The National Comprehensive Cancer Network (NCCN) has issued its first-ever clinical practice guidelines for the treatment of gestational trophoblastic neoplasia (GTN), a rare, serious complication of pregnancy that can often be cured, but can have devastating consequences if mismanaged or if treatment is needlessly delayed.

David Mutch, MD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, who heads the NCCN Clinical Practice Guidelines in Oncology Committee for GTN, explained the critical importance of the GTN guidelines.

“It’s a rare disease, people weren’t that familiar with it, and they often are patients treated with single-agent therapy when they should be treated with multi-agent therapy,” he said in an interview.

“There wasn’t a clear understanding of what to do except by those people who treated these patients regularly. The only thing most people knew was that it was very chemosensitive and should be curable, but it’s only curable if you follow the appropriate algorithms,” he continued.

The algorithms he referred to were established by a handful of centers with expertise and experience in diagnosing and treating these rare conditions, including noninvasive hydatidiform mole, invasive mole, and choriocarcinoma, the most aggressive form of GTN.

Neil Horowitz, MD, director of clinical research in gynecologic oncology at the Dana-Farber Cancer Institute in Boston, works with colleagues in one of those referral centers, the New England Trophoblastic Disease Center, and is familiar with the new guidelines. As with other rare malignancies, there are data to suggest that patients with GTN who are treated in centers of excellence with higher patient volumes have better outcomes than do similar patients treated in a community setting, he said in an interview.
 

Placental origins

GTNs arise from placental rather than maternal tissue. They most commonly present with vaginal bleeding and a rapidly enlarging uterus, and may be accompanied by pelvic pain or pressure, anemia, severe nausea/vomiting (hyperemesis gravidarum), hyperthyroidism, or early-pregnancy preeclampsia.

The overall reported incidence of GTN in the United States, including hydatidiform mole, is approximately 110 to 120 per 100,000 pregnancies, and the reported incidence of choriocarcinoma is about 2 to 7 per 100,000, according to the National Cancer Institute.

The GTN guidelines provide evidence-based recommendations about optimal approaches to GTN in all of its known forms. For example, the section on noninvasive hydatidiform mole recommends the tests that should be routinely performed during workup, followed by surgery with either suction, dilation and curettage – preferably under ultrasound guidance – or hysterectomy for women who are older or who do not wish to preserve fertility.

The guidelines also specify steps that should be taken for diagnosis and staging of GTN as well as risk-based therapeutic approaches.

For example, the guidelines recommend therapy with either methotrexate alone or alternating with leucovorin, or dactinomycin alone for patients with confirmed low risk GTN, defined as a prognostic score less than 7.

The prognostic scoring index, also included in the guidelines, considers risk factors such as age, prior pregnancies, interval from an index pregnancy, pretreatment human chorionic gonadotropin (hCG) levels, site and number of metastases, largest tumor size, and previous chemotherapy failure.

For patients with high-risk GTN, defined as FIGO (Fédération Internationale de Gynécologie et d’Obstétrique) stages II-III with a prognostic score of 7 or greater, or FIGO stage IV, chemotherapy with the EMA/CO regimen is recommended. This aggressive regimen consists of etoposide, methotrexate, dactinomycin (the “EMA “component) plus cyclophosphamide and vincristine (the “CO” component).

“In my mind, the most important part of the guidelines is reiterating how the diagnosis of GTN should be made, and importantly, how the score should be calculated so that women are put in the appropriate low-risk or high-risk category, so they get the right treatment,” Dr. Horowitz said.
 

Reassuring insurers

Dr. Mutch said that he and his colleagues in GTN centers sometimes treat patients with intermediate or high-risk disease who were started on single-agent therapy or suboptimal therapies and present with advanced, drug-resistant disease.

“These guidelines were established so that people could see exactly what needs to be done when,” he said.

The guidelines also are critical for convincing third-party payers about the need for specific treatments, he added.

“I had a high-risk patient who needed EMA/CO, and the insurance company said ‘well, there’s no NCCN guidelines – we won’t approve it.’ So then I had to wait 3 days while it went through peer review. Meanwhile, the tumor doubled in size, and then the nurse who was reviewing it declined the ‘CO’ part, so that was delayed a week, and it really jeopardized this patient’s survival,” Dr. Mutch said.

The guidelines also include recommendations for patients with special clinical situations, such as women with clinical responses to EMA/CO who continue to have plateauing low levels of hCG or have a re-elevation of hCG levels after having a complete response to EMA/CO.

There are also specific recommendations for treatment of two even rarer intermediate trophoblastic tumor types: placental-site trophoblastic tumor and epithelioid trophoblastic tumor.

The guidelines are supported by the NCCN. Dr. Mutch reported consulting/advisory board participation for Clovis. Dr. Horowitz reported having no relationships to disclose.

SOURCE: Gestational Trophoblastic Neoplasia. NCCN.org, Version 1.2019, published Aug. 9, 2018.

The National Comprehensive Cancer Network (NCCN) has issued its first-ever clinical practice guidelines for the treatment of gestational trophoblastic neoplasia (GTN), a rare, serious complication of pregnancy that can often be cured, but can have devastating consequences if mismanaged or if treatment is needlessly delayed.

David Mutch, MD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, who heads the NCCN Clinical Practice Guidelines in Oncology Committee for GTN, explained the critical importance of the GTN guidelines.

“It’s a rare disease, people weren’t that familiar with it, and they often are patients treated with single-agent therapy when they should be treated with multi-agent therapy,” he said in an interview.

“There wasn’t a clear understanding of what to do except by those people who treated these patients regularly. The only thing most people knew was that it was very chemosensitive and should be curable, but it’s only curable if you follow the appropriate algorithms,” he continued.

The algorithms he referred to were established by a handful of centers with expertise and experience in diagnosing and treating these rare conditions, including noninvasive hydatidiform mole, invasive mole, and choriocarcinoma, the most aggressive form of GTN.

Neil Horowitz, MD, director of clinical research in gynecologic oncology at the Dana-Farber Cancer Institute in Boston, works with colleagues in one of those referral centers, the New England Trophoblastic Disease Center, and is familiar with the new guidelines. As with other rare malignancies, there are data to suggest that patients with GTN who are treated in centers of excellence with higher patient volumes have better outcomes than do similar patients treated in a community setting, he said in an interview.
 

Placental origins

GTNs arise from placental rather than maternal tissue. They most commonly present with vaginal bleeding and a rapidly enlarging uterus, and may be accompanied by pelvic pain or pressure, anemia, severe nausea/vomiting (hyperemesis gravidarum), hyperthyroidism, or early-pregnancy preeclampsia.

The overall reported incidence of GTN in the United States, including hydatidiform mole, is approximately 110 to 120 per 100,000 pregnancies, and the reported incidence of choriocarcinoma is about 2 to 7 per 100,000, according to the National Cancer Institute.

The GTN guidelines provide evidence-based recommendations about optimal approaches to GTN in all of its known forms. For example, the section on noninvasive hydatidiform mole recommends the tests that should be routinely performed during workup, followed by surgery with either suction, dilation and curettage – preferably under ultrasound guidance – or hysterectomy for women who are older or who do not wish to preserve fertility.

The guidelines also specify steps that should be taken for diagnosis and staging of GTN as well as risk-based therapeutic approaches.

For example, the guidelines recommend therapy with either methotrexate alone or alternating with leucovorin, or dactinomycin alone for patients with confirmed low risk GTN, defined as a prognostic score less than 7.

The prognostic scoring index, also included in the guidelines, considers risk factors such as age, prior pregnancies, interval from an index pregnancy, pretreatment human chorionic gonadotropin (hCG) levels, site and number of metastases, largest tumor size, and previous chemotherapy failure.

For patients with high-risk GTN, defined as FIGO (Fédération Internationale de Gynécologie et d’Obstétrique) stages II-III with a prognostic score of 7 or greater, or FIGO stage IV, chemotherapy with the EMA/CO regimen is recommended. This aggressive regimen consists of etoposide, methotrexate, dactinomycin (the “EMA “component) plus cyclophosphamide and vincristine (the “CO” component).

“In my mind, the most important part of the guidelines is reiterating how the diagnosis of GTN should be made, and importantly, how the score should be calculated so that women are put in the appropriate low-risk or high-risk category, so they get the right treatment,” Dr. Horowitz said.
 

Reassuring insurers

Dr. Mutch said that he and his colleagues in GTN centers sometimes treat patients with intermediate or high-risk disease who were started on single-agent therapy or suboptimal therapies and present with advanced, drug-resistant disease.

“These guidelines were established so that people could see exactly what needs to be done when,” he said.

The guidelines also are critical for convincing third-party payers about the need for specific treatments, he added.

“I had a high-risk patient who needed EMA/CO, and the insurance company said ‘well, there’s no NCCN guidelines – we won’t approve it.’ So then I had to wait 3 days while it went through peer review. Meanwhile, the tumor doubled in size, and then the nurse who was reviewing it declined the ‘CO’ part, so that was delayed a week, and it really jeopardized this patient’s survival,” Dr. Mutch said.

The guidelines also include recommendations for patients with special clinical situations, such as women with clinical responses to EMA/CO who continue to have plateauing low levels of hCG or have a re-elevation of hCG levels after having a complete response to EMA/CO.

There are also specific recommendations for treatment of two even rarer intermediate trophoblastic tumor types: placental-site trophoblastic tumor and epithelioid trophoblastic tumor.

The guidelines are supported by the NCCN. Dr. Mutch reported consulting/advisory board participation for Clovis. Dr. Horowitz reported having no relationships to disclose.

SOURCE: Gestational Trophoblastic Neoplasia. NCCN.org, Version 1.2019, published Aug. 9, 2018.

The National Comprehensive Cancer Network (NCCN) has issued its first-ever clinical practice guidelines for the treatment of gestational trophoblastic neoplasia (GTN), a rare, serious complication of pregnancy that can often be cured, but can have devastating consequences if mismanaged or if treatment is needlessly delayed.

David Mutch, MD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, who heads the NCCN Clinical Practice Guidelines in Oncology Committee for GTN, explained the critical importance of the GTN guidelines.

“It’s a rare disease, people weren’t that familiar with it, and they often are patients treated with single-agent therapy when they should be treated with multi-agent therapy,” he said in an interview.

“There wasn’t a clear understanding of what to do except by those people who treated these patients regularly. The only thing most people knew was that it was very chemosensitive and should be curable, but it’s only curable if you follow the appropriate algorithms,” he continued.

The algorithms he referred to were established by a handful of centers with expertise and experience in diagnosing and treating these rare conditions, including noninvasive hydatidiform mole, invasive mole, and choriocarcinoma, the most aggressive form of GTN.

Neil Horowitz, MD, director of clinical research in gynecologic oncology at the Dana-Farber Cancer Institute in Boston, works with colleagues in one of those referral centers, the New England Trophoblastic Disease Center, and is familiar with the new guidelines. As with other rare malignancies, there are data to suggest that patients with GTN who are treated in centers of excellence with higher patient volumes have better outcomes than do similar patients treated in a community setting, he said in an interview.
 

Placental origins

GTNs arise from placental rather than maternal tissue. They most commonly present with vaginal bleeding and a rapidly enlarging uterus, and may be accompanied by pelvic pain or pressure, anemia, severe nausea/vomiting (hyperemesis gravidarum), hyperthyroidism, or early-pregnancy preeclampsia.

The overall reported incidence of GTN in the United States, including hydatidiform mole, is approximately 110 to 120 per 100,000 pregnancies, and the reported incidence of choriocarcinoma is about 2 to 7 per 100,000, according to the National Cancer Institute.

The GTN guidelines provide evidence-based recommendations about optimal approaches to GTN in all of its known forms. For example, the section on noninvasive hydatidiform mole recommends the tests that should be routinely performed during workup, followed by surgery with either suction, dilation and curettage – preferably under ultrasound guidance – or hysterectomy for women who are older or who do not wish to preserve fertility.

The guidelines also specify steps that should be taken for diagnosis and staging of GTN as well as risk-based therapeutic approaches.

For example, the guidelines recommend therapy with either methotrexate alone or alternating with leucovorin, or dactinomycin alone for patients with confirmed low risk GTN, defined as a prognostic score less than 7.

The prognostic scoring index, also included in the guidelines, considers risk factors such as age, prior pregnancies, interval from an index pregnancy, pretreatment human chorionic gonadotropin (hCG) levels, site and number of metastases, largest tumor size, and previous chemotherapy failure.

For patients with high-risk GTN, defined as FIGO (Fédération Internationale de Gynécologie et d’Obstétrique) stages II-III with a prognostic score of 7 or greater, or FIGO stage IV, chemotherapy with the EMA/CO regimen is recommended. This aggressive regimen consists of etoposide, methotrexate, dactinomycin (the “EMA “component) plus cyclophosphamide and vincristine (the “CO” component).

“In my mind, the most important part of the guidelines is reiterating how the diagnosis of GTN should be made, and importantly, how the score should be calculated so that women are put in the appropriate low-risk or high-risk category, so they get the right treatment,” Dr. Horowitz said.
 

Reassuring insurers

Dr. Mutch said that he and his colleagues in GTN centers sometimes treat patients with intermediate or high-risk disease who were started on single-agent therapy or suboptimal therapies and present with advanced, drug-resistant disease.

“These guidelines were established so that people could see exactly what needs to be done when,” he said.

The guidelines also are critical for convincing third-party payers about the need for specific treatments, he added.

“I had a high-risk patient who needed EMA/CO, and the insurance company said ‘well, there’s no NCCN guidelines – we won’t approve it.’ So then I had to wait 3 days while it went through peer review. Meanwhile, the tumor doubled in size, and then the nurse who was reviewing it declined the ‘CO’ part, so that was delayed a week, and it really jeopardized this patient’s survival,” Dr. Mutch said.

The guidelines also include recommendations for patients with special clinical situations, such as women with clinical responses to EMA/CO who continue to have plateauing low levels of hCG or have a re-elevation of hCG levels after having a complete response to EMA/CO.

There are also specific recommendations for treatment of two even rarer intermediate trophoblastic tumor types: placental-site trophoblastic tumor and epithelioid trophoblastic tumor.

The guidelines are supported by the NCCN. Dr. Mutch reported consulting/advisory board participation for Clovis. Dr. Horowitz reported having no relationships to disclose.

SOURCE: Gestational Trophoblastic Neoplasia. NCCN.org, Version 1.2019, published Aug. 9, 2018.

University Hospitals Seidman Cancer Center in Cleveland has launched a phase 1 clinical trial to study the safety of CAR T therapy for non-Hodgkin lymphoma.

The trial will enroll 12-15 adult patients with non-Hodgkin lymphoma who have not responded to standard therapies, according to a statement from University Hospitals Seidman Cancer Center.

The principal investigator for the trial will be Paolo Caimi, MD, of UH Seidman and Case Western Reserve University.

UH Seidman, affiliated with Case Western Reserve University, is one of a handful of centers that has the ability to manufacture the CAR T cells from the patient’s own genetically modified T cells on site in the shared Case Western Reserve University National Center for Regenerative Medicine and the UH Seidman Cellular Therapy Laboratory, saving time for patients.

“Having the ability to make cells on-site means there will be a shorter turnaround time in having the cells available for the patient, compared to shipping them off-site,” said Dr. Caimi in the press statement.

[email protected]

University Hospitals Seidman Cancer Center in Cleveland has launched a phase 1 clinical trial to study the safety of CAR T therapy for non-Hodgkin lymphoma.

The trial will enroll 12-15 adult patients with non-Hodgkin lymphoma who have not responded to standard therapies, according to a statement from University Hospitals Seidman Cancer Center.

The principal investigator for the trial will be Paolo Caimi, MD, of UH Seidman and Case Western Reserve University.

UH Seidman, affiliated with Case Western Reserve University, is one of a handful of centers that has the ability to manufacture the CAR T cells from the patient’s own genetically modified T cells on site in the shared Case Western Reserve University National Center for Regenerative Medicine and the UH Seidman Cellular Therapy Laboratory, saving time for patients.

“Having the ability to make cells on-site means there will be a shorter turnaround time in having the cells available for the patient, compared to shipping them off-site,” said Dr. Caimi in the press statement.

[email protected]

University Hospitals Seidman Cancer Center in Cleveland has launched a phase 1 clinical trial to study the safety of CAR T therapy for non-Hodgkin lymphoma.

The trial will enroll 12-15 adult patients with non-Hodgkin lymphoma who have not responded to standard therapies, according to a statement from University Hospitals Seidman Cancer Center.

The principal investigator for the trial will be Paolo Caimi, MD, of UH Seidman and Case Western Reserve University.

UH Seidman, affiliated with Case Western Reserve University, is one of a handful of centers that has the ability to manufacture the CAR T cells from the patient’s own genetically modified T cells on site in the shared Case Western Reserve University National Center for Regenerative Medicine and the UH Seidman Cellular Therapy Laboratory, saving time for patients.

“Having the ability to make cells on-site means there will be a shorter turnaround time in having the cells available for the patient, compared to shipping them off-site,” said Dr. Caimi in the press statement.

[email protected]

David Henry, MD, the Editor-in-Chief of  The Journal of Community and Supportive Oncology, shares his top selections in hematology and bone health from this year's line-up of abstracts at the annual meeting of the American Society of Clinical Oncology in Chicago.

8004 Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed refractory myeloma (Luciano J Costa et al). Of 17 patients evaluated after completing at least two cycles of therapy, 3 had complete responses, 2 had very good partial response, 3 had partial response, 3 experienced stable disease, and 2 had progressive disease (response data for 4 patients still to come). The study drug combination was well tolerated, and phase 3 trial is planned.

8008 FDA analysis of pembrolizumab trials in multiple myeloma: immune-related adverse events and response (Aviva C Krauss et al). An evaluation of the KEYNOTE-183 and KEYNOTE-185 trials of nearly 250 patients showed no significant myeloma response with pembrolizumab compared with the control arm of pomalidomide+dexamethasone. 

10113 Prospsective phase II pilot study to evaluate the use of intravenous iron in the treatment of anemia in cancer patients (Youjin Kim et al). IV iron supplementation alone showed encouraging results in improving anemia, with hepcidin level possibly predicting response to IV iron and may be superior to the TSAT test.

500 Adjuvant denosumab in early breast cancer: disease free survival analysis of postmenopausal patients in the ABCSG-18 trial (Michael Gnant et al). In this double-blind placebo controlled trial, disease-free survival in the denosumab group was 89% at 5 years and 80% at 8 years, compared with 87% and 77%, respectively, for placebo.

David Henry, MD, the Editor-in-Chief of  The Journal of Community and Supportive Oncology, shares his top selections in hematology and bone health from this year's line-up of abstracts at the annual meeting of the American Society of Clinical Oncology in Chicago.

8004 Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed refractory myeloma (Luciano J Costa et al). Of 17 patients evaluated after completing at least two cycles of therapy, 3 had complete responses, 2 had very good partial response, 3 had partial response, 3 experienced stable disease, and 2 had progressive disease (response data for 4 patients still to come). The study drug combination was well tolerated, and phase 3 trial is planned.

8008 FDA analysis of pembrolizumab trials in multiple myeloma: immune-related adverse events and response (Aviva C Krauss et al). An evaluation of the KEYNOTE-183 and KEYNOTE-185 trials of nearly 250 patients showed no significant myeloma response with pembrolizumab compared with the control arm of pomalidomide+dexamethasone. 

10113 Prospsective phase II pilot study to evaluate the use of intravenous iron in the treatment of anemia in cancer patients (Youjin Kim et al). IV iron supplementation alone showed encouraging results in improving anemia, with hepcidin level possibly predicting response to IV iron and may be superior to the TSAT test.

500 Adjuvant denosumab in early breast cancer: disease free survival analysis of postmenopausal patients in the ABCSG-18 trial (Michael Gnant et al). In this double-blind placebo controlled trial, disease-free survival in the denosumab group was 89% at 5 years and 80% at 8 years, compared with 87% and 77%, respectively, for placebo.

David Henry, MD, the Editor-in-Chief of  The Journal of Community and Supportive Oncology, shares his top selections in hematology and bone health from this year's line-up of abstracts at the annual meeting of the American Society of Clinical Oncology in Chicago.

8004 Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed refractory myeloma (Luciano J Costa et al). Of 17 patients evaluated after completing at least two cycles of therapy, 3 had complete responses, 2 had very good partial response, 3 had partial response, 3 experienced stable disease, and 2 had progressive disease (response data for 4 patients still to come). The study drug combination was well tolerated, and phase 3 trial is planned.

8008 FDA analysis of pembrolizumab trials in multiple myeloma: immune-related adverse events and response (Aviva C Krauss et al). An evaluation of the KEYNOTE-183 and KEYNOTE-185 trials of nearly 250 patients showed no significant myeloma response with pembrolizumab compared with the control arm of pomalidomide+dexamethasone. 

10113 Prospsective phase II pilot study to evaluate the use of intravenous iron in the treatment of anemia in cancer patients (Youjin Kim et al). IV iron supplementation alone showed encouraging results in improving anemia, with hepcidin level possibly predicting response to IV iron and may be superior to the TSAT test.

500 Adjuvant denosumab in early breast cancer: disease free survival analysis of postmenopausal patients in the ABCSG-18 trial (Michael Gnant et al). In this double-blind placebo controlled trial, disease-free survival in the denosumab group was 89% at 5 years and 80% at 8 years, compared with 87% and 77%, respectively, for placebo.

In this interview, Dr David Henry, the Editor-in-Chief of The Journal of Community and Supportive Oncology, and Dr Ken Anderson, the Kraft Family Professor of Medicine at Harvard Medical School and an international thought leader and investigator in myeloma, discuss three cases of patients with myeloma that are indicative of the remarkable therapeutic advances in oncology in general, and in myeloma in particular. 

Listen to the podcast below

In this interview, Dr David Henry, the Editor-in-Chief of The Journal of Community and Supportive Oncology, and Dr Ken Anderson, the Kraft Family Professor of Medicine at Harvard Medical School and an international thought leader and investigator in myeloma, discuss three cases of patients with myeloma that are indicative of the remarkable therapeutic advances in oncology in general, and in myeloma in particular. 

Listen to the podcast below

In this interview, Dr David Henry, the Editor-in-Chief of The Journal of Community and Supportive Oncology, and Dr Ken Anderson, the Kraft Family Professor of Medicine at Harvard Medical School and an international thought leader and investigator in myeloma, discuss three cases of patients with myeloma that are indicative of the remarkable therapeutic advances in oncology in general, and in myeloma in particular. 

Listen to the podcast below

There were a number of landmark approvals by the US Food and Drug Administration (FDA) in 2017 for cancer therapies, among them, the approval of the first two chimeric antigen receptor (CAR) T-cell therapies for cancer: tisagenlecleucel (in August) and axicabtagene ciloluecel (in October).¹ CAR T-cells are a type of adoptive cell therapy or immunotherapy, in which the patient’s own immune cells are genetically engineered to target a tumor-associated antigen, in this case CD19. In tisagenlecleucel, CD19 proteins on B cells are targeted in the treatment of B-cell precursor acute lymphoblastic leukemia. Axicabtagene ciloluecel, the second anti-CD19 CAR T-cell therapy, was approved for the treatment of refractory, aggressive B-cell non-Hodgkin lymphoma.

Tisagenlecleucel

Tisagenlecleucel was approved for the treatment of pediatric patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) whose disease is refractory to treatment or who have relapsed after second-line therapy or beyond.² Approval was based on the pivotal ELIANA trial, a single-arm, global phase 2 trial conducted at 25 centers worldwide during April 2015 through April 2017. Patients were eligible for enrollment if they had relapsed or refractory B-cell ALL and were at least 3 years of age at screening and no older than 21 years of age at diagnosis, had at least 5% lymphoblasts in the bone marrow at screening, had tumor expression of CD19, had adequate organ function, and a Karnofsky (adult) or Lansky (child) Performance Status of ≥50 (with the worst allowable score, 50, indicating a patient who requires considerable assistance and frequent medical care [Karnofsky] and lying around much of the day, but gets dressed; no active playing but participates in all quiet play and activities [Lansky]). Exclusion criteria included previous receipt of anti-CD19 therapy, concomitant genetic syndromes associated with bone marrow failure, previous malignancy, and/or active or latent hepatitis B or C virus (HBV/HCV) infection.

The overall remission rate (ORR) was evaluated in 75 patients who were given a single dose of tisagenlecleucel (a median weight-adjusted dose of 3.1 x 10⁶ transduced viable T cells per kg of body weight) within 14 days of completing a lymphodepleting chemotherapy regimen. The confirmed ORR after at least 3 months of follow-up, as assessed by independent central review, was 81%, which included 60% of patients in complete remission (CR) and 21% in complete remission with incomplete hematologic recovery, all of whom were negative for minimal residual disease.

The most common adverse events (AEs) associated with tisagenlecleucel treatment were cytokine release syndrome (CRS), hypogammaglobulinemia, infection, pyrexia, decreased appetite, headache, encephalopathy, hypotension, bleeding episodes, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, fatigue, acute kidney injury, and delirium. AEs were of grade 3/4 severity in 84% of patients.³

To combat serious safety issues, including CRS and neurologic toxicities, the FDA approved tisagenlecleucel with a Risk Evaluation and Mitigation Strategy (REMS) that, in part, requires health care providers who administer the drug to be trained in their management. It also requires the facility where treatment is administered to have immediate, onsite access to the drug tocilizumab, which was approved in conjunction with tisagenlecleucel for the treatment of patients who experience CRS.

In addition to information about the REMS, the prescribing information details warnings and precautions relating to several other common toxicities. These include hypersensitivity reactions, serious infections, prolonged cytopenias, and hypogammaglobulinemia.

Patients should be monitored for signs and symptoms of infection and treated appropriately. Viral reactivation can occur after tisagenlecleucel treatment, so patients should be screened for HBV, HCV, and human immunodeficiency virus before collection of cells.

The administration of myeloid growth factors is not recommended during the first 3 weeks after infusion or until CRS has resolved. Immunoglobulin levels should be monitored after treatment and hypogammaglobulinemia managed using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement according to standard guidelines.

Patients treated with tisagenlecleucel should also be monitored for life for secondary malignancies, should not be treated with live vaccines from 2 weeks before the start of lymphodepleting chemotherapy until immune recovery after tisagenlecleucel infusion, and should be aware of the potential for neurological events to impact their ability to drive and use dangerous machinery.⁴

Tisagenlecleucel is marketed as Kymriah by Novartis Pharmaceuticals. The recommended dose is 1 infusion of 0.2-5 x 10⁶ CAR-positive viable T cells per kilogram of body weight intravenously (for patients ≤50kg) and 0.1-2.5 x 10⁸ cells/kg (for patients >50kg), administered 2-14 days after lymphodepleting chemotherapy.

Axicabtagene ciloleucel

Axicabtagene ciloleucel was approved for the treatment of adult patients with certain types of relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.⁵ It is not indicated for the treatment of patients with primary central nervous system lymphoma.

Approval followed positive results from the phase 2 single-arm, multicenter ZUMA-1 trial.⁶ Patients were included if they were aged 18 years of age and older, had histologically confirmed aggressive B-cell non-Hodgkin lymphoma that was chemotherapy refractory, had received adequate previous therapy, had at least 1 measurable lesion, had completed radiation or systemic therapy at least 2 weeks before, had resolved toxicities related to previous therapy, and had an Eastern Cooperative Oncology Group Performance Status of 0 (asymptomatic) or 1 (symptomatic), an absolute neutrophil count of ≥1000/µL, a platelet count of ≥50,000/µL, and adequate hepatic, renal and cardiac function. They were treated with a single infusion of axicabtagene ciloleucel after lymphodepleting chemotherapy.

Patients who had received previous CD19-targeted therapy, who had concomitant genetic syndromes associated with bone marrow failure, who had previous malignancy, and who had active or latent HBV/HCV infection were among those excluded from the study.

Patients were enrolled in 2 cohorts; those with DLBCL (n = 77) and those with PMBCL or transformed follicular lymphoma (n = 24). The primary endpoint was objective response rate, and after a primary analysis at a minimum of 6 months follow-up, the objective response rate was 82%, with a CR rate of 52%. Among patients who achieved CR, the median duration of response was not reached after a median follow-up of 7.9 months.

A subsequent updated analysis was performed when 108 patients had been followed for a minimum of 1 year. The objective response rate was 82%, and the CR rate was 58%, with some patients having CR in the absence of additional therapies as late as 15 months after treatment. At this updated analysis, 42% of patients continued to have a response, 40% of whom remained in CR.

The most common grade 3 or higher AEs included febrile neutropenia, fever, CRS, encephalopathy, infections, hypotension, and hypoxia. Serious AEs occurred in 52% of patients and included CRS, neurologic toxicity, prolonged cytopenias, and serious infections. Grade 3 or higher CRS or neurologic toxicities occurred in 13% and 28% of patients, respectively. Three patients died during treatment.

To mitigate the risk of CRS and neurologic toxicity, axicabtagene ciloleucel is approved with an REMS that requires appropriate certification and training before hospitals are cleared to administer the therapy.

Other warnings and precautions in the prescribing information relate to serious infections (monitor for signs and symptoms and treat appropriately), prolonged cytopenias (monitor blood counts), hypogammaglobulinemia (monitor immunoglobulin levels and manage appropriately), secondary malignancies (life-long monitoring), and the potential effects of neurologic events on a patient’s ability to drive and operate dangerous machinery (avoid for at least 8 weeks after infusion).⁷

Axicabtagene ciloleucel is marketed as Yescarta by Kite Pharma Inc. The recommended dose is a single intravenous infusion with a target of 2 x 10⁶ CAR-positive viable T cells per kilogram of body weight, preceded by fludarabine and cyclophosphamide lymphodepleting chemotherapy.

There were a number of landmark approvals by the US Food and Drug Administration (FDA) in 2017 for cancer therapies, among them, the approval of the first two chimeric antigen receptor (CAR) T-cell therapies for cancer: tisagenlecleucel (in August) and axicabtagene ciloluecel (in October).¹ CAR T-cells are a type of adoptive cell therapy or immunotherapy, in which the patient’s own immune cells are genetically engineered to target a tumor-associated antigen, in this case CD19. In tisagenlecleucel, CD19 proteins on B cells are targeted in the treatment of B-cell precursor acute lymphoblastic leukemia. Axicabtagene ciloluecel, the second anti-CD19 CAR T-cell therapy, was approved for the treatment of refractory, aggressive B-cell non-Hodgkin lymphoma.

Tisagenlecleucel

Tisagenlecleucel was approved for the treatment of pediatric patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) whose disease is refractory to treatment or who have relapsed after second-line therapy or beyond.² Approval was based on the pivotal ELIANA trial, a single-arm, global phase 2 trial conducted at 25 centers worldwide during April 2015 through April 2017. Patients were eligible for enrollment if they had relapsed or refractory B-cell ALL and were at least 3 years of age at screening and no older than 21 years of age at diagnosis, had at least 5% lymphoblasts in the bone marrow at screening, had tumor expression of CD19, had adequate organ function, and a Karnofsky (adult) or Lansky (child) Performance Status of ≥50 (with the worst allowable score, 50, indicating a patient who requires considerable assistance and frequent medical care [Karnofsky] and lying around much of the day, but gets dressed; no active playing but participates in all quiet play and activities [Lansky]). Exclusion criteria included previous receipt of anti-CD19 therapy, concomitant genetic syndromes associated with bone marrow failure, previous malignancy, and/or active or latent hepatitis B or C virus (HBV/HCV) infection.

The overall remission rate (ORR) was evaluated in 75 patients who were given a single dose of tisagenlecleucel (a median weight-adjusted dose of 3.1 x 10⁶ transduced viable T cells per kg of body weight) within 14 days of completing a lymphodepleting chemotherapy regimen. The confirmed ORR after at least 3 months of follow-up, as assessed by independent central review, was 81%, which included 60% of patients in complete remission (CR) and 21% in complete remission with incomplete hematologic recovery, all of whom were negative for minimal residual disease.

The most common adverse events (AEs) associated with tisagenlecleucel treatment were cytokine release syndrome (CRS), hypogammaglobulinemia, infection, pyrexia, decreased appetite, headache, encephalopathy, hypotension, bleeding episodes, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, fatigue, acute kidney injury, and delirium. AEs were of grade 3/4 severity in 84% of patients.³

To combat serious safety issues, including CRS and neurologic toxicities, the FDA approved tisagenlecleucel with a Risk Evaluation and Mitigation Strategy (REMS) that, in part, requires health care providers who administer the drug to be trained in their management. It also requires the facility where treatment is administered to have immediate, onsite access to the drug tocilizumab, which was approved in conjunction with tisagenlecleucel for the treatment of patients who experience CRS.

In addition to information about the REMS, the prescribing information details warnings and precautions relating to several other common toxicities. These include hypersensitivity reactions, serious infections, prolonged cytopenias, and hypogammaglobulinemia.

Patients should be monitored for signs and symptoms of infection and treated appropriately. Viral reactivation can occur after tisagenlecleucel treatment, so patients should be screened for HBV, HCV, and human immunodeficiency virus before collection of cells.

The administration of myeloid growth factors is not recommended during the first 3 weeks after infusion or until CRS has resolved. Immunoglobulin levels should be monitored after treatment and hypogammaglobulinemia managed using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement according to standard guidelines.

Patients treated with tisagenlecleucel should also be monitored for life for secondary malignancies, should not be treated with live vaccines from 2 weeks before the start of lymphodepleting chemotherapy until immune recovery after tisagenlecleucel infusion, and should be aware of the potential for neurological events to impact their ability to drive and use dangerous machinery.⁴

Tisagenlecleucel is marketed as Kymriah by Novartis Pharmaceuticals. The recommended dose is 1 infusion of 0.2-5 x 10⁶ CAR-positive viable T cells per kilogram of body weight intravenously (for patients ≤50kg) and 0.1-2.5 x 10⁸ cells/kg (for patients >50kg), administered 2-14 days after lymphodepleting chemotherapy.

Axicabtagene ciloleucel

Axicabtagene ciloleucel was approved for the treatment of adult patients with certain types of relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.⁵ It is not indicated for the treatment of patients with primary central nervous system lymphoma.

Approval followed positive results from the phase 2 single-arm, multicenter ZUMA-1 trial.⁶ Patients were included if they were aged 18 years of age and older, had histologically confirmed aggressive B-cell non-Hodgkin lymphoma that was chemotherapy refractory, had received adequate previous therapy, had at least 1 measurable lesion, had completed radiation or systemic therapy at least 2 weeks before, had resolved toxicities related to previous therapy, and had an Eastern Cooperative Oncology Group Performance Status of 0 (asymptomatic) or 1 (symptomatic), an absolute neutrophil count of ≥1000/µL, a platelet count of ≥50,000/µL, and adequate hepatic, renal and cardiac function. They were treated with a single infusion of axicabtagene ciloleucel after lymphodepleting chemotherapy.

Patients who had received previous CD19-targeted therapy, who had concomitant genetic syndromes associated with bone marrow failure, who had previous malignancy, and who had active or latent HBV/HCV infection were among those excluded from the study.

Patients were enrolled in 2 cohorts; those with DLBCL (n = 77) and those with PMBCL or transformed follicular lymphoma (n = 24). The primary endpoint was objective response rate, and after a primary analysis at a minimum of 6 months follow-up, the objective response rate was 82%, with a CR rate of 52%. Among patients who achieved CR, the median duration of response was not reached after a median follow-up of 7.9 months.

A subsequent updated analysis was performed when 108 patients had been followed for a minimum of 1 year. The objective response rate was 82%, and the CR rate was 58%, with some patients having CR in the absence of additional therapies as late as 15 months after treatment. At this updated analysis, 42% of patients continued to have a response, 40% of whom remained in CR.

The most common grade 3 or higher AEs included febrile neutropenia, fever, CRS, encephalopathy, infections, hypotension, and hypoxia. Serious AEs occurred in 52% of patients and included CRS, neurologic toxicity, prolonged cytopenias, and serious infections. Grade 3 or higher CRS or neurologic toxicities occurred in 13% and 28% of patients, respectively. Three patients died during treatment.

To mitigate the risk of CRS and neurologic toxicity, axicabtagene ciloleucel is approved with an REMS that requires appropriate certification and training before hospitals are cleared to administer the therapy.

Other warnings and precautions in the prescribing information relate to serious infections (monitor for signs and symptoms and treat appropriately), prolonged cytopenias (monitor blood counts), hypogammaglobulinemia (monitor immunoglobulin levels and manage appropriately), secondary malignancies (life-long monitoring), and the potential effects of neurologic events on a patient’s ability to drive and operate dangerous machinery (avoid for at least 8 weeks after infusion).⁷

Axicabtagene ciloleucel is marketed as Yescarta by Kite Pharma Inc. The recommended dose is a single intravenous infusion with a target of 2 x 10⁶ CAR-positive viable T cells per kilogram of body weight, preceded by fludarabine and cyclophosphamide lymphodepleting chemotherapy.

There were a number of landmark approvals by the US Food and Drug Administration (FDA) in 2017 for cancer therapies, among them, the approval of the first two chimeric antigen receptor (CAR) T-cell therapies for cancer: tisagenlecleucel (in August) and axicabtagene ciloluecel (in October).¹ CAR T-cells are a type of adoptive cell therapy or immunotherapy, in which the patient’s own immune cells are genetically engineered to target a tumor-associated antigen, in this case CD19. In tisagenlecleucel, CD19 proteins on B cells are targeted in the treatment of B-cell precursor acute lymphoblastic leukemia. Axicabtagene ciloluecel, the second anti-CD19 CAR T-cell therapy, was approved for the treatment of refractory, aggressive B-cell non-Hodgkin lymphoma.

Tisagenlecleucel

Tisagenlecleucel was approved for the treatment of pediatric patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) whose disease is refractory to treatment or who have relapsed after second-line therapy or beyond.² Approval was based on the pivotal ELIANA trial, a single-arm, global phase 2 trial conducted at 25 centers worldwide during April 2015 through April 2017. Patients were eligible for enrollment if they had relapsed or refractory B-cell ALL and were at least 3 years of age at screening and no older than 21 years of age at diagnosis, had at least 5% lymphoblasts in the bone marrow at screening, had tumor expression of CD19, had adequate organ function, and a Karnofsky (adult) or Lansky (child) Performance Status of ≥50 (with the worst allowable score, 50, indicating a patient who requires considerable assistance and frequent medical care [Karnofsky] and lying around much of the day, but gets dressed; no active playing but participates in all quiet play and activities [Lansky]). Exclusion criteria included previous receipt of anti-CD19 therapy, concomitant genetic syndromes associated with bone marrow failure, previous malignancy, and/or active or latent hepatitis B or C virus (HBV/HCV) infection.

The overall remission rate (ORR) was evaluated in 75 patients who were given a single dose of tisagenlecleucel (a median weight-adjusted dose of 3.1 x 10⁶ transduced viable T cells per kg of body weight) within 14 days of completing a lymphodepleting chemotherapy regimen. The confirmed ORR after at least 3 months of follow-up, as assessed by independent central review, was 81%, which included 60% of patients in complete remission (CR) and 21% in complete remission with incomplete hematologic recovery, all of whom were negative for minimal residual disease.

The most common adverse events (AEs) associated with tisagenlecleucel treatment were cytokine release syndrome (CRS), hypogammaglobulinemia, infection, pyrexia, decreased appetite, headache, encephalopathy, hypotension, bleeding episodes, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, fatigue, acute kidney injury, and delirium. AEs were of grade 3/4 severity in 84% of patients.³

To combat serious safety issues, including CRS and neurologic toxicities, the FDA approved tisagenlecleucel with a Risk Evaluation and Mitigation Strategy (REMS) that, in part, requires health care providers who administer the drug to be trained in their management. It also requires the facility where treatment is administered to have immediate, onsite access to the drug tocilizumab, which was approved in conjunction with tisagenlecleucel for the treatment of patients who experience CRS.

In addition to information about the REMS, the prescribing information details warnings and precautions relating to several other common toxicities. These include hypersensitivity reactions, serious infections, prolonged cytopenias, and hypogammaglobulinemia.

Patients should be monitored for signs and symptoms of infection and treated appropriately. Viral reactivation can occur after tisagenlecleucel treatment, so patients should be screened for HBV, HCV, and human immunodeficiency virus before collection of cells.

The administration of myeloid growth factors is not recommended during the first 3 weeks after infusion or until CRS has resolved. Immunoglobulin levels should be monitored after treatment and hypogammaglobulinemia managed using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement according to standard guidelines.

Patients treated with tisagenlecleucel should also be monitored for life for secondary malignancies, should not be treated with live vaccines from 2 weeks before the start of lymphodepleting chemotherapy until immune recovery after tisagenlecleucel infusion, and should be aware of the potential for neurological events to impact their ability to drive and use dangerous machinery.⁴

Tisagenlecleucel is marketed as Kymriah by Novartis Pharmaceuticals. The recommended dose is 1 infusion of 0.2-5 x 10⁶ CAR-positive viable T cells per kilogram of body weight intravenously (for patients ≤50kg) and 0.1-2.5 x 10⁸ cells/kg (for patients >50kg), administered 2-14 days after lymphodepleting chemotherapy.

Axicabtagene ciloleucel

Axicabtagene ciloleucel was approved for the treatment of adult patients with certain types of relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.⁵ It is not indicated for the treatment of patients with primary central nervous system lymphoma.

Approval followed positive results from the phase 2 single-arm, multicenter ZUMA-1 trial.⁶ Patients were included if they were aged 18 years of age and older, had histologically confirmed aggressive B-cell non-Hodgkin lymphoma that was chemotherapy refractory, had received adequate previous therapy, had at least 1 measurable lesion, had completed radiation or systemic therapy at least 2 weeks before, had resolved toxicities related to previous therapy, and had an Eastern Cooperative Oncology Group Performance Status of 0 (asymptomatic) or 1 (symptomatic), an absolute neutrophil count of ≥1000/µL, a platelet count of ≥50,000/µL, and adequate hepatic, renal and cardiac function. They were treated with a single infusion of axicabtagene ciloleucel after lymphodepleting chemotherapy.

Patients who had received previous CD19-targeted therapy, who had concomitant genetic syndromes associated with bone marrow failure, who had previous malignancy, and who had active or latent HBV/HCV infection were among those excluded from the study.

Patients were enrolled in 2 cohorts; those with DLBCL (n = 77) and those with PMBCL or transformed follicular lymphoma (n = 24). The primary endpoint was objective response rate, and after a primary analysis at a minimum of 6 months follow-up, the objective response rate was 82%, with a CR rate of 52%. Among patients who achieved CR, the median duration of response was not reached after a median follow-up of 7.9 months.

A subsequent updated analysis was performed when 108 patients had been followed for a minimum of 1 year. The objective response rate was 82%, and the CR rate was 58%, with some patients having CR in the absence of additional therapies as late as 15 months after treatment. At this updated analysis, 42% of patients continued to have a response, 40% of whom remained in CR.

The most common grade 3 or higher AEs included febrile neutropenia, fever, CRS, encephalopathy, infections, hypotension, and hypoxia. Serious AEs occurred in 52% of patients and included CRS, neurologic toxicity, prolonged cytopenias, and serious infections. Grade 3 or higher CRS or neurologic toxicities occurred in 13% and 28% of patients, respectively. Three patients died during treatment.

To mitigate the risk of CRS and neurologic toxicity, axicabtagene ciloleucel is approved with an REMS that requires appropriate certification and training before hospitals are cleared to administer the therapy.

Other warnings and precautions in the prescribing information relate to serious infections (monitor for signs and symptoms and treat appropriately), prolonged cytopenias (monitor blood counts), hypogammaglobulinemia (monitor immunoglobulin levels and manage appropriately), secondary malignancies (life-long monitoring), and the potential effects of neurologic events on a patient’s ability to drive and operate dangerous machinery (avoid for at least 8 weeks after infusion).⁷

Axicabtagene ciloleucel is marketed as Yescarta by Kite Pharma Inc. The recommended dose is a single intravenous infusion with a target of 2 x 10⁶ CAR-positive viable T cells per kilogram of body weight, preceded by fludarabine and cyclophosphamide lymphodepleting chemotherapy.

Primary cardiac tumors are extremely rare neoplasms with an incidence of less than 0.4%.^1-3 Primary cardiac lymphoma (PCL), the majority of which is non-Hodgkin lymphoma, accounts for around 2% of cardiac tumors and less than 0.5% of extranodal lymphomas.^1,4-6 Primary lymphoma involving cardiac valves has been described in few case reports and small case series owing to its rarity.^7-10 Most cases of PCL present with manifestations of congestive heart failure or cardiac arrhythmias,¹¹ whereas primary valve-associated lymphoma (PV-AL) is usually diagnosed incidentally during valve repair or replacement. The pathophysiology remains unclear, but a few cases have been associated with Epstein Barr virus (EBV).⁷ Cases previously described in the literature carried an overall poor prognosis and to date there is no standardized treatment approach. We provide here an unusual case of primary prosthetic valve-associated cardiac large B-cell lymphoma, which was successfully treated with adjuvant chemotherapy after valve repair and which resulted in an excellent long-term outcome.

Case presentation and summary

The patient presented in 2012 as a 65-year-old man with a history of ascending aortic aneurysm with secondary aortic insufficiency who in 2004 had undergone composite valve replacement of the aortic valve (AV) root and ascending aorta with a St Jude Toronto root. In June 2011, he was found to have a right parietal intraparenchymal hemorrhage that was thought to be a thromboembolic hemorrhagic ischemic stroke. In March 2012, he had routine follow-up brain magnetic resonance imaging that incidentally showed a left frontal ischemic stroke with hemorrhagic conversion. In June 2012, he was found to have first degree atrioventricular block with episodic runs of supraventricular tachycardia.

In September 2012, transthoracic echocardiography was done for further evaluation of possible recurrent cryptogenic strokes. The results showed a hypo-echogenic mass within the proximal ascending aortic root, but this was not confirmed on transesophageal echocardiography. A chest computed-tomography (CT) scan was therefore performed, and it showed aneurysmal dilatation of the aortic root with an irregular marginal filling defect just above the AV suggestive of intraluminal thrombus. The patient was placed on full anticoagulation with warfarin and referred for cardiothoracic surgery to consider graft and valve replacement. However, 3 weeks later and before the surgery, the patient developed a third thromboembolic ischemic event (transient ischemic attack). The recurrent strokes were attributed to thromboembolic events secondary to prosthetic AV thrombosis.

A repeat transthoracic echocardiography was significant for an abnormal AV bioprosthesis with associated thrombus extending to the ascending aorta. Surgical excision and replacement of the AV conduit explant were performed in November 2012. The final pathology was consistent with EBV-associated large B-cell lymphoma (Figure). The initial staging evaluation, including a CT and positron-emission tomography scan and bone marrow biopsy, was negative for any systemic disease. The patient received 4 cycles of R-CHOP-21 (rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m² , vincristine 2 mg, and prednisone 100 mg) every 3 weeks in an “adjuvant” setting (because patient had no evidence of disease when given the systemic chemotherapy). The patient tolerated chemotherapy well without significant complications, and he is now over 36 months post-treatment without evidence of recurrent disease.

Discussion

Cardiac lymphoma limited only to prosthetic valves is rare, but it has been reported increasingly over the past few years. Until 2010, only six cases of PV-AL had been reported in the literature.⁷ Including our case, we identified four additional PubMed-indexed cases (using a PubMed search through February 2015). The patient characteristics and treatments received for all identified cases are described in the accompanying Table. The pathology from all of the cases revealed non-Hodgkin lymphoma of large B-cell subtype. PV-AL predominated among men (60%) and older patients with a median age of 62.5 years at diagnosis (range, 48-80 years). Patients had a median duration of 8 years (range, 4-24 years) from date of prosthesis placement to date of lymphoma diagnosis. The three most common presenting manifestations were valvular dysfunction, stroke, and congestive heart failure. All of the patients had surgical intervention on initial presentation. However, management after surgery was not uniform, with only 3 patients reported to have received systemic chemotherapy (Table). None of the patients received adjuvant radiation therapy. Calculated from date of diagnosis, survival duration ranged from less than a month⁷ to more than 36 months (as reported in our case).

The pathophysiology of PV-AL is not well understood given the rarity of the condition. Similar to other prosthetic-related neoplasms (metallic implants, breast implants),^12-14 it has been hypothesized that chronic inflammation and EBV infection may play an essential role in the pathogenesis of this entity. Further, it has been suggested that Dacron, which is used in composite cardiac valve replacements, is carcinogenic and may play a role in some cases.^7,15 PV-AL should be highly considered in the differential diagnosis of a suspicious prosthetic valve mass. Various imaging modalities, including echocardiography, CT, and magnetic resonance imaging have been described to have a role in the preoperative evaluation of cardiac tumors by assessing the cardiac function and defining the location and extent of the cardiac tumors.^16-19

Given the rarity of this disease entity, there is no standardized approach for treatment. Surgical resection along with repair or replacement of primary involved prosthetic valve is essential for initial treatment. However, there is no consensus about the best approach for subsequent therapy. We cannot be conclusive about the optimum treatment, because of the limited number of published cases, but based on our reading of those cases, it would seem that early surgical intervention and “adjuvant” systemic therapy may have influenced prognosis. We speculate that poor outcomes in the first 6 months were most likely related to primary cardiopulmonary deterioration, whereas later poor outcomes were more likely to be attributable to recurrent lymphoma, particularly for patients who received suboptimal systemic chemotherapy treatment after surgery. All 3 patients who received chemotherapy had no evidence of recurrent disease at last follow-up. Of the 4 patients who received no chemotherapy and survived longer than 6 months (all except 1 died; Table), 2 had recurrent valve lymphoma, 1 had secondary systemic lymphoma, and 1 died of metastatic breast cancer. Those outcomes are in contrast to the 2 out of 3 patients who received adjuvant chemotherapy and who were reported to be alive at 16 and 36 months after diagnosis.

In conclusion, cardiac PV-AL is an increasingly recognized entity that warrants greater awareness among health care providers for early diagnosis and timely surgical intervention. Most of the cases are large B-cell lymphoma. Similar to patients with limited-stage DLBCL, fit patients should be highly considered for “adjuvant” systemic chemotherapy to optimize long-term outcomes. Reporting of similar cases is highly encouraged to better define this rare iatrogenic malignancy.

Primary cardiac tumors are extremely rare neoplasms with an incidence of less than 0.4%.^1-3 Primary cardiac lymphoma (PCL), the majority of which is non-Hodgkin lymphoma, accounts for around 2% of cardiac tumors and less than 0.5% of extranodal lymphomas.^1,4-6 Primary lymphoma involving cardiac valves has been described in few case reports and small case series owing to its rarity.^7-10 Most cases of PCL present with manifestations of congestive heart failure or cardiac arrhythmias,¹¹ whereas primary valve-associated lymphoma (PV-AL) is usually diagnosed incidentally during valve repair or replacement. The pathophysiology remains unclear, but a few cases have been associated with Epstein Barr virus (EBV).⁷ Cases previously described in the literature carried an overall poor prognosis and to date there is no standardized treatment approach. We provide here an unusual case of primary prosthetic valve-associated cardiac large B-cell lymphoma, which was successfully treated with adjuvant chemotherapy after valve repair and which resulted in an excellent long-term outcome.

Case presentation and summary

The patient presented in 2012 as a 65-year-old man with a history of ascending aortic aneurysm with secondary aortic insufficiency who in 2004 had undergone composite valve replacement of the aortic valve (AV) root and ascending aorta with a St Jude Toronto root. In June 2011, he was found to have a right parietal intraparenchymal hemorrhage that was thought to be a thromboembolic hemorrhagic ischemic stroke. In March 2012, he had routine follow-up brain magnetic resonance imaging that incidentally showed a left frontal ischemic stroke with hemorrhagic conversion. In June 2012, he was found to have first degree atrioventricular block with episodic runs of supraventricular tachycardia.

In September 2012, transthoracic echocardiography was done for further evaluation of possible recurrent cryptogenic strokes. The results showed a hypo-echogenic mass within the proximal ascending aortic root, but this was not confirmed on transesophageal echocardiography. A chest computed-tomography (CT) scan was therefore performed, and it showed aneurysmal dilatation of the aortic root with an irregular marginal filling defect just above the AV suggestive of intraluminal thrombus. The patient was placed on full anticoagulation with warfarin and referred for cardiothoracic surgery to consider graft and valve replacement. However, 3 weeks later and before the surgery, the patient developed a third thromboembolic ischemic event (transient ischemic attack). The recurrent strokes were attributed to thromboembolic events secondary to prosthetic AV thrombosis.

A repeat transthoracic echocardiography was significant for an abnormal AV bioprosthesis with associated thrombus extending to the ascending aorta. Surgical excision and replacement of the AV conduit explant were performed in November 2012. The final pathology was consistent with EBV-associated large B-cell lymphoma (Figure). The initial staging evaluation, including a CT and positron-emission tomography scan and bone marrow biopsy, was negative for any systemic disease. The patient received 4 cycles of R-CHOP-21 (rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m² , vincristine 2 mg, and prednisone 100 mg) every 3 weeks in an “adjuvant” setting (because patient had no evidence of disease when given the systemic chemotherapy). The patient tolerated chemotherapy well without significant complications, and he is now over 36 months post-treatment without evidence of recurrent disease.

Discussion

Cardiac lymphoma limited only to prosthetic valves is rare, but it has been reported increasingly over the past few years. Until 2010, only six cases of PV-AL had been reported in the literature.⁷ Including our case, we identified four additional PubMed-indexed cases (using a PubMed search through February 2015). The patient characteristics and treatments received for all identified cases are described in the accompanying Table. The pathology from all of the cases revealed non-Hodgkin lymphoma of large B-cell subtype. PV-AL predominated among men (60%) and older patients with a median age of 62.5 years at diagnosis (range, 48-80 years). Patients had a median duration of 8 years (range, 4-24 years) from date of prosthesis placement to date of lymphoma diagnosis. The three most common presenting manifestations were valvular dysfunction, stroke, and congestive heart failure. All of the patients had surgical intervention on initial presentation. However, management after surgery was not uniform, with only 3 patients reported to have received systemic chemotherapy (Table). None of the patients received adjuvant radiation therapy. Calculated from date of diagnosis, survival duration ranged from less than a month⁷ to more than 36 months (as reported in our case).

The pathophysiology of PV-AL is not well understood given the rarity of the condition. Similar to other prosthetic-related neoplasms (metallic implants, breast implants),^12-14 it has been hypothesized that chronic inflammation and EBV infection may play an essential role in the pathogenesis of this entity. Further, it has been suggested that Dacron, which is used in composite cardiac valve replacements, is carcinogenic and may play a role in some cases.^7,15 PV-AL should be highly considered in the differential diagnosis of a suspicious prosthetic valve mass. Various imaging modalities, including echocardiography, CT, and magnetic resonance imaging have been described to have a role in the preoperative evaluation of cardiac tumors by assessing the cardiac function and defining the location and extent of the cardiac tumors.^16-19

Given the rarity of this disease entity, there is no standardized approach for treatment. Surgical resection along with repair or replacement of primary involved prosthetic valve is essential for initial treatment. However, there is no consensus about the best approach for subsequent therapy. We cannot be conclusive about the optimum treatment, because of the limited number of published cases, but based on our reading of those cases, it would seem that early surgical intervention and “adjuvant” systemic therapy may have influenced prognosis. We speculate that poor outcomes in the first 6 months were most likely related to primary cardiopulmonary deterioration, whereas later poor outcomes were more likely to be attributable to recurrent lymphoma, particularly for patients who received suboptimal systemic chemotherapy treatment after surgery. All 3 patients who received chemotherapy had no evidence of recurrent disease at last follow-up. Of the 4 patients who received no chemotherapy and survived longer than 6 months (all except 1 died; Table), 2 had recurrent valve lymphoma, 1 had secondary systemic lymphoma, and 1 died of metastatic breast cancer. Those outcomes are in contrast to the 2 out of 3 patients who received adjuvant chemotherapy and who were reported to be alive at 16 and 36 months after diagnosis.

In conclusion, cardiac PV-AL is an increasingly recognized entity that warrants greater awareness among health care providers for early diagnosis and timely surgical intervention. Most of the cases are large B-cell lymphoma. Similar to patients with limited-stage DLBCL, fit patients should be highly considered for “adjuvant” systemic chemotherapy to optimize long-term outcomes. Reporting of similar cases is highly encouraged to better define this rare iatrogenic malignancy.

Primary cardiac tumors are extremely rare neoplasms with an incidence of less than 0.4%.^1-3 Primary cardiac lymphoma (PCL), the majority of which is non-Hodgkin lymphoma, accounts for around 2% of cardiac tumors and less than 0.5% of extranodal lymphomas.^1,4-6 Primary lymphoma involving cardiac valves has been described in few case reports and small case series owing to its rarity.^7-10 Most cases of PCL present with manifestations of congestive heart failure or cardiac arrhythmias,¹¹ whereas primary valve-associated lymphoma (PV-AL) is usually diagnosed incidentally during valve repair or replacement. The pathophysiology remains unclear, but a few cases have been associated with Epstein Barr virus (EBV).⁷ Cases previously described in the literature carried an overall poor prognosis and to date there is no standardized treatment approach. We provide here an unusual case of primary prosthetic valve-associated cardiac large B-cell lymphoma, which was successfully treated with adjuvant chemotherapy after valve repair and which resulted in an excellent long-term outcome.

Case presentation and summary

The patient presented in 2012 as a 65-year-old man with a history of ascending aortic aneurysm with secondary aortic insufficiency who in 2004 had undergone composite valve replacement of the aortic valve (AV) root and ascending aorta with a St Jude Toronto root. In June 2011, he was found to have a right parietal intraparenchymal hemorrhage that was thought to be a thromboembolic hemorrhagic ischemic stroke. In March 2012, he had routine follow-up brain magnetic resonance imaging that incidentally showed a left frontal ischemic stroke with hemorrhagic conversion. In June 2012, he was found to have first degree atrioventricular block with episodic runs of supraventricular tachycardia.

In September 2012, transthoracic echocardiography was done for further evaluation of possible recurrent cryptogenic strokes. The results showed a hypo-echogenic mass within the proximal ascending aortic root, but this was not confirmed on transesophageal echocardiography. A chest computed-tomography (CT) scan was therefore performed, and it showed aneurysmal dilatation of the aortic root with an irregular marginal filling defect just above the AV suggestive of intraluminal thrombus. The patient was placed on full anticoagulation with warfarin and referred for cardiothoracic surgery to consider graft and valve replacement. However, 3 weeks later and before the surgery, the patient developed a third thromboembolic ischemic event (transient ischemic attack). The recurrent strokes were attributed to thromboembolic events secondary to prosthetic AV thrombosis.

A repeat transthoracic echocardiography was significant for an abnormal AV bioprosthesis with associated thrombus extending to the ascending aorta. Surgical excision and replacement of the AV conduit explant were performed in November 2012. The final pathology was consistent with EBV-associated large B-cell lymphoma (Figure). The initial staging evaluation, including a CT and positron-emission tomography scan and bone marrow biopsy, was negative for any systemic disease. The patient received 4 cycles of R-CHOP-21 (rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m² , vincristine 2 mg, and prednisone 100 mg) every 3 weeks in an “adjuvant” setting (because patient had no evidence of disease when given the systemic chemotherapy). The patient tolerated chemotherapy well without significant complications, and he is now over 36 months post-treatment without evidence of recurrent disease.

Discussion

Cardiac lymphoma limited only to prosthetic valves is rare, but it has been reported increasingly over the past few years. Until 2010, only six cases of PV-AL had been reported in the literature.⁷ Including our case, we identified four additional PubMed-indexed cases (using a PubMed search through February 2015). The patient characteristics and treatments received for all identified cases are described in the accompanying Table. The pathology from all of the cases revealed non-Hodgkin lymphoma of large B-cell subtype. PV-AL predominated among men (60%) and older patients with a median age of 62.5 years at diagnosis (range, 48-80 years). Patients had a median duration of 8 years (range, 4-24 years) from date of prosthesis placement to date of lymphoma diagnosis. The three most common presenting manifestations were valvular dysfunction, stroke, and congestive heart failure. All of the patients had surgical intervention on initial presentation. However, management after surgery was not uniform, with only 3 patients reported to have received systemic chemotherapy (Table). None of the patients received adjuvant radiation therapy. Calculated from date of diagnosis, survival duration ranged from less than a month⁷ to more than 36 months (as reported in our case).

The pathophysiology of PV-AL is not well understood given the rarity of the condition. Similar to other prosthetic-related neoplasms (metallic implants, breast implants),^12-14 it has been hypothesized that chronic inflammation and EBV infection may play an essential role in the pathogenesis of this entity. Further, it has been suggested that Dacron, which is used in composite cardiac valve replacements, is carcinogenic and may play a role in some cases.^7,15 PV-AL should be highly considered in the differential diagnosis of a suspicious prosthetic valve mass. Various imaging modalities, including echocardiography, CT, and magnetic resonance imaging have been described to have a role in the preoperative evaluation of cardiac tumors by assessing the cardiac function and defining the location and extent of the cardiac tumors.^16-19

Given the rarity of this disease entity, there is no standardized approach for treatment. Surgical resection along with repair or replacement of primary involved prosthetic valve is essential for initial treatment. However, there is no consensus about the best approach for subsequent therapy. We cannot be conclusive about the optimum treatment, because of the limited number of published cases, but based on our reading of those cases, it would seem that early surgical intervention and “adjuvant” systemic therapy may have influenced prognosis. We speculate that poor outcomes in the first 6 months were most likely related to primary cardiopulmonary deterioration, whereas later poor outcomes were more likely to be attributable to recurrent lymphoma, particularly for patients who received suboptimal systemic chemotherapy treatment after surgery. All 3 patients who received chemotherapy had no evidence of recurrent disease at last follow-up. Of the 4 patients who received no chemotherapy and survived longer than 6 months (all except 1 died; Table), 2 had recurrent valve lymphoma, 1 had secondary systemic lymphoma, and 1 died of metastatic breast cancer. Those outcomes are in contrast to the 2 out of 3 patients who received adjuvant chemotherapy and who were reported to be alive at 16 and 36 months after diagnosis.

In conclusion, cardiac PV-AL is an increasingly recognized entity that warrants greater awareness among health care providers for early diagnosis and timely surgical intervention. Most of the cases are large B-cell lymphoma. Similar to patients with limited-stage DLBCL, fit patients should be highly considered for “adjuvant” systemic chemotherapy to optimize long-term outcomes. Reporting of similar cases is highly encouraged to better define this rare iatrogenic malignancy.

Editor’s note: SHM occasionally puts the spotlight on our most active members who are making substantial contributions to hospital medicine. Visit www.hospitalmedicine.org for more information on how you can lend your expertise to help improve the care of hospitalized patients.

This month, The Hospitalist spotlights Ramin Yazdanfar, MD, hospitalist and Harrisburg (Pa.) site medical director at UPMC Pinnacle. Dr. Ramin has been a member of SHM since 2016, has attended two annual conferences as well as Leadership Academy, and together with his team received SHM’s Award of Excellence in Teamwork.
 

How did you learn about SHM and why did you become a member?

I first heard about SHM during my initial job out of residency. At that time, our medical director encouraged engagement in the field of hospital medicine, and he was quite involved in local meetings and national conferences. I became a member because I felt it would be a good way to connect with other hospitalists who might have been going through similar experiences and struggles, and in the hopes of gaining something I could take back to use in my daily practice.

Which SHM conferences have you attended and why?

I have attended two national conferences thus far. The first was the 2016 SHM Annual Conference in San Diego, where our hospitalist team won the Excellence in Teamwork and Quality Improvement Award for our active bed management program under Mary Ellen Pfeiffer, MD, and William “Tex” Landis, MD, among others. I also attended the 2017 Leadership Academy in Scottsdale, Ariz. As a new site director for a new hospitalist group, I thought it would be a valuable learning experience, with the goal of improving my communication as a leader. I also will be attending the 2018 SHM Leadership Academy in Vancouver. I am excited to reconnect with peers I met last year and to advance my leadership skills further.

What were the main takeaways from Leadership: Mastering Teamwork, and how have you applied them in your practice?

My most vivid and actionable memory of Leadership: Mastering Teamwork was the initial session around the five dysfunctions of a team and how to build a cohesive leadership team. Allowing ourselves to be vulnerable and open creates the foundation of trust, on which we can build everything else, such as handling conflict and creating commitment, accountability, and results. I have tried to use these principles in our own practice, at UPMC Pinnacle Health in Harrisburg, Pa. We have an ever-growing health system with an expanding regional leadership team. We base our foundation on trust in one another, and in our vision, so the rest follows suit.

As a separate takeaway, I really enjoyed sessions with Leonard Marcus, PhD, on SWARM Intelligence and Meta-Leadership. He is a very engaging speaker whom I would recommend to anyone considering the Mastering Teamwork session.
 

What advice do you have for early-career hospitalists looking to advance their career in hospital medicine?

My advice to early-career hospitalists is to be open to opportunity. There is so much change and development in the field of hospital medicine. While the foundation of our job is in the patient care realm, many of us find a niche that interests us. My advice is pursue it and be open to what follows, without forgetting that we do this for our patients and community.

Ms. Steele is a marketing communications specialist at the Society of Hospital Medicine.

Editor’s note: SHM occasionally puts the spotlight on our most active members who are making substantial contributions to hospital medicine. Visit www.hospitalmedicine.org for more information on how you can lend your expertise to help improve the care of hospitalized patients.

This month, The Hospitalist spotlights Ramin Yazdanfar, MD, hospitalist and Harrisburg (Pa.) site medical director at UPMC Pinnacle. Dr. Ramin has been a member of SHM since 2016, has attended two annual conferences as well as Leadership Academy, and together with his team received SHM’s Award of Excellence in Teamwork.
 

How did you learn about SHM and why did you become a member?

I first heard about SHM during my initial job out of residency. At that time, our medical director encouraged engagement in the field of hospital medicine, and he was quite involved in local meetings and national conferences. I became a member because I felt it would be a good way to connect with other hospitalists who might have been going through similar experiences and struggles, and in the hopes of gaining something I could take back to use in my daily practice.

Which SHM conferences have you attended and why?

I have attended two national conferences thus far. The first was the 2016 SHM Annual Conference in San Diego, where our hospitalist team won the Excellence in Teamwork and Quality Improvement Award for our active bed management program under Mary Ellen Pfeiffer, MD, and William “Tex” Landis, MD, among others. I also attended the 2017 Leadership Academy in Scottsdale, Ariz. As a new site director for a new hospitalist group, I thought it would be a valuable learning experience, with the goal of improving my communication as a leader. I also will be attending the 2018 SHM Leadership Academy in Vancouver. I am excited to reconnect with peers I met last year and to advance my leadership skills further.

What were the main takeaways from Leadership: Mastering Teamwork, and how have you applied them in your practice?

My most vivid and actionable memory of Leadership: Mastering Teamwork was the initial session around the five dysfunctions of a team and how to build a cohesive leadership team. Allowing ourselves to be vulnerable and open creates the foundation of trust, on which we can build everything else, such as handling conflict and creating commitment, accountability, and results. I have tried to use these principles in our own practice, at UPMC Pinnacle Health in Harrisburg, Pa. We have an ever-growing health system with an expanding regional leadership team. We base our foundation on trust in one another, and in our vision, so the rest follows suit.

As a separate takeaway, I really enjoyed sessions with Leonard Marcus, PhD, on SWARM Intelligence and Meta-Leadership. He is a very engaging speaker whom I would recommend to anyone considering the Mastering Teamwork session.
 

What advice do you have for early-career hospitalists looking to advance their career in hospital medicine?

My advice to early-career hospitalists is to be open to opportunity. There is so much change and development in the field of hospital medicine. While the foundation of our job is in the patient care realm, many of us find a niche that interests us. My advice is pursue it and be open to what follows, without forgetting that we do this for our patients and community.

Ms. Steele is a marketing communications specialist at the Society of Hospital Medicine.

Editor’s note: SHM occasionally puts the spotlight on our most active members who are making substantial contributions to hospital medicine. Visit www.hospitalmedicine.org for more information on how you can lend your expertise to help improve the care of hospitalized patients.

This month, The Hospitalist spotlights Ramin Yazdanfar, MD, hospitalist and Harrisburg (Pa.) site medical director at UPMC Pinnacle. Dr. Ramin has been a member of SHM since 2016, has attended two annual conferences as well as Leadership Academy, and together with his team received SHM’s Award of Excellence in Teamwork.
 

How did you learn about SHM and why did you become a member?

I first heard about SHM during my initial job out of residency. At that time, our medical director encouraged engagement in the field of hospital medicine, and he was quite involved in local meetings and national conferences. I became a member because I felt it would be a good way to connect with other hospitalists who might have been going through similar experiences and struggles, and in the hopes of gaining something I could take back to use in my daily practice.

Which SHM conferences have you attended and why?

I have attended two national conferences thus far. The first was the 2016 SHM Annual Conference in San Diego, where our hospitalist team won the Excellence in Teamwork and Quality Improvement Award for our active bed management program under Mary Ellen Pfeiffer, MD, and William “Tex” Landis, MD, among others. I also attended the 2017 Leadership Academy in Scottsdale, Ariz. As a new site director for a new hospitalist group, I thought it would be a valuable learning experience, with the goal of improving my communication as a leader. I also will be attending the 2018 SHM Leadership Academy in Vancouver. I am excited to reconnect with peers I met last year and to advance my leadership skills further.

What were the main takeaways from Leadership: Mastering Teamwork, and how have you applied them in your practice?

My most vivid and actionable memory of Leadership: Mastering Teamwork was the initial session around the five dysfunctions of a team and how to build a cohesive leadership team. Allowing ourselves to be vulnerable and open creates the foundation of trust, on which we can build everything else, such as handling conflict and creating commitment, accountability, and results. I have tried to use these principles in our own practice, at UPMC Pinnacle Health in Harrisburg, Pa. We have an ever-growing health system with an expanding regional leadership team. We base our foundation on trust in one another, and in our vision, so the rest follows suit.

As a separate takeaway, I really enjoyed sessions with Leonard Marcus, PhD, on SWARM Intelligence and Meta-Leadership. He is a very engaging speaker whom I would recommend to anyone considering the Mastering Teamwork session.
 

What advice do you have for early-career hospitalists looking to advance their career in hospital medicine?

My advice to early-career hospitalists is to be open to opportunity. There is so much change and development in the field of hospital medicine. While the foundation of our job is in the patient care realm, many of us find a niche that interests us. My advice is pursue it and be open to what follows, without forgetting that we do this for our patients and community.

Ms. Steele is a marketing communications specialist at the Society of Hospital Medicine.

Compared with patients who underwent drainage for treatment of symptomatic malignant pleural effusions that was guided by symptoms, patients who underwent once-daily drainage had similar breathless scores but an increased rate of spontaneous pleurodesis and better quality of life scores, according to recent research published in the Lancet Respiratory Medicine.

Nephron/Wikimedia Commons/CC-BY-SA-3.0

“In patients in whom pleurodesis is an important goal (e.g., those undertaking strategies involving an indwelling pleural catheter plus pleurodesing agents), aggressive drainage should be done for at least 60 days,” Sanjeevan Muruganandan, FRACP, MBBS, from Sir Charles Gairdner Hospital in Perth, Australia, and his colleagues wrote in their study. “Future studies will need to establish if more aggressive (e.g., twice daily) regimens for the initial phase could further enhance success rates.”

Dr. Muruganandan and his colleagues evaluated 87 patients with symptomatic malignant pleural effusions between July 2015 and January 2017 from 11 centers in Australia, New Zealand, Hong Kong, and Malaysia in the randomized controlled AMPLE-2 trial, in which patients received either once daily (43 patients) or symptom-guided (44 patients) drainage for 60 days with a 6-month follow-up. Patients were excluded if they had a pleural infection, were pregnant, had a previous pneumonectomy or ipsilateral lobectomy, had “significant loculations likely to preclude effective fluid drainage,” or had an estimated survival of less than 3 months. Patients were identified and grouped based on whether they had mesothelioma- or nonmesothelioma-type cancer, with cancer type being minimalized during randomization.

At 60 days, patients in the aggressive daily drainage group had a mean daily breathless score of 13.1 mm (geometric means; 95% confidence interval, 9.8-17.4), compared with a mean of 17.3 mm (95% CI, 13.0-22.0) in the symptom-guided drainage group. In the aggressive drainage group, 16 of 43 patients (37.2%) achieved spontaneous pleurodesis at 60 days, compared with 11 of 44 patients (11.4%) in the symptom-guided drainage group (P = .0049). At 6 months, 19 of 43 (44.2%) patients in the aggressive drainage group had spontaneous pleurodesis, compared with 7 of 44 patients (15.9%; P = .004) in the symptom-guided drainage group (hazard ratio, 3.287; 95% CI, 1.396-7.740; P = .0065).

In each group, the investigators noted adverse events: 11 of 43 (25.6%) patients in the aggressive drainage group and 12 of 44 patients (27.3%) in the symptom-guided drainage group reported a severe adverse event. There were no significant differences in mortality, pain scores, and hospital stay between the groups. Regarding quality of life, the investigators found patients in the aggressive drainage group reported better scores using the EuroQoL-5 Dimensions-5 Levels assessment (estimated means, 0.713; 95% CI, 0.647-0.779) than did patients in the symptom-guided group (0.601; 95% CI, 0.536-0.667), with an estimated difference in means of 0.112 (95% CI, 0.0198-0.204; P = .0174).

The investigators suggested that aggressive drainage may have some unmeasured benefits. “Daily removal of the fluid might have provided benefits in symptoms not captured with our breathlessness and pain measurements. The higher pleurodesis rate, with resultant freedom from fluid (and symptom) recurrence and of the catheter, might have contributed to the better reported quality of life. Additionally, it has been suggested that indwelling pleural catheter drainage gives patients an important sense of control when they are feeling helpless with their advancing cancer.”

They concluded, “For patients whose primary care aim is palliation (e.g., those with very limited life expectancy or significant trapped lung where pleurodesis is unlikely), our data show that symptom-guided drainage offers an effective means of breathlessness control without the inconvenience and costs of daily drainages. The ability to predict the likelihood of pleurodesis will help guide the choice of regimen and should be a topic of future studies.”

Three authors reported serving on the advisory board of CareFusion/BD, two authors reported an educational grant from Rocket Medical (UK), and one author reported an educational grant from CareFusion/BD. The other authors reported no relevant conflicts of interest.

SOURCE: Muruganandan S et al. Lancet Respir Med. 2018 July 20. doi: 10.1016/S2213-2600(18)30288-1.

Compared with patients who underwent drainage for treatment of symptomatic malignant pleural effusions that was guided by symptoms, patients who underwent once-daily drainage had similar breathless scores but an increased rate of spontaneous pleurodesis and better quality of life scores, according to recent research published in the Lancet Respiratory Medicine.

Nephron/Wikimedia Commons/CC-BY-SA-3.0

“In patients in whom pleurodesis is an important goal (e.g., those undertaking strategies involving an indwelling pleural catheter plus pleurodesing agents), aggressive drainage should be done for at least 60 days,” Sanjeevan Muruganandan, FRACP, MBBS, from Sir Charles Gairdner Hospital in Perth, Australia, and his colleagues wrote in their study. “Future studies will need to establish if more aggressive (e.g., twice daily) regimens for the initial phase could further enhance success rates.”

Dr. Muruganandan and his colleagues evaluated 87 patients with symptomatic malignant pleural effusions between July 2015 and January 2017 from 11 centers in Australia, New Zealand, Hong Kong, and Malaysia in the randomized controlled AMPLE-2 trial, in which patients received either once daily (43 patients) or symptom-guided (44 patients) drainage for 60 days with a 6-month follow-up. Patients were excluded if they had a pleural infection, were pregnant, had a previous pneumonectomy or ipsilateral lobectomy, had “significant loculations likely to preclude effective fluid drainage,” or had an estimated survival of less than 3 months. Patients were identified and grouped based on whether they had mesothelioma- or nonmesothelioma-type cancer, with cancer type being minimalized during randomization.

At 60 days, patients in the aggressive daily drainage group had a mean daily breathless score of 13.1 mm (geometric means; 95% confidence interval, 9.8-17.4), compared with a mean of 17.3 mm (95% CI, 13.0-22.0) in the symptom-guided drainage group. In the aggressive drainage group, 16 of 43 patients (37.2%) achieved spontaneous pleurodesis at 60 days, compared with 11 of 44 patients (11.4%) in the symptom-guided drainage group (P = .0049). At 6 months, 19 of 43 (44.2%) patients in the aggressive drainage group had spontaneous pleurodesis, compared with 7 of 44 patients (15.9%; P = .004) in the symptom-guided drainage group (hazard ratio, 3.287; 95% CI, 1.396-7.740; P = .0065).

In each group, the investigators noted adverse events: 11 of 43 (25.6%) patients in the aggressive drainage group and 12 of 44 patients (27.3%) in the symptom-guided drainage group reported a severe adverse event. There were no significant differences in mortality, pain scores, and hospital stay between the groups. Regarding quality of life, the investigators found patients in the aggressive drainage group reported better scores using the EuroQoL-5 Dimensions-5 Levels assessment (estimated means, 0.713; 95% CI, 0.647-0.779) than did patients in the symptom-guided group (0.601; 95% CI, 0.536-0.667), with an estimated difference in means of 0.112 (95% CI, 0.0198-0.204; P = .0174).

The investigators suggested that aggressive drainage may have some unmeasured benefits. “Daily removal of the fluid might have provided benefits in symptoms not captured with our breathlessness and pain measurements. The higher pleurodesis rate, with resultant freedom from fluid (and symptom) recurrence and of the catheter, might have contributed to the better reported quality of life. Additionally, it has been suggested that indwelling pleural catheter drainage gives patients an important sense of control when they are feeling helpless with their advancing cancer.”

They concluded, “For patients whose primary care aim is palliation (e.g., those with very limited life expectancy or significant trapped lung where pleurodesis is unlikely), our data show that symptom-guided drainage offers an effective means of breathlessness control without the inconvenience and costs of daily drainages. The ability to predict the likelihood of pleurodesis will help guide the choice of regimen and should be a topic of future studies.”

Three authors reported serving on the advisory board of CareFusion/BD, two authors reported an educational grant from Rocket Medical (UK), and one author reported an educational grant from CareFusion/BD. The other authors reported no relevant conflicts of interest.

SOURCE: Muruganandan S et al. Lancet Respir Med. 2018 July 20. doi: 10.1016/S2213-2600(18)30288-1.

Compared with patients who underwent drainage for treatment of symptomatic malignant pleural effusions that was guided by symptoms, patients who underwent once-daily drainage had similar breathless scores but an increased rate of spontaneous pleurodesis and better quality of life scores, according to recent research published in the Lancet Respiratory Medicine.

Nephron/Wikimedia Commons/CC-BY-SA-3.0

“In patients in whom pleurodesis is an important goal (e.g., those undertaking strategies involving an indwelling pleural catheter plus pleurodesing agents), aggressive drainage should be done for at least 60 days,” Sanjeevan Muruganandan, FRACP, MBBS, from Sir Charles Gairdner Hospital in Perth, Australia, and his colleagues wrote in their study. “Future studies will need to establish if more aggressive (e.g., twice daily) regimens for the initial phase could further enhance success rates.”

Dr. Muruganandan and his colleagues evaluated 87 patients with symptomatic malignant pleural effusions between July 2015 and January 2017 from 11 centers in Australia, New Zealand, Hong Kong, and Malaysia in the randomized controlled AMPLE-2 trial, in which patients received either once daily (43 patients) or symptom-guided (44 patients) drainage for 60 days with a 6-month follow-up. Patients were excluded if they had a pleural infection, were pregnant, had a previous pneumonectomy or ipsilateral lobectomy, had “significant loculations likely to preclude effective fluid drainage,” or had an estimated survival of less than 3 months. Patients were identified and grouped based on whether they had mesothelioma- or nonmesothelioma-type cancer, with cancer type being minimalized during randomization.

At 60 days, patients in the aggressive daily drainage group had a mean daily breathless score of 13.1 mm (geometric means; 95% confidence interval, 9.8-17.4), compared with a mean of 17.3 mm (95% CI, 13.0-22.0) in the symptom-guided drainage group. In the aggressive drainage group, 16 of 43 patients (37.2%) achieved spontaneous pleurodesis at 60 days, compared with 11 of 44 patients (11.4%) in the symptom-guided drainage group (P = .0049). At 6 months, 19 of 43 (44.2%) patients in the aggressive drainage group had spontaneous pleurodesis, compared with 7 of 44 patients (15.9%; P = .004) in the symptom-guided drainage group (hazard ratio, 3.287; 95% CI, 1.396-7.740; P = .0065).

In each group, the investigators noted adverse events: 11 of 43 (25.6%) patients in the aggressive drainage group and 12 of 44 patients (27.3%) in the symptom-guided drainage group reported a severe adverse event. There were no significant differences in mortality, pain scores, and hospital stay between the groups. Regarding quality of life, the investigators found patients in the aggressive drainage group reported better scores using the EuroQoL-5 Dimensions-5 Levels assessment (estimated means, 0.713; 95% CI, 0.647-0.779) than did patients in the symptom-guided group (0.601; 95% CI, 0.536-0.667), with an estimated difference in means of 0.112 (95% CI, 0.0198-0.204; P = .0174).

The investigators suggested that aggressive drainage may have some unmeasured benefits. “Daily removal of the fluid might have provided benefits in symptoms not captured with our breathlessness and pain measurements. The higher pleurodesis rate, with resultant freedom from fluid (and symptom) recurrence and of the catheter, might have contributed to the better reported quality of life. Additionally, it has been suggested that indwelling pleural catheter drainage gives patients an important sense of control when they are feeling helpless with their advancing cancer.”

They concluded, “For patients whose primary care aim is palliation (e.g., those with very limited life expectancy or significant trapped lung where pleurodesis is unlikely), our data show that symptom-guided drainage offers an effective means of breathlessness control without the inconvenience and costs of daily drainages. The ability to predict the likelihood of pleurodesis will help guide the choice of regimen and should be a topic of future studies.”

Three authors reported serving on the advisory board of CareFusion/BD, two authors reported an educational grant from Rocket Medical (UK), and one author reported an educational grant from CareFusion/BD. The other authors reported no relevant conflicts of interest.

SOURCE: Muruganandan S et al. Lancet Respir Med. 2018 July 20. doi: 10.1016/S2213-2600(18)30288-1.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The anti-tumor immune response

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

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

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

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

Exploiting nature’s weapon of mass destruction

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

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

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

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

Releasing the brakes

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

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

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

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

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

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

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

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

Stepping on the gas

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

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

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

Combinations are key

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

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

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

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

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

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

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

The anti-tumor immune response

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

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

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

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

Exploiting nature’s weapon of mass destruction

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

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

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

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

Releasing the brakes

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

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

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

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

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

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

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

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

Stepping on the gas

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

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

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

Combinations are key

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

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

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

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

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

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

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

The anti-tumor immune response

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

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

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

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

Exploiting nature’s weapon of mass destruction

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

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

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

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

Releasing the brakes

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

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

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

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

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

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

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

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

Stepping on the gas

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

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

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

Combinations are key

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

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

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

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

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

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