Reem Karmali, MD, MS, assistant professor of medicine, Northwestern University Feinberg School of Medicine, discusses the limitations of intensive therapy in older and medically unfit patients with mantle cell lymphoma (MCL).

MCL is a rare and aggressive subtype of B-cell non-Hodgkin lymphoma, says Karmali. The majority of patients who are diagnosed with MCL are older. Additionally, these patients may have comorbidities or be medically unfit, thereby limiting their ability to undergo intensive chemoimmunotherapy with or without an autologous stem cell transplant (ASCT).

As such, these patients may have poorer outcomes, says Karmali. To that end, researchers conducted an analysis that evaluated the practice patterns and survival outcomes of patients 65 years of age or older with newly diagnosed MCL. The results were presented during the 2020 ASCO Virtual Scientific Program.

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Reem Karmali, MD, MS, discusses the limitations of intensive therapy in older and medically unfit patients with mantle cell lymphoma (MCL).

Dr. Karmali on Limitations of Intensive Therapy in Older/Medically Unfit Patients With MCL

Reem Karmali, MD, MS, assistant professor of medicine, Northwestern University Feinberg School of Medicine, discusses the next steps for research regarding the use of ibrutinib (Imbruvica) as maintenance therapy in mantle cell lymphoma (MCL).

A study that examined ibrutinib maintenance following intensive induction therapy showed that the approach is feasible and the toxicities are manageable, says Karmali. However, longer follow-up data are needed, as well as analysis of patients’ minimal residual disease (MRD) status. The primary objective of the study was to look at efficacy, which was assessed according to the rate of 3-year progression-free survival (PFS) rates.

However, an exploratory analysis looked at MRD status and an IgH polymerase chain reaction, based methodology. Investigators believe that MRD will provide better insight into whether patients can achieve deeper responses with ibrutinib maintenance. With this analysis, researchers hope to show a correlation between MRD status and PFS and overall survival that would warrant further exploration of ibrutinib maintenance, concludes Karmali.

Dr. Karmali on Next Steps of Research Regarding Ibrutinib Maintenance in MCL

Reem Karmali, MD, MS, assistant professor of medicine, Northwestern University Feinberg School of Medicine, discusses challenges in the field of mantle cell lymphoma (MCL).

Chemoimmunotherapy induces high response rates in MCL; however, there is no standardized frontline approach. Treatments are variable and they depend on several different patient factors, says Karmali. When a symptomatic patient presents with a relatively aggressive disease, treatments can range from rituximab (Rituxan) monotherapy to chemoimmunotherapy with or without autologous stem cell transplant (ASCT).

However, it is unclear whether patients should be consolidated with an ASCT and whether rituximab maintenance is appropriate, depending on the type of induction therapy the patient is started on. Importantly, the US Cooperative Group study is looking to address this question of whether an ASCT is needed across the board in MCL.

Apart from picking the right therapy for patients, one of the biggest challenges is the fact that relapse is quite common, and when patients relapse, their outcomes are poor, concludes Karmali.

Dr. Karmali on Challenges in MCL

Reem Karmali, MD, MS, assistant professor of medicine, Northwestern University Feinberg School of Medicine, discusses the toxicity profile of ibrutinib (Imbruvica) maintenance therapy after induction therapy in patients with mantle cell lymphoma (MCL).

Among the 36 patients who received ibrutinib as maintenance at a dose of 560 mg daily for up to 4 years or until disease progression or unacceptable toxicity, investigators reported toxicities that were in line with what one would expect from ibrutinib's safety profile. Overall, with treatment exposures, patients tolerated the drug quite well, says Karmali. At a follow-up of 19 months, the median number of cycles delivered were 16.5. One-quarter of patients have already completed 2 or more years of ibrutinib maintenance; of these patients, 2 of them have completed the full 4 years of treatment.

Regarding toxicities, approximately two-thirds of patients had treatment-related adverse events that required dose modification. About 20% of patients required a permanent dose modification or reduction and 25% of patients discontinued ibrutinib permanently. Atrial fibrillation was the main cause for discontinuation, and it was reported in 9 patients, concludes Karmali.

Dr. Karmali on the Toxicity Profile of Ibrutinib Maintenance in MCL

Reem Karmali, MD, MS, assistant professor of medicine, Northwestern University Feinberg School of Medicine, discusses the use of novel agents in patients with relapsed/refractory mantle cell lymphoma (MCL).

Despite best efforts, MCL remains an incurable disease, says Karmali. However, several advances have resulted in improvements in survival. Most notably, the BTK inhibitors ibrutinib (Imbruvica) and acalabrutinib (Calquence) which have shown significant activity in the relapsed/refractory setting. Investigators anticipated that these agents would result in high response rates since BTK is an important protein of B-cell receptor signaling, which is a critical component of MCL differentiation, proliferation, and survival, explains Karmali. To date, both agents have shown response rates as high as 70% to 80%.

Given the impressive activity of these agents in such a heavily pretreated patient population, researchers are hoping to move these agents into earlier lines of therapy. However, whether their efficacy will translate to the frontline setting remains unclear, says Karmali.

Dr. Karmali on Novel Agents in Relapsed/Refractory MCL

Reem Karmali, MD, MS, assistant professor of medicine, Northwestern University Feinberg School of Medicine, discusses the preliminary results of a study which examined ibrutinib (Imbruvica) maintenance following induction in treatment-naïve patients with mantle cell lymphoma (MCL).

In the study, investigators used ibrutinib as maintenance therapy in treatment-naïve patients who required intensive induction therapy. Patients could have been treated with chemoimmunotherapy with or without an autologous stem cell transplant. Patients who achieved a partial response (PR) or complete response (CR) were enrolled on the trial and received ibrutinib as maintenance at a dose of 560 mg daily for up to 4 years or until disease progression or unacceptable toxicity, explains Karmali.

A total of 36 patients have been accrued to the trial, the majority of whom have advanced-stage disease. Fifty percent of patients have intermediate- or high-risk disease, according to the Mantle Cell Lymphoma International Prognostic Index, and 25% of patients have extranodal disease. Forty-seven percent of patients received bendamustine and rituximab (Rituxan) as induction therapy, whereas 25% received R-HyperCVAD. The remaining patients received R-CHOP with or without cytarabine-containing cycles. Following induction, 33 of 36 patients achieved a CR. Notably, half of patients did receive a transplant, adds Karmali. With the addition of ibrutinib maintenance, 1 patient who achieved a PR achieved a CR. With 19 months of follow-up, investigators note that 24 of the 36 patients remain on ibrutinib, further supporting the feasibility of the approach.

Reem Karmali, MD, MS

Articles

Dr. Karmali on Limitations of Intensive Therapy in Older/Medically Unfit Patients With MCL

Dr. Karmali on Next Steps of Research Regarding Ibrutinib Maintenance in MCL

Dr. Karmali on Challenges in MCL

Dr. Karmali on the Toxicity Profile of Ibrutinib Maintenance in MCL

Dr. Karmali on Novel Agents in Relapsed/Refractory MCL

Dr. Karmali on Ibrutinib Maintenance Following Induction in Untreated MCL