Paul A. Hamlin, MD, chief, Basking Ridge Medical Oncology Service, Memorial Sloan Kettering Cancer Center, discusses the importance of the ZUMA-I trial results in the field of B-cell lymphoma.

One of the big stories in diffuse large B-cell lymphoma that came out of the 2017 ASH Annual Meeting was the use of CAR T cells. CAR T-cell therapy have been shown to be active in patients with relapsed large cell lymphoma and induce meaningful response rates.

Updated data from the 2017 ASH Annual Meeting showed that patients can achieve durable remissions. This follow-up data, now approaching 1.5 years, is an important landmark in large cell lymphoma. Typically, the first 18 months are when events happen, especially in the upfront setting. In the relapsed setting, it’s even sooner. In the trial, about 30% to 40% of patients who responded to CAR T-cell therapy have maintained their response.

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Dr. Hamlin on the Significance of the ZUMA-I Trial

Paul A. Hamlin, MD, chief of the Medical Oncology Service at Memorial Sloan Kettering Cancer Center, discusses a phase II study investigating cerdulatinib in patients with non-Hodgkin lymphoma.

There is an increasing amount of oral agents that will be available for patients with a good safety margin and the possibility of combinations, states Hamlin.

According to Hamlin, we are entering an era where the understanding of biology will allow us to address the patients

Dr. Hamlin on Key Points of a Study on Cerdulatinib in Non-Hodgkin Lymphoma

Paul A. Hamlin, MD, medical oncologist, chief, Basking Ridge Medical Oncology Service, Memorial Sloan Kettering Cancer Center, discusses future potential combination strategies in the mantle cell lymphoma (MCL) landscape.

This is likely where researchers are heading as a field, Hamlin explains. In MCL, the focus has really been in incorporating novel agents into treatment paradigms, as well as challenging whether or not autologous stem cell transplantation needs to be part of an induction regimen or whether or not the novel agents can give patients the same benefit in terms of disease control. Nevertheless, US and European investigators are looking at novel combinations, including a BCL-2 inhibitor plus a BCR inhibitor or PI3K inhibitor.

These are active areas of research, especially with incorporating these agents into a backbone of chemotherapy induction.

Dr. Hamlin on Future Combination Strategies in the MCL Landscape

Paul A. Hamlin, MD, of Memorial Sloan Kettering Cancer Center, discusses the next steps following a phase I dose-escalation study of buparlisib plus ibrutinib (Imbruvica) in patients with mantle cell lymphoma (MCL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL).

The initial experience as a phase I study has been encouraging, Hamlin explains, especially in the MCL cohort. These are patients with fairly aggressive disease and with blastic features whom experienced prominent responses to the therapy and were durable. It is likely that there will be more options in the future thats attack both processes, he adds.

Researchers already know that ibrutinib is effective as a single agent in MCL; therefore, attacking more than 1 pathway is what likely leads to the more durable responses, he concludes.

Dr. Hamlin on Next Steps With Ibrutinib/Buparlisib in MCL, FL, and DLBCL

Paul A. Hamlin, MD, of Memorial Sloan Kettering Cancer Center, discusses the toxicities reported in a phase I dose-escalation study of buparlisib plus ibrutinib (Imbruvica) in patients with mantle cell lymphoma (MCL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL).

Both buparlisib and ibrutinib (Imbruvica) have known toxicities, Hamlin explains. When combined, fatigue, gastrointestinal complaints, and rash were the most common toxicities reported. These were reduced with dose reductions. Buparlisib, he adds, is also associated with mood disturbances as well, which were also reported on the study.

Both of these small molecule inhibitors have mechanisms of resistance, creating the synergy between the two, he says.

Dr. Hamlin on Toxicities Associated With Ibrutinib and Buparlisib in MCL, FL, and DLBCL

Paul A. Hamlin, MD, chief of the Medical Oncology Service at Memorial Sloan Kettering Cancer Center, discusses results of cerdulatinib in chronic lymphocytic leukemia (CLL), follicular lymphoma and T-cell lymphoma.

The interim results of a study of cerdulatinib in non-Hodgkin lymphoma showed partial responses (PRs) in most of the cohorts. The CLL/small lymphocytic leukemia population saw the highest rate activity with 67% of patients achieving a PR.

Additionally, a complete response was seen in the first patient with relapsed/refractory peripheral T-cell lymphoma to be enrolled on the study.

Dr. Hamlin on Results of Cerdulatinib in CLL, Follicular Lymphoma and T-Cell Lymphoma

Paul A. Hamlin, MD, chief of the Medical Oncology Service at Memorial Sloan Kettering Cancer Center, discusses a study of cerdulatinib in non-Hodgkin lymphoma.

Cerdulatinib is an oral dual Syk/JAK inhibitor that is currently being evaluated in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and indolent lymphomas such as follicular lymphoma and peripheral T-cell lymphoma.

This is an open-label, phase II cohort-driven expansion study, preliminary results of which are being presented at the 2017 European Hematology Association Congress.

Dr. Hamlin on Study of Cerdulatinib in Non-Hodgkin Lymphoma

Paul A. Hamlin, MD, of Memorial Sloan Kettering Cancer Center, discusses a phase I dose-escalation study of buparlisib plus ibrutinib (Imbruvica) in patients with mantle cell lymphoma (MCL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL).

Connie Batlevi, MD, reported the findings of this study at the 2017 ASCO Annual Meeting, Hamlin explains. The novel combination is comprised of buparlisib, which is a pan-PI3K inhibitor and ibrutinib, which is a BTK inhibitor. Much of what is done in oncology involves dual blocking of pathways that promote survival of cancer cells or resistance mechanisms. The study was done to determine whether these 2 agents can be safely combined and elicit activity.

The initial results are promising, Hamlin explains. Clinical activity was validated; however, toxicities were reported and will be a challenge going forward as further studies with this combination are conducted.

Dr. Hamlin on Early Study of Ibrutinib/Buparlisib in MCL, FL, and DLBCL

Paul A. Hamlin, MD, Clinical Director, Lymphoma Outpatient Unit, Memorial Sloan-Kettering Cancer Center, discusses the integration of brentuximab vedotin (Adcetris), an antidrug conjugate, into the treatment paradigm for Hodgkin lymphoma.

Hamlin explains that we have entered a new era for cancer treatment. Targeted therapies are becoming more specific to smaller subtypes of disease. Antidrug conjugates mark specific proteins on the surface of a cell; tumors without this antigen are not suitable to receive the drug. In the case of brentuximab vedotin it is limited to lymphomas that express the CD30 antigen, which is generally a marker for Hodgkin's lymphoma.

Clinical trials investigated the agent after the failure of either autologous stem cell transplant (ASCT) or 2 or more multi-agent chemotherapy regimens. Cure rates are generally high for patients with Hodgkin lymphoma, even in advanced disease; the main challenge for new agents is to maintain the high cure rate while lowering or eliminating toxicities.

The initial approval for brentuximab vedotin was for a minority of patients, but it is still a life altering addition to the armament. Clinical trials are underway examining this agent in the first-line setting, initially to gauge its efficacy in untreated, elderly patients with Hodgkin lymphoma.

Dr. Paul Hamlin, from Memorial Sloan-Kettering Cancer Center, Discusses Integrating Brentuximab Vedotin

Dr. Hamlin on Integrating Brentuximab Vedotin

Paul A. Hamlin, MD, Clinical Director, Lymphoma Outpatient Unit, Memorial Sloan-Kettering Cancer Center, discusses the drug brentuximab vedotin (Adcetris), which was approved in August 2011 for refractory anaplastic large cell lymphoma and Hodgkin lymphoma.

Hamlin explains that brentuximab vedotin is part of a new branch of drugs known as antibody-drug conjugates. These agents combine the specificity of an antibody, which can target antigens directly on the surface of the cancer cell, with the ability to directly deliver a targeted cytotoxic payload.

The payload agent in brentuximab vedotin is monomethyl auristatin E, which is a microtubulin inhibitor that prevents neoplastic cells from replicating.

Dr. Paul Hamlin from the Memorial Sloan-Kettering Cancer Center on Brentuximab Vedotin Pharmacology

Paul A. Hamlin, MD

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