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Phase II Trial of Pembrolizumab Plus Gemcitabine, Vinorelbine, and Liposomal Doxorubicin as Second-Line Therapy for Relapsed or Refractory Classical Hodgkin Lymphoma
, MD1; Gunjan Shah, MD2; Heiko Schöder , MD1; Nivetha Ganesan, MPH1; Esther Drill , PhD3; Helen Hancock, NP1; Theresa Davey, PA1; Leslie Perez, RN1; Sunyoung Ryu, RN1; Samia Sohail, MBS1; Alayna Santarosa, MPH1; Natasha Galasso, MSW1; Rachel Neuman, MBA1; Brielle Liotta, BS1; William Blouin , MBA1; Anita Kumar , MD1; Oscar Lahoud , MD1; Connie L. Batlevi , MD1; Paul Hamlin, MD1; David J. Straus, MD1; Ildefonso Rodriguez-Rivera , MD1; Colette Owens, MD1; Philip Caron, MD1; Andrew M. Intlekofer , MD1; Audrey Hamilton, MD1; Steven M. Horwitz , MD1; Lorenzo Falchi , MD1; Erel Joffe , MD1; William Johnson , DO1; Christina Lee, MD1; M. Lia Palomba , MD1; Ariela Noy, MD1; Matthew J. Matasar , MD1; Georgios Pongas, MD4; Gilles Salles , MD1; Santosha Vardhana , MD1; Beatriz Wills Sanin, MD1; Gottfried von Keudell , MD1; Joachim Yahalom , MD1; Ahmet Dogan , MD1; Andrew D. Zelenetz , MD1; and Craig H. Moskowitz, MD4 Show More
Abstract
We conducted a phase II study evaluating pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin (pembro-GVD) as second-line therapy for relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) (ClinicalTrials.gov identifier: NCT03618550).
Transplant eligible patients with rel/ref cHL following first-line therapy were treated with two to four cycles of pembrolizumab (200 mg intravenous [IV], day 1), gemcitabine (1,000 mg/m2 IV, days 1 and 8), vinorelbine (20 mg/m2 IV, days 1 and 8), and liposomal doxorubicin (15 mg/m2, days 1 and 8), given on 21-day cycles. The primary end point was complete response (CR) following up to four cycles of pembro-GVD. Patients who achieved CR by labeled fluorodeoxyglucose-positron emission tomography (Deauville ≤ 3) after two or four cycles proceeded to high-dose therapy and autologous hematopoietic cell transplantation (HDT/AHCT). HDT/AHCT was carried out according to institutional standards, and brentuximab vedotin maintenance was allowed following HDT/AHCT.
Of 39 patients enrolled, 41% had primary ref disease and 38% relapsed within 1 year of frontline treatment. 31 patients received two cycles of pembro-GVD, and eight received four cycles. Most adverse events were grade 1 or two, whereas few were grade 3 and included transaminitis (n = 4), neutropenia (n = 4), mucositis (n = 2), thyroiditis (n = 1), and rash (n = 1). Of 38 evaluable patients, overall and CR rates after pembro-GVD were 100% and 95%, respectively. Thirty-six (95%) patients proceeded to HDT/AHCT, two received pre-HDT/AHCT involved site radiation, and 13 (33%) received post-HDT/AHCT brentuximab vedotin maintenance. All 36 transplanted patients are in remission at a median post-transplant follow-up of 13.5 months (range: 2.66-27.06 months).
Classical Hodgkin lymphoma (cHL) is often cured with frontline therapy; however, up to 25% of patients with advanced stage and up to 10% with early stage will have relapsed or refractory (rel/ref) disease.1-3 The standard approach for these patients is second-line therapy (SLT) followed by consolidation with high-dose therapy and autologous hematopoietic cell transplant (HDT/AHCT). The role of HDT/AHCT in rel/ref cHL was established by two randomized studies, published in 1993 and 2002, which showed that 55% of patients who respond to second-line cytotoxic chemotherapy can be cured with HDT/AHCT.4,5 More recent studies show considerably better outcomes for rel/ref disease with a 2-year progression-free survival (PFS) of about 70% or better.6,7 Two main factors account for the improved outcomes observed in recent studies: the establishment of pre-HDT/AHCT labeled fluorodeoxyglucose-positron emission tomography (FDG-PET) response as the single most important prognostic factor predicting post-HDT/AHCT outcome and the introduction of SLT containing newer agents for cHL, such as brentuximab vedotin (BV).
Key Objective
Up to 25% of patients with classical Hodgkin lymphoma (cHL) develop relapsed or refractory (rel/ref) disease following frontline therapy, and the standard treatment for these patients is administration of second-line therapy (SLT) followed by consolidation with high-dose therapy and autologous hematopoietic cell transplant (HDT/AHCT). Achievement of complete response (CR) on labeled fluorodeoxyglucose-positron emission tomography before HDT/AHCT is the strongest prognostic factor for long-term outcome in rel/ref cHL. There is no one standard SLT; however, optimal SLTs are associated with high rates of CR and favorable tolerability. Given the increasing use of brentuximab vedotin in the frontline setting for cHL, highly active SLTs that do not include brentuximab vedotin are needed. Building upon the efficacy of programmed cell death protein-1 blockade in cHL, this study aimed to assess the CR rate to pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin (pembro-GVD) for transplant eligible patients with rel/ref cHL after frontline treatment.
Knowledge Generated
Pembrolizumab plus GVD as SLT for cHL is associated with a CR rate of 95% and favorable toxicity profile. This regimen efficiently and safely bridged patients with rel/ref cHL to HDT/AHCT.
Relevance (J.W. Friedberg)
The high activity of pembrolizumab plus GVD as SLT for patients with Hodgkin lymphoma warrants further investigation in prospective randomized trials.*
Relevance section written by JCO Editor-in-Chief Jonathan W. Friedberg, MD.
We previously reported that the 5-year event-free survival for rel/ref cHL patients with negative pre-HDT/AHCT functional imaging (gallium or FDG-PET) was 75% compared with 31% for patients with persistent abnormalities on functional imaging.8 Numerous other groups reported similar findings, suggesting that normalization of FDG-PET following SLT should be a goal for patients proceeding to HDT/AHCT.9-14 There is no single standard SLT for cHL, and traditional options include platinum-based regimens such as ifosfamide, carboplatin, and etoposide (ICE) or dexamethasone, cytarabine, and cisplatin (DHAP) and gemcitabine-based regimens such as ifosfamide, gemcitabine, and etoposide (IGEV), gemcitabine, dexamethasone, and cisplatin (GDP), or gemcitabine, vinorelbine, and doxil (GVD).15-19 Although these traditional second-line chemotherapy-based regimens induce complete responses (CRs) in about 50%-60% of patients, modern regimens incorporating BV, programmed cell death protein-1 (PD-1) blockade, and/or bendamustine produce CR rates ranging from 67% to 75%.6,7,15,17,19-25
Data regarding the incorporation of PD-1 blockade into SLT are limited. The most established regimen is BV plus nivolumab, which has the advantage of outpatient administration and good tolerability. Importantly, it is highly effective, associated with a CR rate of 67% and a 3-year PFS of 77%.26 One disadvantage of this regimen is that it includes BV, which is increasingly being used in the frontline setting, making it less desirable for SLT.
Building upon the high activity observed with the checkpoint inhibitors pembrolizumab and nivolumab in rel/ref cHL, we aimed to develop a novel immunotherapy-based SLT regimen for cHL.27,28 We sought to develop an SLT regimen that is well-tolerated, outpatient administrated, and associated with high CR rates. We chose the GVD regimen as the backbone for use in this study for its favorable toxicity profile and outpatient compatibility. GVD was first evaluated in a phase I or II multicenter study sponsored by the Cancer and Leukemia Group B in both transplant-naïve and previously transplanted patients. The overall response rate (ORR) by computed tomography (CT) alone was 70%.17 Each drug in the GVD regimen can potentially stimulate tumor-specific immune responses through various mechanisms, and thus, we hypothesized that the off-target immunologic effects of GVD would enhance the efficacy of pembrolizumab in patients with cHL.29 In this phase II study, we aimed to establish the safety and efficacy of pre-HDT/AHCT pembrolizumab combined with GVD for rel/ref cHL.
This was a multicenter, investigator-initiated, single-arm, phase II study conducted at Memorial Sloan Kettering Cancer Center and the University of Miami Sylvester Comprehensive Cancer Center. Eligible patients had biopsy-proven rel/ref cHL following one line of multiagent chemotherapy. Patients age ≥ 18 years with Eastern Cooperative Oncology Group performance score ≤ 1 and adequate organ function (defined as an absolute neutrophil count ≥ 1,000/µL, platelets ≥ 50,000/µL, hemoglobin ≥ 8 g/dL, creatinine ≤ 1.5 × upper limit of normal (ULN), total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN if liver involvement is present, AST/ALT ≤ 2.5 × ULN or ≤ 5 × ULN if liver involvement is present, hemoglobin-adjusted diffusing capacity for carbon monoxide ≥ 50%, and a cardiac ejection fraction ≥ 45%) were eligible. Patients were excluded if they had autoimmune disease requiring immunosuppressive therapy within 2 years before enrollment, known active HIV, hepatitis B or C, or history of pneumonitis requiring steroid treatment. This study was approved by the institutional review boards at Memorial Sloan Kettering Cancer Center and Miami Sylvester Comprehensive Cancer Center and registered at ClinicalTrials.gov identifier: NCT03618550. All patients provided informed consent.
Patients received pembrolizumab 200 mg intravenous (IV) (flat) on day 1 and gemcitabine 1,000 mg/m2 IV (days 1 and 8), vinorelbine 20 mg/m2 IV (days 1 and 8), and liposomal doxorubicin 15 mg/m2 IV (days 1 and 8) on 21-day cycles. Growth factor support with pegfilgrastim or equivalent was administered on day 9 of each cycle. To reduce the rate of liposomal doxorubicin infusion–related reactions on cycle 1, day 1, patients received premedication with diphenhydramine, famotidine, and dexamethasone and liposomal doxorubicin was administered over 2 hours.
Patients were assessed for response by FDG-PET/CT after two and four cycles of treatment. Patients with CR (defined as Deauville ≤ 3) after two cycles were eligible to proceed to HDT/AHCT. Patients with less than CR after two cycles of pembrolizumab-GVD received an additional two cycles followed by FDG-PET/CT and consideration for HDT/AHCT.
Stem-cell mobilization and collection were performed as per institutional guidelines after 2-4 cycles of pembrolizumab-GVD. Conditioning for HDT/AHCT was as per treating physician preference and according to institutional guidelines. Initiation of high-dose chemotherapy occurred 3-6 weeks after the last cycle of pembrolizumab-GVD. Administration of pre-HDT/AHCT involved site radiation, or post-HDT/AHCT maintenance therapy with BV was at the discretion of the treating physician. Because of relatively high rates of engraftment syndrome (ES) previously observed at Memorial Sloan Kettering Cancer Center following PD-1 blockade–containing salvage, there was a low threshold for diagnosing and treating ES in this study. ES was defined as high-grade noninfectious fever (> 38.5°C) and was typically treated with dexamethasone 0.2 mg/kg IV daily × 3 days (or longer for prolonged symptoms) followed by oral steroid taper.
To evaluate safety, an initial safety run-in was conducted with the first six patients. These patients were treated and observed for dose-limiting toxicities (DLTs) for a minimum of 5 weeks following initiation of cycle 2 of pembrolizumab-GVD. If not more than one patient experienced DLT, enrollment would continue to the two-stage design described below. Otherwise, dose modifications would have been considered before moving forward.
The primary objective of the study was to evaluate CR rate after treatment with pembro-GVD. Traditional second-line chemotherapy, such as ICE or GVD, produces CR rates of about 50%.15,17 Sample size calculation for this study was based on the assumption that a CR rate of at least 70% with pembro-GVD would be considered promising. To that end, we used Simon's two-stage minimax design. In the first stage, we enrolled 23 eligible patients and at least 12 patients were required to achieve CR to proceed to stage II. In stage II, an additional 16 patients were enrolled. Among the total 39 patients, if 24 or more patients achieved CR, this treatment regimen would be declared promising. This decision rule had a type I error rate of 0.10 and a type II error rate of 0.10.
By Protocol (online only), ORR (partial response [PR] or CR) is summarized along with 95% CIs. Predetermined secondary objectives included assessing PFS and overall survival (OS), with follow-up starting at the initiation of therapy. In the group of patients who went on to HDT/AHCT after the end of pembro-GVD, post-HDT/AHCT PFS and OS were assessed with follow-up starting after transplant. Exploratory current PFS and OS rates were calculated using the method of Kaplan-Meier. Patient characteristics were reported with median and range for continuous variables and counts and percentage for categorical variables. Associations between immune-related adverse events (AEs) and number of cycles, ES and immune-related AEs, and ES and sex were assessed with Fisher's exact test. Adverse events are reported for all patients accrued to this trial.
Between August 2018 and October 2020, 39 patients were recruited into the study and their characteristics are shown in Table 1. In brief, the median age was 38 years (21-71 years), 41% had primary refractory disease (no CR to frontline therapy), and an additional 38% had relapsed within the first year of completing frontline therapy. Most patients received doxorubicin, bleomycin, vinblastine, and dacarbazine as frontline therapy.
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No DLT events were seen in the safety phase of the study. All 39 patients were evaluated for AEs related to pembro-GVD, and the data are shown in Table 2. Most AEs were grade 1 or 2. The few grade 3 AEs included rash (n = 1), elevated AST/ALT (n = 4), mucositis (n = 2), neutropenia (n = 4), and hyperthyroidism (n = 1). All eight infusion-related reactions were related to liposomal doxorubicin. They occurred with the first dose only and improved with administration of additional diphenhydramine and slowing the rate of liposomal doxorubicin. There was one serious AE in a patient admitted for nausea, vomiting, and diarrhea because of thyroiditis.
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Immune-related AEs included hyperthyroidism (n = 5), transaminitis (n = 16), and rash (n = 19). Hyperthyroidism developed within the first two cycles of treatment for all five patients. Two patients recovered, and the other three subsequently developed hypothyroidism and remained stable on levothyroxine. With regard to transaminitis and rash, grade 3 events were typically treated with steroids and/or treatment delays. Although the package insert for pembrolizumab recommends permanent discontinuation of pembrolizumab for AST or ALT elevations > 8× the upper limit of normal, we did not permanently discontinue pembrolizumab following grade 3 transaminitis because we assumed that gemcitabine was likely contributing to this toxicity. Overall, 5 (13%) patients received systemic steroids (prednisone) for transaminitis (n = 4) or grade 3 rash (n = 1); the median prednisone dose was 50 mg/day (range 40-80 mg/day), given for a median of 8 days (range 4-14 days). There was no significant difference in the frequency of immune-related events in patients receiving two versus four cycles of pembro-GVD (P = .2). All events of hepatitis and rash resolved upon completion of pembro-GVD.
Overall, 9 of 39 (23%) patients required a treatment delay lasting a median of 6 days (range 4-14 days). Reasons for treatment delays included transaminitis (n = 4), rash (n = 1), mucositis (n = 1), neutropenia (n = 1), and upper respiratory infection (n = 2). Only two patients had dose reductions; one had a 20% dose reduction of gemcitabine on cycle 2, day 8 for transaminitis, and the other had a 25% dose reduction of GVD on cycle 4, day 8 for grade 3 mucositis. No patient required treatment delay or reduction on more than one occasion.
One patient was excluded from the efficacy analysis because of the presence of composite lymphoma (transformed follicular lymphoma along with cHL, see the footnote of Table 3 for details). Among 38 patients eligible for response assessment, 35 (92%) achieved CR after two cycles of pembro-GVD and three (8%) achieved PR (Table 3). Eight patients (of which seven were evaluable) received two additional cycles of pembro-GVD (including three patients with initial PR and four patients with initial CR requiring delay of HDT/AHCT because of COVID [n = 3] or personal reasons [n = 1]). Following four cycles of pembro-GVD, one response improved from PR to CR, two patients remained with PR, and the other four patients had sustained CR. In summary, the overall CR rate and ORR after salvage therapy with pembro-GVD were 95% (95% CI, 82 to 99) and 100% (95% CI, 91 to 100), respectively.
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Among 38 evaluable patients, 36 (95%) proceeded to HDT/AHCT following two (n = 30) or four (n = 6) cycles of pembro-GVD (Fig 1). Two patients received pre-HDT/AHCT involved site radiation, including one patient with initially bulky disease and CR after two cycles of pembro-GVD and a second patient with PR after four cycles of pembro-GVD. Details regarding mobilization, conditioning, engraftment, and post-AHCT immune–related events, including ES, are provided in the Data Supplement (online only).
FIG 1. CONSORT diagram. BV, brentuximab vedotin; CR, complete response; HDT/AHCT, high-dose therapy and autologous hematopoietic cell transplantation; ISRT, involved site radiation therapy; pembro-GVD, pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin; PR, partial response.
Following HDT/AHCT, 13 (33%) patients received maintenance with brentuximab vedotin (n = 12) or brentuximab vedotin plus nivolumab (n = 1, on a clinical trial) for a median of five cycles (range, 1-11 cycles).
Of the two patients who did not proceed to HDT/AHCT, one withdrew from the study for personal reasons after achieving a CR to two cycles of pembro-GVD; the other patient declined HDT/AHCT and instead received treatment with single-agent pembrolizumab (off-study). That individual remains on pembrolizumab and in remission 16 months after completion of pembro-GVD.
With a median follow-up of 13.5 months (2.66-27.06 months) after HDT/AHCT, all patients are alive and in remission (Appendix Fig A1, online only). Five patients developed FDG-avid abnormalities after HDT/AHCT; however, biopsies did not demonstrate cHL. Details regarding the false-positive FDG-PET findings are discussed in the Data Supplement.
This phase II study of SLT with pembrolizumab plus GVD for rel/ref cHL showed high efficacy, good tolerability, and high rate of HDT/AHCT completion. In particular, 95% of patients achieved CR (92% after only two cycles) and all but two patients (because of patient preference) proceeded to HDT/AHCT. Efficacy was observed across rel/ref risk groups as 41% of patients had primary refractory disease, another 38% relapsed within their first year of treatment, and 59% had advanced-stage disease upon enrollment. Furthermore, remissions appear durable as no relapses have occurred to date after a median follow-up of 13.5 months (range: 2.66-27.06 months) post-HDT/AHCT. This compares favorably with our previous study evaluating PET-adapted second-line therapy with BV and augmented ICE in which the 6-year PFS was 73% and 80% of lymphoma-related events occurred within 1 year of HDT/AHCT.30 In addition to its high efficacy, pembro-GVD was associated with fairly good tolerability. Notable toxicities, including rash and transaminitis, were manageable, reversible, and resulted in few treatment delays or reductions.
The CR rate observed with frontline administration of single-agent pembrolizumab is 37%, whereas CR rates with GVD alone are not higher than 50%.15,17,31 We hypothesize that the high CR rate associated with pembro-GVD observed in this study is due to immune modulation by one or more drugs within GVD, working to enhance the impact of pembrolizumab. In particular, preclinical data demonstrated that gemcitabine could enhance cell immunity through increasing cross-presentation of antigen to CD8 cells following apoptosis, increasing major histocompatibility complex-1 expression on tumor cells, and augmenting dendritic cell maturation and function. Furthermore, gemcitabine was shown to reduce myeloid-derived suppressor cells in the tumor microenvironment (TME).32 Doxorubicin has been shown to enhance the proliferation of tumor antigen–specific CD8+ T cells in tumor-draining lymph nodes and promote tumor infiltration by IL-17–secreting γδ T cells and activated IFNγ-secreting CD8+ T cells. Finally, although enhanced antitumor immunity has not specifically been shown with vinorelbine, another vinca alkaloid (vincristine) has been shown to stimulate dendritic cell–mediated antigen presentation.29 It is unknown whether one or all of the drugs in GVD are needed for the efficacy we observed with pembro-GVD; however, similarly, high overall efficacy was observed with frontline sequential therapy with pembrolizumab and AVD31 and with frontline nivolumab given sequentially or concomitantly with AVD,33 suggesting that AVD may enhance the activity of PD-1 blockade as well.
A fascinating story is developing regarding the mechanism of PD-1 blockade in treatment-naïve and previously treated patients with cHL. The phase II randomized study of frontline treatment with either sequential or concomitant treatment with nivolumab and AVD for early-stage unfavorable cHL by Bröckelmann and colleagues showed high rates of CR after single-agent nivolumab (51%) and following completion of chemoimmunotherapy (83%-84%).33 Analysis of pretreatment and on-treatment biopsies from patients initially treated with single-agent nivolumab demonstrated early changes in the TME, suggesting that response to therapy occurred as a result of withdrawal of critical survival factors from the TME rather than induction of antitumor immunity.34,35 In particular, reduction in type I T-regulatory cells and PD-L1–positive macrophages accompanied the disappearance of Hodgkin Reed-Sternberg cells 2-15 days following treatment initiation with single-agent nivolumab, whereas no evidence of an adoptive cytotoxic immune response was observed. Interestingly, markedly different findings in patients with rel/ref cHL indicate a distinct mechanism of action in this patient population. In the CheckMate-205 study, which evaluated single-agent nivolumab in rel/ref patients, the mechanism of action appeared dependent on an antitumor immune response characterized by expansion of CD4+ cytotoxic T cells.36 This was evident by the finding of greater baseline T-cell receptor diversity among complete responders, coupled with treatment-associated expansion of T-cell receptor diversity and circulating CD4+ T cells in patients with the deepest response to therapy. The patients analyzed from the CheckMate-205 study had all received prior HDT/AHCT and thus were more heavily treated than the patients with rel/ref enrolled in our study. We suspect that the patients enrolled in our study are more immunologically similar to the untreated patients with cHL from Bröckelmann's nivolumab-AVD study and Allen's pembrolizumab-AVD study and that the high rate of brisk CRs we observed with pembro-GVD may similarly be a result of elimination of prosurvival immune cells (perhaps further aided by one of the chemotherapy agents in GVD).31,33
Frontline treatment of cHL has undergone significant modifications throughout the past 30 years. The initial approach was to optimize frontline therapy with intensive, full-course combination chemotherapy and, in many cases, radiation. With time, interim FDG-PET emerged as an important predictor of outcome and we learned that treatment can be modified on the basis of interim FDG-PET response.37,38 This has led to elimination of radiation for patients with bulky disease who achieve PET CR, reduced exposure to bleomycin for PET-2–negative advanced-stage patients, and significantly reduced use of radiation for early-stage patients.3,38,39 Likewise, the length of treatment can be reduced to as little as three cycles for the most favorable early-stage patients who achieve PET CR.40 Following frontline treatment failure, high-dose chemotherapy and autologous hematopoietic stem-cell transplant have been our best tool for improving the chance of cure. Given the high efficacy of pembro-GVD, we now face similar questions previously asked for frontline therapy. In particular, does every patient require aggressive therapy with HDT/AHCT? Can we now consider less-intensive approaches in the second-line setting and shift HDT/AHCT to the third-line setting for those who still need it? In the future, perhaps a regimen such as pembro-GVD could provide a path toward reducing the need for HDT/AHCT in the second-line setting; however, this question will need to be answered through a randomized study. In the meantime, consolidation with HDT/AHCT remains standard of care and the optimal pre-HDT/AHCT second-line therapy is the one that is well-tolerated and associated with a high rate of CR. Given the increasing use of BV in the frontline setting, SLT options that do not contain BV are needed. Pembro-GVD represents a highly active option for patients requiring SLT and is reasonable to consider for patients without contraindications for PD-1 blockade. To further define the role of PD-1 blockade in SLT, the Eastern Cooperative Oncology Group group is currently developing a randomized study of second-line chemotherapy with or without PD-1 blockade before HDT/AHCT.
In conclusion, for rel/ref cHL, second-line therapy with pembrolizumab plus GVD is highly effective and serves to efficiently bridge patients to consolidation with HDT/AHCT. The tolerability of pembro-GVD is acceptable, it is compatible with outpatient administration, and its efficacy compares favorably with other SLT regimens used in cHL. Furthermore, pembro-GVD as SLT is a promising option for patients previously treated with BV. The most important test of this regimen will be durability of response, and longer follow-up is needed to determine whether disease remissions are sustained and whether risk factors emerge as predictive of outcome.
See accompanying Oncology Grand Rounds on page 3097
The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp.
Presented in part at the American Society of Hematology meetings of 2019 (December 7-10, 2019, Orlando, FL) and 2020 (Virtual).
Supported by Investigator-Initiated Studies Program of Merck Sharp & Dohme Corp. A.J.M. is a Scholar in Clinical Research of The Leukemia & Lymphoma Society.
Memorial Sloan Kettering Cancer Center supports the International Committee of Medical Journal Editors and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on ClinicalTrials.gov when required as a condition of Federal awards, other agreements supporting the research, and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months after publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to crdatashare@mskcc.
Conception and design: Alison J. Moskowitz, Heiko Schöder, Helen Hancock, Paul Hamlin, David J. Straus, Gottfried von Keudell
Administrative support: Alison J. Moskowitz, Heiko Schöder, Nivetha Ganesan, Samia Sohail, Natasha Galasso, Rachel Neuman, Gilles Salles, Craig H. Moskowitz
Provision of study materials or patients: Alison J. Moskowitz, Heiko Schöder, Nivetha Ganesan, Helen Hancock, Connie L. Batlevi, Paul Hamlin, Philip Caron, Andrew M. Intlekofer, Audrey Hamilton, Steven M. Horwitz, Erel Joffe, Ariela Noy, Santosha Vardhana, Beatriz Wills Sanin, Gottfried von Keudell, Joachim Yahalom, Ahmet Dogan, Andrew D. Zelenetz
Collection and assembly of data: Alison J. Moskowitz, Gunjan Shah, Heiko Schöder, Nivetha Ganesan, Helen Hancock, Theresa Davey, Leslie Perez, Sunyoung Ryu, Samia Sohail, Alayna Santarosa, Natasha Galasso, Rachel Neuman, Brielle Liotta, William Blouin, Oscar Lahoud, Connie L. Batlevi, Ildefonso Rodriguez-Rivera, Colette Owens, Philip Caron, Andrew M. Intlekofer, Audrey Hamilton, Erel Joffe, Christina Lee, M. Lia Palomba, Georgios Pongas, Santosha Vardhana, Beatriz Wills Sanin, Gottfried von Keudell, Joachim Yahalom, Ahmet Dogan, Craig H. Moskowitz
Data analysis and interpretation: Alison J. Moskowitz, Gunjan Shah, Heiko Schöder, Esther Drill, Brielle Liotta, Anita Kumar, Oscar Lahoud, Connie L. Batlevi, Paul Hamlin, David J. Straus, Colette Owens, Steven M. Horwitz, Lorenzo Falchi, William Johnson, Ariela Noy, Matthew J. Matasar, Gilles Salles, Joachim Yahalom, Ahmet Dogan, Andrew D. Zelenetz, Craig H. Moskowitz
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Alison J. Moskowitz
Honoraria: Seattle Genetics
Consulting or Advisory Role: Seattle Genetics, Takeda, Imbrium Therapeutics, Merck, Janpix, Kyowa Kirin International, miRagen, ADC Therapeutics, Bristol Myers Squibb
Research Funding: Incyte, Seattle Genetics, Merck, Bristol Myers Squibb, miRagen, ADC Therapeutics, BeiGene
Gunjan Shah
Research Funding: Janssen, Amgen
Anita Kumar
Stock and Other Ownership Interests: Bridgebio
Consulting or Advisory Role: Celgene, Kite, a Gilead company, AstraZeneca/MedImmune
Research Funding: AbbVie/Genentech, Adaptive Biotechnologies, Celgene, Seattle Genetics, AstraZeneca/MedImmune, Pharmacyclics
Oscar Lahoud
Consulting or Advisory Role: MorphoSys
Travel, Accommodations, Expenses: MorphoSys
Open Payments Link: https://openpaymentsdata.cms.gov/physician/225358/summary
Connie L. Batlevi
Stock and Other Ownership Interests: Moderna Therapeutics, Novavax, Pfizer, Bristol Myers Squibb, Regeneron, Viatris
Honoraria: DAVAOncology
Consulting or Advisory Role: Lifesci Capital, GLG, Juno Therapeutics, Celgene, Seattle Genetics, Kite, a Gilead company, TG Therapeutics, Karyopharm Therapeutics
Research Funding: Janssen Biotech, Novartis, Epizyme, Xynomic Pharma, Bayer, Roche, Autolus
Open Payments Link: https://openpaymentsdata.cms.gov/physician/2778694
Paul Hamlin
Consulting or Advisory Role: Juno Therapeutics, Karyopharm Therapeutics, Celgene, Sandoz, AstraZeneca/Merck
Research Funding: Spectrum Pharmaceuticals, Seattle Genetics, Janssen, Portola Pharmaceuticals, GlaxoSmithKline, Molecular Templates, Incyte
David J. Straus
Consulting or Advisory Role: Takeda, Seagen, Epizyme
Research Funding: Takeda
Ildefonso Rodriguez-Rivera
Stock and Other Ownership Interests: Pfizer
Philip Caron
Stock and Other Ownership Interests: AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Johnson & Johnson/Janssen, Novartis, Pfizer, Teva
Steven M. Horwitz
Consulting or Advisory Role: Celgene, Millennium, Kyowa Hakko Kirin, Seattle Genetics, ADC Therapeutics, Verastem, Takeda, Astex Pharmaceuticals, Kura Oncology, Acrotech Biopharma, C4 Therapeutics, Janssen Oncology, Trillium Therapeutics, Vividion Therapeutics, Myeloid Therapeutics, Ono Pharmaceutical, Secura Bio, Shoreline Biosciences Inc, Tubulis
Research Funding: Celgene, Seattle Genetics, Takeda, Kyowa Hakko Kirin, Aileron Therapeutics, ADC Therapeutics, Verastem, 47, Trillium Therapeutics, Daiichi Sankyo, Affimed Therapeutics, Secura Bio
Lorenzo Falchi
Consulting or Advisory Role: Genmab
Research Funding: Roche, Genmab
Erel Joffe
Consulting or Advisory Role: AstraZeneca, Epizyme
Christina Lee
Honoraria: WebMD
Consulting or Advisory Role: Intellisphere LLC
M. Lia Palomba
Stock and Other Ownership Interests: Seres Therapeutics
Honoraria: Flagship Biosciences, Evelo Therapeutics, Jazz Pharmaceuticals, Therakos, Amgen, Merck, Seres Therapeutics
Consulting or Advisory Role: Flagship Biosciences, Novartis, Evelo Therapeutics, Jazz Pharmaceuticals, Therakos, Amgen, Merck, Seres Therapeutics, Kite, a Gilead company, Novartis, BeiGene
Research Funding: Seres Therapeutics
Patents, Royalties, Other Intellectual Property: Intellectual Property Rights, Juno intellectual property rights
Ariela Noy
Consulting or Advisory Role: MorphoSys, Janssen Biotech, Prime Oncology
Research Funding: Pharmacyclics, Rafael Pharmaceuticals
Travel, Accommodations, Expenses: Pharmacyclics, Janssen Oncology
Matthew J. Matasar
Stock and Other Ownership Interests: Merck
Honoraria: Genentech, Roche, Bayer, Pharmacyclics, Seattle Genetics, Takeda, Immunovaccine, ADC Therapeutics, Karyopharm Therapeutics
Consulting or Advisory Role: Genentech, Bayer, Merck, Juno Therapeutics, Roche, Teva, Rocket Medical, Seattle Genetics, Daiichi Sankyo, Takeda
Research Funding: Genentech, Roche, GlaxoSmithKline, Bayer, Pharmacyclics, Janssen, Rocket Medical, Seattle Genetics, Immunovaccine, IGM Biosciences
Travel, Accommodations, Expenses: Genentech, Roche, Seattle Genetics, Bayer
Georgios Pongas
Honoraria: Atara Biotherapeutics, Curio Science, OncLive/MJH Life Sciences
Travel, Accommodations, Expenses: Atara Biotherapeutics
Gilles Salles
Honoraria: Roche/Genentech, Janssen, Celgene, Gilead Sciences, Novartis, AbbVie, MorphoSys
Consulting or Advisory Role: Roche/Genentech, Gilead Sciences, Janssen, Celgene, Novartis, MorphoSys, Epizyme, Alimera Sciences, Genmab, Debiopharm Group, Velosbio, BMS, BeiGene, Incyte, Miltenyi Biotec, Ipsen
Santosha Vardhana
Honoraria: Agios
Consulting or Advisory Role: Immunai, ADC Therapeutics
Gottfried von Keudelll
Honoraria: Pharmacyclics
Consulting or Advisory Role: Pharmacyclics, Merck, Incyte
Ahmet Dogan
Consulting or Advisory Role: Seattle Genetics, Takeda, EUSA Pharma, AbbVie, Peerview, Physicans' Education Resource
Research Funding: Roche/Genentech
Andrew D. Zelenetz
Honoraria: NCCN, Clinical Care Options, Oncology Information Group, PER, Plexus
Consulting or Advisory Role: Gilead Sciences, Amgen, Genentech/Roche, Celgene, AstraZeneca, DAVAOncology, MorphoSys, BeiGene, MEI Pharma, Vaniam Group, Verastem, Pharmacyclics, Karyopharm Therapeutics, Debiopharm Group, Seattle Genetics, Quant Health Ltd, Kite, a Gilead company, Curis, Coherus Biosciences, Juno/Celgene/Bristol Myers Squibb, Curio Science
Research Funding: Genentech/Roche, Gilead Sciences, MEI Pharma, BeiGene
Craig H. Moskowitz
Consulting or Advisory Role: Merck Sharp & Dohme, Molecular Templates, Takeda, AstraZeneca, Incyte
Research Funding: AstraZeneca, Merck Sharp & Dohme
No other potential conflicts of interest were reported.
ACKNOWLEDGMENT
We are grateful for support from the Adam R. Spector Foundation.
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