Successful treatment with fludarabine and cyclophosphamide in a VEXAS syndrome patient with associated myelodysplastic syndrome: a case report and systematic review.

Vacuoles, E1 syndrome, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a chronic inflammatory disorder that affects various organ systems. It is associated with hematologic malignancies and is generally refractory to therapies. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be considered for selected patients. We report a case wherein systemic and hematological manifestations completely resolved in a patient with VEXAS and associated myelodysplastic syndrome (MDS), following the administration of fludarabine and cyclophosphamide as part of the preparation for allo-HSCT. We conducted a systematic literature review and included 86 patients with VEXAS syndrome and associated MDS. Most cases presented with musculoskeletal involvement (71%) and anemia (72%) with lower-risk MDS. Most patients responded to corticosteroids (CS) but had a recurrence of symptoms with CS taper and were refractory to other immunosuppressive agents. Hypomethylating agents and Janus kinase inhibitors achieved a complete response in some cases. Further research is needed to develop more effective treatment strategies.

Use of Endpoints in Phase III Randomized Controlled Trials for Hematopoietic Stem Cell Transplantation Over the Last 15 Years: A Systematic Review.

This systematic review aimed to evaluate the proportion of primary and secondary endpoints in hematopoietic stem cell transplant (HSCT) phase III randomized clinical trials (RCTs) and analyze their trends in time and study sponsorship status. The Chi-square test and logistic regression analyses were performed using SPSS version 28. A total of 147 HSCT phase III RCTs from 2006 to 2021 reported 197 primary and 600 secondary endpoints. Overall survival (OS, 17 %), progression-free survival (PFS, 15 %), graft versus host disease (GVHD, 8 %), event-free survival (EFS, 8 %), and organ function (8 %) were the most common primary endpoints. GVHD (12.3 %, n = 74), safety/toxicity/adverse events (11.8 %, n = 71), OS (11.5 %, n = 69), PFS (9.3 %, n = 56), and relapse rate (RR; 7.5 %, n = 45) were the most common secondary endpoints during 2006-2021. After 2013, an increase was noted in the use of PFS as a primary endpoint (12 %-18 %, p = 0.196), while the use of OS as a primary endpoint declined (20 %-13 %, p = 0.170). An increase was observed in using the secondary endpoints RR (5 %-10 %, p = 0.047) and NRM (3 %-6 %, p = 0.047). EFS was used more (14 % vs. 4 %, p = 0.012) than ORR (11 % vs. 2 %, p = 0.003) as a primary endpoint in pharmaceutical-compared to non-pharmaceutical-sponsored studies. As secondary endpoints, the use of EFS (4 % vs. 1 %, p = 0.013) and ORR (4 % vs. 1 %, p = 0.028) was higher, whereas that of organ systems/functions (1.5 % vs. 5.5 %, p = 0.022) and GVHD (6.5 % vs. 15 %, p = 0.002) was lower in pharmaceutical-compared to non-pharmaceutical sponsored studies. GVHD-free relapse-free survival was reported as a primary endpoint in 2 % of studies, while only 5 % reported quality of life as a secondary endpoint. We described commonly used endpoints in HSCT phase III RCTs and patterns in their use over time by funding source and study intervention category.

Predictors of cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation: Insights from a real-world experience.

BACKGROUND: We aimed to investigate factors associated with cytomegalovirus (CMV) viremia and CMV disease and its impact on post-transplant outcomes including overall survival (OS) following allogeneic hematopoietic stem cell transplantation (Allo-SCT). METHODS: We conducted a single-center retrospective study including 452 Allo-SCT recipients (matched unrelated donor, MUD 61%; haploidentical, haplo 39%) from 2016 to 2021. Data were analyzed using SPSS v28. Descriptive (chi-square and t-test), Kaplan-Meier and regression analyses were conducted. RESULTS: The median age was 57 years. Sixty-one percent were males and 84.3% were Caucasians. CMV serostatus was positive in 59.1% of recipients. The median follow-up was 24.4 months. CMV viremia and CMV disease were observed in 181 (40%) and 32 (7%) patients, respectively. Among CMV seropositive recipients, 65% developed CMV viremia and 11% were noted to have CMV disease compared to 4% and 1% in seronegative recipients, respectively (p < 0.001). Patients with CMV disease had significantly lower OS than those without CMV disease (median 14.1 months vs. not reached, p = 0.024); however, OS was not associated with CMV viremia (median not reached in both groups, p = 0.640). Letermovir prophylaxis was used in 66% (n = 176/267) of CMV seropositive recipients, but no impact was observed on the incidence of CMV viremia or CMV disease and OS. CONCLUSIONS: CMV disease leads to significantly inferior survival after an allogeneic hematopoietic cell transplantation. Recipient CMV seropositive status was associated with the risk of CMV viremia and CMV disease, and this was not abrogated with the use of Letermovir prophylaxis.

Geographic and Racial Disparities in Chimeric Antigen Receptor-T Cells and Bispecific Antibodies Trials Access for Diffuse Large B-Cell Lymphoma.

BACKGROUND: We investigate the geographical and racial disparities in accessing CAR-T and bispecific antibodies trials for DLBCL. MATERIALS AND METHODS: ClinicalTrials.gov was searched, and 75 trials with at least 1 open site in the US were included. 2020 US Census Bureau data was used to obtain data on race and ethnicity. SPSS version 26 was used for analysis. RESULTS: There were 62 CAR-T and 13 bispecific antibodies trials with 6221 enrolled or expected to enroll patients. Eighty-five percent of the clinical trials were only open in the US, and the majority 64% were pharmaceutical-funded. There were 126 unique study sites distributed over 31 states with 11 (0-51) mean number of trials per state and 4.5 (1-26) and 4.4 (1-24) mean number of CAR-T and bispecific antibodies trials per site, respectively. Southern states had the most number of trials 31%, followed by Midwestern 25%, Northeastern 24%, and Western 20%. The highest number of study locations were in California 13, New York 9, and Pennsylvania 9, while the highest number of open studies were in California 51, Texas 32, and New York 23. Twenty states had no open CAR-T or bispecific antibodies trials. Only 33% of African Americans (AA) lived in a county with a trial, and 7 out of 10 states with the highest proportion of AA residents (18.6%-41.4%) have no or less than 4 trial sites. Of the 62 counties analyzed, 92% were White predominant, while only 8% were AA predominant (P = .009). CONCLUSIONS: Strategies should be framed to address the observed disparities and to improve access.

Outcomes with allogeneic hematopoietic stem cell transplantation in TP53-mutated myelodysplastic syndrome: A systematic review and meta-analysis.

We conducted a systematic review and meta-analysis to evaluate outcomes after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) in TP53-mutated myelodysplastic syndromes (MDS). A literature search was performed on PubMed, Cochrane, Embase, and Clinicaltrials.gov. After screening 626 articles, eight studies were included. Data were extracted following the PRISMA guidelines and analyzed using the meta-package by Schwarzer et al. We analyzed 540 patients. The pooled median 3 (1-5) year overall survival was 21% (95% CI 0.08-0.37, I2=91%, n=540). The pooled relapse rate was 58.9% (95% CI 0.38-0.77, I2=93%, n=487) at a median of 1.75 (1-3) years. The pooled 4-year progression- free survival was 34.8% (95% CI 0.15-0.57, I2=72%, n=105). Outcomes of Allo-HSCT for TP53-mutated MDS patients remain poor, with 21% OS at three years; however, Allo-HSCT confers a survival advantage as compared to non-transplant palliative therapies. Our findings suggest the need to explore novel therapeutic agents in prospective clinical trials.

Outcomes with HLA-matched unrelated donor versus haploidentical hematopoietic cell transplantation.

We investigated the outcomes after adult haploidentical (haplo) and matched unrelated donor (MUD) hematopoietic cell transplantation (HCT) in a single-center study (n = 452) including 276 MUD and 176 haplo transplants. Myeloablative (37%) and reduced-intensity conditioning (63%) were performed. Graft sources included peripheral blood (50%) and bone marrow (50%). GVHD prophylaxis included tacrolimus/methotrexate (53%) and post-transplant cyclophosphamide-based (47%). In MUD versus haplo HCT recipients, a similar incidence of neutrophil engraftment (18 vs 17 days, p = 0.895), grade II-IV acute GVHD (51% vs 50%, p = 0.773), relapse (26% vs 23%, p = 0.578), non-relapse mortality (22% vs 23%, p = 0.817), 1-year disease-free survival (62% vs 63%. p = 0.921), and 1-year overall survival (73% vs 74%, p = 0.744) were observed. Earlier platelet engraftment (22 vs 27 days, p < 0.001) and higher chronic GVHD (45% vs 35%, p = 0.040) were noted in MUD as compared to haplo HCT. Allogeneic transplantation should be done promptly whenever indicated, utilizing either matched unrelated or haploidentical donors.

The immune regulatory function of B7-H3 in malignancy: spotlight on the IFN-STAT1 axis and regulation of tumor-associated macrophages.

B7-H3 is a member of the B7 superfamily and a putative inhibitory immune checkpoint molecule. Several early-phase clinical trials have reported promising anti-tumor activity and safety of anti-cancer drugs targeting B7-H3, suggesting that it may be a promising target for a potential next-generation immune checkpoint inhibitor. Despite ongoing clinical studies, most B7-H3-targeted drugs being currently investigated rely on direct cytotoxicity as their mechanisms of action rather than modulating its function as an immune checkpoint, at least in part due to its incompletely understood immune regulatory function. Recent studies have begun to elucidate the role of B7-H3 in regulating the tumor microenvironment (TME). Emerging evidence suggests that B7-H3 may regulate the interferon-STAT1 axis in the TME and promote immune suppression. Similarly, increasing evidence shows B7-H3 may be implicated in promoting M1 to M2 polarization of tumor-associated macrophages (TAMs). There is also accumulating evidence suggesting that B7-H3 may play a role in the heterotypic fusion of cancer stem cells and macrophages, thereby promoting tumor invasion and metastasis. Here, we review the recent advances in the understanding of B7-H3 cancer immunobiology with a focus on highlighting its potential role in the interferon priming of TAMs and the heterotypic fusion of TAMs with cancer stem cells and suggest future direction in elucidating its immune checkpoint function.

Lessons learned from COVID-19 pandemic: outcomes after SARS-CoV-2 infection in hematopoietic cell transplant and cell therapy recipients.

We investigated the outcomes after Coronavirus disease 2019 (COVID) in hematopoietic cell transplant (HCT) or chimeric antigen receptor-T cell (CART) therapy recipients in a single-centre study including all (n = 261)HCT/CART recipients (allogeneic-HCT 49%, autologous-HCT 40%, CART 11%). The median age was 60 (22-80) years. COVID severity was mild (74%), moderate (11%), and severe/critical (16%) with a mortality rate of 7% and a median duration of infection of 5.7 weeks. Significant predictors of COVID severe disease or mortality included concurrent infection (HR 14.9, 95% CI 2.2-5.6) and immunosuppressive therapy (OR 4.8, 95% CI 1.2-3.4).HCT/CART recipients have a higher risk of mortality with COVID and warrant vigilant interventions.

Clinical Research in Chronic Lymphocytic Leukemia in Pakistan; A Systematic Review.

Background: Significant advances have been made in the treatment of chronic lymphocytic leukemia (CLL) since the turn of the new millennium. However, most clinical trials were done in developed countries where minority ethnicities were underrepresented. Materials and Methods: To gauge the quality of research in CLL being done in Pakistan, we conducted a comprehensive literature search using PubMed, Clinicaltrials.gov, and Google Scholar on 14 January 2022 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. Results: A total of 16 studies met the inclusion criteria. The most common study design was cross-sectional. Eight studies evaluated the clinicohematological profile of CLL patients and the effect of various cytogenic abnormalities through fluorescence in situ hybridization (FISH) technique on disease progression and prognosis. Five studies discussed the prevalence of abnormalities such as autoimmune cytopenias and other serum chemistry derangements. Only two studies evaluated treatment outcomes, among which one study reported a 2-year overall survival of 65% among patients with 17p deletion. None of the studies had patients on novel targeted agents. No pharmaceutical sponsored or funded clinical trials were found. Conclusions: Our review suggests that although small clinical studies continue to be performed across the country, multiple financial and logistical barriers need to be addressed for larger, more impactful clinical trials to be conducted that will help answer demographic-specific questions and decrease reliance on foreign studies.

Poor hospitalization outcomes in patients undergoing allogeneic hematopoietic stem cell transplant with hospital acquired influenza infection.

INTRODUCTION: Although hospital-acquired influenza infection (HAII) is a known complication among immunocompromised patients, the data in the setting of hospitalization for allogeneic hematopoietic stem cell transplant (allo-HSCT) are scarce. METHODS: A retrospective study using the National Inpatient sample database was done to determine the impact of HAII on hospitalization outcomes among patients admitted for allo-HSCT. RESULTS: The data for 77 103 allo-HSCT weighted hospitalizations were collected between 2002 and 2019. Among these, only 314 (0.4%) allo-HSCT cases were billed for HAII. Patients with influenza were more likely to have comorbid conditions like chronic obstructive lung disease, diabetes mellitus, hypertension, and myocardial infarction. Multivariate logistic regression revealed that patients with influenza had a higher risk of all-cause mortality: (odds ratio = 4.87, 95% confidence interval: 3.63-6.54; p < .01). Patients with influenza also had statistically higher odds of developing acute kidney injury, septic shock, and respiratory failure requiring mechanical ventilation. They also had a significantly longer length of stay (34 days versus 26 days) and adjusted cost for hospitalization ($195 345 versus $121 967). CONCLUSION: Our large analysis of real-world data reveals that patients undergoing allo-HSCT that develop HAII are at substantially higher risk of inpatient complications and death.

Outcomes with chimeric antigen receptor t-cell therapy in relapsed or refractory acute myeloid leukemia: a systematic review and meta-analysis.

Background: We conducted a systematic review and meta-analysis to evaluate outcomes following chimeric antigen receptor T cell (CAR-T) therapy in relapsed/refractory acute myeloid leukemia (RR-AML). Methods: We performed a literature search on PubMed, Cochrane Library, and Clinicaltrials.gov. After screening 677 manuscripts, 13 studies were included. Data was extracted following PRISMA guidelines. Pooled analysis was done using the meta-package by Schwarzer et al. Proportions with 95% confidence intervals (CI) were computed. Results: We analyzed 57 patients from 10 clinical trials and 3 case reports. The pooled complete and overall response rates were 49.5% (95% CI 0.18-0.81, I2 =65%) and 65.2% (95% CI 0.36-0.91, I2 =57%). The pooled incidence of cytokine release syndrome, immune-effector cell associated neurotoxicity syndrome, and graft-versus-host disease was estimated as 54.4% (95% CI 0.17-0.90, I2 =77%), 3.9% (95% CI 0.00-0.19, I2 =22%), and 1.6% (95%CI 0.00-0.21, I2 =33%), respectively. Conclusion: CAR-T therapy has demonstrated modest efficacy in RR-AML. Major challenges include heterogeneous disease biology, lack of a unique targetable antigen, and immune exhaustion.

Trends and in-hospital cardiac complications in patients with atrial fibrillation undergoing allogeneic stem cell transplant: A National Inpatient Sample analysis (2002-2019).

BACKGROUND: Cardiovascular comorbidities increase the risk of transplant-associated complications. However, the impact of atrial fibrillation (AF) as an independent risk factor remains limited. METHODS: The National Inpatient Sample (NIS) database was queried using the International Classification of Diseases codes to identify patients admitted for allogeneic stem cell transplant (ASCT). The patients were then subclassified into with and without AF. Subsequently, a multivariate logistic regression model was constructed to account for patient demographics, comorbidities, and hospital characteristics to evaluate the impact of AF on the primary outcome of interest: all-cause mortality, and secondary outcomes of interest that included common hospitalization complications. RESULTS: The data for 77 157 cases of ASCT were collected between 2002 and 2019. Among these 5086 (6.6%) cases had concurrent AF. Multivariate logistic regression revealed patients undergoing ASCT with AF had almost a three times higher risk of all-cause mortality (odds ratio = 2.99 [95% confidence interval: 2.73-3.28]; p < .01). AF patients also had a higher risk for cardiac arrest, cardiogenic shock, acute kidney injury, and need for hemodialysis (all p < .01). CONCLUSION: AF causes a higher risk of death and cardiovascular complications among patients undergoing ASCT. This signifies the importance of pretransplant consultation and optimization for cardiovascular comorbidities to improve hospitalization outcomes.

Risks and outcomes of hospitalizations in patients with chronic lymphocytic leukemia admitted with immune thrombocytopenia: an analysis of the National Inpatient Sample Database.

Immune thrombocytopenia (ITP) is a known autoimmune complication of chronic lymphocytic leukemia (CLL). Currently, there is limited data regarding the risk CLL confers on hospitalization outcomes in patients admitted with ITP.The National Inpatient Sample (NIS) database was queried using the International Classification of Diseases (ICD) codes to identify hospitalizations for ITP and then subclassified the data into hospitalizations with and without CLL. A multivariate logistic regression was designed to account for patient characteristics and comorbidities. The primary outcome was all-cause mortality. Secondary outcomes included major bleeding, gastrointestinal bleeding, intracranial bleeding, and the need for platelet transfusions, intravenous immunoglobulin, and splenectomy. Among 662,171 cases of ITP between 2005 and 2019, 15,672 had concurrent CLL. CLL patients were significantly older and had more comorbidities compared to patients without CLL. Multivariate analysis revealed CLL patients with ITP had a risk of all-cause mortality (odds ratio: 1.28, 95% CI: 1.19-1.37; p < 0.01). CLL patients also had a higher risk of complications, second-line ITP treatments, blood transfusions, and bleeding, with the exception of intracranial hemorrhage. Our study suggests CLL is an independent risk factor for increased morbidity and mortality among hospitalized patients with ITP. Prospective studies are needed to determine if refractoriness to conventional treatments for ITP can account these results.

Outcomes of Tyrosine Kinase Inhibitors Maintenance Therapy with or without Allogeneic Hematopoietic Stem Cell Transplantation in Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia in First Complete Remission: A Systematic Review and Meta-Analysis.

We conducted a systematic review and meta-analysis to compare outcomes of tyrosine kinase inhibitor (TKI) maintenance therapy with or without allogeneic hematopoietic stem cell transplantation (HSCT) in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in first remission (CR1). A literature search was performed on PubMed, Cochrane, and Clinical trials.gov. After screening 1720 articles, 12 studies were included. Proportions and odds ratios (OR) with 95% confidence intervals (CI) were computed. I2 provides an estimate of the percentage of variability in results across studies that is due to real differences and not due to chance. Of 1039 patients, 635 (61%) had TKI alone and 404 (39%) patients had HSCT followed by TKI. At 3 years, a trend towards poor overall survival (OS; OR 0.67, 95% CI 0.39-1.15, I2 = 68%), (disease-free survival; OR 0.58, 95% CI 0.26-1.29, I2 = 76%), and higher relapse rate (RR; OR = 2.52, 95% CI = 1.66-3.83, I2 = 26%) was seen with TKI alone compared to HSCT-TKI. Although HSCT followed by TKI maintenance in Ph+ ALL has long been considered standard of care, the introduction of potent third-generation TKIs and bispecific T-cell engagers such as Blinatumomab has significantly improved outcomes while sparing the need for HSCT in newly diagnosed patients.

Use of endpoints in phase III randomized controlled trials for acute myeloid leukemia over the last 15 years: a systematic review.

We systematically evaluated the primary and secondary endpoints used in acute myeloid leukemia (AML) phase III randomized controlled trials (RCTs). We included 238 phase III AML RCTs in the past 15 years that reported 279 primary endpoints and 657 secondary endpoints. Overall survival (OS), progression-free survival (PFS), event-free survival (EFS), and complete remission (CR) were primary endpoints in 120 (43%), 34 (12%), 30 (11%), and 41 (15%) studies, respectively. OS (12.5%), PFS (13.2%), CR (14%), safety (11%), and EFS (9%) were commonly reported secondary endpoints. Among primary endpoints, a higher use of OS (OR 2.03, 95%CI 1.10-3.75, p = 0.023) and lower use of PFS (OR 0.25, 95%CI 0.12-0.52, p < 0.001) was observed from 2014 to 2021 compared to 2006-2013; CR was frequently used in relapsed/refractory compared to frontline RCTs (OR 2.20, 95%CI 1.11-4.38, p = 0.025); EFS was frequently used in frontline compared to relapsed/refractory AML RCTs (OR 10.11, 95%CI 1.34-76.34, p = 0.025). A higher trend in the use of clinically meaningful and objective endpoint of OS over the last 15 years.

Outcomes with mismatched unrelated donor allogeneic hematopoietic stem cell transplantation in adults: A systematic review and meta-analysis.

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for various hematologic disorders. Alternative donor strategies such as mismatched unrelated donors (MMUD) offer the option of HSCT to patients lacking a human leukocyte antigen (HLA)-matched donor. We conducted a systematic review and meta-analysis to evaluate outcomes after MMUD-HSCT. Methods: A literature search was performed on PubMed, Cochrane Library, and ClinicalTrials.gov from the inception date through April 6, 2022. After screening 2477 manuscripts, 19 studies were included. Data was extracted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Pooled analysis was done using the meta-package by Schwarzer et al. Proportions with 95% confidence intervals (CI) were computed. Results: A total of 3336 patients from 19 studies were included. The median age was 52.1 years, and 53% of recipients were males. The graft source was bone marrow in 19% and peripheral blood stem cells in 81% of recipients. The median time to transplant from hematologic diagnosis was 10 (1-247) months. Hematologic diagnoses included myeloid (82.9%), lymphoid (41.1%), and other disorders (3%). The reduced intensity and myeloablative conditioning were used in 65.6% and 32% of recipients, respectively. In-vivo T-cell depletion was performed in 56.7% of the patients. Most patients had one (87.9%) or two (11.4%) antigen HLA-mismatch. The pooled 1-year overall survival (OS) was 63.9% (95% CI 0.57-0.71, n=1426/2706), and the pooled 3-year OS was 42.1% (95% CI 0.34.2-0.50, n=907/2355). The pooled progression-free survival was 46.6% (95% CI 0.39-0.55, n=1295/3253) after a median follow-up of 1.8 (range 1-6) years. The pooled relapse rate was 26.8% (95% CI 0.22-0.32, n=972/3253) after a median follow-up of 2.25 (1-3) years. The pooled incidence of acute (grade II-IV) graft-versus-host disease (GVHD) and chronic GVHD was 36.4% (95% CI 0.31-0.42, n=1131/3030) and 41.2% (95% CI 0.35-0.48, n=1337/3228), respectively. The pooled non-relapse mortality was 22.6% (95% CI 0.17-0.29, n=888/3196) after a median follow-up of 2.6 (1-5) years. Conclusion: MMUD-HSCT has demonstrated favorable outcomes with an acceptable toxicity profile. It represents a promising option in patients lacking an HLA-matched or haploidentical donor and may expand HSCT access to underrepresented racial and ethnic populations.