A Review of Selected Presentations From the All-Virtual 62nd ASH Meeting and
Exposition • December 5-8, 2020
Frontline Brentuximab Vedotin as Monotherapy or in Combination for Older Hodgkin Lymphoma Patients
Older patients with relapsed/refractory classical Hodgkin lymphoma have high rates of response and encouraging progression-free survival (PFS) when treated with brentuximab vedotin as monotherapy or in combination with other single agents, according to the results of a phase 2 study presented by Dr Christopher A. Yasenchak.1 Outcomes with standard chemotherapy in patients ages 60 years and older are markedly inferior to those in younger patients because of intrinsic differences in disease biology, as well as increased rates of baseline comorbidities, advanced disease, and treatment-related morbidity and mortality.2-4 In previous studies of patients ages 60 years and older with relapsed/refractory classical Hodgkin lymphoma, single-agent brentuximab vedotin achieved high response rates,5 and in combination with nivolumab, it produced objective response rates (ORRs) reaching 95%.6,7
The current study evaluated brentuximab vedotin at 1.8 mg/kg administered every 3 weeks for up to 16 cycles, either as a single agent (n=26) or in combination with dacarbazine at 375 mg/m2 (n=20), bendamustine at 70 mg/m2 (n=20), or nivolumab at 3 mg/kg (n=21). The patients’ median age was 74 years (range, 60-92).
The ORR was 92% (complete response [CR] rate, 72%) with brentuximab vedotin as a single agent. For the combination regimens, the ORR was 100% (CR rate, 68%) with dacarbazine, 100% (CR rate, 88%) with bendamustine, and 95% (CR rate, 79%) with nivolumab. The median PFS was 10.4 months, 47 months, 40 months, and not reached, respectively (Figure 1). The median overall survival was 8.2 months with single-agent brentuximab vedotin, 46.9 months with the bendamustine combination, and not reached with the dacarbazine and nivolumab combinations (Figure 2).
Enrollment in the bendamustine arm closed early owing to multiple acute toxicities. Grade 3 or higher treatment-related adverse events (AEs) occurred in 50% of the group treated with brentuximab vedotin as a single agent and in 40% of the dacarbazine group, 80% of the bendamustine group, and 62% of the nivolumab group. Peripheral neuropathy was the most common AE (27%, 25%, 15%, 19%). Serious treatment-related AEs occurred in 12%, 15%, 45%, and 5% of the patients, respectively. No treatment-related deaths occurred. Treatment discontinuation due to related AEs occurred in 42%, 40%, 60%, and 38% of patients, respectively.
The study investigators concluded that brentuximab vedotin monotherapy and combination therapy can be considered for older patients with relapsed/refractory classical Hodgkin lymphoma for whom conventional chemotherapy is unsuitable. Additional long-term follow-up is ongoing.
References
1. Yasenchak C, Bordoni R, Patel-Donnelly D, et al. Frontline brentuximab vedotin as monotherapy or in combination for older Hodgkin lymphoma patients [ASH abstract 471]. Blood. 2020;136(suppl 1).
2. Bachanova V, Connors JM. Hodgkin lymphoma in the elderly, pregnant, and HIV-infected. Semin Hematol. 2016;53(3):203-208.
3. Engert A, Ballova V, Haverkamp H, et al; German Hodgkin’s Study Group. Hodgkin’s lymphoma in elderly patients: a comprehensive retrospective analysis from the German Hodgkin’s Study Group. J Clin Oncol. 2005;23(22):5052-5060.
4. Evens AM, Hong F, Gordon LI, et al. The efficacy and tolerability of Adriamycin, bleomycin, vinblastine, dacarbazine and Stanford V in older Hodgkin lymphoma patients: a comprehensive analysis from the North American intergroup trial E2496. Br J Haematol. 2013;161(1):76-86.
5. Stefoni V, Marangon M, Re A, et al. Brentuximab vedotin in the treatment of elderly Hodgkin lymphoma patients at first relapse or with primary refractory disease: a phase II study of FIL ONLUS. Haematologica. 2020;105(10):e512.
6. Yasenchak CA, Bordoni R, Yazbeck V, et al. Phase 2 study of frontline brentuximab vedotin plus nivolumab in patients with Hodgkin lymphoma aged ≥60 years [ASH abstract 237]. Blood. 2019;134(suppl 1).
7. Advani RH, Moskowitz AJ, Bartlett NL, et al. Phase 1/2 study of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory classic Hodgkin lymphoma: part 3 (concurrent dosing) results and updated progression-free survival results from parts 1 and 2 (staggered dosing) [ASH abstract 1635]. Blood. 2018;132(suppl 1).
Phase II Study of Pembrolizumab Plus Gemcitabine, Vinorelbine, and Liposomal Doxorubicin as Second-Line Therapy for Relapsed or Refractory Classical Hodgkin Lymphoma
Second-line therapy with pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin (pembrolizumab-GVD) is a highly effective and well-tolerated regimen that can be used efficiently to bridge patients with relapsed/refractory classical Hodgkin lymphoma to high-dose consolidation and autologous stem cell transplant (ASCT), according to data from a phase 2 study presented by Dr Alison J. Moskowitz.1 No standard regimen exists for second-line therapy in classical Hodgkin lymphoma. Options include regimens containing platinum, gemcitabine, and brentuximab vedotin. CR rates achieved with these regimens range from 50% to 70%.2-10 Brentuximab vedotin is being used increasingly in the frontline setting; therefore, effective second-line regimens that do not include this agent are needed. Pembrolizumab is an inhibitor of programmed death 1 (PD-1) that appears to be highly active in the setting of relapsed/refractory disease.10,11
The study enrolled transplant-eligible patients with relapsed/refractory classical Hodgkin lymphoma after induction therapy. The regimen consisted of a 21-day cycle in which the following agents were administered intravenously (IV): pembrolizumab at 200 mg on day 1, gemcitabine at 1000 mg/m2 on days 1 and 8, vinorelbine at 20 mg/m2 on days 1 and 8, and liposomal doxorubicin at 15 mg/m2 on days 1 and 8. Patients with a CR (Deauville score ≤3) according to positron emission tomography (PET) after 2 or 4 cycles proceeded to consolidation with high-dose therapy and ASCT. The primary endpoint was the CR rate after 2 or 4 cycles of pembrolizumab-GVD.
Among 39 enrolled patients, 59% had stage III/IV disease, 31% had extranodal disease, 41% had prior refractory disease, and 38% had recurrent disease within 12 months after induction treatment. The median age was 31 years (range, 21-71), and 54% were female. Of the 2 patients not included in the analysis, one was still receiving the first 2 cycles of treatment and the other was found to have composite lymphoma.
Thirty-seven patients were evaluable for response. After 2 cycles of pembrolizumab-GVD, 34 patients had a CR (92%) and 3 had a partial response (PR; 8%). One patient with a CR was lost to follow-up. The 3 patients with a PR and 4 of those with a CR after the first 2 cycles received an additional 2 cycles of pembrolizumab-GVD. One patient converted from a PR to a CR, for an overall CR rate of 95%. Among the 7 patients who received an additional 2 cycles, one declined ASCT, and 6 underwent ASCT. Of the 35 patients who underwent ASCT, 11 received consolidation with brentuximab vedotin. No cases of disease progression occurred after a median follow-up of 11.2 months following ASCT.
The treatment was well tolerated, with rash the most common AE (46%, n=17; Figure 3). Grade 3 AEs included rash (n=1), elevated levels of aspartate aminotransferase/alanine aminotransferase (AST/ALT, n=3), oral mucositis (n=2), and neutropenia (n=3). No treatment discontinuations occurred owing to AEs.
The investigators concluded that pembrolizumab-GVD is highly effective and well tolerated in patients with relapsed/refractory classical Hodgkin lymphoma. They aim to evaluate a transplant-free approach in which pembrolizumab-GVD is administered for 4 cycles, after which patients with a CR will continue treatment with 13 doses of pembrolizumab maintenance rather than proceed to ASCT.
References
1. Moskowitz A, Shah G, Schöder H, et al. Phase II study of pembrolizumab plus GVD as second-line therapy for relapsed or refractory classical Hodgkin lymphoma [ASH abstract 470]. Blood. 2020;136(suppl 1).
2. Moskowitz CH, Matasar MJ, Zelenetz AD, et al. Normalization of pre-ASCT, FDG-PET imaging with second-line, non-cross-resistant, chemotherapy programs improves event-free survival in patients with Hodgkin lymphoma. Blood. 2012;119(7):1665-1670.
3. Josting A, Rudolph C, Reiser M, et al; Participating Centers. Time-intensified dexamethasone/cisplatin/cytarabine: an effective salvage therapy with low toxicity in patients with relapsed and refractory Hodgkin’s disease. Ann Oncol. 2002;13(10):1628-1635.
4. Bartlett NL, Niedzwiecki D, Johnson JL, et al; Cancer Leukemia Group B. Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin’s lymphoma: CALGB 59804. Ann Oncol. 2007;18(6):1071-1079.
5. Baetz T, Belch A, Couban S, et al. Gemcitabine, dexamethasone and cisplatin is an active and non-toxic chemotherapy regimen in relapsed or refractory Hodgkin’s disease: a phase II study by the National Cancer Institute of Canada Clinical Trials Group. Ann Oncol. 2003;14(12):1762-1767.
6. Santoro A, Magagnoli M, Spina M, et al. Ifosfamide, gemcitabine, and vinorelbine: a new induction regimen for refractory and relapsed Hodgkin’s lymphoma. Haematologica. 2007;92(1):35-41.
7. Herrera AF, Moskowitz AJ, Bartlett NL, et al. Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2018;131(11):1183-1194.
8. LaCasce AS, Bociek RG, Sawas A, et al. Brentuximab vedotin plus bendamustine: a highly active first salvage regimen for relapsed or refractory Hodgkin lymphoma. Blood. 2018;132(1):40-48.
9. Santoro A, Mazza R, Pulsoni A, et al. Five-year results of the BEGEV salvage regimen in relapsed/refractory classical Hodgkin lymphoma. Blood Adv. 2020;4(1):136-140.
10. Vassilakopoulos TP, Asimakopoulos JV, Konstantopoulos K, Angelopoulou MK. Optimizing outcomes in relapsed/refractory Hodgkin lymphoma: a review of current and forthcoming therapeutic strategies. Ther Adv Hematol. 2020;11:2040620720902911.
11. Chen R, Zinzani PL, Fanale MA, et al; KEYNOTE-087. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol. 2017;35(19):2125-2132.
Consolidation With Nivolumab and Brentuximab Vedotin After Autologous Hematopoietic Cell Transplantation in Patients With High-Risk Hodgkin Lymphoma
Consolidation treatment with brentuximab vedotin plus nivolumab after autologous hematopoietic cell transplant (AHCT) is promising in patients with relapsed/refractory Hodgkin lymphoma, even those with high-risk factors, according to a presentation by Dr Alex F. Herrera.1 The combination regimen was generally well tolerated, although more immune-related toxicity was observed in the post-transplant setting than is usually observed before transplant.
Since their advent, effective immunotherapies have been investigated in the post-transplant setting. In the phase 3 AETHERA trial, 16 cycles of brentuximab vedotin after AHCT improved 5-year PFS in patients with high-risk relapsed/refractory disease in comparison with placebo (59% vs 41%; hazard ratio [HR], 0.521; 95% CI, 0.379-0.717). However, the rate of peripheral neuropathy in this study was high, as was the rate of treatment discontinuation due to AEs.2,3 A phase 2 study of 30 patients with relapsed/refractory disease investigated the use of 8 doses of pembrolizumab after AHCT. The 19-month overall PFS rate was 81%. Therapy was generally well tolerated, with only 3 patients experiencing grade 3/4 AEs and 4 patients discontinuing treatment because of toxicity.4
On the basis of these data, the current study investigated the efficacy and safety of brentuximab vedotin plus nivolumab as consolidation after AHCT. Eligible adult patients had undergone AHCT and had at least one of the following risk factors: primary refractory disease, relapse within 1 year after completion of frontline therapy, extranodal disease or B symptoms at relapse, more than 1 salvage treatment before AHCT, and lack of a CR according to PET imaging after AHCT. Prior exposure to brentuximab vedotin or a PD-1 inhibitor was allowed if disease had not progressed during treatment. Post-transplant consolidative radiation therapy was allowed if it had occurred before the initiation of study treatment. Patients with grade 2 or higher peripheral neuropathy and those without adequate organ function were excluded. Starting between days 30 and 75 after AHCT, patients received brentuximab vedotin at 1.8 mg/kg and nivolumab at 3 mg/kg every 21 days for a planned 8 cycles. Discontinuation of one drug did not preclude continuation of the other. Response and progression of disease were assessed according to the 2014 Lugano Classification. The primary endpoint was PFS. Secondary endpoints included overall survival and the response rate in patients without a CR at baseline.
The median age of the 59 enrolled patients was 30 years (range, 18-72), and 58% were male; 33% had primary refractory disease, 24% had B symptoms at relapse, 39% had extranodal disease at relapse, 25% had required 2 or more salvage regimens before transplant, and 19% were not in CR according to PET imaging at the time of transplant. In addition, 65% of the patients had 2 high-risk factors, and 24% had 3 or more high-risk factors. Previous treatment included brentuximab vedotin in 51%, a PD-1 inhibitor in 42%, and radiation in 24%.
Approximately 49% of the patients completed all 8 cycles of both agents, and 76% completed all 8 cycles of at least one of the agents. The overall 19-month PFS rate was 92% (95% CI, 79%-97%; Figure 4). The PFS rate varied with the number of high-risk factors (Figure 5). Of the 6 patients without a CR at baseline, 5 converted to CR during study treatment, whereas 1 continued to have a PR until disease progression. The overall 19-month overall survival rate was 98% (95% CI, 88%-100%). One patient died of pneumonia that was not related to study treatment.
The most commonly reported AEs were peripheral sensory neuropathy (51%), neutropenia (42%), and fatigue (38%). The most common grade 3 or higher AEs were neutropenia (31%), pneumonitis (7%), and ALT elevation (5%). Immune-related AEs requiring systemic corticosteroids were recorded for 27% of the patients. The most frequent immune-related AEs included elevated liver function tests (14%), pneumonitis (14%), rash (12%), and hypothyroidism (7%).
The study investigators concluded that the administration of 8 cycles of brentuximab vedotin and nivolumab consolidation after AHCT in patients with high-risk, relapsed or refractory Hodgkin lymphoma is a promising approach. The combination was tolerable, although more immune-related toxicity occurred in the post-transplant setting than is usually observed before transplant. This combination warrants further study.
References
1. Herrera A, Chen L, Nieto Y, et al. Consolidation with nivolumab and brentuximab vedotin after autologous hematopoietic cell transplantation in patients with high-risk Hodgkin lymphoma [ASH abstract 472]. Blood. 2020;136(suppl 1).
2. Moskowitz CH, Nademanee A, Masszi T, et al; AETHERA Study Group. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385(9980):1853-1862.
3. Moskowitz CH, Walewski J, Nademanee A, et al. Five-year PFS from the AETHERA trial of brentuximab vedotin for Hodgkin lymphoma at high risk of progression or relapse. Blood. 2018;132(25):2639-2642.
4. Armand P, Chen Y-B, Redd RA, et al. PD-1 blockade with pembrolizumab for classical Hodgkin lymphoma after autologous stem cell transplantation. Blood. 2019;134(1):22-29.
Preliminary Results of a Phase 2 Study of Camidanlumab Tesirine (Cami), a Novel Pyrrolobenzodiazepine-Based Antibody-Drug Conjugate, in Patients With Relapsed or Refractory Hodgkin Lymphoma
Camidanlumab tesirine is an investigational agent in which an anti-CD25 antibody is conjugated to a pyrrolobenzodiazepine dimer. The antibody portion binds to CD25-expressing tumor cells, and the dimer causes cell death via the formation of cytotoxic DNA cross-links that block cell division.1 Data from the phase 1 trial demonstrated an ORR of 86.5% (CR of 48.6%) with a dose of 45 μg/kg in patients with relapsed/refractory classical Hodgkin lymphoma.2 The agent had a generally acceptable safety profile, although Guillain-Barré syndrome developed in 5 of 77 patients.
An ongoing multicenter, open-label, phase 2 trial is recruiting patients with relapsed/refractory classical Hodgkin lymphoma who have previously received 3 or more lines of treatment, including both brentuximab vedotin and a PD-1 inhibitor.3 The study is investigating the efficacy and safety of administering 2 cycles of camidanlumab tesirine at 45 µg/kg, followed by camidanlumab tesirine at 30 µg/kg from cycle 3 onward, for up to 1 year. The primary objective is the ORR. Secondary endpoints include the CR rate, PR rate, and number of patients continuing to ASCT.
At the time of data cutoff on August 24, 2020, 51 patients were enrolled in the study. Their median age was 36 years (range, 20-74), and 71% were male. The patients received a median of 5 cycles of treatment (range, 1-11). The median number of prior therapies was 7, and 73% of the patients had previously undergone ASCT. Approximately 49% of the patients had disease that was refractory to their most recent therapy.
The results were promising, with an ORR of 83%, a CR rate of 38%, and a PR rate of 45% (Figure 6). Stable disease was observed in 11% of patients, and 1 patient had progressive disease. Of the treated patients, 5 went on to receive a consolidated ASCT.
The most common treatment-emergent AEs included fatigue (51%), fever (39%), nausea (37%), and maculopapular rash (35.3%). The most common grade 3/4 treatment-emergent AEs were hypophosphatemia (12%) and increased gamma-glutamyltransferase. The most common treatment-emergent AEs thought to be associated with the pyrrolobenzodiazepine dimer were skin reactions and nail disorders (72.5%) and liver function test abnormalities (33%). In 6 patients, treatment-emergent AEs led to a dose reduction or delay. In 7 patients, treatment-emergent AEs led to a discontinuation of treatment.
Enrollment was paused after investigators reported 2 cases of Guillain-Barré syndrome, in addition to other relevant severe neurologic toxicity. An independent review identified 1 case of grade 4 Guillain-Barré syndrome, 1 case of grade 2 Guillain-Barré syndrome, and 1 case of grade 2 radiculopathy. These numbers are comparable with those observed in the phase 1 study.1 After the review, the enrollment pause was lifted.
References.
1. Collins G, Horwitz S, Hamadani M, et al. Analysis of clinical determinants driving safety and efficacy of camidanlumab tesirine (ADCT-301, cami) in relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). Abstract presented at: the 15th International Conference on Malignant Lymphoma; June 18-22, 2019; Lugano, Switzerland. Abstract 055.
2. Flynn MJ, Zammarchi F, Tyrer PC, et al. ADCT-301, a pyrrolobenzodiazepine (PBD) dimer-containing antibody-drug conjugate (ADC) targeting CD25-expressing hematological malignancies. Mol Cancer Ther. 2016;15(11):2709-2721.
3. Herrera A, Carlo-Stella C, Collins GP, et al. Preliminary results of a phase 2 study of camidanlumab tesirine (cami), a novel pyrrolobenzodiazepine-based antibody-drug conjugate, in patients with relapsed or refractory Hodgkin lymphoma [ASH abstract 474]. Blood. 2020;136(suppl 1)
Brentuximab Vedotin With Chemotherapy for Patients With Previously Untreated, Stage III/IV Classical Hodgkin Lymphoma: 5-Year Update of the ECHELON-1 Study
The phase 3 ECHELON-1 trial compared brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with newly diagnosed stage III/IV classical Hodgkin lymphoma. The modified 2-year PFS was 82.1% with A+AVD vs 77.2% with ABVD (HR, 0.77; 95% CI, 0.60 to 0.98; P=.04).1 Follow-up studies revealed a 42-month PFS rate of 82.4% with A+AVD vs 76.2% with ABVD (HR, 0.697; 95% CI, 0.547-0.890). The PFS benefit with A+AVD vs ABVD was independent of interim PET scan status, disease stage, and baseline disease risk factor score. Dr David J. Straus presented updated efficacy and safety results from the ECHELON-1 study after a median follow-up of 55.6 months.2
ECHELON-1 randomly assigned patients to receive 6 cycles of A+AVD (n=664) or ABVD (n=670) IV on days 1 and 15 of a 28-day cycle. An interim PET scan after cycle 2 was required. Patients were assessed every 3 months through month 36 and every 6 months thereafter. An exploratory analysis of PFS data was conducted with a cutoff date of May 18, 2020. The severity of peripheral neuropathy in patients with ongoing symptoms at the end of treatment was monitored. The investigators also assessed the rate of secondary malignancies and the incidence and outcomes of pregnancies among patients and partners.
The 5-year PFS rate was 82.2% (95% CI, 79.0%-85.0%) for the A+AVD arm and 75.3% (95% CI, 71.7%-78.5%) for the ABVD arm (HR, 0.691; 95% CI, 0.543-0.880; P=.003; Figure 7). The PFS benefits of A+AVD over ABVD were seen regardless of the interim PET scan status, number of risk factors (per the International Prognostic Factors Project on Advanced Hodgkin’s Disease), baseline disease stage (III or IV), presence or absence of B symptoms at baseline, presence or absence of extranodal sites at baseline, and sex.
Among the patients with treatment-emergent peripheral neuropathy, 84% of those in the A+AVD arm and 85% of those in the ABVD arm who had symptoms at the end of treatment reported complete resolution or improvement of their symptoms after 5 years of follow-up. Of the 127 patients (29%) with ongoing peripheral neuropathy in the A+AVD arm, a maximum severity of grade 1, 2, 3, or 4 was seen in 17%, 9%, 3%, and 0.2%, respectively (Figure 8). Of the 59 patients (21%) with ongoing peripheral neuropathy in the ABVD arm, a maximum severity of grade 1, 2, 3, or 4 was seen in 14%, 6%, 1% and 0, respectively.
Secondary malignancies were reported in 2.9% of the A+AVD arm and 4.3% of the ABVD arm. A total of 150 pregnancies were reported among patients and their partners (89 in the A+AVD arm and 61 in the ABVD arm). The proportions of live births in the female patients and the partners of male patients were similar in the 2 arms.
The investigators concluded that A+AVD continues to demonstrate a robust and durable treatment benefit over ABVD after a 5-year follow-up that is independent of disease stage, risk factor score, and interim PET scan status. A+AVD may be considered as a preferred treatment option for patients with previously untreated stage III or IV classical Hodgkin lymphoma.
References
1. Connors JM, Jurczak W, Straus DJ, et al; ECHELON-1 Study Group. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2018;378(4):331-344.
2. Straus DJ, Dlugosz-Danecka M, Connors JM, et al. Brentuximab vedotin with chemotherapy for patients with previously untreated, stage III/IV classical Hodgkin lymphoma: 5-year update of the ECHELON-1 Study [ASH abstract 2973]. Blood. 2020;136(suppl 1).
Everolimus Plus Itacitinib in Relapsed/Refractory Classical Hodgkin Lymphoma: Results of a Phase I/II Investigator Initiated Trial (EVITA Study)
The open-label, phase 1/2 EVITA study evaluated everolimus plus itacitinib in adult patients with an inadequate response to at least 2 prior lines of therapy and who underwent ASCT or who were ineligible for transplant.1 Eligible patients also had an inadequate response to brentuximab vedotin and a PD-1 inhibitor or were ineligible for treatment with these agents. All patients received everolimus at 5 mg daily. The starting dose of itacitinib was 300 mg daily, with escalation to 400 mg daily or de-escalation to 200 mg daily, in a traditional 3+3 trial design. Treatment was planned for up to 24 cycles of 28 days each. All patients received Pneumocystis jirovecii pneumonia prophylaxis and, after an amendment, antiviral prophylaxis. Dose-limiting toxicities in the phase 1 portion were defined as any grade 3 or higher nonhematologic AE or selected grade 4 hematologic AEs that occurred during the first cycle. The primary objective of the phase 2 portion was to evaluate efficacy (per the 2014 Lugano Classification). Enrollment began in February 2019, and the data cutoff for this report was November 2020.
The median age of the evaluable patients (n=16) was 37 years (range, 22-68), and 69% were male. The median number of prior therapies was 5 (range, 4-9). All patients had previously received treatment with brentuximab vedotin, 94% had previously received PD-1 inhibitors, 69% had undergone ASCT, 19% had undergone allogeneic AHCT, and 13% had previously received anti-CD30 chimeric antigen receptor T cells.
No dose-limiting toxicities were identified during the first cycle in phase 1. The phase 2 doses were everolimus at 5 mg daily and itacitinib at 400 mg daily. Hematologic AEs were common, and included thrombocytopenia (88%), neutropenia (50%), and anemia (50%; Figure 9). Notable nonhematologic AEs that were generally attributed to everolimus included hypercholesterolemia (50%), acneiform rash (44%), and mucositis dermatitis (12%). Grade 3/4 AEs, most of which were hematologic, included thrombocytopenia (38%), neutropenia (19%), anemia (7%), infection (7%), and hypertension (7%). There was one case of disseminated shingles requiring rehospitalization, but the patient recovered and resumed therapy. No treatment-related deaths occurred, and no patients discontinued treatment owing to AEs. Dose modification for hematologic toxicities was required for 6 patients (38%) after the first cycle.
The ORR in the combined phase 1/2 cohorts was 75% (CR rate, 12.5%), and 12.5% of the patients had stable disease. At a median follow-up of 10.7 months (range, 1.8-20.9), the median duration of response was 9.6 months (range, 1.6 to not determined). After they had left the study, 2 patients died; one death was from progressive disease and the other from complications of allogeneic stem cell transplant.
Reference
1. Svoboda J, Barta SK, Landsburg DJ, et al. Everolimus plus itacitinib in relapsed/refractory classical Hodgkin lymphoma: results of a phase I/II investigator initiated trial (EVITA study) [ASH abstract 473]. Blood. 2020;136(suppl 1).
2. Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 2016;375(9):819-829.
3. Márk Á, Hajdu M, Váradi Z, et al. Characteristic mTOR activity in Hodgkin-lymphomas offers a potential therapeutic target in high risk disease—a combined tissue microarray, in vitro and in vivo study. BMC Cancer. 2013;13:250.
4. Johnston PB, Pinter-Brown LC, Warsi G, White K, Ramchandren R. Phase 2 study of everolimus for relapsed or refractory classical Hodgkin lymphoma. Exp Hematol Oncol. 2018;7:12.
5. Phillips TJ, Forero-Torres A, Sher T, et al. Phase 1 study of the PI3Kδ inhibitor INCB040093 ± JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma. Blood. 2018;132(3):293-306.
PET-Guided Strategy Improves the Safety of BEACOPP-Based Treatment in Advanced Hodgkin Lymphoma: Prolonged Follow-Up of the Lysa AHL 2011 Phase 3 Study
Previous results from the phase 3 AHL2011 study demonstrated that 84% of patients with previously untreated Hodgkin lymphoma with PET negativity after 2 cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escalated BEACOPP) could be switched to 4 cycles of ABVD, allowing an immediate reduction in treatment toxicity without loss of tumor control.1 Dr Olivier Casasnovas reported the updated AHL2011 results.2
AHL2011 was a randomized phase 3 study (n=823) of patients with newly diagnosed and untreated advanced Hodgkin lymphoma, excluding the nodular lymphocyte predominant subtype. The median age was 30 years (range, 16-60 years), and 63% were male. Escalated BEACOPP consisted of the following: bleomycin at 10 mg/m2 and vincristine at 1.4 mg/m2 IV on day 8, etoposide at 200 mg/m2 IV on days 1 through 3, doxorubicin at 35 mg/m2 and cyclophosphamide at 1250 mg/m2 IV on day 1, procarbazine at 100 mg/m2 orally on days 1 through 7, and prednisone at 40 mg/m2 orally on days 1 through 14. Escalated BEACOPP was given every 21 days. ABVD consisted of the following: doxorubicin at 25 mg/m2, bleomycin at 10 mg/m2, vinblastine at 6 mg/m2, and dacarbazine at 375 mg/m2 IV on days 1 and 15. ABVD was given every 28 days.
All enrolled patients received 2 cycles of escalated BEACOPP followed by a PET assessment. In the standard treatment protocol, patients completed 4 additional cycles of escalated BEACOPP induction therapy irrespective of their PET findings. In the PET-driven protocol, patients with positive PET results received 4 additional cycles of escalated BEACOPP, whereas those with negative PET results were switched to ABVD. The primary endpoint of this noninferiority study was PFS, with secondary endpoints of overall survival, safety, and fertility.
After a median follow-up of 67.2 months, the 5-year PFS rates were similar in the PET-driven and standard-protocol arms (PFS rates, 86.7% vs 87.5%; HR, 1.09; 95% CI, 0.75-1.58; P=.68). The overall survival rate was 97.7% in both arms (HR, 1.027; 95% CI, 0.5-2.1; P=.943). The rates of positive PET results after cycle 2 and cycle 4 did not differ significantly between the 2 arms. PET positivity after cycle 2 and cycle 4 was used to stratify patients, revealing 3 statistically significant different subsets for predicting PFS (P<.0001) and overall survival (P=.028). Patients who were PET-negative after cycles 2 and 4 (n=654) had a 5-year PFS rate of 92.3% and an overall survival rate of 98.2%, whereas those who were PET-positive after cycle 2 and PET-negative after cycle 4 (n=62) had a 5-year PFS rate of 75.4% and an overall survival rate of 93.5% (Figure 10). Those who were PET-positive after both cycle 2 and cycle 4 (n=43) had the worst outcomes, with a 5-year PFS rate of 46.5% and an overall survival rate of 91.9%.
The safety profile was tolerable in both arms. Statistically significant differences in the incidence of grade 3/4 AEs were noted for anemia (11% standard vs 2% PET-driven), leukopenia (85% vs 74%), thrombocytopenia (44% vs 15%), and sepsis (7% vs 3%). Serious AEs were reported in 27% of patients in the standard arm and 17% of those in the PET-driven arm (P<.002). A secondary primary malignancy was reported in 3.2% vs 2.2%, respectively.
A fertility analysis included 145 women and 424 men ages 16 years to 45 years. In the fertility substudy, 32 female patients had primary ovarian insufficiency at years 5 to 6 (46% in the standard arm vs 15% in the PET-driven arm; HR, 0.20; 95% CI, 0.08-0.5; P<.001). Severe oligospermia at years 4 to 5 was seen in 50% of the male patients in the standard arm vs 93% of those in the PET-driven arm (P<.01). In the standard group, the total number of pregnancies was 37 among women and 7 among partners of male patients. The number of pregnancies was 39 and 22, respectively, in the PET-driven group. The PET-driven strategy provided a statistically significant improvement in male fertility (7 pregnancies vs 22 pregnancies; P=.004).
The study investigators concluded that the PET-driven induction strategy allowing 4 cycles of ABVD treatment in patients who are PET-negative after 2 cycles of escalated BEACOPP treatment is noninferior in comparison with a standard protocol of 6 cycles of escalated BEACOPP induction treatment. The PET-driven treatment significantly reduces the incidence of some grade 3/4 hematologic AEs, and also significantly decreases the risk for infertility in both sexes.
References
1. Casasnovas RO, Bouabdallah R, Brice P, et al. PET-adapted treatment for newly diagnosed advanced Hodgkin lymphoma (AHL2011): a randomised, multicentre, non-inferiority, phase 3 study. Lancet Oncol. 2019;20(2):202-215.
2. Casasnovas O, Racape J, Dechene J, et al. PET-guided strategy improves the safety of BEACOPP-based treatment in advanced Hodgkin lymphoma: prolonged follow-up of the Lysa AHL2011 phase 3 study [ASH abstract 475]. Blood. 2020;136(suppl 1).
Survival Outcomes for US and Canadian Patients Diagnosed With Hodgkin Lymphoma Before and After Brentuximab Vedotin Approval for Relapsed/Refractory Disease: A Retrospective Cohort Study
Insurance status affects the overall survival of patients with Hodgkin lymphoma treated in the United States.1 Universal health care in Canada provides broad coverage, but approvals of new drugs can be delayed. Brentuximab vedotin was approved in the United States in 2011 and in Canada in 2014. The current retrospective cohort study compared overall survival in US and Canadian patients who received a diagnosis of classical Hodgkin lymphoma before and after brentuximab vedotin was approved in the United States. Dr Gwynivere A. Davies and colleagues hypothesized that existing differences in overall survival within the United States according to insurance type would widen after the approval, and that a survival gap would emerge between privately insured US and Canadian patients owing to delayed approval in Canada.2
The study enrolled patients ages 16 to 64 years whose disease was diagnosed between 2007 and 2010 (period 1) or between 2011 and 2014 (period 2) and who were listed in the US Surveillance, Epidemiology, and End Results (SEER) Program or the Canadian Cancer Registry.
A total of 12,003 US and 4210 Canadian patients were included in the study. Patients in the United States demonstrated improved overall survival in period 2 vs period 1 in the adjusted analysis (adjusted HR, 0.80; 95% CI, 0.71-0.91; P<.05). Canadian patients showed significantly improved overall survival in period 2 vs period 1 in the unadjusted analysis (unadjusted HR, 0.72; 95% CI, 0.54-0.95; P<.05), but not after adjustment. A comparison of all patients by country in the 2 periods showed no significant difference between overall survival in the US patients and the Canadian patients. Stratifying the US patients by insurance and comparing overall survival between period 2 and period 1 demonstrated stable overall survival for those with private insurance, significantly improved overall survival for those with Medicaid, and slightly worse overall survival for uninsured patients (a difference that did not reach statistical significance; Figure 11).
In the analysis of overall survival by insurance type, with use of universal insurance as the reference and after adjustment for time period, age, sex, and lymphoma subtype, an increased risk for death was found in uninsured patients (HR, 1.80; 95% CI, 1.46-2.20; P<.0001) and in Medicaid patients (HR, 2.36, 95% CI, 2.02-2.76; P<.0001). A reduced risk for death was reported among patients with private insurance (HR, 0.87, 95% CI, 0.77-1.00; P=.044). A 36-month comparison of overall survival in the 2 time periods according to insurance status identified a 7.4% improvement among Medicaid patients and a 2.4% improvement among universal insurance patients in period 2 vs period 1. No change between the 2 time periods was found in privately insured patients. A 4.1% decrease in survival was noted for uninsured patients.
References
1. Parikh RR, Grossbard ML, Green BL, Harrison LB, Yahalom J. Disparities in survival by insurance status in patients with Hodgkin lymphoma. Cancer. 2015;121(19):3515-3524.
2. Davies G, Orav J, Brantley K. Survival outcomes for US and Canadian patients diagnosed with Hodgkin lymphoma before and after brentuximab vedotin approval for relapsed/refractory disease: a retrospective cohort study [ASH abstract 309]. Blood. 2020;136(suppl 1).
Highlights in Hodgkin Lymphoma From the 62nd American Society of Hematology Annual Meeting and Exposition: Commentary
Andrew M. Evens, DO, MSc, FACP
Several studies presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition provided insight into the management of patients with Hodgkin lymphoma. New data were presented for targeted treatments such as brentuximab vedotin, pembrolizumab, and camidanlumab tesirine. I review here key data in Hodgkin lymphoma, as well as several select abstracts in B-cell non-Hodgkin lymphoma.
Brentuximab Vedotin
Dr David Straus provided results from a 5-year update of the ECHELON-1 study, which compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (AVD) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with newly diagnosed, advanced-stage Hodgkin lymphoma.1 Previous results from the ECHELON-1 study were published in the New England Journal of Medicine and presented at earlier meetings.2-4
It is important for studies in Hodgkin lymphoma to continue to follow patients for at least 5 years. Among these patients, particularly those with advanced-stage disease, most relapses occur in the first 2 years. However, an additional 15% to 20% of patients may relapse through the 5-year mark.5 In addition, prognosis is worse among patients with an early positive positron emission tomography (PET) scan, but they represent a small minority of cases. Thus, most of the patients with advanced-stage Hodgkin lymphoma who relapse have a negative PET scan early in the disease course.
This long-term analysis of the ECHELON-1 study showed that the efficacy benefit reported with brentuximab vedotin at 2 years persisted through years 3, 4, and 5.1 At 5 years, progression-free survival was 82% with brentuximab vedotin plus AVD vs 75% with ABVD, for a hazard ratio of 0.68. Therefore, brentuximab vedotin plus AVD was associated with a 32% risk reduction in progression and death. The analysis also found that treatment-related toxicity improved with time. The investigators focused on peripheral neuropathy, which was increased in the brentuximab vedotin/AVD arm. Year after year, peripheral neuropathy improved or completely resolved among patients in both arms, including the brentuximab vedotin/AVD arm. By 5 years, neuropathy had either never occurred or completely resolved in 71% of patients treated with brentuximab vedotin, and neuropathy improved in 13%.
Dr Alex Herrera presented accrual data for the National Cancer Institute’s phase 3 randomized study of nivolumab plus AVD vs brentuximab vedotin plus AVD in patients with newly diagnosed advanced-stage Hodgkin lymphoma.6 The S1826 trial is a collaboration among SWOG, the Children’s Oncology Group (COG), the Eastern Cooperative Oncology Group/American College of Radiology Imaging Network (ECOG/ACRIN), the Alliance for Clinical Trials in Oncology, and the Canadian Cancer Trials group. The trial is evaluating patients ages 12 years and older in North America. Because the study is not including bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) in a treatment arm, there is no upper age limit, allowing for more inclusive enrollment. Any study that includes BEACOPP must limit enrollment to patients younger than 60 years.
The standard-of-care arm in this study was drawn from the ECHELON-1 trial, and consists of brentuximab vedotin and AVD given for 6 cycles.2 The experimental arm is nivolumab plus AVD. To date, the study has accrued approximately 240 patients. The planned enrollment is approximately 990 patients. I recommend that clinicians who treat patients with advanced-stage Hodgkin lymphoma contact the Clinical Trials of the Cancer Trials Support Unit about potentially opening this study at their institution. In addition, the trial design incorporates a host of important correlative studies, including quality of life, circulating tumor DNA, quantitative imaging, and economic analyses.
Dr Christopher Yasenchak presented results of our study evaluating brentuximab vedotin as monotherapy or in combination regimens as frontline treatment for older patients with Hodgkin lymphoma.7 In classical Hodgkin lymphoma, older patients (>60 years) have a significantly worse outcome compared with those who are younger. Before 2000, rates of survival at 3 and 5 years were only approximately 50% to 60% in older patients, compared with 90% in younger patients.
Researchers are increasingly using geriatric measurements to distinguish between older patients who are stronger, or “fit,” from those who are frail, or “unfit.” The study by Dr Yasenchak focused on older patients who were unfit. The study did not follow a formal geriatric assessment to define eligibility, but an overarching entry criteria permitted investigators to enroll patients who were not medically fit for multi-agent chemotherapy. This phase 2 study began treatment with brentuximab vedotin monotherapy, and then evaluated varied doublets by adding dacarbazine, bendamustine, or nivolumab (for a novel doublet). The patients’ median age was 74 years.
The bendamustine arm closed early owing to multiple acute toxicities. Therefore, in older patients, the combination of bendamustine plus brentuximab vedotin is not recommended. For the other treatment arms, the overall response rates were high, above 90%. The rates of complete response ranged from 68% to 88%. The median duration of response ranged from 17 months to 23 months, so there was a drop-off from the high rates of complete remission. With that said, in most of the arms, there appeared to be a plateau at the 50% to 60% range for patients who achieved complete remission. This observation is important because these patients were newly diagnosed, and several had ended treatment with brentuximab vedotin monotherapy 3, 4, or even 5 years before the analysis. Even some patients treated with the doublets had stopped therapy years earlier. Although the rate of complete remissions might have been lower than hoped, it should be noted that the patients were older and unfit. In addition, the regimens were free of anthracycline. Based on this study, brentuximab vedotin as monotherapy or in combination with bendamustine or nivolumab are valid options for these unfit older Hodgkin lymphoma patients.
Dr Alex Herrera presented data from a phase 2 study of consolidation with brentuximab vedotin and nivolumab after autologous stem cell transplant.8 In the AETHERA trial, which led the US Food and Drug Administration (FDA) to approve brentuximab vedotin for consolidation after an autologous transplant in relapsed/refractory classical Hodgkin lymphoma, the 5-year progression-free survival was approximately 60%.9 The benefit was even greater in patients with relapsed/refractory disease and multiple risk factors. The study by Dr Herrera aimed to improve upon this progression-free survival. The population was similar to that in AETHERA. Patients had at least 1 of the following characteristics: high-risk disease that was primary refractory or had relapsed within a year, extranodal involvement, B symptoms, lack of complete remission at transplant, and need for more than 1 salvage therapy. Treatment consisted of the doublet of brentuximab vedotin and nivolumab, given every 21 days for 8 cycles.
Overall, the treatment was well tolerated. Among 54 patients, the 19-month progression-free survival was 92%. These data are early, but highly encouraging. Longer follow-up is needed. An ongoing randomized study from ECOG is comparing the doublet of brentuximab vedotin and nivolumab with or without ipilimumab.10 It will be interesting to compare data from these studies. Multiple abstracts presented at the ASH meeting tested the strategy of integrating novel therapeutic agents earlier into the treatment armamentarium for patients with Hodgkin lymphoma.
Dr Pier Luigi Zinzani presented an interesting analysis of the randomized KEYNOTE-204 study, a phase 3 trial that compared brentuximab vedotin vs pembrolizumab in patients with relapsed or refractory classical Hodgkin lymphoma.11 Patients were randomly assigned to treatment with brentuximab vedotin at the usual dose of 1.8 mg/kg every 3 weeks or pembrolizumab at 200 mg intravenously every weeks. The KEYNOTE-204 study met its primary endpoint, showing that pembrolizumab had superior progression-free survival compared with brentuximab vedotin.12
The analysis by Dr Zinzani focused on health-related quality of life.11 The investigators evaluated global health, as well as quality-of-life ratings for different functional domains (cognitive and emotional) and symptoms related to treatment, such as fatigue, nausea, vomiting, pain, and dyspnea. Overall, the health-related quality-of-life data favored pembrolizumab. This was not the case for all of the measures. Fatigue and pain showed an improvement with pembrolizumab over brentuximab vedotin, and this improvement remained stable over time. When considering treatments for patients with lymphoma, response rate and progression-free survival are important, but quality of life should also be considered.
Pembrolizumab Plus Gemcitabine, Vinorelbine, and Liposomal Doxorubicin
Dr Alison Moskowitz presented data from an important phase 2 study evaluating the tolerability and efficacy of pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin in patients with relapsed/refractory Hodgkin lymphoma.13 The combination of gemcitabine, vinorelbine, and liposomal doxorubicin is a well-known active regimen.14 There are a host of different options in this setting. Most treatments have been studied in single-arm studies, phase 2 trials, or even retrospective analyses. There is a paucity of comparative research. As a general benchmark, chemotherapy has been associated with complete remission rates ranging from 40% to 50%. With novel regimens, such as sequential brentuximab vedotin used with ifosfamide, carboplatin and etoposide (ICE) or brentuximab vedotin combined with chemotherapy, the complete remission rates are higher, reaching 60% to 70%.2,15
The study by Dr Moskowitz and colleagues aimed to find a tolerable treatment with as good, or better, rates of complete remission that can be administered on an outpatient basis. Complete remission is the goal of first salvage therapy in relapsed Hodgkin lymphoma. It is known that patients who are in a complete remission at the time of transplant have superior outcomes.
In this phase 2 study, the combination of pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin was effective.13 Among 37 evaluable patients, the complete remission rate was 95%, which is among the best ever reported. At a median follow-up of 11.2 months, there were no cases of progressive disease. Progression-free survival was therefore 100%. The treatment was well tolerated. Longer follow-up is needed, and the regimen must be evaluated in a larger number of patients. However, these data were striking.
Camidanlumab Tesirine
Dr Alex Herrera presented results from an open-label, multicenter phase 2 study of the antibody-drug conjugate camidanlumab tesirine (also known as cami) in patients with relapsed or refractory Hodgkin lymphoma.16 Camidanlumab tesirine is a CD25 antibody that is conjugated to a pyrrolobenzodiazepine dimer as the cytotoxic agent. It is administered in a 30-minute intravenous infusion that is given every 3 weeks. Most of the patients in this trial had undergone an autologous stem cell transplant, and almost 100% of patients had experienced an inadequate response to previous treatment with brentuximab vedotin and programmed death 1 blockade. The overall response rate was an impressive 83%, with a complete remission rate of 38%. I am interested in seeing the data for the durability of this regimen. Overall, camidanlumab tesirine was well-tolerated. The most common grade 3 or higher treatment-emergent adverse events included low phosphate levels (12%), increased liver enzymes (6% to 10%), and rash (6%). A treatment-emergent adverse event led 14% of patients to withdraw from therapy.
Studies in Other Types of Lymphoma
Bispecific Antibodies
Several abstracts presented at the ASH meeting provided data for bispecific antibodies that target CD20 and CD3. These agents were highly efficacious in patients with relapsed/refractory B-cell lymphoma, in particular, diffuse large B-cell lymphoma and follicular lymphoma.17-19 They were associated with very high response rates, including complete remissions. Response rates were lower in patients who were resistant or refractory to CD19 chimeric antigen receptor (CAR) T-cell therapy, but any response rate with some degree of durability is an important finding in this group.
I am hopeful that at least one of the agents will be approved in 2021, which will add to the treatment armamentarium in B-cell lymphoma. It will also be interesting to see how these agents are sequenced with CAR T-cell therapy and other recently FDA-approved agents. Bispecific antibodies are associated with some toxicities, including immunosuppression. There is a slight increased risk of infections, some of which are cell-mediated. Cytokine release syndrome can occur, but the frequency and severity are far less than that seen in trials of CAR T-cell therapy.
Axicabtagene Ciloleucel
CD19 CAR T-cell therapy is currently approved by the FDA for the treatment of relapsed/refractory diffuse large B-cell lymphoma and mantle cell lymphoma. Dr Caron Jacobson presented results from the ZUMA-5 study, a phase 2 trial of axicabtagene ciloleucel in patients with relapsed/refractory indolent non-Hodgkin lymphoma.20 The trial administered axicabtagene ciloleucel to 124 patients with follicular lymphoma and 22 patients with marginal cell lymphoma. Treatment was active in both groups. Among patients with follicular lymphoma, the overall response rate was 94%, including a complete remission rate of 80%. The duration of response appeared to be markedly more durable in patients who were in a complete remission. Among all patients, at a median follow-up of 17.5 months, the median duration of response was not reached. According to the Kaplan-Meier curves at 24 months, the duration of response appeared to be just under 80% in patients with a complete remission. These data are impressive for this one-time treatment.
The side effects were similar to those seen in prior studies of CAR T-cell therapy. Grade 3/4 cytokine release syndrome was reported in 6% of patients with follicular lymphoma. Grade 3/4 neurologic events occurred in 15% of these patients. The study also included exploratory analyses of the association between CAR T-cell expansion and clinical outcomes, as well as a longitudinal profile of serum cytokines to identify any biomarkers of efficacy or neurologic events. These pharmacokinetic and pharmacodynamic analyses are early, but should provide important data. Before treatment, it would be helpful to have the ability to predict which patients are likely to garner the best benefit and to tolerate therapy well. Biomarker analyses will be important to study.
The Burkitt Lymphoma International Prognostic Index
My colleagues and I presented results from an analysis that aimed to develop a prognostic index for patients with follicular lymphoma.21 We examined data from more than 1000 patients across the world with newly diagnosed Burkitt lymphoma with the goal of creating a contemporary, validated prognostic index. The derivation cohort included 570 patients with Burkitt lymphoma. A validation cohort consisted of 457 patients throughout multiple countries in Europe, Canada, and Australia. We identified 4 dominant prognostic factors for progression-free survival and overall survival: ECOG performance status, age 40 years and older, levels of lactate dehydrogenase that were 3 times the upper limit of normal, and any central nervous system lymphoma involvement. The more of these factors the patient had, the worse the outcome. Among patients with zero factors in the derivation cohort, 3-year progression-free survival was 92%, and 3-year overall survival was 96%. Among patients with 2 or more of these factors, these survival rates were 53% and 59%, respectively. It is hoped that future prospective clinical studies will integrate these data. It may be possible for patients with favorable profiles to receive less-intense treatment, whether fewer drugs or fewer treatment cycles. Patients with a worse prognosis would need more novel therapeutics added to current treatment paradigms.
Disclosure
Dr Evens has received grant/research support from ORIEN and the Leukemia & Lymphoma Society. He is a member of the advisory boards (research-related) of Seattle Genetics, MorphoSys, Miltenyi, Karyopharm, Epizyme, Novartis, AbbVie, and Pharmacyclics. He is a consultant (educational-related) to Research to Practice, Curio, Cota, Patient Power, Curio Science, and OncLive.
References
1. Straus DJ, Dlugosz-Danecka M, Connors JM, et al. Brentuximab vedotin with chemotherapy for patients with previously untreated, stage III/IV classical Hodgkin lymphoma: 5-year update of the ECHELON-1 study [ASH abstract 2973]. Blood. 2020;136(suppl 1).
2. Connors JM, Jurczak W, Straus DJ, et al; ECHELON-1 Study Group. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2018;378(4):331-344.
3. Straus DJ, Długosz-Danecka M, Alekseev S, et al. Brentuximab vedotin with chemotherapy for stage III/IV classical Hodgkin lymphoma: 3-year update of the ECHELON-1 study. Blood. 2020;135(10):735-742.
4. Bartlett NL, Straus DJ, Dlugosz-Danecka M, et al. Brentuximab vedotin with chemotherapy for stage 3/4 classical Hodgkin lymphoma (cHL): 4-year update of the ECHELON-1 study [ASH abstract 4026]. Blood. 2019;134(suppl 1).
5. Stephens DM, Li H, Schöder H, et al. Five-year follow-up of SWOG S0816: limitations and values of a PET-adapted approach with stage III/IV Hodgkin lymphoma. Blood. 2019;134(15):1238-1246.
6. Herrera AF, Li H, Castellino SM, et al. SWOG S1826: a phase III, randomized study of nivolumab plus AVD or brentuximab vedotin plus AVD in patients with newly diagnosed advanced stage classical Hodgkin lymphoma [ASH abstract 2969]. Blood. 2020;136(suppl 1).
7. Yasenchak C, Bordoni R, Patel-Donnelly D, et al. Frontline brentuximab vedotin as monotherapy or in combination for older Hodgkin lymphoma patients [ASH abstract 471]. Blood. 2020;136(suppl 1).
8. Herrera A, Chen L, Nieto Y, et al. Consolidation with nivolumab and brentuximab vedotin after autologous hematopoietic cell transplantation in patients with high-risk Hodgkin lymphoma [ASH abstract 472]. Blood. 2020;136(suppl 1).
9. Moskowitz CH, Nademanee A, Masszi T, et al; AETHERA Study Group. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385(9980):1853-1862.
10. ClinicalTrials.gov. Brentuximab vedotin and nivolumab with or without ipilimumab in treating patients with relapsed or refractory Hodgkin lymphoma. ttps://www.clinicaltrials.gov/ct2/show/NCT01896999. Identifier: NCT01896999. Accessed January 29, 2021.
11. Zinzani PL, Ramchandren R, Santoro A, et al. Effect of pembrolizumab monotherapy versus brentuximab vedotin on symptoms associated with health-related quality of life in relapsed/refractory classical Hodgkin lymphoma in the randomized, phase 3, KEYNOTE-204 study [ASH abstract 374]. Blood. 2020;136(suppl 1).
12. Kuruvilla J, Ramchandren R, Santoro A, et al. KEYNOTE‐204: randomized, open‐label, phase III study of pembrolizumab (pembro) versus brentuximab vedotin (BV) in relapsed or refractory classic Hodgkin lymphoma (R/R cHL) [ASCO abstract 8005]. J Clin Oncol. 2020;38(15 suppl).
13. Moskowitz A, Shah G, Schöder H, et al. Phase II study of pembrolizumab plus GVD as second-line therapy for relapsed or refractory classical Hodgkin lymphoma [ASH abstract 470]. Blood. 2020;136(suppl 1).
14. Bartlett NL, Niedzwiecki D, Johnson JL, et al; Cancer Leukemia Group B. Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin’s lymphoma: CALGB 59804. Ann Oncol. 2007;18(6):1071-1079.
15. Stamatoullas A, Ghesquieres H, Filliatre LC, et al. Brentuximab vedotin in first refractory/relapsed classical Hodgkin lymphoma patients treated by chemotherapy (ICE) before autologous transplantation. Final analysis of phase II study [ASH abstract 132]. Blood. 2019;134(suppl 1).
16. Herrera AF, Carlo-Stella C, Collins GP, et al. Preliminary results of a phase 2 study of camidanlumab tesirine (Cami), a novel pyrrolobenzodiazepine-based antibody-drug conjugate, in patients with relapsed or refractory Hodgkin lymphoma [ASH abstract 374]. Blood. 2020;136(suppl 1).
17. Bannerji R, Allan JN, Arnason JE, et al. Odronextamab (REGN1979), a human CD20 × CD3 bispecific antibody, induces durable, complete responses in patients with highly refractory B-cell non-Hodgkin lymphoma, including patients refractory to CAR T therapy [ASH abstract 400]. Blood. 2020;136(suppl 1).
18. Kim TM, Alonso A, Prince M, et al. A phase 2 study of odronextamab (REGN1979), a CD20 × CD3 bispecific antibody, in patients with relapsed/refractory B-cell non-Hodgkin lymphoma [ASH abstract 3029]. Blood. 2020;136(suppl 1).
19. Hutchings M, Mous R, Clausen MR, et al. Subcutaneous epcoritamab induces complete responses with an encouraging safety profile across relapsed/refractory B-cell non-Hodgkin lymphoma subtypes, including patients with prior CAR-T therapy: updated dose escalation data [ASH abstract 402]. Blood. 2020;136(suppl 1).
20. Jacobson CA, Chavez JC, Sehgal AR, et al. Primary analysis of ZUMA-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) [ASH abstract 700]. Blood. 2020;136(suppl 1).
21. Olszewski AJ, Jakobsen LH, Collins GP, et al. The Burkitt Lymphoma International Prognostic Index (BL-IPI) [ASH abstract 705]. Blood. 2020;136(suppl 1).