Hematology Times

Micrograph showing CLL

Recent advances in chronic lymphocytic leukemia (CLL) have prompted an update to the 2008 International Workshop in Chronic Lymphocytic Leukemia (iwCLL) consensus guidelines.

The updated iwCLL guidelines include new information on genomic alterations, the use of clinical staging and prognostic markers/scores, response assessment, minimal residual disease (MRD), and viral diseases in CLL patients.

The update was recently published in Blood.

Diagnosis, prognosis, and staging

To verify CLL diagnosis, the iwCLL guidelines recommend obtaining complete blood counts and differential counts as well as immunophenotyping of peripheral blood lymphocytes. A panel of CD19, CD5, CD20, CD23, κ, and λ typically suffices to establish a diagnosis.

Other tests that may help in prognosis or assessing tumor burden include molecular cytogenetics for del(13q), del(11q), del(17p), and add(12) in peripheral blood lymphocytes and determining TP53 and IGHV mutational status.

These tests can help identify poor-prognosis patients who are not likely to benefit from standard chemotherapy but are likely to benefit from small-molecule inhibitors of BTK, PI3K, or BCL2.

In addition, serum markers such as β2-microglogulin provide insight into overall survival and progression-free survival.

With regard to clinical staging, the guidelines highlight the Binet and Rai systems, which are routinely used in clinical practice and clinical trials.

However, the guidelines also note that “there are a large number of biomarkers that can provide additional prognostic information,” and, recently, “several prognostic scores and stratification systems have been proposed based on multivariate analyses.”

For example, the CLL international prognostic index (CLL-IPI) provides a weighted score that uses clinical stage, age, IGHV mutational status, β2-microglogulin, and the presence of del(17p) and/or TP53 mutations.

Indications for treatment

The guidelines note that active disease must be documented to initiate therapy. At least 1 of the following criteria must be met:

• Evidence of progressive marrow failure
• Massive, progressive, or symptomatic splenomegaly
• Progressive/symptomatic lymphadenopathy or massive nodes
• Progressive lymphocytosis
• Autoimmune complications
• Extranodal involvement
• Disease-related symptoms (unintentional weight loss, significant fatigue, fevers, night sweats for over a month without evidence of infection).

Following relapse, subsequent lines of treatment should follow the same principles as those used for initial treatment decisions.

Response, MRD, and more

The guidelines say 2 groups of parameters must be assessed to determine response to therapy:

• Group A: lymphoid tumor load and constitutional symptoms, including liver and/or spleen size, lymph node evaluation, and circulating lymphocyte count
• Group B: the hematopoietic system (platelet count, hemoglobin, and marrow).

For therapies with a defined treatment duration, response should be assessed at least 2 months after treatment is completed. For continued therapies or maintenance, response should be assessed at a predefined time point or at least 2 months after patients achieve their maximum response.

The guidelines also say MRD should be assessed in clinical trials aimed at maximizing the depth of remission. Furthermore, it “may be important” to confirm MRD negativity in the blood and marrow, as there are therapies that preferentially clear the blood but not the marrow (such as monoclonal antibodies).

In addition to the aforementioned recommendations, the updated iwCLL guidelines also include information on patient eligibility for clinical trials, guidance regarding treatment-related toxicities, and recommendations for supportive care and managing complications.

Micrograph showing CLL

Recent advances in chronic lymphocytic leukemia (CLL) have prompted an update to the 2008 International Workshop in Chronic Lymphocytic Leukemia (iwCLL) consensus guidelines.

The updated iwCLL guidelines include new information on genomic alterations, the use of clinical staging and prognostic markers/scores, response assessment, minimal residual disease (MRD), and viral diseases in CLL patients.

The update was recently published in Blood.

Diagnosis, prognosis, and staging

To verify CLL diagnosis, the iwCLL guidelines recommend obtaining complete blood counts and differential counts as well as immunophenotyping of peripheral blood lymphocytes. A panel of CD19, CD5, CD20, CD23, κ, and λ typically suffices to establish a diagnosis.

Other tests that may help in prognosis or assessing tumor burden include molecular cytogenetics for del(13q), del(11q), del(17p), and add(12) in peripheral blood lymphocytes and determining TP53 and IGHV mutational status.

These tests can help identify poor-prognosis patients who are not likely to benefit from standard chemotherapy but are likely to benefit from small-molecule inhibitors of BTK, PI3K, or BCL2.

In addition, serum markers such as β2-microglogulin provide insight into overall survival and progression-free survival.

With regard to clinical staging, the guidelines highlight the Binet and Rai systems, which are routinely used in clinical practice and clinical trials.

However, the guidelines also note that “there are a large number of biomarkers that can provide additional prognostic information,” and, recently, “several prognostic scores and stratification systems have been proposed based on multivariate analyses.”

For example, the CLL international prognostic index (CLL-IPI) provides a weighted score that uses clinical stage, age, IGHV mutational status, β2-microglogulin, and the presence of del(17p) and/or TP53 mutations.

Indications for treatment

The guidelines note that active disease must be documented to initiate therapy. At least 1 of the following criteria must be met:

• Evidence of progressive marrow failure
• Massive, progressive, or symptomatic splenomegaly
• Progressive/symptomatic lymphadenopathy or massive nodes
• Progressive lymphocytosis
• Autoimmune complications
• Extranodal involvement
• Disease-related symptoms (unintentional weight loss, significant fatigue, fevers, night sweats for over a month without evidence of infection).

Following relapse, subsequent lines of treatment should follow the same principles as those used for initial treatment decisions.

Response, MRD, and more

The guidelines say 2 groups of parameters must be assessed to determine response to therapy:

• Group A: lymphoid tumor load and constitutional symptoms, including liver and/or spleen size, lymph node evaluation, and circulating lymphocyte count
• Group B: the hematopoietic system (platelet count, hemoglobin, and marrow).

For therapies with a defined treatment duration, response should be assessed at least 2 months after treatment is completed. For continued therapies or maintenance, response should be assessed at a predefined time point or at least 2 months after patients achieve their maximum response.

The guidelines also say MRD should be assessed in clinical trials aimed at maximizing the depth of remission. Furthermore, it “may be important” to confirm MRD negativity in the blood and marrow, as there are therapies that preferentially clear the blood but not the marrow (such as monoclonal antibodies).

In addition to the aforementioned recommendations, the updated iwCLL guidelines also include information on patient eligibility for clinical trials, guidance regarding treatment-related toxicities, and recommendations for supportive care and managing complications.

Micrograph showing CLL

Recent advances in chronic lymphocytic leukemia (CLL) have prompted an update to the 2008 International Workshop in Chronic Lymphocytic Leukemia (iwCLL) consensus guidelines.

The updated iwCLL guidelines include new information on genomic alterations, the use of clinical staging and prognostic markers/scores, response assessment, minimal residual disease (MRD), and viral diseases in CLL patients.

The update was recently published in Blood.

Diagnosis, prognosis, and staging

To verify CLL diagnosis, the iwCLL guidelines recommend obtaining complete blood counts and differential counts as well as immunophenotyping of peripheral blood lymphocytes. A panel of CD19, CD5, CD20, CD23, κ, and λ typically suffices to establish a diagnosis.

Other tests that may help in prognosis or assessing tumor burden include molecular cytogenetics for del(13q), del(11q), del(17p), and add(12) in peripheral blood lymphocytes and determining TP53 and IGHV mutational status.

These tests can help identify poor-prognosis patients who are not likely to benefit from standard chemotherapy but are likely to benefit from small-molecule inhibitors of BTK, PI3K, or BCL2.

In addition, serum markers such as β2-microglogulin provide insight into overall survival and progression-free survival.

With regard to clinical staging, the guidelines highlight the Binet and Rai systems, which are routinely used in clinical practice and clinical trials.

However, the guidelines also note that “there are a large number of biomarkers that can provide additional prognostic information,” and, recently, “several prognostic scores and stratification systems have been proposed based on multivariate analyses.”

For example, the CLL international prognostic index (CLL-IPI) provides a weighted score that uses clinical stage, age, IGHV mutational status, β2-microglogulin, and the presence of del(17p) and/or TP53 mutations.

Indications for treatment

The guidelines note that active disease must be documented to initiate therapy. At least 1 of the following criteria must be met:

• Evidence of progressive marrow failure
• Massive, progressive, or symptomatic splenomegaly
• Progressive/symptomatic lymphadenopathy or massive nodes
• Progressive lymphocytosis
• Autoimmune complications
• Extranodal involvement
• Disease-related symptoms (unintentional weight loss, significant fatigue, fevers, night sweats for over a month without evidence of infection).

Following relapse, subsequent lines of treatment should follow the same principles as those used for initial treatment decisions.

Response, MRD, and more

The guidelines say 2 groups of parameters must be assessed to determine response to therapy:

• Group A: lymphoid tumor load and constitutional symptoms, including liver and/or spleen size, lymph node evaluation, and circulating lymphocyte count
• Group B: the hematopoietic system (platelet count, hemoglobin, and marrow).

For therapies with a defined treatment duration, response should be assessed at least 2 months after treatment is completed. For continued therapies or maintenance, response should be assessed at a predefined time point or at least 2 months after patients achieve their maximum response.

The guidelines also say MRD should be assessed in clinical trials aimed at maximizing the depth of remission. Furthermore, it “may be important” to confirm MRD negativity in the blood and marrow, as there are therapies that preferentially clear the blood but not the marrow (such as monoclonal antibodies).

In addition to the aforementioned recommendations, the updated iwCLL guidelines also include information on patient eligibility for clinical trials, guidance regarding treatment-related toxicities, and recommendations for supportive care and managing complications.

Image by Ed Uthman

The US Food and Drug Administration (FDA) has granted orphan drug designation to CPI-613 for the treatment of Burkitt lymphoma (BL).

CPI-613 is a novel lipoic acid analogue that inhibits multiple enzyme targets within the tricarboxylic acid cycle.

The drug is in development as a treatment for hematologic malignancies and solid tumors.

In a phase 1 trial of patients with advanced hematologic malignancies, CPI-613 produced a response in a patient with relapsed BL.

Now, Rafael Pharmaceuticals, Inc., the company developing CPI-613, is launching a phase 2 trial of the drug in patients with relapsed or refractory BL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6.

In the phase 1 trial, the patient with relapsed BL achieved a partial response to CPI-613 monotherapy and was ultimately cleared of disease after surgery.

The patient, a 19-year-old female, began taking CPI-613 (2940 mg/m²) after her second relapse. She achieved a radiographic partial response after the third cycle of CPI-613.

The patient completed 17 cycles of CPI-613 over 51 weeks. She decided to stop treatment after the 17th cycle to pursue a surgical resection of residual tumor. The pathology of the surgical specimen revealed BL with extensive necrosis.

Clinical follow-up on the patient showed no evidence of disease more than 36 months later. And CPI-613 was considered well tolerated in this patient.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Image by Ed Uthman

The US Food and Drug Administration (FDA) has granted orphan drug designation to CPI-613 for the treatment of Burkitt lymphoma (BL).

CPI-613 is a novel lipoic acid analogue that inhibits multiple enzyme targets within the tricarboxylic acid cycle.

The drug is in development as a treatment for hematologic malignancies and solid tumors.

In a phase 1 trial of patients with advanced hematologic malignancies, CPI-613 produced a response in a patient with relapsed BL.

Now, Rafael Pharmaceuticals, Inc., the company developing CPI-613, is launching a phase 2 trial of the drug in patients with relapsed or refractory BL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6.

In the phase 1 trial, the patient with relapsed BL achieved a partial response to CPI-613 monotherapy and was ultimately cleared of disease after surgery.

The patient, a 19-year-old female, began taking CPI-613 (2940 mg/m²) after her second relapse. She achieved a radiographic partial response after the third cycle of CPI-613.

The patient completed 17 cycles of CPI-613 over 51 weeks. She decided to stop treatment after the 17th cycle to pursue a surgical resection of residual tumor. The pathology of the surgical specimen revealed BL with extensive necrosis.

Clinical follow-up on the patient showed no evidence of disease more than 36 months later. And CPI-613 was considered well tolerated in this patient.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Image by Ed Uthman

The US Food and Drug Administration (FDA) has granted orphan drug designation to CPI-613 for the treatment of Burkitt lymphoma (BL).

CPI-613 is a novel lipoic acid analogue that inhibits multiple enzyme targets within the tricarboxylic acid cycle.

The drug is in development as a treatment for hematologic malignancies and solid tumors.

In a phase 1 trial of patients with advanced hematologic malignancies, CPI-613 produced a response in a patient with relapsed BL.

Now, Rafael Pharmaceuticals, Inc., the company developing CPI-613, is launching a phase 2 trial of the drug in patients with relapsed or refractory BL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6.

In the phase 1 trial, the patient with relapsed BL achieved a partial response to CPI-613 monotherapy and was ultimately cleared of disease after surgery.

The patient, a 19-year-old female, began taking CPI-613 (2940 mg/m²) after her second relapse. She achieved a radiographic partial response after the third cycle of CPI-613.

The patient completed 17 cycles of CPI-613 over 51 weeks. She decided to stop treatment after the 17th cycle to pursue a surgical resection of residual tumor. The pathology of the surgical specimen revealed BL with extensive necrosis.

Clinical follow-up on the patient showed no evidence of disease more than 36 months later. And CPI-613 was considered well tolerated in this patient.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

The 23rd Congress of the European Hematology Association

STOCKHOLM—Follow-up data suggest that ropeginterferon alfa-2b (ropeg) provides an advantage over hydroxyurea (HU) for patients with polycythemia vera (PV), regardless of their age.

Two-year results from an extension study have shown that, compared to HU, ropeg produces higher rates of complete hematologic response (CHR) and molecular response (MR) in PV patients, including patients age 60 and older.

Additionally, rates of adverse events (AEs) and serious AEs were similar between the ropeg and HU arms.

“In all, I think these data suggest that ropeginterferon alfa-2b provides a valuable, efficacious, and safe new treatment option for PV patients of all ages, including those older than 60 years,” said Jean-Jacques Kiladjian, MD, PhD, of Hôpital Saint-Louis, Université Paris Diderot in Paris, France.

Dr Kiladjian presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S132.

The research was sponsored by AOP Orphan Pharmaceuticals AG.

Dr Kiladjian presented data from CONTINUATION-PV, an extension trial of PROUD-PV. Results from PROUD-PV were presented at the 2016 ASH Annual Meeting.

PROUD-PV enrolled 254 patients who were treatment-naive or pretreated with HU. They were randomized to receive ropeg (n=127) or HU (n=127).

CONTINUATION-PV included 95 of the patients on ropeg and 76 of the patients on HU. Dr Kiladjian noted that baseline characteristics were similar between these groups.

CHR

At 24 months, the rate of CHR was 70.5% (67/95) in the ropeg arm and 49.3% (33/67) in the HU arm (RR=1.42, P<0.05).

In patients younger than 60, the rate of CHR was 77.6% in the ropeg arm and 55.9% in the HU arm. In patients age 60 and older, rates of CHR were 63% and 42.4%, respectively.

Dr Kiladjian noted that CHR rates increased over time in ropeg recipients. In PROUD-PV, CHR rates were similar between the ropeg and HU arms at 12 months. However, at 24 months, the CHR rates were higher in ropeg recipients.

Ropeg recipients were also more likely than HU recipients to maintain their CHR from the first occurrence to 24 months.

In patients younger than 60, 49% of the ropeg arm and 17.9% of the HU arm maintained a CHR (P<0.001). In patients age 60 and older, rates of CHR maintenance were 37% and 18.9%, respectively.

MR and JAK2V617F allele burden

Rates of MR at 24 months were 68.1% (64/94) in the ropeg arm and 34.7% (26/75) in the HU arm (RR=1.85, P<0.01).

In patients younger than 60, the rate of MR was 77.1% in the ropeg arm and 33.3% in the HU arm (P<0.001). In patients age 60 and older, MR rates were 58.7% and 36.1%, respectively.

For patients younger than 60, the reduction in JAK2V617F allele burden at 12 months was 29.9% in the ropeg arm and 42.3% in the HU arm. At 24 months, the reductions were 54.8% and 4.5%, respectively (P<0.001).

For patients 60 and older, the reduction in JAK2V617F allele burden at 12 months was 25.2% in the ropeg arm and 37.5% in the HU arm. At 24 months, the reductions were 35.1% and 18.4%, respectively.

Safety          

“I think an important point here is the safety because we assume that [ropeg] is not well tolerated in elderly patients,” Dr Kiladjian said. “So what are the results in this prospective, controlled trial? There was a comparable number of adverse events and serious adverse events in the treatment arms, irrespective of age.”

Dr Kiladjian also pointed out that the number of adverse drug reactions (ADRs) was comparable between the treatment arms for younger patients, and there was a trend toward a lower number of ADRs in the ropeg arm for the patients age 60 and older.

The 4 serious ADRs in the HU patients age 60 and older were acute leukemia, anemia, leukopenia, and granulocytopenia.

The 23rd Congress of the European Hematology Association

STOCKHOLM—Follow-up data suggest that ropeginterferon alfa-2b (ropeg) provides an advantage over hydroxyurea (HU) for patients with polycythemia vera (PV), regardless of their age.

Two-year results from an extension study have shown that, compared to HU, ropeg produces higher rates of complete hematologic response (CHR) and molecular response (MR) in PV patients, including patients age 60 and older.

Additionally, rates of adverse events (AEs) and serious AEs were similar between the ropeg and HU arms.

“In all, I think these data suggest that ropeginterferon alfa-2b provides a valuable, efficacious, and safe new treatment option for PV patients of all ages, including those older than 60 years,” said Jean-Jacques Kiladjian, MD, PhD, of Hôpital Saint-Louis, Université Paris Diderot in Paris, France.

Dr Kiladjian presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S132.

The research was sponsored by AOP Orphan Pharmaceuticals AG.

Dr Kiladjian presented data from CONTINUATION-PV, an extension trial of PROUD-PV. Results from PROUD-PV were presented at the 2016 ASH Annual Meeting.

PROUD-PV enrolled 254 patients who were treatment-naive or pretreated with HU. They were randomized to receive ropeg (n=127) or HU (n=127).

CONTINUATION-PV included 95 of the patients on ropeg and 76 of the patients on HU. Dr Kiladjian noted that baseline characteristics were similar between these groups.

CHR

At 24 months, the rate of CHR was 70.5% (67/95) in the ropeg arm and 49.3% (33/67) in the HU arm (RR=1.42, P<0.05).

In patients younger than 60, the rate of CHR was 77.6% in the ropeg arm and 55.9% in the HU arm. In patients age 60 and older, rates of CHR were 63% and 42.4%, respectively.

Dr Kiladjian noted that CHR rates increased over time in ropeg recipients. In PROUD-PV, CHR rates were similar between the ropeg and HU arms at 12 months. However, at 24 months, the CHR rates were higher in ropeg recipients.

Ropeg recipients were also more likely than HU recipients to maintain their CHR from the first occurrence to 24 months.

In patients younger than 60, 49% of the ropeg arm and 17.9% of the HU arm maintained a CHR (P<0.001). In patients age 60 and older, rates of CHR maintenance were 37% and 18.9%, respectively.

MR and JAK2V617F allele burden

Rates of MR at 24 months were 68.1% (64/94) in the ropeg arm and 34.7% (26/75) in the HU arm (RR=1.85, P<0.01).

In patients younger than 60, the rate of MR was 77.1% in the ropeg arm and 33.3% in the HU arm (P<0.001). In patients age 60 and older, MR rates were 58.7% and 36.1%, respectively.

For patients younger than 60, the reduction in JAK2V617F allele burden at 12 months was 29.9% in the ropeg arm and 42.3% in the HU arm. At 24 months, the reductions were 54.8% and 4.5%, respectively (P<0.001).

For patients 60 and older, the reduction in JAK2V617F allele burden at 12 months was 25.2% in the ropeg arm and 37.5% in the HU arm. At 24 months, the reductions were 35.1% and 18.4%, respectively.

Safety          

“I think an important point here is the safety because we assume that [ropeg] is not well tolerated in elderly patients,” Dr Kiladjian said. “So what are the results in this prospective, controlled trial? There was a comparable number of adverse events and serious adverse events in the treatment arms, irrespective of age.”

Dr Kiladjian also pointed out that the number of adverse drug reactions (ADRs) was comparable between the treatment arms for younger patients, and there was a trend toward a lower number of ADRs in the ropeg arm for the patients age 60 and older.

The 4 serious ADRs in the HU patients age 60 and older were acute leukemia, anemia, leukopenia, and granulocytopenia.

The 23rd Congress of the European Hematology Association

STOCKHOLM—Follow-up data suggest that ropeginterferon alfa-2b (ropeg) provides an advantage over hydroxyurea (HU) for patients with polycythemia vera (PV), regardless of their age.

Two-year results from an extension study have shown that, compared to HU, ropeg produces higher rates of complete hematologic response (CHR) and molecular response (MR) in PV patients, including patients age 60 and older.

Additionally, rates of adverse events (AEs) and serious AEs were similar between the ropeg and HU arms.

“In all, I think these data suggest that ropeginterferon alfa-2b provides a valuable, efficacious, and safe new treatment option for PV patients of all ages, including those older than 60 years,” said Jean-Jacques Kiladjian, MD, PhD, of Hôpital Saint-Louis, Université Paris Diderot in Paris, France.

Dr Kiladjian presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S132.

The research was sponsored by AOP Orphan Pharmaceuticals AG.

Dr Kiladjian presented data from CONTINUATION-PV, an extension trial of PROUD-PV. Results from PROUD-PV were presented at the 2016 ASH Annual Meeting.

PROUD-PV enrolled 254 patients who were treatment-naive or pretreated with HU. They were randomized to receive ropeg (n=127) or HU (n=127).

CONTINUATION-PV included 95 of the patients on ropeg and 76 of the patients on HU. Dr Kiladjian noted that baseline characteristics were similar between these groups.

CHR

At 24 months, the rate of CHR was 70.5% (67/95) in the ropeg arm and 49.3% (33/67) in the HU arm (RR=1.42, P<0.05).

In patients younger than 60, the rate of CHR was 77.6% in the ropeg arm and 55.9% in the HU arm. In patients age 60 and older, rates of CHR were 63% and 42.4%, respectively.

Dr Kiladjian noted that CHR rates increased over time in ropeg recipients. In PROUD-PV, CHR rates were similar between the ropeg and HU arms at 12 months. However, at 24 months, the CHR rates were higher in ropeg recipients.

Ropeg recipients were also more likely than HU recipients to maintain their CHR from the first occurrence to 24 months.

In patients younger than 60, 49% of the ropeg arm and 17.9% of the HU arm maintained a CHR (P<0.001). In patients age 60 and older, rates of CHR maintenance were 37% and 18.9%, respectively.

MR and JAK2V617F allele burden

Rates of MR at 24 months were 68.1% (64/94) in the ropeg arm and 34.7% (26/75) in the HU arm (RR=1.85, P<0.01).

In patients younger than 60, the rate of MR was 77.1% in the ropeg arm and 33.3% in the HU arm (P<0.001). In patients age 60 and older, MR rates were 58.7% and 36.1%, respectively.

For patients younger than 60, the reduction in JAK2V617F allele burden at 12 months was 29.9% in the ropeg arm and 42.3% in the HU arm. At 24 months, the reductions were 54.8% and 4.5%, respectively (P<0.001).

For patients 60 and older, the reduction in JAK2V617F allele burden at 12 months was 25.2% in the ropeg arm and 37.5% in the HU arm. At 24 months, the reductions were 35.1% and 18.4%, respectively.

Safety          

“I think an important point here is the safety because we assume that [ropeg] is not well tolerated in elderly patients,” Dr Kiladjian said. “So what are the results in this prospective, controlled trial? There was a comparable number of adverse events and serious adverse events in the treatment arms, irrespective of age.”

Dr Kiladjian also pointed out that the number of adverse drug reactions (ADRs) was comparable between the treatment arms for younger patients, and there was a trend toward a lower number of ADRs in the ropeg arm for the patients age 60 and older.

The 4 serious ADRs in the HU patients age 60 and older were acute leukemia, anemia, leukopenia, and granulocytopenia.

Photo by Bill Branson

A survey of more than 15,000 childhood cancer survivors (CCSs) revealed that many were unconcerned about their risk of health problems.

Thirty-one percent of CCSs said they were “not at all” or “not very” concerned about their future health, and 40% said they were “not at all” or “not very” concerned about developing new cancers.

Researchers say it isn’t clear what’s driving this lack of concern, but it is possible that some CCSs don’t know they have an increased risk of new malignancies and other health problems.

“Other possibilities include that some survivors may actually be aware of their increased risks and choose not to be concerned, or it may even be that some survivors are, indeed, following health guidelines and working with healthcare providers, leading to their lack of concern,” said Todd Gibson, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Gibson and his colleagues conducted this research and reported the results in Cancer.

The researchers analyzed data on 15,620 CCSs and 3991 of their siblings who did not have a history of cancer. The data came from questionnaires administered to participants in the Childhood Cancer Survivor Study.

At baseline, the median time from CCSs’ cancer diagnosis was 17 years (interquartile range [IQR], 14-21). Their median age at baseline was 26 (IQR, 22-31 years), and the siblings’ median age was 29 (IQR, 24-35).

When respondents were asked about their level of concern regarding their future health, the answers were as follows:

• 12% of both CCSs and siblings were “not at all concerned”
• 18.7% of CCSs and 21.6% of siblings were “not very concerned”
• 23.2% of CCSs and 24.1% of siblings were “concerned”
• 21.4% of CCSs and 22.2% of siblings were “somewhat concerned”
• 24.8% of CCSs and 20.1% of siblings were “very concerned.”

When respondents were asked to rate their level of concern about developing a new cancer, the answers were as follows:

• 17.2% of CCSs and 16.3% of siblings were “not at all concerned”
• 22.8% of CCSs and 22.2% of siblings were “not very concerned”
• 21.1% of CCSs and 25.1% of siblings were “concerned”
• 18.3% of CCSs and 18.4% of siblings were “somewhat concerned”
• 20.6% of CCSs and 18.1% of siblings were “very concerned.”

When the researchers adjusted for age, sex, race/ethnicity, education, and decade of diagnosis, CCSs were only slightly more likely than siblings to report concern about future health (relative risk, 1.12) or subsequent cancer (relative risk, 1.02).

“That similarity [between CCS and sibling answers] was really the major surprise in our findings,” Dr Gibson said. “Despite the fact that survivors have such a greatly increased risk of both second cancers and other health problems, their perception of risk was not always commensurate with their actual risk.”

The researchers did find that CCSs were more likely to report concern about future health or developing cancer if they were female, non-Hispanic black or Hispanic, older, identified as having clinical anxiety, or had already experienced a grade 3/4 chronic condition or subsequent cancer.

However, it isn’t clear why some CCSs are concerned about their future health and others are not.

“At this point, we can only speculate, but the most obvious reason [for lack of concern] would be that survivors may not fully understand their risks,” Dr Gibson said. “We do know from prior studies that not all survivors are fully aware of the specific treatments they received and how those might increase their risks of late effects.”

“If, however, survivors are aware but not motivated or sufficiently aroused to be concerned, then more motivational education will have to be developed. In any case, these findings offer a teaching point that we can use to emphasize to all survivors that they need to understand their risks.”

Photo by Bill Branson

A survey of more than 15,000 childhood cancer survivors (CCSs) revealed that many were unconcerned about their risk of health problems.

Thirty-one percent of CCSs said they were “not at all” or “not very” concerned about their future health, and 40% said they were “not at all” or “not very” concerned about developing new cancers.

Researchers say it isn’t clear what’s driving this lack of concern, but it is possible that some CCSs don’t know they have an increased risk of new malignancies and other health problems.

“Other possibilities include that some survivors may actually be aware of their increased risks and choose not to be concerned, or it may even be that some survivors are, indeed, following health guidelines and working with healthcare providers, leading to their lack of concern,” said Todd Gibson, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Gibson and his colleagues conducted this research and reported the results in Cancer.

The researchers analyzed data on 15,620 CCSs and 3991 of their siblings who did not have a history of cancer. The data came from questionnaires administered to participants in the Childhood Cancer Survivor Study.

At baseline, the median time from CCSs’ cancer diagnosis was 17 years (interquartile range [IQR], 14-21). Their median age at baseline was 26 (IQR, 22-31 years), and the siblings’ median age was 29 (IQR, 24-35).

When respondents were asked about their level of concern regarding their future health, the answers were as follows:

• 12% of both CCSs and siblings were “not at all concerned”
• 18.7% of CCSs and 21.6% of siblings were “not very concerned”
• 23.2% of CCSs and 24.1% of siblings were “concerned”
• 21.4% of CCSs and 22.2% of siblings were “somewhat concerned”
• 24.8% of CCSs and 20.1% of siblings were “very concerned.”

When respondents were asked to rate their level of concern about developing a new cancer, the answers were as follows:

• 17.2% of CCSs and 16.3% of siblings were “not at all concerned”
• 22.8% of CCSs and 22.2% of siblings were “not very concerned”
• 21.1% of CCSs and 25.1% of siblings were “concerned”
• 18.3% of CCSs and 18.4% of siblings were “somewhat concerned”
• 20.6% of CCSs and 18.1% of siblings were “very concerned.”

When the researchers adjusted for age, sex, race/ethnicity, education, and decade of diagnosis, CCSs were only slightly more likely than siblings to report concern about future health (relative risk, 1.12) or subsequent cancer (relative risk, 1.02).

“That similarity [between CCS and sibling answers] was really the major surprise in our findings,” Dr Gibson said. “Despite the fact that survivors have such a greatly increased risk of both second cancers and other health problems, their perception of risk was not always commensurate with their actual risk.”

The researchers did find that CCSs were more likely to report concern about future health or developing cancer if they were female, non-Hispanic black or Hispanic, older, identified as having clinical anxiety, or had already experienced a grade 3/4 chronic condition or subsequent cancer.

However, it isn’t clear why some CCSs are concerned about their future health and others are not.

“At this point, we can only speculate, but the most obvious reason [for lack of concern] would be that survivors may not fully understand their risks,” Dr Gibson said. “We do know from prior studies that not all survivors are fully aware of the specific treatments they received and how those might increase their risks of late effects.”

“If, however, survivors are aware but not motivated or sufficiently aroused to be concerned, then more motivational education will have to be developed. In any case, these findings offer a teaching point that we can use to emphasize to all survivors that they need to understand their risks.”

Photo by Bill Branson

A survey of more than 15,000 childhood cancer survivors (CCSs) revealed that many were unconcerned about their risk of health problems.

Thirty-one percent of CCSs said they were “not at all” or “not very” concerned about their future health, and 40% said they were “not at all” or “not very” concerned about developing new cancers.

Researchers say it isn’t clear what’s driving this lack of concern, but it is possible that some CCSs don’t know they have an increased risk of new malignancies and other health problems.

“Other possibilities include that some survivors may actually be aware of their increased risks and choose not to be concerned, or it may even be that some survivors are, indeed, following health guidelines and working with healthcare providers, leading to their lack of concern,” said Todd Gibson, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Gibson and his colleagues conducted this research and reported the results in Cancer.

The researchers analyzed data on 15,620 CCSs and 3991 of their siblings who did not have a history of cancer. The data came from questionnaires administered to participants in the Childhood Cancer Survivor Study.

At baseline, the median time from CCSs’ cancer diagnosis was 17 years (interquartile range [IQR], 14-21). Their median age at baseline was 26 (IQR, 22-31 years), and the siblings’ median age was 29 (IQR, 24-35).

When respondents were asked about their level of concern regarding their future health, the answers were as follows:

• 12% of both CCSs and siblings were “not at all concerned”
• 18.7% of CCSs and 21.6% of siblings were “not very concerned”
• 23.2% of CCSs and 24.1% of siblings were “concerned”
• 21.4% of CCSs and 22.2% of siblings were “somewhat concerned”
• 24.8% of CCSs and 20.1% of siblings were “very concerned.”

When respondents were asked to rate their level of concern about developing a new cancer, the answers were as follows:

• 17.2% of CCSs and 16.3% of siblings were “not at all concerned”
• 22.8% of CCSs and 22.2% of siblings were “not very concerned”
• 21.1% of CCSs and 25.1% of siblings were “concerned”
• 18.3% of CCSs and 18.4% of siblings were “somewhat concerned”
• 20.6% of CCSs and 18.1% of siblings were “very concerned.”

When the researchers adjusted for age, sex, race/ethnicity, education, and decade of diagnosis, CCSs were only slightly more likely than siblings to report concern about future health (relative risk, 1.12) or subsequent cancer (relative risk, 1.02).

“That similarity [between CCS and sibling answers] was really the major surprise in our findings,” Dr Gibson said. “Despite the fact that survivors have such a greatly increased risk of both second cancers and other health problems, their perception of risk was not always commensurate with their actual risk.”

The researchers did find that CCSs were more likely to report concern about future health or developing cancer if they were female, non-Hispanic black or Hispanic, older, identified as having clinical anxiety, or had already experienced a grade 3/4 chronic condition or subsequent cancer.

However, it isn’t clear why some CCSs are concerned about their future health and others are not.

“At this point, we can only speculate, but the most obvious reason [for lack of concern] would be that survivors may not fully understand their risks,” Dr Gibson said. “We do know from prior studies that not all survivors are fully aware of the specific treatments they received and how those might increase their risks of late effects.”

“If, however, survivors are aware but not motivated or sufficiently aroused to be concerned, then more motivational education will have to be developed. In any case, these findings offer a teaching point that we can use to emphasize to all survivors that they need to understand their risks.”

Image by Lance Liotta

The US Food and Drug Administration (FDA) has accepted for priority review a new drug application (NDA) for glasdegib, an oral SMO inhibitor.

With this NDA, Pfizer is seeking approval for glasdegib in combination with low-dose cytarabine (LDAC) as a treatment for adults with previously untreated acute myeloid leukemia (AML).

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

The FDA expects to make a decision on the NDA for glasdegib by December 2018.

The NDA is supported by results from the phase 2 BRIGHT 1003 study. Results from this trial were presented at the 2016 ASH Annual Meeting.

The trial was a comparison of glasdegib plus LDAC (n=88) to LDAC alone (n=44) in patients with previously untreated AML or high-risk myelodysplastic syndromes who were not eligible for intensive chemotherapy.

Results demonstrated a significant improvement in overall survival with glasdegib. The median overall survival was 8.8 months in the glasdegib arm and 4.9 months in the LDAC-alone arm.

This difference represented a 49.9% reduction in the risk of death for patients treated with glasdegib plus LDAC (hazard ratio=0.501; 95% CI: 0.334, 0.752; one-sided P-value=0.0003).

The most frequent adverse events—occurring in at least 30% of patients in the glasdegib arm and LDAC-alone arm, respectively—were anemia (45% vs 42%), febrile neutropenia (36% vs 27%), nausea (36% vs 12%), decreased appetite (32% vs 12%), fatigue (31% vs 20%), and thrombocytopenia (30% vs 27%).

The most frequently reported serious adverse events—occurring in at least 15%  of patients in the glasdegib and LDAC-alone arms, respectively—were febrile neutropenia (29% vs 20%) and pneumonia (21% vs 17%).

A phase 3 trial of glasdegib in AML began enrolling earlier this year. In this trial (BRIGHT AML 1019; NCT03416179), researchers are evaluating glasdegib plus intensive or non-intensive chemotherapy in patients with newly diagnosed AML.

Image by Lance Liotta

The US Food and Drug Administration (FDA) has accepted for priority review a new drug application (NDA) for glasdegib, an oral SMO inhibitor.

With this NDA, Pfizer is seeking approval for glasdegib in combination with low-dose cytarabine (LDAC) as a treatment for adults with previously untreated acute myeloid leukemia (AML).

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

The FDA expects to make a decision on the NDA for glasdegib by December 2018.

The NDA is supported by results from the phase 2 BRIGHT 1003 study. Results from this trial were presented at the 2016 ASH Annual Meeting.

The trial was a comparison of glasdegib plus LDAC (n=88) to LDAC alone (n=44) in patients with previously untreated AML or high-risk myelodysplastic syndromes who were not eligible for intensive chemotherapy.

Results demonstrated a significant improvement in overall survival with glasdegib. The median overall survival was 8.8 months in the glasdegib arm and 4.9 months in the LDAC-alone arm.

This difference represented a 49.9% reduction in the risk of death for patients treated with glasdegib plus LDAC (hazard ratio=0.501; 95% CI: 0.334, 0.752; one-sided P-value=0.0003).

The most frequent adverse events—occurring in at least 30% of patients in the glasdegib arm and LDAC-alone arm, respectively—were anemia (45% vs 42%), febrile neutropenia (36% vs 27%), nausea (36% vs 12%), decreased appetite (32% vs 12%), fatigue (31% vs 20%), and thrombocytopenia (30% vs 27%).

The most frequently reported serious adverse events—occurring in at least 15%  of patients in the glasdegib and LDAC-alone arms, respectively—were febrile neutropenia (29% vs 20%) and pneumonia (21% vs 17%).

A phase 3 trial of glasdegib in AML began enrolling earlier this year. In this trial (BRIGHT AML 1019; NCT03416179), researchers are evaluating glasdegib plus intensive or non-intensive chemotherapy in patients with newly diagnosed AML.

Image by Lance Liotta

The US Food and Drug Administration (FDA) has accepted for priority review a new drug application (NDA) for glasdegib, an oral SMO inhibitor.

With this NDA, Pfizer is seeking approval for glasdegib in combination with low-dose cytarabine (LDAC) as a treatment for adults with previously untreated acute myeloid leukemia (AML).

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

The FDA expects to make a decision on the NDA for glasdegib by December 2018.

The NDA is supported by results from the phase 2 BRIGHT 1003 study. Results from this trial were presented at the 2016 ASH Annual Meeting.

The trial was a comparison of glasdegib plus LDAC (n=88) to LDAC alone (n=44) in patients with previously untreated AML or high-risk myelodysplastic syndromes who were not eligible for intensive chemotherapy.

Results demonstrated a significant improvement in overall survival with glasdegib. The median overall survival was 8.8 months in the glasdegib arm and 4.9 months in the LDAC-alone arm.

This difference represented a 49.9% reduction in the risk of death for patients treated with glasdegib plus LDAC (hazard ratio=0.501; 95% CI: 0.334, 0.752; one-sided P-value=0.0003).

The most frequent adverse events—occurring in at least 30% of patients in the glasdegib arm and LDAC-alone arm, respectively—were anemia (45% vs 42%), febrile neutropenia (36% vs 27%), nausea (36% vs 12%), decreased appetite (32% vs 12%), fatigue (31% vs 20%), and thrombocytopenia (30% vs 27%).

The most frequently reported serious adverse events—occurring in at least 15%  of patients in the glasdegib and LDAC-alone arms, respectively—were febrile neutropenia (29% vs 20%) and pneumonia (21% vs 17%).

A phase 3 trial of glasdegib in AML began enrolling earlier this year. In this trial (BRIGHT AML 1019; NCT03416179), researchers are evaluating glasdegib plus intensive or non-intensive chemotherapy in patients with newly diagnosed AML.

Daria Pagliara, MD, PhD

STOCKHOLM—Researchers have identified a “highly effective” transplant strategy for pediatric patients with primary immunodeficiencies who lack a suitable HLA-compatible donor, according to a speaker at the 23rd Congress of the European Hematology Association (EHA).

The strategy involves α/β T-cell- and B-cell-depleted haploidentical hematopoietic stem cell transplant (haplo-HSCT) followed by infusion of the T-cell product BPX-501.

Children treated with this strategy in a phase 1/2 trial had disease-free and overall survival rates that compared favorably with rates observed in recipients of matched, unrelated transplants.

In addition, the incidence of severe acute and chronic graft-versus-host disease (GHVD) was low in this trial.

Daria Pagliara, MD, PhD, of Ospedale Pediatrico Bambino Gesu in Rome, Italy, presented these results at the recent EHA Congress as abstract S871.

The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity. Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

Dr Pagliara explained that T cells are collected from donors via non-mobilized apheresis, the cells are modified to create the BPX-501 product, and the product is infused in HSCT recipients at day 14 after transplant (+/- 4 days).

The patients do not receive GVHD prophylaxis after transplant but are given rimiducid if they develop GVHD that does not respond to standard therapy.

Patients and transplant characteristics

Dr Pagliara reported results with BPX-501 in 59 patients. They had a median age of 1.85 years (range, 0.21 to 17.55), and 57.6% were male.

Patients had severe combined immune deficiency (32%), Wiskott–Aldrich syndrome (15%), chronic granulomatous disease (12%), hemophagocytic lymphohistiocytosis (10%), combined immunodeficiency disease (7%), major histocompatibility complex class II deficiency (5%), and “other” immunodeficiencies (19%).

The patients received BPX-501 after an α/β T-cell-depleted, B-cell-depleted haplo-HSCT. Most patients had a parent donor (94.9%), and 5.1% had a sibling donor. The median donor age was 34 (range, 21-52).

About half of patients (49.2%) received treosulfan-based conditioning, 39% received busulfan-based conditioning, and 11.9% received other conditioning.

The median CD34 dose was 22.0 x 10⁶/kg, and the median α/β T-cell dose was 0.4 x 10⁵/kg.

The median time to BPX-501 infusion was 15 days (range, 11-56). The median time to discharge was 40 days (range, 18-204).

The median follow-up was 536 days (range, 32-1252).

Engraftment and survival

The median time to neutrophil engraftment was 16 days, and the median time to platelet engraftment was 11 days.

Three patients had primary graft failure (5.1%), but 1 of these patients was successfully re-transplanted from the same donor.

The cumulative incidence of transplant-related mortality was 8.7%.

There were 5 cases of transplant-related mortality, which were due to graft failure/disseminated fungal infection, cytomegalovirus (CMV) encephalitis, worsening juvenile dermatomyositis/macrophage activation syndrome, bronchopulmonary hemorrhage, and CMV/adenovirus.

“I would like to underline that 3 of these 5 patients died of infectious complications that were present before the transplant—1 fungal invasive infection, 1 encephalitis due to CMV reactivation, and 1 pulmonary infection due to the presence of adenovirus and cytomegalovirus,” Dr Pagliara said.

The rate of disease-free survival and overall survival were both 87.6%.

GVHD and adverse events

Dr Pagliara said there were low rates of acute GVHD in the first 100 days.

The rate of grade 2-4 acute GVHD was 8.9%, and the rate of grade 3-4 acute GVHD was 1.8%. There were 4 cases of grade 2 GVHD—three stage 3 skin and one stage 1 upper gastrointestinal. There was a single case of grade 3 GVHD—stage 3 liver.

Of the 19 patients who developed acute GVHD, 7 received at least 1 dose of rimiducid. These patients had visceral involvement or GVHD that was not responsive to standard care.

Four patients had a complete response to rimiducid, and 1 had a partial response. One patient did not respond, and 1 was not evaluable. The non-evaluable patient was on corticosteroids and cyclosporine with controlled GVHD but was unable to be weaned off corticosteroids. Rimiducid was given in an attempt to wean the patient off corticosteroids.

“Most importantly, only 1 patient out of 59 developed chronic GVHD, with only mild involvement of the skin,” Dr Pagliara said. This patient did not receive rimiducid.

Nine patients (15.2%) had at least 1 adverse event (AE).

AEs occurring after BPX-501 administration were grade 1 or 2 in nature. They included diarrhea, vomiting, pyrexia, CMV viremia, rhinovirus infection, hypokalemia, pruritus, and rash.

There were no severe AEs attributed to BPX-501.

Daria Pagliara, MD, PhD

STOCKHOLM—Researchers have identified a “highly effective” transplant strategy for pediatric patients with primary immunodeficiencies who lack a suitable HLA-compatible donor, according to a speaker at the 23rd Congress of the European Hematology Association (EHA).

The strategy involves α/β T-cell- and B-cell-depleted haploidentical hematopoietic stem cell transplant (haplo-HSCT) followed by infusion of the T-cell product BPX-501.

Children treated with this strategy in a phase 1/2 trial had disease-free and overall survival rates that compared favorably with rates observed in recipients of matched, unrelated transplants.

In addition, the incidence of severe acute and chronic graft-versus-host disease (GHVD) was low in this trial.

Daria Pagliara, MD, PhD, of Ospedale Pediatrico Bambino Gesu in Rome, Italy, presented these results at the recent EHA Congress as abstract S871.

The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity. Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

Dr Pagliara explained that T cells are collected from donors via non-mobilized apheresis, the cells are modified to create the BPX-501 product, and the product is infused in HSCT recipients at day 14 after transplant (+/- 4 days).

The patients do not receive GVHD prophylaxis after transplant but are given rimiducid if they develop GVHD that does not respond to standard therapy.

Patients and transplant characteristics

Dr Pagliara reported results with BPX-501 in 59 patients. They had a median age of 1.85 years (range, 0.21 to 17.55), and 57.6% were male.

Patients had severe combined immune deficiency (32%), Wiskott–Aldrich syndrome (15%), chronic granulomatous disease (12%), hemophagocytic lymphohistiocytosis (10%), combined immunodeficiency disease (7%), major histocompatibility complex class II deficiency (5%), and “other” immunodeficiencies (19%).

The patients received BPX-501 after an α/β T-cell-depleted, B-cell-depleted haplo-HSCT. Most patients had a parent donor (94.9%), and 5.1% had a sibling donor. The median donor age was 34 (range, 21-52).

About half of patients (49.2%) received treosulfan-based conditioning, 39% received busulfan-based conditioning, and 11.9% received other conditioning.

The median CD34 dose was 22.0 x 10⁶/kg, and the median α/β T-cell dose was 0.4 x 10⁵/kg.

The median time to BPX-501 infusion was 15 days (range, 11-56). The median time to discharge was 40 days (range, 18-204).

The median follow-up was 536 days (range, 32-1252).

Engraftment and survival

The median time to neutrophil engraftment was 16 days, and the median time to platelet engraftment was 11 days.

Three patients had primary graft failure (5.1%), but 1 of these patients was successfully re-transplanted from the same donor.

The cumulative incidence of transplant-related mortality was 8.7%.

There were 5 cases of transplant-related mortality, which were due to graft failure/disseminated fungal infection, cytomegalovirus (CMV) encephalitis, worsening juvenile dermatomyositis/macrophage activation syndrome, bronchopulmonary hemorrhage, and CMV/adenovirus.

“I would like to underline that 3 of these 5 patients died of infectious complications that were present before the transplant—1 fungal invasive infection, 1 encephalitis due to CMV reactivation, and 1 pulmonary infection due to the presence of adenovirus and cytomegalovirus,” Dr Pagliara said.

The rate of disease-free survival and overall survival were both 87.6%.

GVHD and adverse events

Dr Pagliara said there were low rates of acute GVHD in the first 100 days.

The rate of grade 2-4 acute GVHD was 8.9%, and the rate of grade 3-4 acute GVHD was 1.8%. There were 4 cases of grade 2 GVHD—three stage 3 skin and one stage 1 upper gastrointestinal. There was a single case of grade 3 GVHD—stage 3 liver.

Of the 19 patients who developed acute GVHD, 7 received at least 1 dose of rimiducid. These patients had visceral involvement or GVHD that was not responsive to standard care.

Four patients had a complete response to rimiducid, and 1 had a partial response. One patient did not respond, and 1 was not evaluable. The non-evaluable patient was on corticosteroids and cyclosporine with controlled GVHD but was unable to be weaned off corticosteroids. Rimiducid was given in an attempt to wean the patient off corticosteroids.

“Most importantly, only 1 patient out of 59 developed chronic GVHD, with only mild involvement of the skin,” Dr Pagliara said. This patient did not receive rimiducid.

Nine patients (15.2%) had at least 1 adverse event (AE).

AEs occurring after BPX-501 administration were grade 1 or 2 in nature. They included diarrhea, vomiting, pyrexia, CMV viremia, rhinovirus infection, hypokalemia, pruritus, and rash.

There were no severe AEs attributed to BPX-501.

Daria Pagliara, MD, PhD

STOCKHOLM—Researchers have identified a “highly effective” transplant strategy for pediatric patients with primary immunodeficiencies who lack a suitable HLA-compatible donor, according to a speaker at the 23rd Congress of the European Hematology Association (EHA).

The strategy involves α/β T-cell- and B-cell-depleted haploidentical hematopoietic stem cell transplant (haplo-HSCT) followed by infusion of the T-cell product BPX-501.

Children treated with this strategy in a phase 1/2 trial had disease-free and overall survival rates that compared favorably with rates observed in recipients of matched, unrelated transplants.

In addition, the incidence of severe acute and chronic graft-versus-host disease (GHVD) was low in this trial.

Daria Pagliara, MD, PhD, of Ospedale Pediatrico Bambino Gesu in Rome, Italy, presented these results at the recent EHA Congress as abstract S871.

The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity. Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

Dr Pagliara explained that T cells are collected from donors via non-mobilized apheresis, the cells are modified to create the BPX-501 product, and the product is infused in HSCT recipients at day 14 after transplant (+/- 4 days).

The patients do not receive GVHD prophylaxis after transplant but are given rimiducid if they develop GVHD that does not respond to standard therapy.

Patients and transplant characteristics

Dr Pagliara reported results with BPX-501 in 59 patients. They had a median age of 1.85 years (range, 0.21 to 17.55), and 57.6% were male.

Patients had severe combined immune deficiency (32%), Wiskott–Aldrich syndrome (15%), chronic granulomatous disease (12%), hemophagocytic lymphohistiocytosis (10%), combined immunodeficiency disease (7%), major histocompatibility complex class II deficiency (5%), and “other” immunodeficiencies (19%).

The patients received BPX-501 after an α/β T-cell-depleted, B-cell-depleted haplo-HSCT. Most patients had a parent donor (94.9%), and 5.1% had a sibling donor. The median donor age was 34 (range, 21-52).

About half of patients (49.2%) received treosulfan-based conditioning, 39% received busulfan-based conditioning, and 11.9% received other conditioning.

The median CD34 dose was 22.0 x 10⁶/kg, and the median α/β T-cell dose was 0.4 x 10⁵/kg.

The median time to BPX-501 infusion was 15 days (range, 11-56). The median time to discharge was 40 days (range, 18-204).

The median follow-up was 536 days (range, 32-1252).

Engraftment and survival

The median time to neutrophil engraftment was 16 days, and the median time to platelet engraftment was 11 days.

Three patients had primary graft failure (5.1%), but 1 of these patients was successfully re-transplanted from the same donor.

The cumulative incidence of transplant-related mortality was 8.7%.

There were 5 cases of transplant-related mortality, which were due to graft failure/disseminated fungal infection, cytomegalovirus (CMV) encephalitis, worsening juvenile dermatomyositis/macrophage activation syndrome, bronchopulmonary hemorrhage, and CMV/adenovirus.

“I would like to underline that 3 of these 5 patients died of infectious complications that were present before the transplant—1 fungal invasive infection, 1 encephalitis due to CMV reactivation, and 1 pulmonary infection due to the presence of adenovirus and cytomegalovirus,” Dr Pagliara said.

The rate of disease-free survival and overall survival were both 87.6%.

GVHD and adverse events

Dr Pagliara said there were low rates of acute GVHD in the first 100 days.

The rate of grade 2-4 acute GVHD was 8.9%, and the rate of grade 3-4 acute GVHD was 1.8%. There were 4 cases of grade 2 GVHD—three stage 3 skin and one stage 1 upper gastrointestinal. There was a single case of grade 3 GVHD—stage 3 liver.

Of the 19 patients who developed acute GVHD, 7 received at least 1 dose of rimiducid. These patients had visceral involvement or GVHD that was not responsive to standard care.

Four patients had a complete response to rimiducid, and 1 had a partial response. One patient did not respond, and 1 was not evaluable. The non-evaluable patient was on corticosteroids and cyclosporine with controlled GVHD but was unable to be weaned off corticosteroids. Rimiducid was given in an attempt to wean the patient off corticosteroids.

“Most importantly, only 1 patient out of 59 developed chronic GVHD, with only mild involvement of the skin,” Dr Pagliara said. This patient did not receive rimiducid.

Nine patients (15.2%) had at least 1 adverse event (AE).

AEs occurring after BPX-501 administration were grade 1 or 2 in nature. They included diarrhea, vomiting, pyrexia, CMV viremia, rhinovirus infection, hypokalemia, pruritus, and rash.

There were no severe AEs attributed to BPX-501.

Photo from UAB Hospital

Patients who receive red blood cell (RBC) transfusions before, during, or immediately after surgery may have an increased risk of venous thromboembolism (VTE), a new study suggests.

In this retrospective study, transfusion recipients had twice the risk of VTE as patients who did not receive RBC transfusions during the perioperative period.

Investigators say these findings require validation, but they suggest a need for physicians to consider non-transfusion alternatives to treat anemia in patients undergoing surgery.

“These findings reinforce the importance of following rigorous perioperative patient blood management practices for transfusions,” said Ruchika Goel, MD, of Weill Cornell Medicine in New York, New York.

Dr Goel and her colleagues reported their findings in JAMA Surgery.

The investigators analyzed data on 750,937 patients who underwent surgery in 2014. In all, 6.3% (n=47,410) of patients received at least one RBC transfusion.

Within 30 days of surgery, 0.8% (n=6309) of all patients had a VTE. This included 0.6% (n=4336) with deep vein thrombosis (DVT), 0.3% (n=2514) with pulmonary embolism (PE), and 0.1% (n=541) with DVT and PE.

Analyses showed that patients who received RBC transfusions were twice as likely to develop VTE as those who did not receive transfusions (adjusted odds ratio [aOR]=2.1). This was true for both DVT (aOR=2.2) and PE (aOR=1.9).

“We also saw this risk across different surgical disciplines, ranging from neurosurgery to cardiac surgery,” said study author Aaron Tobian, MD, PhD, of Johns Hopkins University School of Medicine in Baltimore, Maryland.

Furthermore, VTE risk increased with the number of RBC transfusions a patient received. The aORs were 2.1 for 1 transfusion, 3.1 for 2 transfusions, and 4.5 for 3 or more transfusions (compared to patients who did not receive any transfusions).

“This retrospective study demonstrates that there may be additional risks to blood transfusion that are not generally recognized in the community,” Dr Tobian said. “While additional research is needed to confirm these results, the findings reinforce the need to limit blood transfusions to only when necessary.”

Photo from UAB Hospital

Patients who receive red blood cell (RBC) transfusions before, during, or immediately after surgery may have an increased risk of venous thromboembolism (VTE), a new study suggests.

In this retrospective study, transfusion recipients had twice the risk of VTE as patients who did not receive RBC transfusions during the perioperative period.

Investigators say these findings require validation, but they suggest a need for physicians to consider non-transfusion alternatives to treat anemia in patients undergoing surgery.

“These findings reinforce the importance of following rigorous perioperative patient blood management practices for transfusions,” said Ruchika Goel, MD, of Weill Cornell Medicine in New York, New York.

Dr Goel and her colleagues reported their findings in JAMA Surgery.

The investigators analyzed data on 750,937 patients who underwent surgery in 2014. In all, 6.3% (n=47,410) of patients received at least one RBC transfusion.

Within 30 days of surgery, 0.8% (n=6309) of all patients had a VTE. This included 0.6% (n=4336) with deep vein thrombosis (DVT), 0.3% (n=2514) with pulmonary embolism (PE), and 0.1% (n=541) with DVT and PE.

Analyses showed that patients who received RBC transfusions were twice as likely to develop VTE as those who did not receive transfusions (adjusted odds ratio [aOR]=2.1). This was true for both DVT (aOR=2.2) and PE (aOR=1.9).

“We also saw this risk across different surgical disciplines, ranging from neurosurgery to cardiac surgery,” said study author Aaron Tobian, MD, PhD, of Johns Hopkins University School of Medicine in Baltimore, Maryland.

Furthermore, VTE risk increased with the number of RBC transfusions a patient received. The aORs were 2.1 for 1 transfusion, 3.1 for 2 transfusions, and 4.5 for 3 or more transfusions (compared to patients who did not receive any transfusions).

“This retrospective study demonstrates that there may be additional risks to blood transfusion that are not generally recognized in the community,” Dr Tobian said. “While additional research is needed to confirm these results, the findings reinforce the need to limit blood transfusions to only when necessary.”

Photo from UAB Hospital

Patients who receive red blood cell (RBC) transfusions before, during, or immediately after surgery may have an increased risk of venous thromboembolism (VTE), a new study suggests.

In this retrospective study, transfusion recipients had twice the risk of VTE as patients who did not receive RBC transfusions during the perioperative period.

Investigators say these findings require validation, but they suggest a need for physicians to consider non-transfusion alternatives to treat anemia in patients undergoing surgery.

“These findings reinforce the importance of following rigorous perioperative patient blood management practices for transfusions,” said Ruchika Goel, MD, of Weill Cornell Medicine in New York, New York.

Dr Goel and her colleagues reported their findings in JAMA Surgery.

The investigators analyzed data on 750,937 patients who underwent surgery in 2014. In all, 6.3% (n=47,410) of patients received at least one RBC transfusion.

Within 30 days of surgery, 0.8% (n=6309) of all patients had a VTE. This included 0.6% (n=4336) with deep vein thrombosis (DVT), 0.3% (n=2514) with pulmonary embolism (PE), and 0.1% (n=541) with DVT and PE.

Analyses showed that patients who received RBC transfusions were twice as likely to develop VTE as those who did not receive transfusions (adjusted odds ratio [aOR]=2.1). This was true for both DVT (aOR=2.2) and PE (aOR=1.9).

“We also saw this risk across different surgical disciplines, ranging from neurosurgery to cardiac surgery,” said study author Aaron Tobian, MD, PhD, of Johns Hopkins University School of Medicine in Baltimore, Maryland.

Furthermore, VTE risk increased with the number of RBC transfusions a patient received. The aORs were 2.1 for 1 transfusion, 3.1 for 2 transfusions, and 4.5 for 3 or more transfusions (compared to patients who did not receive any transfusions).

“This retrospective study demonstrates that there may be additional risks to blood transfusion that are not generally recognized in the community,” Dr Tobian said. “While additional research is needed to confirm these results, the findings reinforce the need to limit blood transfusions to only when necessary.”

Red blood cells

Erytech Pharma said it plans to stop development of eryaspase for acute lymphoblastic leukemia (ALL).

This means withdrawal of the European marketing authorization application for eryaspase as a treatment for relapsed and refractory ALL.

However, Erytech will continue development of eryaspase as a treatment for certain solid tumor malignancies.

Eryaspase consists of L-asparaginase encapsulated inside donor-derived red blood cells. These enzyme-loaded red blood cells function as bioreactors to eliminate circulating asparagine and “starve” cancer cells, thereby inducing their death.

Erytech noted that eryaspase has produced favorable efficacy and safety results in ALL.

However, based on recent feedback from regulatory agencies in Europe and the US, the company believes significant additional investment would be required to seek regulatory approval of eryaspase for the treatment of ALL. Erytech also believes there would be a limited market opportunity for eryaspase in ALL.

Therefore, the company decided to cease further clinical development efforts in ALL. The resources that will become available as a result of this decision will be allocated to the development of eryaspase in solid tumors.

In 2017, Erytech announced results from a phase 2b clinical trial of eryaspase plus chemotherapy in patients with second-line metastatic pancreatic cancer. The company expects to begin enrollment in a phase 3 trial of this patient population in the third quarter of 2018.

In addition, Erytech is preparing for a pair of phase 2 proof-of-concept trials of eryaspase. One is in first-line pancreatic cancer, and the other is in metastatic triple-negative breast cancer. The company is also evaluating development options in additional solid tumor indications with high unmet medical need.

To ensure an adequate supply of eryaspase, Erytech is constructing a large-scale manufacturing facility in Princeton, New Jersey, and is expanding its manufacturing capacity in Lyon, France. The company expects both facilities to be operational for clinical production at the expanded capacity in the first quarter of 2019.

Red blood cells

Erytech Pharma said it plans to stop development of eryaspase for acute lymphoblastic leukemia (ALL).

This means withdrawal of the European marketing authorization application for eryaspase as a treatment for relapsed and refractory ALL.

However, Erytech will continue development of eryaspase as a treatment for certain solid tumor malignancies.

Eryaspase consists of L-asparaginase encapsulated inside donor-derived red blood cells. These enzyme-loaded red blood cells function as bioreactors to eliminate circulating asparagine and “starve” cancer cells, thereby inducing their death.

Erytech noted that eryaspase has produced favorable efficacy and safety results in ALL.

However, based on recent feedback from regulatory agencies in Europe and the US, the company believes significant additional investment would be required to seek regulatory approval of eryaspase for the treatment of ALL. Erytech also believes there would be a limited market opportunity for eryaspase in ALL.

Therefore, the company decided to cease further clinical development efforts in ALL. The resources that will become available as a result of this decision will be allocated to the development of eryaspase in solid tumors.

In 2017, Erytech announced results from a phase 2b clinical trial of eryaspase plus chemotherapy in patients with second-line metastatic pancreatic cancer. The company expects to begin enrollment in a phase 3 trial of this patient population in the third quarter of 2018.

In addition, Erytech is preparing for a pair of phase 2 proof-of-concept trials of eryaspase. One is in first-line pancreatic cancer, and the other is in metastatic triple-negative breast cancer. The company is also evaluating development options in additional solid tumor indications with high unmet medical need.

To ensure an adequate supply of eryaspase, Erytech is constructing a large-scale manufacturing facility in Princeton, New Jersey, and is expanding its manufacturing capacity in Lyon, France. The company expects both facilities to be operational for clinical production at the expanded capacity in the first quarter of 2019.

Red blood cells

Erytech Pharma said it plans to stop development of eryaspase for acute lymphoblastic leukemia (ALL).

This means withdrawal of the European marketing authorization application for eryaspase as a treatment for relapsed and refractory ALL.

However, Erytech will continue development of eryaspase as a treatment for certain solid tumor malignancies.

Eryaspase consists of L-asparaginase encapsulated inside donor-derived red blood cells. These enzyme-loaded red blood cells function as bioreactors to eliminate circulating asparagine and “starve” cancer cells, thereby inducing their death.

Erytech noted that eryaspase has produced favorable efficacy and safety results in ALL.

However, based on recent feedback from regulatory agencies in Europe and the US, the company believes significant additional investment would be required to seek regulatory approval of eryaspase for the treatment of ALL. Erytech also believes there would be a limited market opportunity for eryaspase in ALL.

Therefore, the company decided to cease further clinical development efforts in ALL. The resources that will become available as a result of this decision will be allocated to the development of eryaspase in solid tumors.

In 2017, Erytech announced results from a phase 2b clinical trial of eryaspase plus chemotherapy in patients with second-line metastatic pancreatic cancer. The company expects to begin enrollment in a phase 3 trial of this patient population in the third quarter of 2018.

In addition, Erytech is preparing for a pair of phase 2 proof-of-concept trials of eryaspase. One is in first-line pancreatic cancer, and the other is in metastatic triple-negative breast cancer. The company is also evaluating development options in additional solid tumor indications with high unmet medical need.

To ensure an adequate supply of eryaspase, Erytech is constructing a large-scale manufacturing facility in Princeton, New Jersey, and is expanding its manufacturing capacity in Lyon, France. The company expects both facilities to be operational for clinical production at the expanded capacity in the first quarter of 2019.

Photo from EHA

STOCKHOLM—An ongoing phase 2 study suggests voxelotor (GBT440) can benefit adolescents with sickle cell disease (SCD).

In the HOPE-KIDS 1 study, voxelotor produced sustained improvements in hemoglobin levels and a reduction in clinical measures of hemolysis in a cohort of adolescents with SCD, most of whom were also receiving hydroxyurea (HU).

The most common adverse events (AEs) related to voxelotor were nausea, vomiting, headache, and rash.

These results were presented in a poster (abstract PF709) at the 23rd Congress of the European Hematology Association (EHA).

HOPE-KIDS 1 is sponsored by Global Blood Therapeutics, Inc.

In this study, researchers are evaluating voxelotor in SCD patients ages 6 to 17. In part A, researchers evaluated a 600 mg daily dose of voxelotor. In part B, they are testing voxelotor at daily doses of 900 mg and 1500 mg in patients ages 12 to 17.

At EHA, the researchers presented data on 25 patients who received voxelotor at 900 mg/day for 24 weeks in part B. Eighty-eight percent of the patients (n=22) were also taking HU.

The patients’ median age was 14 (range, 12-17), and 56% were male. Ninety-six percent (n=24) had the HbSS genotype.

Forty-eight percent of patients had 1 to 4 vaso-occlusive crises (VOCs) in the past year, 8% had more than 4 VOCs, and 44% had 0 VOCs.

At baseline, the median hemoglobin was 8.9 g/dL, the median fetal hemoglobin was 10.8 g/dL, and the median time-averaged mean of maximum velocity was 110 cm/s.

All 25 patients were dosed with voxelotor, and 22 completed 24 weeks of dosing. One patient withdrew consent, 1 was lost to follow-up, and 1 patient discontinued due to noncompliance.

Of the 22 patients who completed 24 weeks of voxelotor treatment, all but 3 were receiving concurrent HU.

Results

Voxelotor-related AEs occurring in at least 2 patients included nausea (12%, n=3), vomiting (8%, n=2), headache (8%, n=2), and rash (8%, n=2).

There was 1 case of grade 3 urticaria, which resolved and did not recur with continued dosing. There were no discontinuations of voxelotor due to AEs.

Patients experienced increased hemoglobin levels and improved clinical measures of hemolysis at 24 weeks, as evaluated by changes from baseline in hemoglobin, percent of reticulocytes, and percent of unconjugated bilirubin.

In all, 43% of patients (9/21) achieved a hemoglobin response (>1 g/dL) at 24 weeks. The median hemoglobin change from baseline was 0.7 g/dL, the median reduction in reticulocytes was 22.9%, and the median reduction in unconjugated bilirubin was 38.6%.

Sixty-two percent of patients (13/21) had a reduction in daily symptoms at 24 weeks, as assessed by total symptom scores (TSS). There was a 39% median reduction in TSS from baseline.

Fifty-five percent of patients (11/20) had a numerical decrease in transcranial doppler (TCD) flow at 24 weeks. Among hemoglobin responders (>1 g/dL), 88% (7/8) had a numerical decrease in TCD at 24 weeks.

“We continue to be encouraged by the results of the ongoing HOPE-KIDS 1 study, which are consistent with inhibition of HbS polymerization by voxelotor and support its ongoing clinical evaluation as a potential disease-modifying therapy for both adults and adolescents with SCD,” said Ted W. Love, MD, president and chief executive officer of Global Blood Therapeutics.

“Results to date support our ongoing development of voxelotor in a broad range of patients, including in our phase 3 HOPE study, which is also evaluating voxelotor at doses of 900 mg and 1500 mg per day in adolescents and adults. We continue to expect to announce top-line clinical data from part A of the HOPE study by the end of this quarter.”

Photo from EHA

STOCKHOLM—An ongoing phase 2 study suggests voxelotor (GBT440) can benefit adolescents with sickle cell disease (SCD).

In the HOPE-KIDS 1 study, voxelotor produced sustained improvements in hemoglobin levels and a reduction in clinical measures of hemolysis in a cohort of adolescents with SCD, most of whom were also receiving hydroxyurea (HU).

The most common adverse events (AEs) related to voxelotor were nausea, vomiting, headache, and rash.

These results were presented in a poster (abstract PF709) at the 23rd Congress of the European Hematology Association (EHA).

HOPE-KIDS 1 is sponsored by Global Blood Therapeutics, Inc.

In this study, researchers are evaluating voxelotor in SCD patients ages 6 to 17. In part A, researchers evaluated a 600 mg daily dose of voxelotor. In part B, they are testing voxelotor at daily doses of 900 mg and 1500 mg in patients ages 12 to 17.

At EHA, the researchers presented data on 25 patients who received voxelotor at 900 mg/day for 24 weeks in part B. Eighty-eight percent of the patients (n=22) were also taking HU.

The patients’ median age was 14 (range, 12-17), and 56% were male. Ninety-six percent (n=24) had the HbSS genotype.

Forty-eight percent of patients had 1 to 4 vaso-occlusive crises (VOCs) in the past year, 8% had more than 4 VOCs, and 44% had 0 VOCs.

At baseline, the median hemoglobin was 8.9 g/dL, the median fetal hemoglobin was 10.8 g/dL, and the median time-averaged mean of maximum velocity was 110 cm/s.

All 25 patients were dosed with voxelotor, and 22 completed 24 weeks of dosing. One patient withdrew consent, 1 was lost to follow-up, and 1 patient discontinued due to noncompliance.

Of the 22 patients who completed 24 weeks of voxelotor treatment, all but 3 were receiving concurrent HU.

Results

Voxelotor-related AEs occurring in at least 2 patients included nausea (12%, n=3), vomiting (8%, n=2), headache (8%, n=2), and rash (8%, n=2).

There was 1 case of grade 3 urticaria, which resolved and did not recur with continued dosing. There were no discontinuations of voxelotor due to AEs.

Patients experienced increased hemoglobin levels and improved clinical measures of hemolysis at 24 weeks, as evaluated by changes from baseline in hemoglobin, percent of reticulocytes, and percent of unconjugated bilirubin.

In all, 43% of patients (9/21) achieved a hemoglobin response (>1 g/dL) at 24 weeks. The median hemoglobin change from baseline was 0.7 g/dL, the median reduction in reticulocytes was 22.9%, and the median reduction in unconjugated bilirubin was 38.6%.

Sixty-two percent of patients (13/21) had a reduction in daily symptoms at 24 weeks, as assessed by total symptom scores (TSS). There was a 39% median reduction in TSS from baseline.

Fifty-five percent of patients (11/20) had a numerical decrease in transcranial doppler (TCD) flow at 24 weeks. Among hemoglobin responders (>1 g/dL), 88% (7/8) had a numerical decrease in TCD at 24 weeks.

“We continue to be encouraged by the results of the ongoing HOPE-KIDS 1 study, which are consistent with inhibition of HbS polymerization by voxelotor and support its ongoing clinical evaluation as a potential disease-modifying therapy for both adults and adolescents with SCD,” said Ted W. Love, MD, president and chief executive officer of Global Blood Therapeutics.

“Results to date support our ongoing development of voxelotor in a broad range of patients, including in our phase 3 HOPE study, which is also evaluating voxelotor at doses of 900 mg and 1500 mg per day in adolescents and adults. We continue to expect to announce top-line clinical data from part A of the HOPE study by the end of this quarter.”

Photo from EHA

STOCKHOLM—An ongoing phase 2 study suggests voxelotor (GBT440) can benefit adolescents with sickle cell disease (SCD).

In the HOPE-KIDS 1 study, voxelotor produced sustained improvements in hemoglobin levels and a reduction in clinical measures of hemolysis in a cohort of adolescents with SCD, most of whom were also receiving hydroxyurea (HU).

The most common adverse events (AEs) related to voxelotor were nausea, vomiting, headache, and rash.

These results were presented in a poster (abstract PF709) at the 23rd Congress of the European Hematology Association (EHA).

HOPE-KIDS 1 is sponsored by Global Blood Therapeutics, Inc.

In this study, researchers are evaluating voxelotor in SCD patients ages 6 to 17. In part A, researchers evaluated a 600 mg daily dose of voxelotor. In part B, they are testing voxelotor at daily doses of 900 mg and 1500 mg in patients ages 12 to 17.

At EHA, the researchers presented data on 25 patients who received voxelotor at 900 mg/day for 24 weeks in part B. Eighty-eight percent of the patients (n=22) were also taking HU.

The patients’ median age was 14 (range, 12-17), and 56% were male. Ninety-six percent (n=24) had the HbSS genotype.

Forty-eight percent of patients had 1 to 4 vaso-occlusive crises (VOCs) in the past year, 8% had more than 4 VOCs, and 44% had 0 VOCs.

At baseline, the median hemoglobin was 8.9 g/dL, the median fetal hemoglobin was 10.8 g/dL, and the median time-averaged mean of maximum velocity was 110 cm/s.

All 25 patients were dosed with voxelotor, and 22 completed 24 weeks of dosing. One patient withdrew consent, 1 was lost to follow-up, and 1 patient discontinued due to noncompliance.

Of the 22 patients who completed 24 weeks of voxelotor treatment, all but 3 were receiving concurrent HU.

Results

Voxelotor-related AEs occurring in at least 2 patients included nausea (12%, n=3), vomiting (8%, n=2), headache (8%, n=2), and rash (8%, n=2).

There was 1 case of grade 3 urticaria, which resolved and did not recur with continued dosing. There were no discontinuations of voxelotor due to AEs.

Patients experienced increased hemoglobin levels and improved clinical measures of hemolysis at 24 weeks, as evaluated by changes from baseline in hemoglobin, percent of reticulocytes, and percent of unconjugated bilirubin.

In all, 43% of patients (9/21) achieved a hemoglobin response (>1 g/dL) at 24 weeks. The median hemoglobin change from baseline was 0.7 g/dL, the median reduction in reticulocytes was 22.9%, and the median reduction in unconjugated bilirubin was 38.6%.

Sixty-two percent of patients (13/21) had a reduction in daily symptoms at 24 weeks, as assessed by total symptom scores (TSS). There was a 39% median reduction in TSS from baseline.

Fifty-five percent of patients (11/20) had a numerical decrease in transcranial doppler (TCD) flow at 24 weeks. Among hemoglobin responders (>1 g/dL), 88% (7/8) had a numerical decrease in TCD at 24 weeks.

“We continue to be encouraged by the results of the ongoing HOPE-KIDS 1 study, which are consistent with inhibition of HbS polymerization by voxelotor and support its ongoing clinical evaluation as a potential disease-modifying therapy for both adults and adolescents with SCD,” said Ted W. Love, MD, president and chief executive officer of Global Blood Therapeutics.

“Results to date support our ongoing development of voxelotor in a broad range of patients, including in our phase 3 HOPE study, which is also evaluating voxelotor at doses of 900 mg and 1500 mg per day in adolescents and adults. We continue to expect to announce top-line clinical data from part A of the HOPE study by the end of this quarter.”

Photo courtesy of Janssen

The US Food and Drug Administration (FDA) has accepted for priority review a supplemental new drug application (sNDA) for ibrutinib (Imbruvica®) to be used in combination with rituximab in patients with Waldenström’s macroglobulinemia (WM).

The FDA intends to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

Ibrutinib is a first-in-class Bruton’s tyrosine kinase inhibitor jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

Ibrutinib is already FDA-approved to treat chronic lymphocytic leukemia/small lymphocytic lymphoma, previously treated mantle cell lymphoma, previously treated marginal zone lymphoma, previously treated chronic graft-versus-host disease, and WM.

If the new sNDA is approved, the use of ibrutinib in WM will extend beyond its current approved use as a single agent.

Phase 3 trial

The sNDA for ibrutinib and rituximab in WM is supported by data from the phase 3 iNNOVATE study. Results from this trial were presented at the 2018 ASCO Annual Meeting (abstract 8003) and were simultaneously published in NEJM.

iNNOVATE is a placebo-controlled, double-blind, phase 3 study that enrolled 150 patients with relapsed/refractory and treatment-naïve WM.

All patients received rituximab at 375 mg/m² with weekly infusions at weeks 1 to 4 and 17 to 20. They also received either ibrutinib (420 mg) or placebo once daily continuously until criteria for permanent discontinuation were met.

Overall response rates were significantly higher in the ibrutinib arm than the placebo arm—92% and 47%, respectively (P<0.0001). Complete response rates were 3% and 1%, respectively.

The median time to next treatment was not reached for the ibrutinib arm and was 18 months for the placebo arm (hazard ratio=0.096; P<0.0001). Of the patients randomized to ibrutinib plus rituximab, 75% continued on treatment at last follow-up.

The 30-month progression-free survival rates were 82% in the ibrutinib arm and 28% in the placebo arm. The median progression-free survival was not reached in the ibrutinib arm and was 20.3 months in the placebo arm (hazard ratio=0.20; P<0.0001).

The 30-month overall survival rates were 94% in the ibrutinib arm and 92% in the placebo arm.

Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 60% of patients in the ibrutinib arm and 61% in the placebo arm.

Serious AEs occurred in 43% and 33% of patients, respectively. There were no fatal AEs in the ibrutinib arm and 3 in the rituximab arm.

Grade 3 or higher AEs that occurred more frequently in the ibrutinib arm than the placebo arm included atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%).

AEs that occurred less frequently in the ibrutinib arm than the placebo arm included grade 3 or higher infusion reactions (1% vs 16%) and any-grade IgM flare (8% vs 47%).

Photo courtesy of Janssen

The US Food and Drug Administration (FDA) has accepted for priority review a supplemental new drug application (sNDA) for ibrutinib (Imbruvica®) to be used in combination with rituximab in patients with Waldenström’s macroglobulinemia (WM).

The FDA intends to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

Ibrutinib is a first-in-class Bruton’s tyrosine kinase inhibitor jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

Ibrutinib is already FDA-approved to treat chronic lymphocytic leukemia/small lymphocytic lymphoma, previously treated mantle cell lymphoma, previously treated marginal zone lymphoma, previously treated chronic graft-versus-host disease, and WM.

If the new sNDA is approved, the use of ibrutinib in WM will extend beyond its current approved use as a single agent.

Phase 3 trial

The sNDA for ibrutinib and rituximab in WM is supported by data from the phase 3 iNNOVATE study. Results from this trial were presented at the 2018 ASCO Annual Meeting (abstract 8003) and were simultaneously published in NEJM.

iNNOVATE is a placebo-controlled, double-blind, phase 3 study that enrolled 150 patients with relapsed/refractory and treatment-naïve WM.

All patients received rituximab at 375 mg/m² with weekly infusions at weeks 1 to 4 and 17 to 20. They also received either ibrutinib (420 mg) or placebo once daily continuously until criteria for permanent discontinuation were met.

Overall response rates were significantly higher in the ibrutinib arm than the placebo arm—92% and 47%, respectively (P<0.0001). Complete response rates were 3% and 1%, respectively.

The median time to next treatment was not reached for the ibrutinib arm and was 18 months for the placebo arm (hazard ratio=0.096; P<0.0001). Of the patients randomized to ibrutinib plus rituximab, 75% continued on treatment at last follow-up.

The 30-month progression-free survival rates were 82% in the ibrutinib arm and 28% in the placebo arm. The median progression-free survival was not reached in the ibrutinib arm and was 20.3 months in the placebo arm (hazard ratio=0.20; P<0.0001).

The 30-month overall survival rates were 94% in the ibrutinib arm and 92% in the placebo arm.

Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 60% of patients in the ibrutinib arm and 61% in the placebo arm.

Serious AEs occurred in 43% and 33% of patients, respectively. There were no fatal AEs in the ibrutinib arm and 3 in the rituximab arm.

Grade 3 or higher AEs that occurred more frequently in the ibrutinib arm than the placebo arm included atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%).

AEs that occurred less frequently in the ibrutinib arm than the placebo arm included grade 3 or higher infusion reactions (1% vs 16%) and any-grade IgM flare (8% vs 47%).

Photo courtesy of Janssen

The US Food and Drug Administration (FDA) has accepted for priority review a supplemental new drug application (sNDA) for ibrutinib (Imbruvica®) to be used in combination with rituximab in patients with Waldenström’s macroglobulinemia (WM).

The FDA intends to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

Ibrutinib is a first-in-class Bruton’s tyrosine kinase inhibitor jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

Ibrutinib is already FDA-approved to treat chronic lymphocytic leukemia/small lymphocytic lymphoma, previously treated mantle cell lymphoma, previously treated marginal zone lymphoma, previously treated chronic graft-versus-host disease, and WM.

If the new sNDA is approved, the use of ibrutinib in WM will extend beyond its current approved use as a single agent.

Phase 3 trial

The sNDA for ibrutinib and rituximab in WM is supported by data from the phase 3 iNNOVATE study. Results from this trial were presented at the 2018 ASCO Annual Meeting (abstract 8003) and were simultaneously published in NEJM.

iNNOVATE is a placebo-controlled, double-blind, phase 3 study that enrolled 150 patients with relapsed/refractory and treatment-naïve WM.

All patients received rituximab at 375 mg/m² with weekly infusions at weeks 1 to 4 and 17 to 20. They also received either ibrutinib (420 mg) or placebo once daily continuously until criteria for permanent discontinuation were met.

Overall response rates were significantly higher in the ibrutinib arm than the placebo arm—92% and 47%, respectively (P<0.0001). Complete response rates were 3% and 1%, respectively.

The median time to next treatment was not reached for the ibrutinib arm and was 18 months for the placebo arm (hazard ratio=0.096; P<0.0001). Of the patients randomized to ibrutinib plus rituximab, 75% continued on treatment at last follow-up.

The 30-month progression-free survival rates were 82% in the ibrutinib arm and 28% in the placebo arm. The median progression-free survival was not reached in the ibrutinib arm and was 20.3 months in the placebo arm (hazard ratio=0.20; P<0.0001).

The 30-month overall survival rates were 94% in the ibrutinib arm and 92% in the placebo arm.

Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 60% of patients in the ibrutinib arm and 61% in the placebo arm.

Serious AEs occurred in 43% and 33% of patients, respectively. There were no fatal AEs in the ibrutinib arm and 3 in the rituximab arm.

Grade 3 or higher AEs that occurred more frequently in the ibrutinib arm than the placebo arm included atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%).

AEs that occurred less frequently in the ibrutinib arm than the placebo arm included grade 3 or higher infusion reactions (1% vs 16%) and any-grade IgM flare (8% vs 47%).