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Ibrutinib salvage therapy effective for relapsed CLL following transplantation
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Salvage therapy with ibrutinib following allogeneic hematopoietic stem cell transplant conferred minimal residual disease negativity without causing graft-versus-host disease in patients with relapsed chronic lymphocytic leukemia, according to a study published in Blood.
Ibrutinib also selectively depleted pregerminal B cells and Th2 helper cells and enhanced donor Th1 T cell–mediated graft-versus-leukemia (GVL) effects.
Effective therapeutic agents are needed for the setting of post-allogeneic HSCT relapse. Ibrutinib (Imbruvica; Janssen, Pharmacyclics) — an inhibitor of Bruton’s tyrosine kinase (BTK) and interleukin-2 inducible kinase (ITK) — has led to high response rates and prolonged PFS and OS in patients with relapsed or refractory CLL.
“The inhibition of ITK is of unique interest following allogeneic transplant because we
postulate that the Th1–mediated graft-versus-leukemia benefit will reduce leukemia relapse risk,” David B. Miklos, MD, PhD, associate professor of medicine at the Stanford University Medical Center, and colleagues wrote.
The researchers evaluated data from 27 patients with relapsed CLL following allogeneic HSCT who benefitted from ibrutinib salvage therapy — including 16 patients from multi-institutional clinical trials and 11 patients treated at Stanford University following FDA approval of ibrutinib.
Of those from the clinical trials, 15 patients with evaluable lymphadenopathy experienced a median 88.6% reduction in lymph node size.
Patients in the clinical trials demonstrated an overall response rate of 87.5% — including two patients who achieved a complete response, 10 patients with a partial response and two patients who had partial responses with lymphocytosis — as well as a 24-month PFS of 77% and 24-month OS of 75%.
These patients were treated for a median of 19 months with no dose reductions reported.
The most common adverse event was diarrhea (n = 11), followed by upper respiratory tract infection, cough, contusion and arthralgia (n = 5 for each).
Patients treated at Stanford University showed an ORR of 91% — including seven patients who achieved a complete response, three patients with a partial response.
Median duration of treatment was 8.4 months, and six patients continued treatment.
Three patients died while on ibrutinib.
Adverse events in this cohort included fatigue (n = 7), diarrhea, nausea and pericardial effusion (n = 1 for each).
After 6 months of treatment, patients achieved an average 73% reduction of in lymph node size.
Of the nine patients who had mixed chimerism-associated CLL relapse, four converted to full donor chimerism following ibrutinib initiation in association with disease response.
Four patients evaluated by ClonoSeq (Adaptive Biotechnologies) achieved CLL minimal residual disease negativity, which persisted even after ibrutinib was discontinued.
Miklos and colleagues noted one patient — who had persistent chronic GVHD prior to ibrutinib initiation — experienced full resolution of chronic GHVD symptoms within 6 months of treatment.
Among all 27 patients, none developed graft-versus-host disease following ibrutinib initiation.
The researchers postulated that ibrutinib may increase graft-versus-leukemia benefit through a T cell–mediated effect.
A comprehensive immune phenotype characterization of peripheral B and T cells from treated patients demonstrated that ibrutinib selectively targets pregerminal B cells and depletes Th2 helper cells. These effects persisted after drug discontinuation.
“Ongoing studies of mixed lymphocyte reactions with patient T cells against primary CLL before and after ibrutinib exposure will provide further elucidation,” Miklos and colleagues wrote.
The researchers acknowledged the study was limited by the heterogeneity of the patient population and its small size.
“This will be the groundwork for future studies that continue to investigate the mechanisms by which ibrutinib mediates both effective suppression of CLL and Th2 T cells and enhancement of donor Th1 T cell–mediated graft-versus-leukemia benefit,” they added. – by Kristie L. Kahl
Disclosure: Ryan reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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