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Sunday, December 6, 2015

John Leonard’s Top 10 Lymphoma Abstracts at ASH15 (Online First)

 

BY ROBERT H. CARLSON

 

It's time for another “Leonard List” (#LeonardList) a selection of noteworthy lymphoma abstracts from a major medical meeting, broadcast via Twitter by John P. Leonard, MD (@JohnPLeonardMD), Distinguished Professor of Hematology and Medical Oncology at Weill Cornell Medical College.

 

Speaking by telephone a few days before the start of this year’s American Society of Hematology Annual Meeting, he explained his 10 choices from the meeting and how he makes them: “I scan all the lymphoma-related abstracts, focusing less on the biology and more on the therapy. I look at both oral and poster abstracts because I think people might miss posters that are of interest and worth highlighting. And I focus on ideas I think are either practice changing, or intriguing, or 'out of the box,' that people might otherwise not see.”

 

The abstracts ought to be thought-provoking, he said, although in some cases fellow Twitter users have disagreed with his picks, thinking that a particular abstract was less exciting than he did or pointing to one he missed: “Certainly people can disagree, and as you can see from the tweets, people have different thoughts. But that's great--it's part of my intention to have people point out different perspectives.”

 

Some picks include very early data, he admits, and some are from very small trials.

 

“On one level I want to highlight practice-changing ideas, but on another level I want to pique people's interest and perhaps start a dialogue on how research might move forward as those early studies mature.”

 

1.  Abstract 578:  “Initial Results of US Intergroup Trial of Response-Adapted Chemotherapy or Chemotherapy/Radiation Therapy Based on PET for Non-Bulky Stage I and II Hodgkin Lymphoma (CALGB/Alliance 50604),” by David J. Straus et al.

 

“This study highlights the differences in criteria that are used in different studies for positive and negative PET in PET-guided Hodgkin lymphoma therapy,” Leonard said. “If you are making decisions on further treatment, intensive treatment, or the use of radiotherapy or no radiotherapy, the actual criteria of positive or negative are very important.

 

“It also highlights the fact that if we use more liberal criteria to call something negative we still can have a good outcome, and that ultimately spares some patients the potential toxicities of radiation.”

 

 

2.  Abstract 473:  “Phase I Study of Tazemetostat (EPZ-6438), an Inhibitor of Enhancer of Zeste-Homolog 2 (EZH2): Preliminary Safety and Activity in Relapsed or Refractory Non-Hodgkin Lymphoma Patients,” by Vincent Ribrag et al.

 

“EZH2 mutations are an epigenetic target becoming more and more important not only in non-Hodgkin lymphoma but also in a variety of solid tumors,” Leonard said.

 

“A couple of EZX2 inhibitors are now in trial and we are starting to see clinical data. This trial has a limited number of patients but across the spectrum of various lymphoma subtypes we do see meaningful, objective response, and it's very exciting that EZX2 is a potential target in different subtypes.”

 

 

3.  Abstract 811:  “Randomized Phase II Open-Label Study of R-CHOP ± Bortezomib in Patients with Untreated Non-Germinal Center B-Cell-like Subtype Diffuse Large Cell Lymphoma: Results from the Pyramid Trial (NCT00931918),” by John P. Leonard et al.

 

“I don't like to put my own papers in, but Dr Jonathan Friedberg [Director of the Wilmot Cancer Institute in  Rochester, NY] follows this [the list], and he said I have to put it in.

 

“These are important results questioning the role of cell of origin as a predictive factor for induction therapy. This was a somewhat negative trial; we did not see a benefit for the addition of bortezomib, but the key take-home message is that trials selecting patients based on cell of origin have very large selection biases inherent to the study design.

 

“In this study, roughly 80 percent of patients did well even in the control arm, in contrast to the retrospective studies that identified non-germinal center as a less favorable subtype with long-term favorable outcomes of about 40 percent.

 

“Clearly that's a prospective study versus a retrospective study with the same therapy but with very different results, I think because the procedures the patient has to go through to be selected to go on a trial end up selecting against the less favorable patients who could benefit.

 

“I think all trials that are picking patients based on cell of origin need to consider this phenomenon.”

 

 

4.  Abstract 3986:  “Phase Ib Study of PD-1 Blockade with Pembrolizumab in Patients with Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma,” by Pier Luigi Zinzani et al.

 

“There is clearly a lot of activity of checkpoint inhibitors in Hodgkin lymphoma, and there are a lot of molecular and clinical similarities between Hodgkin lymphoma and primary mediastinal B cell lymphoma,” Leonard said.

 

“This is a small report, very preliminary but with meaningful response rates: four out of nine patients had an objective response. The idea is quite interesting that this is a subset that could potentially benefit from this approach. Also, this subset frequently harbors 9p24.1 genetic alterations that have been associated with response, and yet some of these patients did not respond. The question of interest is why did they not respond if they had the 'selection marker'?

 

These are tantalizing data that are grounds for further pursuit in clinical trials.”

 

 

5.  Abstract 585:  “Preliminary Safety and Efficacy of the Combination of Brentuximab Vedotin and Ipilimumab in Relapsed/Refractory Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Cancer Research Group (E4412),” by Catherine S. Diefenbach et al.

 

“This small ECOG study looked at patients with recurrent Hodgkin lymphoma treated with brentuximab vedotin, the CD-30-directed immunotoxin conjugate, and ipilimumab, a checkpoint inhibitor.

 

“The idea of using combination immunotherapies in Hodgkin lymphoma got my attention because we know the immunologic aspects of Hodgkin lymphoma are quite interesting and important to pathogenesis. While preliminary at this point, it is exciting to be entering the age of combination immunotherapy for Hodgkin lymphoma.”

 

 

6.  Abstract 3935:  “Results of the Mantle Cell Lymphoma Subset from a Phase IIa Study of Copanlisib, a Novel PI3K Inhibitor, in Patients with Indolent and Aggressive Lymphoma,” by David Cunningham et al.

 

“PI3 kinase-delta inhibitors have activity in mantle cell lymphoma as well as elsewhere, but responses are quite short lived, in part because there is an up-regulation of the alpha isoform when you treat a patient with a drug that targets the delta isoform, and patients develop resistance quite rapidly,” Leonard explained.

 

“Copanlisib is an alpha-delta dual inhibitor. This is a substantial study overall, with only 11 patients with mantle cell lymphoma, but there is activity across the lymphoma spectrum.

 

“Roughly two-thirds of the mantle cell patients responded--this suggests that copanlisib may be of interest in mantle cell. We and others are interested in pursuing this in patients whose disease has become resistant to ibrutinib, which is now very commonly used in mantle cell in the recurrent disease setting.”

 

 

7.  Abstract 518:  “Pre-Transplant R-Bendamustine Induces High Rates of Minimal Residual Disease in Mantle Cell Lymphoma Patients: Updated Results of S1106: U.S. Intergroup Study of a Randomized Phase II Trial of R-HCVAD Versus R-Bendamustine Followed By Autologous Stem Cell Transplants for Patients with Mantle Cell Lymphoma,” by Robert Chen et al.

 

“R-bendamustine is very commonly used for older patients with mantle cell lymphoma, and this trial looked at getting patients to autologous stem cell transplant with either R-bendamustine or the R-HCVAD regimen that was more commonly used at the time this multicenter cooperative-group study developed.

 

“The study closed prematurely with only 53 patients, but there is an interesting take-home point, that R-HCVAD was relatively toxic and led to low levels of mobilization of stem cells, which was the main reason the study was stopped by the National Cancer Institute.

 

“R-bendamustine did seem to be a very effective induction regimen to get patients into remission prior to autologous transplant.

 

“The intriguing thing is, when you look at minimal residual disease [MRD] negativity, the vast majority of patients treated with R-bendamustine who were assessable were in an MRD-negative state. That's becoming more and more a target of induction, and it seems to correlate with outcome longer term, at least with respect to progression-free survival.

 

“Two more important take-home messages here: the idea of using R-bendamustine as a platform, and that validating MRD negativity is something that adds value.”

 

 

8.  Abstract 181:  “Multicenter Phase II Study of Lenalidomide in Patients with Relapsed Adult T-Cell Leukemia-Lymphoma,” by Hiroshi Fujiwara et al.

 

“Adult T-cell leukemia and lymphoma is a subtype of T-cell lymphoma typically associated with HTLV infection, which is more common in Asia, generally speaking,” Leonard said.

 

“The important point of this multicenter Phase II study is that lenalidomide has activity in this type of lymphoma. Treatment options are quite limited for relapsed adult T-cell leukemia and lymphoma  patients--generally a poor prognosis group.

 

“To have an oral drug we know well from other settings that has meaningful activity to these patients is of some interest. A number of these patients had received prior mogamulizumab, an anti-CCR4 antibody only recently available. That lenalidomide could work in this patient population where mogamulizumab had stopped working is also of interest.”

 

 

9.  Abstract 587:  “Brentuximab Vedotin in Combination with Dacarbazine or Bendamustine for Frontline Treatment of Hodgkin Lymphoma in Patients Aged 60 Years and Above: Interim Results of a Multi-Cohort Phase II Study,” by Christopher A. Yasenchak et al.

 

“Patients with Hodgkin lymphoma over age 60 have a less favorable outcome; they don't do as well with the standard ABVD both with respect to efficacy and toxicity,” Leonard explained. “There was a study of brentuximab as single agent, upfront treatment for this population which showed reasonably high response rates but short responses.

 

“This is the first effort in this patient population to avoid the toxicities of ABVD by adding one chemotherapy drug to the brentuximab to make it more effective.

 

“It is an ongoing Phase II study but we see response rates in the range of 100 percent. Durability remains to be seen but at least with the dacarbazine regimen it seems to be fairly durable with the relatively short follow-up they have.

 

“This essentially is a step forward for older patients who tend to do less well--using brentuximab plus a limited amount of chemotherapy that will hopefully be better tolerated than the standard chemotherapy but have better efficacy than single-agent brentuximab.”

 

 

10.  Abstract 333:  “A Clinicogenetic Risk Model (m7-FLIPI) Prospectively Identifies One-Half of Patients with Early Disease Progression of Follicular Lymphoma after First-Line Immunochemotherapy,” by Jurinovic Vindi et al.

 

“We know that patients with follicular lymphoma who have progressed within two years of their front-line therapy have an unfavorable prognosis long term, whereas those who progress late than two years have a much more favorable prognosis.

 

“The question is, how can we identify these patients earlier and, potentially through clinical trials and hopefully in clinical practice, treat them differently?

 

“Using the m-7 FLIPI prognostic score plus some molecular markers may identify a group of patients who will progress relatively early after front-line immunochemotherapy. Identifying them in advance of treating them and waiting to see what happens is a positive step in that direction.”

 

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John Leonard’s Top 10 Lymphoma Abstracts from #ASCO15

Check out OT's article about John Leonard's Top 5 lymphoma abstracts from the most recent American Society of Clinical Oncology Annual Meeting.