Ibrutinib for Chronic Graft-versus-Host Disease After Failure of Prior Therapy: 1-Year Update of a Phase 1b/2 Study.

Chronic graft-versus-host disease (cGVHD) is a life-threatening complication of allogeneic stem cell transplantation. In a Phase 1b/2, open-label study (PCYC-1129; ClinicalTrials.gov identifier NCT02195869) involving 42 patients with active cGVHD who were steroid-dependent or -refractory, the activity and safety of ibrutinib, a once-daily inhibitor of Bruton's tyrosine kinase, was demonstrated. Here we report extended follow-up for patients in this study. After a median follow-up of 26 months (range, .53 to 36.7 months), best overall response rate in the all treated population was 69% (29 of 42), with 13 patients (31%) achieving a complete response and 16 patients (38%) achieving a partial response. Sustained responses of ≥20, ≥32, and ≥44 weeks were seen in 20 (69%), 18 (62%), and 16 (55%) of the 29 responders, respectively. Of 26 patients with ≥2 involved organs, 19 (73%) showed responses in ≥2 organs. Six of 10 patients (60%) with ≥3 involved organs showed responses in ≥3 organs. Eleven of 18 patients (61%) who had sclerosis at baseline showed a sclerotic response (39% with complete response, 22% with partial response). Twenty-seven of 42 patients (64%) reached a corticosteroid dose of <.15 mg/kg/day during the study; 8 discontinued corticosteroid treatment and remained off corticosteroid at study closure. Safety findings for this updated analysis were consistent with the safety profile seen at the time of the original analysis. Common grade ≥3 adverse events (AEs) were pneumonia (n = 6), fatigue (n = 5), and diarrhea (n = 4). The onset of new grade ≥3 AEs decreased from 71% in the first year of treatment to 25% in the second year (n = 12). AEs leading to discontinuation occurred in 18 patients (43%). At a median follow-up of >2 years, ibrutinib continued to produce durable responses in patients with cGVHD who had failed previous systemic therapy. In this pretreated, high-risk population, clinically meaningful benefit and an acceptable safety profile were observed with additional follow-up for ibrutinib. These results demonstrate a substantial advance in the therapeutic management of patients with cGVHD.

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

Magrolimab in Combination With Azacitidine in Patients With Higher-Risk Myelodysplastic Syndromes: Final Results of a Phase Ib Study.

PURPOSE: Magrolimab is a monoclonal antibody that blocks cluster of differentiation 47, a don't-eat-me signal overexpressed on cancer cells. Cluster of differentiation 47 blockade by magrolimab promotes macrophage-mediated phagocytosis of tumor cells and is synergistic with azacitidine, which increases expression of eat-me signals. We report final phase Ib data in patients with untreated higher-risk myelodysplastic syndromes (MDS) treated with magrolimab and azacitidine (ClinicalTrials.gov identifier: NCT03248479). PATIENTS AND METHODS: Patients with previously untreated Revised International Prognostic Scoring System intermediate-/high-/very high-risk MDS received magrolimab intravenously as a priming dose (1 mg/kg) followed by ramp-up to a 30 mg/kg once-weekly or once-every-2-week maintenance dose. Azacitidine 75 mg/m2 was administered intravenously/subcutaneously once daily on days 1-7 of each 28-day cycle. Primary end points were safety/tolerability and complete remission (CR) rate. RESULTS: Ninety-five patients were treated. Revised International Prognostic Scoring System risk was intermediate/high/very high in 27%, 52%, and 21%, respectively. Fifty-nine (62%) had poor-risk cytogenetics and 25 (26%) had TP53 mutation. The most common treatment-emergent adverse effects included constipation (68%), thrombocytopenia (55%), and anemia (52%). Median hemoglobin change from baseline to first postdose assessment was -0.7 g/dL (range, -3.1 to +2.4). CR rate and overall response rate were 33% and 75%, respectively. Median time to response, duration of CR, duration of overall response, and progression-free survival were 1.9, 11.1, 9.8, and 11.6 months, respectively. Median overall survival (OS) was not reached with 17.1-month follow-up. In TP53-mutant patients, 40% achieved CR with median OS of 16.3 months. Thirty-four patients (36%) had allogeneic stem-cell transplant with 77% 2-year OS. CONCLUSION: Magrolimab + azacitidine was well tolerated with promising efficacy in patients with untreated higher-risk MDS, including those with TP53 mutations. A phase III trial of magrolimab/placebo + azacitidine is ongoing (ClinicalTrials.gov identifier: NCT04313881 [ENHANCE]).

Up to 6.5 years (median 4 years) of follow-up of first-line ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and high-risk genomic features: integrated analysis of two phase 3 studies.

Genomic abnormalities, including del(17p)/TP53 mutation, del(11q), unmutated IGHV, and mutations in BIRC3, NOTCH1, SF3B1, and XPO1 predict poor outcomes with chemoimmunotherapy in chronic lymphocytic leukemia. To better understand the impact of these high-risk genomic features on outcomes with first-line ibrutinib-based therapy, we performed pooled analysis of two phase 3 studies with 498 patients randomized to receive ibrutinib- or chlorambucil-based therapy with median follow-up of 49.1 months. Ibrutinib-based therapy improved overall response rates (ORRs), complete response rates, and progression-free survival (PFS) versus chlorambucil-based therapy across all subgroups. In ibrutinib-randomized patients with versus without specified genomic features, ORR and PFS were comparable across subgroups. PFS hazard ratio (95% CI) for del(17p)/TP53 mutated/BIRC3 mutated: 1.05 (0.54-2.04); del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV: 1.11 (0.69-1.77); unmutated IGHV: 1.79 (0.99-3.24); and NOTCH1 mutated 1.05 (0.65-1.69). This integrated analysis demonstrated efficacy of first-line ibrutinib-based treatment irrespective of cytogenetic and mutational risk features.Registered at ClinicalTrials.gov (NCT01722487 and NCT02264574).

Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study.

RESONATE-2 is a phase 3 study of first-line ibrutinib versus chlorambucil in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients aged ≥65 years (n = 269) were randomized 1:1 to once-daily ibrutinib 420 mg continuously or chlorambucil 0.5-0.8 mg/kg for ≤12 cycles. With a median (range) follow-up of 60 months (0.1-66), progression-free survival (PFS) and overall survival (OS) benefits for ibrutinib versus chlorambucil were sustained (PFS estimates at 5 years: 70% vs 12%; HR [95% CI]: 0.146 [0.098-0.218]; OS estimates at 5 years: 83% vs 68%; HR [95% CI]: 0.450 [0.266-0.761]). Ibrutinib benefit was also consistent in patients with high prognostic risk (TP53 mutation, 11q deletion, and/or unmutated IGHV) (PFS: HR [95% CI]: 0.083 [0.047-0.145]; OS: HR [95% CI]: 0.366 [0.181-0.736]). Investigator-assessed overall response rate was 92% with ibrutinib (complete response, 30%; 11% at primary analysis). Common grade ≥3 adverse events (AEs) included neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), and hyponatremia (6%); occurrence of most events as well as discontinuations due to AEs decreased over time. Fifty-eight percent of patients continue to receive ibrutinib. Single-agent ibrutinib demonstrated sustained PFS and OS benefit versus chlorambucil and increased depth of response over time.

Ibrutinib restores immune cell numbers and function in first-line and relapsed/refractory chronic lymphocytic leukemia.

Ibrutinib positively modulates many T-cell subsets in chronic lymphocytic leukemia (CLL). To understand ibrutinib's effects on the broader landscape of immune cell populations, we comprehensively characterized changes in circulating counts of 21 immune blood cell subsets throughout the first year of treatment in patients with relapsed/refractory (R/R) CLL (n = 55, RESONATE) and previously untreated CLL (n = 50, RESONATE-2) compared with untreated age-matched healthy donors (n = 20). Ibrutinib normalized abnormal immune cell counts to levels similar to those of age-matched healthy donors. Ibrutinib significantly decreased pathologically high circulating B cells, regulatory T cells, effector/memory CD4+ and CD8+ T cells (including exhausted and chronically activated T cells), natural killer (NK) T cells, and myeloid-derived suppressor cells; preserved naive T cells and NK cells; and increased circulating classical monocytes. T-cell function was assessed in response to T-cell receptor stimulation in patients with R/R CLL (n = 21) compared with age-matched healthy donors (n = 18). Ibrutinib significantly restored T-cell proliferative ability, degranulation, and cytokine secretion. Over the same period, ofatumumab or chlorambucil did not confer the same spectrum of normalization as ibrutinib in multiple immune subsets. These results establish that ibrutinib has a significant and likely positive impact on circulating malignant and nonmalignant immune cells and restores healthy T-cell function.