Case report: Pulse cyclophosphamide for treatment of multi-agent-refractory hepatic graft-versus-host disease.

Graft-versus-host disease (GVHD) is a common complication in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is characterized as either acute or chronic based on symptomatology and histopathological findings. Despite advancements in disease-targeting therapeutics, steroid-refractory GVHD remains a significant contributor to mortality in HSCT recipients, highlighting the gaps in our understanding of its pathophysiology and treatment strategies. We present the case of a 46-year-old woman diagnosed with acute undifferentiated leukemia, who exhibited persistently elevated levels of serum total bilirubin (T.Bili), alkaline phosphatase (ALP), and liver function tests (LFTs) beginning on [day +201] post-haploidentical peripheral blood stem cell (PBSC) transplantation. The patient received fludarabine/total body irradiation (Flu/TBI) as a myeloablative conditioning regimen and post-transplant cyclophosphamide/tacrolimus/mycophenolate mofetil (PTCy/Tac/MMF) as GVHD prophylaxis. A liver biopsy confirmed the diagnosis of GVHD, while other possible etiologies were excluded by corresponding tests. Initial treatment with prednisone and tacrolimus, and the later addition of ruxolitinib, all showed poor response indicated by worsening T.Bili, ALP, and LFTs at the same time. Based on a multidisciplinary comprehensive assessment, we decided to administer 1,000 mg/m2 (1,600 mg) of cyclophosphamide ("pulse Cy"), which resulted in a dramatic improvement in T.Bili and transaminases starting from the very next day. A durable response to pulse cyclophosphamide was observed, as all indicators normalized ("complete response") within 55 days without relapses. The patient remains in good health with no recurrence of hepatic GVHD. To our knowledge, this is the first case in which Grade IV hepatic GVHD, refractory to multiple agents including steroids, tacrolimus, and ruxolitinib, demonstrated a complete response to pulse cyclophosphamide. The success highlights the potential therapeutic role of cyclophosphamide, a potent and cost-effective chemotherapy agent, in treating multi-agent-refractory GVHD. Large-scale clinical trials are warranted to validate its efficacy in this setting.

Graft Versus Host Disease Prophylaxis in Matched Donor Stem Cell Transplantation: Post-transplantation Cyclophosphamide Combinations Versus Methotrexate/Tacrolimus.

BACKGROUND: The use of post-transplant cyclophosphamide (PTCy) is highly effective in preventing graft versus host disease (GVHD) for haploidentical allogeneic hematopoietic stem cell transplantation (allo-HSCT). There is limited data on the role of PTCy as GVHD prophylaxis in matched-sibling and fully matched-unrelated donor (MSD/MUD) allo-HSCT. METHODS: Our single-center retrospective study aims to compare outcomes of PTCy alone or in combination with mycophenolate mofetil and tacrolimus (PTCy/MMF/TAC) relative to methotrexate and tacrolimus (MTX/TAC). The primary endpoint of our study was GVHD-free, relapse free survival (GRFS). Secondary endpoints were overall survival (OS), disease free survival (DFS), and incidence of severe acute and chronic GVHD. We identified 74 adult patients who underwent MSD/MUD allo-HSCT at our institution from 2015 to 2023. RESULTS: Within our cohort, 33.8% (n = 25) received MTX/TAC, while 54.0% (n = 40) received PTCy/MMF/TAC, and 12.2% (n = 9) received PTCy alone. Patients receiving PTCY had the longest time to neutrophil engraftment relative to MTX/TAC (15 days vs. 12 days, P = .010). PTCy/MMF/TAC was associated with improved GRFS relative to MTX/TAC (hazard ratio [HR] = HR 0.42, 95% CI 0.19-0.93, P = .031), which persisted when controlling for age. Incidence of chronic GVHD was lower in the PTCy/MMF/TAC group compared to MTX/TAC (1-year 9.0% vs. 30.1%, HR 0.19, 95% CI 0.06-0.59, P = .005). However, OS and DFS were comparable across all groups. CONCLUSIONS: Our results demonstrate decreased rates of severe chronic GVHD resulting in improved GRFS when using PTCy/TAC/MTX as GVHD prophylaxis compared to MTX/TAC in MSD/MUD.

Donor matters: Donor selection impact on hematopoietic stem cell transplantation outcomes in Hispanic patients with B-cell acute lymphocytic leukemia: Insights from a myeloablative HSCT study.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a pivotal treatment for high-risk acute lymphocytic leukemia (ALL), although limited by suitable human leukocyte antigen (HLA)-matched sibling donors (MSD). This study evaluates the impact of donor selection on outcomes in post-HSCT Hispanic B-cell ALL patients. METHODOLOGY: This single-center retrospective study evaluates outcomes in 88 adult Hispanic B-cell ALL patients who underwent haploidentical, MSD, or MUD myeloablative HSCT between 2013 and 2023. RESULTS: Compared to Haploidentical transplants, MSD exhibited worse cumulative incidence of relapse (CIR) (HR = 3.39; P = 0.014) and disease-free survival (DFS) (HR = 2.44; P = 0.048) whereas MUD outcomes did not differ. This effect persisted even when controlling for pre-HSCT stage and Minimal residual disease (MRD) status. In addition, Ph-like was a significant predictor of worse DFS (HR = 3.60; P=0.014) and CIR (HR = 2.97; P=0.035) on multivariate analysis. Older donor age correlated with worse GVHD-free, relapse-free survival (GRFS) in haploidentical transplants (HR = 1.05; P=0.036). CONCLUSION: Our data highlights improved outcomes with younger, haploidentical donors among Hispanic B-cell ALL patients undergoing myeloablative HSCT. This underscores the importance of donor selection in optimizing outcomes for ALL patients.

Impact of Prior Inotuzumab Ozogamicin Treatment on Brexucabtagene Autoleucel outcomes in Adults with B-cell ALL.

The effect of prior inotuzumab ozogamicin (InO) treatment on brexucabtagene autoleucel (brexu-cel) outcomes remains unclear in adults with acute lymphoblastic leukemia (ALL), particularly the influence off previous InO response and the timing of administration. We conducted a retrospective multicenter analysis of 189 patients with relapsed/refractory (r/r) ALL treated with brexu-cel. Over half of the patients received InO before brexu-cel (InO-exposed). InO-exposed patients were more heavily pretreated (p= 0.02) and frequently had active marrow disease pre-apheresis (p= 0.03). Response rate and toxicity profile following brexu-cel were comparable for InO-exposed and InO-naïve; however, consolidation therapy post brexu-cel response was utilized at a higher rate in InO-naïve patients (p= 0.005). With a median follow up of 11.4 months, InO-exposed patients had inferior progression-free survival (PFS) (p=0.013) and overall survival (OS) (p=0.006) in univariate analyses; however, prior InO exposure did not influence PFS (HR 1.20, 95%CI, 0.71-2.03) in multivariate models. When InO-exposed patients were stratified according to prior InO response, InO responders had superior PFS (p=0.002) and OS (p<0.0001) relative to InO-refractory. The timing of administering InO did not affect brexu-cel outcomes, with comparable PFS (p=0.51) and OS (p=0.86) for patients receiving InO as bridging therapy or pre-apheresis. In conclusion, while InO exposure was associated with inferior survival outcomes following brexu-cel in unadjusted analyses, these associations were no longer significant in multivariate analyses, suggesting it is unlikely that InO negatively impacts brexu-cel efficacy. Our data instead imply that InO-exposed recipients of brexu-cel tend to be higher-risk patients with intrinsic adverse leukemia biology.