Allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a curative therapeutic option for patients with high-risk hematologic malignancies. When a fully matched donor is unavailable, haploidentical hematopoietic stem cell transplantation (haplo-HCT) provides a viable alternative. Over time, haplo-HCT procedures have significantly evolved, improving outcomes in treatment related mortality (TRM), especially in graft-versus-host disease (GvHD). However, challenges such as delayed immune reconstitution and disease relapse persist. Advances in in vivo graft manipulation techniques, such as post-transplant cyclophosphamide (PTCy) and ex vivo approaches, including TCRα/β and CD19 depletion, have shown promise in reducing the risk of severe GvHD without increasing the relapse rates. Innovative strategies, such as haploidentical donor lymphocyte infusions, "suicide-switch" mechanisms, ORCA-Q product infusions, and CAR based therapies offer potential to further optimize outcomes. This review examines the graft manipulation modalities in the haplo-HCT setting, highlighting their role in advancing cellular therapies and providing new hope in the fight against life-threatening diseases.

Myelodysplastic syndromes/neoplasms (MDS) are a diverse group of clonal myeloid disorders. Advances in molecular technology lead to the development of new classification systems. However, large-scale epidemiological studies on MDS in Asian countries are currently scarce.

Data were retrospectively collected from 1,095 patients with primary MDS, Patients with prior chemotherapy, radiotherapy, or hematologic malignancies were excluded.

Patients with cryopreserved bone marrow (BM) samples were sequenced using the TruSight Myeloid Panel and HiSeq platform. KaplanMeier analysis was used to generate survival curves, with significance assessed via the log-rank test.

This analysis revealed significant changes in MDS subtypes, treatments, and prognoses over time, with more patients receiving hypomethylating agents (HMA) with and without venetoclax and allogeneic hematopoietic stem cell transplantation (HSCT) in recent years. Survival analysis revealed that both IPSS-R and IPSS-M did well stratified MDS patients and improved outcomes in the patients who underwent HSCT. Although the number of patients was limited in current study, combination therapy with HMA and venetoclax resulted in improved treatment responses and a higher rate of successful bridging to HSCT. These findings underscore the need for further large-scale studies to investigate the impact of combination treatment on MDS patients undergoing transplantation.

The use of post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis in severe aplastic anemia (SAA) remains understudied, particularly beyond haploidentical transplants. We analyzed outcomes of SAA patients who underwent stem cell transplantation (SCT) with PTCy from haploidentical donors (n = 209), HLA-matched sibling donors (MSD, n = 70), and unrelated donors (UD, n = 69) using EBMT data from 2010 to 2022. Median age was 22 years, and median time to transplantation was 8.6 months. For haploidentical, MSD, and UD cohorts, the 100-day cumulative incidence of grade II-IV acute GVHD was 19%, 11%, and 14% (p = 0.15), while grade III-IV was 6%, 3%, and 2% (p = 0.1). Two-year chronic and extensive chronic GVHD were 14%, 13%, and 14% (p = 0.1) and 5%, 6%, and 2% (p = 0.5), respectively. Non-relapse mortality at two years was 24% for haploidentical, 7% for MSD, and 10% for UD (p = 0.003). Two-year overall survival (OS) and GVHD- and relapse-free survival were 66% and 54% for haploidentical, 92% and 70% for MSD, and 81% and 66% for UD (p < 0.001, p = 0.06). In multivariable analysis, MSD and UD were associated with superior OS and GRFS compared to haploidentical. PTCy is safe and effective in SAA patients, though haploidentical SCT had higher NRM, leading to lower survival.

High-dose posttransplantation cyclophosphamide (HD-PTCy), given at 50 mg/kg/day on days +3/+4, is a standard-of-care graft-versus-host disease (GVHD) prophylaxis for allogeneic hematopoietic cell transplantation (HCT). Our murine MHC-haploidentical HCT studies suggested intermediate-dose PTCy produces superior GVHD control compared with HD-PTCy and PTCy is maximally effective on day +4. We conducted a single-institutional prospective phase 1/2 trial to reduce PTCy dosing to 25 mg/kg/day on days +3/+4 or on day +4 only for myeloablative HLA-haploidentical bone marrow HCT using PTCy, sirolimus, and mycophenolate mofetil. Among 35 patients, 89% were ethnic/racial minorities, 46% had high/very-high-risk disease, and median comorbidity score was 3. The phase 1 dose-limiting-toxicity, grade III-IV acute GVHD, was not observed after either reduced-PTCy dose level. PTCy 25 mg/kg/day on days +3/+4 (intermediate-dose (ID)-PTCy; n = 23), the phase 2 dose, resulted in no grade II-IV acute GVHD; 2-year cumulative incidences of chronic GVHD requiring systemic immunosuppression, nonrelapse mortality, and relapse were 13%, 17%, and 22%, and 2-year overall survival, disease-free survival, and GVHD-free/relapse-free survival were 61%, 61%, and 52%. In exploratory analysis compared with HD-PTCy (n = 5), ID-PTCy resulted in significantly faster engraftment and T-cell reconstitution, fewer transfusions, less mucositis, and reduced severity of BK-virus-associated cystitis/urethritis; area-under-the-curve exposure of 4-hydroxycyclophosphamide (4HCY), a key cyclophosphamide metabolite, correlated with these outcomes but not with chronic GVHD occurrence. Ideal-body-weight-based PTCy dosing best approximated 4HCY exposure. ID-PTCy is effective and has apparent clinical benefits compared with HD-PTCy. Before broader implementation, further studies are needed to confirm these findings and define optimal PTCy dosing across various donor/graft types. This trial was registered at www.clinicaltrials.gov as #NCT03983850.

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a serious complication following allogeneic hematopoietic cell transplantation (HCT). Although post-transplant cyclophosphamide (PTCy) is increasingly used for graft-versus-host disease prophylaxis, data on its impact in the context of SOS/VOD remain limited.

This study aimed to assess the incidence, clinical characteristics, prognostic factors, treatment approaches, and outcomes of SOS/VOD in HCT recipients receiving GVHD prophylaxis with PTCY, sirolimus or tacrolimus, and mycophenolate mofetil (MMF) across all donor types.

This single-center observational study included all 532 consecutive adults who underwent HCT with PTCy between January 2017 and February 2024. Patient demographics, transplant procedures, toxicities, and complications were prospectively collected. Clinical charts were reviewed as needed to address inconsistencies or missing information.

Myeloablative conditioning was administered to 96% of recipients, who received grafts from matched sibling donors (MSD, 36%), matched unrelated donors (MUD, 34%), haploidentical donors (26%), or mismatched unrelated donors (MMUD, 4%). SOS/VOD was diagnosed in 35 patients and classified according to EBMT criteria as probable (n=10), clinical (n=23), or proven (n=2). Classical SOS/VOD occurred in 21 patients (60%), while 14 (40%) had late-onset disease. EBMT severity grading showed 3% mild, 20% moderate, 37% severe, and 40% very severe cases. The 100-day cumulative incidence was 6.6% (95% CI:4.7-8.9). Multivariable analysis identified prior transplantation, prior antibody-drug conjugates and higher CD3+ cell dose as risk factors. Patients with very severe or severe SOS/VOD (based on clinical features but not those upgraded solely due to the presence of risk factors) received defibrotide. Four patients (11.4%) died from SOS/VOD; all classified as very severe, and three of them had undergone prior transplantation (two autologous, one allogeneic). Despite high severity, SOS/VOD analyzed as a time-dependent variable showed no association with overall survival or non-relapse mortality.

SOS/VOD remains a challenging but clinically manageable complication with a modest incidence following HCT with PTCy. Although many cases were classified as severe or very severe, the associated mortality rate was relatively low. The identification of key risk factors, such as prior transplantation, antibody-drug conjugate exposure, and higher CD3⁺ cell doses, along with the notable proportion of late-onset cases, underscores the need for vigilant monitoring and individualized management strategies.

Acute myeloid leukemia (AML) presents a significant global health challenge due to its aggressive behavior and mortality rates. Traditionally, AML treatment has relied on intensive chemotherapy-anthracyclines and cytarabine. However, recent breakthroughs in targeted therapies are transforming clinical practices. This review examines current treatment strategies, including breakthrough therapies. Also, a global perspective on AML management includes the disparity in treatment availability, particularly the difficulties faced by low- and middle-income countries due to the high cost and restricted access to novel therapies.

Post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis is now being used beyond haploidentical (HID) allogeneic hematopoietic cell transplant (alloHCT). However, the kinetics of chimerism in patients receiving PTCy and its impact on post-transplant relapse is unknown. In this study we describe the kinetics of donor chimerism in patients receiving PTCy, factors predisposing to mixed donor chimerism, and the associated survival outcomes.

Patients undergoing alloHCT at Mayo Clinic, Rochester, from January 2018 to June 2023 were included in the study. Full donor chimerism was defined as donor cell fraction ≥95%, and mixed chimerism as donor cell fraction <95%. Analysis of covariance was used to assess the trend of tacrolimus levels in patients with mixed vs. full donor CD3 chimerism. Relapse-free survival (RFS) and overall survival (OS) from transplant were determined using the Kaplan-Meier method. Mixed donor chimerism was considered a time-dependent covariate in multivariate analysis.

A total of 500 patients were evaluated. A total of 189 (37.8%) patients received myeloablative conditioning (MAC); 27 (14.3%) of whom received PTCy and 162 (85.7%) received methotrexate (MTX) for GVHD prophylaxis. Among patients receiving PTCy, HID and mismatched donor transplants were significantly associated with a lower risk of mixed CD3 chimerism. In patients receiving PTCy, myeloablative busulfan/fludarabine (BuFlu), compared to non-busulfan MAC regimens, was associated with an increased risk of day +90 mixed chimerism (OR 10.47, P=0.02). However, reduced intensity (RIC) BuFlu was not associated with an increased risk of mixed CD3 chimerism (OR 0.71, P=0.7). Among patients receiving MAC and PTCy, those with high tacrolimus levels (≥11 mcg/ml) beyond the 2nd week post-transplant period were more likely to have mixed CD3 chimerism (F1,145 = 4.15, P=0.043). In patients receiving MAC and PTCy, day +90 mixed CD3 chimerism was associated with an inferior RFS (1-year RFS: 89.16% vs. 40.0%, P = 0.009). Multivariate analysis showed that mixed donor CD3 chimerism was associated with an inferior RFS in patients receiving MAC and PTCy (HR 6.53, 95% CI 1.18 - 36.15, P=0.032).

Among patients receiving MAC and PTCy, detection of mixed donor CD3 chimerism at any timepoint after transplant portends an inferior RFS. A high tacrolimus level beyond 2nd week of transplant in this subset of patients was associated with mixed CD3 chimerism. The detection of mixed CD3 chimerism provides an opportunity to implement strategies that may help in decreasing the risk of relapse in this subset of patients.

Despite recent advances in graft-versus-host disease (GVHD) prophylaxis, novel approaches to effective prevention of chronic GVHD (cGVHD) remain of high importance. In this prospective, multicenter, phase 2 trial, ruxolitinib, an oral inhibitor of Janus kinase (JAK) 1 and 2, was administered as maintenance therapy after reduced-intensity allogeneic hematopoietic cell transplantation (HCT). GVHD prophylaxis consisted of tacrolimus and methotrexate. Ruxolitinib began between day +30 to 100 and was administered continuously in 28-day cycles for up to 24 cycles. Seventy-eight participants were enrolled before HCT; 63 participants received the intervention. The median start date of ruxolitinib after HCT was day +45. The most common grade ≥3 adverse events were neutropenia, thrombocytopenia, and anemia. Seven participants experienced grade ≥3 infectious events. GVHD-free, relapse-free survival at 1 year after HCT, the primary end point, was 70%. Grade 3 to 4 acute GVHD at 6 months was 4.8%, and moderate-severe cGVHD at 2 years was 16%. cGVHD requiring systemic therapy was 9.5% at 1 year and 13% at 2 years. Overall survival and progression-free survival at 2 years were 76% and 68%, respectively. Prolonged administration of ruxolitinib following HCT is associated with low rates of clinically significant cGVHD. The incorporation of JAK inhibition into GVHD prevention approaches warrants further investigation. This trial was registered at www.clinicaltrials.gov as #NCT03286530.

Whether one or two agents added to post-transplant cyclophosphamide (PTCy) are needed in HLA-matched allogeneic hematopoietic stem cell transplantation (allo-HSCT) with peripheral blood stem cells (PBSC) is debated. We retrospectively compared PTCy in association with a calcineurin inhibitor (PTCy+CNI) or with a CNI plus mycophenolate mofetil (PTCy+CNI+MMF) in adult patients transplanted for acute myeloid leukemia in first complete remission and receiving PBSC in the period from 2010 to 2020. Propensity score matching was performed using exact matching for donor type (related or unrelated) and the nearest neighbor for other variables (i.e. age, adverse cytogenetics, Karnofsky performance status, patient and donor cytomegalovirus serology, conditioning intensity). Each group comprised 146 patients, with 63% in total undergoing matched unrelated-allo-HSCT. Median follow up was longer for PTCy+CNI (36 [IQR 31-39] months versus 25 [IQR 19-30] months for PTCy+CNI+MMF, p < 0.01). At 2 years, PTCy+CNI was associated with a higher incidence of extensive chronic GVHD (16% [95% CI 10-22] versus 6% [95% CI 3-12] for PTCy+CNI+MMF, p < 0.03) while no differences were observed for all the other transplant outcomes. Addition of MMF to PTCy and CNI may help to prevent extensive chronic GVHD in HLA-matched allo-HSCT with PBSC.

Hematopoietic progenitor cell transplantation was the first form of cell therapy to be developed [...].

Haploidentical allogeneic hematopoietic cell transplantation (haplo-HCT) using post-transplant cyclophosphamide (PTCY) has become a standard approach for patients lacking HLA-matched donors. While effective in reducing graft-versus-host disease (GVHD), concerns about PTCY-associated cardiovascular toxicity remain. This study investigates the incidence, predictors, and impact of early cardiac events (ECE) in haplo-HCT recipients.

We conducted a retrospective, multicenter analysis of 268 patients with acute myeloid leukemia (AML) treated with anthracycline-based induction regimens and undergoing their first haplo-HCT with PTCY (50 mg/kg/day on days +3 and +4) between 2011 and 2022. ECEs, defined as any new cardiac event within 100 days post-transplant, were analyzed using cumulative incidence functions considering death and relapse as competing risks. Risk factors and the impact on non-relapse mortality (NRM) and overall survival (OS) were assessed via univariate and multivariate regression models.

The median patient age was 57 years (range: 18-79), and pre-transplant comorbidities included hypertension (22.4%), dyslipidemia (13.1%), diabetes mellitus (6.7%), and prior cardiac history (14.2%). ECEs occurred in 23 patients (8.6%) at a median of 19 days post-transplant (IQR: 5-66), with a day +100 cumulative incidence of 8.6% (95% CI: 6.1-12.3). The most frequent complications were pericardial effusion/pericarditis (43.5%), arrhythmias (30.4%), and heart failure (17.4%). Severe ECEs (CTCAE grade 3-4) were observed in 30.4% of cases, and four deaths (17.4%) were directly attributed to ECEs. Univariate analysis identified dyslipidemia (HR: 3.87, p=0.001), hypertension (HR: 2.76, p=0.015), and moderate-severe veno-occlusive disease (HR: 4.94, p=0.002) as significant predictors of ECE. ECEs were associated with lower OS (HR: 1.78, p=0.04) and higher NRM (HR: 2.87, p=0.005).

While the incidence of ECEs following haplo-HCT with PTCY was relatively low, their occurrence significantly worsened transplant outcomes. These findings underscore the importance of cardiovascular risk assessment and structured cardiac monitoring to mitigate complications in haplo-HCT recipients.

Fludarabine and melphalan (FM) conditioning offers effective disease control with an acceptable toxicity profile. Post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis has improved transplant outcomes. We retrospectively reviewed patients receiving FM-based transplants with PTCy at City of Hope. Of 248 patients included, 89 (35.9%) received hematopoietic cell transplant (HCT) from a matched related/unrelated donor (MRD/MUD), 118 (47.6%) from a haploidentical (HID) donor, and 49 (19.8%) from a mismatched unrelated donor (MMUD). There were no differences in acute and chronic GVHD based on donor type. The 2-year overall survival (OS) for patients receiving HID, MMUD, and MRD/MUD was 58%, 55%, and 70%; disease-free survival (DFS) was 52%, 48%, and 66%; and graft-versus-host/relapse-free survival (GRFS) were 48%, 40%, and 59%, respectively. OS, DFS, and GRFS were similar regardless of donor type on multivariable analysis. However, donor age ≥35 years was associated with lower OS and GRFS and higher 2-year non-relapse mortality (NRM) on multivariable analysis across all patients, regardless of donor type. FM with PTCy appears to produce similar outcomes between MRD/MUD, MMUD, and HID when adjusting for donors <35 years, and donor age seems to be the most important factor when selecting a donor with this regimen.

This meta-analysis assesses the efficacy of TCRαβ+/CD19+ depleted hematopoietic stem cell transplantation (HSCT) in pediatric patients with hematological malignancies, bridging the gap in the heterogeneous results of published studies. We analyzed post-HSCT complications and survival outcomes in 1068 children across 14 studies, using both aggregated and patient-level data from acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) and acute lymphoblastic leukemia (ALL) studies, employing the IPDfromKM technique for time-to-event data reconstruction. The analysis reveals a 95 % engraftment success rate (95 % CI: 93-97) and 6-year overall survival and disease-free survival (DFS) rates of 67.2 % and 66.3 %, respectively, with no significant differences in DFS between haploidentical and unrelated donors (hazard ratio = 0.9, 95 % CI: 0.53-1.55). Acute graft-versus-host disease (GvHD) grades III-IV and chronic GvHD incidences were 8 % (95 % CI: 6-11) and 17 % (95 % CI: 10-27). The relapse rate was 27 % (95 % CI: 21-33), with relapse-related mortality at 21 % (95 % CI: 15-28) and HSCT-related mortality at 12 % (95 % CI: 7-19). Relapse was significantly lower in patients (mostly ALL) receiving total body irradiation (risk ratio = 0.53, P = 0.04). These findings underscore TCRαβ/CD19-depleted HSCT as a valuable option for patients without HLA-matched donors, highlighting the need for larger, multicenter studies.

Prevention of graft-versus-host disease (GVHD) is critical to successful allogeneic hematopoietic cell transplantation (HCT), but for many years was difficult to achieve. Advances in the understanding of allogeneic HCT biology and immunology have paved the way for novel clinical approaches to GVHD prophylaxis, highlighted by the broad adoption of posttransplant cyclophosphamide and the approval of abatacept by the US Food and Drug Administration to prevent acute GVHD. Patients undergoing allogeneic HCT are now experiencing severe acute GVHD at historically low rates, and significant improvements in preventing chronic GVHD are also being achieved. This review highlights key pharmacological approaches and graft manipulation strategies being used or investigated for GVHD prophylaxis. Furthermore, we discuss the ongoing unmet needs in GVHD prevention and the challenges in addressing these areas in future clinical trials.

Posttransplant high-dose cyclophosphamide (PTCy) is effective in overcoming the negative impact of HLA disparity in the haploidentical setting. In light of these results, we investigated the efficacy of PTCy, in improving clinical outcomes of hematopoietic stem cell transplantation (HSCT) from a mismatched unrelated donor (MMUD) in patients with acute myeloid malignancies by reducing the incidence and severity of acute graft-versus-host disease (aGVHD). A prospective, single-arm, phase 2 study (PHYLOS) was conducted by the Gruppo Italiano Trapianto di Midollo Osseo. The ethical committees of the participating centers approved the study (EURODRACT 2017-003530-85). A total of 77 consecutive patients (acute myeloid leukemia: 64; myelodysplastic syndrome: 13) were enrolled at 26 Italian transplant centers (January 2020-November 2022). Median age of the patients was 53 (range, 19-65) years. The 100-day cumulative incidence of grades 2 to 4 aGVHD was 18.2% (95% CI, 10.6-27.6) and of grades 3 to 4 was 6.5% (95% CI, 3.1-15.1). Seventy-one patients (92%) had full-donor chimerism with complete neutrophil engraftment by day +30. One-year cumulative incidence of chronic GVHD was 13.4% (95% CI, 6.9-22.1). One-year cumulative incidence of nonrelapse mortality was 9.1% (95% CI, 4.0-16.9), and the relapse rate was 23.8% (95% CI, 14.9-33.9). One-year overall survival and graft relapse-free survival were 78.6% (95% CI, 67.4-86.3) and 55.3% (95% CI, 43.4-65.7), respectively. Our study in a homogeneous patient cohort suggests that PTCy leads to a low rate of aGVHD and improves clinical outcomes of HSCT from MMUD. This trial was registered at www.clinicaltrials.gov as #NCT03270748.

Bone marrow transplantation is considered a cornerstone in the treatment of hematologic malignancies and blood disorders. While it may offer the possibility of a cure through the use of high-dose chemotherapy and radiation, outcomes are significantly impacted by biological and medical factors. Herein, aging is associated with reduced hematopoiesis, immune function, and overall regenerative capacity of tissues. Growth arrest, a crucial property of cellular senescence, inhibits bone marrow function, lowers immune surveillance in aged adults, and reduces the efficiency of bone marrow transplantation. The clinical course for older recipients is further complicated by the presence of prolonged immunosuppression, slower recovery, and higher complication rates, including life-threatening graft-versus-host disease. Accordingly, there is increasing interest in explaining how aging, cellular senescence, and transplant outcomes are interrelated. The current chapter outlines the mechanisms whereby aging and senescence contribute to the immunological dysregulation and poor bone marrow transplantation outcomes observed in elderly cancer patients. The authors' goal is to suggest therapeutic approaches that will enhance the quality of life and survival rates of elderly bone marrow transplant recipients.

Background: T-prolymphocytic leukemia (T-PLL) is a rare lymphoid neoplasm with particularly poor prognosis. Although it is no longer recognized as a distinct entity by the World Health Organization (WHO), B-prolymphocytic leukemia (B-PLL) comprises conditions with unfavorable outcomes. Both diseases most frequently affect patients in the seventh decade of their lives. Allogeneic hematopoietic stem cell transplantation (alloHSCT) significantly improves outcomes for selected PLL cases, as shown by several, mostly retrospective, analyses. Methods: In this article, we provide a review of existing PLL analyses, followed by a summary of cases treated at our center. We describe outcomes of six T-PLL and three B-PLL cases receiving alloHSCT at our institution between 2015 and 2022. Results: Despite a post-transplant 4-year cumulative relapse incidence of 61% in our T-PLL series, the median OS was 78 months, because relapse therapy was remarkably successful. All B-PLL patients are alive and relapse-free, with a median follow-up of 54 (range of 11-74) months. A poor pre-transplant Karnofsky performance status (KPS) (≤ 80%) and an HCT comorbidity index (HCT-CI) of ≥3 were significantly associated with post-transplant mortality. Conclusions: The comparatively favorable outcomes in our case series underline the increasing value of alloHSCT in PLL in the current era, as it offers a prospect of cure in selected patients with otherwise very poor prognosis.

Over the last decades, the donor network for hematopoietic cell transplantation (HCT) has grown exponentially, including unrelated and haploidentical (Haplo) donors. This study aimed to describe HCT outcomes with MSD, Haplo, and matched unrelated donors (MUD) in an early period of Haplo with posttransplant cyclophosphamide in a developing country with a large unrelated donor registry.

This study was conducted in collaboration with the CIBMTR. We included patients with acute leukemias undergoing HCT between 2014-2018.

With 595 patients, 2-year overall survival (OS) was 69% for the MSD, 65% for the Haplo, and 71% for MUD (p=0.24) in CR1, confirmed in multivariable analysis. Relapse rate was lower for MUD (HR=0.35, p=0.0005) than MSD in patients with CR2+, leading to higher OS. Relapse was also higher with Haplo compared with MUD (HR=2.06, p=0.03).

Only survival bias can explain these findings in CR2+, suggesting some high-risk MUD patients, in which HCT timing is crucial, may not achieve HCT. Alternative donors were associated with higher non-relapse mortality, while PTCy-based Haplo offered the best protection against chronic graft-versus-host disease. Our study suggests Haplo and MUD are acceptable options for patients lacking MSD in developing countries like ours.

In recent years, treatments in the field of hematologic malignancies have undergone significant evolution; allogeneic hematopoietic stem cell transplantation (allo-HSCT) has shifted from an "ultimate" therapy to becoming a component of a comprehensive therapeutic strategy for acute myeloid leukemia (AML). Advances in risk stratification (including molecular profiling and measurable residual disease assessment), conditioning regimens, and graft-versus-host disease (GVHD) prophylaxis-such as post-transplant cyclophosphamide-have improved outcomes and expanded donor selection and transplant eligibility. We should not only focus on the transplantation procedure but also consider various therapeutic components, including chemotherapy, targeted therapy (possibly including chimeric antigen receptor T-cell therapy), and post-transplant maintenance therapy, which need to be orchestrated within the broader context of leukemia treatment. In this review, we summarized key developments in allo-HSCT for AML and aim to "decipher" each component of transplantation.

Post-transplant cyclophosphamide (PT-CY) has been pivotal in controlling graft-versus-host disease (GvHD) following T-cell-replete haploidentical bone marrow transplantation (haplo-BMT). However, the widely adopted regimen is associated with high relapse rates, particularly in patients without GvHD. Our preclinical studies indicate that pre- or post-transplant bendamustine (PT-BEN) may reduce GvHD, enhance graft-versus-leukemia (GvL) effects, and induce significant alterations in the proportion, phenotype, and function of various immune cell subsets.

We initiated a Phase Ia/Ib, single-center trial with a standard 3 + 3 dose-escalation design, sequentially replacing post-transplant (PT)-CY with BEN (PT-CY/BEN). Multi-parameter flow cytometry and TCR β sequencing of genomic DNA was performed on isolated PBMCs on PT days +30, +60, +100, +180, and +365.

Overall, the PT-CY/BEN (n=14) regimen was associated with earlier neutrophil and platelet engraftment, reduced transfusion requirements, and comparable clinical outcomes to PT-CY (n=10), including survival and relapse rates. PT-CY/BEN patients exhibited distinct immune reconstitution patterns, characterized by earlier CD4+ T-cell recovery, impaired CD8+ T-cell engraftment, and reduced NK-cell counts. Notably there were no significant changes in B-cells, Tregs, or MDSCs. Enhanced T-cell repertoire diversity in the PT-CY/BEN cohort was associated with improved CMV control.

Our Phase Ia findings demonstrate the well-tolerability of PT-CY/BEN and its association with early engraftment, a more diverse T-cell repertoire, and earlier CD4+ T-cell reconstitution. Future studies are warranted to confirm our findings and investigate potential additional benefits of PT-CY/BEN over PT-CY alone.

Diabetic nephropathy (DN) is a prevalent complication of diabetes, with current treatment options offering limited effectiveness, particularly in advanced stages. Human pluripotent stem cells (hPSCs), particularly induced PSCs (iPSCs), show promising potential in the treatment of DN due to their pluripotency, capacity for differentiation into kidney-specific cells, and suitability for personalized therapies. iPSC-based personalized approaches can effectively mitigate immune rejection, a common challenge with allogeneic transplants, thus enhancing therapeutic outcomes. Clustered regularly interspaced short palindromic repeats (CRISPR) gene editing further enhances the potential of hPSCs by enabling the precise correction of disease-associated genetic defects, increasing both the safety and efficacy of therapeutic cells. In addition to direct treatment, hPSCs have proven valuable in disease modeling and drug screening, particularly for identifying and validating disease-specific targets. Kidney organoids derived from hPSCs replicate key features of DN pathology, making them useful platforms for validating therapeutic targets and assessing drug efficacy. Comparatively, both hPSCs and mesenchymal SCs (MSCs) have shown promise in improving renal function in preclinical models, with hPSCs offering broader differentiation capacity. Integration with tissue engineering technologies, such as three-dimensional bioprinting and bioengineered scaffolds, expands the regenerative potential of hPSCs by supporting the formation of functional renal structures and enhancing in vivo integration and regenerative capacity. Despite current challenges, such as tumorigenicity, genomic instability, and limited direct research, advances in gene editing, differentiation protocols, and tissue engineering promise to address these barriers. Continued optimization of these approaches will likely lead to successful clinical applications of hPSCs, potentially revolutionizing treatment options for DN.

The effects of donor characteristics on outcomes after T-cell-replete (TCR) haploidentical donor peripheral blood stem cell transplantation (PBSCT) with post-transplant cyclophosphamide (PTCy) or low-dose antithymocyte globulin (ATG) remain unclear. We evaluated the impact in 1,677 patients who received a PTCy protocol (PTCy-haplo; n = 1,107) or low-dose ATG protocol (ATG-haplo; n = 570). A low CD34+ cell dose (<4 ×106/kg) was the only donor characteristic associated with worse overall survival (OS) after PTCy-haplo (adjusted hazard ratios [aHR] = 1.49, P = 0.008), whereas increasing donor age by decade (aHR = 1.12, P = 0.008) and human leukocyte antigen 2-3 antigen mismatches (aHR = 1.46, P = 0.010), compared to HLA 0-1 antigen mismatches, were associated with worse OS after ATG-haplo. Increasing donor age was associated with a high risk of grade III-IV acute GVHD both after PTCy-haplo (HR: 1.32, P = 0.009) and ATG-haplo (HR: 1.22, P = 0.006). Offspring donors had better relapse-free survival and GVHD-free relapse-free survival than sibling donors after ATG-haplo. Our data highlights the donor characteristics associated with improved transplant outcomes after TCR haploidentical donor PBSCT with PTCy or low-dose ATG.

Although post-transplant cyclophosphamide (PTCY)-based prophylaxis has become a widely adopted strategy for preventing graft-versus-host disease (GVHD) in 9 out of 10 HLA-mismatched unrelated donors (MMUDs), allogeneic hematopoietic cell transplants (allo-HCTs), data on the safety and efficacy of PTCY in this setting remain limited. This single-center study investigates the outcomes of 94 adults with hematological malignancies undergoing MMUD allo-HCT with PTCY and tacrolimus (Tac) (PTCY-Tac) between 2014 and 2023. The median age was 53 years, and 60.6% were male. Peripheral blood stem cells were infused in all cases. By Day +100, the cumulative incidence of Grades II-IV and Grades III and IV acute GVHD were 33.0% and 9.7%, with 2-year incidence of moderate-to-severe chronic GVHD at 12.6%. By Day +30, 40.8% of patients experienced bacterial bloodstream infections, and 52.4% had cytomegalovirus (CMV) reactivation before letermovir prophylaxis. With letermovir's introduction, CMV reactivation rates dropped significantly, with only one case reported. At 3 years, overall survival was 60.8%, non-relapse mortality was 23%, and the cumulative incidence of relapse was 24.5%. HLA Class I or II mismatches did not affect key outcomes or GVHD rates. These findings demonstrate that PTCY-Tac offers effective GVHD prevention and favorable outcomes in MMUD allo-HCT, supporting its application for patients without fully matched donors.

Acute myeloid leukemia (AML)-specific target antigens are difficult to identify. Here we demonstrate that HLA-DRB1 can serve as a leukemia-specific target of chimeric antigen receptor (CAR) T cells in patients with AML after allogeneic hematopoietic stem cell transplantation (allo-HCT). We identified KG2032 as a monoclonal antibody specifically bound to AML cells in about half of patients, but not to normal leukocytes other than B lymphocytes. KG2032 reacted with a subset of HLA-DRB1 molecules, specifically those in which the 86th amino acid was not aspartic acid. KG2032 reacted minimally with nonhematopoietic tissues. These results indicate that KG2032 reactivity is highly specific for AML cells in patients who carry KG2032-reactive HLA-DRB1 alleles and who received allo-HCT from a donor carrying KG2032-nonreactive HLA-DRB1 alleles. KG2032-derived CAR T or natural killer cells showed significant anti-leukemic activity in preclinical models in female mice, suggesting that they may cure patients with AML who are incurable with allo-HCT.

Haploidentical allogeneic hematopoietic cell transplant recipients (allo-HCTr) receiving posttransplant cyclophosphamide (haplo-PTCy) are at higher risk for infectious complications, including viral infections.

We performed a retrospective, single-center, propensity-score matched-pair study including adult haplo-PTCy and allo-HCTr from human leukocyte antigen (HLA)-matched donors, undergoing transplantation in our institution between 2016 and 2022. For each patient, 4 blood samples (day [D] 0, D30, D90, and D180 posttransplantation) were extracted from the biobank and tested with metagenomic next-generation sequencing (mNGS) to describe the blood virome and identify viral RNA/DNA signatures potentially unrecognized by routinely available tests. Routine and symptom-driven polymerase chain reaction (PCR) test results performed during the study period were reviewed.

Twenty-five matched pairs of haplo-PTCy and HLA-matched allo-HCTr were included in the analysis. Plasma mNGS detected a total of 155 and 190 different viral RNA/DNA signatures in haplo-PTCy and HLA-matched allo-HCTr, respectively between D0 and D180. The number of viral signatures was significantly lower in the haplo-PTCy group compared to HLA-matched allo-HCTr at D90 (-1.0 [95% confidence interval {CI}, -1.7 to -.3]; P = .01) and during the period between D30 and D180 (-1.9 [95% CI, -3.3 to -.5]; P = .01). Certain viral species (Anelloviridae, Epstein-Barr virus) were more prevalent in HLA-matched patients. Symptom-driven PCR tests showed higher infection rates of usual viral pathogens in haplo-PTCy versus HLA-matched allo-HCTr (P = .02).

Frequently deployed, targeted PCR tests showed increased viral infection prevalence in haplo-PTCy patients. Conversely, mNGS testing applied at specific timepoints revealed a lower number of commensal viruses in this patient group. More studies on routine use of mNGS are needed to further assess its clinical relevance and value.