Month: July 2024

Prioty Islam, MD, MSc, attending physician, medical oncologist, Leukemia, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, discusses how the approval of the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) has transformed the treatment of patients with mantle cell lymphoma (MCL), and where this agent fits in to the current treatment armamentarium. Pirtobrutinib received FDA approval in January, 2023, for the treatment of patients with relapsed/refractory MCL who have been previously exposed to at least 2 prior lines of systemic therapy, including a BTK inhibitor. This approval was supported by data from the phase 1/2 BRUIN trial (NCT03740529), in which a subset of patients with MCL achieved a high overall response rate (ORR) with the agent. Historically, patients with relapsed/refractory MCL experienced poor prognosis and did not respond well to chemoimmunotherapy regimens, Islam begins. However, the introduction of single-agent, oral targeted BTK inhibitors, such as pirtobrutinib, to the treatment armamentarium has improved the durability of patient responses to treatment, Islam states, as well as patients’ quality of life. Accordingly, this drug class has significantly affected the treatment of relapsed/refractory MCL, she says. Much like its activity in chronic lymphocytic leukemia, pirtobrutinib has been shown to successfully restore BTK inhibitor dependency in patients with MCL, as well as induce responses in those who previously progressed on a different BTK inhibitor, Islam continues. Although there is interest in moving pirtobrutinib into earlier lines of therapy in MCL, efforts to accomplish this remain both a challenge and a subject of debate due to a lack of data on patient responses after progression on pirtobrutinib, Islam cautions. The ongoing, randomized phase 3 BRUIN-MCL-321 trial (NCT04662255) is investigating pirtobrutinib vs investigator’s choice of BTK inhibitor in patients with pretreated, BTK inhibitor–naïve MCL. Findings from the trial are hoped to illuminate the feasibility of utilizing pirtobrutinib in the frontline, as the current FDA indication for this agent is after progression on or intolerance to a prior covalent BTK inhibitor, Islam says. Disclosures: Dr Islam reports consulting roles with AbbVie, AstraZeneca, BeiGene, DAVA Oncology, and LOXO Oncology; as well as speaking roles with Targeted Oncology and The Video Journal of Hematologic Oncology (VJHemOnc).

Raajit K. Rampal, MD, PhD 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 (HMAs) can lead to spleen and symptom burden reductions, according to Raajit K. Rampal, MD, PhD. 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

Francois Lemonnier, MD, PhD Second-line treatment with axicabtagene ciloleucel (axi-cel; Yescarta) led to an investigator-assessed, 3-month complete metabolic response (CMR) rate of 71.0% (95% CI, 58.05%-81.80%) in patients with large B-cell lymphoma who were ineligible for autologous stem cell transplant (ASCT), according to data from the final analysis of the phase 2 ALYCANTE trial (NCT04531046). Findings presented at the 2023 EHA Congress showed that evaluable patients (n = 62) experienced a 3-month objective response rate (ORR) of 75.8%, including a partial response (PR) rate of 4.8%, per investigator assessment. No patients had stable disease (SD), 11.3% of patients had progressive disease, and 12.9% of patients were not evaluated. Notably, 59.7% of patients remained in CMR at 6 months. Per investigator assessment of best response, the ORR was 90.3%, including a CMR rate of 79.0%, a PR rate of 11.3%, and SD and progressive disease rates of 4.8% each. “The study met its primary end point with a CMR [rate] of 71% at 3 months vs a 12% expected [CMR rate] with historical controls,” presenting study author Francois Lemonnier, MD, PhD, of the Lymphoid Malignancies Unit at Henri-Mondor University Hospital in Créteil, France, said. The single-arm, open-label, multicenter trial conducted at 20 centers in France enrolled patients with aggressive B-cell non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBCL), and grade 3B follicular lymphoma, who were relapsed or refractory within 12 months of first-line chemoimmunotherapy. Patients needed to be ineligible for ASCT per physician assessment and at least 1 of the following: At least 65 years of age At least 18 years of age with a Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score of at least 3 At least 18 years of age and underwent prior ASCT as first-line consolidation Other key inclusion criteria included an ECOG performance status of 0 to 2, adequate vascular access for leukapheresis, an absolute neutrophil count of at least 1 G/L, a platelet count of at least 75 G/L, an absolute lymphocyte count of at least 0.1 G/L, creatinine clearance of at least 40 mL/min, serum alanine transaminase/aspartate transaminase of no more than 2.5 times the upper limit of normal (ULN), a total bilirubin of no more than 26 µmol/L (unless a patient had Gilbert’s syndrome), a left ventricular ejection fraction of at least 45%, and a baseline oxygen saturation of at least 92% on room air. Following leukapheresis, bridging therapy with 1 or 2 cycles of R-GEMOX or corticosteroids was optional. After patients underwent lymphodepleting chemotherapy with 30 mg/m2 of fludarabine per day plus 500 mg/m2 of cyclophosphamide per day for 3 days, they received a single infusion of axi-cel. Patients underwent a PET scan and circulating tumor DNA (ctDNA) analysis on day 14 and at months 1, 3, 6, 9, and 12. Patients were enrolled between April 26, 2021, and June 15, 2022, and the data cutoff for the final analysis was January 19, 2023. The median follow-up was 12 months (range, 2.1-17.9). Investigator-assessed 3-month CMR rate was the primary end point. Secondary end points included 3-month CMR rate per independent review committee (IRC) assessment, event-free survival (EFS), duration of response, progression-free survival (PFS), overall survival (OS), safety, and health-related quality of life. The median age for patients treated with axi-cel was 70 years (range, 49-81), and 53.2% of patients were at least 70 years of age. Additionally, 75.8% of patients were male, 3.2% of patients underwent prior ASCT, and 32.3% of patients had a HCT-CI score of at least 3. The majority of patients had an ECOG performance status of 0 or 1 (98.4%), an International Prognostic Index score of 2 or higher (88.8%), Ann Arbor stage III or IV disease (74.2%), and were refractory to their first line of therapy (54.8%). Furthermore, 11.3% of patients had lactate dehydrogenase of at least the ULN at baseline, and 19.4% had a C-reactive protein serum level of more than 30 mg/L at infusion. Regarding histology, 83.9% of patients had DLBCL, 9.7% had HGBCL with MYC and BCL2 rearrangements with or without BCL6 rearrangements, 1.6% had follicular lymphoma with possible transformation to DLBCL not otherwise specified, 1.6% had grade 3B follicular lymphoma, and 3.2% had grade 1, 2, or 3A follicular lymphoma. Additionally, 83.9% of patients underwent bridging therapy. Among these patients, 98.1% received R-GEMOX, and 17.3% were given corticosteroids. The best response to bridging therapy included CMR (7.7%), partial metabolic response (26.9%), no response/stable disease (26.9%), progressive metabolic disease (36.5%), and not evaluated (1.9%). The median time between inclusion and axi-cel infusion was 41.5 days (min, 21; max, 71). A total of 69 patients underwent leukapheresis, and 7 patients were not infused with axi-cel due to death (n = 1), cutaneous nocardiosis (n = 1), complete remission prior to the infusion of CAR T-cell therapy (n = 1), absence of documented relapsed on biopsy prior to axi-cel infusion (n = 1), withdrawal of consent (n = 1), progressive disease (n = 1), and receipt of an investigational medical product and second-line chemotherapy for progression (n = 1). Five patients infused with axi-cel died prior to month 3 due to adverse effects (AEs; n = 3) and lymphoma (n = 2). At data cutoff, 50 patients were still alive, and 7 more deaths were reported due to AEs (n = 3), lymphoma (n = 3), and unknown (n = 1). Additional data showed that per IRC assessment, the 3-month ORR was 69.4%, including CMR, PR, SD, and progressive disease rates of 66.1%, 3.2%, 1.6%, and 14.5%, respectively. Notably, 14.5% of patients were not evaluated for 3-month response. Regarding best response, the IRC ORR was 91.9%, including CMR, PR, SD, and progressive disease rates of 82.3%, 9.7%, 1.6%, and 6.5%. Lemonnier noted that 3-month CMR rates were similar across evaluated subgroups. At day 14 following axi-cel infusion, 61.1% of evaluable patients (n = 33/54) had a negative PET-CT, and 48.1% (n = 25/52) had undetectable ctDNA. The median EFS was 12.3 months, and the 12-month EFS rate was 51.2% (95% CI, 38.3%-62.8%).