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Department of Medicine
Harvard Medical School
Director, Center for Lymphoma
Massachusetts General Hospital
Jeremy S. Abramson, MD, MMSc, has disclosed that he has received consulting fees from AbbVie, Allogene, AstraZeneca, BeiGene, Bluebird, C4 Therapeutics, Celgene, EMD Serono, Genentech, Incyte, Karyopharm, Kite, Morphosys, and Novartis.
There were numerous presentations of clinical interest for healthcare professionals treating patients with lymphoma and chronic lymphocytic leukemia (CLL) at the virtual 2020 ASH conference. In this commentary, I briefly discuss key studies poised to affect clinical practice.
Approved and Investigational Targeted Therapeutics for CLL
Exciting data were presented at ASH 2020 regarding new treatments for patients with CLL. The BCL-2 inhibitor venetoclax was approved in combination with the anti‑CD20 monoclonal antibody obinutuzumab as frontline treatment for patients with CLL based on the phase III CLL14 trial, which randomized untreated patients with CLL to this combination or chlorambucil plus obinutuzumab, each given for 1 year as fixed‑duration therapy. At ASH 2020, 52‑month follow up data from this trial were presented and showed that the 4‑year PFS rate was 74% with venetoclax plus obinutuzumab vs only 35% with control treatment. These exciting data demonstrate durable remissions with fixed‑duration venetoclax plus obinutuzumab in previously untreated CLL. The majority of those patients receiving this treatment achieved undetectable measurable residual disease (MRD) and, not surprisingly, patients who achieved undetectable MRD had a longer PFS compared with those who did not.
We also saw long‑term follow up data from the phase III MURANO trial. Results from this trial previously established 2 years of fixed-duration venetoclax plus rituximab as a standard of care in relapsed/refractory (R/R) CLL, with this regimen demonstrating superior PFS and OS compared with bendamustine plus rituximab. Data were reported at ASH 2020 with a median follow-up of 5 years and demonstrated a median PFS of 54 months with venetoclax plus rituximab vs only 17 months with control treatment. At 5 years, 38% of patients treated with venetoclax plus rituximab remained progression free and 82% remained alive.
These presentations demonstrated encouraging remission durability with venetoclax combined with either obinutuzumab in the upfront setting or rituximab in the R/R setting for patients with CLL.
Another exciting presentation described the evaluation of a novel, noncovalent, investigational BTK inhibitor called pirtobrutinib (formerly LOXO‑305), which was evaluated in the phase I/II BRUIN study predominantly in previously treated patients with CLL and other non‑Hodgkin lymphoma subtypes. What is notable about pirtobrutinib is that, unlike the currently approved BTK inhibitors, this agent has activity against CLL with a BTK C481S mutation, which renders resistance to the other BTK inhibitors.
BRUIN evaluated pirtobrutinib in 170 patients with a median of 3 previous therapies; 86% of patients had received a previous BTK inhibitor, with two thirds stopping this treatment due to refractory disease. Pirtobrutinib was well tolerated and did not significantly increase risks of bleeding, bruising, arthralgias, hypertension, or atrial fibrillation, which are adverse events of interest with first generation BTK inhibitors. The ORR was encouraging at 63%, and no difference in response rate was observed in patients who had previously been exposed to a BTK inhibitor vs those who had not. At a median follow-up of 6 months, 94% of patients had ongoing responses; additional follow-up is needed to assess the durability of these responses.
In other subsets of this trial, among 56 patients with mantle cell lymphoma, an ORR of 52% and a CR rate of 25% were observed, with 83% of patients experiencing ongoing responses at 6 months. I think pirtobrutinib is an exciting next-generation BTK inhibitor that appears to minimize off‑target toxicity and overcome resistance to BTK C481S mutations. I look forward to more data with this agent in the near future.
Investigational CAR T-Cell Therapy for Indolent Lymphomas, CLL, and Mantle Cell Lymphoma
Looking beyond CLL, we saw exciting data at ASH 2020 with CD19-targeted CAR T‑cell therapies for patients with indolent non‑Hodgkin lymphomas. Data were presented from the pivotal ZUMA‑5 study of axicabtagene ciloleucel in patients with R/R follicular or marginal zone lymphomas. This study included 146 evaluable patients who had received a median of 3 previous lines of therapy. The ORR was a remarkable 92%, with 76% of patients achieving a CR. Remissions appeared durable, with a 1‑year PFS rate of 74%, although with indolent lymphomas, a much longer‑term follow-up will be required to confirm durability of responses. Of note, the key CAR T-cell therapy–associated toxicities cytokine-release syndrome (CRS) and neurologic events were seen in 82% and 60% of patients, respectively, with severe CRS or neurologic events seen in 7% and 19% of patients, respectively, although events were largely manageable and reversible.
We also saw interim data from the phase II ELARA study of tisagenlecleucel for patients with R/R follicular lymphoma. Among the 52 evaluable patients, the ORR was 83%, with two thirds of patients achieving a CR and 69% of responses ongoing at a median follow-up of 10 months. Once again, longer follow-up is clearly required. Of note, tisagenlecleucel is a 4‑1BB costimulated CAR T‑cell that has been associated with lower rates of CRS and neurotoxicity; these occurred in 49% and 9% of patients, respectively, in the ELARA study and were almost entirely low grade.
In addition, we also saw CAR T‑cell therapy data with lisocabtagene maraleucel (liso-cel) emerge in both CLL and mantle cell lymphoma. Updated data were presented from the phase I/II TRANSCEND CLL 004 study of liso-cel for patients with R/R CLL/SLL. The 23 patients evaluated had received a median of 4 previous lines of therapy, 100% had received a previous BTK inhibitor, and nearly half had received previous venetoclax. The ORR in this high‑risk CLL population was 82%, with 46% of patients demonstrating a CR by the International Workshop on Chronic Lymphocytic Leukemia criteria. Of importance, more than two thirds of patients achieved undetectable MRD in the peripheral blood, with a median duration of response that has not been reached and a PFS rate of 50% at 1 year. Long‑term follow-up with this treatment with greater number of patients is required.
Data with liso-cel were also reported from an interim evaluation of the mantle cell lymphoma cohort of the phase I TRANSCEND NHL 001 study. This study included 32 heavily pretreated patients, with nearly 90% having received a previous BTK inhibitor. In this population, the ORR was 84% and CR rate was 66%.
Bispecific Antibodies and Other Investigational Targeted Agents for Lymphomas
Numerous studies of bispecific antibodies for hematologic malignancies reported results at ASH 2020. CAR T-cells are effective in many different forms of relapsed B‑cell lymphomas, but they can be expensive and challenging to produce. By using bispecific antibodies, the hope is to have an off-the-shelf product that can be administered quickly and with high efficacy.
Odronextamab is a novel bispecific antibody targeting CD3 and CD20. This agent was assessed in a 136‑patient phase I study that included patients with B-cell non-Hodgkin lymphoma, including diffuse large B‑cell lymphoma (DLBCL) and follicular lymphoma. Patients had received a median of 3 previous lines of therapy. The efficacy of odronextamab in follicular lymphoma (n = 38) was remarkable, with an ORR of 90% and a CR rate of 70% observed. In patients with DLBCL, the ORR was 40%, with one third of patients achieving a CR. The durability of responses was encouraging, albeit with limited follow-up, so longer‑term follow up is required. There were responses seen in patients who had previous CAR T‑cell therapy, which is notable because these are patients can be difficult to salvage in the R/R setting. The incidence of CRS was 61%, but most events were low grade and diminished over time.
Data were also reported for epcoritamab, another CD20/CD3 bispecific antibody. In a phase I/II study, 68 patients (46 with DLBCL and 12 with follicular lymphoma) with a median of 3 previous lines of therapy received epcoritamab. Of note, this agent is given as a subcutaneous injection. In the follicular lymphoma subset, the ORR was 87%, with 53% of patients achieving a CR. In patients with R/R DLBCL, the ORR was a very encouraging 76%, with a CR rate of 48%. CRS occurred in 60% of patients on this study, but all events were grade 1 or 2. The durability of responses with this agent appear encouraging, although again additional follow-up is needed.
Glofitamab is a novel bispecific antibody with a 2:1 molecular configuration: 2 CD20-binding sites and 1 CD3-binding site. Data were reported at ASH 2020 from 52 patients with DLBCL and follicular lymphoma who were treated with this agent in a phase I study; patients had received a median of 3 previous lines of therapy. Among all treated patients, the ORR was 64%, with 54% of patients achieving a CR. Of note, response rates were quite similar in both the aggressive and indolent histologies. The incidence of CRS was 64%, but decreased with ongoing dosing. As with the previous products mentioned, encouraging response durability was observed with limited follow-up, which will require updating.
Mosunetuzumab is another CD20/CD3 bispecific antibody for which data were previously reported in DLBCL. At ASH 2020, we saw data with this agent in treating R/R follicular lymphoma in a phase I/Ib dose-escalation study. Among 62 patients with a median of 3 previous lines of therapy, the ORR was 68%, the CR rate was 52%, and an encouraging median duration of response of 20 months was observed. Of note, treatment with this agent was associated with a low risk of CRS (18%, all of which were low grade events).
Bispecific antibodies continue to demonstrate encouraging responses in both DLBCL and follicular lymphoma, with manageable toxicity. If they were to be approved, these agents could represent an appealing off-the-shelf product for patients with R/R lymphomas.
Finally, loncastuximab tesirine is an investigational antibody–drug conjugate in which an anti-CD19 antibody is conjugated to a pyrrolobenzodiazepine dimer toxin. At ASH 2020, data with this agent from a pivotal phase II study in patients with relapsed/refractory DLBCL (N = 145) were reported. Treatment with loncastuximab tesirine produced an ORR in of 48%, with a CR rate of 25% and a median duration of response of 13 months. A median PFS of 5 months was observed. The drug was generally well tolerated and represents another potential off-the-shelf product. Because this was a pivotal study, it is expected that this agent will receive FDA approval, providing an additional CD19-targeted therapy in patients with R/R DLBCL.
Brentuximab Vedotin for Older Patients With Hodgkin Lymphoma
Classical Hodgkin lymphoma predominantly affects younger adults and most are cured with initial chemotherapy. However, this disease also occurs in older patients, and it has long been recognized that standard chemotherapy has a high rate of toxicity (including treatment‑related mortality) in these patients. This has led to investigations of the use of initial targeted therapy and minimization of chemotherapy in older populations with Hodgkin lymphoma.
At ASH 2020, results were presented from an open-label phase II study of brentuximab vedotin—an anti‑CD30 antibody–drug conjugate that is approved in R/R disease or in combination with AVD as upfront therapy for advanced‑stage disease—alone or in combination with dacarbazine, bendamustine, or nivolumab for patients 60 years of age or older with treatment-naive classical Hodgkin lymphoma. When given as a single agent (n = 26), brentuximab vedotin produced an ORR of 92% and a CR rate of 72%. Even though this agent was associated with encouraging ORR and CRs, the median duration of response was unfortunately relatively brief at 9 months.
Twenty patients were treated with brentuximab vedotin plus dacarbazine. The ORR was 100% and CR rate 68% with this combination; most notably, the median duration of response was 45 months. As such, this well-tolerated combination was very encouraging in this older population (median age: 74 years) not only in terms of responses but also in the durability of those responses. Brentuximab vedotin was also studied in 20 patients in combination with bendamustine, which also produced an ORR of 100% and an encouraging median duration of response of 39 months. However, this was a more toxic combination, and some patients experienced adverse events, including neutropenic fever, infections, neuropathy, and asthenia, with 60% of patients having to discontinue treatment due to adverse events. This arm was not recommended moving forward.
The last combination that was studied and the one with the least follow-up was brentuximab vedotin plus the immune checkpoint inhibitor nivolumab. This combination was assessed in 21 patients, producing an ORR of 95% and CR rate of 79%. The median duration of response has not yet been reached in this subset, but the median follow-up is only 28 months.
I think these data do provide some encouraging evidence for how to treat our older patients with previously untreated classical Hodgkin lymphoma. For this truly older population, brentuximab plus dacarbazine produced a very encouraging response rate with durable remission and very manageable and acceptable toxicity. We await further follow-up data with the brentuximab plus nivolumab combination, which also has very encouraging early results.Your Thoughts