Transplant-related Toxicity Research Articles

Relapsed primary central nervous system lymphoma treated with CD19 chimeric antigen receptor T-cell therapy and allogeneic hematopoietic stem cell transplantation

Relapsed and/or refractory (R/R) primary central nervous system lymphoma (PCNSL) has a poor prognosis. A 57-year-old man diagnosed with PCNSL achieved a complete response by high-dose methotrexate-based chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT). The disease was not cured, so he was treated with the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel after the third relapse. However, the disease relapsed again 28 days after CAR T-cell therapy. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was attempted as curative therapy after bridging with second ASCT and tirabrutinib monotherapy. Although a temporary response was achieved, the disease relapsed 98 days after allo-HSCT. While receiving tirabrutinib for relapse after allo-HSCT, the patient developed acute respiratory failure due to transplant-related toxicity and post-transplant thrombotic microangiopathy. He died 175 days after allo-HSCT. Although various treatments for PCNSL have been investigated in recent years, the treatment strategy for R/R PCNSL has not been established. Further studies are warranted to improve the outcomes of patients with R/R PCNSL.

Outcomes and Late Complications after Umbilical Cord Blood Transplantation for Fanconi Anemia: A Study on Behalf of Eurocord and Severe Aplastic Anemia Working Party - EBMT

Fanconi Anemia (FA) remains a disease with poor prognosis for which hematopoïetic cell transplantation (HCT) offers the only available curative option, with particular good results observed after matched sibling donor transplants. This study aimed to assess transplant outcomes and describe late complications in a large cohort of patients with FA who underwent umbilical cord blood transplantation (UCBT) in the European Society for Blood and Marrow Transplantation (EBMT) affiliated centres. Methods: We retrospectively reviewed all cases of FA whoreceived UCBT as first allogeneic transplant between 1988 and 2021. Data on late effects were collected with a questionnaire completed by transplant centres for patients who survived >2 years (y) after UCBT. Results: A total of 205 patients with FA received UCBT (55 related and 150 unrelated) in 77 transplant centres. Indications for UCBT were bone marrow failure in 191 patients (BMF, 93%) and acute leukemia/myelodysplasia in 14 patients (AL/MDS, 7%). Median age at transplant was 8.8 y (1.2-43) and 90% (n=185) were children <18y old. Graft sources included single (n=164), double (n=23) or UCB co-infused with other cell sources (n=18). Recipients and UCB pairs had 0-1/6 HLA mismatches in 48% (n=99). Most patients (n=196, 97%) received reduced intensity conditioning. Flu Cy-based (n=116; 57%) and Bu Cy ± Flu (n=48, 23%) were the most frequently used regimens. Total body irradiation (TBI) or total lymphoid irradiation (TLI) were administered to 28% (n=58) of patients at doses < 8 Gy. Serotherapy consisted of anti-thymocyte globulin (ATG, n=159; 78%) or alemtuzumab (n=8; 4%). Graft- vs-host disease (GVHD) prophylaxis was mainly based on CSA ± steroids (65%) or MMF ± steroids (32%). Median follow-up was 88 months (3-345). The cumulative incidence (CI) of neutrophil recovery was 79% (67-79) at day 60,with a median time of 20 (7-62) days (d). The 100d CI of grades II-IV acute GVHD (aGVHD) was 29.8% (24-37). The 5y CI of chronic GVHD (cGVHD) was 30.4% (24-38) with 12% extensive forms. The 1y-CI of non-relapse mortality (NRM) was 37.4% (31-45). At 5y follow-up, event-free survival (EFS) was54% ± 3 and overall survival (OS) was 55% ± 3. In multivariate analysis, HLA matching 0-1/6 (HR 2.0, p=0.01) and related UCBT (HR 2.4; p=0.001) were predictive of better engraftment. None of the tested factors had statistical significant impact on incidence of aGVHD or cGVHD. Negative recipient CMV serology (HR 0.29, p=0.003) and transplant year ≥2013 (HR 0.29; p=0.004) were the only factors associated with improved OS. Both factors were also predictive of better NRM and EFS. Fifty-one recipients of UCBT (3 related and 48 unrelated) experienced primary graft failure (GF). Twenty-six patients underwent subsequent allogeneic HCT within a median of 1.8 months (0.8 -6.8) after first UCBT. Seven subsequent HCT recipients (1 related bone marrow (BM), 1 related peripheral blood, 1 unrelated BM, and 4 unrelated UCB) were alive at last follow-up. Second neoplasms developed in 8 patients (4%) within a median interval of 9.7 y post-UCBT (3.6-13.5) and included one donor derived-AML and 7 solidtumors (1 skin, 2 upper GI, 4 oral cavity) . A totalof93 patients (45%) died from transplant related toxicity (n=85, including 42 who died after GF), second neoplasms (n=6) or unknown cause (n=2). Survival >2y was observed in 106 patients, but comprehensive data for late transplant complications were available only in 45 long-term survivors. For these 45, median post transplant follow-up was 8.7y (2.7-28.8). Late organ impairments ( table 1) included: endocrine disorders (32%), lung (24%), eyes (20%), kidneys (20%), immune system (18%), liver (16%), musculoskeletal, and bone (16%) diseases. Other dysfunctions involved: oral mucosa (11%), neurologic system (7%), gastrointestinal (4%), genital (13%) and urinary tracts (4%). Cardiovascular complications were rare (1 case of chronic pericarditis). Conclusion: Improved outcomes have been observed in recent years in FA patients receiving unrelated UCBT likely due to improved conditioning regimens, effective post-transplant care and better HLA parity. With longer survival, late multi-organ complications are observed. Identification of risk factors and life-long screening for early management of organ impairments and second neoplasms are mandatory to improve quality of life of transplant survivors and decrease late mortality.

Transplant Outcomes for Acute Myeloid Leukemia or Myelodysplastic Syndromes Secondary to Acquired Aplastic Anemia or Paroxysmal Nocturnal Hemoglobinuria: A Report from the EBMT Severe Aplastic Anemia Working Party

Introduction Clonal evolution into myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) is the most concerning late event among non-transplanted acquired aplastic anemia (AA) or paroxysmal nocturnal hemoglobinuria (PNH) patients, occurring in nearly 10% of cases. MDS/AML secondary to AA differ from primary MDS/AML, presenting with higher risk cytogenetics and poorer prognosis, usually involving abnormalities in chromosome 7 (Gurnari C. et al., JCO 2023). The survival is poor, and the only curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT). We present the HSCT outcomes of secondary MDS/AML following AA/PNH. Methods We have extracted data from the EBMT database for patients with AA or PNH diagnosed after 2010, who later presented a clonal evolution into AML, MDS, or isolated cytogenetic abnormality insufficient for MDS diagnosis according to WHO 2016 classification, who have undergone HSCT after the clonal evolution diagnosis. We have excluded AA/PNH patients with HSCT before clonal evolution, inherited bone marrow failure syndromes, and non-transplanted patients. Our primary objective was to describe the overall survival (OS). The secondary aims were transplant outcomes according to clonal evolution category and conditioning regimen intensity. Results: We have studied 278 patients from 114 different EBMT centers, 250 patients diagnosed with AA, and 28 with classical PNH. The median age at AA/PNH diagnosis was 34.7 (20.5-51.7) years. At first evolution, 153 (56.5%) patients had a diagnosis of MDS, 45 (16.6%) AML, and 73 (26.9%) isolated abnormal cytogenetics insufficient for a diagnosis of MDS (missing data for 7 patients). The median interval from AA/PNH diagnosis to clonal evolution was 30.1 (8.1-67) and 39.8 (21.5-82.6) months for MDS and AML, respectively. The interval from clonal evolution to HSCT was 5 (3-10.2) and 3.4 (2.3-5.1) months for MDS and AML, respectively. We present transplant characteristics in Table 1. With a median follow-up of 5 (4.3 - 5.9) years, the 5-year overall survival (OS) was 65% for the entire cohort. A subgroup analysis did not find a significant 5-year OS difference among groups: 73, 62, and 60% for isolated cytogenetic abnormality, MDS, and AML, respectively (p=0.3, Figure 1). The main causes of death were transplant-related toxicities (66.7% and 75% for isolated cytogenetic abnormality and MDS, respectively) and relapse or progression for AML (43.8%). AML patients relapsed more frequently than MDS patients by 5 years [cumulative incidences of 22 (9-35) vs. 10% (4-17) for AML and MDS (p=0.046), respectively]. The 5-year non-relapse mortality (NRM) was 19 (7-31) and 28% (19-36) for AML and MDS patients, respectively (p=0.3). When stratifying by conditioning regimen intensity, the 5-year NRM was 34% (19-40) for myeloablative (MAC) vs. 18% (9-26) for reduced-intensity (RIC, p=0.025), with similar incidence of relapse in both groups (4 vs 10% for MAC and RIC, respectively, p=0.2). AML patients were more prone to have presented acute graft-versus-host disease (GvHD) by day+100 than MDS or isolated cytogenetic abnormality patients (cumulative incidences of 36, 26, and 14% respectively, p=0.022). Likewise, AML patients had more chronic GvHD (43, 28, and 12% respectively, p=0.008). Graft-failure, GvHD, relapse-free survival (GGRFS) was 71 (61-82), 60 (51-68), and 45% (29-60) for isolated abnormality, MDS, and AML, respectively (p=0.026). Discussion This study is the largest cohort of transplanted patients with secondary MDS/AML following AA/PNH. The major limitations of our study are its retrospective nature, non-adjusted analyses, and missing data on complete cytogenetics. We found a 5-year OS higher than 60% for MDS/AML compared to 45% in the previously published EBMT study (Hussein A. et al., BBMT 2014) and did not find a survival difference between AML and MDS. Interestingly, the main cause of death for MDS patients was HSCT complications. Furthermore, MAC was also associated with a higher NRM. Clinicians should indicate HSCT with discretion for post-AA/PNH MDS or isolated cytogenetic abnormality, considering the transplant toxicity, especially with MAC, and the risk of primary disease progression. For patients with AML and a high risk of relapse, early tapering of immunosuppressive agents and post-transplant maintenance, such as hypomethylating agents and donor lymphocyte infusion, should be considered.

Prevention of CMV/EBV Reactivation By Double-Specific T Cells in Patients after Allogeneic Stem Cell Transplantation: Results from the Randomized Phase I/IIa Multivir-01 Study

Allogeneic stem cell transplantation (aSCT) is used to cure hematologic malignancies or deficiencies of the hematopoietic system. It is associated with severe immunodeficiency of the host early after transplant and therefore early reactivation of latent herpesviruses such as CMV and EBV within the first 100 days are frequent. Small studies and case series indicated that application of herpes virus specific T cells can control and prevent disease in this patient population. Study Design: A randomized, controlled, phase I/IIa multi-center study was conducted in 5 centers in Germany between 2013 and 2018 (ClinicalTrials.gov Identifier: NCT02227641). The study aimed at prevention or pre-emptive treatment of reactivation of CMV and EBV post aSCT. Major inclusion criteria were male or female HLA matched (10/10) unrelated or related donor seropositive for CMV and EBV, patient age between 18 and 75, the use of PBSC as stem cell source and the presence of on of the following HLA alleles: A*01:01, A*02:01, B07:02, B*08:01, B*35:01, C*07:02. CMV/EBV specific T cells were generated from a fraction of the allogeneic stem cell graft by stimulation with peptide pools for both viruses developed at the University Hospital Erlangen. Three doses of 5x10E4 CD3+ T cells per kilogram body weight were applied with an interval of at least 30 days without dose escalation starting earliest at day 30 after aSCT. Observation period was 204 days after aSCT. Primary endpoint of the study was toxicity of the T-cell-product assessed as acute transfusion reaction and acute GvHD due to the infusion of activated T cells. Results: 33 patients were screened and 29 patients were randomized. 16 patients were randomized into the treatment group of who 3 patients crossed over to the control arm due to failure of manufacturing the product or due to not meeting release criteria. Four patients were excluded from the study before receiving the first dose due to transplant related toxicity or withdrawal of consent. In total 9 patients were treated with 25 doses of the T cell product (dose range 2.1-4.1x10E4/kg CD3+ T cells). The earliest infusion was on day 30 (range: 30-69) post aSCT. There was no statistical difference between the groups regarding disease, patient age, donor type, performance status and comorbidities. The median follow up for both groups was 930 days. None of the patients treated experienced any acute transfusion reaction. Two patients developed acute GvHD after the second infusion and did not receive the third dose. Overall there was no statistical significant difference regarding survival (A) (treatment: 55.9% vs. control 69.2%, p=0.44), transplant related mortality (B) (22.2% vs. 7.1%, p=0.28), relapse (C) (11.1% vs. 14.3%) and acute GvHD (D,E) (33.3% vs. 46.2%, p=0.44). Number of AE per patient (27.1±24.6 vs. 24.4±11.2, p=0.60) and severity of AE (1.60±0.39 vs. 1.64±0.24) were similar in both groups. The incidence of reactivation of CMV (44.4% vs. 64.3%, p=0.16) and EBV (77.8% vs. 44.4%, p=0.12) was not statistically different and not associated with the treatment as several reactivations of occurred before application of the first dose. Within the treatment group we observed in several cases substantial expansion of CMV and EBV specific T cells in the peripheral blood which could not attributed to the presence viral antigens in case of reactivation. Conclusion: The study met its primary endpoint as there was no toxicity of the T-cell product observed. The cumulative incidence of acute GvHD as the primary endpoint was not statistically different in both groups and there was no acute toxicity related to the product. The study suffered from slow recruitment due to the market approval of Letermovir and low patient numbers did not allow for conclusive analysis of secondary endpoints such as the use of antiviral therapy.

Treosulfan-Based Reduced-Toxicity Conditioning for Elderly Patients with High-Risk Myelodysplastic and Myeloproliferative Disease for Allogeneic Hematopoietic Stem Cell Transplantation

Introduction Allogeneic hematopoietic stem cell transplantation (alloHCT) is the only potential curative treatment for patients (pts) with high-risk myeloid malignancies. Despite advances in the supportive care over the past decades, alloHCT is still associated with significant toxicity, especially in the elderly population. The choice of an adequate conditioning regimen has become essential in order to prevent treatment-related morbidity and mortality. Since myeloablative conditioning (MAC) is mostly restricted to the younger population due to the high toxicity, reduced-intensity conditioning (RIC) provides an alternative solution. However, especially for pts with high-risk disease, a potential increase in the incidence of relapse must be taken into account. The advent of reduced-toxicity conditioning regimens (RTC), mostly based on treosulfan in combination with fludarabine, offers a balance between a favorable toxicity profile and a strong anti-neoplastic effect. Considering the increasing rates of alloHCT among older pts in the past decades, finding the optimal conditioning regimen is still an unmet need for this collective. The objective of this study is to analyze the outcome of pts aged ≥60 years who underwent alloHCT for myelodysplastic or myeloproliferative disease and received a treosulfan-based conditioning. In order to maximize the anti-leukemic effect of the conditioning in this population we chose the myeloablative dose of treosulfan of 14g/m2 daily. Materials and methods We retrospectively analyzed the outcome of adult pts ≥60 years with myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) or myelofibrosis (MF) who underwent their first allo-HCT from a matched or mismatched donor over a period of 10 years at the adult Bone Marrow Transplantation Unit of our institution. The conditioning consisted of a combination of treosulfan 14 g/m2/day on days -6 to -4, fludarabine, 30 mg/m2/day on days -6 to -2, alone or combined with 2 Gy TBI (day 0) for MDS and treosulfan, 14 g/m2/day on days -6 to -4, fludarabine, 30 mg/m2/day on days -6 to -3 for CMML and MF. Endpoints of this analysis were engraftment rate (together with time to engraftment), relapse-free survival (RFS), overall survival (OS), and non-relapse mortality (NRM). Continuous variables were illustrated as median values. NRM, RFS and OS for the whole cohort were analyzed with the Kaplan-Meier method and presented as survival functions. Results Between 01/2012 and 12/2022 91 consecutive elderly pts were eligible for this analysis. Patient and transplant characteristics are listed in Table 1. The median follow-up after allo-HCT was 3.12 years (4 months-10.5 years). Median age was 65 years, 76% (n = 69) of patients had an EBMT (European Society for Blood and Marrow Transplantation) risk score of ≥ 4. In 20 of 91 pts (22%) a 9/10 matched unrelated donor was selected, due to the lack of a more suitable donor. The standard graft versus host disease (GVHD) prophylaxis was a combination of calcineurin inhibitors (CNI) +/- mycophenolate mofetil and Anti-T-lymphocyte globulin (ATG) (n= 85, 94%). Neutrophil engraftment was achieved in 98% (n= 89) of pts. The median time to engraftment was 13 days (12, 15). Fourteen of 91 pts (15%) developed severe (grade III-IV) acute GVHD, and 44% (n= 40) had chronic GVHD of any grade. Considering early toxicity, 2 patients of 91 (2%) died before day +30 after alloHCT due to transplant-related toxicity, overall 6 of 91 (7%) in the first 100 days after alloHCT. The 2-year OS was 55% (95% CI, 44.7-.66.2) (Figure 1) and RFS was 48.5% (95% CI, 38.9-60.5). The 2-year NRM was 37% (95% CI, 33.5-39.5). No significant differences have been observed in the outcome of the different disease entities. Main causes of death were infections (n= 15, 32%), GVHD (n=13, 27.7%) and disease relapse (n= 13, 27.7%). Conclusions Our retrospective analysis suggests that a treosulfan-based RTC with myeloablative potential in an elderly and frail population of pts with high-risk myeloid diseases is feasible, with an excellent engraftment rate and a limited early toxicity, and promotes disease control. We report a 2-year NRM of 37%, which was partially due to severe GvHD in a cohort of pts with a relatively high-proportion of mismatched donors (20%). The role of post-transplant cyclophosphamide as backbone of the GvHD prophylaxis of RTC regimes should be further evaluated, in prospective trials.

Considering Older Patients As Candidates for Auto Stem Cell Transplants: A Comprehensive Study on Toxicities and Survival Analysis

Introduction: High-dose chemotherapy and autologous stem cell transplantation (ASCT) are commonly used for relapsed/refractory (R/R) Hodgkin (HL) and non-Hodgkin lymphoma (NHL). However, concerns about treatment-related mortality (TRM) and toxicity limit its use in older patients (pts). Existing evidence suggests higher rates of complications and inferior overall survival (OS) in older pts, but conflicting findings suggest that outcomes may be influenced by comorbidities rather than age ( Lahoud O, Curr Oncol Rep. 2015). Our study comparing ASCT outcomes and toxicities in lymphoma pts in younger and older age groups. Methods: In this retrospective study, we analyzed lymphoma pts who underwent ASCT at the Princess Margaret Cancer Centre from January 2015 to December 2019. After Institutional Review Board approval, clinical data was collected from institutional databases and patient charts. The hematopoietic cell transplantation comorbidity index (HCT-CI) and Charlson Comorbidity Index (CCI) were retrospectively calculated. Response assessment was done by Lugano 2014 classification. Grade 3-5 nonhematologic toxicities were collected from admission to day 100 using Common Terminology Criteria for Adverse Events version 5. Overall survival (OS) and progression-free survival (PFS) were calculated from date of transplant to death or disease progression. OS and PFS assessed via Kaplan-Meier; log rank tests and Cox regression performed. The patients were divided into two age groups: Group A (<65 years) and Group B (≥65 years). Results: There were 334 pts who underwent ASCT. 332 pts were analyzed; 2 pts were lost to follow-up and 16 pts were day 1 transfers, making acute toxicity data unavailable. The median age was 53 (range: 18-71), 17% of pts being aged ≥65. The majority of pts (69%) had NHL (table 1). The Eastern Cooperative Oncology Group (ECOG) performance status was ≤1 for 91%. Group B had a higher proportion of pts with ECOG score =2 (18% vs 7%, p < 0.001 ) and higher CCI (88% vs 27% , p < 0.001). NHL and mantle cell lymphoma (MCL) were more prevalent in Group B (93%, 23% vs 68%, 12% respectively, p< 0.001). Thirteen percent of NHL pts were transformed disease. Both groups had similar percentage of pts with central nervous system (CNS) lymphoma (~ 5%). Conditioning regimens varied based on lymphoma type: most of the HL/aggressive lymphomas: Etoposide+Melphalan (ML), CNS lymphoma: Thiotepa based regimen, and MCL Cytarabine + ML+/- Total Body Irradiation. The majority (83%) were treated for R/R disease, while 17% received it as first-line treatment. Prior to transplant, 76% of pts were in CR. Median follow-up was 38 months. Median OS was not reached for Group A, and 73 months for Group B. Five year OS were 82% and 74% respectively (p = 0.05). Median PFS was 75.2 months for Group A and 43.0 months for Group B, with 5-year PFS of 54% and 47% respectively (p = 0.2). Twenty percent of pts died during follow-up, with only 4% being NRM. From the entire cohort 3% of patients died within 100 days post-transplant, with no difference between groups. Three pts died within 100 days of ASCT with 2 deaths from sepsis (Group A) and 1 death from Respiratory failure (Group B). Common transplant-related toxicities did not differ significantly between groups (figure 1). Group B had significantly higher rates of Renal (7%vs 18%), Respiratory (16% vs 6%), and Metabolism abnormalities (14% vs 5%) (p = 0.021-0.028). Group B needed more blood product transfusions by 100 days post-transplant: Packed Cells (mean) 1.7 vs 1.1 units (p 0.08), Platelets (mean) 3 vs 1.9 units (p 0.002). Group B had a longer average length of stay 18 days vs. 14 days (p < 0.001). About 6% of pts required ICU admission, and 4% were discharged to rehabilitation/long-term care facilities, with no group differences. Conclusions: The study concludes that ASCT can be safely performed in appropriately selected elderly pts. TRM rates were not significantly higher in older compared to younger pts with lymphoma. However, older pts did experience higher rates of specific toxicities including renal failure, pulmonary complications, metabolism abnormalities, longer hospital stays, and increased transfusion requirements. In the multivariate analysis, older pts exhibited shorter OS, influenced by lymphoma type and treatment response. Further research is needed to develop risk stratification and geriatric assessments to improve toxicity prediction in elderly pts undergoing ASCT.

A Phase IB/II Study of Blinatumomab in Patients with B-Cell Acute Lymphoblastic Leukemia (ALL) and B-Cell Non-Hodgkin Lymphoma (NHL) As Post-Allogeneic Blood or Marrow Transplant (alloBMT) Remission Maintenance

Background: AlloBMT can be curative as consolidation for high risk B ALL and NHL. However, transplant-related toxicity and disease relapse limit survival. Post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis limits GVHD and facilitates alternative allograft sources. Following PTCy, cellular immune reconstitution is favorable for strategies to augment anti-tumor immunity. Blinatumomab (blina) is effective in the treatment of CD19+ ALL and NHL. Blina leads to T cell activation that may enhance post-transplant tumor-specific T cell responses, leading to a more potent graft-versus-tumor effect. A study of 21 B ALL pts demonstrated the feasibility of post-transplant blina but did not improve survival when pts universally remained on immunosuppression for at least 1 cycle of treatment (Gaballa. Blood. 2022). We present results of a phase Ib/II trial to assess the tolerability and preliminary efficacy of blina as post-alloBMT remission maintenance in B-cell ALL and NHL in pts off immunosuppression. Methods: Pts ≥1 month-old with high risk CD19+ B ALL or ≥18 years-old with NHL who underwent alloBMT with PTCy were eligible. Pts had to be 60-180 days post-transplant with count recovery and in remission. Pts had to be off immunosuppression for ≥4 weeks prior to treatment, and without a history of grade ≥3 acute GVHD or severe chronic GVHD. Pts could receive 2 cycles of blina if they had evidence of disease (including MRD) at their pre- and/or post-transplant evaluations but otherwise received 1 cycle. Blina was given as a continuous infusion at 9 mcg/day on C1D1-7 and 28 mcg/day on C1D8-28 and C2D1-28. Results: The study closed to accrual on January 31, 2023 following enrollment of 42 pts (26 male/16 female) with a median age of 54 (Range 30-73). Among enrolled pts, 19 had Ph-negative B ALL and 23 had B-cell NHL. All pts underwent reduced-intensity conditioning alloBMT using a regimen of fludarabine, cyclophosphamide, and total body irradiation. Median prior lines of therapy were 2 (range 1-6). Additional transplant details are presented in Table 1. All B ALL pts were in an MRD-negative CR by flow cytometry at a sensitivity of 0.01% at alloBMT. All pts received a single cycle of therapy. Pts started blina a median of 137 days post-transplant (range, 90-182). Four pts failed to complete a full cycle due to G4 transaminitis (1), G4 neutropenia (1), relapse (1), and patient preference in the setting of tremors (1). Grade 3 or 4 adverse events felt to be at least possibly related to the study drug included G3 neutropenia (7%), G4 neutropenia (19%), anemia (5%), G3 ALT (5%), G4 AST (2%), G3 AST (2%), and neurotoxicity (7%). Two pts (5%) developed chronic GVHD following blina requiring the resumption of immunosuppression. At a median follow-up of 40 months post-alloBMT, the 3-year relapse-free survival is 73% (95% CI 54-85%) due to a 24% (95% CI 12-39%) incidence of relapse and a 4% (95% CI 0-17%) incidence of non-relapse mortality, as shown in Figure 2. All 3 (100%) relapsed B ALL pts and 2/6 (33%) relapsed B NHL pts presented with CNS involvement. Four pts with CNS relapse (80%) had CNS involvement prior to alloBMT. Among 2 pts who died without relapse, 1 was unrelated to alloBMT, while the other died of therapy-related myeloid neoplasm. Data on biomarkers including changes in T cell subpopulations in both BM and PB, and co-signaling molecule expression will be presented. Conclusions: Post-alloBMT maintenance therapy with blina is feasible with minimal toxicity in pts off immunosuppression. Initial survival outcomes are promising with the majority of relapses involving the CNS. A randomized trial of maintenance with blina after alloBMT with PTCy is needed to confirm efficacy in this high-risk population.

The Effect of Allogeneic Hematopoietic Stem Cell Transplantation on Sickle Cell Disease-Related Organ Damage: A Systematic Review and Meta-Analysis

Background Allogeneic hematopoietic stem cell transplantation (HSCT) is the only established curative treatment option for patients with sickle cell disease (SCD). One of the main indications for HSCT is SCD-related organ damage, which is a major cause of morbidity and early mortality. However, whether HSCT is effective in recovering SCD-related organ dysfunction has not been systematically reviewed. Methods This is a systematic review and meta-analysis investigating the effects of HSCT on organ function in patients with SCD. We performed a comprehensive search in MEDLINE/PubMed and EMBASE up to June 2023, focusing on studies reporting pulmonary, cardiac, renal, splenic, and/or cerebral function parameters, as well as retinopathy and/or avascular osteonecrosis (AVN) before and after HSCT. Continuous data were analyzed using the weighted inverse-variance random effects meta-analyses, reported as standardized mean difference (SMD) and 95% confidence intervals (95%-CI). Binomial data were analyzed using the Mantel-Haenszel random effects meta-analyses, reported as risk ratio (RR) and 95%-CI. A negative SMD indicates an improvement and a positive SMD indicates a worsening of the measured parameter post-HSCT. A RR <1 indicates a result in favor of the transplantation and a RR >1 indicates a worsening of the measured parameter after HSCT. The ‘Newcastle-Ottawa Quality Assessment Scale’ and the ‘Clinical Diversity in Meta-analysis’ (CDIM) tool were used to assess the quality and the clinical heterogeneity of the studies. Results Thirty-two of 476 studies met our inclusion criteria, of which 17 were used for the meta-analyses and 15 for the qualitative part of the review. Of the studies that were included in the meta-analyses, 4 comprised adult patients (n=184) and 13 pediatric and/or young adults <22 years old (n=591). The majority of donors were matched sibling donors (86.4%), and studies with both myeloablative and/or reduced intensity conditioning regimens were included. The CDIM score was low or moderate for all performed meta-analyses, suggesting fair clinical comparability among the studies. Summary plots of the meta-analyses are shown in Figure 1. Pulmonary function test parameters remained stable following HSCT (SMD -0.08, p=0.64 for forced expiratory volume in 1 second; SMD -0.13, p=0.35 for forced vital capacity; and SMD -0.95, p=0.30 for diffusing capacity). Mean tricuspid regurgitation velocity (TRV) did not change significantly in the meta-analysis (SMD -0.34, p=0.14). However, 3 studies used for the qualitative review reported normalization in patients with prior elevated TRV. Whole brain cerebral blood flow improved significantly after transplantation (SMD -1.39, p=<0.01). Several studies reported an absent or very low incidence of new (silent) cerebral infarcts and a decrease of transcranial Doppler velocities following successful HSCT. In pediatric patients, creatinine clearance decreased significantly after HSCT (SMD -0.80, p=0.01) and the presence of proteinuria increased (RR 2.00, p=<0.01). Furthermore, splenic uptake ( 99mTc) and phagocytic function of the spleen improved (RR 0.31, p=<0.01 and RR 0.23, p=<0.01, respectively). Retinopathy and AVN before and after HSCT were investigated in only 1 study in children with SCD, both showing no significant changes post-HSCT. Discussion and Conclusion Allogeneic HSCT has the potential to stabilize or recover pulmonary and cardiac function parameters in SCD patients. In pediatric patients, splenic function parameters showed impressive improvement following HSCT. On the other hand, creatinine clearance decreased significantly in children. This might be a reflection of either normalization of SCD-related hyperfiltration or transplantation-related toxicity, which may also have contributed to the increased prevalence of proteinuria after HSCT. With respect to cerebral damage, cerebral perfusion parameters improved and progression of silent cerebral infarctions was prevented following HSCT. Last, we demonstrate a paucity of evidence regarding the course of renal function, retinopathy, and AVN in adult SCD transplant recipients. More research is needed to define which patients with SCD-related organ damage might benefit most from HSCT and which organs are less likely to recover.

Safety and Efficacy of Outpatient Myeloablative Busulfan Conditioning in Allogeneic Stem Cell Transplantation

INTRODUCTION: Busulfan-based regimens are the backbone of myeloablative conditioning (MAC) in allogeneic hematopoietic stem cell transplant (allo-HSCT), particularly for patients (pts) with Acute Myelogenous Leukemia (AML). However, literature on busulfan conditioning administered in the outpatient (OP) setting is limited. Here, we investigate the safety and efficacy of OP busulfan as compared to standard inpatient (IP) administration. METHODS: Pts > 18 years of age who received pharmacokinetically dose adjusted IV busulfan (130 mg/m2 x 4 days) conditioning prior to HSCT between January 2019 and April 2023 at our institution were included in this retrospective analysis. Pts who received non-myeloablative conditioning or who underwent a haploidentical HSCT were excluded. All pts undergoing HSCT were classified as having low-, intermediate-, or high-risk disease by the Disease Risk Index. Pts with AML were classified as having favorable, intermediate, or adverse disease by 2022 ELN classification. CIBMTR guidelines were used to determine neutrophil and platelet engraftment. Oral mucositis was graded per the World Health Organization scale. Clinical grading of acute graft-vs-host disease (AGVHD) was assigned per standard criteria. Adverse events (AEs) were reported in accordance with the CTCAE, v.5. Categorical variables were compared using the Fisher's Exact test. Continuous variables were compared using the Wilcoxon Rank-Sum test. Overall survival (OS) was defined as time from HSCT to time of death from all-cause mortality. Relapse-free survival (RFS) was defined as time from HSCT to time of relapse or non-relapse mortality. The Kaplan-Meier method was used to estimate OS and RFS. Survival differences between cohorts were compared using the Log-rank test. All hypothesis testing was two-sided and conducted at a significance level of 0.05. RESULTS: In total, 54 pts met eligibility criteria; 43 IP and 11 OP. The OP cohort was younger than the IP cohort (35 years vs 47 years median age; p=0.0284). All other patient, disease, and transplant characteristics were similar between cohorts. The majority of pts were male (IP: 56%, OP: 55%) and White/Caucasian (IP: 100%, OP: 91%). AML (IP: 88%, OP: 82%) was the most common indication for HSCT. Most pts were in CR1 (IP: 74%, OP: 89%) and had intermediate risk disease by both DRI (IP: 84%, OP: 64%) and 2022 ELN classification (IP: 62%, OP: 67%). PBSCT (IP: 88%, OP: 91%) and 10/10 MUD (IP: 67%, OP: 45%) were the most common types of HSCT. The majority of pts received a conditioning regimen of Flu/Bu4 (IP: 58%, OP: 55%). The use of PTCy was comparable between groups (p=0.6593). Of the 11 pts who received OP busulfan, 1 had to complete their conditioning IP after experiencing a seizure in the setting of prior meningitis. Between the 2 cohorts, there was no significant difference in the incidence of AEs > grade 2 (p=1), grade 2 AEs (p=0.8695), grade 3 AEs (p=0.7592), grade 4 AEs (p=0.2487), and grade 5 AEs (p=0.6457) within 30 days of conditioning. Incidences of transplant-related GI toxicities, including nausea (p=1), vomiting (p=0.4979), diarrhea/enteritis (p=1), and mucositis (oral: p=0.6102, GI: p=0.2821) were similar. There was no difference in time to neutrophil (p=0.1606) or platelet engraftment (p=0.9742). Length of hospitalization was shorter in the OP vs IP cohort (18 vs 24 days; p<0.0001). During hospitalization, there was no difference in the incidences of neutropenic fever (p=1), infection (p=0.5104), ICU transfer (p=1), or engraftment syndrome (p=0.7076). Number of infections per patient during hospitalization were comparable (p=0.3764). D30 chimerism was similar IP vs OP. Within 180 days of HSCT, there was no difference in the incidence of AGVHD (p=0.5152) or Grade II-IV AGVHD (p=1). Differences in 2-year OS (LR=0.2200) and 4-year RFS (LR=0.3144) were not significant. CONCLUSION: In pts undergoing MAC allo-HSCT with IV busulfan,OP administration shortens the length of hospitalization without delaying engraftment or increasing the risk of toxicity, neutropenic fever, infection, or ICU admission. Additionally, D30 chimerism, rates of engraftment syndrome and AGVHD, and survival were not affected. This makes OP busulfan an attractive option for transplant centers and their pts.

Allogeneic Hematopoietic Cell Transplantation with Sequential-Based Conditioning in Refractory / Relapsed Acute Myeloid Leukemia: Experience from a Single Institution

INTRODUCTION: Despite improvements in the treatment and outcomes of patients with acute myeloid leukemia (AML), in nearly 10-20% of the cases, a morphological remission (CR) after administrating induction regimens is not achieved. In other cases, and despite initial CR, early disease relapse may occur, with only a minority of patients durably benefiting from salvage regimens. Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative strategy for patients with relapsed / refractory (R/R) AML. However, the prognostic of these patients after allo-HCT remains dismal, with reported survival rates ranging from 20% to 35% in different publications. Allo-HCT using peripheral blood and sequential-based conditioning regimens has been the transplant platform used at our institution for R/R AML during the last decade. During the study period the use of post-transplant cyclophosphamide (PTCY) combined with tacrolimus (TK) has been implemented on this allo-HCT setting. This study evaluates the results obtained from a single institution obtained from using sequential allo-HCT for patients with R/R AML, and the effectiveness of having implemented the use of PTCY in this type of transplant. Very few studies have evaluated the safety of including PTCY-based in sequential-based conditioning allo-HCTs. METHODS: This study includes the 21 patients with R/R AML who underwent allo-HCT with sequential-based conditioning regimens at our institution between 2011 and 2022. Retrospective data were collected during June 2023. Sequential regimens combined fludarabine (150 mg/m2), cytarabine (2 g/m2 x 5 days), and idarubicin (12 mg/m2 x 3 days) chemotherapy with low doses of Bu (n=3), melphalan (n=17), or treosulfan (n=1). Six adults transplanted after November 2016 received PTCY (50mg/kg/24h) on day +3 and +4 followed by TK from day +5 to day +90 for GvHD prevention. RESULTS: The main baseline characteristics of the study cohort and according to the GVHD prophylaxis are shown in Table 1 . The median age was 53 years (range 31-68), 11 (52%) patients were males, and all patients had R/R AML after having received at least one line of induction chemotherapy with curative intent. Fourteen (66.7%) patients received grafts from HLA-matched donors, and 7 (33.3%) from 9/10 HLA mismatched unrelated donors (MMUD). Baseline characteristics between patients who received PTCY and those who did not were balanced, except for the proportion of allo-HCT performed from MMUD which was higher in the PTCY group (66.7% vs. 20.0% p=0.03). Post-transplant results are shown in Table 2. All patients engrafted (100%). Patients who received PTCY experienced similar median of days to neutrophil engraftment (18 vs. 15 days, P=0.103) and a longer median of time to platelet engraftment (25 vs. 13 days, P=0.046). The day +100 cumulative incidences (CI) of grade II-IV and III-IV aGVHD, and 2-year CI of moderate/severe cGVHD were 33.3%, 0% and 0% for patients who received PTCY-TK, and 40% (p=0.823), 33% (p=0.118), and 40.4% (p=0.099) for those who did not. During the first 2-years after allo-HCT, 8 (38%) out of 21 patients died and 7 (21%) relapsed. The main causes of death were relapse (n=4, 19%) and infection (n=2, 9.5%), and the 2-year OS, PFS, NRM and CIR were 61.5%, 51.9%, 14.3%, and 33.3%. As shown in Table 2 patients who received PTCY had comparable rates of OS (2-y: 50.0% vs. 66.7%, p=0.903) and RFS (2-y: 50.0% vs. 53.3%, p=0.873) and those who did not. In addition, and although no patient who received PTCY died secondary to transplant-related toxicity (2-y 0 vs. 20%, p=0.254), a non-significant trend to higher cumulative incidence of relapse (2-y: 50.0% vs. 26.7%, p=0.282) was observed in this group of patients. Lastly, a non-significant trend to higher GRFS was documented in patients who received PTCY (2-y: 50.0% and 25.0%, p=0.266). CONCLUSIONS: At our institution, 50% of the patients with R/R AML going thought allo-HCT performed using sequential-based conditioning regimens survived after two years. The implementation of PTCY as part of the GVHD prophylaxis results decreased rates clinically relevant GVHD and NRM, resulting on a trend to better GRFS. Although the results provided by this analysis suggest that using PTCY in this allo-HCT is safe and effective, caution is still recommended considering the trend to higher relapse rates observed among these patients and the limited sample size.

Bortezomib and Vorinostat Therapy as Maintenance Therapy Post-Autologous Transplant for Non-Hodgkin’s Lymphoma Using R-BEAM or BEAM Transplant Conditioning Regimen

Introduction: The success of autologous stem cell transplantation (ASCT) for treating non-Hodgkin’s lymphoma (NHL) is limited by its high relapse rates. To reduce the risk of relapse, additional maintenance therapy can be added post-transplant. In a non-transplant setting at the time of initiation of this study, both bortezomib and vorinostat had been studied alone or in combination for some NHL histology and showed some clinical activity. At our center, this combination therapy post-transplant for multiple myeloma showed acceptable toxicity. Therefore, it seemed reasonable to study this combination therapy post-ASCT for NHL. Methods: NHL patients underwent conditioning for ASCT with rituximab, carmustine, etoposide, cytarabine, melphalan/carmustine, etoposide, cytarabine, melphalan. After recovery from the acute transplant-related toxicity, combination therapy with IV bortezomib and oral vorinostat (BV) was started and was given for a total of 12 (28-day) cycles. Results: Nineteen patients received BV post-ASCT. The most common toxicities were hematologic, gastrointestinal, metabolic, fatigue, and peripheral neuropathy. With a median follow-up of 10.3 years, 11 patients (58%) are alive without disease progression and 12 patients (63%) are alive. Conclusions: BV can be given post-ASCT for NHL and produces excellent disease-free and overall survival rates.

The two-step approach to allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) provides the only potentially curative option for multiple hematological conditions. However, allogeneic HSCT outcomes rely on an optimal balance of effective immune recovery, minimal graft-versus-host disease (GVHD), and lasting control of disease. The quest to attain this balance has proven challenging over the past few decades. The two-step approach to HSCT was conceptualized and pioneered at Thomas Jefferson University in 2005 and remains the main platform for allografting at our institution. Following administration of the transplant conditioning regimen, patients receive a fixed dose of donor CD3+ cells (HSCT step one-DLI) as the lymphoid portion of the graft on day -6 with the aim of optimizing and controlling T cell dosing. Cyclophosphamide (CY) is administered after the DLI (days -3 and -2) to induce donor-recipient bidirectional tolerance. On day 0, a CD34-selected stem cell graft is given as the myeloid portion of the graft (step two). In this two-step approach, the stem cell graft is infused after CY tolerization, which avoids exposure of the stem cells to an alkylating agent, allowing rapid count recovery. Here, the two-step platform is described with a focus on key results from studies over the past two decades. Finally, this review details lessons learned and current strategies to optimize the graft-versus-tumor effect and limit transplant-related toxicities.

The Present Condition of Sickle Cell Disease: An Overview of Stem Cell Transplantation as a Cure

AbstractTreatment of sickle cell disease (SCD) remains largely palliative. While it can enhance living standards, persons having SCD still suffer from extreme sickling crises, end-organ destruction, and reduced life expectancy. Increasing research has resulted in the recognition and advancement of stem cell transplantation and gene therapy as possible solutions for SCDs. However, there have been various factors that have hindered their clinical application. The more advantageous of the two, stem cell transplantation, is constrained by a small donor pool, transplant difficulties, and eligibility requirements. The current article reviewed the literature on SCDs, current treatment options, and more particularly the progress of stem cell transplants. It outlined various challenges of stem cell transplant and proposed ways to increase the donor pool using alternative strategies and modifications of regimen conditioning with minimal transplant-related toxicities and associated complications.

The results of therapy in patients with high-risk neuroblastoma: the experience of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

Treatment of patients with high-risk neuroblastoma (NB) is a complex challenge, and it is based on response to certain elements of therapy. The development and introduction of new treatment approaches, such as GD2-targeted immunotherapy (IT), leads to improved survival in this cohort of patients. The aim of the study was to retrospectively assess the effectiveness of therapy in patients with high-risk NB before the introduction of IT into clinical practice. We retrospectively analyzed the data of 151 NB patients stratified into a high-risk group who had received treatment in accordance with the modified NB2004 protocol of the German Society for Pediatric Oncology and Hematology (GPOH) at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology from 01.2012 to 12.2017. This study was approved by the Independent Ethics Committee and the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. All the study subjects (or their legal representatives) signed a voluntary informed consent form indicating their agreement to treatment and use of their data for research purposes. Overall survival (OS), event-free survival (EFS), and risk factors were analyzed in the patients with high-risk NB including those who had completed multimodal therapy with autologous hematopoietic stem cell transplantation and post-consolidation therapy with isotretinoin and had achieved a satisfactory response to induction therapy (complete response (CR), very good partial response (VGPR), partial response (PR)) (population of special interest). The main unfavorable prognostic clinical and molecular genetic factors affecting survival in the high-risk NB patients were older age, MYCN gene amplification, and stage 4 of the disease. The use of the modified GPOH NB2004 protocol resulted in a satisfactory response (CR/VGPR/PR) to the induction therapy in most patients: 124/151 (82.1 %). Surgery (other than primary tumor biopsy) led to improved survival, with no statistical difference between macroscopic radical surgery and macroscopic residual tumor. At the same time, radiation therapy (RT), as the second element of local control, had a significant impact on EFS in the group of the patients with stage 4 disease: the 3-year EFS was 39.4 % (95 % confidence interval (CI) 23.1–55.4) in the patients with RT versus 25.7 % (95 % CI 17.5–34.7) in the patients without RT (p = 0.0295). The introduction of a new high-dose TreoMel chemotherapy regimen did not result in worse survival rates but led to a decrease in transplant-related toxicity. The 5-year OS and 5-year EFS were 49.4 % (95 % CI 40.9–57.3 %) and 33.3 % (95 % CI 25.9–40.9) respectively for all the study subjects, and 81.6 % (95 % CI 70.3–88.9) and 55.1 % (95 % CI 43.1–65.5) respectively for the patients from the population of special interest. The analysis of the results of therapy in the high-risk NB patients who had received treatment at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, yielded results comparable to those of the original GPOH NB2004 protocol. The patients with CR/VGPR/PR to the induction therapy who had completed the protocol treatment with autologous hematopoietic stem cell transplantation and isotretinoin post-consolidation therapy demonstrated higher 5-year EFS rates. However, there remains a need to develop more effective treatment regimens for high-risk NB.

Clinical considerations at the intersection of hematopoietic cell transplantation and hereditary hematopoietic malignancy.

In recent years, advances in genetics and the integration of clinical-grade next-generation sequencing (NGS) assays into patient care have facilitated broader recognition of hereditary hematopoietic malignancy (HHM) among clinicians, in addition to the identification and characterization of novel HHM syndromes. Studies on genetic risk distribution within affected families and unique considerations of HHM biology represent exciting areas of translational research. More recently, data are now emerging pertaining to unique aspects of clinical management of malignancies arising in the context of pathogenic germline mutations, with particular emphasis on chemotherapy responsiveness. In this article, we explore considerations surrounding allogeneic transplantation in the context of HHMs. We review pre- and post-transplant patient implications, including genetic testing donor selection and donor-derived malignancies. Additionally, we consider the limited data that exist regarding the use of transplantation in HHMs and safeguards that might be pursued to mitigate transplant-related toxicities.

Faecal microbiota transplantation to prevent complications after allogeneic stem cell transplantation for haematological malignancies: a study protocol for a randomised controlled phase-II trial (the FMT-allo study)

IntroductionAllogeneic haematopoietic stem-cell transplantation (allo-HSCT) is a major treatment for many haematological malignancies. The procedure has a good success rate but high transplant-related toxicity (TRM). TRM is mostly related to...

Physical, Mental, and Social Health of Adult Patients with Sickle Cell Disease after Allogeneic Hematopoietic Stem Cell Transplantation: A Mixed-Methods Study

Patients with sickle cell disease (SCD) experience a considerable physical and psychosocial disease burden. In recent years, the application of allogeneic hematopoietic stem cell transplantation (HSCT) to treat adults with SCD has increased. A thorough understanding of patients' physical, mental, and social health before and after cure is needed to meet the needs of this growing group of patients. We aimed to explore the perspectives of adult SCD patients on the changes in their experienced health and personal life goals after being cured. A mixed-methods approach was used, comprising a semistructured interview and a set of 9 Patient Reported Outcomes Measurement Information System (PROMIS) measures. Adult SCD patients who underwent HSCT at least 1 year earlier were eligible to participate in the study. Interviews were thematically analyzed using MAXQDA software. PROMIS T scores were compared with reference scores of the general population using SPSS Statistics. Ten patients participated in the study; their median age was 29.5 years (range, 19 to 49 years), and their median time since HSCT was 2.7 years (range, 1.0 to 3.5 years). Themes from the interviews were (1) pain/living pain free, (2) physical well-being, (3) mental well-being, (4) perspective/ outlook, (5) education/work, (6) family/friends, and (7) activities/participation. Following the PROMIS framework, we described these themes in a narrative synthesis according to health domain and categorized in 4 chronological time phases: before HSCT, first year post-transplantation, current situation, and future expectations. Physical health improved greatly, but transplantation-related toxicity, ongoing pain from avascular osteonecrosis, and fatigue negatively impacted quality of life in some patients. Furthermore, emotional struggles during the post-transplantation period were common, and patients expressed a need for psychological help. Patients reported improvements in social health and the ability to pursue personal life goals. The mean T scores of all PROMIS measures fell within the normal symptom limits compared with reference data of the general population, although, large variations were observed among the participants, matching our qualitative findings. In general, adult SCD patients experienced improved physical, mental, and social health after cure by HSCT and were able to pursue personal life goals. Yet they found themselves confronted with a new and unfamiliar reality that brought different challenges. Pain due to irreversible avascular osteonecrosis continued to have a negative impact. Clinicians should aim to help patients have realistic expectations before transplantation and offer timely psychological care.

The Current State of Sickle Cell Disease Management: A Concise Review on Stem Cell Transplant as a Cure

Treatment of sickle cell disease remains largely palliative. While it may improve the quality of life, persons with sickle cell disease still suffer from extreme sickling crises, end-organ damage, and reduced life expectancy. Increasing studies have led to the identification and advancement of stem cell transplant and gene therapy as potential curative strategies for sickle cell disease. However, there have been various factors that have hindered their clinical application. Stem cell transplantation, the more propitious of the two, is limited by restricted transplant donor pool, transplant complications, and selection criteria. The current paper reviewed the literature on sickle cell disease, current treatment options, and more particularly on the progress of stem cell transplants. It outlined various challenges of stem cell transplant and proposed ways to increase the donor pool using alternative strategies and modifications of regimen conditioning with minimal transplant-related toxicities and associated complications. Keywords: Cord blood, Haploidentical, Sickle cell disease, Stem cell transplantation

Outcomes of blood and marrow transplantation in children less than 2-years of age

Allogeneic hematopoietic cell transplantation (Allo-HCT) is a curative option for children with various malignant and non-malignant diseases. Most reports studied all age groups amongst children. Herein we analyzed our data in children transplanted at or less than 2-years of age. We reviewed medical charts of 618 patients who underwent 666 transplantation at our center between 1993 and 2015. There were 340 boys and 278 girls. Median age was 0.7 years (range 0.04-2). Stem cell source was bone marrow (BM) in 492 (73.9%), unrelated umbilical cord blood (UCB) in 161 (24.2%) followed by peripheral blood stem cell (PBSC) in 13 (2%) patients. Matched siblings were the most common donors (n=356, 53.5%), followed by unrelated (n=161, 24.2%) with haploidentical family member donors in 29 (4.4%) transplants. Disease groups were categorized as benign hematology (Thalassemia, Fanconi, Aplastic anemia etc.), benign neoplasm (Langerhans cell histiocytosis, Hemophagocytic Lymphohistiocytosis etc.), non-neoplasms (metabolic disorders, immunodeficiency disorders etc.) and Leukemia/lymphomas (myeloid and lymphoid malignancies etc.). Cumulative incidence of acute GvHD (I-IV) was 31.5% (n=210) and grade III-IV GvHD was 8.7% (n=58). At median follow-up of 115.1 months, the cumulative probability of overall survival (OS) at 5 years was 70.0%±1.9%. Our mortality rate was 31.2% (n=193). The five-year OS was significantly better in patients transplanted for benign hematological disorders (P=.001). Patients transplanted using BM/PBSC as source of stem cells fared significantly better compared to those in which CB was used (P<.001). Post-transplant graft failure remains the leading cause requiring further transplants in this age group. In conclusion, the cumulative probability of OS at 5 years was about 70.0% for all with an OS of 61% in our haploidentical recipients. Analyzing our institutional data over time has enabled us to develop tentative strategies to minimize transplant related toxicities in very young children who are candidates for allo-HCT.

Allogeneic but Not Autologous Stem Cell Transplantation Improves Outcome in HTLV-1-Associated North American Adult T-Cell Leukemia/Lymphoma

Background: Adult T-cell leukemia/lymphoma (ATLL) is a rare mature T-cell malignancy driven by the human T-cell lymphotropic virus type I (HTLV-1) that remains challenging to treat and is associated with a dismal prognosis. While some reports have shown encouraging results with allogeneic stem-cell transplantation (allo-SCT), data remains scarce and mostly limited to Japanese patients. Patients and Methods: This is a retrospective single center analysis with 100 HTLV-1-associated North American ATLL patients. Variables collected included age, sex, ethnicity, CMV/HTLV1 serologies, karnofsky performance score (KPS), diagnosis date, disease subtype, number of prior therapy lines, transplant type, status at transplant, transplant date, prior SCT, donor sex, CMV/HTLV1 serologies, stem cell source, donor type, in-vivo T-cell depletion, engraftment, conditioning regimen, GVHD prophylaxis, maximum acute and chronic GVHD grade, relapse date when applicable, and main cause of death. The Kaplan-Meier method was used to calculate overall survival (OS) and progression-free survival (PFS). Cumulative incidence functions were used to estimate relapse incidence (RI) and non-relapse mortality (NRM) in a competing risk setting. Death and relapse were considered as competing events for acute and chronic GVHD. Univariate analyses were done using the Gray's test for cumulative incidence functions and the log rank test for OS and PFS. A Cox proportional hazards model was used for multivariate regression, results were expressed as hazard ratio (HR) with a 95% confidence interval (CI). All tests were two-sided, type-1 error was fixed at 5%. Results: One hundred patients met eligibility criteria, 18-87 years old, 69 of which were Black, 27 Hispanic, and 2 of Asian descent. Sixty-seven patients had acute ATLL and 22 lymphomatous. In total, 22 patients underwent SCT with 17 allo-SCT and 5 autologous SCT (ASCT) between 2005-2020 with a median follow-up of 62 months. Ten patients (45%) were transplanted in first complete remission (CR1), and 15 (68%) had KPS ≥90. Among patients undergoing allo-SCT, 41% had matched sibling donors (MSD), 18% matched unrelated (MUD), and 35% haploidentical. The 1-year and 3-years rates of overall survival from diagnosis of the cohort were 42% and 21%, respectively. Acute ATLL subtype was a strong predictor of worse outcome (Figure 1) with 1-year and 3-years OS of 32% vs 71% (p=0.004) and 11% vs 46% (p=0.002), respectively, compared to lymphomatous disease. To account for immortal time bias, 37 non-transplanted patients with early mortality within 4 months of diagnosis that were not able to make it to transplant were excluded from the Kaplan-Meier survival analysis. Patients undergoing transplant had improved outcomes compared to non-transplanted patients (Figure 1, Table 1), with allo-SCT reaching statistical significance in multivariate analysis compared to the non-transplant group with OS HR of 0.3 (p=0.004) compared to 0.7 (p=0.6) in ASCT vs non-transplant. In transplanted patients, the 3-year RI and NRM were 51% and 37%, respectively, and 3-year PFS and OS were 31% and 39%, respectively. Four of five patients who received ASCT rapidly relapsed with 3 dying from disease progression and one lost to follow-up, with 1-year RI of 80% vs 30% in allo-SCT (p=0.03). In exploratory multivariate analysis, patients achieving CR1 and with good baseline performance scores (KPS >90) had significantly better outcomes compared to their counterparts regardless of transplant type, and surprisingly, race was a strong and significant predictor of outcomes affecting PFS and OS with Hispanic vs Black PFS and OS HRs of 6 (p=0.04) and 10 (p=0.04), respectively. Thirteen patients died within 2 years, eight from relapse/progression including 3 ASCT patients, and 4 from transplant-related toxicities. Conclusion: Our data suggest that allo-SCT, but not ASCT, is a valid option in select ATLL patients. It also appears that patients of Hispanic descent have worse outcome post-transplant but not overall, which could be explained by lack of compatible donors or barriers to early transplant. Although this is the largest NA-ATLL transplant cohort presented to date outside of Japan and Europe, further studies are necessary to fully explain these discrepancies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal