Allogeneic Hematopoietic Cell Transplantation Research Articles

Impact of TP53 alteration on allogeneic hematopoietic cell transplantation outcomes for myelodysplastic syndromes.

The poor outcome of TP53 alteration has been reported in myelodysplastic syndrome (MDS) patients. However, the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in TP53 alteration patients remains debated. Previous studies showed that TP53 mutations had no effect on the prognosis of patients with acute leukemia after haploidentical HSCT (haplo-HSCT). The effect of haplo-HSCT on MDS patients with TP53 alterations remains to be further elucidated. We aimed to reveal the role of TP53 alterations in the prognosis of MDS patients undergoing allo-HSCT, especially haplo-HSCT. 261 MDS patients with known TP53 status were enrolled, including thirty-seven patients with TP53 mutation/deletion (TP53mut/del). TP53mut/del patients showed a worse rate of 2-year cumulative incidence of relapse (CIR) and 2-year disease-free survival (DFS) than TP53 wild type (TP53wt) patients (46.2% vs 17.0%, P < 0.001; 41.8% vs 68.9, P < 0.001) after allo-HSCT, even for those with haplo-HSCT (CIR: P < 0.001; DFS: P = 0.002). However, the prognostic effect of TP53 alteration on overall survival (OS) was not observed in patients with haplo-HSCT (66.7% vs 75.2%, P = 0.108). Positivity of post-transplantation measurable residual disease (post-MRD) and time from diagnosis to transplantation were independent risk factors for MDS patients. TP53 alterations do not affect OS in patients undergoing haplo-HSCT requires further validation.

Pediatric Transplant and Cellular Therapy Consortium RESILIENT Conference on Pediatric Chronic Graft-versus-Host Disease Survivorship after Hematopoietic Cell Transplantation: Part II. Organ Dysfunction and Immune Reconstitution Considerations for children with chronic GVHD after Hematopoietic Cell Transplantation.

While highly morbid forms of chronic graft versus host disease (cGVHD) and severe late effects of allogeneic hematopoietic cell transplant (HCT) can impact children and adults alike, unique considerations arise in pediatric cases regarding diagnosis, monitoring, treatment, and likelihood of resolution. As children can present with atypical features of cGVHD, and with more significant disease due to inability to communicate symptoms, they may be at increased risk for highly morbid forms of cGVHD and incur greater subsequent late effects, which may be more pronounced in those with underlying chromosomal breakage syndromes, with higher prevalence in pediatric HCT recipients. The long-term effects of cGVHD and its therapies include impaired immune reconstitution, leading to increased risks of infection and secondary malignant neoplasms. However, children also have the greatest potential for full immune reconstitution, due to thymus recovery that could impact the timing of vaccination with respect to tolerance and restoration of optimal immunity. Developing strategies to mitigate the late effects incurred with, and as a result of cGVHD, is of critical importance. The working group recommends surveillance strategies for late effects in patients with cGVHD, increased utilization of emerging diagnostic tools, integration of monitoring for cGVHD treatment response, development of new treatments, and provides aims for future research endeavors.

Real-World Experience With Maribavir for Treatment of Refractory or Resistant Cytomegalovirus Infection in Hematopoietic Cell Transplant Recipients and Hematologic Malignancy Patients.

Refractory and/or resistant (R/R) cytomegalovirus (CMV) infection is a serious complication after allogeneic hematopoietic cell transplantation (HCT). Maribavir, an oral antiviral agent, was approved in November 2021 for the treatment of R/R CMV in transplant recipients. However, real-world data on the use of maribavir in HCT recipients and hematologic malignancy (HM) patients are limited. We described our early experience with the use of maribavir in the year after its Food and Drug Administration approval in HCT recipients and HM patients. We performed a retrospective study of all patients who received maribavir for treatment of CMV infection at our center from November 2021 to December 2022. Clinical characteristics and outcomes of CMV infection were collected for each case. Descriptive statistics were calculated. Our study included 13 patients (11 of whom were HCT recipients and two with HM) who received a median of 58 days of maribavir therapy. While on maribavir, nine (69%) patients had a resolution of CMV infection. Treatment-emergent maribavir resistance was documented in one patient with a CMV UL97 C480F mutation. Patients with higher baseline viral loads were less likely to achieve CMV resolution compared to those with lower levels. Additionally, six patients received combination therapy with maribavir. Six patients developed dysgeusia, none requiring maribavir discontinuation. Maribavir is an effective and safe option for the treatment of R/R CMV infections in HCT recipients and HM patients. Our study highlights the complexities of managing CMV infections in this patient population and some challenges associated with maribavir therapy.

Post-transplant TKIs for Ph+ ALL: practices to date and clinical significance.

Post-transplant tyrosine kinase inhibitors (TKIs) show promise in preventing relapse after allogeneic hematopoietic cell transplantation (allo-HCT) for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). However, their real-world use and efficacy remain unclear. A comprehensive study across seven centers included Ph+ALL patients who underwent allo-HCT between 2002 and 2022. Post-transplant TKIs were administered in 28% of patients (49 of 173 transplanted in complete remission): 7% as prophylaxis during complete molecular remission (CMR), and 21% in response to measurable residual disease (MRD) positivity. Median first post-transplant TKI duration was 13.7 months for the prophylactic group and 4.0 months for the MRD-triggered group. Prophylactic TKIs appear particularly beneficial for patients not in CMR at allo-HCT, showing a trend towards higher 5-year relapse-free survival (RFS) compared to those not receiving prophylactic TKIs (100% vs. 73%; P = 0.11). Significant RFS differences were observed between the prophylactic, non-TKI, and MRD-triggered groups. However, patients with white blood cell counts <15000/µl at diagnosis and no additional chromosomal abnormalities-an MRD-triggered high efficacy cluster-demonstrated comparable 5-year RFS regardless of TKI strategy (100% vs. 85% vs. 80%; P = 0.87). This cluster highlights the potential effectiveness of MRD-triggered TKI administration in select low-risk patients, suggesting tailored TKI strategies based on risk factors.

Efficacy and safety of olverembatinib as maintenance therapy after allogeneic hematopoietic cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Experience using olverembatinib as maintenance therapy in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) after allogeneic hematopoietic cell transplantation (allo-HCT) is limited. We retrospectively collected data from 26 patients with Ph+ ALL who received only olverembatinib as maintenance therapy after allo-HCT. Olverembatinib was administered as prophylaxis in 18 patients (69.2%), and preemptively in 8 patients (30.8%). The median time of olverembatinib initiation after transplantation was 2.5 months (range, 1-7.3). The median starting dose of olverembatinib was 35mg qod (range, 15-40). The median duration of olverembatinib treatment was 12.5 months (range, 6-23). Olverembatinib maintenance treatment was discontinued in 8 patients (8/26,30%), seven stopped the drug for a long-lasting BCR-ABL1 negativity and 1 for recurrent fever associated with the drug. BCR-ABL1 turned positive in 3 patients in 2, 3 and 6 months after discontinuation. During olverembatinib treatment, three patients developed grade ≥ 3 hematologic side effects, which resolved with dose interruption or dose reduction. The median follow-up time after allo-HCT were 17.75 months (range 7-31). The hematologic relapse rate was 7.7% (2/26), with no event in the preemptive group. The 3-year probability of overall survival and relapse free survival after allo-HCT was 91.7% and 79.1%, respectively. Only one patient in prophylaxis group died of central central nervous system (CNS) relapse. Thus, our data suggest that olverembatinib is effective and safe as maintenance treatment in patients with Ph+ ALL who underwent allo-HSCT. The main adverse effect was hematologic toxicity, which was tolerated.

“They knew the same struggles”: perceptions of a group coping skills intervention in patients with chronic graft-versus-host disease

PurposeChronic graft-versus-host-disease (cGVHD), an inflammatory condition affecting allogeneic hematopoietic cell transplantation (HCT) survivors, is associated with a range of debilitating physical and psychological sequela. Yet HCT recipients with cGVHD are virtually absent from survivorship intervention research. We conducted a randomized clinical trial to evaluate the feasibility and preliminary efficacy of a multidisciplinary group coping skills intervention (Horizons) tailored to meet these patients’ unique needs. For this follow-up qualitative analysis, we evaluated the perceived impact of the Horizons intervention by the group participants.MethodsWe purposefully selected a subset of Horizons participants (n = 19) to complete audio-recorded exit interviews via semi-structured interview guide. We used rapid analysis to characterize participant feedback in three domains: (1) motivations to participate, (2) perceived benefits of participation, and (3) impacts of participation.ResultsFindings highlight participants’ motivations to participate centered on desires to connect with others living with cGVHD and to help future patients. Perceived benefits of participation focused on the following categories: (1) connecting with other survivors, (2) learning about cGVHD, and (3) learning coping strategies to manage specific cGVHD symptoms. Impacts of participation on everyday life variably reflected categories of (1) increased sense of empowerment to contact their care team with questions and concerns, (2) increased support and validation in their struggles with cGVHD, and (3) renewed motivation or progress toward personal and health-specific goals.ConclusionStudy findings demonstrate participants’ appreciation for a group-based opportunity to connect with others living with cGVHD and strengthen skills for navigating cGVHD challenges. Results support the ongoing need for evidence-based interventions to improve quality of life among HCT survivors.Trial registrationwww.ClinicalTrials.gov, identifier NCT04479995. Date of Registration: July 21, 2020.

Incidence, risk factors, and outcomes of transplant-associated thrombotic microangiopathy in pediatric patients after allogeneic hematopoietic cell transplantation: a single-institution prospective study.

Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication in hematopoietic cell transplantation (HCT). Given the rarity of prospective pediatric studies on TA-TMA, this study aimed to evaluate the incidence, survival outcomes, and risk factors for predicting early the development of TA-TMA in a pediatric population following allogeneic HCT. We conducted a prospective analysis of 173 pediatric patients to evaluate the incidence, survival outcome, and risk factors of TA-TMA. The cumulative incidence of TA-TMA at one-year post-HCT was 4.7% (95% CI, 2.2-8.6%). Patients with TA-TMA showed significantly poorer 1-year overall survival (OS) rate, 50.0% ± 17.7% compared to 85.4% ± 2.8% in those without TA-TMA (p = 0.008). Additionally, the non-relapse mortality (NRM) rate was higher in the TA-TMA group at 12.5% (95% CI, 3.7-55.8%) versus 7.0% (95% CI, 2.8-10.1%) (p = 0.598). A urine protein/creatinine ratio ≥ 1 mg/mg on day 30 post-HCT was significantly associated with TA-TMA occurrence (adjusted HR, 9.5; [95% CI], 1.28-70.39; p = 0.028). This study showed the significantly unfavorable clinical outcomes associated with TA-TMA in pediatric patients and emphasized the importance of early identification of patients at risk. Further research is needed to explore additional strategies for early detection and intervention to improve outcomes.

Impacts of donor age and HLA mismatch on HCT outcomes differ according to the donor CMV serostatus in unrelated allo-HCT.

In unrelated allogeneic hematopoietic cell transplantation (allo-HCT), older and/or HLA-mismatched donors are known risk factors for survival outcomes. In healthy individuals, cytomegalovirus (CMV) seropositivity is associated with impaired adaptive immune systems. We assessed whether the adverse effects of donor risk factors are influenced by the donor CMV serostatus. We analyzed 5836 CMV seropositive patients who received unrelated allo-HCT. We divided the entire cohort into two cohorts according to the donor CMV serostatus: CMV-positive (DP) and -negative (DN). We also stratified each cohort into four groups based on donor age (≥ 40 or < 40) and HLA parity (8/8 or 7/8): Young88, Old88, Young78, and Old78. In the CMV-DP cohort, the Old88 (HR 1.20, P = 0.012), Young78 (HR 1.35, P < 0.001), and Old78 (HR 1.60, P < 0.001) groups were associated with inferior OS compared with the Young88 group. On the other hand, in the CMV-DN cohort, neither donor age nor HLA disparity was associated with inferior OS. The adverse impact of donor age was different between the cohorts (CMV-DP; HR 1.19, P = 0.001, CMV-DN; HR 1.04, P = 0.53; P for interaction 0.070), as was the impact of HLA (CMV-DP; HR 1.34, P < 0.001, CMV-DN; HR 1.08 P = 0.23; P for interaction 0.012). The impacts of donor age and HLA mismatch on OS might differ according to the donor CMV serostatus. In unrelated allo-HCT from a CMV seronegative donor, an HLA-mismatched older donor may be able to be selected without affecting OS.

Donor Regulatory T-Cell Therapy to Prevent Graft-Versus-Host Disease.

Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy limited by graft-versus-host disease (GVHD). In preclinical studies and early-phase clinical studies enrichment of donor regulatory T cells (Tregs) appears to prevent GVHD and promote healthy immunity.We enrolled 44 patients on an open-label, single-center, phase 2 efficacy study investigating if a precision selected and highly purified Treg cell therapy manufactured from donor mobilized peripheral blood improves one-year GVHD-free relapse free survival (GRFS) after myeloablative conditioning (trial NCT01660607). We compared this study arm to a concomitant standard of care (SOC) cohort. All donor Treg cell products were successfully manufactured and administered without cryopreservation within 72 hours. Participants had a one-year incidence of acute grade III-IV GVHD of 7%, moderate to severe chronic GVHD of 11% and non-relapse mortality rate of 4.5%. The primary endpoint of significantly improved one-year GRFS was achieved at 64% evaluated against a predicted incidence of 40% (p = 0.002) with a realized incidence of 36% in the SOC comparitor. For those trial patients whow developed grade II-IV acute GVHD, 91% responded to front-line steroid therapy wheras 50% responded in the SOC comparator group. Trial participants had a reduced incidence and burden of GVHD and improved GRFS, as compared to rates common to highly variable unmanipulated donor grafts and multi-agent immune suppression.

Shared Local Oncology Care After Allogeneic Hematopoietic Cell Transplantation

Although sharing care with local oncologists after allogeneic hematopoietic cell transplantation (HCT) has been proposed for patients living far from HCT centers, it is not known whether a shared strategy is safe or improves patient quality of life (QOL). To determine the efficacy and safety of sharing follow-up care after HCT between the HCT specialty center and local oncologists. This was a multicenter collaborative randomized clinical trial of patients undergoing HCT at Dana-Farber Cancer Institute (DFCI)-a high volume HCT center in Boston (Massachusetts)-and 8 local oncology practices. Eligible patients were enrolled from December 2017 to December 2021 and were randomized 1:1 to shared vs usual care after neutrophil engraftment, stratified by local sites in Massachusetts, Rhode Island, New Hampshire, New York, and Maine. Data analyses were performed in January 2024. Shared care involved alternating post-HCT visits at DFCI and local oncology practices through day 100; for usual care, all post-HCT visits occurred only at DFCI. Coprimary outcomes were nonrelapse mortality (NRM) at day 100, and QOL measured by the FACT-BMT (Functional Assessment of Cancer Therapy-Bone Marrow Transplantation) instrument and the QLQ-C30 (European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire) at day 180. Prespecified secondary outcomes included day 100 QOL and 1-year overall survival. A total of 302 participants (median [range] age, 63 [20-79] years; 117 [38.7%] females; 185 [61.3%] males) were included in the analysis; 152 were randomized to shared care and 150 to usual care. Day 100 NRM was noninferior for shared vs usual care (2.6% [95% CI, 0.7% to 6.6%] vs 2.7% [95% CI, 0.7% to 6.7%]; P = .98). There were no differences at day 180 for the FACT-BMT total score (mean difference, 3.8; 95% CI, -2.1 to 9.6; P = .20) or QLQ-C30 global score (1.9; 95% CI, -4.9 to 8.8; P = .58). At day 100, the FACT-BMT total score was better for shared care (mean difference, 6.6; 95% CI, 1.0 to 12.1; P = .02) as was the QLQ-C30 global score (8.8; 95% CI, 1.8 to 15.7; P = .02). This randomized clinical trial found that shared care resulted in noninferior NRM at day 100 but similar QOL at day 180, with improved QOL at day 100. These data suggest that shared care is safe, improves QOL early on, and has the potential to become a routine model for post-HCT care. ClinicalTrials.gov Identifier: NCT03244826.

Current status and perspectives of hematopoietic cell transplantation in patients with paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare complement-driven acquired hemolytic anemia with specific presentations of hemoglobinuria, abdominal pain, fatigue, and thrombosis. To review the current therapeutic strategies for PNH, including anti-complement therapy and allogeneic hematopoietic cell transplantation (alloHCT), focusing on the tailoring of the approach to the disease subtype. The outcome of alloHCT varies depending on disease severity, thrombotic history, and response to prior therapies. Non-transplant PNH therapies include anti-C5 monoclonal antibodies that reduce terminal complement activation (eculizumab, ravulizumab, and crovalimab) and proximal complement pathway inhibitors such as pegcetacoplan (C3 inhibitor), iptacopan (complement factor B inhibitor), and danicopan (complement factor D inhibitor). Although complement inhibitors have revolutionized treatment, alloHCT remains the only curative therapy, particularly for patients who are refractory to medical management or have severe cytopenia. This review outlines the conditioning regimens used in alloHCT and summarizes recent studies showing that overall survival rates improve with less toxic conditioning protocols. AlloHCT can be used to manage PNH, particularly in patients who are resistant to or without access to complement-targeted therapies. Any potential cure offered by alloHCT must be counterbalanced by the significant procedure risks, including graft-versus-host disease and transplant-related mortality, particularly in patients with comorbidities. In the case of severe aplastic anemia with an associated PNH clone, immunoablative protocols based on anti-thymocyte globulin serotherapy with fludarabine and cyclophosphamide are recommended. The use of reduced toxicity protocols with fludarabine has been well-documented in patients with classic PNH. A treosulfan/fludarabine-based regimen is recommended; however, there is no consensus on optimal drug selection.

Frailty assessment in adults undergoing allogeneic hematopoietic cell transplantation: insights from a multicenter GETH-TC study to optimize outcomes and care.

This multicenter prospective study sponsored by the Grupo Español de Transplante Hematopoyético y Terapia Celular (GETH-TC) explores the use of frailty assessments in allo-HCT candidates. Frailty was measured using the HCT Frailty Scale at first consultation and HCT admission in 404 adults from 15 HCT programs in Spain. Based on the results, patients were classified into fit, pre-frail and frail categories. Allo-HCT outcomes were analyzed according to the results obtained from the HCT Frailty Scale. Data was collected prospectively and all patients signed informed consent. At first consultation, 102 (26.2%) patients were classified as fit, 248 (61.4%) as pre-frail, and 50 (12.4%) as frail. During the study, 62 (15.2%) patients participated in a pre-habilitation program. Among non-pre-habilitated patients (n=342), the proportion of fit patients decreased from 26.6% to 16.7%, while frail patients increased from 12.7% to 19.9%. In contrast, pre-habilitated patients (n=62) showed improvements, with fit patients increasing from 24.2% to 46.8%, and frail patients decreasing from 9.7% to 3.2%. Multivariate analysis confirmed lower OS (HR 2.52, P=0.002) and higher NRM (HR 2.69, P=0.013) in frail patients at HCT admission compared to fit ones, with a trend towards lower OS in pre-frail patients (HR 1.54, P=0.097). This study highlights the feasibility of incorporating the HCT Frailty Scale into clinical practice, confirms its negative impact of frailty on transplant outcomes, and suggests that frailty is dynamic and potentially reversible through pre-transplant interventions.

Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Patients Aged 70 Years and Older: A Systematic Review and Meta-Analysis.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potential cure for many hematological malignancies. Historically, older adults were not considered eligible for allo-HCT due to increased toxicity and mortality concerns. This systematic review and meta-analysis aim to explore the outcomes of allo-HCT in patients aged 70 years or older. Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, a comprehensive literature search was performed on PubMed, Cochrane Register of Controlled Trials, and Clinicaltrials.gov using MeSH terms and keywords for "Hematopoietic Stem Cell Transplantation" AND "Outcome Assessment" from the date of inception to June 30, 2024. Our search produced 102 articles. After excluding irrelevant and review articles during primary and secondary screening, eight original studies reporting outcomes of allo-HCT in patients aged 70 years or older were included. The survival data were retrieved from Kaplan-Meier (KM) curves using an online plot digitizer tool to calculate the overall survival (OS) and disease-free survival (DFS). The pooled KM curves were plotted and analyzed using the "MetaSurvival" package of R software version 4.2.1. Proportions and 95% confidence intervals (CIs) were extracted as well. A total of 2519 patients aged 70 years or older with allo-HCT were included in the analysis. The included patients' age ranged from 70 to 84 years, and 68% were male. Median follow-up was 23.2 (0.4 to 122.5) months. The combined median OS was 14.84 months (95% CI: 11.61 to 19.50), with OS rates at 6, 12, 24, and 36 months of 71.8%, 54.5%, 41.9%, and 34.9%, respectively. The estimated pooled mean OS was 28.62 months (95% CI: 23.41 to 31.44). The pooled median DFS was 10.54 months (95% CI: 7.93 to 14.17), with DFS rates at 6, 12, 24, and 36 months of 61.5%, 47.5%, 37%, and 30.6%, respectively. The estimated pooled mean DFS was 24.45 months (95% CI: 18.30 to 23.74). The relapse rate ranged from 28% to 55.6%, while non-relapsed mortality ranged from 5.6% to 42%. The acute graft versus host disease (GvHD) incidence varied from 9.3% to 32%, while chronic GvHD rates ranged from 10% to 43%. Allo-HCT provides promising outcomes for patients aged 70 or older with transplant-eligible diseases. Disease progression, followed by infections, is the leading cause of mortality, underscoring the need for improved post-transplant care, including optimized GvHD regimens and strategies to reduce infection risk.

Impact of Underlying Disease and Total Body Irradiation on the Incidence of Graft-Versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation.

Multiple factors have been described to influence the risk of acute or chronic graft-versus-host disease (aGVHD or cGVHD) after allogeneic hematopoietic cell transplantation (HCT), including underlying chronic myeloid leukemia (CML) and high-dose total body irradiation (TBI). However, the impact of the underlying disease or low-dose TBI on the risk of GVHD in the modern era has not been determined. To determine risk factors for GVHD in the modern era in the setting of antithymocyte globulin (ATG)-based GVHD prophylaxis. This retrospective study included 1219 patients with hematologic malignancy who underwent first peripheral blood allogeneic HCT using myeloablative fludarabine and busulfan conditioning ± low-dose total body irradiation, along with ATG, cyclosporine, and methotrexate as GVHD prophylaxis. The adjusted cumulative incidence of GVHD was compared between patient subgroups using multivariable competing risks regression. When disregarding the underlying disease, risk factors for grade 2-4 aGVHD were donor type other than matched sibling donor (non-MSD) and lack of low-dose TBI (non-TBI). Risk factors for grade 3-4 aGVHD were non-MSD, non-TBI, and CMV donor negative/recipient positive serostatus (D-R+). Risk factors for moderate-severe cGVHD were ≤9/10 HLA match, nonmale/male, and non-TBI. In models including the underlying disease, additional significant risk factors were chronic lymphocytic leukemia (CLL) for grade 2 to 4 aGVHD (sub-hazard ratio over acute myeloid leukemia [SHR] 3.16, 95% CI 1.97-5.08, P < .001); CLL and acute lymphoblastic leukemia (ALL) for grade 3-4 aGVHD (SHR for CLL 3.54, 95% CI 1.54-8.17, P = .003 and SHR for ALL 2.26, 95% CI 1.26-4.04, P = .006); and myelofibrosis (MF) for moderate-severe cGVHD (SHR 2.14, 95 CI 1.34-3.41, P = .001). In the modern era when using ATG for GVHD prophylaxis, newly identified risk factors include CLL and non-TBI for grade 2-4 aGVHD; CLL, ALL, and non-TBI for grade 3-4 aGVHD; and MF and non-TBI for moderate-severe cGVHD. These findings, if confirmed in a separate cohort, should be taken into consideration when tailoring the prophylaxis of and monitoring for GVHD.

DIFFERENTIAL IMPACT OF CD34+ CELL DOSE FOR DIFFERENT AGE GROUPS IN ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION FOR ACUTE LEUKEMIA: A MACHINE LEARNING-BASED DISCOVERY

Allogeneic hematopoietic cell transplantation (allo-HCT) presents a potentially curative treatment for hematologic malignancies, yet carries associated risks and complications. Continuous research focuses on predicting outcomes and identifying risk factors. Notably, the influence of CD34+ cell dose on overall survival (OS) has been the subject of numerous studies yielding contradictory results. We developed machine learning (ML) models to predict allo-HCT outcomes and through the application of SHAP (SHapley Additive exPlanations), an explainable artificial intelligence (XAI) technique, enabled the identification of new and clinically relevant feature-outcome relationships. In particular, we identified clear interaction between CD34+ cell dose of peripheral blood stem cell (PBSC) grafts and patient age at allo-HCT for acute leukemia patients. Results of multivariable analysis validated the interaction effect: On young acute leukemia patients (≤45-year-old), low dose of CD34+ cells (<4.3 × 106 CD34+/kg) was associated with better OS against high dose (≥7 × 106 CD34+/kg) (hazard ratio [HR] 0.38, p=0.019), while for older acute leukemia patients (>45-year-old), low CD34+ cell dose (<3.8 × 106 CD34+/kg) was associated with worse OS against high dose (≥6.1 × 106 CD34+/kg) (HR 1.58, P = 0.033). In conclusion, our findings suggest that tailoring CD34+ cell dose by patient age may benefit acute leukemia patients undergoing allo-HCT, while XAI showcases excellent proficiency in revealing such interactions.

Second Allogeneic Hematopoietic Cell Transplantation Following Graft Failure in Children

Second Allogeneic Hematopoietic Cell Transplantation Following Graft Failure in Children

Donor Type Does Not Impact Late Graft Failure Following Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis.

Post-transplant cyclophosphamide (PTCy) is a commonly used graft-vs-host disease (GVHD) prophylaxis, particularly in the setting of haploidentical (haplo) hematopoietic cell transplantation (HCT). The rate of graft failure has been reported to be as high as 12% to 20% in haplo-HCT recipients using PTCy. The objective of this study was to determine whether donor type influenced the risk of late graft failure following reduced-intensity conditioning (RIC) HCT using PTCy-based GVHD prophylaxis. A retrospective cohort analysis using the Center for International Blood and Marrow Transplant Research (CIBMTR) database among adult patients who underwent first RIC haplo or 8/8 matched unrelated donor (MUD) HCT between 2011 and 2018 for acute myeloblastic leukemia (AML), acute lymphoblastic leukemia (ALL) or myelodysplastic syndrome (MDS) with PTCy GVHD prophylaxis. The primary outcome was incidence of late graft failure, defined as secondary graft loss in the absence of relapse or poor graft function requiring a cellular therapy intervention. A total of 1336 patients met the eligibility criteria (1151 haplo, 185 MUD). Patients in the MUD group were older (65 vs. 61 years), less ethnically diverse (95% vs. 72% White), received fewer bone marrow grafts (45% vs. 16%), and had younger donors (median age, 28 vs. 37 years old). Conditioning regimens were predominately fludarabine, cyclophosphamide, and total body irradiation (TBI; 87% haplo and 38% MUD). At 2 years, the adjusted probabilities of late graft failure for the haplo group was 6.5% (95% confidence interval [CI], 5.2-8.0) versus 5.9% (95% CI, 2.7%-10.9%) for the MUD group (P = .79). Multivariate analysis for risk factors associated with late graft failure found associations with a diagnosis of MDS (HR, 1.98; 95% CI, 1.22-3.20; P = .005), and earlier year of HCT (2015-2018 vs. 2011-2014; HR, 0.39; 95% CI, 0.24-0.64; P = .0002). A post-hoc sensitivity analysis was performed to evaluate the effect of donor age and use of peripheral blood stem cell (PBSC) grafts. Graft failure did not differ between haplo and MUD HCT (HR, 1.19; P = .67) when adjusted for donor age nor when restricted to PBSC grafts only (HR, 0.85; P = .70). In this registry-based analysis of patients undergoing RIC HCT for AML, ALL, or MDS using GVHD prophylaxis with PTCy, there was no significant difference in late graft failure rates between haplo and MUD donors. Overall rates of late graft failure were high.

Impact of Obesity on GVHD in Patients Undergoing Allogeneic Hematopoietic Cell Transplant for Hematologic Malignancies.

The relationship between obesity and graft-versus-host disease (GVHD) has been studied in both pre-clinical and clinical studies with varying results. We aimed to investigate the impact of obesity, as measured by body mass index (BMI), on the incidence, severity, and response to therapy of GVHD in a contemporary cohort. We conducted a retrospective study of patients undergoing allogeneic hematopoietic cell transplant (HCT) for acute myelogenous leukemia and myelodysplastic syndrome between January 2010 and December 2021 at the Cleveland Clinic. Incidence, grade, organ involvement, and response to therapy of acute and chronic GVHD were compared between patients with obesity (BMI ≥30) and without obesity. Secondary outcomes included relapse, non-relapse mortality (NRM), and overall survival (OS). 531 patients were identified, with a median follow-up of 19 months (range, 7-49). Mean (SD) BMI at time of HCT was 29.1 (6.3) kg/m2. There was no significant difference in demographic and HCT characteristics between patients with obesity (N=199) and without obesity (N=332). Development of any acute (42% vs. 43%) or chronic (29% vs. 30%) GVHD was similar in patients with and without obesity. Patients with obesity were less likely to have gastrointestinal involvement from chronic GVHD (28% vs. 48%, p=0.01). Skin (64% vs 56%), mouth (45% vs 35%) and eye (35% vs 27%) involvements were higher in patients with obesity, although statistically not significant. There were no significant differences in OS, NRM, or relapse. There were no significant differences in incidence of GVHD among patients with and without obesity. Additional studies are needed to further understand potential differences in organ involvement.

Non-selective b adrenergic receptor inhibitors impair hematopoietic regeneration in mice and humans after hematopoietic cell transplants.

Peripheral nerves promote mouse bone marrow regeneration by activating b2 and b3 adrenergic receptor signaling, raising the possibility that non-selective b blockers could inhibit engraftment after hematopoietic cell transplants (HCTs). We observed no effect of b blockers on steady-state mouse hematopoiesis. However, mice treated with a non-selective b blocker (carvedilol), but not a b1-selective inhibitor (metoprolol), exhibited impaired hematopoietic regeneration after syngeneic or allogeneic HCTs. At two institutions, patients who received non-selective, but not b1-selective, b blockers after allogeneic HCT exhibited delayed platelet engraftment and reduced survival. This was particularly observed in patients who received post-transplant chemotherapy for graft-versus-host disease prophylaxis, which also accentuated the inhibitory effect of carvedilol on engraftment in mice. In patients who received autologous HCTs, non-selective b blockers were associated with little or no delay in engraftment. The inhibitory effect of non-selective b blockers after allogeneic HCT was overcome by transplanting larger doses of hematopoietic cells.

FDA-approved therapies for chronic GVHD.

Despite novel prophylactic regimens, chronic graft-versus-host disease (cGVHD) remains a challenging complication after allogeneic hematopoietic cell transplantation. Chronic GVHD can affect multiple organs and reduces quality of life, and treatment can cause serious side effects. In the last ten years, the drugs ibrutinib, ruxolitinib, belumosudil and axatilimab were FDA-approved for cGVHD. Here we discuss which signaling pathways and cell types are targeted, the clinical studies that were the basis for FDA-approval, and future directions for clinical research.