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May 10, 2021

Dr. John Sweetenham, associate director for Clinical Affairs at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center and Editor-in-Chief of ASCO Daily News, discusses key abstracts on hematologic malignancies featured at the 2021 ASCO Annual Meeting.



ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll. My guest today is Dr. John Sweetenham, the associate director for clinical affairs at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center. Dr. Sweetenham is also the editor-in-chief of the ASCO Daily News, and joins me to discuss key abstracts on hematologic malignancies featured at the 2021 ASCO annual meeting.

Dr. Sweetenham reports no conflicts of interest relating to our discussion today, and full disclosures relating to all episodes of the podcast are available on our transcripts at Dr. Sweetenham, it's lovely to have you back on the podcast.

Dr. John Sweetenham: Thanks, Geraldine. It's a pleasure to be able to speak with you again.

ASCO Daily News: Dr. Sweetenham, there are some really promising developments in therapies for adult patients with acute lymphoblastic leukemia. Can you tell us about these studies?

Dr. John Sweetenham: Yes. There are two abstracts in particular at this year's meeting, which I think are of particular interest for adult patients with acute lymphoblastic leukemia. This is typically a difficult disease to treat in adults. And two abstracts in particular caught my eye. The first of these is Abstract 7001. And this describes a phase II study of a combination of a tyrosine kinase inhibitor, ponatinib, and a bispecific T cell engaging antibody, blinatumomab, which is directed against CD19 for patients with a particularly refractory type of ALL, and that's patients with Philadelphia chromosome positive ALL.

This is a single arm phase II study for patients with both newly-diagnosed and relapsed or refractory Philadelphia-positive ALL. And in the protocol as described, the patients received up to five cycles of blinatumomab as a continuous infusion of the standard approved dose. And combined with this was ponatinib initially at a dose of 30 milligrams daily during cycle 1, and then subsequently reduced to half that dose until a complete molecular remission was achieved.

Thereafter, the patient was continued on ponatinib for at least 5 years. And the treatment was also supplemented by intrathecal prophylaxis. Only 28 patients are on this small study. But nevertheless, I think the results are very intriguing. 95% of the patients responded to this treatment. And in the previously untreated patients, the response rate was 100%, compared with 88% in the relapsed and refractory group. And among the responding patients, 86% achieved a complete molecular remission.

Remarkably, none of the patients in the newly diagnosed cohort required stem cell transplantation. And overall, with a median follow-up now of 14 months--so still relatively early, admittedly--the estimated 1 year overall survival rate is 94%, with an event-free survival rate of 81% for the entire study population.

In the previously untreated cohort, no patients have relapsed or died. The 1-year overall and event-free survival rate in this particular subgroup is 100%. So what, to me, is really intriguing and exciting about this is a chemotherapy-free regimen for the upfront treatment of a particularly difficult-to-treat subtype of adult ALL. So these are truly encouraging and really quite remarkable results. Of course, they need to be qualified because it's very early days, small numbers, relatively limited follow-up, but intriguing nevertheless.

The second study, which I think is really confirmatory of some earlier results, is described in Abstract 7002. And this describes the phase II results of the so-called ZUMA-3 study evaluating a CAR T-cell products directed against CD19 in adult patients with relapsed and refractory B-cell acute lymphoblastic leukemia.

The phase I efficacy results were previously reported a couple of years ago at ASH. And this study represents the follow-up phase II study. Eligible patients for this study all had relapsed and refractory B-cell ALL treated with CAR T-cells that the dose that was described from the original phase I study, with a primary endpoint of complete remission rates. And key secondary endpoints in the study included duration of remission, relapse-free survival, overall survival, and the presence or absence of measurable residual disease by flow cytometry.

As of September 2020 when this study was originally reported, 55 of the 71 enrolled patients that received their CAR T cell products and the complete response rate combining CR and CRI rate was 71%. And 31% of the responders had ongoing responses. Looking at the median duration of response, relapse-free survival, and overall survival, these were respectively 12.8, 11.6, and 18.2 months.

But for those patients who responded, the relapse-free and overall survival were respectively 14.3 months and not yet reached. So, again, relatively early results, but nevertheless very interesting, showing after a median follow-up of 16.4 months, there was clear and quite compelling clinical benefits in heavily pretreated adults with relapsed and refractory B-cell ALL, with a median overall survival not yet being reached.

So, given, again, that this is a particularly difficult group of patients to treat, it's another example of a very promising result from CAR T cell therapy in a difficult clinical situation.

ASCO Daily News: Absolutely, some very interesting advances there in ALL. Well, patients who have received a stem cell transplant have felt especially vulnerable during the COVID-19 pandemic. A couple of abstracts assess the outcomes of allogeneic stem cell transplant recipients amid the pandemic. What are your thoughts on these studies?

Dr. John Sweetenham: Yes, thanks. So, two abstracts of particular interest, Abstract 7033 is a study which addresses the outcomes for all patients undergoing hematopoietic stem cell transplants and cellular therapy, both autologous and allogeneic, as well as a few patients with CAR T cell therapy during the COVID-19 pandemic, really just looking overall at outcomes compared with essentially, historical controls.

It was a single center prospective study, which included in all, approximately 40 patients undergoing either hematopoietic stem cell therapy or other cellular therapies who were diagnosed with COVID-19 between April of 2020 and January of 2021. As I mentioned, 40 patients were included, 25 of whom underwent allogeneic transplants, 13 autologous transplants, and 2 underwent CAR T cell therapy.

And these were done for a variety of hematologic malignancies. And in the allogeneic patients, a variety of STEM cell sources were chosen. And the patients had a number of treatments for their COVID-19, directed specifically at the COVID-19, which included remdesivir, convalescent plasma, dexamethasone, and some monoclonal antibodies.

The bottom line from the study, and perhaps this is really not too surprising, is that the patients undergoing hematopoietic stem cell transplantation with COVID-19 had an increased risk of mortality. And that particularly related to undergoing allogeneic versus other types of cellular therapy and the presence of concurrent immune suppression.

So this study demonstrated something which I think is intuitive, but for which there hasn't been a lot of literature yet, essentially saying that patients who undergo transplant in the presence of active COVID-19 have relatively poor outcomes compared with those who are non-COVID-19 positive.

The other abstract which drew my attention was Abstract 7032, a very different abstract in many ways, in that it looked at the association of COVID-19 with distress and the quality of life for patients undergoing hematopoietic stem cell transplantation. And this was a cross-sectional analysis of data from 205 patients with hematologic malignancies undergoing stem cell transplantation and enrolled in a multi-site randomized supportive care trial that they compared baseline pre-transplant distress which included depression, anxiety, and post-traumatic stress disorder symptoms, and quality of life between participants enrolled pre-COVID-19 and during the COVID-19 pandemic.

Prior to the COVID-19 pandemic, 124 participants enrolled, and then 81 enrolled during the COVID-19 pandemic. Interestingly enough, in multivariate regression models, enrollment during COVID-19 was not associated with pre-transplant depression, anxiety, PTSD symptoms, or quality of life. So the conclusion is interesting in that this study reports that contrary to the generally held notion that the COVID-19 pandemic has worsened distress in patients with cancer, there was no difference in distress or quality of life in these patients with hematologic malignancies prior to or during the COVID-19 pandemic.

ASCO Daily News: Yes, that's an interesting conclusion as you say, and a little unexpected. Well, let's focus on chronic lymphocytic leukemia. Are there any new therapies on the horizon for patients with CLL?

Dr. John Sweetenham: So, two abstracts this year's ASCO [Annual Meeting] describe what I think is significant advances with newer therapies, which I think are now really finding their place in the therapeutic algorithm for CLL. Abstract 7500 reports the results of a large randomized comparison on a head-to-head basis between ibrutinib, the first in class Bruton tyrosine kinase inhibitor, and a more selective tyrosine kinase inhibitor, acalabrutinib.

This was a randomized, head-to-head non-inferiority study which compared acalabrutinib with ibrutinib in patients with previously treated CLL of all risk groups. And overall, 533 patients were randomly assigned between these two therapies. And at the median follow-up of around 41 months. Now, acalabrutinib was found to be non-inferior to ibrutinib, with a median progression-free survival of 38.4 months in both arms of the study.

But importantly, acalabrutinib was found to be superior to ibrutinib in terms of toxicities, which included the incidence of atrial fibrillation. Among the other secondary endpoints of the study were incidences of grade 3 infection, which were comparable between the two arms, as was the rates of Richter's transformation.

Not surprisingly, because the routine tyrosine kinase inhibitors are such effective drugs in CLL, the median overall survival was not reached in either arm of the study. Acalabrutinib demonstrated a lower incidence of hypertension, arthralgia, and diarrhea compared with ibrutinib, but a somewhat higher incidence of headache, 34% versus 20%, and cough at 28% versus 21%.

And of note, adverse events led to treatment discontinuation in just over 14% of patients on acalabrutinib versus 21% of those treated with ibrutinib. So in summary, acalabrutinib demonstrated a non-inferior progression-free survival with less cardiotoxicity and fewer discontinuations due to adverse events when compared with ibrutinib.

So I think that this does pave the way for some of the later generation tyrosine kinase inhibitors, which certainly appear to maintain the efficacy of ibrutinib, but appear to have somewhat lower toxicity. This study was conducted in the relapse refractory setting. And clearly, the next question is going to be whether in the frontline setting, we would expect to see similar findings with acalabrutinib.

The other study of note, I think, from the CLL abstracts this time is Abstract 7501. And this is a summary of the so-called CAPTIVATE study. This is a multi-center phase II study of first line ibrutinib combined with venetoclax, a BCO2 inhibitor, for patients with CLL.

The study is important because it uses a fixed duration regimen. And to give that some context, many of the newer treatments, oral treatments for CLL with ibrutinib being the initial drug of this type, have been given continuously into either disease progression or until the patient becomes intolerant of the treatment because of side effects.

And so there has been an ongoing series of investigations looking at whether it's possible to give these treatments in a fixed duration way rather than indefinitely because of the risks of long-term toxicity and so on. So in this study, patients less than age 70 with previously untreated CLL received three cycles of ibrutinib, and then 12 cycles of the combination of ibrutinib plus venetoclax, and then study was completed at the end of those 12 cycles.

The primary endpoint of this study was the complete response rates with secondary endpoints of overall response rate, duration of response, minimal residual disease rate, and then progression-free and overall survival. To date, 159 patients have been enrolled on this study, with a median time on study of around 27.9 months.

With a fixed duration combination, the complete response rate was reported at 55%, and the overall population was consistent across all of the high-risk groups, including those with adverse cytogenetic findings. Of the 88 patients who achieved a complete response, 78, representing 89%, had a duration of greater than 1 year. And the overall response rate for the entire group was 96%.

And as I mentioned, there was no difference in those patients who had a 19p deletion, so another example of a novel first line regimen given at fixed duration which is chemotherapy-free and is providing really quite remarkable and intriguing results in the upfront setting for patients with CLL.

ASCO Daily News: Great. Thanks for highlighting those two interesting studies on CLL. So focusing on Hodgkin lymphoma, can you tell us about advances using PET-directed therapy? And how do you see this evolving in the future?

Dr. John Sweetenham: Yeah, absolutely. So, Abstract 7507 describes what I think is a very important study further investigating the use of functional imaging in therapy of that adaptation in patients with Hodgkin lymphoma. So typically, in the early-stage setting for patients with non-bulky early-stage Hodgkin lymphoma, there is now a wealth of evidence that interim PET scanning after a couple of cycles of ABVD chemotherapy, or other induction therapy, is a strong predictor of eventual outcome and can enable you to tailor the use of radiotherapy and potentially omit radiation therapy in patients who are PET negative early in the course of their chemotherapy.

In patients with bulk early-stage Hodgkin lymphoma, that's been a little more controversial as to whether PET scanning on an interim basis early in the course of treatment is really reliable. So this is really quite an important Alliance study, CALGB 50801, which has tested the PET adapted approach in patients with bulk Hodgkin lymphoma.

So eligible patients had stage IA through IIB classical Hodgkin lymphoma with disease bulk, which was defined as greater than 10 centimeters or more than 1/3 of the maximum intrathoracic diameter on a conventional chest X-ray. And the patients received two cycles of ABVD chemotherapy followed by a centrally viewed PET scan. If the PET scan was negative, defined as Deauville 1 through 3, patients who were PET negative received four additional cycles of chemotherapy but no radiation therapy.

If the PET after two cycles was positive, the patients received intensified chemotherapy with escalated BEACOPP plus 30 Gray of involved site radiation therapy, with a primary endpoint in this study of progression-free survival. 101 patients have been enrolled on the study, of whom 94% were evaluable.

78% of these patients were PET negative after two cycles of ABVD. And in this group, the progression-free survival is 93.1. Of the remaining patients who were PET positive after two cycles of ABVD and went on to receive more intensified chemotherapy plus radiation therapy, the progression-free survival was also impressive at 89.7%.

The overall survival in the study is also excellent. But the take-home message here is that excellent progression-free survival outcomes can be observed in patients with early-stage bulk Hodgkin lymphoma if they are PET negative after two cycles of ABVD, go on to complete six full cycles, but did not receive radiation therapy. And this is really a further important advance and omits the long-term risks of radiation therapy for a very significant proportion of these patients with bulk disease.

Similarly, for those who are PET positive after two cycles and their treatment has escalated to more intensive chemotherapy retaining radiation, their long-term progression-free and overall survival is excellent. So, I think this is one more piece of evidence for the usefulness of functional imaging as a biomarker for response in patients with Hodgkin lymphoma which can lead to de-escalation of therapy in those patients with a good prognosis, and escalation of therapy for those who are likely to need more intensive therapy to achieve an equivalent outcome.

ASCO Daily News: Excellent. Well, that's great news. Well, my last question is about mantle cell lymphoma. There's an interesting study that has real-world data for outcomes in MCL in community-based practices across the United States. What can you tell us about this study, Abstract 7504?

Dr. John Sweetenham: Yes, thanks. So, as you mentioned, this is a study which is retrospective in nature and included patients with adult mantle cell lymphoma [who were] treated over a 10-year period from 2011 through the end of 2020. Just over 3,400 patients were included in this analysis, of whom 85% had been treated in a community oncology setting, and 85% were patients undergoing front line therapy.

From a demographic point of view, the disease characteristics were very consistent with published data. Chemoimmunotherapy was the most common first line treatment, usually with either bendamustine and rituximab or R-CHOP. And the cytarabine-based regimens comprised a minority with only 14% of patients receiving these. 667 patients received rituximab maintenance in this study, and 243 received a frontline stem cell transplant in first remission, most of these transplants being autologous.

The median follow-up for survival on this study was 45.3 months. The 36-month overall survival for the entire group was 67%. This large real-world cohort of patients primarily treated in community-based practices demonstrates outcomes which are somewhat inferior to those which we've seen reported from prospective trials. This suggests the need to focus on developing treatments that can be delivered effectively in the community setting.

And perhaps the best example of this is that the use of stem cell transplantation in a community setting was uncommon even in those patients who are less than age 65. And what this gives us a clue to is the fact that maybe real-world considerations, including access to trials, access to treatments as a whole, suggests that these considerations may influence the eligibility for stem cell transplantation and some of the other more intensive approaches to treatment.

ASCO Daily News: Absolutely. Well, thank you so much, Dr. Sweetenham, for highlighting these interesting advances in therapy for hematologic malignancies. It's always a great pleasure to speak with you.

Dr. John Sweetenham: Thanks, a pleasure to speak with you too, Geraldine. And thanks for giving me the opportunity to talk about some of these exciting data.

ASCO Daily News: Of course. And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate and review us wherever you get your podcasts.



Dr. John Sweetenham: None disclosed


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