To complement The ASCO Post’s continued comprehensive coverage of the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition, here are several abstracts selected from the meeting proceedings focusing on the assessment and treatment of patients with B-cell and T-cell non-Hodgkin lymphomas (NHL). For full details of these study abstracts, visit ashpublications.org.
Syed Ali Abutalib, MD
Julie M. Vose, MD, MBA, FASCO
Burkitt Lymphoma
ABSTRACT 705: The Burkitt lymphoma (BL) international prognostic index (BL-IPI)—An international validation cohort1
Background: BL is a rare, high-grade, B-cell lymphoma that is often studied in trials with small sample sizes. Historical definitions of “low-risk BL” vary between studies and identify a small favorable group, leaving 80% to 90% of patients in an undifferentiated “high-risk” category.
In 2019, investigators identified four clinical factors independently prognostic for outcome (age ≥ 40 years; lactate dehydrogenase [LDH] level > 3 × upper limit of normal [ULN]; ECOG performance status ≥ 2; and central nervous system [CNS] involvement) in adult patients with BL treated across 30 U.S. centers over 9 years.2 The current investigators sought to validate the BL-IPI prognostic model using an international cohort (n = 457).
Methods: Investigators analyzed the performance of the BL-IPI model in an external retrospective data set of adult patients with BL treated contemporaneously in centers from the United Kingdom, Scandinavia, Canada, and Australia.
Results: In the multivariable model, age ≥ 40 years, LDH level > 3 × ULN, performance status ≥ 2, and CNS involvement were selected as four independent prognostic factors; adding stage did not enhance the model. The model was simplified to three groups, with none of these factors (low risk), one factor (intermediate risk; hazard ratio [HR] = 3.14; 95% confidence interval [CI] = 1.61–6.14), or two to four factors (high risk; HR = 6.52; 95% CI = 3.48–12.20) associated with a 3-year progression-free survival of 92%, 72%, and 53%, respectively (P < .001). Median progression-free survival was reached in the high-risk group alone (46 months, 95% CI = 19–53 months). BL-IPI was similarly prognostic for overall survival (P < .001). Among patients with stage III or IV disease (historically classified as “high-risk” and constituting 78% of all patients in the cohort), the BL-IPI further discriminated the subgroups, with a 3-year progression-free survival of 87%, 71%, and 52%, respectively (P < .001).
In the international validation cohort, the BL-IPI categories were of similar size (low-risk, 15%; intermediate-risk, 35%; high-risk, 50%) and provided similar risk discrimination (Harrell’s C = .65 in both data sets). The progression-free survival at 3 years was 96%, 82%, and 63% in the three risk groups, respectively (P < .001), and overall survival was 99%, 85%, and 64% (P < .001). In the validation cohort, BL-IPI remained prognostic in the subsets receiving rituximab (P < .001) and with advanced-stage disease (P < .001).
Clinical Implications: BL-IPI is a novel prognostic index specific to BL, which was validated to allow for simplified stratification and comparison of risk distribution in geographically diverse cohorts. The index identified a low-risk group, with progression-free survival of 90% to 95%, which could be targeted with future strategies for treatment de-escalation. Conversely, only about 55% to 60% of patients in the high-risk group achieved cure with currently available immunochemotherapy regimens for aggressive NHLs.
Older Adults With New Diagnosis of DLBCL: Mosunetuzumab
ABSTRACT 401: Phase I/II study with mosunetuzumab—Single-agent mosunetuzumab chemotherapy-free regimen for elderly or unfit patients with previously untreated diffuse large B-cell lymphoma (DLBCL; ClinicalTrials.gov identifier NCT03677154)3
Background: Mosunetuzumab is a full-length, fully humanized IgG1 CD20/CD3 bispecific antibody that redirects T cells to engage and eliminate malignant B cells. Single-agent mosunetuzumab has shown promising efficacy (including durable complete responses) and tolerable safety in patients with relapsed or refractory DLBCL in a phase I study (NCT02500407).
Methods: Two safety evaluation cohorts were planned to receive mosunetuzumab at 13.5 mg and 30 mg, followed by an expansion phase. No safety concerns emerged following evaluation of the two safety cohorts. Eligible patients were were at least 80 years old or between 60 and 79 years old with impairment in at least one activity of daily living (ADL) or instrumental ADL, or with impairment in cardiac, renal, or liver function precluding the use of full-dose chemoimmunotherapy. Investigators reported safety, pharmacokinetics, and preliminary efficacy data from cohort B (n = 19).
Results: Among 19 patients, 16 experienced at least one adverse event, 13 had at least one adverse event related to mosunetuzumab, and 7 had a grade 3 to 4 adverse event, of which 4 were related to mosunetuzumab. No fatal events were observed. The most common (> 10%) treatment-emergent adverse events were grade 1 cytokine-release syndrome (n = 9), rash (n = 4,), neutropenia, nausea, decreased appetite, dry mouth, fatigue, pain, and muscle spasms (all n = 2). Grade 2 neurotoxicity was observed in one patient. Eight patients discontinued mosunetuzumab early due to progressive disease between cycles 2 and 6. No patient discontinued treatment due to an adverse event.
The overall response rate was 58% (11 of 19). The complete response rate was 42% (8 of 19).
Clinical Implications: Early clinical data indicate that single-agent mosunetuzumab confers notable efficacy and remarkable tolerability for previously untreated elderly or unfit patients with DLBCL. The long-term durability of these responses will require further follow-up.
Relapsed/Refractory B-Cell NHL: Novel Targets and Bispecific Antibodies
ABSTRACT 117: Phase I/II BRUIN Study—LOXO-305, a next-generation, highly selective, noncovalent Bruton’s tyrosine kinase (BTK) inhibitor in previously treated (≥ 2 prior therapies) mantle cell lymphoma (MCL), Waldenström’s macroglobulinemia (WM), and other NHLs (NCT03740529)4
Background: Despite the marked efficacy of covalent BTK inhibitors, treatment failure can occur through the development of resistance and discontinuation of treatment for adverse events. LOXO-305 inhibits both wild-type and C481-mutated BTK.
Methods: The primary endpoint was maximum tolerated dose/recommended phase II dosing identification. Safety was assessed in all patients (chronic lymphocytic leukemia/small lymphocytic lymphoma [CLL/SLL] and NHL, n = 186). Response was assessed every 8 weeks from cycle 3, and every 12 weeks from cycle 13. About 92% of patients with MCL had received a prior BTK inhibitor; 87% received at least one anti-CD20 antibody, chemotherapy, and BTK inhibitors; 10 patients had received transplant/CAR T-cell therapy; 71% of patients with WM had received a prior BTK inhibitor.
Results: At the efficacy cutoff date, 24 patients with MCL (63%) and 35 other patients with NHL (65%) remained on therapy. Among the subset of 20 efficacy-evaluable patients with MCL who started at the recommended phase II dosing (200 mg/d), the overall response rate was 65%, including 7 complete responses, 6 partial responses, and 4 with stable disease. Among the 15 efficacy-evaluable patients with WM, the overall response rate was 60%.
There were no dose-limiting toxicities or dose reductions. However, treatment emergent adverse events regardless of attribution or grade seen in ≥ 10% of patients were fatigue (16%) and diarrhea (15%).
Clinical Implications: LOXO-305 demonstrated promising efficacy in heavily pretreated, poor-prognosis patients with MCL, including those for whom currently available covalent BTK inhibitors had failed. Early efficacy was also observed in BTK-treated WM and other heavily pretreated NHLs. Another presentation at the ASH meeting described the promising efficacy of LOXO-305 in heavily pretreated, poor-prognosis patients with CLL/SLL following multiple prior lines of therapy.5 LOXO-305 was well tolerated and exhibited a wide therapeutic index.
Abstract 121: Phase I study of VLS-101, a receptor tyrosine kinase–like orphan receptor 1 (ROR1)-targeting antibody-drug conjugate, demonstrates a predictable safety profile and clinical efficacy in patients (n = 32) with heavily pretreated MCL (n = 15) and DLBCL (n = 5; NCT03833180).6
Background: ROR1 is an oncofetal protein that is physiologically expressed during embryogenesis and largely disappears by birth but can be reexpressed pathologically in transformed tissues of many hematologic and solid cancers. VLS-101 is an antibody-drug conjugate comprising a rapidly internalizing, humanized monoclonal antibody (UC-961) that recognizes extracellular ROR1, a cleavable linker, and the antimicrotubule cytotoxin monomethyl auristatin E (MMAE).
Methods: The median patient age was 70 years (range = 54–84). Patients had received a median of four prior systemic therapies. Among patients with MCL, 100% had received a BTK inhibitor. VLS-101 was infused over 30 minutes every 3 weeks until cancer progression or intolerable toxicity.
Results: Regarding dose-limiting toxicity, grade 4 neutropenia occurred in 9 of 32 patients; 1 of 32 had neutropenic fever. Granulocyte colony-stimulating factor successfully ameliorated neutropenia. On-study reversible grade 3 neuropathy occurred in 3 of 32 patients; no grade 4 neuropathy occurred.
Objective tumor responses were not seen in patients with other tumor types (CLL/SLL, follicular lymphoma [FL], marginal zone lymphoma [MZL]) but were observed in 47% (7 of 15) of patients with MCL (3 complete and 4 partial responses) and in 80% (4 of 5) of patients with DLBCL (2 complete and 2 partial responses). The VLS-101 recommended dosing regimen was 2.5 mg/kg every 3 weeks.
Clinical Implications: In heavily pretreated patients, VLS-101 infusions were well tolerated and demonstrated a predictable safety profile consistent with an MMAE-containing antibody-drug conjugate. Tumor selectivity was confirmed, with no evidence of ROR1-mediated toxicities or non-MMAE toxicities that would suggest normal tissue binding. Efficacy results provided clinical proof of concept for targeting ROR1 with VLS-101 and demonstrated durable objective responses in patients with advanced MCL or DLBCL, including those who had received prior BTK inhibitors or cellular therapies. Phase I/II studies of VLS-101 monotherapy and combination therapy in patients with hematologic cancers and solid tumors are planned.
Bispecific Antibodies: Odronextamab and Epcoritamab
ABSTRACT 400: Phase I study of odronextamab (REGN1979), a human CD20 × CD3 bispecific antibody, induces durable, complete responses in patients with highly refractory B-cell NHL, including patients refractory to chimeric antigen receptor (CAR) T-cell therapy (NCT02290951)7
Background: Odronextamab is a first-in-class, hinge-stabilized, fully human, IgG4-based CD3 × CD20 bispecific antibody that has demonstrated encouraging safety, tolerability, and preliminary efficacy in patients with relapsed or refractory B-cell NHLs.
Methods: Investigators presented safety and efficacy data from the dose-escalation and early dose-expansion phase of the ongoing study. The study included patients with DLBCL (n = 71), FL grade 1–3a (n = 37), MCL (n = 11), MZL (n = 6), and other B-cell NHLs (n = 2). Median follow-up was 3.9 months (range = 0.4–37.6 months).
Results: The maximum tolerated dose was not reached with odronextamab doses up to 320 mg weekly. However, the most frequent treatment-related adverse events of any grade were pyrexia (76.4%), cytokine-release syndrome (62.2%), and chills (48.0%).
Grade 3 cytokine-release syndrome occurred in eight patients (6.3%), and a grade 4 cytokine-release syndrome occurred in one patient. No patient discontinued odronextamab treatment due to cytokine-release syndrome. Dexamethasone premedication and step-up dosing mitigated the risk for cytokine-release syndrome. Grade 3 neurologic adverse events were noted in five patients, of which only three (2.3%) were considered treatment-related. None of these events required treatment discontinuation.
In relapsed or refractory FL, odronextamab demonstrated a broad window of therapeutic activity. In patients treated at doses ≥ 5 mg (n = 28), the objective response rate was 92.9%, and the complete response rate was 75.0%; the median duration of response was 7.7 months, with 13 of 21 complete responses ongoing at last tumor assessment.
In patients with relapsed or refractory DLBCL who had not received prior CAR T-cell therapy, treated at doses ≥ 80 mg (n = 10), the overall and complete response rates were 60%; the median observed duration of response was 10.3 months, with four of six complete responses ongoing at last tumor assessment.
In patients with DLBCL who were refractory to prior CAR T-cell therapy, treated at doses ≥ 80 mg (n = 21), the overall response rate was 33.3%, and the complete response rate was 23.8%; the median observed duration of response was 2.8 months, with five of five complete responses ongoing at last tumor assessment.
Clinical Implications: Odronextamab has demonstrated encouraging single-agent antitumor activity in patients with highly refractory B-cell NHLs, with a treatment-related discontinuation rate of 5.5%. Durable complete responses have been observed in patients with indolent and aggressive B-cell NHLs, including in those refractory to CAR T-cell therapy. A global phase II trial investigating odronextamab in the relapsed or refractory B-cell NHL is ongoing.
Abstract 402: Phase I/II study of epcoritamab—Updated dose-escalation data of epcoritamab across relapsed or refractory B-cell NHL subtypes, including patients with prior CAR T-cell therapy (NCT03625037)8
Background: Epcoritamab is a novel bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on B cells, inducing activation and cytotoxic activity of T cells for killing target lymphoma cells. In an open-label, phase I/II trial, initial data demonstrated an encouraging safety profile and potent single-agent clinical activity, even at low doses, in heavily pretreated patients with relapsed or refractory B-cell NHL.9
Methods: Investigators presented updated dose-escalation data, including initial results for the 48-mg recommended phase II dose and for patients with MCL. As of July 6, 2020, 67 patients were enrolled, which included 45 patients with DLBCL, 12 with FL, and 4 with MCL. More than half of patients were refractory to their most recent systemic therapy.
Results: Epcoritamab was well tolerated, and there were no treatment discontinuations due to treatment-related adverse events. The most common treatment-emergent adverse events were pyrexia (70%), local injection-site reactions (48%), and fatigue (45%). Cytokine-release syndrome events were all grade 1 and 2 (58%). Limited and transient neurotoxicity was observed.
In patients with relapsed or refractory DLBCL (n = 18) receiving epcoritamab ≥ 12 mg, the overall response rate was 66.7%, with six patients achieving a complete response. Of the seven patients who received epcoritamab ≥ 48 mg (48 mg recommended phase II dosing, n = 4; 60 mg, n = 3), all achieved a response, including complete responses in two patients with limited follow-up. All patients with DLBCL who were previously treated with CAR T-cell therapy achieved a response.
Patients with relapsed/refractory FL (n = 8) had an overall response rate of 100% receiving epcoritamab ≥ 0.76 mg, with two patients achieving a complete response. Among those with relapsed/refractory MCL (n = 4), responses have been observed in two patients with blastoid-variant MCL (one complete and one partial response).
Clinical Implications: Subcutaneous epcoritamab induces complete responses with an encouraging safety profile across relapsed or refractory B-cell NHL subtypes, including patients who had received prior CAR T-cell therapy.
T-Cell Non-Hodgkin Lymphomas
ABSTRACT 39: Phase III randomized study on behalf of LYSA—Final analysis of romidepsin plus cyclophosphamide, doxorubicin, vincristine, and prednisone (Ro-CHOP) in patients with peripheral T-cell lymphoma (PTCL; NCT01796002)10
Background: Romidepsin is a histone deacetylase inhibitor approved by the U.S. Food and Drug Administration (FDA) for patients with PTCL who have received at least one prior therapy.
Methods: The study compared Ro-CHOP with CHOP in patients with previously untreated PTCL.
Results: The addition of romidepsin to CHOP did not improve progression-free survival, the primary endpoint of the study, and response rates and overall survival appeared similar with the combination. The toxicity profile of Ro-CHOP was consistent with phase Ib/II data. The high rates of treatment-emergent adverse events with the addition of romidepsin hampered the ability to adequately administer six cycles of CHOP.
Clinical Implications: The combination of CHOP plus romidepsin does not represent an advance in the standard of care for patients with previously untreated PTCL. Additional exploratory analyses to compare Ro-CHOP outcomes in specific patient subgroups are ongoing.
Abstract 44: Phase II PRIMO Study—Duvelisib in patients with relapsed or refractory PTCL: Dose optimization efficacy update and expansion phase initial results (NCT03372057)11
Background: Relapsed or refractory PTCL is an aggressive lymphoma associated with a median overall survival of 6 months. Most approved therapies produce overall response rates less than 30%, low complete response rates, and short progression-free survival. Duvelisib, a dual PI3K-δ,γ inhibitor, is FDA-approved at 25 mg twice daily for the treatment of relapsed or refractory CLL/SLL after at least two lines of prior therapy and relapsed or refractory FL after at least two prior systemic therapies.
Duvelisib monotherapy demonstrated an overall response rate of 50% in patients with relapsed or refractory PTCL in a phase I study across multiple subtypes.12 In the phase II, open-label, multicenter PRIMO trial of duvelisib in relapsed or refractory PTCL, the initial results of the dose-optimization phase (n = 33) showed a 54% overall response rate with 75 mg twice a day (n = 13) and 35% with 25 mg twice a day (n = 20) by investigator assessment.13
Methods: In the dose-optimization phase, patients received duvelisib at 25 mg or 75 mg twice a day. Patients were evaluable if they completed one cycle (28 days) of duvelisib and had at least one efficacy assessment. The dose-expansion phase is ongoing, with a targeted enrollment of 100 patients. Subjects were eligible if they had histologically confirmed relapsed or refractory PTCL after at least two cycles of a prior standard regimen and a CD4 lymphocyte count ≥ 50/mm3 (0.05 × 109/L). For those receiving 25 mg twice a day, it was permitted for the dose to be re-escalated to 75 mg twice a day if assessment showed progressive disease and the patient did not require a dose modification due to toxicity.
Results: The mature dose-optimization phase results demonstrated a median duration of response of 12.2 months for the cohort receiving 75 mg twice a day. The preliminary results from the PRIMO dose-expansion cohort (75 mg twice a day followed by 25 mg twice a day) showed an overall response rate of 40% and a complete response rate of 30% (6 of 20) by investigator assessment. The most frequent adverse events were decreased neutrophil count (25%), increased alanine aminotransferase (21%), decreased white blood cell count (21%), and decreased lymphocyte count (21%).
Clinical Implications: Duvelisib at 75 mg twice daily shows promising activity in patients with relapsed or refractory PTCL, with a manageable toxicity profile.
Dr. Abutalib is Associate Director of the Hematology and BMT/Cellular Therapy Programs and Director of the Clinical Apheresis Program at the Cancer Treatment Centers of America, Zion, Illinois; Associate Professor at Rosalind Franklin University of Medicine and Science; and Founder of the journal Advances in Cell and Gene Therapy. Dr. Vose is the Neumann M. and Mildred E. Harris Professor and Chief of the Division of Oncology/Hematology at the Buffett Cancer Center, University of Nebraska Medical Center, Omaha.
DISCLOSURE: Dr. Abutalib has served on an advisory board for AstraZeneca.
Dr. Vose has received research support from AstraZeneca, BMS, Incyte, Kite Pharma, Novartis, Seattle Genetics, Loxo, and Epizyme and has received honoraria for consulting from AbbVie, Vaniam Group, Janssen/Pharmacyclics, Kite Pharma, AstraZeneca, Verastem, Miltenyi, Loxo, Allogene, Celgene, Roche, Genentech, Karyopharm, and Morphosis.
REFERENCES
1. Olszewski AJ, Jakobsen LH, Collins GP, et al: Aggressive lymphoma (diffuse large B-cell and other aggressive B-cell non-Hodgkin lymphomas). 2020 ASH Annual Meeting & Exposition. Abstract 705. Presented December 7, 2020.
2. Evens AM, Danilov AV, Jagadeesh D, et al: Burkitt lymphoma in the modern era. Blood 137:374-386, 2020.
3. Olszewski AJ, Avigdor A, Babu S, et al: Single-agent mosunetuzumab is a promising safe and efficacious chemotherapy-free regimen for elderly/unfit patients with previously untreated diffuse large B-cell lymphoma. 2020 ASH Annual Meeting & Exposition. Abstract 401. Presented December 6, 2020.
4. Wang M, Shah NV, Alencar AJ, et al: LOXO-305, A next generation, highly selective, non-covalent BTK inhibitor in previously treated mantle cell lymphoma, Waldenström’s macroglobulinemia, and other non-Hodgkin lymphomas. 2020 ASH Annual Meeting & Exposition. Abstract 117. Presented December 5, 2020.
5. Mato AR, Pagel JM, Coombs CC, et al: LOXO-305, a next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL. 2020 ASH Annual Meeting & Exhibition. Abstract 542. Presented December 7, 2020.
6. Wang M, Barrientos JC, Furman RR, et al: VLS-101, a ROR1-targeting antibody-drug conjugate, demonstrates a predictable safety profile and clinical efficacy in patients with heavily pretreated mantle cell lymphoma and diffuse large B-cell lymphoma. 2020 ASH Annual Meeting & Exhibition. Abstract 121. Presented December 5, 2020.
7. 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. 2020 ASH Annual Meeting & Exhibition. Abstract 400. Presented December 6, 2020.
8. 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. 2020 ASH Annual Meeting & Exhibition. Abstract 402. Presented December 6, 2020.
9. Lugtenburg P, Mous R, Clausen MR, et al: First-in-human, phase 1/2 trial to assess the safety and clinical activity of subcutaneous GEN3013 (DuoBody-CD3×CD20) in B-cell non-Hodgkin lymphomas. Blood 134(suppl 1):758, 2019.
10. Bachy E, Camus V, Thieblemont C, et al: Final analysis of the Ro-CHOP phase III study. 2020 ASH Annual Meeting & Exhibition. Abstract 39. Presented December 5, 2020.
11. Pro B, Brammer JE, Casulo C, et al: Duvelisib in patients with relapsed/refractory peripheral T-cell lymphoma from the phase 2 PRIMO trial. 2020 ASH Annual Meeting & Exhibition. Abstract 44. Presented December 5, 2020.
12. Horwitz SM, Koch R, Porcu P, et al: Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma. Blood 131:888-898, 2018.
13. Horwitz SM, Mehta-Shah N, Pro B, et al: Dose optimization of duvelisib in patients with relapsed or refractory peripheral T-cell lymphoma from the phase 2 PRIMO trial. Blood 134(suppl 1):1567, 2019.
