Evolving Drug Classes Expand Treatment Options Across Hematologic Malignancies

August 18, 2023

Individualized myelofibrosis treatment begins with correctly identifying a patient’s disease subtype and considering their symptoms, from which accurate decisions regarding the use of JAK inhibitors vs radiation vs hypomethylating agents can lead to spleen and symptom burden reductions.

During an OncLive^® State of the Science Summit™ on hematologic malignancies, Rampal and colleagues highlighted the role of JAK inhibitors in myelofibrosis; considerations for CAR T-cell therapy in follicular lymphoma (FL); efficacy and safety findings with asciminib (Scemblix) in chronic myeloid leukemia (CML); the future of BTK inhibitors in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL); unmet needs in diffuse large B-cell lymphoma (DLBCL); and research on the horizon in lower-risk myelodysplastic syndrome (MDS).

Rampal, who chaired the event, is the director of the Myeloproliferative Neoplasms Program and an associate attending physician at Memorial Sloan Kettering Cancer Center in New York, New York.

Rampal was joined by his colleagues:

Alexander P. Boardman, MD, assistant attending physician, Memorial Sloan Kettering Cancer Center
Michael J. Mauro, MD, leader, Myeloproliferative Neoplasm Program, Leukemia Service, Memorial Sloan Kettering Cancer Center
Prioty Islam, MD, MSc, assistant attending physician, Memorial Sloan Kettering Cancer Center
Jennifer K. Lue, MD, clinical director, Lymphoma Service, Memorial Sloan Kettering Cancer Center
Jan Philipp Bewersdorf, MD, hematology/oncology fellow, Memorial Sloan Kettering Cancer Center

Below, Rampal, Boardman, Mauro, Islam, Lue, and Bewersdorf summarize the main messages from their presentations.

Current and Emerging Treatments in Myelofibrosis

Rampal: [Myelofibrosis] treatment depends on the issue. This is 1 of the major principles in treating [patients with] myelofibrosis. It’s not a monolithic entity. This disease has different manifestations, and we need to treat the manifestation that is causing the patient the major issue. [When] some patients [present with myelofibrosis], anemia is the major [symptom] they’re [experiencing], not spleen [issues]––nothing else, just anemia. For those patients, a JAK inhibitor may not necessarily be the right choice, but [treatments such as] erythropoiesis-stimulating agents [ESAs], danazol, corticosteroids, or even immunomodulatory agents may be an appropriate first-line choice.

However, for patients with symptomatic splenomegaly or constitutional symptoms, JAK inhibitors have made their mark. Compared with [treatments such as] hydroxyurea, JAK inhibitors have superior efficacy, reducing both spleen size and symptom burden. We have 3 FDA-approved [JAK inhibitors] currently.

For other manifestations of this disease, there are other [treatments] we can use. For patients with extramedullary hematopoiesis in the lungs or bones, radiation is appropriate. For patients who are early in their disease, sometimes pegylated interferon can be useful; some data support that. When patients progress to accelerated or blast-phase disease, HMAs are the backbone of therapy, usually in combination with other agents.

CAR T-Cell Therapy in FL

Boardman: CAR T-cell therapy is clearly active in relapsed/refractory FL, with high response rates, and is effective in patients with high-risk disease. Current data suggest that these remissions are durable but given [that FL is] an indolent lymphoma, we need more time to [confirm these data]. Adverse effects [AEs] [including] cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome are common and must be considered when weighing treatment options for patients, especially those who may be frailer. Lastly, the optimal timing of CAR T-cell therapy vs bispecific antibodies and other targeted agents will require further study.

Current and Novel TKIs in CML

Mauro: We might think of ponatinib [Iclusig] being favored [over asciminib] in patients with primary resistance [and] high transcript levels. For patients with compound mutations and pan cytopenias, neither drug may be successful. These can be challenges. Patients with a mixture of intolerance and resistance who have perhaps more preserved response or at least more residual response from prior therapy exposure may have a better AE experience and better long-term outcomes with asciminib, at least speculatively.

The T315I [mutation] is up for grabs. [Either ponatinib or asciminib may effectively target this mutation] because [both drugs seem to have activity there], and we don’t have concerns about the differences in dosing [between] asciminib [and ponatinib].

Looking into the future, other drugs are under further study. Olverembatinib, which is approved In China, is the drug that is closest to ponatinib and is in trials in the United States [US] now. [Regarding] other agents, we have some trials at Memorial Sloan Kettering Cancer Center. The [phase 1] ELVN-001 trial [NCT05304377] is open, [investigating an] ATP-competitive inhibitor that’s probably [similar to] ponatinib in its activity but may be much safer. Some other second-line allosteric inhibitors, such as TERN-701, [will also be investigated in clinical trials].

[The evolution of TKIs in CML is] a good story. A growing number of patients with CML are surviving CML, so survivorship is another effort and project at Memorial Sloan Kettering Cancer Center. The number of patients living with CML in the US will probably be 10 times what it used to be by the middle of the century. Asciminib will be a big help, [because] it offers better safety [than other TKIs]. We’ll see how other trials look.

BTK Inhibitors in CLL and MCL

Islam: BTK inhibition with small-molecule–targeted drugs has transformed the way we treat [patients with] B-cell malignancies over the past decade, ever since the advent of ibrutinib [Imbruvica] in the early 2010s. Newer-generation BTK inhibitors continue to improve safety and efficacy and are now even trying to overcome the resistance mechanisms we’ve seen with covalent BTK inhibitors. These drugs are being studied as monotherapies and have promising efficacy as single agents. [They] are also being combined with already-approved and emerging therapies. This has been a paradigm shift in both CLL and MCL, away from combination chemoimmunotherapy and more intensive therapies like autologous stem cell transplantation, potentially. There’s much to come, and many exciting data will be published in the next couple of years.

Updates in DLBCL Management

Lue: POLA-R-CHP [rituximab (Rituxan), cyclophosphamide, doxorubicin, polatuzumab vedotin-piiq (Polivy), and prednisone], has become the standard of care [(SOC) for patients with DLBCL with an] International Prognostic Index [score of] 2 and activated B-cell biology. We still believe dose-adjusted R-EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab] or more intensive therapies for high-grade B-cell lymphoma or double-hit or triple-hit lymphoma should be the SOC. The role of central nervous system prophylaxis in DLBCL is controversial. [We may] need to develop ways to identify truly high-risk patients, [such as through] novel assays like cell-free DNA to find subclone populations. Long-term follow-up for CD19-targeting CAR T-cell therapies [demonstrated] an overall survival benefit in refractory patients, and bispecific antibodies are having significant efficacy in the relapsed/refractory setting, although patients who relapse after bispecific antibodies and CD19-targeting agents [have] an unmet need.

Updates in Lower-Risk MDS Management

Bewersdorf: The treatment landscape for anemia in lower-risk MDS is finally moving. The [phase 3] COMMANDS trial [NCT03682536] showed luspatercept-aamt [Reblozyl] to be superior to ESA in patients with lower-risk MDS. In the second-line setting, imetelstat seems to be an effective option in ESA-refractory patients, independent of their [disease’s] molecular subtype.

At this point, [the role of] roxadustat is unclear. We’ll see what the final presentation of the [phase 3] MATTERHORN trial [NCT03263091] yields. There are still many open questions in the field. How do we sequence luspatercept and imetelstat? What do intriguing data [regarding] allele fraction reduction [show about roxadustat] as a disease-modifying effect? There’s more work to be done, but finally [we’re seeing] some progress.

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