Guest Editors
Syed Ali Abutalib, MD
Sonali M. Smith, MD, FASCO
To complement The ASCO Post’s continued comprehensive coverage of the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition, here are several abstracts selected from the meeting proceedings focusing on novel therapies for patients with non-Hodgkin lymphomas (NHLs). For full details of these study abstracts, visit ashpublications.org.
Newly Diagnosed Diffuse Large B-Cell Lymphoma
ABSTRACT 349: Positron-emission tomography (PET)-directed therapy for patients with limited-stage diffuse large B-cell lymphoma (DLBCL; n = 132): Results of Intergroup NCTN study S1001 (ClinicalTrials.gov identifier NCT01359592)1
Background: Limited-stage disease accounts for 30% to 40% of cases of DLBCL, with better overall survival than in advanced-stage disease, but with increased late relapses regardless of treatment strategy. Preferred treatment for early-stage nonbulky (< 7.5 cm) disease has been R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone) × 3 cycles followed by involved-site radiation therapy; in patients with an International Prognostic Index (IPI) of 0, the preferred regimen is R-CHOP × 3 cycles followed by two doses of rituximab. For patients with early-stage bulky (≥ 7.5 cm) disease, the preferred treatment is R-CHOP × 6 cycles with or without involved-site radiation therapy.
Methods: Patients had nonbulky (defined in this study1 as < 10 cm) stages I (62%) and II untreated DLBCL (68% were germinal center DLBCL), with a median age of 62 years. Patients with mediastinal, HIV-associated, testicular, central nervous system, and indolent lymphomas were excluded. Patients received standard R-CHOP therapy with an interim PET scan between days 15 to 18 of cycle 3. Patients with a negative PET scan (Deauville score of 1 to 3) proceeded with one additional cycle of R-CHOP. Patients with a positive PET scan (Deauville score of 4 or 5) initiated 36 Gy of involved-field radiation therapy, plus an additional boost to the fluorodeoxyglucose-avid area up to 9 Gy within 5 weeks of the third cycle of R-CHOP. This was followed by ibritumomab tiuxetan (radioimmunotherapy) 3 to 6 weeks after completing involved-field radiation therapy. A final PET scan was performed 12 weeks after treatment completion.
Results: The 5-year progression-free survival and overall survival estimates were 87% and 90%, respectively, with interim PET-positive and interim PET-negative patients having similar outcomes. The 5-year progression-free survival by stage–modified IPI was 97% for those with a score of 0, 86% for those with a score of 1 and 2, and 30% for those with a score of 3. Patients with germinal center DLBCL had a 5-year progression-free survival of 95% vs 70% for patients with activated B-cell type and 47% for patients with unclassifiable DLBCL. Double-expressor patients had a 5-year progression-free survival of 70% vs 89% for non–double-expressor patients. All four patients with double-hit lymphoma maintain remission.
Clinical Implications: The S1001 study demonstrated that 89% of patients maintained excellent outcomes after R-CHOP × 4 with PET-directed therapy. The study, due to the small number of lymphoma events, cannot draw definitive conclusions in patients with activated B-cell type (23%), double-expressor (16%), stage-modified IPI > 1, or double-hit (3%) lymphomas. Also, it is important to compare the S1001 study1 with the FLYER study,2 which established R-CHOP x 4 followed by two rituximab infusions (n = 293) in early-stage I or II “favorable-group” patients with DLBCL; these patients are defined as being between the ages of 18 and 60 with an Eastern Cooperative Oncology Group (ECOG) performance status score of 1 or 2, normal lactate dehydrogenase, and nonbulky (< 7.5 cm) disease who had noninferior outcomes with R-CHOP × 6 (n = 295). As a result of these two trials, abbreviated cycles of chemoimmunotherapy are now the standard of care in select patients with limited-stage DLBCL.
Relapsed or Refractory Follicular Lymphoma
ABSTRACT 123: Tazemetostat in patients with relapsed or refractory follicular lymphoma: Open-label, multicenter, phase II study (NCT01897571)3
Background: Relapsed or refractory follicular lymphoma remains a difficult-to-treat disease, especially for high-risk patients who are refractory or relapse within 24 months of front-line therapy. Currently, tazemetostat, which blocks activity of EZH2 methyltransferase, is U.S. Food and Drug Administration (FDA)-approved for patients with metastatic or locally advanced epithelioid sarcoma and are not eligible for complete resection. EZH2 regulates gene expression by controlling histone methylation. The gene is mutated in about 20% to 25% of patients with follicular lymphoma, and these alterations may drive the cancer by preventing germinal center formation.
Abbreviated cycles of chemoimmunotherapy are now the standard of care in select patients with limited-stage DLBCL.— SYED ALI ABUTALIB, MD, AND SONALI M. SMITH, MD, FASCO
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Methods: The primary endpoint was objective response rate. Tazemetostat was administered orally twice daily at a dose of 800 mg until progressive disease or study withdrawal. Patients with follicular lymphoma (n = 99), who had received at least two prior treatments (including at least one anti–CD20-based regimen), with a performance status of between 0 and 2 and measurable disease, were prospectively assigned to cohorts according to EZH2 mutational status: EZH2 mutation–type cohort, EZH2 wild-type cohort.
Results: Interim data were available for 99 patients (mutated EZH2, n = 45 [17 of whom experienced progression of disease within 2 years]; wild-type EZH2, n = 54 [30 of whom experienced progression of disease within 2 years]). Of the 33 patients (73%) with mutated EZH2 cohort who obtained an objective response, 15 had a response at ≥ 6 months, 7 at ≥ 12 months, and 4 at ≥ 16 months. Of the 18 patients (33%) in the wild-type cohort with an objective response, 15 had a response at ≥ 6 months, 9 at ≥ 12 months, and 6 at ≥ 16 months. Data from the mutated cohort continue to mature, with 11 patients (24%) enrolled in the past year and 17 patients (38%) still on treatment.
Treatment-related grade ≥ 3 adverse events were reported in 17% of all patients and 15% of patients in the subgroup of patients who experienced progression of disease within 2 years. The most frequently reported adverse events were similar across the total population and the subgroup of patients who experienced progression of disease within 2 years; they included thrombocytopenia (3%), anemia (2%), asthenia (2%), vomiting (1%), and fatigue (1%). A total of 5% of all patients discontinued treatment, and 9% had dose reductions due to treatment-related adverse events.
Clinical Implications: Tazemetostat demonstrated clinically durable, single-agent activity in patients with relapsed or refractory follicular lymphoma, including high-risk subgroups, with more responses in patients with EZH2 mutations. Based on these data, a new drug application has been submitted to the FDA for accelerated approval of tazemetostat in this patient population.
Relapsed or Refractory B-Cell Lymphoma
ABSTRACT 6: Mosunetuzumab induces complete remissions in poor-prognosis NHL, including those who are resistant to or relapsing after chimeric antigen receptor (CAR) T-cell therapies, and is active in treatment through multiple lines: Multicenter, phase I/Ib, dose-escalation and -expansion study (NCT02500407)4
Background: Mosunetuzumab is a bispecific, fully humanized, monoclonal antibody that binds to CD20 on the surface of malignant B cells and to CD3 on the surface of cytotoxic T cells, resulting in crosslinking of the T-cell receptor and subsequent activation of an immunologic T-cell response. In preclinical lymphoma models, mosunetuzumab induced T-cell proliferation and B-cell death. Mosunetuzumab is an off-the-shelf product, requiring no time for manufacturing, whereas the manufacture of CAR T cells is a laborious process that takes up to 3 to 4 weeks and relies on the use of each patient’s own T cells.
Methods: Outcome measures included best objective response rate (overall response rate) by revised International Working Group criteria, maximum tolerated dose, and tolerability.
Results: A total of 23 patients had prior CAR T-cell therapy (12 DLBCL, 6 transformed follicular lymphoma, 5 follicular lymphoma), and 16 were evaluable for efficacy (7 DLBCL, 5 transformed follicular lymphoma, 4 follicular lymphoma). Overall response and complete response rates were 43.8% (7 of 16) and 25.0% (4 of 16 [2 DLBCL and 2 follicular lymphoma]), respectively. The complete responses appeared to be durable. One complete and two partial responses were observed with mosunetuzumab retreatment.
Tazemetostat demonstrated clinically durable, single-agent activity in patients with relapsed or refractory follicular lymphoma.— SYED ALI ABUTALIB, MD, AND SONALI M. SMITH, MD, FASCO
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Adverse events leading to treatment withdrawal were uncommon (12 of 218; 5.5%). Cytokine-release syndrome was observed in 28.4% of patients and was mostly grade 1 to 2. Neurologic adverse events were reported in 44% of patients (grade 1, 28.0%; grade 2, 12.8%; grade 3, 3.2%). Common neurologic adverse events were headache (14.7%), insomnia (10.1%), and dizziness (9.2%). Potential immune effector cell–associated neurotoxicity syndrome–like neurologic adverse events of grade 1 or 2 confusional state occurred in three patients during cycles 1 and 2.
Clinical Implications: Preliminary data support further testing of mosunetuzumab based on favorable tolerability and durable efficacy in heavily pretreated patients with relapsed or refractory B-cell NHL, including in those whose disease did not respond to CAR T-cell therapy. Investigators suggest that sequencing mosunetuzumab with CAR T-cell therapy, or combining them, might allow for greater benefit in highly refractory patients. Moreover, contrary to CAR T-cell therapy, mosunetuzumab, if approved, would be more readily available (“off-the-shelf”), and retreatment might also be possible in a subgroup of patients.
Relapsed or Refractory T-Cell NHL
ABSTRACT 1001: Cerdulatinib demonstrates good tolerability and clinical response in relapsed or refractory peripheral T-cell lymphoma (PTCL; n = 38) and cutaneous T-cell lymphoma (CTCL; n = 22): A phase IIa study (CELTIC-1; NCT04021082)5
Background: Cerdulatinib is a small-molecule, reversible, ATP-competitive inhibitor of SYK and JAK family members. Data suggest that dual inhibition of SYK and JAK may perturb multiple and independent survival mechanisms in PTCL and CTCL.
Methods: The primary endpoint is response according to either the Lugano criteria (PTCL) or Global Assessment (CTCL). Patients are treated until disease progression, intolerance, or response adequate to allow allogeneic hematopoietic cell transplantation.
Results:
- In the PTCL cohort: A total of 26 patients were evaluable for response, and 12 patients had yet to reach their first assessment. The overall response rate was 35%, and the complete response rate was 31%. Responses have been observed in patients with angioimmunoblastic T-cell lymphoma, PTCL not otherwise specified, and gamma-delta T-cell lymphoma.
- In the CTCL cohort: A total of 10 patients were evaluable for response, and 12 had yet to be evaluated. The overall response rate was 50%, and the complete response rate was 10%. All responders and two patients with stable disease remain on drug therapy. Responses have been seen in patients with mycosis fungoides and Sezary syndrome. Rapid improvements in pruritus appear to correlate with clinical response.
- Adverse events: Among all patients, the most common adverse events of any grade were diarrhea (30%), increase in lipase levels (20%), increase in amylase levels (18%), nausea (13%), and neutropenia (12%). The increase in amylase and lipase levels occurred without clinical pancreatitis and resolved with dose reduction or dose interruption.
Clinical Implications: Cerdulatinib has shown good tolerability and sufficient activity in patients with PTCL and CTCL.
DISCLOSURE: Dr. Abutalib has served on the advisory board for AstraZeneca and Partner Therapeutics. Dr. Smith has served as a consultant or advisor to AbbVie/Genentech, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Gilead Sciences, Kite Pharma, Pharmacyclics, Portola Pharmaceuticals, Seattle Genetics, and TG Therapeutics; and has received research funding from Acerta Pharma/AstraZeneca, Celgene, and Pharmacyclics/Janssen.
REFERENCES
1. Persky DO, Li H, Stephens DM, et al: PET-directed therapy for patients with limited-stage diffuse large B-cell lymphoma: Results of Intergroup NCTN study S1001. Blood 134(suppl 1):349, 2019.
2. Poeschel V, Held G, Ziepert M, et al: Excellent outcome of young patients (18–60 years) with favorable-prognosis diffuse large B-cell lymphoma treated with 4 cycles of CHOP plus 6 applications of rituximab: Results of the 592 patients of the FLYER trial of the Dshnhl/GLA. Blood 132(suppl 1):781, 2019.
3. Morschhauser F, Tilly H, Chaidos A, et al: Phase II multicenter study of tazemetostat, an EZH2 inhibitor, in patients with relapsed or refractory follicular lymphoma. Blood 134(suppl 1):123, 2019.
4. Schuster SJ, Bartlett NL, Assouline S, et al: Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor T-cell therapies, and is active in treatment through multiple lines. Blood 134(suppl 1):6, 2019.
5. Horwitz SM, Feldman TA, Hess BT, et al: A phase II study of the dual SYK/JAK inhibitor cerdulatinib demonstrates good tolerability and relapsed/refractory peripheral T-cell lymphoma and cutaneous T-cell lymphoma. Blood 134(suppl 1):466, 2019.
