Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis.

BACKGROUND: In patients undergoing allogeneic hematopoietic stem-cell transplantation (HSCT), a calcineurin inhibitor plus methotrexate has been a standard prophylaxis against graft-versus-host disease (GVHD). A phase 2 study indicated the potential superiority of a post-transplantation regimen of cyclophosphamide, tacrolimus, and mycophenolate mofetil. METHODS: In a phase 3 trial, we randomly assigned adults with hematologic cancers in a 1:1 ratio to receive cyclophosphamide-tacrolimus-mycophenolate mofetil (experimental prophylaxis) or tacrolimus-methotrexate (standard prophylaxis). The patients underwent HSCT from an HLA-matched related donor or a matched or 7/8 mismatched (i.e., mismatched at only one of the HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci) unrelated donor, after reduced-intensity conditioning. The primary end point was GVHD-free, relapse-free survival at 1 year, assessed in a time-to-event analysis, with events defined as grade III or IV acute GVHD, chronic GVHD warranting systemic immunosuppression, disease relapse or progression, and death from any cause. RESULTS: In a multivariate Cox regression analysis, GVHD-free, relapse-free survival was significantly more common among the 214 patients in the experimental-prophylaxis group than among the 217 patients in the standard-prophylaxis group (hazard ratio for grade III or IV acute GVHD, chronic GVHD, disease relapse or progression, or death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P = 0.001). At 1 year, the adjusted GVHD-free, relapse-free survival was 52.7% (95% CI, 45.8 to 59.2) with experimental prophylaxis and 34.9% (95% CI, 28.6 to 41.3) with standard prophylaxis. Patients in the experimental-prophylaxis group appeared to have less severe acute or chronic GVHD and a higher incidence of immunosuppression-free survival at 1 year. Overall and disease-free survival, relapse, transplantation-related death, and engraftment did not differ substantially between the groups. CONCLUSIONS: Among patients undergoing allogeneic HLA-matched HSCT with reduced-intensity conditioning, GVHD-free, relapse-free survival at 1 year was significantly more common among those who received cyclophosphamide-tacrolimus-mycophenolate mofetil than among those who received tacrolimus-methotrexate. (Funded by the National Heart, Lung, and Blood Institute and others; BMT CTN 1703 ClinicalTrials.gov number, NCT03959241.).

Novel developments in the prophylaxis and treatment of acute GVHD.

Acute graft-versus-host disease (aGVHD) is a major life-threatening complication after allogeneic hematopoietic cell transplant. Traditional standard prophylaxis for aGVHD has included a calcineurin inhibitor plus an antimetabolite, whereas treatment has relied mainly on corticosteroids, followed by multiple nonstandard second-line options. In the past decade, this basic framework has been reshaped by approval of antithymocyte globulin products, the emergence of posttransplant cyclophosphamide, and recent pivotal trials studying abatacept and vedolizumab for GVHD prophylaxis, whereas ruxolitinib was approved for corticosteroid-refractory aGVHD treatment. Because of this progress, routine acute GVHD prophylaxis and treatment practices are starting to shift, and results of ongoing trials are eagerly awaited. Here, we review recent developments in aGVHD prevention and therapy, along with ongoing and future planned clinical trials in this space, outlining what future goals should be and the limitations of current clinical trial designs and end points.

Association between the choice of the conditioning regimen and outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis.

Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with reduced-intensity conditioning (RIC) or myeloablative conditioning (MAC) is not well known. Using the Center for International Blood and Marrow Transplant Research database, we identified adults aged ≥18 years with myelofibrosis undergoing allo-HCT between 2008-2019 and analyzed the outcomes separately in the RIC and MAC cohorts based on the conditioning regimens used. Among 872 eligible patients, 493 underwent allo-HCT using RIC (fludarabine/ busulfan n=166, fludarabine/melphalan n=327) and 379 using MAC (fludarabine/busulfan n=247, busulfan/cyclophosphamide n=132). In multivariable analysis with RIC, fludarabine/melphalan was associated with inferior overall survival (hazard ratio [HR]=1.80; 95% confidenec interval [CI]: 1.15-2.81; P=0.009), higher early non-relapse mortality (HR=1.81; 95% CI: 1.12-2.91; P=0.01) and higher acute graft-versus-host disease (GvHD) (grade 2-4 HR=1.45; 95% CI: 1.03-2.03; P=0.03; grade 3-4 HR=2.21; 95%CI: 1.28-3.83; P=0.004) compared to fludarabine/busulfan. In the MAC setting, busulfan/cyclophosphamide was associated with a higher acute GvHD (grade 2-4 HR=2.33; 95% CI: 1.67-3.25; P<0.001; grade 3-4 HR=2.31; 95% CI: 1.52-3.52; P<0.001) and inferior GvHD-free relapse-free survival (GRFS) (HR=1.94; 95% CI: 1.49-2.53; P<0.001) as compared to fludarabine/busulfan. Hence, our study suggests that fludarabine/busulfan is associated with better outcomes in RIC (better overall survival, lower early non-relapse mortality, lower acute GvHD) and MAC (lower acute GvHD and better GRFS) in myelofibrosis.

Impact of sociodemographic factors on early mortality in acute promyelocytic leukemia in the United States: A time-trend analysis.

BACKGROUND: The survival of patients with acute promyelocytic leukemia (APL) has dramatically improved with the use of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, because of the complexity of the initial management, early mortality (EM) remains a major contributor to treatment failure. It is less known whether advances in treatment, urgent access to specialized care, and broad availability of ATRA/ATO have reduced EM in the last 2 decades. Furthermore, the influence of sociodemographic factors on the risk of EM also remains unclear. METHODS: This study used the Surveillance, Epidemiology, and End Results program to characterize the impact of sociodemographic factors on the rates of EM and overall survival (OS) in patients with APL diagnosed between 1992 and 2015. RESULTS: In all, 2224 cases were identified (895 who were younger than 40 years and 1329 who were 40 years old or older); 47.9% had a county-level median household income of $59,630 or higher, 49.0% belonged to counties where more than 31% of adults held at least a bachelor's degree, and 86.0% resided in urban areas. The rate of EM declined from 31.5% in 1992-1995 to 15.9% in 2012-2015 for all patients. It improved for patients younger than 40 years (27.4% in 1992-1995 vs 5.4% in 2012-2015; P < .001) and for patients 40 years old or older but not to the same extent (35.2% in 1992-1995 vs 22.2% in 2012-2015; P = .02). Importantly, improvements in EM were not seen among patients residing in rural areas, with the rate remaining higher than 20% in 2012-2015. The 3-year OS rate was 49.2% for patients with APL diagnosed in 1992-1995 and 76.4% for patients diagnosed in 2012-2015. CONCLUSIONS: These findings confirm consistent improvements in EM and OS for patients with APL and point to the challenge of further extending these improvements in EM rates to older patients and to those living in rural areas.

Impact of insurance status on the survival of younger patients diagnosed with acute promyelocytic leukemia in the United States.

BACKGROUND: Survival among patients diagnosed with acute promyelocytic leukemia (APL) has significantly improved with the use of all-trans retinoic acid and arsenic trioxide. However, the need for immediate diagnosis and access to specialized care and the cost associated with APL management can potentially act as barriers for disadvantaged patients. The influence of sociodemographic factors on the outcomes of patients with APL remains unclear. METHODS: The authors used the National Cancer Institute's Surveillance, Epidemiology, and End Results program to characterize the impact of sociodemographic factors on survival in patients younger than 65 years with APL. RESULTS: The authors identified 1787 cases: 816 who were younger than 40 years and 971 who were 40 years old or older. Insured patients who were younger than 40 years had an improved 5-year overall survival (OS) rate in comparison with patients without insurance. Among patients who were 40 years or older, having insurance (other than Medicaid) was associated with better survival than being a Medicaid beneficiary or being uninsured, whereas patients with Medicaid had improved 5-year OS in comparison with uninsured patients. In a multivariate analysis of patients younger than 40 years, a higher risk of death was associated with being male, being diagnosed in earlier years, and being uninsured. For patients who were 40 years old or older, mortality increased with increasing age and for both Medicaid and uninsured patients in comparison with insured patients. CONCLUSIONS: Despite the high cure rate experienced by patients with APL, patients younger than 65 years without insurance and those 40 years old or older with Medicaid are at a significant disadvantage in comparison with patients with insurance. These findings point to an opportunity to improve survival in APL by addressing access to care.

Emerging first line treatment options for bladder cancer: a review of phase II and III therapies in the pipeline.

INTRODUCTION: The treatment of urothelial carcinoma (UC) had remained unchanged for several years until the recent FDA approval of immune checkpoint inhibitors (CPIs) in the salvage setting. Novel dual CPI-CPI and CPI-chemotherapy combinations are now being investigated aggressively as first line therapy for metastatic disease. Areas covered: We discuss the recent insights into the tumor biology of UC, which may impact the prognosis as well as assist in developing precision medicine. This is followed by an overview of existing treatment including conventional chemotherapy as well as the trials that led to the recent approval of PD-1 and PD-L1 inhibitors. Ongoing phase II and phase III trials developing PD-1/PD-L1 inhibitors, CTLA-4 inhibitors and VEGF inhibitors as first-line therapy are discussed. Expert opinion: The treatment paradigm for the first-line therapy of UC is expected to shift from conventional platinum-based combination chemotherapy towards novel therapy incorporating CPI immunotherapy. Finding the right combination of drugs in the appropriate disease setting and identifying the right patient population based on biomarkers are important questions to be answered. Another major challenge will be the financial burden associated with these new drugs.

Treatment-Free Remission in Chronic Myeloid Leukemia.

With the discovery of tyrosine kinase inhibitors (TKIs), overall survival in patients with chronic myeloid leukemia (CML) now approaches that of the general population. While these TKIs have proven to be lifesaving, remaining on them lifelong creates both physical and financial burdens for patients. Recently, multiple trials have begun looking into the efficacy of trialing patients off these TKIs to see if they can sustain treatment-free remission (TFR). TFR eligibility is currently limited to a small population of patients with both robust and sustained responses to TKIs. Currently, for those who attempt a trial of TFR, the average success rates are promising, with anywhere from 38 to 54% of patients experiencing sustained TFR. For those who fail to maintain sustained TFR, safety results to date are reassuring, with almost all patients successfully responding to the re-initiation of TKIs, with death and disease progression being very rare complications. Moving forward, research is being conducted to more accurately risk stratify patients at diagnosis and pair them with optimized upfront treatment regimens aimed at increasing candidacy for the trial of TFR.

Post-Transplant Maintenance Therapy in Acute Myeloid Leukemia.

Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for patients with acute myeloid leukemia (AML). However, the post-transplant relapse rate ranges from 40 to 70%, particularly with reduced intensity conditioning, and remains a major cause of treatment failure for these patients due to the limited efficacy of salvage therapy options. Strategies to mitigate this risk are urgently needed. In the past few years, the basic framework of post-transplant maintenance has been shaped by several clinical trials investigating targeted therapy, chemotherapy, and immunomodulatory therapies. Although the practice of post-transplant maintenance in AML has become more common, there remain challenges regarding the feasibility and efficacy of this strategy. Here, we review major developments in post-transplant maintenance in AML, along with ongoing and future planned studies in this area, outlining the limitations of available data and our future goals.

Low-dose decitabine plus venetoclax as post-transplant maintenance for high-risk myeloid malignancies.

Relapse remains a major cause of treatment failure following allogeneic stem cell transplantation (allo-SCT) for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We retrospectively investigated low-dose decitabine and venetoclax (DEC/VEN) as post-transplant maintenance in 26 older patients with AML and MDS. The cumulative incidence of day 100 gIII-IV acute graft versus host disease (GVHD) and 1-year moderate-severe chronic GVHD was 5% and 26%, respectively. One patient relapsed 14 m after transplant. The 1-year non-relapse mortality and survival were 11% and 84%, respectively. DEC/VEN is a safe and potentially effective strategy to reduce the risk of post-transplant relapse.

Vedolizumab for the prevention of intestinal acute GVHD after allogeneic hematopoietic stem cell transplantation: a randomized phase 3 trial.

Acute graft-versus-host disease (aGVHD) of the lower gastrointestinal (GI) tract is a major cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). Vedolizumab is a gut-selective anti-α4ß7 integrin monoclonal antibody that reduces gut inflammation by inhibiting migration of GI-homing T lymphocytes. The efficacy and safety of vedolizumab added to standard GVHD prophylaxis (calcineurin inhibitor plus methotrexate/mycophenolate mofetil) was evaluated for prevention of lower-GI aGVHD after unrelated donor allo-HSCT in a randomized, double-blind, placebo-controlled phase 3 trial. Enrollment closed early during the COVID-19 pandemic with 343 patients randomized (n = 174 vedolizumab, n = 169 placebo), and 333 received ≥1 intravenous dose of 300 mg vedolizumab (n = 168) or placebo (n = 165) and underwent allo-HSCT. The primary end point was met; Kaplan-Meier (95% confidence interval) estimated rates of lower-GI aGVHD-free survival by day +180 after allo-HSCT were 85.5% (79.2-90.1) with vedolizumab versus 70.9% (63.2-77.2) with placebo (hazard ratio, 0.45; 95% confidence interval, 0.27-0.73; P < 0.001). For the 5 key secondary efficacy end points analyzed by day +180 after allo-HSCT, rates of lower-GI aGVHD-free and relapse-free survival and grade C-D aGVHD-free survival were significantly higher with vedolizumab versus placebo. No significant treatment differences were found for the other key secondary end points of non-relapse mortality, overall survival and grade B-D aGVHD-free survival, respectively. Incidence of treatment-related serious adverse events analyzed in patients receiving ≥1 dose of study treatment (n = 334) was 6.5% (n = 11 of 169) vedolizumab versus 8.5% (n = 14 of 165) placebo. When added to standard calcineurin inhibitor-based GVHD prevention, lower-GI aGVHD-free survival was significantly higher with vedolizumab versus placebo. ClinicalTrials.gov identifier: NCT03657160 .

Assessing the efficacy of allogeneic hematopoietic cell transplantation in VEXAS syndrome: results of a systematic review and meta-analysis.

VEXAS syndrome is an X-linked monogenic disease with adult-onset inflammatory disease and myeloid dysplasia, with clinical presentation ensuing in the fifth decade of life or later. Inflammatory symptoms associated with VEXAS syndrome are treated with several lines of therapy, eventually requiring allogeneic hematopoietic cell transplantation (allo-HCT). No evidence from randomized controlled trials exists on allo-HCT versus other treatments in patients not responding to front-line therapy(ies). We show results of a systematic review/meta-analysis (SR/MA) following a search using EMBASE, PUBMED/MEDLINE and Web of Science on April 5, 2024. We extracted outcomes based on benefits (overall response rate (ORR), complete remission (CR), event-free survival (EFS) and overall survival (OS), and harms (non-relapse mortality (NRM) and acute and chronic graft-versus-host disease (GVHD)). The search identified 88 studies. Four studies (39 patients) met inclusion criteria. Median follow-up time after allo-HCT ranged from 8 to 18.5 months. Pooled EFS and OS rates were 56% and 86%, respectively. Pertaining to harms, pooled NRM rate was 14%. Pooled rates of acute and chronic GVHD were 42% and 13%, respectively. Allo-HCT is an effective treatment for VEXAS syndrome. We hope these results would increase awareness about this underdiagnosed and underreported disease.

Addition of single dose gemtuzumab ozogamicin to intensive induction chemotherapy in core-binding factor acute myeloid leukemia.

In a meta-analysis of 5 trials, the addition of gemtuzumab ozogamicin (GO) to intensive induction chemotherapy led to a survival benefit in patients with core-binding factor (CBF) acute myeloid leukemia (AML). Given the heterogeneous incorporation of GO in clinical trials, the ideal dose and schedule remains unclear. We conducted a single-center retrospective analysis to compare outcomes of patients with CBF-AML treated with intensive induction chemotherapy, with or without a single dose of GO 3 mg/m2, during induction only. We included 87 patients (GO=32, control=55). The composite complete remission (cCR) rate was higher in the control group (93%) compared to the GO group (82%) (p<0.001). The rate of measurable residual disease (MRD) negative cCR, by flow cytometry, was similar between both groups. There were no significant differences between the two groups in terms of toxicity. The 3-year relapse-free survival (RFS) for both groups was similar (71% vs 68%, p=0.5). The 3-year overall survival (OS) for the GO group was 68%, compared to 66% for the control group (p=0.9).In multivariable analysis, age and MRD positive status were risk factors for inferior outcomes. We find that survival of patients with CBF-AML is favorable in the real-world setting. The addition of single-dose GO, during induction, did not lead to a higher remission rate or survival benefit, when compared to intensive chemotherapy without GO. Further investigation into the incorporation of GO in the treatment algorithm for CBF-AML is needed.

Donor types and outcomes of transplantation in myelofibrosis: a CIBMTR study.

ABSTRACT: We evaluate the impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using the Center for International Blood and Marrow Transplant Research registry data for HCTs done between 2013 and 2019. In all 1597 patients, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study-eligible 1032 patients who received peripheral blood grafts for chronic-phase myelofibrosis, 38% of recipients of haploidentical HCT were non-White/Caucasian. Matched sibling donor (MSD)-HCTs were associated with superior overall survival (OS) in the first 3 months (haploidentical hazard ratio [HR], 5.80 [95% confidence interval (CI), 2.52-13.35]; matched unrelated (MUD) HR, 4.50 [95% CI, 2.24-9.03]; mismatched unrelated HR, 5.13 [95% CI, 1.44-18.31]; P < .001). This difference in OS aligns with lower graft failure with MSD (haploidentical HR, 6.11 [95% CI, 2.98-12.54]; matched unrelated HR, 2.33 [95% CI, 1.20-4.51]; mismatched unrelated HR, 1.82 [95% CI, 0.58-5.72]). There was no significant difference in OS among haploidentical, MUD, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months after HCT, relapse, disease-free survival, or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. Although MSD-HCTs were superior, there is no significant difference in HCT outcomes from haploidentical and MUDs. These results establish haploidentical HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries.

Impact of pre-transplant individual comorbidities on risk of ICU admission and survival outcomes following allogeneic hematopoietic stem cell transplantation.

Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-hsct) can require intensive care unit (ICU) admission in the post-transplant period. Whereas outcomes of ICU admission are poor, little is known about the pre-transplant risk factors leading to them. We conducted a retrospective analysis to investigate the impact of pre-transplant individual comorbidities on acute inpatient complications, focusing on ICU admission, ventilator support and multi-system organ failure, following allo-hsct. During the initial hospitalization, 33 (11%) patients required ICU admission, 29 (10%) required ventilator support and 33 (11%) developed multi-system organ failure. Risk factors for ICU admission and ventilator support included pre-transplant infection, pre-transplant diabetes, time to neutrophil engraftment, donor type and older transplant decade (2008-2010). Risk factors for multi-system organ failure included pre-transplant diabetes, time to neutrophil engraftment and older transplant decade (2008-2010). For ICU patients, the 60-day and 6-month mortality was 58% and 67%, respectively and the median overall survival was 1.4 months. Patients with diabetes and infection at the time of HSCT and longer time to neutrophil engraftment during transplant are at an increased risk for ICU admission, ventilator support and multi-system organ failure. Patients admitted to the ICU are also at a high risk for mortality leading to poor survival.

Goals, preferences, and concerns of patients with acute myeloid leukemia at time of treatment decision.

INTRODUCTION: Current cancer value-based models require documentation of patient goals of care and an evidence-based treatment course commensurate with patient goals. This feasibility study assessed the utility of an electronic tablet-based questionnaire to elicit patient goals, preferences, and concerns at a treatment decision making time point in patients with acute myeloid leukemia. MATERIALS AND METHODS: Seventy-seven patients were recruited from three institutions prior to seeing the physician for treatment decision-making visit. Questionnaires included demographics, patient beliefs, and decision-making preferences. Analyses included standard descriptive statistics appropriate for the level of measurement. RESULTS: Median age was 71 (range = 61-88), 64.9% female, 87.0% white, and 48.6% college educated. On average, patients completed the surveys unassisted in 16.24 min and providers reviewed the dashboard in 3.5 min. All but one patient completed the survey prior to starting treatment (98.7%). Providers reviewed the survey results prior to seeing the patient 97.4% of the time. When asked their goals of care, 57 (74.0%) patients agreed with the statement "my cancer is curable" and 75 (97.4%) agreed that the treatment goal was to get rid of all cancer. Seventy-seven (100%) agreed the goal of care is to feel better and 76 (98.7%) agreed the goal of care is live longer. Forty-one (53.9%) indicated they wanted to make treatment decisions together with the provider. The top two concerns were understanding treatment options (n = 24; 31.2%) and making the right decision (n = 22; 28.6%). DISCUSSION: This pilot demonstrated the feasibility of using technology for decision-making at the point of care. Eliciting patient goals of care, treatment outcomes expectations, decision-making preferences, and top concerns may provide clinicians with information to inform the treatment discussion. A simple electronic tool may provide valuable insight into patient understanding of disease to better tailor patient-provider discussion and treatment decision-making.

Integrating electronic geriatric assessment and frailty screening for adults with acute myeloid leukemia to drive personalized treatment decisions.

PURPOSE: Evidenced based guidelines for patients with Acute Myeloid Leukemia (AML) acknowledge increasing importance of frailty assessment when deciding on treatment, yet comprehensive geriatric assessment (GA) results are not easily incorporated into clinic workflows and the electronic health record. This study assessed the feasibility of electronic GA use in a real-world environment. METHODS: Patients with AML, ≥ 60 years and at a treatment decision-making point were recruited at three academic institutions. An electronic GA (eGA) was completed by patients prior to starting treatment. Results were immediately available on a dashboard. Data on feasibility, useability and acceptability of the intervention were collected immediately after the clinical visit. Patients completed follow up surveys at 3 months and chart reviews were done to capture treatment and toxicities. RESULTS: 77 patients were enrolled with a median age of 71 years (range=61-88). The eGA results were 25 fit (31.0 %), 22 (32.0 %) intermediate, and 23 (31.0 %) frail. There was 62.7 % (n = 47) provider concordance with the eGA result and 27 (36.0 %) post visit reports indicated that the eGA results influenced the treatment decision. On average, patients completed the surveys unassisted in 16.24 min and providers reviewed the dashboard in 3.5 min. CONCLUSION: Patients easily completed an eGA prior to starting treatment. Results were reviewed by the physician and considered in the decision for optimal treatment. One third of physician reports indicated the results were used to inform the treatment decision. Feasibility of completing the eGA in the clinic without workflow disruption and utility of the results was demonstrated.