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.

Long-term follow up of the combination of ofatumumab, high-dose methylprednisolone, and lenalidomide for untreated chronic lymphocytic leukemia with biomarker analysis.

BACKGROUND: Advancements in frontline therapy and chemotherapy-sparing treatments in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have altered the treatment algorithms of this disease. We present a frontline alternative for treatment- naïve (TN) CLL/SLL patients. METHODS: This was a single-center, phase 2 study of high-dose methylprednisolone (HDMP) and ofatumumab with lenalidomide and ofatumumab consolidative therapy for all comers with TN CLL/SLL. Treatment was continued until disease progression or intolerable side effects. Patients were assessed for response per iwCLL 2008 criteria after completing cycles 3 and 12. RESULTS: Forty-five patients were enrolled (median age, 62.6 years). High-risk features included del17p (18%), Del11q (22%), and unmutated IGHV gene (76%). Median treatment duration was 32·2 (2·7-75·9) months. Thirty-six patients discontinued treatment due to disease progression (22%), adverse events (40%), allogeneic hematopoietic cell transplantation (allo-HCT) (7%), consent withdrawal (4%), and secondary malignancies (7%). The best overall and complete response rates were 96& and 29% respectively. At median follow-up of 61·7 (5·6-84·9) months, 9 patients remained on treatment. Median progression-free survival was 54·4 (2·9-77·6) months. Three patients underwent allo-HCT after a median of 3 (3-4) treatment cycles. Treatment was well tolerated, with a grade 3/4 infusion reaction in one patient. The most common grade 3/4 hematological adverse event was neutropenia (69%). Four patients had grade 3/4 infections. No grade 3/4 tumor flares, tumor lysis syndrome, or thrombosis were observed. CONCLUSION: The combination of ofatumumab, HDMP, and lenalidomide was effective and relatively well tolerated in treatment-naive CLL/SLL. Its role in the frontline setting remains unclear given the current available and effective treatment options. FUNDING: The funders had no role in the study.

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.

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.

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.

Insights into the Impact of Hesitancy on Cancer Care and COVID-19.

World Health Organization findings indicate that the COVID-19 pandemic adversely affected cancer diagnosis and management. The COVID-19 pandemic disrupted the optimal management of outpatient appointments, scheduled treatments, and hospitalizations for cancer patients because of hesitancy among patients and health-care providers. Travel restrictions and other factors likely affected medical, surgical, and radiation treatments during the COVID-19 pandemic. Cancer patients were more likely to be affected by severe illness and complications if they contracted COVID-19. A compromised immune system and comorbidities in cancer patients may have contributed to this increased risk. Hesitancy or reluctance to receive appropriate therapy or vaccination advice might have played a major role for cancer patients, resulting in health-care deficits. The purpose of this review is to evaluate the impact of COVID-19 on screening, entry into clinical trials, and hesitancy among patients and health-care professionals, limiting adjuvant and metastatic cancer treatment.

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.

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.

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.

The Impact of Atrial Fibrillation on hospitalization Outcomes for Patients With Chronic Lymphocytic Leukemia Using the National Inpatient Sample Database.

BACKGROUND: The incidence of atrial fibrillation (AF) in patients with chronic lymphocytic leukemia (CLL) has been on the rise. However, the excess burden added by AF to the morbidity and mortality of CLL patients especially in the hospitalized setting is undetermined. METHODS: The National Inpatient Sample (NIS) database was accessed to gather data of hospitalized CLL patients with AF from 2009 to 2018. Propensity-score matching (PSM) and logistic regression model were performed to control for baseline patient factors to match 7265 CLL patient admissions with AF and 7265 CLL patient admissions without AF. The primary outcome was all-cause mortality (ACM), while the secondary outcomes included acute coronary syndrome (ACS), acute myocardial infarction (AMI), and the need for percutaneous coronary intervention (PCI), acute heart failure (AHF), acute hypoxic respiratory failure (AHRF), cardiac arrest (CA), cardiogenic shock (CS), stroke, and the total cost of hospitalization. RESULTS: CLL patients with AF had a higher rate of ACM (6.06% vs 4.47%; odds ratio [OR] 1.39, 95% confidence interval [CI] 1.19-1.61; P =< .001). All other secondary outcomes including ACS, AMI, PCI, AHRF, CA, CS, and stroke were observed at a significantly higher rate in the AF group as well. The median total hospital cost was also higher in the AF group ($9097 vs. $7646; P value < .0001) CONCLUSION: CLL patients with AF are at a significantly increased risk of all-cause mortality, cardiac-related mortality, and stroke. For this population, a multidisciplinary approach should be orchestrated for better management and outcomes.

Effect of Ibrutinib on Hmphocytic Leukemia: a Single-Center Experience.

OBJECTIVE/BACKGROUND: In the era of novel agents, Bruton tyrosine kinase (BTK) inhibitors have changed the dynamics of treating chronic lymphocytic leukemia. However, small studies have shown conflicting results regarding the additive humoral dysfunction with their use. METHODS: We prospectively compared vaccine responses in patients on ibrutinib (n = 10) with matched controls (n = 16) and analyzed whether a protein-based (tetanus-diphtheria toxoid) or a carbohydrate (Pneumovax) moiety will result in an improved immunological response. RESULTS: An appropriate serological response in IgG titers for diphtheria was seen in 40% of patients on ibrutinib and 31% of patients in the control group. About 30% of patients on ibrutinib and 44% of patients in the control group had an adequate response to tetanus toxoid. None of the patients on ibrutinib mounted an adequate response to Pneumovax, while 31% of patients in the control arm responded appropriately. These differences in the results were considered insignificant as all p values were greater than the cut-off of 0.05. CONCLUSION: Our study did not show significant detrimental vaccine responses with ibrutinib and calls for larger multicenter studies to elucidate long-term effects, especially in patients with prior exposure to anti-CD20 monoclonal antibodies.

Leg ulcer with long-term hydroxyurea use.

Long-term use of hydroxyurea can cause leg ulcers which usually do not heal unless the drug is discontinued. Patients should be counseled regarding alternative lines of treatment like anagrelide and pegylated-interferon.

Delayed Recognition of Levetiracetam-induced Pancytopenia.

Blood dyscrasias associated with levetiracetam use can be difficult to identify, especially when other potential differential diagnoses are concurrently present. Here we present a 57-year-old man with metastatic adenocarcinoma of unknown primary origin on levetiracetam who initially presented with an in-stent thrombosis of the right external iliac vein and then developed worsening thrombocytopenia followed by pancytopenia. Levetiracetam was not identified as the culprit until other causes like platelet consumption, heparin-induced thrombocytopenia, idiopathic immune thrombocytopenic purpura, and bone marrow involvement by metastatic disease were ruled out. LEARNING POINTS: Levetiracetam can cause both acute and delayed-onset pancytopenia through bone marrow suppression.The phenomenon is normally reversible and blood counts improve with drug cessation.Clinicians should consider checking a complete blood profile within a month of drug initiation, particularly in high-risk patients.

Massive splenomegaly in hairy cell leukemia causing urinary retention.

Hairy cell leukemia can cause massive splenomegaly which may lead to urinary retention and constipation. Patients usually require a splenectomy for relief of symptoms.