pci-32765 and Chronic-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

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

Treatment standards for chronic lymphocytic leukemia (CLL) have been transformed with the advent of effective inhibitors of B-cell receptor signaling such as ibrutinib - a first-in-class inhibitor of BTK. Off-target kinase inhibitions by ibrutinib are thought to contribute to its adverse events. Zanubrutinib is a next-generation BTK inhibitor with minimal off-target effects, sustained BTK occupancy in peripheral blood mononuclear cells and lymph nodes from patients with B-cell malignancies and promising responses in patients with CLL. Described here is a head-to-head Phase III study comparing the efficacy and safety of zanubrutinib with those of ibrutinib in patients with CLL/small lymphocytic lymphoma in the relapsed/refractory setting.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Chronic Disease; Clinical Trials, Phase III as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Outcome Assessment, Health Care; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Safety

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

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

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

Topics: Central Nervous System Neoplasms; Chronic Disease; Humans; Lymphoma; Neoplasm Recurrence, Local; Retinal Neoplasms; Vitreous Body

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

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

Topics: Adenine; Aged; Alemtuzumab; Antineoplastic Agents, Immunological; Antiviral Agents; Chronic Disease; Disease Progression; Hepatitis E; Hepatitis E virus; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Pyrazoles; Pyrimidines; Ribavirin

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

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

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Chronic Disease; Humans; Leukemia, Lymphoid; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Topics: Adenine; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Antineoplastic Agents; Chronic Disease; Disease Management; Drug Administration Schedule; Humans; Lymphoma, Non-Hodgkin; Oligonucleotides; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Rituximab; Standard of Care