Combined Chemotherapy and Targeted Molecular Therapy Boosts Response in Chronic Lymphocytic Leukaemia

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Highlights:

• Patients less than 65 years diagnosed with chronic lymphocytic leukaemia (CLL) showed significantly better response when treated with a combination of chemotherapy and targeted molecular therapy
• Average age of diagnosis in CLL is over 70 years; however elderly patients do not tolerate chemotherapy very well

Novel treatment regimen using a combination of targeted oral agent ibrutinib and chemotherapy could greatly improve outcome in CLL according to a recent investigator-initiated multi-center phase II clinical trial conducted by the Center for Chronic Lymphocytic Leukemia, Dana-Farber Cancer Institute. The findings of the study were reported in an oral presentation at the 59th American Society of Hematology (ASH) Annual Meeting and Exposition in Atlanta. Matthew Davids MD, MMSc, Associate Director, Center for Chronic Lymphocytic Leukemia, Dana-Farber Cancer Institute said "We’re combining the most potent chemotherapy regimen with a highly active novel agent, trying to develop an optimal regimen for younger patients."

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Novel Ibrutinib–FCR (iFCR) Treatment Regimen For Younger CLL Patients

• Chronic lymphocytic leukaemia (CLL) is a blood disorder in the elderly with average age at diagnosis being about 72 years.
• Since older patients do not tolerate chemotherapy well due to toxicities and adverse effects, the combination of Fludarabine, cyclophosphamide, and rituximab (FCR) is the standard chemoimmunotherapy regimen used for younger patients with CLL.
• Although this treatment is very effective in controlling the disease, it does not cure CLL.
• In the current study, the research team combined ibrutinib a newer agent, with the standard FCR chemotherapy regimen for CLL to determine whether this combination (iFCR) is safe and more effective for younger patients with CLL.

"With older, frailer patients, in the past few years we’ve been moving away from chemotherapy and toward novel targeted oral agents such as ibrutinib alone or in combination with other novel agents," said David.

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Methods Of The Study

• The study included only physically fit patients 65 years or younger and who had not received any prior treatment, for this trial.
• Participants of the trial initially got approximately six months of a combination of FCR (fludarabine, cyclophosphamide, and rituximab) chemotherapy along with the targeted oral agent ibrutinib.
• This regimen was then followed by ongoing maintenance with ibrutinib.

How Superior Is The Novel Treatment Regimen - Findings Of The Study

• All of the 35 patients who received this "iFCR" combination responded to this treatment
• Following the end of the initial part of the treatment with iFCR, 37 percent obtained complete response with no evidence of minimal residual disease (MRD) in the bone marrow, compared to the 20 percent response with FCR alone
• Following initial treatment, during the maintenance period, the proportion of MRD-negative complete response increased to 57%, with 83% showing nil residual disease in the bone marrow
• Patients given iFCR treatment showed relatively lower rates of infection and blood toxicity (although this could also be due to mandatory prophylaxis with antimicrobials and growth factor support given to these patients)

FCR regimen alone which is the standard regimen currently for younger patients with CLL provides prolonged periods of disease-free survival in patients with the mutated immunoglobulin heavy chain variable region (IGHV) gene, but less durable responses for patients with unmutated IGHV.

• However, in this trial even among patients with the high-risk unmutated IGHV gene, about 71 percent showed no evidence of residual disease in the bone marrow.

"As far as we know, that’s the highest rate anyone has ever reported for this group with any regimen in CLL," Davids said.

Thus the findings of the study suggest that iFCR combination regimen achieves better and more lasting response in CLL patients compared to FCR alone.

"Previous studies have demonstrated that when we use ibrutinib alone, it is very effective at controlling the disease but it doesn’t eradicate it," Davids said. "A goal in our field now is to try to combine targeted agents such as ibrutinib with other drugs."

Novel Agent Ibrutinib – An Overview

Ibrutinib is a BTK (Bruton Tyrosine Kinase) inhibitor, and blocks this protein which is necessary for CLL cells to survive. It was approved by the Food & Drug Administration (FDA) for the treatment of newly diagnosed CLL in 2016. It is administered orally.

It is used to treat chronic lymphocytic leukemia, Waldenstrom’s macroglobulinemia, and as a second-line treatment for marginal zone lymphoma, mantle cell lymphoma, and chronic graft vs host disease. Common side effects of Ibrutinib include the following

• Decreased platelets causing easy bruising and bleeding
• Nausea, vomiting and diarrhea
• Decreased neutrophil count
• Decreased hemoglobin
• Tiredness
• Musculoskeletal pain
• Swelling
• Upper respiratory tract infection

Future Plans

• To enlarge upon the current study, it is planned to recruit 50 patients more supported by the Blood Cancer Research Partnership, a research consortium codirected by Davids with started with funds given from the Leukemia and Lymphoma Society.
• In that study, the participants will stop getting ibrutinib maintenance after two years if they are MRD negative in the bone marrow.

He is hopeful that a phase III clinical study will be launched sometime soon to compare the iFCR regimen to standard of care in younger CLL patients.

References:

1. A Phase II Study of Ibrutinib Plus FCR in Previously Untreated, Younger Patients With Chronic Lymphocytic Leukemia (iFCR) - (https://clinicaltrials.gov/ct2/show/NCT02251548)
2. About Ibrutinib - (http://chemocare.com/chemotherapy/drug-info/ibrutinib.aspx)

Source-Medindia