This article is more than 5 years old. Information may no longer be current.
Chemoimmunotherapy regimen effective in CLL patients with IGHV mutations
ORLANDO — A chemoimmunotherapy regimen containing ibrutinib, fludarabine, cyclophosphamide and obinutuzumab resulted in high rates of clinical remission and undetectable minimal residual disease in previously untreated patients with chronic lymphocytic leukemia who harbor IGHV mutations but lack 17p deletions and TP53 mutations, according to data presented at the ASH Annual Meeting and Exposition.
Previous results of the CLL10 trial established fludarabine, cyclophosphamide and rituximab (Rituxan; Genentech, Biogen), or FCR, as the preferred first-line chemoimmunotherapy regimen for young, fit patients with CLL, according to Nitin Jain, MD, associate professor in the department of leukemia at The University of Texas MD Anderson Cancer Center, and colleagues. More recent findings from the E1912 trial showed that ibrutinib (Imbruvica; Pharmacyclics, Janssen) plus rituximab improved PFS and OS vs. FCR in this patient population. However, there was no significant difference in PFS among patients with IGHV mutations.
“With the FCR studies, it is already known that the long-term benefit is seen in patients with [IGHV] mutations,” Jain and colleagues wrote. “In the MD Anderson Cancer Center FCR trial, long-term follow up demonstrated that the PFS at 10 years was approximately 55% for IGHV-mutated patients with a plateau after 8 years, suggesting that these patients may be cured of their CLL. Hence, chemoimmunotherapy remains an appropriate first-line option for patients with [IGHV mutations] with fixed duration treatment and expectation for long treatment-free interval.”
In 2014, the researchers developed a new chemoimmunotherapy regimen that replaced rituximab with obinutuzumab (Gazyva, Genentech) based on findings from the CLL11 trial, which showed obinutuzumab was associated with a higher rate of undetectable MRD compared with rituximab. They also added ibrutinib to the regimen, which similarly was associated with an increased rate of undetectable MRD when combined with chemoimmunotherapy in the HELIOS trial. To decrease the amount of chemotherapy exposure, the researchers only administered three cycles of chemotherapy in the ibrutinib, fludarabine, cyclophosphamide and obinutuzumab (iFCG) regimen.
“We hypothesized that achieving higher undetectable MRD would improve PFS and OS and reducing the amount of chemotherapy might lower the risk of [therapy-associated leukemia],” the researchers wrote.
The regimen was administered to 45 treatment-naive patients (median age, 60 years) with CLL and IGHV mutations without 17p deletions or TP53 mutations. After three cycles of iFCG, patients who achieved a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) and undetectable MRD in the bone marrow received nine additional courses of ibrutinib and three additional courses of obinutuzumab. All other patients received nine additional courses of both agents. After 12 cycles, patients stopped therapy, including ibrutinib, if they achieved undetectable MRD in the bone marrow.
After a median follow up of 34.2 months, the best response in an intent-to-treat analysis was a 69% CR/CRi rate and 98% undetectable MRD rate. The CR/CRi rate improved in time from 38% at 3 months to 67% at 1 year. The rate of undetectable MRD in bone marrow was consistent throughout the treatment duration and higher than the undetectable MRD rate observed in prior studies evaluating FCR and FCR plus ibrutinib in patients with IGHV mutations.
Treatment was discontinued in four patients, including one patient who developed a pulmonary mycobacterium avium complex infection, one patient who experienced an infusion reaction to obinutuzumab, one patient who withdrew consent, and a 26-year-old patient who died congestive heart failure after starting a weight loss supplement. The death is possibly related to treatment with ibrutinib, according to the researchers.
The remaining 41 patients reached 1 year of follow up. All patients had undetectable MRD and stopped ibrutinib treatment per study protocol. One recurrence of MRD was reported in a patient 2.5 years after discontinuing ibrutinib. The patient is now in clinical remission. To date, no cases of disease progression have been reported.
rade 3 or 4 neutropenia and thrombocytopenia 40%.
The researchers concluded that iFCG with only three chemotherapy cycles is an effective time-limited treatment for young patients with M-IGHV mutations who lack 17 deletions and TP53 mutations. – by Stephanie Viguers
Reference:
Jain N, et al. Abstract 357. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosure: Jain reports receiving research funding from AbbVie, Adaptive Biotechnologies, ADC Therapeutics, AstraZeneca, Bristol-Myers Squibb, Cellectis, Genentech, Incyte, Pharmacyclics, Precision Biosciences, Servier and Verastem; being a consultant for AbbVie, Adaptive Biotechnologies, ADS Therapeutics, AstraZeneca, Genentech, Janssen, Pfizer, Pharmacyclics, Precision Biosciences, Servier and Verastem; receiving honoraria from AbbVie, Adaptive Biotechnologies, ADC Therapeutics, AstraZeneca, Genentech, Janssen, Pfizer, Pharmacyclics and Precision Biosciences; and membership on an board of directors or advisory committee for AbbVie, Adaptive Biotechnologies, ADS Therapeutics, , Genentech, Janssen, Pharmacyclics, Pfizer, Precision Biosciences, Servier and Veratem. Please see the abstract for all other authors’ relevant financial disclosures.