enrolled in an ongoing phase 1 trial in China showed that 14 had achieved stringent CR, 1 partial remission (PR) and 4 very good partial remission (VGPR).¹⁰

Antibodies evolve

Another type of immunotherapy that has revolutionized the treatment of hematologic malignancies is monoclonal antibodies (mAbs), targeting antigens on the surface of malignant B and T cells, in particular CD20. The approval of CD20-targeting mAb rituximab in 1997 was the first coup for the development of immunotherapy for the treatment of hematologic malignancies. It has become part of the standard treatment regimen for B-cell malignancies, including NHL and CLL, in combination with various types of chemotherapy.

Several other CD20-targeting antibodies have been developed (Table 2), some of which work in the same way as rituximab (eg, ofatumumab) and some that have a slightly different mechanism of action (eg, obinutuzumab).¹¹ Both types of antibody have proved highly effective; ofatumumab is FDA approved for the treatment of advanced CLL and is being evaluated in phase 3 trials in other hematologic malignancies, while obinutuzumab has received regulatory approval for the first-line treatment of CLL, replacing the standard rituximab-containing regimen.¹²

Innovative design

Newer drug designs, which have sought to take mAb therapy to the next level, have also shown significant efficacy in hematologic malignancies. Antibody-drug conjugates (ADCs) combine the cytotoxic efficacy of chemotherapeutic agents with the specificity of a mAb targeting a tumor-specific antigen. This essentially creates a targeted payload that improves upon the efficacy of mAb monotherapy but mitigates some of the side effects of chemotherapy related to their indiscriminate killing of both cancerous and healthy cells.

The development of ADCs has been somewhat of a rollercoaster ride, with the approval and subsequent withdrawal of the first-in-class drug gemtuzumab ozogamicin in 2010, but the field was reinvigorated with the successful development of brentuximab vedotin, which targets the CD30 antigen and is approved for the treatment of multiple different hematologic malignancies, including, most recently, for posttransplant consolidation therapy in patients with Hodgkin lymphoma at high risk of relapse or progression.¹⁸

Brentuximab vedotin may soon be joined by another FDA-approved ADC, this one targeting CD22. Inotuzumab ozogamicin was recently granted priority review for the treatment of relapsed/refractory ALL. The FDA is reviewing data from the phase 3 INO-VATE study in which inotuzumab ozogamicin reduced the risk of disease progression or death by 55% compared with standard therapy, and a decision is expected by August.¹⁹ Other ADC targets being investigated in clinical trials include CD138, CD19, and CD33 (Table 3). Meanwhile, a meta-analysis of randomized trials suggested that the withdrawal of gemtuzumab ozogamicin may have been premature, indicating that it does improve long-term overall survival (OS) and reduces the risk of relapse.²⁰

21

B-cell signaling a ripe target

Beyond immunotherapy, molecularly targeted drugs directed against key drivers of hematologic malignancies are also showing great promise. In particular, the B-cell receptor (BCR) signaling pathway, a central regulator of B-cell function, and its constituent kinases that are frequently dysregulated in B cell malignancies, has emerged as an exciting therapeutic avenue.

A variety of small molecule inhibitors targeting different nodes of the BCR pathway have been developed (Table 4), but the greatest success to date has been achieved with drugs targeting Bruton’s tyrosine kinase (BTK). Their clinical development culminated in the approval of ibrutinib for the treatment of patients with mantle cell lymphoma in 2013 and subsequently for patients with CLL, Waldenström macroglobulinemia, and most recently for patients with marginal zone lymphoma.