Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT

Ryan, Christine E.; Sahaf, Bita; Logan, Aaron C.; O’Brien, Susan; Byrd, John C.; Hillmen, Peter; Brown, Jennifer R.; Dyer, Martin J. S.; Mato, Anthony R.; Keating, Michael J.; Jaglowski, Samantha; Clow, Fong; Rezvani, Andrew R.; Styles, Lori; Coutré, Steven; Miklos, David B.

doi:10.1182/blood-2016-06-715284

Cited by 67 publications

(68 citation statements)

References 42 publications

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“…Thus, although their delayed recurrence pattern may be an indicator of a more indolent disease, the better outcome of the recent relapses probably also reflects the improved rescue options with ibrutinib and other pathway inhibitors that are available nowadays. 12 As shown in the original publication and also in other studies, GVL activity is strongly associated with chronic GVHD in CLL. 7,10 Accordingly, the 2-year chronic GVHD incidence of 73% 7 observed in this trial was unevenly distributed between patients with and without a relapse event.…”

Section: Letters To Bloodmentioning

confidence: 70%

Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial

Krämer

Stilgenbauer

Dietrich

et al. 2017

Blood

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Section: Letters To Bloodmentioning

confidence: 70%

Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial

Krämer

Stilgenbauer

Dietrich

et al. 2017

Blood

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“…28 Similarly, Th1-promoting cytokines, IFN-g and IL-12, were significantly increased only in patients who achieved a response, which suggests that response to ibrutinib in FL could be related to its T-cell immunomodulatory effects, which have also been observed in the post-allogeneic transplantation setting. 14,29 Ibrutinib treatment also produced significant decreases in responders in MCP3 (also known as CCL7) and IP-10 (also known as CXCL10), which have been implicated in tumor development. 30 These results, along with a clinical observation of pseudoprogression in some patients, suggest that the immunomodulatory effects of ibrutinib may be linked to a response to therapy.…”

Section: Discussionmentioning

confidence: 99%

Ibrutinib as Treatment for Patients With Relapsed/Refractory Follicular Lymphoma: Results From the Open-Label, Multicenter, Phase II DAWN Study

Gopal

Schuster

Fowler

et al. 2018

JCO

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Purpose The Bruton's tyrosine kinase inhibitor ibrutinib has demonstrated clinical activity in B-cell malignancies. The DAWN study assessed the efficacy and safety of single-agent ibrutinib in chemoimmunotherapy relapsed/refractory follicular lymphoma (FL) patients. Methods DAWN was an open-label, single-arm, phase II study of ibrutinib in patients with FL with two or more prior lines of therapy. Patients received ibrutinib 560 mg daily until progressive disease/unacceptable toxicity. The primary objective was independent review committee-assessed overall response rate (ORR; complete response plus partial response). Exploratory analyses of T-cell subsets in peripheral blood (baseline/cycle 3) and cytokines/chemokines (baseline/cycle 2) were performed for available samples. Results Between March 2013 and May 2016, 110 patients with a median of three prior lines of therapy were enrolled. At median follow-up of 27.7 months, ORR was 20.9% (95% CI, 13.7% to 29.7%, which did not meet the 18% lower-bound threshold for the primary end point). Twelve patients achieved a complete response (11%; 95% CI, 5.8% to 18.3%). Median duration of response was 19.4 months (range, 1 to ≥ 33 months), with a median progression-free survival of 4.6 months and a 30-month overall survival of 61% (95% CI, 0.51% to 0.70%). Lymphoma symptoms resolved in 67%. Seven of 32 patients who experienced initial radiologic progression responded upon continuing therapy (pseudoprogression). The most common adverse events were diarrhea, fatigue, cough, and muscle spasms; 48.2% of patients reported serious adverse events. In patients who experienced a response, regulatory T cells were downregulated at C3D1 ( P = .02), and Th1-promoting (antitumor) cytokines interferon-γ and interleukin-12 increased ( P ≤ .035). Conclusion With an ORR of 20.9%, ibrutinib failed to meet its primary efficacy end point in chemoimmunotherapy in patients with relapsed/refractory FL, although responses were durable and associated with a reduction in regulatory T cells and increases in proinflammatory cytokines.

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“…25 In a recent analysis of patients with relapsed chronic lymphocytic leukemia after allogeneic hematopoietic stem cell transplantation, ibrutinib was tolerable and effective. 26 Based on the biological rationale and compelling preclinical data, a phase 1b/2 study was designed to evaluate the safety and efficacy of ibrutinib in patients with cGVHD that has failed to respond to at least 1 systemic corticosteroid-based therapy and who needed additional treatment. Supported by the results of this trial, ibrutinib was recently approved in the United States for the treatment of adult patients with cGVHD after failure of 1 or more lines of systemic therapy.…”

Section: Introductionmentioning

confidence: 99%

Ibrutinib for chronic graft-versus-host disease after failure of prior therapy

Miklos

Cutler

Arora

et al. 2017

Blood

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374

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• Ibrutinib induced a high rate of sustained responses for patients with cGVHD and inadequate response to corticosteroid-containing therapy.• This trial supported the approval of ibrutinib for treatment of adult patients with cGVHD after failure of $1 lines of systemic therapy.Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation with few effective options available after failure of corticosteroids. B and T cells play a role in the pathophysiology of cGVHD. Ibrutinib inhibits Bruton tyrosine kinase in B cells and interleukin-2-inducible T-cell kinase in T cells. In preclinical models, ibrutinib reduced severity of cGVHD. This multicenter, open-label study evaluated the safety and efficacy of ibrutinib in patients with active cGVHD with inadequate response to corticosteroid-containing therapies. Forty-two patients who had failed 1 to 3 prior treatments received ibrutinib (420 mg) daily until cGVHD progression. The primary efficacy end point was cGVHD response based on 2005 National Institutes of Health criteria. At a median follow-up of 13.9 months, best overall response was 67%; 71% of responders showed a sustained response for ‡20 weeks. Responses were observed across involved organs evaluated. Most patients with multiple cGVHD organ involvement had a multiorgan response. Median corticosteroid dose in responders decreased from 0.29 mg/kg per day at baseline to 0.12 mg/kg per day at week 49; 5 responders discontinued corticosteroids. The most common adverse events were fatigue, diarrhea, muscle spasms, nausea, and bruising. Plasma levels of soluble factors associated with inflammation, fibrosis, and cGVHD significantly decreased over time with ibrutinib. Ibrutinib resulted in clinically meaningful responses with acceptable safety in patients with ‡1 prior treatments for cGVHD. Based on these results, ibrutinib was approved in the United States for treatment of adult patients with cGVHD after failure of 1 or more lines of systemic therapy. This trial was registered at www.clinicaltrials.gov as #NCT02195869. (Blood. 2017;130(21):2243-2250

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Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT

Cited by 67 publications

References 42 publications

Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial

Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial

Ibrutinib as Treatment for Patients With Relapsed/Refractory Follicular Lymphoma: Results From the Open-Label, Multicenter, Phase II DAWN Study

Ibrutinib for chronic graft-versus-host disease after failure of prior therapy

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