The Future of Hematologic Cancer Care Shifts Toward Personalized and Chemotherapy-Free Regimens

Daniel DeAngelo MD, PhD

In an interview with OncLive® following a State of the Science Summit™ on hematologic malignancies, Daniel DeAngelo MD, PhD, discussed the evolution of management strategies and treatment goals for advanced follicular lymphoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and Philadelphia (Ph) chromosome–positive acute lymphoblastic leukemia (ALL).

DeAngelo was the chair of the event and serves as a professor of medicine at Harvard Medical School, as well as a physician and chief of the Division of Leukemia at Dana-Farber Cancer Institute in Boston, Massachusetts. He noted that there has been a shift in management strategies for advanced follicular lymphoma towards newer agents such as lenalidomide (Revlimid) plus rituximab (Rituxan; R2) and bispecific antibodies for early relapse. He also emphasized the diminishing role of chemotherapy in CLL due to effective BTK inhibitors and venetoclax–based [Venclexa] combinations; and expanded on the transformative impact of chemotherapy-free or low-dose regimens in Ph-positive ALL, which has reduced the need for stem cell transplantation.

DeAngelo also discussed efforts to leverage the efficacy of JAK inhibitors in combination regimens and address the need for improved symptom management for patients with myelofibrosis in another interview.

OncLive: How has the expansion of therapeutic options impacted management strategies for patients with advanced follicular lymphoma, particularly for those experiencing early relapse or refractory disease?

DeAngelo: Advanced follicular lymphoma is not a curative disease, and we typically don't start treatment until patients are symptomatic. Historically, chemotherapy approaches have been the mainstay, and that's still true. [Treatment] with bendamustine and a CD20 monoclonal antibody, typically rituximab, is an initial foray into therapy for patients with follicular lymphoma. What's been changing is that there are patients who do well, and there are patients who don't. We can divide patients into 2 groups: those who [experience] late progression or late recurrence after standard therapy, typically defined as 24 months, and those who have early recurrence or refractory disease. Patients with late recurrence often respond to the same therapies that we have, but it is unclear [how to treat patients with] earlier recurrences.

The R2 regimen has provided an opportunity to salvage many patients. There are now many new therapies for patients with recurrent follicular lymphoma, specifically those patients with early relapse. [These include] the bispecific antibodies mosunetuzumab-axgb [Lunsumio] and epcoritamab-bysp [Epkinly]. Other agents that are being utilized [include the] EZH2 inhibitor [tazemetostat (Tazverik)]. These are all forays to try and improve the outcomes of these highly-refractory or early-relapsed patients.

Lastly, CAR T-cell [therapies] have proven extremely effective for a subset of patients of appropriate age and health, [and we are attempting to leverage] CAR T-cell therapies in earlier lines. Where we had very limited management [approaches] for follicular lymphoma, we now have a lot of management [options] despite the typical incurability of the disease.

How has the shift away from chemotherapy impacted treatment strategies for CLL?

CLL is a disease where we often watch asymptomatic patients with stage 0 disease. However, for patients who develop symptomatic disease, the old standard of chemotherapy has limited utility. Nowadays, a BTK inhibitor is the standard [treatment approach]. Ibrutinib [Imbruvica] was the first, but it is associated with a lot of cardiotoxicities, specifically atrial fibrillation. All BTK inhibitors [are associated with] that risk, but newer agents such as acalabrutinib [Calquence] and zanubrutinib [Brukinsa] have [much] less toxicity; ibrutinib is not used as much anymore.

For those patients who want a time-limited treatment course, or for patients who develop resistance to the standard BTK inhibitors, a combination of venetoclax and obinutuzumab [Gazyva] is commonly [utilized]. There's a new covalent inhibitor, pirtobruintib [Jaypirca], which has just been approved [by the FDA] for patients who develop some resistance.

We now have a plethora of options outside of chemotherapy, and the field has shifted away from chemotherapy [as the standard of care]. Having said that there still may be a role for chemotherapy in young patients with IGH-mutated, favorable disease, or P53 wild-type [disease]. That's a limited group of patients. Most patients nowadays are being treated initially with BTK inhibitors and then progressing on to a combination of venetoclax and a monoclonal CD20 antibody.

How have treatment goals for patients with CML evolved alongside second-generation TKIs?

CML [management] has changed over the past [25 years] that I've been treating [patients with this disease.] Historically, this was a uniformly fatal disease without stem cell transplant. Nowadays, it's a uniformly survivable disease with no transplant, because we have a wealth of ABL inhibitors that are FDA approved.

It's hard to know which ABL inhibitor is best. I remind my staff that imatinib [Gleevec] is a very good drug, even though it's a first-generation [inhibitor] and the oldest. Although [patients may achieve] deeper and faster responses [with newer combinations], there's no survival benefit. Having said that, [achieving] a deep molecular response does have some advantages for most patients, in terms of being able to possibly discontinue the agent. It depends on what the goals of therapy are. For a younger or middle-aged individual, the goal may be to achieve [treatment] discontinuation, and to do that, they need to achieve a complete molecular remission or very close to that. That happens with approximately 40% of patients [treated with] imatinib and approximately 50% to 55% of patients with a second-generation TKI. Approximately half of those patients are able to successfully discontinue [treatment].

This is the advantage of initiating a second-generation TK. [However,] there's more pulmonary and cardiovascular toxicity [associated with these agents], so for an older patient with comorbidities, imatinib has been and remains a good standard.

Pending its FDA approval, how might the allosteric inhibitor asciminib address the need for less-toxic yet effective first-line therapies in CML?

There was a presentation from the 2024 ASCO Annual Meeting on asciminib [Scemblix], which has a very different mechanism of action. So far, all the TKIs that we use up front are ABL TKIs. [Asciminib] is an allosteric inhibitor, or STAMP inhibitor, so it's a different class. Currently, asciminib is only approved in the third line, so patients must [progress on] or become intolerant to 2 prior TKIs.

[The phase 3] AASC4FIRST trial [NCT04971226] compared asciminib in the upfront setting with either imatinib or second-generation TKIs, and it showed a statistically significant improvement [in efficacy with] asciminib over imatinib and a trend in improvement over the second-generation. [Notably,] asciminib did show an improvement in tolerability and safety over second-generation TKIs. This [agent] is likely to get approved [by the FDA] later this year and will probably be line-agnostic. [Hopefully it will] provide another option for our patients with newly diagnosed CML.

How has the use of chemotherapy-free or low-dose chemotherapy regimens impacted the likelihood of achieving deep remission when undergoing transplantation in Ph-positive ALL?

The management of Ph-positive ALL has dramatically changed over the last decade. Historically, all forms of ALL were treated with high-dose chemotherapy, Ph-positive ALL represents very minority of patients under age 21, and approximately one-third of adults over 18. However, the incidence [of Ph-positive ALL] increases with age, so approximately half of patients over age 50 have Ph-positive [disease]. The current treatment strategy at my institution is a chemotherapy-free [approach] with a TKI and steroids or a minimal chemotherapy approach.

With the addition of blinatumomab [Blincyto] to that regimen, we've been able to achieve deep molecular remissions, and even complete molecular remissions. Patients would historically proceed to stem cell transplant almost ubiquitously. Now it's rare that a patient needs to proceed to transplant. We reserve transplantation for patients who have minimal residual disease after blinatumomab and seldom [perform] transplant in our patients. Low-dose chemotherapy, targeted therapy with a the second-generation TKI dasatinib [Sprycel] or even the third-generation TKI ponatinib [Iclusig] plus blinatumomab seems to be the most effective [treatment strategy].