To complement The ASCO Post’s continued coverage of the virtual edition of the 25th European Hematology Association Annual Congress (EHA25 Virtual), here are a few abstracts selected from the meeting proceedings focusing on clinical research in Hodgkin and marginal zone lymphomas.
Dr. Abutalib is Associate Director of the Hematology and Cellular Therapy Program and Director of the Clinical Apheresis Program of the Cancer Treatment Centers of America, Zion, Illinois; Associate Professor at Rosalind Franklin University of Medicine and Science; and Founder and Co-Editor-in-Chief of Advances in Cell & Gene Therapy. Brad Kahl, MD, Professor of Medicine, Washington University School of Medicine; Director of Lymphoma Program, Siteman Cancer Center, St. Louis.
Omission of Radiotherapy in Hodgkin Lymphoma
ABSTRACT S101: Positron-emission tomography (PET)-guided omission of radiation therapy in early-stage “unfavorable” Hodgkin lymphoma: Final results of the international randomized phase III HD17 trial by the German Hodgkin Lymphoma Study Group (GHSG; ClinicalTrials.gov identifier NCT01356680)1
Background: The standard of care in Germany for “GHSG-defined unfavorable disease” (Table 1) is combined-modality therapy with two cycles of eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), plus two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) followed by radiation therapy (HD14 study).2 Combined-modality treatment comprising chemotherapy and consolidation radiotherapy is standard of care for patients with early-stage unfavorable Hodgkin lymphoma. However, the use of radiotherapy raises concerns about long-term sequelae in this young patient cohort. The investigators in the HD17 study asked whether radiotherapy can be omitted in patients achieving a complete metabolic response after “2+2” chemotherapy (two cycles of eBEACOPP followed by two cycles of ABVD) without loss of efficacy.
Methods: The HD17 study aimed to show noninferiority of the PET4-guided strategy in a per protocol analysis regarding progression-free survival, with a noninferiority margin of 8%.
Results: Between January 2012 and March 2017, the HD17 study enrolled 1,100 patients between the ages 16 to 60 years. Of 979 patients with confirmed PET4 results, 651 (66.5%) were PET4-negative (Deauville score 1 or 2), 238 (24.3%) had a Deauville score of 3, and 90 (9.2%) had a Deauville score of 4. Median observation time was 45 months (95% > confidence interval [CI] = 43–47 months) for progression-free survival and 47 months (95% > CI, 46–49 months) for overall survival. In the standard combined-modality therapy group (n = 428), 5-year progression-free-survival was estimated at 97.3% (95% CI = 94.5%–98.7%), as compared with 95.1% (95% CI = 92.0%–97.0%) in the PET4-guided treatment group (n = 477). The 5-year progression-free survival difference between the two groups was –2.2% (95% > CI = –5.3% to 0.9%), excluding the lower margin of –8%. Investigators aimed first to show noninferiority of the PET4-guided strategy in a per protocol analysis regarding progression-free survival, with a noninferiority margin of 8%. The second goal was to confirm PET4 positivity as a risk factor for progression-free survival in an intention-to-treat analysis of patients who received combined-modality therapy.
Clinical Implications: In patients who are PET-negative (defined as Deauville score 1 or 2) after four cycles (two cycles of eBEACOPP followed by two cycles of ABVD), radiation therapy can be safely omitted. Of note, this pattern of chemotherapy administration is rarely utilized in North America. Patients receive two cycles of ABVD chemotherapy, followed by interim PET imaging, and those who are PET-negative (Deauville score 1–3) receive four additional cycles of AVD chemotherapy (bleomycin omitted) and no radiation. Patients who are interim PET-positive receive the escalated BEACOPP regimen followed by involved-field radiation. This strategy allows avoidance of radiation in the vast majority of patients with early-stage unfavorable Hodgkin lymphoma.
It is important to note that the definitions by the National Comprehensive Cancer Network® (NCCN®) and the European Organisation for Research and Treatment of Cancer of early-stage “unfavorable” disease are different from the definition by GHSG (Table 1). In addition, the current 2020 NCCN recommendation for such a group of patients is divided into two major categories (patients ≥ 18 years of age):
Nonbulky disease (any B symptoms or sedimentation rate ≥ 50 or > three sites of nodal disease), → ABVD × two cycles followed by additional two cycles plus radiation therapy, provided PET scan is reported as Deauville score 1 to 2.
Bulky disease (defined as > 10 cm lymph node size or mediastinal mass ratio > 0.33) → ABVD × two cycles followed by an additional two to four cycles with or without radiation therapy, provided PET scan is reported as Deauville score 1 to 3. Of note, there is a lack of clarity in the number of cycles and use of radiation therapy.
Pembrolizumab vs Brentuximab Vedotin in Classic Hodgkin Lymphoma
ABSTRACT LB2600: Phase III, randomized, open-label study of pembrolizumab (n = 148) vs brentuximab vedotin (n = 152) for treatment of patients, older than 18 years of age, with relapsed or refractory classic Hodgkin lymphoma (NCT02684292)3
Background: The anti-PD-1 antibody pembrolizumab is U.S. Food and Drug Administration (FDA)-approved for patients whose disease is refractory or has relapsed after at least three lines of therapy. Single-agent brentuximab vedotin is FDA-approved for patients after failure of autologous hematopoietic cell transplantation or after failure of at least two prior multiagent chemotherapy regimens in patients who are not candidates for hematopoietic cell transplantation.
Methods: Eligible patients had measurable disease, an Eastern Cooperative Oncology Group performance score of 0 or 1, and had either undergone failed autologous hematopoietic cell transplant (n = 112) or were ineligible for the procedure. Patients were randomly assigned 1:1 to pembrolizumab (200 mg intravenous every 3 weeks) or brentuximab vedotin (1.8 mg/kg intravenous every 3 weeks). In all, 15 patients had received prior brentuximab vedotin, and 123 patients had primary refractory disease. Randomization was stratified by status after front-line therapy (primary refractory vs relapsed less than 12 months vs relapsed at least 12 months after the end of front-line therapy) and prior autologous hematopoietic cell transplant. Primary endpoints were progression-free survival by blinded independent central review including clinical and imaging data after autologous hematopoietic cell transplant or allogeneic hematopoietic cell transplantation and overall survival.
Results:
• Complete response rates: Comparable (~24%) for pembrolizumab and brentuximab vedotin.
• Progression-free survival: Statistically significant improvement was observed with pembrolizumab vs brentuximab vedotin (hazard ratio = 0.65 [95% CI = 0.48–0.88; P = .00271]; median 13.2 vs 8.3 months); 12-month progression-free survival analysis rates were 53.9% vs 35.6%, respectively.
• Median (range) duration of response: Pembrolizumab → 20.7 months (0.0–33.2 months); brentuximab vedotin → 13.8 months (0.0–33.9 months). The difference was not clinically significant.
• Treatment-related adverse events: About 74.3% of patients who received pembrolizumab and 77.0% of patients who received brentuximab vedotin experienced a treatment-related adverse event, most commonly hypothyroidism (15.5%) with pembrolizumab and peripheral neuropathy (18.4%) with brentuximab vedotin.
• Serious (grade 3–5) treatment-related adverse events: About 19.6% of patients who received pembrolizumab and 25.0% of patients who received brentuximab vedotin had grade 3 to 5 treatment-related adverse events, most frequently pneumonitis (4.1%) with pembrolizumab and neutropenia (7.2%) with brentuximab vedotin. One death (grade 5) due to pneumonia occurred in a patient receiving pembrolizumab.
Clinical Implications: In the KEYNOTE-204 study, pembrolizumab demonstrated a progression-free survival benefit over brentuximab vedotin in patients with relapsed or refractory classic Hodgkin lymphoma. More patients had serious treatment-related adverse events and discontinued treatment in the pembrolizumab arm (16.2% and 8.8%, respectively) than those in the brentuximab vedotin arm (10.5% and 3.9%, respectively). Moreover, with pembrolizumab, there is a higher risk of early immune-related toxicity after allogeneic hematopoietic cell transplantation; this may be abrogated by cessation of therapy 6 weeks prior to the transplant procedure, infusion of marrow graft (instead of peripheral blood graft), and use of posttransplant cyclophosphamide as part of graft-vs-host disease prophylaxis.4-6 Table 2 outlines selected recommendations for patients with classic Hodgkin lymphoma eligible for allogeneic transplant after failure of autologous transplant receiving immunotherapy. For complete recommendations, see reference 4.
Zanubrutinib in Marginal Zone Lymphoma
ABSTRACT EP1165: Phase I/II study of single-agent zanubrutinib in patients with relapsed or refractory marginal zone lymphoma (n = 20; MAGNOLIA; NCT03846427)7
Background: Zanubrutinib, a selective and irreversible BTK inhibitor, is being tested in relapsed or refractory marginal zone lymphoma.
Methods: The study included a total of 20 patients, with extranodal disease in 9, nodal disease in 5, and splenic disease in 6. The primary efficacy endpoint is overall response rate, according to the Lugano classification. At data cutoff on January 29, 2020, with a median follow-up of 27.1 months (8.3–51.1 months), 12 patients remained on treatment.
Results: The overall response rate was 80% (95% CI = 56.3%–94.3%), with a complete response rate of 15% and a partial response rate of 65%. Of note, patients with nodal marginal zone lymphoma (n = 5) had an overall response rate of 100% (95% CI = 47.8%–100.0%). The median time to response was 2.8 months, and at 18 months, 66.2% of responders were still responding to treatment (95% CI = 32.4%–86%). Progression-free survival at 24 months was 59.4%. Common adverse events of grade 3 or above were neutropenia (15%), anemia (10%), and pyrexia (10%). Serious adverse events were reported in nine patients. One patient discontinued treatment due to an adverse event, and there were no deaths reported.
Clinical Implications: Zanubrutinib produced a high response rate in an early-phase study of 20 patients with relapsed or refractory marginal zone lymphoma. The trial completed accrual, with a total of 68 patients, and results are awaited. Zanubrutinib may provide another active and well tolerated treatment option in the management of marginal zone lymphoma. ν
DISCLOSURE: Dr. Abutalib has served as a consultant to AstraZeneca. Dr. Kahl has served as a consultant to AbbVie, Acerta, AstraZeneca, Beigene, Janssen, Genentech/Roche, and Pharmacyclics.
REFERENCES
1. Borchmann P: Positron emission tomography guided omission of radiotherapy in early-stage unfavorable Hodgkin lymphoma: Final results of the international, randomized phase III HD17 trial by the GHSG. EHA25 Virtual Congress. Abstract S101.
2. von Tresckow B, Plütschow A, Fuchs M, et al: Dose-intensification in early unfavorable Hodgkin’s lymphoma: Final analysis of the German Hodgkin Study Group HD14 trial. J Clin Oncol 30:907-913, 2012.
3. Zinzani PL, Ramchandren R, Santoro A, et al: Phase 3, randomized, open-label study of pembrolizumab versus brentuximab vedotin for treatment of relapsed or refractory classical Hodgkin lymphoma: KEYNOTE-204. EHA25 Virtual Congress. Abstract LB2600.
4. Herbaux C, Merryman R, Devine S, et al: Recommendations for managing PD-1 blockade in the context of allogeneic HCT in Hodgkin lymphoma: Taming a necessary evil. Blood 132:9-16, 2018.
5. Schoch LK, Cooke KR, Wagner-Johnston ND, et al: Immune checkpoint inhibitors as a bridge to allogeneic transplantation with posttransplant cyclophosphamide. Blood Adv 2:2226-2229, 2018.
6. Merryman RW, Kim HT, Zinzani PL, et al: Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma. Blood 129:1380-1388, 2017.
7. Tedeschi A, Trotman J, Tam C, et al: Phase 1/2 study of single-agent zanubrutinib in patients with relapsed/refractory marginal zone lymphoma. EHA25 Virtual Congress. Abstract EP1165.
