Ibrutinib, fludarabine, cyclophosphamide and rituximab for treating chronic lymphocytic leukemia

This study aimed to investigate the combination of ibrutinib with fludarabine, cyclophosphamide, and rituximab (FCR) as a frontline treatment in young, fit patients with chronic lymphocytic leukemia. 

This study concluded that this combination is promising as a time-limited frontline regimen for these patients.  

Fludarabine, cyclophosphamide, and rituximab (FCR) can improve disease-free survival for patients under 65 years with chronic lymphocytic leukemia (CLL) with mutated IGHV. The IGHV mutation can be found in CLL cancer cells. Patients with unmutated IGHV rarely have lasting responses to FCR.  

Fludarabine (Fludara) is a chemotherapy used in the treatment of CLL as well as acute leukemia. Cyclophosphamide (Cytoxan) is a standard chemotherapy. Rituximab (Rituxan) is a monoclonal antibody and can be used to treat certain types of cancer. Ibrutinib (Imbruvica) is a targeted therapy known as a kinase inhibitor. It is used to treat B cell cancers such as CLL. Ibrutinib is active for patients with CLL regardless of IGHV mutation status but continuous treatment is required. 

It was unknown if time-limited ibrutinib with FCR treatment would lead to lasting responses in patients with CLL. 

This study involved 85 patients aged 65 or younger with previously untreated CLL. Patients received ibrutinib for 7 days . This was followed by up to six 28-day cycles of FCR with continuous ibrutinib. The average follow-up time was 16.5 months. 

Patients who responded to treatment continued on ibrutinib maintenance (treatment meant to keep cancer from returning) for up to 2 years. Patients with undetectable minimal residual disease (MRD – small numbers of cancer cells left after treatment) after 2 years were able to end treatment.  

33% of patients achieved a complete response and undetectable MRD in the bone marrow 2 months after the last cycle of ibrutinib and FCR. 84 patients (99%)  achieved a best response (complete or partial response) at any time during the study. Undetectable MRD was achieved by 84% of all patients.

One patient had disease progression and one patient died (cardiac death possibly related to ibrutinib treatment). 74% of patients experienced thrombocytopenia (low platelet levels). 62% of patients experienced neutropenia (low level of white blood cells) and 49% experienced anemia (low level of red blood cells).  

Other side effects included atrial fibrillation (irregular heartbeat) in 4% of patients and pneumocystis jirovecii pneumonia (lung infection) in 2% of patients. 

This study concluded that ibrutinib combined with FCR is a promising time-limited frontline treatment for fit, young patients with CLL. 

This study was funded by Pharmacyclics, the manufacturer of ibrutinib. This study had a small number of participants. Further larger studies are needed.