pci-32765 and Graft-vs-Host-Disease

Recipients of allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk for inflammatory myositis; histological subsets reported include dermatomyositis, necrotising myopathy and chronic graft-versus-host disease (cGVHD)-related myositis. Though corticosteroids and various immunosuppressive therapies have been used, there is a lack of consensus guidelines dictating therapy.. Recent evidence suggests the fascia as a preferential target in cGVHD myositis, with conditioning regimens promoting fascial microtrauma. Positron emission tomography (PET) can be a useful diagnostic tool, and case reports suggest that the Bruton's tyrosine kinase inhibitor ibrutinib may have therapeutic potential. Emerging therapies include targeted B cell depletion with rituximab, and extracorporeal photophoresis. Clinicians need to be vigilant for the development of inflammatory myositis post-allogeneic HSCT as most patients respond to treatment. Advances in immunohistochemistry to determine the dominant cell type and cytokine profile may enable targeted and individualised therapies.

Topics: Adenine; Chronic Disease; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Myositis; Piperidines; Pyrimidines; Rituximab

Despite improvements in prevention and treatment of acute graft-versus-host disease (GVHD), chronic GVHD (cGVHD) remains a significant contributor to morbidity and mortality of allogeneic transplant patients. Chronic GVHD remains a leading cause of late complications posttransplant and is impacted by donor-, patient-, and transplant-related (hematopoietic cell transplant [HCT]) factors. Advances in the biological understanding of cGVHD have provided opportunities to improve clinical interventions for prevention and treatment. Expansion of posttransplantation cyclophosphamide beyond haploidentical HCTs has transformed alternative donor, matched, and mismatch GVHD outcomes and is currently being investigated in two upcoming clinical trials network prophylaxis studies. Although corticosteroids remain the cornerstone therapy, several clinical trials are prospectively investigating the utility of using novel agents in combination with corticosteroids as upfront therapy to mitigate prolonged steroid exposure. Several treatment options for patients with steroid-refractory cGVHD are currently being investigated, and advances have resulted in ibrutinib becoming the first cGVHD agent approved by the U.S. Food and Drug Administration. We review recent advances in understanding of cGVHD pathophysiology and new approaches for the prevention and treatment of cGVHD.

Topics: Adenine; Adrenal Cortex Hormones; Chronic Disease; Cyclophosphamide; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Piperidines

Chronic graft-versus-host disease (cGvHD) is a grave complication of allogeneic hematopoietic cell transplantation (alloHCT). Despite the use of prophylactic regimens for cGvHD, a significant proportion of patients develop cGvHD following alloHCT. The standard first-line therapy for cGvHD is high-dose corticosteroids. However, roughly 50% of patients will exhibit steroid-refractory or steroid-dependent cGvHD, which increases the risk of non-relapse mortality. Ibrutinib was approved by the U.S. Food and Drug Administration (FDA) in August 2017 for the treatment of cGvHD after failure of one or more lines of systemic therapy. The approval was based on a study that demonstrated high rates of sustained responses and manageable toxicities in patients with steroid-refractory or -dependent cGvHD. In this review, we address the mechanisms of action of ibrutinib in cGvHD, as well as preclinical and clinical data supporting its use in patients with this important post-transplant complication.

Topics: Adenine; Animals; Chronic Disease; Drug Interactions; Graft vs Host Disease; Humans; Piperidines; Pyrazoles; Pyrimidines

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is potentially curative for a number of hematologic conditions, both malignant and nonmalignant. However, its success can be limited by the development of acute and chronic graft-versus-host disease (GVHD). Chronic GVHD (cGVHD) is the most common long-term complication following allo-SCT, and patients who develop this condition have significantly higher morbidity and mortality and significantly lower quality of life than patients who do not. Until recently, there were no US Food and Drug Administration (FDA)-approved therapies for cGVHD treatment. In this review article, we describe how ibrutinib was identified as potential cGVHD therapy based on preclinical cGVHD models and clinical studies in B-cell malignancies and elucidation of its mechanisms of action in cGVHD. Results from a phase 2 clinical trial that was designed based on National Institutes of Health Criteria for the grading and staging of cGVHD culminated in the FDA-approval of ibrutinib as second line therapy of steroid-refractory or steroid-resistant cGVHD. Results of ibrutinib studies in phase 3 randomized studies, for cGVHD prophylaxis and as first -line testing along with steroids will be especially important in selecting the preferred indications for ibrutinib in patients at risk for or who have developed cGVHD.

Topics: Adenine; Animals; B-Lymphocytes; Chronic Disease; Drug Approval; Drug Resistance; Graft vs Host Disease; Humans; Neoplasms, Plasma Cell; Piperidines; Pyrazoles; Pyrimidines; Steroids; United States; United States Food and Drug Administration

The B-cell receptor (BCR) pathway plays an important role in the survival, proliferation and trafficking of cancer cells in a variety of B-cell malignancies. Recently, a number of agents have been developed to target various components of the BCR pathway. One such target is Bruton's tyrosine kinase (BTK), a Tec family kinase member found near the cell membrane that is involved in upstream BCR signaling. The biological function of BTK in several B-cell lymphoid malignancies has led to the development of the oral BTK inhibitor ibrutinib. In chronic lymphocytic leukemia (CLL), ibrutinib has demonstrated durable clinical responses in relapsed/refractory (R/R) patients, including those with the high-risk del(17p) cytogenetic abnormality. These findings have paved the way for trials evaluating ibrutinib in previously untreated CLL patients, and also in combination with chemoimmunotherapy or other novel agents. Durable clinical responses have also been demonstrated in mantle cell lymphoma (MCL) and Waldenström's macroglobulinemia (WM) patients treated with ibrutinib. Ibrutinib is generally well tolerated, although current follow-up remains short and patients of advanced age are more likely to discontinue treatment for toxicity. Treatment-specific side effects such as bleeding and atrial fibrillation may, at least partly, be related to off-target inhibition of non-BTK kinases. Studies evaluating other potential indications for BTK inhibition are ongoing, including in post-allogeneic hematopoietic stem cell transplant patients for whom ibrutinib may be effective in modulating graft-versus-host disease. Combination trials of ibrutinib with venetoclax, a Bcl-2 inhibitor, are underway and are supported by sound preclinical rationale. Several next-generation BTK inhibitors are under development with the goal of decreasing treatment-related toxicity and resistance.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Atrial Fibrillation; Drug Discovery; Graft vs Host Disease; Hemorrhage; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Signal Transduction

Topics: Adenine; Adolescent; Chronic Disease; Graft vs Host Disease; Humans; Japan; Piperidines; Pyrazoles; United States

The aim of this retrospective study was to investigate the safety and efficacy of allogeneic hematopoietic cell transplantation (alloHCT) in patients pre-treated with ibrutinib. Eligible were patients aged >18 years allotransplanted for chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) after prior exposure to ibrutinib who were registered with the EBMT registry. Seventy patients (CLL 48, MCL 22) were included. At the time of alloHCT, 73% of the patients were ibrutinib responsive. All patients except one engrafted, and acute GVHD grade 2-4 (3-4) was observed in 49% (12%) of 68 evaluable patients. The cumulative incidence of chronic GVHD was 54% 1 year after transplant. In the CLL group, 12-month non-relapse mortality, relapse incidence (RI), progression-free survival (PFS), and overall survival (OS) were 10, 30, 60, and 72%, respectively, and in the MCL group 5, 19, 76, and 86%, respectively. Pre-transplant ibrutinib failure and poor performance status predicted inferior RI, PFS and OS in the CLL group. In conclusion, ibrutinib does not affect the safety of a subsequent alloHCT. While the relatively high post-transplant relapse risk in ibrutinib-exposed patients with CLL deserves further study, in patients with MCL consolidating disease responses to ibrutinib with alloHCT seems to be a promising option.

Topics: Adenine; Adult; Aged; Allografts; Disease-Free Survival; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Survival Rate

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.

Topics: Adenine; Chronic Disease; Female; Graft vs Host Disease; Humans; Male; Piperidines; Pyrazoles; Pyrimidines; Time Factors

Topics: Adenine; Adult; Aged; Alemtuzumab; Allografts; Antineoplastic Agents, Immunological; Combined Modality Therapy; Disease-Free Survival; Female; Follow-Up Studies; Graft vs Host Disease; Humans; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm, Residual; Peripheral Blood Stem Cell Transplantation; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Salvage Therapy; Treatment Outcome

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.

Topics: Adenine; Adrenal Cortex Hormones; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Biomarkers; Chronic Disease; Demography; Dose-Response Relationship, Drug; Female; Graft vs Host Disease; Humans; Male; Middle Aged; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Severity of Illness Index; Treatment Failure; Young Adult

Ibrutinib, a potent and irreversible small-molecule inhibitor of both Bruton's tyrosine kinase and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here, we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplant (HCT) who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following US Food and Drug Administration approval of ibrutinib; 7 (64%) achieved a complete response, and 3 (27%) achieved a partial response. Of the 9 patients treated at Stanford who had mixed chimerism-associated CLL relapse, 4 (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of 11 (36%) patients evaluated by ClonoSeq achieved minimal residual disease negativity with CLL <1/10 000 white blood cells, which persisted even after ibrutinib was discontinued, in 1 case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following ibrutinib initiation. We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell-mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre-germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD.

Topics: Adenine; Adult; Aged; B-Lymphocytes; Chimerism; Cohort Studies; Female; Germinal Center; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunomodulation; Leukemia, Lymphocytic, Chronic, B-Cell; Lymph Nodes; Lymphocyte Depletion; Male; Middle Aged; Neoplasm, Residual; Piperidines; Pyrazoles; Pyrimidines; Recurrence; Th2 Cells; Tissue Donors; Transplantation, Homologous; Treatment Outcome; Withholding Treatment

Topics: B-Lymphocytes; Bronchiolitis Obliterans Syndrome; Chronic Disease; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Piperidines; Steroids

Topics: Adenine; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Piperidines

Chronic graft-versus-host disease (cGVHD) is a common cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Tyrosine kinase inhibitors (TKIs), including ruxolitinib, imatinib, and ibrutinib, have shown promising efficacy in cGVHD treatment.. A total of 43 patients who developed cGVHD and received at least one line of TKI therapy for cGVHD treatment were evaluated retrospectively. The overall response, clinical benefit (CB), corticosteroid dose reduction, failure-free survival (FFS), and overall survival (OS) were assessed.. A total of 62 lines of TKI therapy were evaluated, including ruxolitinib (n = 18), ibrutinib (n = 13), and imatinib (n = 31). With a 12-month median follow-up duration, 19/58 (32.8%), 20/41 (48.7%), and 17/29 (58.6%) responded to TKI therapy at 3, 6, and 12 months, respectively. The CB was observed in 80% of patients over time, allowing prednisone dose reduction in all 3 TKIs. The FFS rate at 12 months was higher in the imatinib (71%) and ruxolitinib groups (67%) than in the ibrutinib group (46%), while the OS rate at 12 months was similar among the three groups at 96%-100% in patients. In the sclerotic GVHD patient subgroup (n = 39), the overall response rate gradually increased over time. Ruxolitinib appeared to be as effective as imatinib and gradually improved the photographic range of motion score in sclerotic GVHD patients.. TKI drugs ruxolitinib, imatinib, and Ibrutinib are effective and feasible for cGVHD treatment. Ruxolitinib is as effective as imatinib for sclerotic GVHD.

Topics: Chronic Disease; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Imatinib Mesylate; Retrospective Studies; Treatment Outcome

Chronic graft-versus-host disease (cGVHD) is a leading cause of late morbidity and mortality after allogenic hematopoietic stem cell transplantation. Corticosteroid-based therapies are a mainstay of its initial treatment but there is no consensus in how to treat steroid-refractory cGVHD. Ibrutinib is a Bruton tyrosine kinase and IL-2-inducible kinase inhibitor thought to affect pathways driving cGVHD, and it was approved for the treatment of refractory cGVHD by the Food and Drug Administration (FDA) in August 2017 after a landmark phase 1b/2 study. It was the first medication approved for this indication, but how to best treat refractory cGVHD remains an open question, and there has been limited literature on ibrutinib after the FDA approval. This study sought to characterize the utilization and outcomes associated with ibrutinib use in cGVHD via a retrospective single-center study. Fifty-three patients were identified as having been treated with ibrutinib for cGVHD following FDA approval between September 1, 2017, and December 31, 2020, using an institutional data repository. Their records were reviewed for demographics, cGVHD characteristics, and outcomes. For the entire cohort, two-year overall survival was 76% (95% confidence interval [CI], 60% to 86%), with a median follow-up among survivors of 26 months (range, 1.3 to 39.5 months). However, the 2-year failure-free survival (FFS) after initiation of ibrutinib was 9% (95% CI, 2.6% to 20%), and the median FFS was 4.5 months (95% CI, 2.8 to 7.1 months). Events of FFS included treatment change due to lack of response or toxicity, malignant relapse, or non-treatment related mortality. At the time of this report, 11 patients (21%) remained on ibrutinib. At the time of the FFS event or last follow-up, 6 patients (12%) had a complete or partial response, 34 (64%) had stable disease, and 13 (25%) had progressive disease. Ibrutinib use was associated with no reduction in corticosteroid dose between ibrutinib initiation and FFS event or last follow-up (mean difference, 0.00; P = .98). The most frequently used noncorticosteroid cGVHD therapy after ibrutinib was ruxolitinib (n = 14; 33%). The most common adverse events associated with treatment discontinuation were infection (lung, skin, enterocolitis; n = 6), bleeding and bruising (hematoma, epistaxis, gastrointestinal bleed; n = 5), and muscle aches (n = 2). In a real-world setting, ibrutinib is associated with a modest response rate and FFS and its use in a na

Topics: Adenine; Graft vs Host Disease; Humans; Piperidines; Retrospective Studies; Steroids

Topics: Adenine; Chronic Disease; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Mycoses; Piperidines; Pyrazoles; Steroids

Myositis is a known complication of chronic graft-vs-host disease (cGVHD) following allogeneic haematopoietic stem cell transplantation, but can be difficult to diagnose and manage. We present the case of a 57 year old man with cGVHD in whom the full manifestations of myositis were suppressed for some time, likely due to partial treatment of his condition with immunosuppression including ibrutinib. Though initial muscle biopsy showed necrotising myopathy without significant inflammation, on cessation of ibrutinib he developed increasing weakness and creatine kinase levels, with repeat muscle biopsy showing histological changes more in keeping with dermatomyositis. The close temporal correlation of his clinical course with commencement and cessation of ibrutinib suggests a potential role for ibrutinib in treating inflammatory myopathy in cGVHD.

Topics: Adenine; Biopsy; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Myositis; Piperidines; Treatment Outcome

On August 2, 2017, the Food and Drug Administration approved ibrutinib (IMBRUVICA) for the treatment of patients with chronic graft versus host disease (cGVHD) after the failure of one or more lines of systemic therapy. The approval was based on results from a single-arm, multicenter trial that enrolled patients with refractory cGVHD. This paper describes the FDA review of patient-reported outcomes (PRO) data from Study PCYC-1129-CA and the decision to incorporate descriptive PRO data in the FDA label to support the primary clinician-reported outcome results.. In this trial, the Lee Chronic GVHD Symptom Scale (LSS) was used to capture patient-reported symptom bother. The 42 patients who received treatment were included in the analysis and completed the PRO tool. Post hoc descriptive analyses were conducted to further understand the measurement properties of the LSS.. The analysis submitted to FDA reported that 18 patients had a ≥ 7-point improvement on the LSS overall summary score at any point during the assessment period. For 10 patients, the ≥ 7-point improvement was sustained for ≥ 2 consecutive PRO assessments. An assessment of the responder threshold suggested the threshold submitted to the FDA was reasonable and in line with clinical findings.. Overall, study PCYC-1129-CA demonstrated favorable clinician-reported cGVHD efficacy results that were complemented by results from PRO data, supporting the FDA's positive benefit-risk assessment leading to regular approval. Limitations included the single-arm trial design, responder definition, and instrument shortcomings. These limitations were thoroughly explored through additional FDA post hoc analyses.

Topics: Adenine; Adult; Aged; Female; Graft vs Host Disease; Humans; Male; Middle Aged; Patient Reported Outcome Measures; Piperidines; Pyrazoles; Pyrimidines; Quality of Life; Treatment Outcome; United States; United States Food and Drug Administration; Young Adult

Chronic graft-versus-host disease (cGVHD) remains the leading cause of late morbidity and mortality. Despite the growing number of treatment options in cGVHD, evidence remains sparse. The German-Austrian-Swiss GVHD Consortium performed a survey on clinical practice in treatment of cGVHD among transplant centers in Germany, Austria, and Switzerland in 2009 and 2018 and compared the results. The survey performed in 2009 contained 20 questions on first-line treatment and related issues and 4 questions on second-line scenarios followed by a survey on all systemic and topic treatment options known and applied, with 31 of 36 transplant centers (86%) responding. The survey in 2018 repeated 7 questions on first-line treatment and 3 questions on second-line scenarios followed by an updated survey on all current systemic treatment options known and applied, with 29 of 66 centers (43%) responding. In summary, the results show a large overlap of first-line treatment practice between centers and the 2 surveys because of a lack of new data that changes practice, except significant heterogeneity of treatment of cGVHD progressive onset type, which can be explained by the lack of trials focusing on this high-risk entity. In contrast, treatment options applied to second-line therapy vary considerably, with new agents like ibrutinib and ruxolitinib entering clinical practice. Moreover, treatment of bronchiolitis obliterans syndrome demonstrates heterogeneity in applied therapeutic options and sequence because of a lack of controlled data and different conclusions from already existing evidence. In summary, the survey results demonstrate an increasing number of treatment options applied to cGVHD accompanied by a significant heterogeneity in second-line treatment and underline the urgent need for clinical trials and registry analyses on rare entities with high mortality like progressive onset type and lung involvement of cGVHD.

Topics: Adenine; Adult; Austria; Bronchiolitis Obliterans; Chronic Disease; Female; Germany; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppression Therapy; Male; Nitriles; Piperidines; Pyrazoles; Pyrimidines; Switzerland

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Allografts; Autografts; Azetidines; B-Lymphocytes; Cell Separation; Drug Approval; Fetal Blood; Graft vs Host Disease; Hodgkin Disease; Humans; Nitriles; Photopheresis; Piperidines; Problem Solving; Purines; Pyrazoles; Pyrimidines; Stem Cell Transplantation; Sulfonamides; T-Lymphocytes, Regulatory; United States; United States Food and Drug Administration

Topics: Adenine; Drug Approval; Graft vs Host Disease; Humans; Piperidines; Pyrazoles; Pyrimidines

Topics: ADAMTS13 Protein; Adenine; Antibodies, Monoclonal; Antineoplastic Agents; Central Venous Catheters; fms-Like Tyrosine Kinase 3; Genetic Therapy; Graft vs Host Disease; Hematologic Diseases; Hemophilia B; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Multiple Myeloma; Mutation; Piperidines; Protein Kinase Inhibitors; Purpura, Thrombotic Thrombocytopenic; Pyrazoles; Pyrimidines; Recombinant Proteins; Societies, Medical; Thrombosis

Allogeneic stem-cell transplantation (SCT) induces long-term remission in a fraction of patients with high-risk chronic lymphocytic leukemia (CLL) or Richter's transformation (RT). Our purpose was to determine the outcomes of patients whose disease progressed after allogeneic SCT.. We retrospectively analyzed the outcomes of 72 patients (52 with CLL and 20 with RT) who underwent allogeneic SCT between 1998 and 2011 and had documented progression after transplantation. Twenty-two (31%) never had a response, and 50 (69%) had a response but experienced relapse after a median of 7 months (range, 2 to 85 months). Forty-eight patients who were receiving or were candidates to receive post-SCT cell-based therapies were not included in this analysis.. The median age at time of transplantation was 58 years (range, 30 to 72 years). Sixty-two patients (86%) received more than two treatment regimens and 37 (51%) received more than three treatment regimens before SCT. Sixty-six patients (92%) had active disease at the time of transplantation. The 2- and 5-year survival rates were 67% and 38% (patients with CLL) and 36% and 0% (patients with RT). The patients who developed acute or chronic graft-versus-host disease had a longer overall survival (OS; P = .05). In a multivariable analysis, RT or low hemoglobin at the time of SCT predicted shorter OS. Chronic graft-versus-host disease and an initial response to SCT predicted longer OS.. Patients with CLL in whom allogeneic SCT fails may have a response to and benefit from salvage therapies, and their prognosis is relatively good.

Topics: Adenine; Adult; Aged; Antineoplastic Agents; Chronic Disease; Disease Progression; Factor Analysis, Statistical; Female; Graft vs Host Disease; Humans; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Recurrence; Retrospective Studies; Risk Factors; Salvage Therapy; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Homologous; Treatment Failure; Treatment Outcome

Bruton's Tyrosine Kinase (BTK) and IL-2 Inducible T-cell Kinase (ITK) are enzymes responsible for the phosphorylation and activation of downstream effectors in the B-cell receptor (BCR) signaling and T cell receptor (TCR) signaling pathways, respectively. Ibrutinib is an FDA-approved potent inhibitor of both BTK and ITK that impairs B-cell and T-cell function. CD4 T cells and B cells are essential for the induction of chronic graft-versus-host disease (cGVHD). We evaluated these targets by testing the ability of Ibrutinib to prevent or ameliorate cGVHD, which is one of the major complications for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that Ibrutinib significantly alleviated cGVHD across four different mouse models, accompanied by increased long-term survival and reduced clinical score. The clinical improvements in Ibrutinib-treated recipients were associated with decreased serum-autoantibodies, costimulatory molecule activation, B-cell proliferation, and glomerulonephritis compared to vehicle controls. Ibrutinib was also able to alleviate the clinical manifestations in acute GVHD (aGVHD), where the recipients were given grafts with or without B cells, suggesting that an inhibitory effect of Ibrutinib on T cells contributes to a reduction in both aGVHD and cGVHD pathogenesis. An effective prophylactic regimen is still lacking to both reduce the incidence and severity of human cGVHD following allo-HSCT. Our study shows that Ibrutinib is an effective prophylaxis against several mouse models of cGVHD with minimal toxicity and could be a promising strategy to combat human cGVHD clinically.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; B-Lymphocytes; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Lymphocyte Activation; Mice; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Signal Transduction

Chronic graft-versus-host disease (cGVHD) is a life-threatening impediment to allogeneic hematopoietic stem cell transplantation, and current therapies do not completely prevent and/or treat cGVHD. CD4+ T cells and B cells mediate cGVHD; therefore, targeting these populations may inhibit cGVHD pathogenesis. Ibrutinib is an FDA-approved irreversible inhibitor of Bruton's tyrosine kinase (BTK) and IL-2 inducible T cell kinase (ITK) that targets Th2 cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity. Here, we evaluated whether ibrutinib could reverse established cGVHD in 2 complementary murine models, a model interrogating T cell-driven sclerodermatous cGVHD and an alloantibody-driven multiorgan system cGVHD model that induces bronchiolar obliterans (BO). In the T cell-mediated sclerodermatous cGVHD model, ibrutinib treatment delayed progression, improved survival, and ameliorated clinical and pathological manifestations. In the alloantibody-driven cGVHD model, ibrutinib treatment restored pulmonary function and reduced germinal center reactions and tissue immunoglobulin deposition. Animals lacking BTK and ITK did not develop cGVHD, indicating that these molecules are critical to cGVHD development. Furthermore, ibrutinib treatment reduced activation of T and B cells from patients with active cGVHD. Our data demonstrate that B cells and T cells drive cGVHD and suggest that ibrutinib has potential as a therapeutic agent, warranting consideration for cGVHD clinical trials.

Topics: Adenine; Animals; Disease-Free Survival; Drug Evaluation, Preclinical; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Immunologic Factors; Lymphocyte Activation; Mice, Inbred C57BL; Piperidines; Pyrazoles; Pyrimidines