Emerging Options Open the Door to Optimized Treatment Opportunities in Hematologic Malignancies

More tailored selection processes, which have placed a greater emphasis on patient-specific characteristics, such as risk and genomic status, and made possible with a growing number of treatment options, have led to optimized therapeutic decisions for patients with hematologic malignancies, according to a panel of experts from Memorial Sloan Kettering Cancer Center that presented during an OncLive^® Institutional Perspectives in Cancer webinar on leukemia and lymphoma.

During the meeting, faculty spotlighted updates and ongoing research efforts in chronic lymphocytic leukemia (CLL), relapsed/refractory mantle cell lymphoma (MCL), and myelofibrosis, as well as the current and potential future state of CAR T-cell therapy in leukemia and lymphoma.

Notably, the chair of the event, Anthony Mato, MD, MSCE, director of the CLL Program and a hematologic oncologist at Memorial Sloan Kettering Cancer Center (MSK), highlighted the importance of collaboration between medical oncologists as the field continues to grow.

Mato, was joined by fellow MSK faculty:

• Lindsey Roeker, MD, a hematologic oncologist
• Meghan Thompson, MD, a third-year fellow in the Department of Hematology and Medical Oncology
• Anita Kumar, MD, the regional care network medical site director of MSK Basking Ridge
• Raajit K. Rampal, MD, PhD, a hematologic oncologist
• Jae Park, MD, a hematologic oncologist

During the meeting, the panelists provided key take-away messages from their presentations on CLL, MCL, myelofibrosis, and CAR T-cell therapy and shed light on some of the most promising research in their respective fields.

CLL

Roeker and Mato: Novel agent combinations [in CLL] have been explored both as fixed-duration and [minimal residual disease]-guided regimens. These approaches yield high response rates that appear durable with limited follow-up, although further study into optimal patient selection is warranted.

The following factors should be considered when judging the success of a novel regimen in CLL: whether the novel combination approach allows for time-limited administration; [whether the regimen] demonstrated superiority over a clinically relevant control therapy or against sequential monotherapies that comprise the combination; and [whether the regimen] elicits a favorable risk-benefit ratio. Additionally, questions regarding mechanisms of resistance, sequencing, and prolonged survival potential should be addressed before incorporating a novel combination approach [into practice].

Thompson: In the longest follow-up of a phase 3 study of BTK inhibitors in the frontline treatment of CLL, [the RESONATE-2 trial (NCT01722487)], ibrutinib [Imbruvica] monotherapy had a 6.5-year estimated progression-free survival rate of 61%, and 47% of patients remain on ibrutinib. This study highlights that BTK inhibitors are efficacious in the frontline treatment of patients with CLL and that many patients have durable and ongoing responses.

In the frontline setting, many ongoing trials are investigating BTK inhibitors in combination with the BCL2 inhibitor venetoclax [Venclexta] plus or minus an anti-CD20 monoclonal antibody. Recently, data were presented from the fixed-duration cohort of the CAPTIVATE trial [NCT02910583] in which ibrutinib was administered for 3 months followed by 12 months of ibrutinib in combination with venetoclax.

This regimen was very effective with an overall response rate of 96% and a complete response [CR] rate of 52.2%. The fixed-duration [approach] would likely be appealing to patients. Although these combinations are still in clinical trials, if the BTK inhibitor and BCL2 inhibitor combination were to be used in the frontline setting in clinical practice, a key unanswered question is: What should the next line of therapy at relapse be? Should it be BTK inhibitor monotherapy, venetoclax monotherapy, re-treatment with the BTK inhibitor and BCL2 inhibitor combination, or a new agent or combination?

In the relapsed/refractory setting, head-to-head comparisons of covalent BTK inhibitors are now being presented. The ELEVATE-RR trial [NCT02477696] is the first randomized head-to-head comparison of the covalent BTK inhibitors ibrutinib and acalabrutinib [Calquence].

The results showed no difference in efficacy (HR, 1.0) between ibrutinib and acalabrutinib, but a more favorable overall safety profile was shown with acalabrutinib compared with ibrutinib, with less atrial fibrillation/flutter, hypertension, any-grade bleeding, diarrhea, and arthralgia with acalabrutinib treatment compared with ibrutinib treatment.

MCL

Kumar: Patients with relapsed/refractory MCL, particularly those with high-risk disease, tend to have poor survival outcomes. However, novel therapies, such as BTK inhibitors, venetoclax, and CAR T-cell therapy, have improved outcomes for this patient population.

To further advance this field, ongoing clinical trials are evaluating novel combinations with BTK inhibitors plus venetoclax, PI3K inhibitors, and CDK4/6 inhibitors. Combination strategies with venetoclax, lenalidomide [Revlimid], and rituximab [Rituxan] are also under investigation. To improve upon the efficacy observed with the FDA-approved CAR T-cell therapy brexucabtagene autoleucel [Tecartus], CAR T-cell therapy is being evaluated in combination with novel agents, as well as earlier on in the disease course for patients with high-risk MCL. Finally, bispecific antibodies could offer another tool to treat patients with MCL.

Myelofibrosis

Rampal: The major point I would say is that using genomics is now a standard of care and it is fundamental to the care of patients with myelofibrosis. We need to go beyond just looking for JAK1/2 mutations; we need to look at all the other mutations available. That gives us a sense of prognosis.

I would encourage physicians to think about repeating genomic testing during a patient’s course because we know that genomics can evolve, but we don’t always test for genomic evolution. The reason for that is that we may say at one point that a patient looks relatively low risk, but genetically, their disease may evolve and change the patient’s risk. Even though things might seem stable, clinically, in terms of blood counts, there may be a genomic evolution going on that could be an early warning that the disease itself is going to progress and transform.

Acute Lymphoblastic Leukemia

Park: In relapsed/refractory B-cell acute ALL, the FDA-approved, CD19-directed CAR T-cell therapy tisagenlecleucel [Kymriah] induced a CR rate of approximately 80%, even after patients received blinatumomab [Blincyto] and inotuzumab ozogamicin [Besponsa]. Several other phase 1/2 clinical trials are ongoing, evaluating CAR T-cell therapy for this patient population.

In relapsed/refractory T-cell ALL, CAR T-cell therapies directed toward CD7, CD5, CD4, and CD30 are under investigation.

Notably, patients with a low burden of disease appear to derive the most clinical benefit from CAR T-cell therapy, as well as have longer remissions with lower rates of toxicity. As such, CAR T-cell therapy should be considered early for these patients to optimize efficacy and safety.

Finally, novel CAR T-cell therapies, such as affinity-tuned CD19-directed CARs, dual antigen CD19-22 CARs, off-the-shelf products, and natural killer cell–based products are being evaluated to potentially reduce rates of relapse and improve tolerability. However, with the currently available products, prophylactic use of cytokine-directed therapies can be successful in reducing the rates and severity of cytokine release syndrome and neurotoxicity.