Reduced-intensity Regimen Research Articles

Secondary solid malignancies in long-term survivors after total body irradiation

BackgroundTotal body irradiation (TBI)-based allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for selected patients with acute myeloid leukemia (AML). Yet, secondary malignancies contribute to long-term morbidity and mortality with TBI potentially influencing these risks.MethodsThis retrospective study analyzed the cumulative incidences of secondary solid malignancies and precancerous lesions of 89 consecutive AML patients after TBI-based conditioning before 1st allo-HSCT between 2000 and 2016. TBI was performed with an average dose rate of 4 cGy/min and a twice-daily fractionation. Cause-specific hazard models analyzed risk factors for secondary malignancies/precancerous lesions and the competing risks of dying before developing secondary malignancies/precancerous lesions.ResultsThe median patient age at TBI was 42.5 years (interquartile range, 32.5–51.2), while the median follow-up was 15.2 years (interquartile range, 13.0-18.2). Most patients received a myeloablative conditioning (MAC) containing 8 Gy (n = 47) and 12 Gy TBI (n = 11). Reduced-intensity regimens (RIC, 4 Gy TBI) were applied in 31 patients. Of note, patients receiving RIC were older than patients receiving MAC. The most common cancer types were non-squamous cell carcinomas (n = 14) after exclusion of a patient diagnosed with sarcoma within less than a year after TBI. The cumulative incidences of secondary malignancies and precancerous lesions were 8% (95%CI, 4–16), 14% (95%CI, 7–23), and 17% (95%CI, 9–27) at 10, 15 and 20 years, while the cumulative incidences of premature deaths were 59% (95%CI, 48–69), 59% (95%CI, 48–69), and 64% (95%CI, 49–76). In multivariate analyses, higher patient age at TBI was associated with lower rates of secondary malignancies/precancerous lesions, while higher patient age translated into a trend towards premature deaths (before patients could develop malignancies). Higher TBI doses, mainly applied in younger patients, translated into lower rates of secondary malignancies/precancerous lesions while lacking associations with mortality. Chronic GVHD requiring systemic immunosuppression was associated with premature deaths.ConclusionsAlthough this study indicates an inverse relationship between TBI doses applied and treatment-related malignancies, confounding by competing risks is present. The age dependency may be explained by the fact that older patients had a lower life expectancy independent of malignancies, illustrating the pitfalls of competing risks.Trial registrationThe study was retrospectively registered.

Allogeneic Stem Cell Transplantation in Refractory Acute Myeloid Leukaemia.

Refractory acute myeloid leukaemia is very difficult to treat and represents an unmet clinical need. In recent years, new drugs and combinations of drugs have been tested in this category, with encouraging results. However, all treated patients relapsed and died from the disease. The only curative option is allogeneic transplantation through a graft from a healthy donor immune system. Using myeloablative conditioning regimens, the median overall survival regimens is 19%. Several so-called sequential induction chemotherapies followed by allogeneic transplantation conditioned by reduced intensity regimens have been developed, improving the overall survival to 25-57%. In the allogeneic transplantation field, continuous improvements in practices, particularly regarding graft versus host disease prevention, infection prevention, and treatment, have allowed us to observe improvements in survival rates. This is true mainly for patients in complete remission before transplantation and less so for refractory patients. However, full myeloablative regimens are toxic and carry a high risk of treatment-related mortality. In this review, we describe the results obtained with the different modalities used in more recent retrospective and prospective studies. Based on these findings, we speculate how allogeneic stem cell transplantation could be modified to maximise its therapeutic effect on refractory acute myeloid leukaemia.

Single non-blood-related umbilical cord blood transplantation using a reduced-intensity conditioning regimen for the treatment of severe aplastic anemia

Objective: To evaluated the clinical efficacy of a reduced-intensity preconditioning regimen for single non-blood-related umbilical cord blood transplantation (sUCBT) in the treatment of severe aplastic anemia (SAA) . Methods: The clinical data of 63 patients with SAA who underwent sUCBT from January 2021 to July 2023 at the Department of Hematology of the First Affiliated Hospital of USTC were retrospectively analyzed. Fifty-two patients received total body irradiation/total bone marrow irradiation (TMI) combined with fludarabine or a cyclophosphamide- conditioning regimen (non-rATG group) , while 11 patients received rabbit anti-human thymocyte immunoglobulin (rATG) combined with TMI, fludarabine, or the cyclophosphamide-conditioning regimen (rATG group) . All patients received cyclosporine A and mycophenolate mofetil for graft-versus-host disease (GVHD) prophylaxis. Complications post-transplantation and long-term survival were compared between the two groups. Results: The baseline parameters were balanced between the two groups (P>0.05) . In the rATG group, all patients achieved stem cell engraftment, and in the non-rATG group, five patients had primary graft failure. There was no significant difference in the cumulative incidence of neutrophil engraftment at 42 days after transplantation or platelet engraftment at 60 days between the two groups. The incidence of grade Ⅱ-Ⅳ acute GVHD in the rATG group was significantly lower than in the non-rATG group (10.0% vs. 46.2% , P=0.032) , and the differences in the cumulative incidences of grade Ⅲ/Ⅳ acute GVHD and 1-year chronic GVHD were not statistically significant (P=0.367 and P=0.053, respectively) . There were no significant differences in the incidences of pre-engraftment syndrome, bacterial bloodstream infections, cytomegalovirus viremia, or hemorrhagic cystitis between the two groups (P>0.05 for all) . The median follow-up time for surviving patients was 536 (61-993) days, and the 1-year transplantation related mortality (TRM) of all patients after transplantation was 13.0% (95% CI 6.7% -24.3% ) . Among the patients in the non-rATG and rATG groups, 15.5% (95% CI 8.1% -28.6% ) and 0% (P=0.189) , respectively, had mutations. The 1-year overall survival (OS) rate of all patients after transplantation was 87.0% (95% CI 75.7% -93.3% ) . The 1-year OS rates in the rATG group and non-rATG group after transplantation were 100% and 84.5% , respectively (95% CI 71.4% -91.9% ) (P=0.198) . Conclusion: The preliminary results of sUCBT with a low-dose irradiation-based reduced-intensity conditioning regimen with fludarabine/cyclophosphamide for the treatment of patients with SAA showed good efficacy. Early application of low-dose rATG can reduce the incidence of acute GVHD after transplantation without increasing the risk of implantation failure or infection.

Fludarabine and Melphalan Reduced Toxicity Versus a Myeloablative Fludarabine and Busulfan Conditioning Regimen for Acute Myeloid Leukemia

Introduction: The optimal induction regimen for an allogeneic hematopoietic cell transplant (allo-HCT) for a young adult patient diagnosed with acute myeloid leukemia (AML) remains to be defined. Among reduced intensity regimens (RIC), retrospective registry data from both CIBMTR and EBMT would suggest that a Fludarabine / Melphalan (Flu/Mel) regimen was superior to a Fludarabine / Busulfan x 2 (Flu/Bu2) regimen. The need for a myeloablative conditioning regimen over a RIC has been evaluated in at least six randomized clinical trials (RCT), and the results have yet to be uniform. Published meta-analysis suggests equipoise. The studies are further limited by including a heterogenous group of conditioning regimens, especially in the reduced intensity arm; they all come from developed countries, a mix of AML and MDS in most studies, and variation in age groups enrolled in them. In India and developing countries, there remain significant challenges with multi-drug resistant infections, financial constraints, and challenges with intensive care support. We hypothesize that in this setting, a reduced toxicity regimen, such as a combination of Fludarabine with Melphalan (140 mg/m 2) (Flu/Mel), may be preferable to a myeloablative regimen. Methods: A single-center retrospective analysis was undertaken to study the impact of a reduced toxicity Flu/Mel regimen versus a myeloablative Fludarabine combined with Busulfan (130 mg/m 2/day x 4 days) regimen (Flu/Bu4). All consecutive patients in all age groups with a diagnosis of AML who underwent an allo-HCT between Jan 2005 and Dec 2021 were included in this analysis. The conditioning regimen used was as per physician discretion with a broad guideline within the department to use a myeloablative Flu/Bu4 regimen in a young fit patient with high-risk features such as high-risk ELN at diagnosis, CR2, and beyond, or requiring more than one cycle of induction chemotherapy to achieve a complete remission (CR). Results: 439 patients underwent an allo-HCT for a diagnosis of AML at our center in the given time. The median age was 33 years (range: 1 - 63), and there were 267 (60.8%) males. The transplants were done in CR1 in 236 (54%), CR2 in 90 (20.5%), CR3 in 13 (3%), and in relapsed/refractory or with active disease in 100 (22.8%). The majority were matched sibling/related donors (MRD) in 284 (64.7%), followed by matched unrelated (MUD) in 75 (17.1%) and haploidentical in 80 (18.2%). The conditioning regimen used was Flu/Mel in 170 (38.7%), Flu/Bu4 in 185 (42.1%), and a mix of other regimens in 84 (19.1%). At an actuarial median follow-up of 4 years, the overall survival (OS) and event-free survival (EFS) of the entire cohort were 40.8% ± 3.0% and 38.6% ± 3.0%, respectively. The EFS of cases in CR1, CR≥2, and in relapsed/refractory/active disease were 47.7% ± 3.8%, 45.0% ± 5.5%, and 12.3% ± 3.6%, respectively. The baseline characteristics and clinical outcome of cases that received a Flu/Mel condition versus Flu/Bu4 conditioning are summarized in Table 1. In summary, baseline characteristics were comparable between the two groups, except that significantly more cases underwent a haploidentical transplant in the Flu/Bu4 group. In contrast, in the Flu/Mel group, there were significantly more cases in CR1, and the median age was also significantly older. The 5-year KM EFS of the Flu/Mel and Flu/Bu4 cohort was 51.7±3.9% and 43.9±3.9% (P-value = 0.297), respectively (Figure 1). On univariate analysis, only CR1 status before transplant and the presence of chronic GVHD impacted EFS positively, and on multivariate analysis, only CR1 status affected EFS. Conclusion: In conclusion, in one of the most extensive retrospective studies comparing a uniform reduced toxicity conditioning regimen with Flu/Mel versus a standard myeloablative Flu/Bu4 conditioning regimen, we find no significant advantage of Flu/Bu4 over a Flu/Mel conditioning regimen.

Thiotepa, Busulfan and Fludarabine Conditioning Regimen in Adult Patients Undergoing Allogeneic Stem Cell Transplantation for Lymphoid Malignancies. a Study on Behalf of Geth-TC

Background: The optimal conditioning regimen in allogeneic hematopoietic stem cell transplant (alloHCT) for lymphoid malignancies remains unclear. Reduced intensity regimens (RIC) allow older and more comorbid patients to receive alloHCT since lower non-relapse mortality (NRM) is observed, but disease control may still be a concern. The use of reduced toxicity conditioning regimens allows better disease control with a cost of higher toxicity. To date, no data are available regarding the use of thiotepa, busulfan and fludarabine (TBF) in adult patients allografted for lymphoma. Our aim is to describe survival outcomes and treatment-related toxicities of patients with lymphoid malignancies conditioned with TBF. Methods: Between December 2011 and July 2022, 116 patients diagnosed with lymphoid malignancies received a first alloHCT conditioned with a TBF-based regimen in 9 Spanish institutions. All consecutive patients were included in the study and data were collected retrospectively. Low-dose TBF was defined as the use of 5 mg/kg of thiotepa (T5) while a high-dose TBF was considered as the administration of 10 mg/Kg of thiotepa (T10). Main outcome variables were overall survival (OS), progression-free survival (PFS), NRM, relapse incidence (RI), cumulative incidence of acute (aGVHD) and chronic GVHD (cGVHD), and hematological recovery. Probabilities of OS and PFS were calculated using the Kaplan-Meier estimator method, and NRM, RI, GVHD and hematological recovery as cumulative incidences. Results: Baseline characteristics are summarized in Table 1. The median age was 52 (range 23-70) years and 62.1% of the patients were males. Aggressive B-cell lymphoma was the most common diagnosis (43.1%). Seventy-seven (66.4%) patients received T10, and 39 (33.6) T5. Median follow-up among survivors was 46.9 (range 16.9-136.5) months. At 3 years, OS, PFS, NRM and RI were 54.7% (95% confidence interval [CI], 45.5-63.9%) ( Figure 1), 44.9% (95% CI, 35.7-54.1%), 34.9% (95% CI, 27.1-44.9%) and 20.2% (95% CI, 14-29.2%), respectively. Of the 53 patients who died during follow up, causes of death were: 12 relapses and 41 transplant toxicities (16=infections, 8=GVHD, 5=endothelial complications, 1=traumatism, 11=missing). Fifty-one percent of toxicity-related deaths were observed during the first 3 months from transplant. All but 2 patients engrafted. The cumulative incidence of neutrophil engraftment at day +30 was 91.4% (95% CI, 86.3-96.8%). The cumulative incidence of grade II-IV aGVHD at day +100 was 25.4% (95% IC, 18.5-34.9%), with 8 patients presenting grade III-IV aGVHD. The 3-years cumulative incidence of all grade cGVHD was 29.8% (95% CI, 22.5-39.6%), with 15 patients presenting with moderate-severe cGVHD. Seventeen patients developed venooclusive disease (14.7%) with a median time from alloHCT infusion of 14 (range 7-93) days. On univariate analysis, no prognostic factors were found in terms of NRM, OS and PFS. However, higher doses of thiotepa were associated to a lower relapse incidence (13.2% vs 35%, p=0.0075) without differences in terms of NRM. The use of myeloablative conditioning (vs RIC) showed a trend towards a lower relapse incidence although it was not statistically significant (9.4% vs 24.5%, p=0.059) with no impact in NRM rates. On multivariate analysis these results could not be confirmed. Conclusions: In our series, TBF conditioning regimen allows efficient disease control at the expense of increased incidence of severe early toxicities. Despite higher NRM, TBF conditioning regimen showed similar OS rated compared to other regimens used for lymphoid malignancies. This regimen could be considered for fit patients with high-risk lymphoid diseases.

Favorable Outcomes with Low Dose Anti Thymocyte Globulin Based Graft Versus Host Disease Prophylaxis after Mismatched Unrelated Donor Allogenic Hematopoietic Cell Transplantation

DISCUSSION INTRODUCTION Anti thymocyte globulin (ATG) based Graft versus Host disease (GVHD) prophylaxis is widely used for unrelated donor allogeneic hematopoietic cell transplantation (HCT) although the optimal dose remains unclear. Recently, registry based and single centre retrospective analyses have suggested superior outcomes with the PTCy based GVHD prophylaxis regimens when compared to ATG based regimens in mismatched unrelated donor (MMUD) allogeneic HCT, however, these studies all used doses of ATG ≥ 5mg/kg. Outcomes following MMUD allogeneic HCT with lower dose ATG based GVHD prophylaxis regimens have not been extensively studied. Thus, we analysed outcomes of HLA 9/10 MMUD allogeneic HCTs using two low dose ATG based regimens as GVHD prophylaxis at our centre. All adult patients undergoing standard of care allogenic hematopoietic cell transplant at The Ottawa Hospital from January 1 st 2015- December 31, 2022 were included. Data regarding demographics, HLA mismatched allele, conditioning regimen, dose of ATG, time to engraftment, and rates of acute and chronic GVHD was collected. The primary outcome evaluated was overall survival (OS) and secondary outcomes were GVHD-free relapse-free survival (GRFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM). Survival outcomes were analyzed using Kaplan Meier analysis. Predictors of survival were identified using Cox-proportional hazards regression model. 77 patients (Males 62.3% (n=48); Median age - 50 years) underwent allogeneic HCT from MMUD. Most common indication for transplant was MDS/AML in 66.2% (n=51) followed by ALL in 11.3% (n=9) patients. Most frequently mismatched locus was HLA A in 37.7% (n= 29) followed by HLA B in 14.3% (n=11). Myeloablative conditioning regimen was received by 76.6% (n=59) while reduced intensity regimens were used in 23.4% (n=18) patients. Rabbit ATG was part of the GVHD prophylaxis regimen in all patients with majority (81%; n=63) receiving 2.5mg/kg and remaining 18.2% (n=14) receiving 4.5mg/kg of the drug. Grade II-IV acute GVHD occurred in 24.7% (n=19) while chronic GVHD occurred in 32.5% (n= 25) patients. After a median follow up of 21 months, relapse occurred in 28.6% (n=22) patients. Two year OS (Fig 1), and GRFS of the whole cohort were 60.6% and 45.3% respectively. 2-year incidence of non-relapse mortality (NRM) and cumulative incidence of relapse (CIR) were 16.9% and 18.2% respectively. Dose of ATG (2.5 mg/kg vs 4.5 mg/kg) was not a predictor of outcomes in either univariate and multivariate analyses. Age more than 50 years, primary diagnosis of lymphoma, reduced intensity conditioning and mismatch in loci other than HLA C were significant predictors of poor OS after univariate analysis. Only primary diagnosis of lymphoma (Hazard Ratio (HR) - 7.76; p=0.045) and mismatch in loci other than HLA C (HR - 9.53; p=0.03) were significant predictors of poor OS after multivariate analysis. When compared to published single centre and registry-based studies using ATG doses ≥ 5 mg/kg, GVHD prophylaxis using ATG doses ≤4.5 mg/kg seems to provide improved outcomes in patients undergoing allogeneic HCT from mismatched unrelated donors (Table 1). Our findings suggest that further studies are needed directly comparing lower dose ATG based regimens to PTCy based regimens to determine the ideal GVHD prophylaxis regimen for patients undergoing allogeneic HCT from HLA mismatched unrelated donors.

Outcomes of Allogeneic Transplantation for Adult T-Cell Leukemia/Lymphoma in Adolescents and Young Adult (AYA) and Young Patients

Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides a durable remission for patients with adult T-cell leukemia/lymphoma (ATL). Reduced-intensity regimens (RIC) have been increasingly used in ATL patients due to their old age and higher non-relapse mortality. However, the role of RIC regimen has not been fully evaluated among ATL patients aged <50 years. We here conducted a nationwide study to evaluate the prognostic impact of conditioning intensity on the post-transplant outcomes in ATL patients aged <50 years. Methods The clinical data of patients aged <50 years who underwent their first allo-HSCT between January 2001 and December 2020 were collected from the Transplant Registry Unified Management Program of the Japan Society for Hematopoietic Cell Transplantation. Cox proportional hazards regression models were used to evaluate variables potentially affecting overall survival (OS), graft-versus-host disease (GVHD)- and relapse-free survival (GRFS), and chronic GVHD-free survival (CRFS). Fine and Gray proportional hazards models were used to evaluate variables potentially affecting cumulative incidences of relapse (CIR) and non-relapse mortality (NRM). CIR and NRM were estimated using cumulative incidence curves to accommodate competing events. A two-sided P-value ≤0.05 was considered to be significant. To examine the effect modification, a threshold for P interaction <0.10 was used to indicate significant differences across prespecified subgroups. Results This study included 73 and 330 patients who were <40 years old (adolescents and young adults [AYA] patients) and 40-49 years old (young patients), respectively. In AYA patients, the median age at HSCT was 36 years (range, 20-39). RIC regimen was used in 16 out of 57 AYA patients (21.9%), and in 74 out of 330 young patients (22.4%) (P=1.000). There was no significant difference of the patient characteristics regarding comorbidity, performance status at HSCT, disease status, clinical subtype, and donor type. The estimated 3-year OS rates were 61.8% and 43.1% in AYA and young patients, respectively (P=0.005); the estimated 3-year CRFS rates were 35.8% and 22.6% in AYA and young patients, respectively (P=0.008); and the estimated 3-year GRFS rates were 26.7% and 15.1% in AYA and young patients, respectively (P=0.006). The estimated 3-year CIR were 36.3% and 39.3% in AYA and young patients, respectively (P=0.407); and the estimated 3-year NRM were 17.0% and 23.4% in AYA and young patients, respectively (P=0.113). In addition, the use of RIC regimen was associated with lower NRM than that of MAC regimen (P=0.015), but there was no significant difference of OS, CRFS, GRFS, and CIR between MAC and RIC regimens. The multivariate analyses revealed that young patients were significantly associated with worse OS (Hazard ratio (HR) [95% confidential interval], 1.62 [1.10-2.39]; P=0.015), CRFS (HR, 1.51 [1.10-2.06]; P=0.010), and GRFS (HR, 1.49 [1.11-1.99]; P=0.008) than AYA patients. The utilization of RIC regimen was significantly associated with lower NRM (HR, 0.46 [0.24-0.86]; P=0.015). To find the optimal selection of conditioning intensity (MAC vs. RIC) by patient's age, we next evaluated the effect modification. In the subgroup analysis, there was significant interaction of conditioning intensity with patient's age (P interaction=0.002) in NRM but not in OS, CRFS, GRFS, and CIR. Among AYA patients, the estimated 1-year NRM were 12.5% and 18.8% in MAC and RIC regimens, respectively (P=0.085). Among young patients, the estimated 1-year NRM were 23.5% and 8.2% in MAC and RIC regimens, respectively (P<0.001). Conclusion The present study clarified that AYA patients exhibited better post-transplant outcomes than young patients, indicating the prognostic value of patient's age in ATL patients aged <50 years. Moreover, no significant differences were observed in OS, CRFS, GRFS, and CIR between RIC and MAC regimens, but the utilization of RIC regimen would reduce the risk of non-relapse death among young patients. These facts suggested that RIC regimen could be an alternative option for ATL patients aged 40-49 years.

Routinely Calculable Biomarkers Are Associated with the Development of Sinusoidal Obstruction Syndrome after Hematopoietic Stem Cell Transplantation

Introduction: Sinusoidal obstruction syndrome (SOS) is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). As the immediate initiation of SOS treatment has been shown to be associated with a better prognosis, SOS prediction is clinically important. Biomarkers composed of some routine parameters, such as the aspartate aminotransferase to platelet ratio index (APRI), fibrosis-4 index (FIB-4), and albumin-bilirubin (ALBI), have been widely used to evaluate various hepatic diseases. However, the contribution of these hepatic biomarkers to the prediction and diagnosis of SOS has not been estimated yet. Here, we investigated whether routinely calculable biomarkers, endothelial activation and stress index (EASIX), APRI, FIB-4, ALBI, model for end-stage liver disease (MELD), and MELDNa were associated with the development of SOS. Patients and Methods: A total of 141 patients (corresponding to 161 transplant cases) who underwent allogeneic HSCT at our institution between January 2012 and December 2022 were retrospectively analyzed. The median age at transplantation was 52 years (range: 19-69). The primary diseases included AML (n = 59), ALL/LBL (n = 34), MDS (n = 20), malignant lymphoma (n = 15), plasma cell neoplasm (n = 4), CML/MPN (n = 10), bone marrow failure (n = 3), and others (n = 16). The graft sources were from 30 related and 131 unrelated donors. The numbers of bone marrow, peripheral blood, and cord blood sources were 65, 29, and 67, respectively. Conditioning consisted of myeloablative (n = 68) and reduced-intensity (n = 93) regimens. Haplo-identical transplantation was not performed in this cohort. SOS was diagnosed according to the European Society for Blood and Marrow Transplantation diagnostic criteria 2023. The baseline value of each biomarker before conditioning was compared between the SOS-developing and non-SOS groups, using the Kruskal-Wallis test and a post-hoc test with the Bonferroni method. To evaluate the contribution of biomarkers on SOS diagnosis, we configured matched paired controls from non-SOS cases (three non-SOS controls per SOS case), adjusting for age, sex, last follow-up day, HLA mismatch, and hematopoietic cell transplantation-specific comorbidity index. The values of biomarkers in the SOS and matched paired control groups were compared using the Mann-Whitney U test. In the present study, the negative sign of ALBI was reversed for convenience in analysis. Results and Discussion: Twenty cases were diagnosed to have developed clinical SOS (10 classical SOS and 10 late onset SOS cases). All biomarkers at baseline were significantly different for classical SOS versus non-SOS cases. The median values of EASIX, APRI, FIB-4, ALBI, MELD, and MELDNa were 8.70 vs 1.09 (range: 0.57-24.68 vs 0.22-34.10, P < 0.001), 4.97 vs 0.60 (range: 0.33-32.07 vs 0.11-10.30, P < 0.001), 10.80 vs 1.84 (range: 1.37-38.01 vs 0.31-44.69, P < 0.001), 1.84 vs 2.43 (range: 0.83-3.71 vs 1.33-3.27, P = 0.012), 8.0 vs 7.0 (range: 6-12 vs 6-17, P = 0.028), and 9.5 vs 7.0 (range: 6-18 vs 6-17, P = 0.025), respectively. Moreover, among SOS cases, biomarkers at SOS diagnosis were significantly different compared with those of matched paired controls. The median values were 33.67 vs 3.90 (range: 4.54-252.18 vs 0.28-87.22, P < 0.001), 9.90 vs 1.79 (range: 3.33-127.33 vs 0.19-23.94, P < 0.001), 43.00 vs 6.80 (range: 7.91-182.27 vs 0.60-54.92, P < 0.001), 1.06 vs 2.02 (range: 0.37-1.88 vs 0.52-3.19, P < 0.001), 14.0 vs 7.0 (range: 10-30 vs 6-23, P < 0.001), and 16.5 vs 8.5 (range: 10-31 vs 6-29, P < 0.001), respectively. These results indicate that these biomarkers are associated with SOS, as well as support its diagnosis. As these biomarkers were concise, rapidly calculable, and dispensable with special techniques, their use might be clinically superior to other tests. Conclusion: These routinely calculable biomarkers are associated with the development of SOS. Furthermore, these biomarkers are clinically useful for diagnosis of SOS. Further studies are required to improve the performance and discover an optimal biomarker.

Polatuzumab Vedotin, Zanubrutinib and Rituximab Achieved Rapid and Deep Response in Previously Untreated Frail and Elderly Diffuse Large B-Cell Lymphoma Patients

Introduction: The incidence of diffuse large B-cell lymphoma (DLBCL) increases with age, while first-line treatment for frail and elderly DLBCL is a debating topic. R-miniCHOP, a reduced intensity regimen of R-CHOP, is currently the standard of care for this population, yet with limitation due to toxicities (Frédéric Peyrade et al., Lancet Oncol, 2011). Chemo-free regimens combining Bruton kinase inhibitors, rituximab and lenalidomide showed fewer toxicities, but compromised on efficacy in elderly DLBCL in multiple previous reports (Pengpeng Xu et al., Lancet Healthy Longev, 2022; Haiyan Yang et al., ASH 2022). First-line treatment balancing efficacy with safety is urgently needed for frail and elderly DLBCL patients. Since polatuzumab vedotin was approved in China for first-line DLBCL this year and reportedly had synergistic effect with rituximab in cell line research (Natsumi Kawasaki et al., Br J Haematol, 2022), we conducted a study of polatuzumab vedotin plus zanubrutinib and rituximab (ZPR) in previously untreated frail and elderly DLBCL to assess the efficacy and safety. Here we present the characteristics of 12 enrolled patients and preliminary results. Methods: Previously untreated DLBCL patients aged over 70 years old, or aged between 60 to 69 with ECOG score 2 to 4 were enrolled in this study. All patients received a triplet regimen of ZPR. Twenty-one days was a cycle. Zanubrutinib was given 160mg twice a day orally from day 1 to day 21. Rituximab was given 375mg/m 2 intravenously on day 1. Polatuzumab vedotin was administered at a dosage of 1.8mg per kilogram intravenously on day 1. Patients would receive 6 cycles of ZPR regimen if assessed partial response (PR) or complete response (CR) after 3 cycles. If assessed CR after 6 cycles of ZPR, patients would receive zanubrutinib 160mg twice a day alone for another 6 cycles. Whole body 18F-FDG PET/CT scan or contrast-enhanced CT scan of cervical, thoracic, abdominal and pelvic parts was scheduled every 3 cycles. Treatment response was assessed by 2014 Lugano response criteria. Adverse events were graded by CTCAE 5.0. The primary endpoint is overall response rate (ORR) after 6 cycles of ZPR. The secondary endpoints are CR rate after 6 cycles of ZPR, and 2-year progression-free survival (PFS). Other endpoint is safety (Figure 1). Results: Twelve patients were enrolled in our study until Jul 24, 2023. Median age was 75 (range: 67-87). Six patients were female and six patients were male. Nine (75%) patients were classified non-GCB type according to cell of origin by Hans algorithm. Nine (75%) patients were assessed stage Ⅲ to Ⅳ by Ann Arbor staging system. Nine (75%) patients had an international prognostic index (IPI) score of 2 or more. One (11%) patient had double-hit risk factor in 9 patients with gene rearrangement results. Six (75%) patients had MYD88 L265P mutation in 8 patients with sequencing results. After a median follow up of 2.1 months, four patients had PET/CT assessment results after 3 cycles of ZPR, and four (100%) of them achieved CR. The ORR after 3 cycles of ZPR regimen was 100% (Figure 2).Grade 3 to 4 adverse events occurred in two patients, that one patient had grade 3 aspartate aminotransferase increase and alanine aminotransferase increase, and the other patient had grade 3 pneumonitis. Grade 1 to 2 adverse events included neutrophil count decrease (16%), dizziness (8%), and epistaxis (8%). All patients recovered from adverse events under best supportive care. There was no discontinuation of ZPR regimen due to severe adverse events. Conclusion: Based on these results in our study, ZPR regimen showed rapid and deep response in previously untreated frail and elderly DLBCL patients with manageable safety profiles. We registered and initiated a phase 2b trial (NCT05940064) to further evaluate the efficacy and safety of ZPR regimen as first-line treatment for this population. Ongoing treatment and follow up of these twelve patients will also be further updated.

A Phase II Study of Low-Intensity Chemotherapy (Mini-Hyper-CVD) and Ponatinib Followed By Blinatumomab and Ponatinib in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Background Patients with Philadelphia chromosome (Ph)-positive B-cell acute lymphoblastic leukemia (ALL) treated with Hyper-CVAD and ponatinib achieve deep responses and long-term overall survival (OS). We aim to investigate if a reduced intensity regimen of mini-Hyper-CVD (mini-HCVD) with sequential blinatumomab (blina) in combination with ponatinib may further improve outcomes while mitigating the toxicity of intensive chemotherapy and the need for hematopoietic stem cell transplantation (HSCT). Methods Patients age ≥18 years with newly diagnosed (ND) or relapsed/refractory (R/R) Ph-positive ALL, or chronic myeloid leukemia in lymphoid blast phase (CML-LBP) were eligible. Other inclusion criteria included adequate liver, renal and cardiac function, and ECOG performance status ≤2. Patients with baseline central nervous system (CNS) involvement were not excluded. All patients had BCR::ABL1 transcripts and fluorescence in situ hybridization (FISH) for t(9;22) done at baseline. Morphological analysis of FISH patterns was performed in ND patients to identify if the BCR::ABL1 signal was observed in myeloid cells (e.g., segmented neutrophils). Four cycles (C) of mini-HCVD alternating with methotrexate (MTX) + cytarabine were followed by blina 28µg/d given for four weeks every six weeks during C5-8. Patients received ponatinib 30mg daily initially, with a dose reduction to 15mg daily once in complete molecular remission (CMR). CMR was defined as undetectable BCR::ABL1 with an assay sensitivity of 0.01%. Rituximab was given for CD20-positive disease. Maintenance ponatinib, vincristine and prednisone for 15 cycles with blina + ponatinib every three cycles was given, followed by ponatinib for at least five years. All patients without CNS disease received 12 intrathecal injections of MTX or cytarabine. Results 20 patients (12 ND, 4 R/R, 4 CML-LBP) were treated between November 2019 and May 2023. Baseline characteristics are shown in Table 1. One patient with CML-LBP had received prior dasatinib while in chronic phase. The predominant BCR::ABL1 transcript was p190 in 7 (58%) ND patients. All patients achieved a complete remission (CR). Among patients in the ND, R/R, and CML-LBP cohorts, CMR was achieved in 10/12 (83%), 3/4 (75%), and 4/4 (100%) patients, respectively. In the ND cohort, six (50%) patients achieved CMR after C1 and eight (67%) after C3. Five (42%) ND patients had documented BCR::ABL1 signal in myeloid cells by FISH. Four of them achieved CMR, after C1, C3, C4 and C3 maintenance respectively. With a median follow-up of 25 months (range, 2-42), the 2-year continuous remission duration (CRD) and OS rates were 93% and 83% for the entire cohort (Figure 1), and 90% and 82% in the ND cohort, respectively. In the ND cohort, one (8%) patient had isolated CNS relapse (during C4 of maintenance with blina and ponatinib), three (25%) patients died (two in CR due to COVID-19 and one of HSCT complications), and eight (67%) patients are in remission without HSCT. No patients relapsed in the R/R cohort; one patient underwent HSCT, one patient died in CR from MTX-associated disseminated necrotizing leukoencephalopathy, and two patients are in remission without HSCT. None of the CML-LBP relapsed; one patient underwent HSCT in CR. Ponatinib dose was reduced in two patients prior to obtaining CMR (one had pancreatitis, one had cardiomyopathy). One patient switched from ponatinib to dasatinib due to a pulmonary embolism in C2. No patients required dose modification of blina. The 60-day mortality rate was 0%. Conclusion In patients with Ph-positive ALL, the combination of mini-HCVD and ponatinib followed by sequential blina and ponatinib yielded excellent outcomes with durable remissions. The toxicity profile was favorable and HSCT was avoided in most patients with ND disease. Longer follow-up is needed to confirm the durability of responses.

Evaluation of Circulating Endothelial Cells (CECs) As Marker of Endothelial Damage in Allo-Transplanted Patients at High Risk of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS): The Cecinvod Study

INTRODUCTION Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD), is a potentially fatal complication after allogeneic stem cell transplantation (alloSCT). Identifying a predictive biomarker for VOD has been challenging. Since endothelial injury is considered one of the main pathogenic factors for VOD onset, with the CECinVOD prospective study we aimed to evaluate Circulating Endothelial Cells (CEC) in allo-transplanted patients (pts) at higher risk to develop VOD. METHODS From October 2020 to November 2022, 150 pts have been enrolled in the CECinVOD study from 11 Italian Bone Marrow Transplantation Units. All pts must be older than 18 years and undergoing myeloablative alloSCT. CECs were detected using the CellSearch system, the FDA-approved immunomagnetic selection approach incorporating ferrofluid nanoparticles (anti CD146) and fluorophore-labelled antibodies (anti CD105, CD45 and DAPI). CEC were defined as CD146+, CD105+, DAPI+ and CD45-. CEC were collected at the following timepoints: before conditioning regimen (T0), at the end of conditioning regimen and before alloSCT (T1), at the time of neutrophils engraftment (T2), and 7-10 days after engraftment (T3). In pts who developed VOD, additional timepoints were collected as follows: at any time of suspected or proven VOD onset (T4), and then weekly during Defibrotide treatment (T5-T8). SOS/VOD was defined according to the 2016 European Group for Blood and Marrow Transplantation criteria. RESULTS Pts' main characteristics are summarized in Table 1. Six out of 150 pts (4%) developed VOD during the follow up (4 “severe”, and 2 “very severe”). All pts were treated with Defibrotide, obtaining a complete remission in 5 of them, while 1 pt died due to VOD complications. Pts receiving TBI-based regimen were more likely to develop VOD compared to those receiving Treosulfan (10 to 14 g/m2) or Busulfan ev (9.6 to 12.8 mg/kg) (p 0.08). Similarly, higher baseline levels of bilirubin were associated with a higher incidence of VOD (p 0.08). Considering the CECs analysis, 615 samples were evaluated. At the enrollment, CECs levels were not related with any of clinical characteristics analyzed, except for the number of previous treatments. Indeed, those pts with 2 or more previous lines of treatments had higher levels of CECs (OR=0.53; p<0.001). Considering the different timepoints, conditioning regimen and alloSCT result in higher levels of CECs. Thus, CEC were higher at T1 than at T0 (p 0.02), as well as they were even higher at T2 than at T1 (p<0.0001) (Fig.1). Conversely, no significant differences have been observed between T3 and T2. No other clinical characteristic was correlated with CEC counts at the different timepoints. Pts who developed VOD had higher median levels of CEC at all the timepoints analyzed, but this difference has not achieved statistical significance, probably due to the low number of pts in the VOD group. At VOD onset, the pts always had an increase in CEC levels compared with the previous timepoint. After defibrotide treatment, the CEC levels increased in the first week, while they progressively decreased during the VOD treatment (T6 and T7, -50,7% and -71,5%, respectively). Recently, another endothelial activation marker has been considered: the Easix score. We didn't find any relationship between the Easix score at transplant and the VOD onset, even if a trend may be observed. We also investigated whether the CEC levels may be related with Easix score, but we didn't find any relationship at each timepoint. Interestingly, in a subgroup of pts CECs have been observed as a cluster of multiple cells. This data is firstly described in allo-SCT. Its functional significate remains unclear, but we found a relationship between CECs cluster and the number of CECs (p < 0.001). CONCLUSIONS The incidence of VOD in our prospective study was low with respect to the one reported in the literature. This can be explained by the changes in alloSCT from the past (better selection of the pts, lower use of TBI, higher use of reduced intensity regimen) and the retrospective nature of most of the previous reports. We show that CECs can be considered reliable marker of endothelial damage in alloSCT pts, highlighting the impact of previous treatments, the conditioning regimen, and allo-SCT itself. Increased CEC level may be helpful to confirm VOD diagnosis, as well as their monitoring may be useful to evaluate the response to the treatment for VOD.

Allogeneic Transplant for CLL Richter's Transformation: Single Center Retrospective Analysis

Introduction: Richter transformation (RT) describes the emergence of an aggressive lymphoma in the setting of chronic lymphocytic leukemia (CLL). The prognosis is poor, with a median overall survival (OS) of 10 months. Treatment of RT is still challenging despite the availability of novel agents, and stem cell transplant (SCT) is commonly used as a consolidation strategy. Data on outcomes post-allogeneic-SCT for RT is limited. The OS on these reports' ranges from 41 to 75%. Methods: We conducted a retrospective study of patients diagnosed with RT at our center who underwent allogeneic SCT between 2005 and 2022. We evaluated predictors of outcome using Cox's proportional hazards regression analysis for overall and progression-free survival (PFS) and Fine and Grey regression for disease progression and non-relapse mortality (NRM). Results: 88 patients were identified, 85 had a diffuse large lymphoma histology and 3 Hodgkin's lymphoma. The median age was 61 years (range 25-74), and the majority (n=61, 69%) of patients were in complete response (CR, N=21) or partial response (PR, N=40) pre-SCT. Median follow-up among survivors was 74 months (range: 8-168); all outcomes are reported at 6 years. Overall, OS was 45% (95% CI: 34-56), and PFS 32% (95% CI: 22-43). The cumulative incidence of disease progression was 41% (95% CI: 31-53) and NRM 25% (95% CI: 17-36). In the univariate analysis, response prior to transplant was the most significant predictor of disease progression, OS, and PFS. Patients in CR/PR had a lower rate of disease progression (32% vs. 61%, HR: 0.2, 95% CI 0.2-0.6, p=0.002) and higher OS (59% vs 16%, HR: 0.3, 95% CI 0.2-0.5, p<0.001, Figure) and PFS (44% vs. 6%, HR: 0.2 (0.1-0.4), p<0.001) compared with those advanced (>CR2)or progressive disease. In addition, the presence of deletion 17p (del17p) or TP53 mutation was associated with a higher rate of disease progression (HR=3.1, 95% C 1.3 -7.3, p=0.01), but not with PFS or OS. The use of reduced intensity regimens resulted in favorable OS (HR=0.5, 95% CI 0.3-1.0, p=0.05) as compared to non-myeloablative conditioning. Age, HCT-CI score, donor type, donor-to-recipient gender, cell source, and graft-versus-host disease prophylaxis, or the presence of other cytogenetic abnormalities were not significantly associated with OS, PFS, disease progression, or NRM. There was also no advantage for any outcome when comparing individuals who achieved CR versus PR pre-SCT. The independent predictive value of CR/PR was confirmed in multivariate analysis for OS (HR=0.3, 95% CI 0.2-0.5, p<0.001) and disease progression (HR=0.4, 95% CI: 0.2-0.8, p=0.01), after adjusting for conditioning intensity for OS and deletion 17p (del17p) or TP53 mutation for disease progression. Discussion: In this single center series of patients treated with allogeneic SCT as consolidation for RT, disease status prior to SCT (CR/PR) emerged as a strong independent predictor of outcomes. The influence of tumor burden prior to SCT may be related to disease biology (e.g., patients not in CR/PR may have more aggressive RT) or may be related to decreased graft-versus-lymphoma effect. Based on our findings, we recommend that aggressive control of the disease with the goal of achieving a CR or PR should be attempted before allogeneic stem cell transplantation in patients with Richter transformation.

Improving Outcomes with Haploidentical Stem Cell Transplantation [HaploSCT] in Children Using Post-transplant Cyclophosphamide: a Single Center Experience.

Haplo-identical stem cell transplant using post-transplant cyclophosphamide is increasingly being used in children without a matched sibling donor. Between 2010 and June 2021, 127 children underwent 138 transplants with a median age of 7.1years for malignant and non-malignant disorders. Conditioning regimens included both myeloablative and reduced intensity regimens with peripheral blood stem cells as the main graft source. Engraftment occurred in 113 [81.9%] at a median of 16days [range: 10-32] with primary graft failure in 10.2%. Cumulative incidence of grade II-IV acute graft versus host disease (GVHD) was 49.5% and chronic GVHD in 40.7%. Majority [92.7%] had at least one infection with 31% incidence of bacterial infection, 76% incidence of viral and 16% incidence of fungal infection. The 2-year overall survival (OS) is 54.9 ± 4.6% with a lower survival among young children aged 0-5years [28.2 ± 6.4%] compared to 5-10years [71.3 ± 6.8%] and 11-15years [55.7 ± 8.8%] [p = 0.032]. 2-year OS has gradually improved from 25.0 ± 2.1% for 2010-2013 to 47.5 ± 6.2% for 2014-2017 and 67.1 ± 6.6% for 2018-2021 [p = 0.049]. On multivariate analysis, bacterial infection [p = 0.017], invasive fungal disease [p = 0.002] and graft failure [p = 0.029] negatively impacted overall survival. Haplo-identical SCT with post-transplant cyclophosphamide is a reasonable option for children who do not have a matched sibling donor. Strategies to reduce graft failure, infection related mortality and GVHD needs to be explored.

Graft-versus-host disease: teaching old drugs new tricks at less cost.

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic stem cell transplantation (SCT). Currently, more patients can receive SCT. This is attributed to the use of reduced intensity regimens and the use of different GVHD prophylaxis that breaks the barrier of human leukocyte antigen, allowing an increase in the donor pool. Once an area with relatively few clinical trial options, there has been an increase in interest in GVHD prophylaxis and treatment, which has led to many US Food and Drug Administration (FDA) approvals. Although there is considerable excitement over novel therapies, many patients may not have access to them due to geographical or other resource constraints. In this review article, we summarize the latest evidence on how we can continue to repurpose drugs for GVHD prophylaxis and treatment. Drugs covered by our review include those that have been FDA approved for other uses for at least 15 years (since 2008); thus, they are likely to have generic equivalents available now or in the near future.

Favorable outcomes following allogeneic transplantation in adults with hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome marked by a severe hyperinflammatory state characterized by aberrant T- and natural killer-cell activity leading to prolonged hypercytokinemia and can be rapidly fatal if not diagnosed and treated early. While upfront therapy is aimed at reducing hyperinflammation and controlling possible triggers, allogeneic hematopoietic stem cell transplantation (HSCT) is indicated for primary and relapsed/refractory cases to attain sustained remission. While this has been explored extensively in the pediatric population, there are limited data on adults undergoing HSCT for HLH. We analyzed transplant outcomes in an adult HLH population in the modern era who were transplanted at Dana-Farber Cancer Institute from 2010 onwards. Patients were uniformly transplanted on a reduced intensity platform incorporating early administration of alemtuzumab with standard infectious and graft-versus-host disease (GVHD) prophylaxis. Engraftment was documented for all patients. At 3years after transplantation, overall survival (OS) was 75% (95% confidence interval [CI], 51-89) while 3-year progression-free survival (PFS) was 71% (95% CI, 46-86). The 3-year cumulative incidence of relapse was 15% (95% CI, 3.4-33). There were no isolated HLH relapses without relapse of malignancy. The cumulative incidence of nonrelapse mortality at 3 years was 15% (95% CI, 3.5-34). Infectious complications and GVHD outcomes were comparable to standard reduced-intensity conditioning (RIC) transplantation at our institute. Mixed chimerism was common but did not correlate with transplant outcomes. Our data suggest that the immune defect in HLH can be abrogated with allogeneic transplantation using a reduced intensity regimen with early administration of alemtuzumab as preconditioning, providing a potentially curative option for this difficult disease.

Pembrolizumab for the treatment of disease relapse after allogeneic hematopoietic stem cell transplantation.

A failed graft-versus-tumor (GVT) effect is a common mechanism of relapse after allogeneic hematopoietic cell transplantation (alloHCT). Although targeting the PD-1/PD-L1 axis may restore GVT effects, PD-1 blockade exacerbates graft-versus-host disease (GVHD) in murine models, and severe GVHD can occur in patients treated with anti-PD-1 therapy after alloHCT. Therefore, we developed a prospective study to assess the safety and efficacy of pembrolizumab in patients relapsing after alloHCT. Eligible patients received pembrolizumab (200 mg every 3 weeks) for up to 2 years. Twelve patients were enrolled (8patients with acute myeloid leukemia, 1 patient with myelodysplastic syndrome, 1 patient with classical Hodgkin lymphoma, and 2 patients with diffuse large B-cell lymphoma [DLBCL]). All participants received reduced-intensity preparative regimens with invivo T-cell depletion. The median time from alloHCT to enrollment was 587 days (range, 101-4211). Three participants (25%) experienced grade 3 to 4 immune-related adverse events (irAE) (pneumonitis, 2 patients; hyperthyroidism, 1 patient), all occurring after 1 to 2 cycles, and resolving after pembrolizumab discontinuation and corticosteroid treatment. irAEs of any grade occurred in 5 patients (42%). No treatment-emergent GVHD was observed. Overall and complete response (CR) rates were 22% (2/9). Both patients achieving CRs hadPD-L1 gene-amplified lymphomas and diffuse PD-L1 expression on pretreatment biopsies. An acquired EZH2 mutation was identified at relapse in a patient with DLBCL who achieved an initial CR to pembrolizumab, which was associated with downregulated HLAexpression on malignant B cells, implicating EZH2 mutations as a potential immune escape mechanism after PD-1-blockade therapy. In conclusion, after alloHCT, treatment with pembrolizumab is feasible and associated with objective responses in relapsed lymphoid malignancies but can induce severe irAEs, requiring vigilant monitoring. Thistrial was registered at www.clinicaltrials.gov as #NCT02981914.

Secondary Neoplasms After Hematopoietic Cell Transplant for Sickle Cell Disease.

To report the incidence and risk factors for secondary neoplasm after transplantation for sickle cell disease. Included are 1,096 transplants for sickle cell disease between 1991 and 2016. There were 22 secondary neoplasms. Types included leukemia/myelodysplastic syndrome (MDS; n = 15) and solid tumor (n = 7). Fine-Gray regression models examined for risk factors for leukemia/MDS and any secondary neoplasm. The 10-year incidence of leukemia/MDS was 1.7% (95% CI, 0.90 to 2.9) and of any secondary neoplasm was 2.4% (95% CI, 1.4 to 3.8). After adjusting for other risk factors, risks for leukemia/MDS (hazard ratio, 22.69; 95% CI, 4.34 to 118.66; P = .0002) or any secondary neoplasm (hazard ratio, 7.78; 95% CI, 2.20 to 27.53; P = .0015) were higher with low-intensity (nonmyeloablative) regimens compared with more intense regimens. All low-intensity regimens included total-body irradiation (TBI 300 or 400 cGy with alemtuzumab, TBI 300 or 400 cGy with cyclophosphamide, TBI 200, 300, or 400 cGy with cyclophosphamide and fludarabine, or TBI 200 cGy with fludarabine). None of the patients receiving myeloablative and only 23% of those receiving reduced-intensity regimens received TBI. Low-intensity regimens rely on tolerance induction and establishment of mixed-donor chimerism. Persistence of host cells exposed to low-dose radiation triggering myeloid malignancy is one plausible etiology. Pre-existing myeloid mutations and prior inflammation may also contribute but could not be studied using our data source. Choosing conditioning regimens likely to result in full-donor chimerism may in part mitigate the higher risk for leukemia/MDS.

Allogeneic Hematopoietic Cell Transplant Yields Long Term Disease Free Survival in a Significant Number of Patients with Classic Hodgkin Lymphoma

Background: Classic Hodgkin's lymphoma (cHL) is a highly curable disease. A minority of patients, however, will have relapse/refractory (RR) disease and these patients are challenging to manage especially those who relapse after autologous hematopoietic cell transplant (auto-HCT). Even though a number of salvage options are available for these patients none of them is considered curative except allogeneic hematopoietic cell transplant (allo-HCT). Design and Methods: Retrospective analysis of 33 patients who had allo-HCT using matched family donors for cHL between January 2007 and December 2021. Continuous variables were summarized using medians and ranges. Categorical variables were summarized using frequencies and percentages. Probabilities of overall survival (OS) and disease free survival (DFS) were calculated using Kaplan-Meier estimate. Statistical analysis was conducted sing R studio (version 1.3.959 © 2009-2020 RStudio, PBC). Results: The median patient age at allo-HCT was 27 years. Seventeen patients were males and 16 were females. Five patients had early stage disease (Ann Arbor stage I, II) and 28 had advanced stage disease (Ann Arbor III, IV). Regarding the histologic type of cHL, eighteen had nodular sclerosis (NS), eight had mixed cellularity (MC), one had lymphocyte rich (LR), one had lymphocyte depleted (LD) and five cases were labeled as classic HL without further classification. Seventeen patients received brentuximab vedotin and fourteen patients received check point inhibitors prior to allo-HCT. The median number of chemotherapy lines prior to allo-HCT was 4 (range: 2-8). Twenty seven patients had chemosensitive disease (complete or partial remission) while 6 patients had chemoresistant disease (stable or progressive) prior to allo-HCT. Twenty seven patients had undergone auto-HCT prior to allo-HCT. Eighteen patients had elevated (>50) erythrocyte sedimentation rate (ESR) while 15 had normal ESR prior to allo-HCT. The majority of patients were conditioned with a reduced intensity regimen (29 patients versus 4 patients conditioned with myeloablative regimen). Twenty five patients received non-TBI (total body irradiation) based conditioning while 8 patients had TBI based regimen. The most frequently used conditioning regimen was fludarabine + melphalan. Nine patients received ATG (anti thymoglobulin) as a part of the conditioning while 24 patients did not. Thirty one patients received peripheral blood graft while 2 patients received bone marrow graft. The five years DFS was 37.5%. Twenty seven % of patients had acute GVHD (graft versus host disease) and 48% had chronic GVHD. The effect of a number of variables (number of chemotherapy lines, pre-allo-HCT ESR, conditioning intensity, ATG vs no ATG, receipt of pre-allo-HCT brentuximab or check point inhibitors, prior auto-HCT, chemosensitivity pre-allo-HCT and histologic subtype) was tested on the DFS. The only two variable that were statistically associated with a better DFS were pre-allo-HCT chemosensitivity (P=0.006) and non-NS histologic subtype (P=0.027). (Figure 1 and 2). Conclusions: Allogeneic stem cell transplantation can result in long-term progression-free survival in heavily pre-treated patients with Hodgkin's lymphoma. Patients with no response to salvage chemotherapy pre-allo-HCT and patients with NS subtype had detrimental outcomes. Better selection of patients before allo-HCT can result in a higher cure rates. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Post-Transplant Cyclophosphamide, Abatacept and Short Course of Tacrolimus (CAST) for Graft-Versus-Host Disease Prevention Following Haploidentical Peripheral Blood Stem Cell Transplantation

Background: Haploidentical blood and marrow transplantation (BMT) substantially expands the pool of potential hematopoietic stem cell donors, including for minority groups. However, the outcomes of haploidentical transplantation remain inferior to matched unrelated donor (MUD) transplants when a standard post-transplant cyclophosphamide (PTCy)-based graft versus host disease (GvHD) prophylaxis regimen is employed in both settings. To address this issue, we sought to develop a more effective GvHD prevention regimen in haploidentical transplantation. While abatacept (Aba) seems to decrease the incidence of acute GvHD, PTCy is particularly effective in the prevention of chronic GvHD. Therefore, we designed a regimen that combines the merits of both agents and examined whether such approach can allow early withdrawal of tacrolimus (Tac). Methods: We enrolled 46 adult patients with hematological malignancies receiving haploidentical transplantation from a relative in a prospective single center pilot phase Ib-II clinical trial. Patients received non-myeloablative, reduced-intensity or myeloablative preparative regimens followed by G-CSF mobilized peripheral blood transplants and a combination of PTCy (50mg/kg on days +3 and +4), Aba (10mg/kg on days +5, +14 and +28) and Tac at a dose adjusted based on blood level. Tac taper was initiated on day +60 and completed by day +90. After treating 30 patients, the study was amended to administer an additional dose of Aba on day +56 based on the noted timing of acute GvHD development and Aba terminal ½ life. Patients received standard supportive care by institutional practice including G-CSF and anti-microbial prophylaxis. Serologically CMV positive patients also received letermovir prophylaxis. Results: Patient characteristics are summarized in table 1. Importantly, 19 out of 46 (41.3%) patients were from racial or ethnic minorities. The data cutoff date was July 29th, 2022. Three patients were excluded from this analysis due to short follow-up. For the remaining patients, median follow-up was 8.9 months. Median time to neutrophil engraftment was 18 days (13-30). One patient died before achieving platelet (plt) engraftment and 2 patients have not yet achieved plt engraftment. For the remaining 40 patients, median time to plt engraftment was 29 days (16-52). All patients achieved full donor chimerism at the time of count recovery. Tac was successfully tapered off as planned in all but 5 patients. Cumulative incidence of acute GvHD grades II-IV, III-IV and IV with death as competing event was 12.8%, 5.1% and 0%, respectively. One-year (y) cumulative incidence of moderate to severe chronic GvHD was 17.1%. All cases of acute GvHD except 1 grade II acute GvHD were observed in the first 30 patients. Cases of chronic GvHD included 2 cases of overlap syndrome. There was no case of steroid-refractory acute GvHD or GvHD-related death. One-y cumulative incidence of relapse (non-relapse mortality as competing event) was 8.3% (95% CI 0%-17.1%). KM estimates of 1-year relapse-free survival (RFS), overall survival (OS) and GRFS (composite end point of grade III-IV acute GvHD-, chronic GvHD requiring systemic therapy- and relapse-free survival) were 91.7% (95% CI 83%-100%), 90.6% (95% CI 80.9%-100%) and 71.8% (95% CI 57.2%-90%), respectively. None of the safety stopping rules was triggered. There was 1 case of thrombotic microangiopathy due to Tac and 2 cases of sinusoidal occlusive disease, 1 requiring treatment with defibrotide; all 3 patients recovered. There were 2 cases of respiratory failure of undetermined etiology. One-y cumulative incidence of non-relapse mortality (relapse as competing event) was 2.6% (95% CI 0%-7.8%). The incidence of CMV and EBV reactivation was 39.5% and 2.3%, respectively. There was no case of adenovirus or HHV-6 virus reactivation. BK viruria occurred in 27.9% of patients with limited symptomatology (1 patient required treatment with cidofovir). Immune reconstitution results are summarized in figure 1. Conclusion: CAST is a new GvHD prevention regimen that seems safe and effective, yielding excellent outcomes. CAST also allows early discontinuation of Tac. Outcomes with longer follow-up will be presented at the meeting. If the results are confirmed, CAST might be a step forward toward closing an important health disparity gap in BMT, equalizing the outcomes of haploidentical transplantation and MUD transplants. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Differences in Patterns of Infections Among Allogeneic Hematopoietic Cell Transplant Patients Receiving Letermovir Prophylaxis for Cytomegalovirus

Cytomegalovirus (CMV) infection remains a common complication after allogeneic hematopoietic- cell transplantation (HCT) with a significant increase in morbidity and mortality among patients who acquire such infection. Pre-emptive prophylaxis in which antiviral agents are started based on detection of CMV in the blood to prevent clinical disease has been the standard practice for many years. This approach was limited by the toxicity of available anti-CMV medications and increased complications among patients who activate CMV(1, 2). Letermovir, an antiviral agent that inhibits replication by binding to components of the terminase complex (UL51, UL56, or both) was approved in 2017 for prevention of CMV infection and disease among HCT recipients(3). Letermovir has been shown to delay polyfunctional CMV-specific cellular immune reconstitution as well as cause a decrease in absolute polyfunctional CD8+ T cell responses(4). The impact of such delayed immune reconstitution on infections other than CMV has not been widely described especially in the setting of post-transplant cyclophosphamide as GVHD prophylaxis. To study the impact of Letermovir on non-CMV infections during the first 6 months post HCT and to assess its effect on other transplant endpoints including OS, DFS, NRM, relapse, acute and chronic GVHD, we analyzed 409 consecutive patients who received their HCT at our center between 2016 and June of 2021. Letermovir prophylaxis was started at our center in January 2018 and is given to patients receiving MUD or haploidentical transplant and are either CMV+ or donor is CMV+. The final dataset included 321 subjects with the following characteristics: Median age 54 years (19-80); disease AML/ALL/MDS 81%, NHL/HD/Other 19%; donor type haplo (69%), MUD 31%; Cell Source PBSC 88%; Myeloablative conditioning 38% ; Donor/Recipient +/+ 50%, +/- 12%, -/+ 38% . The median follow up for survivors was 31.2 (11.5-52.6) months for letermovir group versus 66.2 (53.1-76.9) months for no letermovir group. Patients in the letermovir group were less likely to have received a reduced intensity regimen (22% vs 33%, p=0.05) and to have received a marrow graft (8% vs 16%, p=0.02). The survival endpoints at 3 years were OS (72.7% vs 68.8% p=0.5), DFS (64.4% vs 58.0% p=0.27), relapse (21.2% vs 28.6% p=0.08) and non-relapse mortality NRM (14.5% vs 13.5% p=0.5) for letermovir compared to no letermovir . The cumulative incidences for grade II-IV acute and moderate-severe chronic GVHD were 50.7% vs 40.2%, p=0.08 and 24.3% vs 24.1%, p=0.85 for Letermovir and no letermovir respectively The cumulative incidence of CMV reactivation was significantly lower for letermovir 24.4% compared to 57.1% for letermovir (p<0.001) figure 1, whereas non-CMV infections were similar between both groups with a trend towards lower infections for letermovir recipients 75.2% vs 83% p=0.07, figure 1. When assessing the difference in non-CMV infections per infection, there was no difference in the mean number of infections at 6 months post-HCT where patients in both groups had a mean of 2.5 infections. When looking at different types of infections between Letermovir and no letermovir groups, there was no difference in mean number of bacterial infections (1.58 vs 1.43), viral infections (0.90 vs 0.95) and fungal infections (0.16 vs 0.22), P =NS for all. Our data shows that in a large cohort of allogeneic HCT recipients, mostly haploidentical with Post-transplant cyclophosphamide, letermovir significantly decreases CMV reactivation without changing the pattern or incidence of non-CMV infections. 1. Teira P, Battiwalla M, Ramanathan M, Barrett AJ, Ahn KW, Chen M, et al. Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood. 2016;127(20):2427-38. 2. Boeckh M, Ljungman P. How we treat cytomegalovirus in hematopoietic cell transplant recipients. Blood. 2009;113(23):5711-9. 3. Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, et al. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. The New England journal of medicine. 2017;377(25):2433-44. 4. Zamora D, Duke ER, Xie H, Edmison BC, Akoto B, Kiener R, et al. Cytomegalovirus-specific T-cell reconstitution following letermovir prophylaxis after hematopoietic cell transplantation. Blood. 2021;138(1):34-43. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal