Factors Influencing Life Space Mobility in Cancer Survivors Following Hematopoietic Stem Cell Transplantation - Physical Function, Depression, Fatigue, Neighborhood Walkability, and Employment Status.

BACKGROUND/OBJECTIVE: The level of physical activity in the daily lives of cancer survivors following hematopoietic stem cell transplantation (HSCT) is crucial for maintaining their physical and mental health. Considering that life space mobility (LSM) may limit physical activity, maintaining and expanding LSM is particularly essential for post-HSCT survivors. This study aimed to identify factors influencing LSM in post-HSCT survivors. METHODS: Thirty cancer survivors after HSCT (14 women, mean age 52.0 ± 12.3 years, 196-3017 days post-HSCT) were included in this cross-sectional study. The assessment encompassed patient characteristics, employment status, life space (Life Space Assessment; LSA), physical function (handgrip strength, isometric knee extension strength, 5 chair standing test, walking speed), depression (Self-rating Depression Scale; SDS), fatigue (Cancer Fatigue Scale), and neighborhood walkability (Walk Score®). The association between LSA and each factor was compared by correlation analysis. Subsequently, multiple regression analysis was conducted, with LSA as the dependent variable and independent variables being outcome measures exhibiting a significant correlation with LSA. RESULTS: Variables significantly correlated with LSA included SDS (r =-0.65, p < .01), employment status (r=-0.60, p < .01), handgrip strength (r = 0.43, p = .02), and isometric knee extension strength (r = 0.40, p = .03). Results of multiple regression analysis show that SDS (ß = -0.53, p < .01), employment status (ß = 0.48, p < .01), and isometric knee extension strength (ß = 0.27, p = .02) were significantly associated with LSA (R2 = 0.74). CONCLUSION: Depression, employment status, and isometric knee extension strength were identified as factors related to LSM in post-HSCT survivors.

Living Donor Lung Transplantation After Hematopoietic Stem Cell Transplantation From the Same Donor: A Risk Worth Taking.

Living donor (LD) lung transplantation (LT) represents an exceptional procedure in Western countries. However, in selected situations, it could be a source of unique advantages, besides addressing organ shortage. We report a successful case of father-to-child single-lobe LT, because of the complications of hematopoietic stem cell transplantation from the same donor, with initial low-dose immunosuppressive therapy and subsequent early discontinuation. Full donor chimerism was hypothesized to be a mechanism of transplant tolerance, and this postulated immunological benefit was deemed to outweigh the risks of living donation and the possible drawbacks of single compared with bilateral LT. Favorable size matching and donor's anatomy, accurate surgical planning, and specific expertise in pediatric transplantation also contributed to the optimal recipient and donor outcomes. Ten months after LD LT, the patient's steadily good lung function after withdrawal of immunosuppressive therapy seems to confirm the original hypothesis.

Impact of prophylactic echinocandin on the development of neurological complications in patients receiving busulfan-containing conditioning regimens for stem cell transplantation: A single-center retrospective study.

BACKGROUND: Although neurotoxicity is a major adverse event associated with busulfan, little information is available regarding the association between drug interactions and neurological symptoms during busulfan-based regimens. This study evaluated the association between prophylactic echinocandins and neurological complications in patients receiving busulfan-containing conditioning regimens for stem cell transplantation. METHODS: We retrospectively included consecutive patients who administered intravenous busulfan as a conditioning regimen at our facility between 2007 and 2022. Prophylactic echinocandin use was defined as the use of an echinocandin antifungal drug to prevent invasive fungal disease in SCT recipients. The primary outcome was the incidence of neurological complications within 7 days of busulfan initiation and was compared between the echinocandin group (patients received prophylactic echinocandin) and nonechinocandin group (patients received prophylactic antifungal drugs other than echinocandin and those without antifungal prophylaxis). RESULTS: Among the 59 patients included in this study, the incidence of neurological complications in the echinocandin (n = 26) and nonechinocandin groups (n = 33) was 30.8% and 63.6%, respectively. We observed a negative association between prophylactic echinocandin use and the development of neurological complications after adjusting for the propensity score for receiving prophylactic echinocandins (adjusted odds ratio 0.294, 95% confidence interval 0.090 to 0.959). We observed a lower incidence of neurological complications in the echinocandin group than in the nonechinocandin group. CONCLUSION: Our results suggested that the choice of antifungal prophylaxis is associated with busulfan neurotoxicity.

Innovations in conditioning and post-transplant maintenance in AML: genomically informed revelations on the graft-versus-leukemia effect.

Acute Myeloid Leukemia (AML) is the prototype of cancer genomics as it was the first published cancer genome. Large-scale next generation/massively parallel sequencing efforts have identified recurrent alterations that inform prognosis and have guided the development of targeted therapies. Despite changes in the frontline and relapsed standard of care stemming from the success of small molecules targeting FLT3, IDH1/2, and apoptotic pathways, allogeneic stem cell transplantation (alloHSCT) and the resulting graft-versus-leukemia (GVL) effect remains the only curative path for most patients. Advances in conditioning regimens, graft-vs-host disease prophylaxis, anti-infective agents, and supportive care have made this modality feasible, reducing transplant related mortality even among patients with advanced age or medical comorbidities. As such, relapse has emerged now as the most common cause of transplant failure. Relapse may occur after alloHSCT because residual disease clones persist after transplant, and develop immune escape from GVL, or such clones may proliferate rapidly early after alloHSCT, and outpace donor immune reconstitution, leading to relapse before any GVL effect could set in. To address this issue, genomically informed therapies are increasingly being incorporated into pre-transplant conditioning, or as post-transplant maintenance or pre-emptive therapy in the setting of mixed/falling donor chimerism or persistent detectable measurable residual disease (MRD). There is an urgent need to better understand how these emerging therapies modulate the two sides of the GVHD vs. GVL coin: 1) how molecularly or immunologically targeted therapies affect engraftment, GVHD potential, and function of the donor graft and 2) how these therapies affect the immunogenicity and sensitivity of leukemic clones to the GVL effect. By maximizing the synergistic action of molecularly targeted agents, immunomodulating agents, conventional chemotherapy, and the GVL effect, there is hope for improving outcomes for patients with this often-devastating disease.

HLA molecular mismatches and induced donor-specific tolerance in combined living donor kidney and hematopoietic stem cell transplantation.

Introduction: We investigated the potential role of HLA molecular mismatches (MM) in achieving stable chimerism, allowing for donor-specific tolerance in patients undergoing combined living donor kidney and hematopoietic stem cell transplantation (HSCT). Methods: All patients with available DNA samples (N=32) who participated in a phase 2 clinical trial (NCT00498160) where they received an HLA mismatched co-transplantation of living donor kidney and facilitating cell-enriched HSCT were included in this study. High-resolution HLA genotyping data were used to calculate HLA amino acid mismatches (AAMM), Eplet MM, three-dimensional electrostatic mismatch scores (EMS-3D), PIRCHE scores, HLA-DPB1 T-cell epitope group MM, HLA-B leader sequence MM, and KIR ligands MM between the donor and recipient in both directions. HLA MM were analyzed to test for correlation with the development of chimerism, graft vs. host disease (GvHD), de novo DSA, and graft rejection. Results: Follow-up time of this cohort was 6-13.5 years. Of the 32 patients, 26 developed high-level donor or mixed stable chimerism, followed by complete withdrawal of immunosuppression (IS) in 25 patients. The remaining six of the 32 patients had transient chimerism or no engraftment and were maintained on IS (On-IS). In host versus graft direction, a trend toward higher median number of HLA-DRB1 MM scores was seen in patients On-IS compared to patients with high-level donor/mixed chimerism, using any of the HLA MM modalities; however, initial statistical significance was observed only for the EMS-3D score (0.45 [IQR, 0.30-0.61] vs. 0.24 [IQR, 0.18-0.36], respectively; p=0.036), which was lost when applying the Bonferroni correction. No statistically significant differences between the two groups were observed for AAMM, EMS-3D, Eplet MM, and PIRCHE-II scores calculated in graft versus host direction. No associations were found between development of chimerism and GvHD and non-permissive HLA-DPB1 T-cell epitope group MM, HLA-B leader sequence, and KIR ligands MM. Conclusion: Our results suggest an association between HLA-DRB1 molecular mismatches and achieving stable chimerism, particularly when electrostatic quality of the mismatch is considered. The non-permissive HLA-DPB1 T-cell epitope group, HLA-B leader sequence, and KIR ligands MM do not predict chimerism and GvHD in this combined kidney/HSCT transplant patient cohort. Further work is needed to validate our findings. Clinical trial registration: https://clinicaltrials.gov/study/NCT00498160, identifier NCT00498160.

Haploidentical and matched unrelated donor allogeneic hematopoietic stem cell transplantation offer similar survival outcomes for acute leukemia.

BACKGROUND: Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has emerged as an effective approach for acute leukemia, primarily due to the inherent difficulty in finding human leukocyte antigen-matched unrelated donors (MUD). Nevertheless, it remains uncertain whether haplo-HSCT and MUD-HSCT can provide comparable outcomes in patients with acute leukemia. AIMS: This study aimed to assess the overall survival (OS) and leukemia-free survival (LFS) outcomes between the MUD-HSCT and haplo-HSCT groups. METHODS AND RESULTS: This retrospective analysis encompassed adult patients with acute leukemia undergoing the initial allo-HSCT. Among these 85 patients, we stratified 33 patients into the MUD-HSCT group and 52 to the haplo-HSCT group. The primary outcomes were OS and LFS. The median OS was not reached in the haplo-HSCT group, while it reached 29.8 months in patients undergoing MUD-HSCT (p = .211). Likewise, the median LFS periods were 52.6 months in the haplo-HSCT group and 12.7 months in the MUD-HSCT group (p = .212). Importantly, neither the OS nor LFS showed substantial differences between the MUD-HSCT and haplo-HSCT groups. Furthermore, univariate analyses revealed that haplo-HSCT did not demonstrate a significantly higher risk of worse LFS (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.38-1.25; p = .216) or OS (HR, 0.67; 95% CI, 0.36-1.26; p = .214) than MUD-HSCT. Notably, a high European Group for Blood and Marrow Transplantation risk score (HR, 1.44; 95% CI, 1.10-1.87; p = .007) and non-complete remission (HR, 2.48; 95% CI, 1.17-5.23; p = .017) were significantly correlated with worse OS. CONCLUSION: Haplo-HSCT may serve as an alternative to MUD-HSCT for the treatment of acute leukemia, offering similar survival outcomes.

Graft failure after allogeneic hematopoietic stem cell transplantation in pediatric patients with acute leukemia: autologous reconstitution or second transplant?

BACKGROUND: Graft failure (GF) is a rare but serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Prevention of graft failure remains the most advisable approach as there is no clear recommendation for the best strategies for reversing this complication. Administration of growth factor, additional hematopoietic progenitor boost, or a salvage HSCT are current modalities recommended for the treatment of GF. Autologous recovery without evidence of disease relapse occurs rarely in patients with GF, and in the absence of autologous recovery, further salvage transplantation following a second conditioning regimen is a potential treatment option that offers the best chances of long-term disease-free survival. The preconditioning regimens of second HSCT have a significant impact on engraftment and outcome, however, currently there is no consensus on optimal conditioning regimen for second HSCT in patients who have developed GF. Furthermore, a second transplant from a different donor or the same donor is still a matter of debate. OBSERVATIONS: We present our experience in managing pediatric patients with acute leukemia who encountered graft failure following stem cell transplantation. CONCLUSIONS AND RELEVANCE: Although a second transplantation is almost the only salvage method, we illustrate that some pediatric patients with acute leukemia who experience graft failure after an allogeneic stem cell transplant using Myeloablative conditioning (MAC) regimen may achieve long-term disease-free survival through autologous hematopoiesis recovery.

Cellular strategies to induce immune tolerance after liver transplantation: Clinical perspectives.

Liver transplantation (LT) has become the most efficient treatment for pediatric and adult end-stage liver disease and the survival time after transplantation is becoming longer due to the development of surgical techniques and perioperative management. However, long-term side-effects of immunosuppressants, like infection, metabolic disorders and malignant tumor are gaining more attention. Immune tolerance is the status in which LT recipients no longer need to take any immunosuppressants, but the liver function and intrahepatic histology maintain normal. The approaches to achieve immune tolerance after transplantation include spontaneous, operational and induced tolerance. The first two means require no specific intervention but withdrawing immunosuppressant gradually during follow-up. No clinical factors or biomarkers so far could accurately predict who are suitable for immunosuppressant withdraw after transplantation. With the understanding to the underlying mechanisms of immune tolerance, many strategies have been developed to induce tolerance in LT recipients. Cellular strategy is one of the most promising methods for immune tolerance induction, including chimerism induced by hematopoietic stem cells and adoptive transfer of regulatory immune cells. The safety and efficacy of various cell products have been evaluated by prospective preclinical and clinical trials, while obstacles still exist before translating into clinical practice. Here, we will summarize the latest perspectives and concerns on the clinical application of cellular strategies in LT recipients.

The state of the art in the treatment of severe aplastic anemia: immunotherapy and hematopoietic cell transplantation in children and adults.

Acquired aplastic anemia (AA) is an immune-mediated bone marrow (BM) failure where marrow disruption is driven by a cytotoxic T-cell-mediated autoimmune attack against hematopoietic stem cells. The key diagnostic challenge in children, but also in adults, is to exclude the possible underlying congenital condition and myelodysplasia. The choice of treatment options, either allogeneic hematopoietic cell transplantation (alloHCT) or immunosuppressive therapy (IST), depends on the patient's age, comorbidities, and access to a suitable donor and effective therapeutic agents. Since 2022, horse antithymocyte globulin (hATG) has been available again in Europe and is recommended for IST as a more effective option than rabbit ATG. Therefore, an update on immunosuppressive strategies is warranted. Despite an improved response to the new immunosuppression protocols with hATG and eltrombopag, some patients are not cured or remain at risk of aplasia relapse or clonal evolution and require postponed alloHCT. The transplantation field has evolved, becoming safer and more accessible. Upfront alloHCT from unrelated donors is becoming a tempting option. With the use of posttransplant cyclophosphamide, haploidentical HCT offers promising outcomes also in AA. In this paper, we present the state of the art in the management of severe AA for pediatric and adult patients based on the available guidelines and recently published studies.

Patients with systemic sclerosis and low CD4 numbers after autologous stem cell transplantation have a favorable outcome.

BACKGROUND: Treatment with high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (aHSCT) is an intensive treatment option for patients with severe forms of systemic sclerosis (SSc). Even though associated with a high treatment related mortality, the results in this high-risk population are generally favourable. The knowledge on the potential mechanism of action of this therapy and how it can improve patients with SSc is crucial to better select the right patients for aHSCT. METHODS: This is a monocentric retrospective study from Tübingen, Germany, including 32 patients who underwent aHSCT. Peripheral blood samples were analysed for different lymphocyte subsets at various timepoints before and after aHSCT. Patients were divided into responders and non-responders according to the modified Rodnan skin score and lung function test in the three years following aHSCT. RESULTS: Responders showed significantly lower levels of cluster of differentiation (CD)4 positive T cells in the first months after aHSCT (month 1 and 3), B cells (month 3 and 6 after aHSCT) and natural killer cells (month 1). Mantel-cox test showed a significant deviation of the probability curves, i.e. patients with lower CD4 + T cells and natural killer cells one month and B cells after 3 months after stem cell transplantation had a higher probability to belong to the responder group. CONCLUSIONS: Taken together, this study supports the theory that a profound CD4 + T cell and B cell lymphopenia is important for patients with SSc to achieve a sustained response after aHSCT.

Current status of conditioning regimens in haploidentical hematopoietic cell transplantation.

The development of effective prophylaxis strategies against graft-versus-host disease (GVHD) has contributed to the widespread use of haploidentical related hematopoietic cell transplantation (Haplo-HCT). Currently, GVHD prophylaxis containing posttransplant cyclophosphamide (PTCY) is considered the standard of care in Haplo-HCT, and recent studies have shown comparable results for PTCY-based Haplo-HCT and HCT from other donor sources. The conditioning regimen plays an important role in eradicating tumor cells to prevent disease relapse and suppressing the recipient's immune system to facilitate engraftment. PTCY-based Haplo-HCT was initially developed using a nonmyeloablative conditioning regimen consisting of fludarabine, cyclophosphamide and low-dose total body irradiation, but high relapse rates reinforced the need to intensify the conditioning regimen. In this respect, various myeloablative and reduced-intensity conditioning regimens have been investigated. However, the optimal conditioning regimens for PTCY-based Haplo-HCT have not yet been established, and this issue needs to be addressed based on data from patients undergoing the procedure. In this article, we review the existing literature on conditioning regimens for PTCY-based Haplo-HCT and discuss future perspectives.

Haploidentical Hematopoietic Stem Cell Transplantation for Patients with Severe Aplastic Anemia-Single-Centre Experience.

Severe aplastic anemia (SAA) is a life-threatening type of aplastic anemia for which allogeneic stem cell transplantation or immunosuppressive therapy are the principal treatment modalities. Only about 25-30% of patients have a matched sibling donor, and finding an unrelated donor in ethnic minorities is a challenge. The use of related haploidentical donor transplants in severe aplastic anemia is uncommon. We would like to report our experience with the first four patients who underwent haploidentical transplants for severe aplastic anemia. This is a retrospective study. We collected data from our transplant database of all haploidentical hematopoietic stem cell transplants for SAA from 1 January 2020 to 31 December 2021. The transplant protocol used was the Hopkins' protocol. There were three patients who underwent haploidentical transplants as primary therapy for SAA. A fourth patient received a haploidentical transplant after immunosuppressive therapy failure. The median age of the patients at transplant was 24 y (range 20-29). All patients were engrafted. Neutrophil engraftment occurred at a median of 21 days (range 17-22). Any active infections resolved with the recovery of blood counts. The median hospitalization time was 27 days (range 22-41). Only one patient had grade 2 acute GVHD involving the skin. There was no chronic GVHD. All patients had complete lymphoid and myeloid donor chimerism on day 60. Based on our experience and the emerging literature, haplo-identical transplantation should be considered for select young patients with SAA who have low chances of responding to immunosuppressive therapy.

G-CSF + plerixafor versus G-CSF alone mobilized hematopoietic stem cells in patients with multiple myeloma and lymphoma: a systematic review and meta-analysis.

AIM: The combination of granulocyte-colony stimulating factor (G-CSF) and plerixafor is one of the approaches for hematopoietic stem cell mobilization in patients with multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), and Hodgkin's lymphoma (HL). This systematic review and meta-analysis aimed to determine the ability of G-CSF + plerixafor to mobilize peripheral blood (PB) CD34+ cells and examine its safety profile. METHODS: We performed a database search using the terms 'granulocyte colony stimulating factor', 'G-CSF', 'AMD3100', and 'plerixafor', published up to May 1, 2023. The methodology is described in further detail in the PROSPERO database (CRD42023425760). RESULTS: Twenty-three studies were included in this systematic review and meta-analysis. G-CSF + plerixafor resulted in more patients achieving the predetermined apheresis yield of CD34+ cells than G-CSF alone (OR, 5.33; 95%, 4.34-6.55). It was further discovered that G-CSF + plerixafor could mobilize more CD34+ cells into PB, which was beneficial for the next transplantation in both randomized controlled (MD, 18.30; 95%, 8.74-27.85) and single-arm (MD, 20.67; 95%, 14.34-27.00) trials. Furthermore, G-CSF + plerixafor did not cause more treatment emergent adverse events than G-CSF alone (OR, 1.25; 95%, 0.87-1.80). CONCLUSIONS: This study suggests that the combination of G-CSF and plerixafor, resulted in more patients with MM, NHL, and HL, achieving the predetermined apheresis yield of CD34+ cells, which is related to the more effective mobilization of CD34+ cells into PB.

Case report: Two pediatric cases of long-term leukemia-free survival with relapsed acute T-lymphoblastic leukemia treated with donor CD7 CAR-T cells bridging to haploidentical stem cell transplantation.

Introduction: Patients with relapsed/refractory (r/r) acute T-lymphoblastic leukemia (T-ALL) have a poor prognosis. We developed donor CD7 chimeric antigen receptor T (CAR-T) cells to salvage r/r T-ALL patients and obtained encouraging results. Patients who had not received allogeneic (allo-) hematopoietic stem cell transplantation (HSCT) before CAR-T therapy would develop pancytopenia and immunodeficiency for a long period after CD7 CAR-T therapy; therefore, allo-HSCT is needed in these patients. Here, we report two pediatric r/r T-ALL patients who received donor CD7 CAR-T bridging to allo-HSCT with leukemia-free survival (LFS) and sustained negative minimal residual disease for >2 years. Case presentation: Patient 1 was a 10-year-old boy who visited our hospital because of a T-ALL relapse with multiple lymphadenopathies without discomfort. The patient did not achieve remission after one course of induction chemotherapy. The patient then received donor (his father) CD7 CAR-T cells and achieved complete remission (CR). Thirty days after the first CAR-T cell infusion, he received allo-HSCT, and his father was also the donor. His LFS was >3 years. Patient 2 was an 8-year-old boy who was admitted to our hospital with relapsed T-ALL with fever, cough, and mild dyspnea. He did not achieve remission after one course of induction chemotherapy; therefore, he received donor (his father) CD7 CAR-T cells and achieved CR. Twenty-six days after CAR-T cell infusion, the patient received allo-HSCT, with his father as the donor. He has survived for >2 years free of leukemia. At the last follow up, both patients were alive and presented a good quality of life. Conclusion: The long-term survival of these two patients supports the use of CD7 CAR-T therapy bridging to allo-HSCT as an effective and safe treatment with the capacity to make r/r T-ALL a curable disease, similar to r/r acute B-lymphoblastic leukemia.

Impact of CRISPR/HDR editing versus lentiviral transduction on long-term engraftment and clonal dynamics of HSPCs in rhesus macaques.

For precise genome editing via CRISPR/homology-directed repair (HDR), effective and safe editing of long-term engrafting hematopoietic stem cells (LT-HSCs) is required. The impact of HDR on true LT-HSC clonal dynamics in a relevant large animal model has not been studied. To track the output and clonality of HDR-edited cells and to provide a comparison to lentivirally transduced HSCs in vivo, we developed a competitive rhesus macaque (RM) autologous transplantation model, co-infusing HSCs transduced with a barcoded GFP-expressing lentiviral vector (LV) and HDR edited at the CD33 locus. CRISPR/HDR-edited cells showed a two-log decrease by 2 months following transplantation, with little improvement via p53 inhibition, in comparison to minimal loss of LV-transduced cells long term. HDR long-term clonality was oligoclonal in contrast to highly polyclonal LV-transduced HSCs. These results suggest marked clinically relevant differences in the impact of current genetic modification approaches on HSCs.

Reduced toxicity matched sibling bone marrow transplant results in excellent outcomes for severe congenital neutropenia.

Severe congenital neutropenia (SCN) is caused by germline mutations, most commonly in ELANE, impacting neutrophil maturation and leading to high risk of life-threatening infections. Most patients with ELANE-mutant SCN can achieve safe neutrophil counts with chronic Granulocyte-Colony Stimulating Factor (G-CSF). However, up to 10% of patients have neutropenia refractory to G-CSF and require allogeneic stem cell transplant. Traditional conditioning for these patients includes busulfan and cyclophosphamide which is associated with significant toxicities. We present five patients with SCN without myeloid malignancy transplanted using a reduced toxicity regimen of busulfan, fludarabine and thymoglobulin. 5 pediatric patients with SCN underwent matched sibling donor bone marrow transplant (MSD-BMT) between 2014-2022 on or per CHP14BT057 (NCT02928991), a prospective, single center trial testing elimination of cyclophosphamide from conditioning in pediatric patients with single lineage inherited BMF syndromes. All patients had MSDs and no evidence of MDS. Conditioning consisted of PK-adjusted busulfan, fludarabine, and thymoglobulin, with calcineurin inhibitor and mycophenolate mofetil GVHD prophylaxis. With median follow-up of 48.4 months, overall and event-free survival were 100%. There was no acute GVHD and one instance of chronic limited GVHD. Patients exhibited >95% donor myeloid chimerism at 5 years post-BMT. Two patients experienced CMV reactivation without end-organ disease, and no other viral reactivation or significant infections occurred. MSD-BMT with reduced toxicity myeloablation for SCN provides excellent outcomes while minimizing toxicity. These data suggest that busulfan, fludarabine, and ATG can be considered an efficacious, low-toxicity standard of care regimen for patients with SCN undergoing MSD-BMT.

Herombopag for the treatment of persistent thrombocytopenia following hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) stands as a pivotal treatment for hematologic malignancies, often considered the sole effective treatment option. A frequent complication following allo-HSCT is poor graft function (PGF), with one of its primary manifestations being persistent thrombocytopenia (PT), comprising prolonged isolated thrombocytopenia (PIT) and secondary failure of platelet recovery (SFPR). Conventional treatment methods have had poor efficacy and a high transplantation-associated mortality rate. In recent years, the efficacy of eltrombopag has been reported in the treatment of post-transplantation PT, and additional thrombopoietin receptor agonists (TPO-RA) have been developed. Herombopag is a next-generation TPO-RA which has strong proliferation-promoting effects on human TPO-R-expressing cells (32D-MPL) and hematopoietic progenitor cells in vitro. We reviewed eighteen patients with transplantation-associated thrombocytopenia who received herombopag when eltrombopag was ineffective or poorly tolerated and evaluated its efficacy including effects on survival. Herombopag was administered at a median time of 197 days post-transplantation. Six patients achieved complete response (CR), with a median time to CR of 56 days. Five patients achieved partial response (PR), and the median time to PR was 43 days. Seven patients were considered to have no response (NR). The overall response (OR) rate was 61.1%, and the cumulative incidence (CI) of OR was 90.2%. No patients developed herombopag-associated grade 3-4 toxicity. The median follow-up period was 6.5 months. Twelve patients survived and six patients died, with an overall survival rate of 66.7%. This is the first study to demonstrate the efficacy and safety of herombopag in transplantation-associated thrombocytopenia after failing eltrombopag, introducing a new approach in the treatment of PT following allo-HSCT.

Comparison of rabbit ATLG and ATG for GVHD prophylaxis in hematological malignancies with haploidentical hematopoietic stem cell transplantation.

Rabbit anti-human T lymphocyte globulin (ATLG) and anti-thymocyte globulin (ATG) are commonly used for graft-versus-host disease (GVHD) prophylaxis in allogeneic hematopoietic stem cell transplantation (HSCT). Yet, their efficacy and safety have seldom been compared in hematological malignancies with haploidentical HSCT. A retrospective analysis with 28 ATLG (total dosage, 20-30 mg/kg) and 18 ATG (total dosage, 8-10 mg/kg) patients were performed. The cumulative incidences of chronic GVHD and relapse were comparable between both groups. ATLG showed a trend towards a lower acute GVHD incidence (28.6% vs. 44.4%, P = 0.242) and 3-year non-relapse mortality (10.7% vs. 27.8%, P = 0.160), and had a significantly higher 3-year overall survival (OS, 64.3% vs. 33.3%, P = 0.033) and GVHD-free and relapse-free survival (GRFS, 32.1% vs. 11.1%, P = 0.045) compared with ATG. Multivariate Cox regression analysis demonstrated ATLG was independently associated with a favorable OS (hazard ratio [HR] = 0.37, 95% confidence interval [CI]: 0.16-0.86, P = 0.020) and GRFS (HR = 0.51, 95%CI: 0.26-1.00, P = 0.051). Furthermore, ATLG had a lower risk of fever (25.0% vs. 61.1%, P = 0.014) and hemorrhage cystitis (7.1% vs. 38.9%, P = 0.008) than ATG-T. In conclusion, ATLG confers more survival benefit and a better safety profile than ATG and can be used in hematological malignancies with haploidentical HSCT. Prospective designed trials with a larger sample size are warranted to confirm the results in the future.

PTCy versus ATG as graft-versus-host disease prophylaxis in mismatched unrelated stem cell transplantation.

There is an increased risk of GVHD and of non-relapse mortality (NRM) after allogeneic stem cell transplantations (alloSCT) when mismatched unrelated donors (MMUD) are used. In Europe, it is standard practice to use rabbit anti-thymocyte globulin (rATG) to reduce the high NRM and GVHD risks after MMUD alloSCT. As an alternative to rATG, post-transplantation Cyclophosphamide (PTCy) is in increasing clinical use. It is currently impossible to give general recommendations regarding preference for one method over another since comparative evidence from larger data sets is lacking. To improve the evidence base, we analyzed the outcome of rATG vs. PTCy prophylaxis in adult patients with hematologic malignancies undergoing first peripheral blood alloSCT from MMUD (9/10 antigen match) between Jan 2018 and June 2021 in the database of the European Society for Blood and Marrow Transplantation (EBMT). We performed multivariate analyses using the Cox proportional-hazards regression model. We included 2123 patients in the final analyses (PTCy, n = 583; rATG, n = 1540). p values and hazard ratios (HR) presented here are multivariate outcomes. Two years after alloSCT we found a lower NRM in the PTCy group of 18% vs. 24.9% in the rATG group; p = 0.028, HR 0.74. Overall survival in the PTCy cohort was higher with 65.7% vs. 55.7% in the rATG cohort; p < 0.001, HR 0.77. Progression-free survival was also better in the PTCy patients with 59.1% vs. 48.8% when using rATG; p = 0.001, 0.78. The incidences of chronic GVHD and acute GVHD were not significantly different between the groups. We found significantly lower NRM as well as higher survival in recipients of peripheral blood alloSCTs from MMUD receiving PTCy as compared to rATG. The results of the current analysis suggest an added value of PTCy as GVHD prophylaxis in MMUD alloSCT.