Promising Long-Term Outcome of Chemo-Free Mantle Cell Lymphoma Treatment Published in Blood Journal

The long-term outcome of the first-ever study of a non-chemotherapy frontline treatment approach to mantle cell lymphoma (MCL) was recently published in the American Society of Hematology’s prestigious Blood Journal.

Led by Dr. Jia Ruan, clinical investigators at four medical centers across the United States launched a phase two clinical trial in 2011 to evaluate the novel biological pairing of lenalidomide plus rituximab as induction (initial) and maintenance (relapse prevention) therapy. The team’s treatment goals were to provide disease control and extend survival, while maintaining quality of life.

Read more about the study here.

Of 36 evaluable patients, about 92 percent responded to treatment, with 64 percent achieving complete remission. At five-year follow-up, 77 percent of participants were alive and well, and 64 percent remained free of disease progression.

To determine how well the lenalidomide plus rituximab combination works, the team also measured the status of minimal residual disease (MRD) – the small amount of cancer cells that may be left after treatment that have the potential to lead to relapse. Eight out of a subset of ten evaluable patients tested MRD-negative.

Overall, the chemotherapy-free drug combination has produced durable remission rates with potential to achieve MRD-negative remissions. Chronic maintenance therapy with lenalidomide and rituximab has manageable side effects, including infections, cytopenias (low blood count), and some expected secondary primary malignancies.

This outcome represents a major stride in treatment and care of the MCL patient population, who harbor a rare and generally incurable disease where intensive chemotherapy regimens do not necessarily translate to cure and may not be tolerated by all patients.

Ruan Face“The introduction of novel agents – including the immunomodulatory agent lenalidomide and Bruton’s tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib, which are FDA-approved for MCL – is poised to transform MCL management by making effective ‘chemo-free’ treatment accessible to all patients in both relapsed/refractory and frontline settings,” says Jia Ruan, MD, PhD.

 

Dr. Jia Ruan and Colleagues Encouraged by Long-Term Results of Chemo-Free MCL Treatment Regimen

Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin lymphoma that occurs primarily in older adults. The disease is typically managed in the initial treatment setting with a combination of chemotherapy and immunotherapy, which tends not to be curative and may impart toxic side effects in some patients.

In search of an effective, less toxic treatment option for those afflicted by MCL, Dr. Jia Ruan and colleagues explored an alternative regimen free of conventional chemotherapy – lenalidomide plus rituximab – to be used in the initial treatment setting. Their multi-center phase II clinical trial of the novel biological pairing was the first-ever study of a non-chemotherapy first-line MCL treatment approach.

Thirty-eight MCL patients enrolled in the trial from July 2011 to April 2014. They received lenalidomide on days 1-21 of a 28-day cycle, and rituximab was administered four times per week during the first cycle, then once every other cycle. The first 12-cycle treatment was considered induction, or initial therapy, and was followed by a maintenance phase, in which therapy is provided to prevent relapse. Treatment was continuous until disease progression, and patients had the option to cease therapy after three years if in remission.

At the 2017 American Society of Hematology Annual Meeting, the researchers examined the long-term outcomes of the trial in a 5-year follow-up analysis to reveal that the drug combination shows promise for effective management of MCL, with the majority of trial participants doing well and maintaining good quality of life. About 90 percent of patients responded to the therapy, and over 60 percent remain in remission.

The research team also measured minimal residual disease (MRD) in patients’ blood, the small number of cancer cells that may be left after treatment that have the potential to grow and cause the patient to relapse. In the small subset of patients with available tumor tissues for MRD analysis, about 80 percent of patients were found to be MRD negative, further demonstrating the novel treatment regimen’s activity and feasibility as an additional therapeutic option for people with MCL.

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Dr. Jia Ruan

“We are encouraged by the quality and durability of the responses with the biologic doublet of lenalidomide plus rituximab as initial therapy for mantle cell lymphoma,” said Dr. Ruan. “We hope to bring this active combination to larger studies where it can be combined with other agents and compared to conventional chemotherapy.”

Monitoring Minimal Residual Disease in Lymphoma: The Italian Experience

Paola Ghione, MD
paola-ghione
Dr. Ghione is a visiting hematology fellow from Torino, Italy who is working with the Weill Cornell Lymphoma Program for six months.

Minimal residual disease (MRD) detection refers to a group of techniques used to find a very small amount of disease, normally undetectable with imaging or clinical exam. Usually, this detection is performed after treatment and, in many cases, is predictive of outcomes such as whether patients will relapse, and how quickly this might happen. Often, the reappearance of MRD can anticipate recurrence of lymphoma before it becomes clinically evident. In other hematologic disorders, such as acute leukemia and chronic myeloid leukemia, MRD is used in standard clinical practice to monitor disease status or to evaluate response to treatment. In the setting of lymphoma, measurement of MRD is still considered experimental, but a lot of research is taking place around the world to find the best way to perform it.

Our laboratory in Torino, Italy, run by Dr. Marco Ladetto and Dr. Simone Ferrero, leads many MRD projects for lymphoma and is part of the EuroMRD Network, an institution born in Europe to standardize MRD techniques. Currently, we look for tumor-specific DNA alterations in the blood before and after treatment using a technique called Allele-Specific Oligonucleotide (ASO)-PCR. Depending on how much tumor DNA is present in the blood, we can figure out the relative amount of tumor left in the body. Unfortunately, ASO-PCR requires an expert laboratory team, and the method is expensive and time-consuming, which makes it hard to use outside of specialized settings. In addition, it seems more reliable if performed directly on bone marrow aspirate (blood from the interior of the bone) than peripheral blood (coming from a normal vein), making it less attractive to clinicians and people with lymphoma.

New techniques that can speed the procedure and reduce the cost are being evaluated. For example, the droplet digital (dd)-PCR is interesting because it is faster and uses less material (i.e., requires less blood for the test). Another interesting method is Next Generation Sequencing (NGS), which allows the detection of several different DNA mutations at once. NGS analysis of cell-free circulating DNA(cfDNA) (the DNA present in circulating blood outside the cells) could give a lot information. Studying cfDNA from the blood could give us a more accurate picture of the lymphoma that in theory could be even better than studying DNA derived from an open biopsy at one site of disease. This is also sometimes referred to as a liquid biopsy. The reason it might be better is that the circulating cfDNA could show us mutations coming from all the sites where the tumor is actively growing, not only the one site from which the open biopsy is taken.

In Italy, although MRD is not yet available in routine clinical practice for treating lymphoma, it is being tested in some innovative clinical trials to guide treatment decisions. In some studies MRD negativity at the end of treatment is the primary goal, while in others reappearance of MRD prompts a preemptive approach. As an example, if MRD reappears when the person is off therapy, we can give a short re-treatment in order to avoid clinical relapse. In one of our clinical trials, evaluation of MRD has been used to rule out the presence of lymphoma in the cells collected prior to autologous stem cell transplantation.

Measurement of MRD has a lot of potential uses, and experience from other diseases proves that it can be practice changing. The challenges provided by more than 50 different lymphoma subtypes as well as the rapid evolution of new laboratory techniques have delayed the adoption of a universal test for MRD. In the near future, however, we expect to see MRD analysis in standard clinical practice everywhere.