Cumulative Incidence Of Acute Graft-versus-host Disease Research Articles

Biologically Randomized Comparison of Haploidentical Versus Human Leukocyte Antigen-Matched Related Donor Reduced-Intensity Conditioning Hematopoietic Cell Transplantation

Using haploidentical donors for allogeneic hematopoietic cell transplantation (HCT) broadens transplant accessibility to a growing number of patients with hematologic disorders. Moreover, haploidentical HCT with post-transplant cyclophosphamide (PTCy) has become widespread practice due to accumulating evidence demonstrating favorable rates of survival and graft-versus-host disease (GvHD). Most studies comparing outcomes by donor sources have been confounded by variability in conditioning regimens, graft type (peripheral blood [PB] or bone marrow), and post-transplant GvHD prophylaxis (PTCy or non-PTCy), making it difficult to define the effect of donor source on outcomes. Levine Cancer Institute started a transplant and cellular therapy program in 2014, with both haploidentical and matched related donor (MRD) transplants initially performed using a uniform reduced-intensity conditioning (RIC) regimen, PB grafts, and PTCy-based GvHD prophylaxis. This retrospective observational study was conducted to compare the clinical outcomes associated with RIC haploidentical HCT and MRD HCT in patients receiving identical conditioning regimens, graft types, and supportive care. Our transplant database was queried to evaluate demographic characteristics, clinical features, and outcomes of RIC HCT for consecutive patients with hematologic malignancies who received haploidentical or MRD grafts between March 2014 and December 2017. An MRD was the preferred donor source; when unavailable, a haploidentical donor was used. Sixty-seven patients underwent haploidentical HCT and 25 MRD HCT. Overall, characteristics of transplant recipients were similar for the haploidentical and MRD groups; however, haploidentical donors were younger than MRDs (median 36 yr versus 57 yr, P < .0001). Results of univariable analysis showed similar overall survival (OS) for haploidentical and MRD HCT (hazard ratio [HR], 1.15; 95% CI, 0.61 to 2.15; P = .669). One-year, 1-yr, and 5-yr OS were 80.2%, 54.7%, and 41.2% for haploidentical HCT and 76.0%, 55.7%, and 51.1% for MRD HCT, respectively. With a median follow-up of 81.90 months, results of multivariable analysis revealed that donor source (haploidentical versus MRD) was not significantly associated with OS (HR, 0.97; 95% CI, 0.51 to 1.87; P = .933), relapse-free survival (HR, 0.75; 95% CI, 0.42 to 1.35; P = .337), cumulative incidence of relapse (HR, 0.81; 95% CI, 0.39 to 1.70; P = .579), or non-relapse mortality (HR, 1.12; 95% CI, 0.40 to 3.14; P = .827). Cumulative incidences of acute GvHD (aGvHD) and chronic GvHD (cGvHD) were not significantly different for haploidentical and MRD HCT (grades II to IV aGvHD: HR, 1.78; 95% CI, 0.72 to 4.37; P = .210; grades III to IV aGvHD: HR, 2.84; 95% CI, 0.34 to 23.63; P = .335; cGvHD: HR, 1.00; 95% CI 0.36 to 2.76; P = .995). With care that was homogenous in terms of conditioning regimens, graft type, GvHD prophylaxis, and supportive care, 92 patients who were biologically randomized to either haploidentical HCT or MRD HCT after RIC with PTCy had comparable outcomes.

Efficacy of Letermovir for Cytomegalovirus Prophylaxis Following Alemtuzumab T-Cell Depleted Allogeneic Hematopoietic Stem Cell Transplant

In vivo T-cell depletion (TCD) using alemtuzumab decreases the risk of Graft vs. Host Disease (GvHD) in recipients of allogeneic hematopoietic stem cell transplant (allo-HSCT). However, this approach increases the risk of infections post-allo-HSCT, including Cytomegalovirus (CMV). Letermovir is approved for the use in CMV prophylaxis post-allo-HSCT. Few studies have investigated the efficacy of letermovir in patients receiving alemtuzumab. This is a single-center retrospective study describing our institutional experience using letermovir in recipients of alemtuzumab TCD allo-HSCT from unrelated donors (URD). The primary outcome was the cumulative incidence of significant CMV infection (defined as viremia leading to preemptive antiviral therapy or CMV disease) within 100 days post-transplant. Secondary outcomes included the cumulative incidence of acute GvHD (grade ≥ 2), the cumulative incidence of extensive chronic GvHD, and overall survival. A total of 84 alemtuzumab TCD URD allo-HSCT recipients were included in the analysis, 30 of whom received letermovir (letermovir group) and 54 who did not receive letermovir (control group). The median age was 59 years (range: 26 - 75 years) and 55.5 years (range: 20 - 73 years) in the letermovir and control group, respectively. Most recipients (66.7%) in both groups received unrelated matched allografts, and myeloid neoplasms were the most common indication for allo-HSCT. A significantly lower cumulative incidence of significant CMV infection within 100 days was seen in the letermovir group compared to the control group (10.0% [95% CI: 2.5 - 23.9%] vs 55.6% [95% CI: 41.2 - 67.8%], p < 0.0001). There was no statistically significant difference in the incidence of acute GvHD (grade ≥ 2) or overall survival between the two groups. However, lower rates of extensive chronic GvHD were noted in the letermovir group (10.5% [95% CI: 2.6 - 24.9%] vs. 36.5% [95% CI: 23.6 - 49.5%], p=0.0126). These results demonstrate the efficacy of letermovir in decreasing the rates of clinically significant CMV infection in patients undergoing alemtuzumab T-cell depleted allo-HSCT.

Post-transplantation cyclophosphamide and cyclosporine A versus methotrexate and cyclosporine A for graft-versus-host disease prophylaxis after allogeneic peripheral stem cell transplantation in adult acute myeloid leukemia patients

BackgroundDifferent prophylactic protocols are available for preventing graft-versus-host disease (GVHD) after matched sibling donor (MSD) allogeneic hematopoietic cell transplantation (allo-HCT). This study aimed to compare the effectiveness of post-transplantation cyclophosphamide plus cyclosporine A (PT-CY/CSA) versus methotrexate plus CSA (MTX/CSA) as GVHD prophylaxis protocols in adult acute myeloid leukemia (AML) patients who received peripheral blood stem cells (PBSC) from fully matched donors. MethodsThe 1-year outcomes of 89 patients treated with PT-CY/CSA and 90 patients treated with MTX/CSA who had MSD allo-HCT for AML using unmanipulated mobilized PBSC were examined and compared. ResultsThe cumulative incidence of acute GVHD at 100 days was considerably lower in the PT-CY/CSA group (4% vs 19.3%, p = 0.002), however there were no statistically significant difference in the cumulative incidence of chronic GVHD at 1-year (19.6% vs 37.4%, p = 0.053). Significant delays in neutrophil and platelet engraftments were reported in the PT-CY/CSA group (17 vs 12 days) and (13 vs 12 days), respectively (p < 0.001). The cumulative incidences of relapse (19.1% vs 13.7%, p = 0.470), overall survival (79.1% vs 77.3%, p = 0.986), non-relapse mortality (16.5% vs 16.8%, p = 0.837), and the GVHD and relapse-free survival (GRFS) (53.7% vs 46.6%, p = 0.478) did not differ statistically at 1-year. ConclusionPT-CY/CSA demonstrated a significant decrease in the rate of acute GVHD. However, it was associated with engraftment delay.

Memory T-cell enriched haploidentical transplantation with NK cell addback results in promising long-term outcomes: a phase II trial

BackgroundRelapse remains a challenge after transplantation in pediatric patients with hematological malignancies. Myeloablative regimens used for disease control are associated with acute and long-term adverse effects. We used a CD45RA-depleted haploidentical graft for adoptive transfer of memory T cells combined with NK-cell addback and hypothesized that maximizing the graft-versus-leukemia (GVL) effect might allow for reduction in intensity of conditioning regimen.MethodsIn this phase II clinical trial (NCT01807611), 72 patients with hematological malignancies (complete remission (CR)1: 25, ≥ CR2: 28, refractory disease: 19) received haploidentical CD34 + enriched and CD45RA-depleted hematopoietic progenitor cell grafts followed by NK-cell infusion. Conditioning included fludarabine, thiotepa, melphalan, cyclophosphamide, total lymphoid irradiation, and graft-versus-host disease (GVHD) prophylaxis consisted of a short-course sirolimus or mycophenolate mofetil without serotherapy.ResultsThe 3-year overall survival (OS) and event-free-survival (EFS) for patients in CR1 were 92% (95% CI:72–98) and 88% (95% CI: 67–96); ≥ CR2 were 81% (95% CI: 61–92) and 68% (95% CI: 47–82) and refractory disease were 32% (95% CI: 11–54) and 20% (95% CI: 6–40). The 3-year EFS for all patients in morphological CR was 77% (95% CI: 64–87) with no difference amongst recipients with or without minimal residual disease (P = 0.2992). Immune reconstitution was rapid, with mean CD3 and CD4 T-cell counts of 410/μL and 140/μL at day + 30. Cumulative incidence of acute GVHD and chronic GVHD was 36% and 26% but most patients with acute GVHD recovered rapidly with therapy. Lower rates of grade III-IV acute GVHD were observed with NK-cell alloreactive donors (P = 0.004), and higher rates of moderate/severe chronic GVHD occurred with maternal donors (P = 0.035).ConclusionThe combination of a CD45RA-depleted graft and NK-cell addback led to robust immune reconstitution maximizing the GVL effect and allowed for use of a submyeloablative, TBI-free conditioning regimen that was associated with excellent EFS resulting in promising long-term outcomes in this high-risk population.The trial is registered at ClinicalTrials.gov (NCT01807611).

Comparable outcomes of allogeneic peripheral blood versus bone marrow hematopoietic stem cell transplantation from a sibling donor for pediatric patients.

Traditionally, bone marrow (BM) has been preferred as a source of stem cells (SCs) in pediatric hematopoietic SC transplantation (HSCT); however, the use of peripheral blood SCs (PBSC) has recently increased. With advancing graft-versus-host disease (GVHD) prophylaxis, whether the BM is still a better SC source than PB in sibling donor HSCT remains controversial. Here, we compared the results of BM transplantation (BMT) and PBSC transplantation (PBSCT) in pediatric patients with malignant or non-malignant diseases receiving sibling HSCT using a total of 7.5mg/kg of anti-thymocyte globulin (ATG). We retrospectively reviewed children who received HSCT from a sibling donor between 2005 and 2020 at Seoul National University Children's Hospital. Of the 86 patients, 40 underwent BMT, and 46 underwent PBSCT. Fifty- six patients had malignant diseases, whereas thirty patients had non-malignant diseases. All conditioning regimens comprised ATG. Busulfan-based myeloablative conditioning regimens were administered to patients with malignant diseases and approximately half of those with non-malignant diseases. The remaining half of the patients with non-malignant diseases were administered cyclophosphamide-based reduced- intensity conditioning regimens. According to studies conducted at our center, all BM donors received G-CSF before harvest to achieve early engraftment. In all 86 patients (47 males and 39 females), the median age at the time of HSCT was 11.4 (range, 0.7 - 24.6) years. The median follow-up period was 57.9 (range, 0.9-228.6) months, and the corresponding values for those with BM and PBSC were 77 (range, 2.4-228.6) months and 48.7 (range, 0.9-213.2) months, respectively. Engraftment failure occurred in one patient with BM and no patient with PBSC. The cumulative incidence of acute GVHD with grades II-IV was higher in PBSC (BM 2.5%, PBSC 26.1%, p = 0.002), but there was no significant difference in those with grades III-IV acute GVHD (BM 0%, PBSC 6.5%, p = 0.3703) and extensive chronic GVHD (BM 2.5%, PBSC 11.6%, p = 0.1004). There were no significant differences in treatment-related mortality (TRM) (BM 14.2%, PBSC 6.8%, p = 0.453), 5-year event-free survival (EFS) (BM 71.5%, PBSC 76.2%, p = 0.874), and overall survival (OS) rates (BM 80.8%, PBSC 80.3%, p = 0.867) between BM and PBSC in the univariate analysis. In the multivariate analysis, which included all factors with p < 0.50 in the univariate analysis, there was no significant prognostic factor for EFS or OS. There was no significant difference in the relapse incidence between BM and PBSC among patients with malignant diseases (BM 14.2%, PBSC 6.8%, p = 0.453). Additionally, there were no significant differences in the TRM, 5-year EFS, and OS rates between malignant and non-malignant diseases nor between the busulfan-based myeloablative regimen and reduced-intensity chemotherapy using cyclophosphamide. In this study, we showed no significant differences in EFS, OS, TRM, and GVHD, except for acute GVHD grades II-IV, between BMT and PBSCT from sibling donors, using ATG (a total of 7.5mg/kg). Therefore, PB collection, which is less invasive for donors and less labor-intensive for doctors, could also be considered an acceptable SC source for sibling donor HSCT in children.

TBI-Containing with T-Cell Replete Full Haplotype Mismatched Hematopoietic Stem Cell Transplantation in Adult Patients with De Novo Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is the 2nd most frequent developing hematologic malignancy with deep heterogeneity, but unfortunately the majority of patients relapse even after allogeneic hematopoietic stem cell transplantation (HSCT) in complete remission (CR). We have developed allogeneic HSCT from familial mismatched/haploidentical donors (FMT) in adult patients with a single disease entity of AML lacking of both HLA-identical siblings and well-matched unrelated donors (WMUD) from the mid 1990s. Previously, several pilot studies of FMT performed with various total body irradiation (TBI)-based conditioning regimens (2~12 gray) with or without post-transplant cyclophosphamide (PT-Cy) as a graft-versus-host disease (GvHD) prophylaxis were reported. Here, we demonstrate about the encouraging outcomes of FMT using unmanipulated peripheral blood donor stem cells (PBSCs) and de-escalated dose of TBI (4~8 gray) containing conditioning regimen without T-cell depletion manner. Although PT-Cy as a specific GvHD prophylaxis regimen is increasingly used for both adult and pediatric FMT, our group investigated the clinical outcomes in adult patients with de novo AML who received full haplotype mismatched HSCT after TBI containing preparation regimen consisted of fractionated TBI (total 4 gray for elderly and 8 gray for &amp;lt;60 years old), fludarabine (150 mg/m 2/day), busulfex (6.4mg/kg/day), and anti-thymocyte globulin (ATG). For GvHD prophylaxis, rabbit ATG (thymoglobulin, Genzyme, 1.25mg/kg/day for 4 days at D-4 to D-1) and a combination of tacrolimus and short-term methotrexate was used. G-CSF mobilized unmanipulated PBSCs were used with a median CD34+ dose of 6.5 x 10 6/kg (1~25.6). From 2008 to the end of 2022, total 429 adult patients were enrolled, and data demonstrated that our trial of intermediate-dose of ATG and reduced toxicity of TBI-containing conditioning regimen to reduce graft-failure even for high levels of donor-specific antibody titer, early transplant-related mortality, critical cytomegalovirus (CMV) disease, and emerging post-transplant lymphoproliferative disease with rapid immune recovery has shown very successful outcomes. Briefly, the median absolute neutrophil count recovery was 12 days (10~26) and the platelet of 14 days (5~38). There was no either primary or secondary graft-failures at all. With a median follow-up of 36.5 months (2~242) for survivors, overall survival rate (OS) and relapse-free survival (RFS) for patients in any CR (n=338) and relapse/refractory status (n=91) were 62.9% vs. 34.3% and 59.5% vs. 32.2%, respectively. Although there was no significant difference in the subgroup analysis, de novo and young aged patients in any CR showed the best OS 73% (Figure 1). Cumulative incidences of acute GvHD and chronic GvHD were 66% (59-73), 70% (63-76), respectively. The incidences of moderate to severe acute GvHD and chronic GvHD were 16.1%, 30.5%, respectively. By univariate and multivariate analyses, patient's age &amp;lt;54 (p=0.043), pre-HSCT CR1 (p &amp;lt;0.001), absence of mod to severe chronic GvHD (p &amp;lt;0.001), and use of post-transplant iron-chelating agent (p=0.001) were the statistically significant in the study. The GvHD-free and relapse-free survival rate in CR1 was 62.4% for younger patients (age &amp;lt;54) and 47.9% for older patients (p=ns). The non-relapse mortality rate was 27.2% for all enrolled patients and 16% for CR patients. The rapidity of immune recovery was also compared with our old control cohort when we performed T-cell depletion using the CliniMACS system, and it showed a significant reconstitution of CD4+ cells (&amp;gt;300/ul) at 3 months post-FMT compared to the much delayed T-cell depleted FMT. Of note, CMV DNAemia was relatively higher (76.9%) than reported in other studies, likely due to the use of ATG and the endemic region of our country. Therefore, we suggest that the strategic reduction of fractionated TBI 4~8 gray-based conditioning with unmanipulated PBSCs graft without PT-Cy seems feasible with favorable outcomes for adult patients with de novo AML undergoing FMT in CR, especially even in a certain subgroup of elderly patients with AML.

Prognostic Factors Impacting Post-Transplant Outcomes in Adult T-Cell Acute Lymphoblastic Leukemia: A Registry-Based Study By the EBMT Acute Leukemia Working Party

Background: T-cell acute lymphoblastic leukemia (T-ALL) predominantly affects individuals in late childhood and young adulthood and historically had high mortality rates. The outcome of Pediatric inspired chemo protocols in the T-ALL have improved in the past years due to the advancement in treatment and supportive care but the data is less mature, although adult patients still face challenges. Limited studies have directly explored the impact of patient- and transplant-related factors on post-transplant outcomes in adult T-ALL patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: A retrospective registry-based analysis was conducted across multiple centers using data from the European Society for Blood and Marrow Transplantation (EBMT) registry. Inclusion criteria were adult T-ALL patients (&amp;gt;18 years old) who underwent their first allo-HSCT in first complete remission from matched sibling donors (MSD), unrelated donors (UD) (10/10 or 9/10) or haploidentical donors between 2010 and 2021. Cord bloods were excluded. Multivariable Cox regression analysis was performed to examine the associations between patient/transplant characteristics and outcomes. Results: A total of 1907 patients were included in the study. The median age at transplant was 33.4 years (18.1-75). The median follow up was 2.9 years (2.6-3.1), and the median year of HSCT was 2016 (2010-2021). Patients were 70 % male with 67% being CMV-positive, at the time of transplant. Donors were predominantly male (64%), and (23%) of transplants involved female donors to male patients. The median period between diagnosis and HSCT was 5.9 months (0 -23.8). Most transplants were from matched sibling donors (MSD) (45%) followed by UD (43%) and 12% were from Haploidentical transplants. Most patients underwent myeloablative conditioning with total body irradiation (TBI)-based regimens (69%) and most patients received peripheral blood stem cells (84%). Cyclosporine with methotrexate was the most common graft-versus-host-disease (GVHD) prophylaxis (54 %). In vivo T cell depletion was used in 44%. The 2-year overall survival (OS) was 69.4%, and leukemia -free survival (LFS) was 62.1%. The cumulative incidence of acute GVHD (aGVHD) grades II-IV at 100 days was 32.6%, and grades III-IV was 10%. The cumulative incidence of chronic GVHD (cGVHD) at 2 years was 37.3%, and extensive cGVHD was 16.8%. Multivariate analysis yielded significant associations between patient/transplant characteristics and outcomes. Advanced age at transplant was associated with poorer outcomes, including LFS (HR=1.11, p=0.004), GVHD-free, relapse-free survival (GRFS) (HR=1.06, p=0.04), OS (HR=1.12, p=0.002), and higher non-relapse mortality (NRM) (HR=1.23, p=0.001); HR for 10y increment. A later year of HSCT was associated with improved GFRS (HR=0.89, p=0.001), OS (HR=0.9, p=0.02), and decreased NRM (HR=0.82, p=0.008), aGVHD II-IV (HR=0.83, p=0.001), and cGVHD (HR=0.8, p=0.001); HR for 3y increment. TBI was specifically superior with improved LFS (HR=0.79, p=0.02), GRFS (HR=0.83, p=0.04), and lower relapse incidence (RI) (HR=0.65, p=0.001). Female-to-male transplant combination had a negative impact on GFRS (HR=1.21, p=0.02), OS (HR=1.23, p=0.048), and on the risk of cGVHD in general (HR=1.39, p=0.002) and specifically extensive cGVHD (HR=1.47, p=0.01). The use of in vivo T-cell depletion had significant benefits in terms of GFRS, aGVHD grade III-IV, cGVHD, and extensive cGVHD. Conclusion: This large study identified prognostic factors, such as age at transplant, donor type, and conditioning regimen, in influencing key outcomes including OS, LFS, GVHD incidence, and NRM in adult T-ALL patients undergoing allo-HSCT. Importantly, a significant improvement over time in post-transplant outcomes was noted. These findings hold great promise for new adapted treatment strategies and can serve as a benchmark for future studies in that setting.

A Multicentre, Randomized, Double-Blinded, Phase 2b Study Evaluating the Efficacy and Safety of MaaT033, an Oral, Pooled Microbiome Ecosystem Therapy in Patients Undergoing Allogenic Hematopoietic Cell Transplantation to Improve Overall Survival: The Phoebus Trial

Background and significance: Allogenic hematopoietic cell transplantation (alloHCT) is a well-established therapy for various life-threatening hematologic malignancies. The use of alloHCT is constantly increasing, with nearly 20 000 transplantations reported to the European Society for Blood and Marrow Transplantation (EBMT) per year. However, this treatment is limited by high morbidity and mortality, mainly related to relapse, infection, graft-versus-host disease (GvHD), and conditioning-related toxicity. Several pioneering studies have shown that the diversity of the gut microbiota of patients not only correlates with the occurrence of medical complications after alloHCT, including GvHD (Jenq et al. 2012, Stein-Thoeringer et al. 2019) and bloodstream infections (Taur et al. 2012), but also with relapse of the underlying disease (Peled et al. 2017). Gut microbiota diversity restoration with fecal microbiotherapy could be an effective treatment to improve patients' clinical outcomes including overall survival (OS) after alloHCT, through the prevention and resolution of gut microbiota dysbiosis. MaaT033 is a freeze-dried, full-ecosystem, high-diversity, fecal microbiota medicinal product, formulated as delayed-release capsules and derived from pooled allogenic human fecal material. The PHOEBUS trial is a phase 2b study to evaluate the efficacy of MaaT033 in improving survival of adult alloHCT patients (Clinicaltrials.gov identifier: NCT05762211) Study design and Methods: 387 subjects aged ≥ 50 years with hematologic malignancies for which an alloHCT is indicated will be randomized 1:1 to receive either MaaT033 (experimental arm) or placebo (control arm) before initiation of the conditioning regimen and after hematopoietic recovery following alloHCT. Stratification of patients will be performed based on disease risk index (low-intermediate versus high-very high) and donor-host compatibility (HLA-identical versus HLA-mismatch). Inclusion criteria include age ≥ 50 years, alloHCT with a reduced-toxicity or reduced-intensity conditioning regimen, neutrophils &amp;gt; 0.5 G/L, and administration of broad-spectrum antibiotics within the last 90 days prior to inclusion. Exclusion criteria comprise non-myeloablative conditioning regimen, conventional myeloablative conditioning regimen, in-vitro T-cell depletion, alloHCT with cord blood cells, alloHCT from an unrelated donor with ≥ 3/10 HLA-mismatches, use of alemtuzumab, vedolizumab or abatacept for GvHD prophylaxis, history of chronic digestive disease. The primary endpoint is to evaluate OS at 12 months after randomization. Secondary endpoints will include evaluation of the safety of MaaT033, GvHD-free survival, cumulative incidence of acute GvHD and chronic GvHD, non-relapse mortality, relapse-free survival, GvHD-free, relapse-free survival, the proportion of patients with severe infections, gut microbiota composition, and quality of life. Exploratory endpoints will describe the impact of MaaT013 on immune recovery, the nutritional status of the patients, and resource utilization. Patients will receive MaaT033 or placebo (3 capsules per day) for 1 week before the start of the conditioning regimen. Experimental treatment (3 capsules per day) will be resumed at neutrophil recovery and pursued up to 90 days after alloHCT. Patients will be followed monthly up to 6 months post alloHCT and then every 3 months up to 12 months. The study is approved in France and Germany; expansion to other countries is planned for 2024. Study start is expected in September 2023.

Impact of Early Anti-Cytomegalovirus Therapy on the Incidence of Chronic Graft-Versus-Host Disease

Introduction: Cytomegalovirus (CMV) infections are associated with poor outcomes in recipients of allogeneic hematopoietic stem cell transplants (HSCTs). Therefore, preventive therapy or preemptive treatment have been developed. Ganciclovir (GCV) and foscarnet (FCN) are essential intravenous anti-CMV agents. A previous regional multicenter study revealed a significantly lower risk of chronic graft-versus-host disease (GVHD) in patients who received preemptive FCN therapy. To validate this observation and to investigate the mechanism or target, we executed a comprehensive nationwide study. Patients and Methods: We defined the early anti-CMV therapy as administration within 180 days after transplantation without evidence of target therapy for CMV infections. We retrospectively analyzed patients who received FCN or GCV as early anti-CMV therapy, and who are not received any anti-CMV agents (no anti-CMV) between June 2005 and December 2019. We excluded patients who received FCN, GCV, valganciclovir, or letermovir as prophylactic therapy; those who began anti-CMV therapy before the day of transplantation; those who received both FCN and GCV; those who underwent T cell-depleting treatment. Results: A total of 19536 adults with hematological malignancies who received their first allogeneic HSCT were included. We compared patients who received FCN (n = 1555) or GCV (n = 7335) as early anti-CMV therapy, and no anti-CMV recipients (n = 10646). FCN or GCV recipients showed higher incidence of acute GVHD than no anti-CMV recipients. The cumulative incidence of acute GVHD 200 days after transplantation were 46% (95% confidence interval [CI], 41%-51%), 47% (95% CI, 45%-50%), and 26% (95% CI, 25%-28%) for FCN, GCV, and no anti-CMV recipients, respectively (P &amp;lt; 0.001). The cumulative incidence of chronic GVHD three years after transplantation were 28% (95% CI, 26%-31%), 37% (95% CI, 36%-38%), and 29% (95% CI, 28%-30%) for FCN, GCV, and no anti-CMV recipients, respectively (P &amp;lt; 0.001). The cumulative incidence of extensive chronic GVHD three years after transplantation were 17% (95% CI, 15%-19%), 22% (95% CI, 22%-23%), and 16% (95% CI, 15%-26%) for FCN, GCV, and no anti-CMV recipients, respectively (P &amp;lt; 0.001) (Figure A). In multivariate analyses adjusted for acute GVHD or other important variables, the risks of extensive chronic GVHD among GCV recipients was higher than FCN recipients (hazard ratio [HR], 1.17; 95% CI, 1.01-1.34; P = 0.031), whereas no-anti CMV recipients and FCN did not showed statistically significance. In further investigations, we performed stratified analyses and revealed that the incidence of extensive chronic GVHD was significantly lower among the FCN recipients than among the GCV recipients only in stratifications that involved male recipients of female donor HSCT (according to sex compatibility). Comparing with GCV, the incidence of extensive chronic GVHD was significantly reduced among male recipients of female donor HSCTs who were taking FCN (HR, 1.63; 95% CI, 1.19-2.23; P = 0.002), but FCN did not affect the incidence of extensive chronic GVHD for other sex compatibility-based stratifications (HR, 1.05; 95% CI, 0.90-1.23; P = 0.51). Among male recipients of female donor transplants, the incidence of extensive chronic GVHD three years after transplantation were 13% (95% CI, 10%-17%), 27% (95% CI, 25%-29%), and 20% (95% CI, 18%-21%) for FCN, GCV, and no anti-CMV recipients, respectively (P &amp;lt; 0.001; Figure B). FCN and no anti-CMV recipients showed similar risk of extensive chronic GVHD (HR, 1.22; 95% CI, 0.89-1.66; P = 0.21). The incidence of extensive chronic GVHD was significantly reduced among FCN recipients who received HSCT from female donors, regardless of stem cell source, GVHD prophylaxis, or previous acute GVHD incidence, in male recipients. Conclusions: In this study, patients requiring early anti-CMV therapy were at a high risk of chronic GVHD, primary due to their increased incidence of acute GVHD. Remarkably, FCN could potentially mitigate the incidence of chronic GVHD for them. Especially, FCN would be beneficial for male recipients of female donor transplants who are typically at high risk for chronic GVHD. These findings pave the way towards a deeper understanding of the mechanism underlying chronic GVHD and overcome the unmet needs of allogeneic HSCT recipients.

CR1 Favors PTCy-haplo over UCB in Allogeneic Stem Cell Transplantation for Adult Patients with AL

[Introduction] HLA-haploidentical stem cell transplantation using post-transplant cyclophosphamide (PTCy-haplo) and umbilical cord blood transplantation (UCB) are alternative to HLA-matched hematopoietic stem cell transplantation (HSCT). However, advantage of PTCy-haplo versus UCB has not been determined in patients with acute lymphoblastic leukemia (ALL). Thus, we compared post-HSCT outcomes of PTCy-haplo and UCB in adult patients with ALL to determine patient subgroups who benefit from PTCy-haplo. [Methods] We analyzed data on adult patients (≥16 years) with ALL who underwent HSCT with PTCy-haplo or single-unit UCB between January 2013 and December 2021, using the Japanese nationwide registry database. Endpoints of the analysis included overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse, non-relapse mortality (NRM), engraftments, acute and chronic graft-versus-host disease (GVHD), and infections. In addition to multivariate analysis, propensity score matching was performed as a sensitivity analysis. [Results] We analyzed 1999 patients (PTCy-haplo, 330; UCB, 1669). Median age at HSCT was 44.5 years (range, 16-73) in PTCy-haplo and 45 years (range, 16-74) in UCB group. The proportion of patients who underwent HSCT in the first complete remission (CR1) (PTCy-haplo, 50.3%; UCB, 48.8%) and median time from diagnosis to HSCT (PTCy-haplo, 7.8 months; UCB, 7.7 months) were comparable between the groups. Regarding conditioning, the proportion of those who received myeloablative conditioning (PTCy-haplo, 50.6%; UCB, 54.8%), or conditioning with total body irradiation (PTCy-haplo, 82.4%; UCB, 79.3%) were comparable between the groups. Multivariate analyses showed that PTCy-haplo recipients had comparable 3-year OS (54.1% vs. 52.3%; adjusted hazard ratio [aHR], 0.93; p = 0.51) and DFS (49.7% vs. 47.1%; aHR, 1.06; p = 0.60) with UCB recipients. PTCy-haplo recipients had a significantly higher 3-year relapse rate (32.2% vs. 26.4%; aHR, 1.47; p = 0.01), but had a significantly lower 3 -year NRM (18.1% vs. 26.5%; aHR, 0.70; p = 0.03) as compared to UCB along with significantly faster neutrophil (median, 16 days vs. 20 days) and platelet (median, 30 days vs. 42 days) engraftments, and lower incidence of viral, fungal and bacterial infections. There was no significant difference in cumulative incidence of acute GVHD (30.9% vs. 36.4%, grade II-IV at 100 days; p = 0.15), or chronic GVHD (22.5% vs. 20.9% at 3 years; p = 0.85) between the two groups. These comparable OS and DFS between the two groups were confirmed after minimizing differences in patient characteristics with propensity score matching analysis (Figure 1A). Then, to identify patient subgroups who benefit from PTCy-haplo rather than UCB transplant, we performed subgroup analyses of OS. Significantly favorable effects of PTCy-haplo over UCB were observed in patients with CR1 at HSCT (HR, 0.66; p = 0.03). Indeed, propensity score matching analysis showed that PTCy-haplo recipients had a significantly higher 3-year OS (76.4% vs. 67.6%; HR, 0.57; p = 0.01) and DFS (70.5% vs. 60.6%; HR, 0.66; p = 0.03) than UCB recipients, along with a significantly lower NRM (12.9% vs. 26.3%; HR, 0.39; p &amp;lt; 0.01), and a comparable relapse rate (16.6% vs. 13.1%; HR, 1.41; p = 0.25) with UCB. These results suggest that the low NRM in PTCy-haplo transplant outweighs potential concerns of relapse among patients transplanted in CR1 (Figure 1B). By contrast, in patients with ≥ 2 nd CR or non-CR at HSCT, survival benefits of PTCy-haplo were not observed. [Conclusions] Our results suggest that while both PTCy-haplo and UCB are suitable alternative donor sources for adult ALL patients without HLA-matched donors, in patients with CR1, selection of PTCy-haplo rather than UCB improves post-transplant prognosis.

The Impact of Graft CD3+ T-Cell Dose on the Outcome of T-Cell Replete Human Leukocyte Antigen-Mismatched Allogeneic Hematopoietic Peripheral Blood Stem Cells Transplantation.

Data on whether the graft CD3-positive (CD3+) T-cell dose in T-cell-replete human leukocyte antigen (HLA)-mismatched allogeneic hematopoietic peripheral blood stem cells transplantation (PBSCT) influences post-transplant outcomes are controversial. Using King Hussein Cancer Center (KHCC) Blood and Marrow Transplantation (BMT) Registry database, 52 adult subjects, receiving the first T-cell-replete HLA-mismatched allogeneic hematopoietic PBSCT for acute leukemias or myelodysplastic syndrome, were identified, from January 2017 to December 2020. The cutoff value of graft CD3+ T-cell dose was identified using the receiver operating characteristic (ROC) formula and Youden's analysis. Subjects were divided into two cohorts: cohort 1 with low CD3+ T-cell dose (n = 34) and cohort 2 with high CD3+ T-cell dose (n = 18). Correlative analyses were performed between CD3+ T-cell dose and the risk of graft-versus-host disease (GvHD), relapse, relapse-free survival (RFS), and overall survival (OS). P-values were two-sided and considered significant when P < 0.05. Subject covariates were displayed. Subject's characteristics were comparable, except for higher nucleated cells and more female donors in the high CD3+ T-cell cohort. The 100-day cumulative incidence of acute GvHD (aGvHD) was 45±7% and 3-year cumulative incidence of chronic GvHD (cGvHD) was 28±6.7%. There was no statistically significant difference between the two cohorts in aGvHD (50% vs. 39%, P = 0.4) or cGvHD (29% vs. 22%, P = 0.7). The 2-year cumulative incidence of relapse (CIR) was 67.5±16.3% for low compared with 14.3±6.8% for high CD3+ T-cell cohort (P = 0.018). Fifteen subjects relapsed and 24 have died, 13 due to disease relapse. There was an improvement in 2-year RFS (94% vs. 83%; P = 0.0022) and 2-year OS (91% vs. 89%; P = 0.025) in low CD3+ T-cell cohort compared with high CD3+ T-cell cohort. Graft CD3+ T-cell dose is the only significant risk factor for relapse (P = 002), and OS (P = 0.030) in univariate analysis which was maintained in multivariate for relapse (P = 0.003), but not for OS (P = 0.050). Our data suggest that high graft CD3+ T-cell dose is associated with lower risk of relapse, and might improve long-term survival, but has no influence on the risk of developing aGvHD or cGvHD.

Outcomes associated with allogeneic hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma in the era of novel agents.

Relapsed or refractory Hodgkin lymphoma (R/R HL) is a challenging disease with limited treatment options beyond brentuximab vedotin and checkpoint inhibitors. Herein we present the time-trend analysis of R/R HL patients who received allogeneic hematopoietic cell transplantation (allo-HCT) at our center from 2001-2017. The patients were divided into two distinct treatment cohorts: era1 (2001-2010), and era2 (2011-2017). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), non-relapse mortality (NRM), and cumulative incidence of acute and chronic graft versus host disease (GVHD). Among the 51 patients included in the study, 29 were in era1, and 22 were in era2. There was decreased use of myeloablative conditioning in era2 (18% vs. 31%) compared to era1 and 95% of patients in era2 previously received brentuximab Vedotin (BV). Haploidentical donors were seen exclusively in era2 (0% vs. 14%) and more patients received alternative donor transplants (7% vs. 32%) in era2. The 4-year OS (34% vs. 83%, p< 0.001) and 4-year PFS (28% vs. 62%, p= 0.001) were significantly inferior in era1 compared to era2. The incidence of 1-year NRM was lower in era2 compared to era1 (5% vs. 34%, p= 0.06). The cumulative incidence of acute GVHD at day 100 was similar in both eras (p= 0.50), but the incidence of chronic GVHD at 1year was higher in era2 compared to era1 (55% vs. 21%, p= 0.03). Despite the advent of novel therapies, allo-HCT remains an important therapeutic option for patients with R/R HL.

Radiation Sparing Reduced Intensity Conditioning for Allogeneic Cell Transplantation in Patients with Dyskeratosis Congenita Comparable to Standard of Care: A Phase III Single Institution Trial

Introduction Dyskeratosis congenita (DKC) is a rare form of inherited multiorgan disease caused by mutations affecting telomere maintenance. Complications include bone marrow failure (BMF), pulmonary and liver fibrosis, and predisposition to malignancy. Allogeneic hematopoietic cell therapy (alloHCT) can rescue affected individuals from hematologic complications. However, toxicity from alkylator and radiation exposure can be lethal or potentially expedite DKC-specific organ complications. In this single institution phase III clinical trial, we aimed to demonstrate non-inferior short-term alloHCT outcomes with a radiation sparing reduced intensity conditioning (RIC) regimen while monitoring for long-term reductions in systemic toxicity. Methods We compared two consecutive cohort of patients with DKC requiring alloHCT for BMF or myelodysplastic syndrome (MDS). Both received RIC with fludarabine 200 mg/m2, cyclophosphamide 50 mg/kg, and alemtuzumab 1 mg/kg. The earlier cohort (4/2006-8/2012) additionally received 200 cGy total body irradiation ("TBI"), while the latter (11/2015-2/2021) "Non-TBI" cohort did not. We restricted our analysis to bone marrow (BM) and peripheral blood stem cell (PBSC) recipients. AlloHCT milestones including neutrophil engraftment, graft failure, disease progression, acute and chronic graft-versus host disease (GvHD), serious infections, and overall survival were prospectively recorded. The cumulative incidence of time-dependent events was compared between cohorts using the Fine-Gray test with death as a competing risk. Infection density over the first 100 days after alloHCT was calculated using the Mantel-Haenszel chi-square test for incidence density. Estimates of overall survival were calculated by Kaplan-Meier curves. Results The TBI cohort included 12 patients aged 2.2-52.2 years (median 20.5), 11 with SAA and 1 with MDS. Stem cell sources were unrelated donor BM in 8, sibling donor PBSCs in 2, and sibling BM in 1, with a median follow-up of 1531 days (range 83-3960). The comparable Non-TBI group included 10 patients aged 1.7-65.9 years (median 9.8), 8 with SAA and 2 with MDS/RAEB. Stem cell donor sources were unrelated donor BM in 8 and sibling BM in 2, with a median follow-up of 870 days (range 303-2420). Neutrophil engraftment occurred at a median of 13 days in the TBI cohort and 8.5 days in the Non-TBI cohort (p<0.001; Fig 1a). Cumulative incidence of acute GvHD by day 100 for the TBI cohort was 0.08 (95% CI <0.01, 0.32) compared to 0.1 (95% CI <0.01, 0.37) for the Non-TBI cohort (p=0.74). Cumulative incidence of chronic GvHD by 3 years for the TBI cohort was 0.17 (95% CI 0.02, 0.43) compared to 0.1 (95% CI <0.01, 0.37) for the Non-TBI cohort (p=0.7). With regard to serious infections the first 100 days after alloHCT, there were no fungal infections in either group and infection density of viral infections, bacteremia, and pneumonia episodes was equivalent between cohorts. In the TBI cohort, one case was recorded as a late graft failure at day +1371, however upon retrospective review, this patient maintained 10% BM cellularity with 100% donor chimerism and experienced cytopenias and death likely resulting from Epstein-Barr viremia and possible post-transplant lymphoproliferative disease. In the Non-TBI cohort, one patient experienced non-neutropenic graft failure/rejection at day +28. A second Non-TBI patient demonstrated graft failure in the form of MDS recurrence at day +359. There was no statistically significant difference in overall survival between the two groups (p=0.4; Fig 1b, Table 1), with the 5.5 years median survival of the TBI cohort and the median survival not achieved for the Non-TBI cohort. Conclusions A successful alloHCT conditioning regimen for DKC must provide myeloablation to allow for sustained donor engraftment and immunosuppression to decrease GvHD risk, while limiting an unfavorable toxicity profile to which DKC patients are more susceptible. Elimination of TBI from the RIC regimen demonstrated equivalent overall survival, acute and chronic GvHD incidence, and day +100 infection density with an expedited neutrophil engraftment and no increase in graft failure risk. While there appears to be a trend toward less lethal DKC late effects like pulmonary failure and secondary malignancy, definitive assessment of such outcomes requires further longitudinal follow-up of both cohorts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CT-098 Impact of T-Cell Dose on Outcome of T Cell–Replete HLA-Mismatched Allogeneic Peripheral Blood Stem Cell Transplantation

The outcome of allogeneic hematopoietic cell transplantation (HCST) relies on both disease-related factors and transplant-related factors including the conditioning regimen and immunotherapy exploiting the graft-versus-tumor (GVT) effect. CD3+ T cells are the main player in the GVT process, but an increased dose of these cells results in an increased risk of acute graft-versus-host disease (GVHD). We aimed to study whether the T-cell dose of allogeneic peripheral blood stem cell (PBSC) products influences transplantation outcomes in our patient population. This is a retrospective chart review study including patients over 18 years of age, diagnosed with AML, ALL, or MDS, who underwent PBSC mismatched allogeneic transplant, including haploidentical, one-antigen mismatched related, or 2-alleles mismatched related transplants at the King Hussein Cancer Center's bone marrow transplant program between January 2010 and December 2020. We calculated the median CD3 cell dose and divided all patients into 2 groups (Low and High dose groups) and then measured the cumulative incidence of acute GVHD, chronic GVHD, and 1- and 2-year overall survival (OS). Thirty-five patients were stratified according to the median CD3+ cell dose into the Low CD3 group, which included 18 (51%) patients with a mean dose of 13.7×107/kg (range: 2.8-19.7), and the High CD3 group, which included 17 (49%) patients with a mean dose of 29.7×107/kg (range: 19.8-93.1) (P-value: 0.000). The cumulative incidence of acute GVHD was 60% (n=12) in the Low CD3 group and 40% (n=8) in the High CD3 group (P-value: 0.24). The cumulative incidence of chronic GVHD was 64% (n=9) in the Low CD3 group and 35% (n=5) in the High CD3 group (P-value: 0.26). The overall survival for the cohort (n=35) at 12 months was 60.9% and reached 49.6% at 24 months. The 12-month OS for the Low and High CD3 groups was 66.7% and 52.9%, respectively. The 24-month OS for the Low and High CD3 groups was 66.7% and 33.1%, respectively (P-value: 0.084). Although the study showed a trend toward better OS in the Low CD3+ dose group, the difference was not statistically significant.

Outcomes After Donor Lymphocyte Infusion in Patients With Hematological Malignancies: Donor Characteristics Matter

In the context of T-cell depletion, failing to achieve full donor chimerism (FDC) entails higher risk of graft loss and disease relapse. Donor lymphocyte infusion (DLI) is an adoptive immunotherapy for mixed chimerism (MC) or relapsed disease after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (HSCT). Nevertheless, little is known of factors associated with attaining FDC or disease remission. We carried out a retrospective study with 100 adult patients to identify patient and donor factors that can predict achievement of FDC and disease remission and describe complications after DLI. Indications for DLI were T-cell MC in 61 patients and relapsed disease in 39 patients. Forty patients (65.6%) with MC attained T-full donor chimerism (T-FDC), with higher responses seen in patients whose donors were female (81.5% versus 52.9%, P = .004) and cytomegalovirus negative (76.5% versus 52%, P = .004). However, only patients with younger donors (<30 years old) compared to older donors (94.4% versus 53.5%, P = .013) and those attaining unfractionated whole blood (UWB) FDC after DLI (76.6% versus 28.6%, P < .001) had a survival benefit and subsequently a better graft-versus-host disease (GvHD)–free/relapse-free survival. Nineteen of 39 patients (48.7%) with relapsed disease achieved remission after DLI. In this cohort, attaining T-FDC impacted favorably in disease control (76.7% versus 12.5%, P = .012) and improved survival (45.5% versus 12.5%, P = .007). In the whole population, the cumulative incidence of acute GvHD (aGvHD) at day 100 after DLI was 23%, and chronic GvHD (cGvHD) at 1 year after DLI was 22%. In the whole population, donor age was also a determining factor for aGvHD, because patients with younger donors had a lower incidence of aGvHD (8% versus 36%, P = .021). The cGvHD was more likely to occur in patients who converted to T-FDC (34% versus 10.3%, P = .025). Donor characteristics are increasingly considered when deciding approaches for HSCT. Donor age should be considered when planning HSCT, as well as doses and scheduling of DLI. As per our experience, this should be done alongside T/UWB chimerism to achieve the maximal clinical benefit with less associated toxicity. Selection of younger male donors from stem cell registries can minimize the risk of GvHD and improve survival.

Outcomes Following Intolerance to Tacrolimus/Sirolimus Graft-versus-Host Disease Prophylaxis for Allogeneic Hematopoietic Cell Transplantation

Although tacrolimus and sirolimus (TAC/SIR) is an accepted graft-versus-host disease (GVHD) prophylaxis regimen following allogeneic hematopoietic cell transplantation (HCT), toxicity from this regimen can lead to premature discontinuation of immunosuppression. There are limited studies reporting outcomes and subsequent treatment of patients with TAC/SIR intolerance. This study was conducted to assess the outcomes of patients with TAC/SIR intolerance and guide their subsequent management. We retrospectively analyzed transplantation outcomes of consecutive adult patients at Moffitt Cancer Center who underwent allogeneic HCT with TAC/SIR as GVHD prophylaxis between 2009 and 2018. TAC/SIR intolerance was defined as discontinuation of either TAC or SIR due to toxicity before post-transplantation day +100. A total of 777 patients met the inclusion criteria. The median duration of follow-up was 22 months (range, 0.2 to 125 months). Intolerance occurred in 13% (n = 104) of the patients at a median of 30 days (range, 5 to 90 days). The most common causes of intolerance were acute kidney injury (n = 53; 51%), thrombotic microangiopathy (n = 31; 28%), and veno-occlusive disease (n = 23; 22%). The cumulative incidence of grade II-IV acute GVHD at 100 days was 50% (95% CI, 39% to 64%) in the TAC/SIR-intolerant patients and 25% (95% CI, 22% to 29%) in patients tolerant to this regimen (P < .0001). In multivariate analyses, the incidence of grade II-IV 4 acute GVHD was significantly higher in the TAC/SIR-intolerant patients (hazard ratio [HR], 2.40; 95% CI, 1.59 to 3.61; P < .0001). Similarly, in multivariate analyses, the TAC/SIR-intolerant patients had a higher incidence of chronic GVHD (HR, 1.48; 95% CI, 1.03 to 2.12; P = .03). The nonrelapse mortality (NRM) at 1 year was 47% (95% CI, 38% to 59%) in the TAC/SIR-intolerant patients and 12% (95% CI, 10% to 15%) in those tolerant to the regimen (P < .0001). The 2-year relapse-free survival was 35% (95% CI, 25% to 44%) in the TAC/SIR-intolerant patients and 60% (95% CI, 57% to 65%) in the TAC/SIR-tolerant patients (HR, 2.30; 95% CI, 1.61 to 3.28; P < .0001). Intolerance stratified by early (≤30 days) versus late (31 to 100 days) significantly affected the cumulative incidence of acute GVHD at 75% (early; 95% CI, 59% to 94%) versus 33% (late; 95% CI, 21% to 50%) (P = .001), as well as the cumulative incidence of NRM at 61% (early; 95% CI, 48% to 77%) versus 35% (late; 95% CI, 24% to 51%) (P = .006). Most patients who developed TAC/SIR intolerance were switched to an alternative 2-drug regimen (71 of 104; 68%), most commonly mycophenolate mofetil in addition to continuing TAC or SIR (68 of 71; 96%). Overall, TAC/SIR intolerance was associated with poorer outcomes. Early intolerance contributed to a higher risk of acute GVHD, increased NRM, and inferior survival. Patients with early intolerance were often switched to an alternative agent, and patients with late intolerance tended to be continued on single-drug therapy without substitution. The use of single-drug versus 2-drug regimens after intolerance did not appear to affect outcomes. Management strategies to mitigate the risks of intolerance are warranted.

Durable outcomes of double cord blood transplantation in adults with acute lymphoblastic leukemia: high-risk features for early and long-term mortality.

Background:Cord blood transplantation (CBT) has been reported as an acceptable option with comparable outcomes to conventional donors in adults with acute lymphoblastic leukemia (ALL). We aimed to analyze the long-term CBT outcomes and risk factors for early and long-term mortalities.Methods:Between 2006 and 2020, 112 patients (median age: 35 years; 62 Ph-negative ALL and 50 Ph-positive ALL) were treated with double CBT. Conditioning regimen consisted of total body irradiation (12 Gy) plus cytarabine (9.0 g/m2) plus fludarabine (150 mg/ m2), and graft-versus-host disease (GVHD) prophylaxis was attempted by administering tacrolimus plus mycophenolate mofetil.Results:The median time for neutrophil and platelet recovery was 25 days (range: 5–59 days) and 34 days (range: 7–185 days), respectively. The cumulative incidence of acute GVHD at 1 year was 43.8%, and the incidence of acute GVHD with grades III–IV was 8.9%. The overall cumulative incidence of chronic GVHD was 22.0%, and the incidence of moderate to severe chronic GVHD was 8.5%. After a median follow-up of 60.1 months (range: 5.7–181.3 months), the 5-year cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) were 15.9% and 28.5% (9.7% and 27.2% for CR1), respectively, and the 5-year overall survival (OS) was 57.9% (66.5% for CR1). In multivariate analysis of 88 patients receiving double CBT in CR1, delayed CR1 was related to high CIR, and age older than 40 years was associated with high NRM and early mortality. Unexpectedly, Ph-positive ALL with MRD had a higher NRM and early mortality than Ph-negative ALL and Ph-positive ALL without MRD subgroups, possibly due to delayed neutrophil and platelet recovery.Conclusion:Our data suggest that double CBT for adult ALL in CR1 has a greater benefit in younger patients and in patients with Ph-positive ALL without MRD or Ph-negative ALL.

Durable Outcomes of a Prospective Double Cord Blood Transplantation Trial in Adults with Acute Lymphoblastic Leukemia: Different Outcomes According to the Presence of Philadelphia Chromosome

▪Background: Alternative donor hematopoietic cell transplantation (HCT) is an emerging topic in acute leukemia for patients without matched sibling donors (MSD) or unrelated donors (MUD). Cord blood transplantation (CBT) has been tried for several years in adult acute lymphoblastic leukemia (ALL), and the long-term survival outcomes were comparable to those treated with conventional donor HCT.Aim : We have conducted double CBT (DCBT) in patients without both MSD and MUD for final step, and here, we report our phase 2 study results of clinical outcomes for adult ALL patients treated with DCBT.Methods: During the period between 2005 and 2016, 67 patients (median age, 37 years [range, 16-59 years]; 34 Ph-negative ALL and 33 Ph-positive ALL) were treated with DCBT in CR1 (n=48), CR2 (n=15), and in advanced status (n=4). The indications for DCBT were unavailability of MSD and MUD, agreement for conduction of the transplantation procedure, and proper performance status and organ function to undertake transplantation. The median time to transplant was 198 days (range, 97-1751 days). All patients received DCBT following total body irradiation (TBI) 12.0 Gy plus cytarabine 9.0 g/m2 plus fludarabine 150 mg/m2, and graft versus host disease (GVHD) prophylaxis was attempted by administering tacrolimus plus mycophenolate mofetil. If residual leukemia was detected in the absence of GVHD at 3 months after transplantation, calcineurin inhibitors were rapidly discontinued.Results: The median time for neutrophil and platelet recovery was 25 days (23 days [range, 12-109] for Ph-negative ALL and 26 days [range, 9-59] for Ph-positive ALL, P=0.336) and 34 days (27.5 days [range, 8-123] for Ph-negative ALL and 40 days [range, 9-185] for Ph-positive ALL, P=0.022), respectively. The median CD34+ cell count was 1.21 x 105/kg (range, 0.4-5.85) and TNC was 4.04 x 107/kg (range, 1.58-7.88). In our data, extramedullary involvements were more frequently observed in Ph-negative ALL, while hyperleukocytosis was frequently observed in Ph-positive ALL. Except for 5 patients who died in aplasia, 28 developed acute GVHD (grade II in 23 and grade III in 5), and the cumulative incidence of acute GVHD at 1-year was 41.8%, and the incidence was 9.0% for acute GVHD with grade III-IV. Except for 11 patients with early deaths within 100 days, 17 developed chronic GVHD (11 mild, 4 moderate, 2 severe), resulting in a 4-year cumulative incidence of 23.0% (3.0% for severe chronic GVHD). After a median follow-up duration of 43.7 months (range: 6.5 - 135.3), the 4-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 15.6% and 29.6% (7.2% and 29.2% for CR1), respectively, and the 4-year disease-free survival (DFS) and overall survival (OS) rates were 52.5% and 53.9% (62.9% and 65.6% for CR1), respectively. The 4-year CIR, NRM and DFS for Ph-negative and Ph-positive subgroup was 9.6% and 21.6% (P=0.140), 21.0% and 38.9% (P=0.107), and 66.5% and 37.7% (P=0.017). The results of Ph-negative and Ph-positive subgroup in CR1 were 4.8% and 9.9% (P=0.357), 19.1% and 43.0% (P=0.088), and 76.1% and 45.0% (P=0.029), respectively. In multivariate analysis, advanced disease status≥CR2 (HR, 5.61; 95% CI, 1.4-22.2; P=0.014) was related with higher CIR rate, and older age (HR, 3.75; 95% CI, 1.5-9.3; P=0.004) and lower CD34+ cell count (HR, 4.96; 95% CI, 1.1-22.3; P=0.037) were related with higher NRM rates. Overall, Ph-chromosome (HR, 2.65; 95% CI, 1.2-5.8; P=0.016), longer time to transplant (HR, 4.18; 95% CI, 1.9-8.9; P <0.001), lower CD34+ cell count (HR, 3.66; 95% CI, 1.4-9.5; P=0.008) and the absence of acute GVHD (HR, 3.19; 95% CI, 1.4-7.4; P=0.006) were related to poorer DFS.Conclusion: Our data showed that DCBT can be a good alternative choice for providing a long-term disease control for adult ALL patients especially in Ph-negative subgroup. Since Ph-positive subgroup was related with poorer DFS and higher NRM rate in our data, another alternative haploidentical HCT should be considered. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Invasive Fungal Disease in Allogeneic Hematopoietic Stem Cell Transplant Recipients Is an Important Risk Factor Not Only for Acute Graft-Versus-Host Disease but Also for Chronic Graft-Versus-Host Disease

Introduction: Infections and graft-versus-host disease (GVHD) are the leading causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). And their close relationship is gaining more and more attentions in recent years. Although it has been demonstrated that invasive fungal disease (IFD) is associated with an increased risk of acute GVHD, the link between IFD and chronic GVHD is rarely reported. This large retrospective study was performed to assess the relationship between IFD and GVHD, especially chronic GVHD.Methods: A total of 684 patients with hematologic malignancies who underwent allo-HSCT at Nanfang Hospital between January 2011 and December 2015 were enrolled in the retrospective study. We defined IFD according to the European Organization for Research and Treatment of Cancer and Mycoses Study Group (EORTC/MSG) revised definitions of 2008 (De Pauw B et. al. Clin Infect Dis 2008) and included proven and probable cases for analysis. Cases of possible IFD were also included if initial antifungal treatments were considered effective, otherwise possible cases were excluded. Acute GVHD was graded from 0 to IV and chronic GVHD was defined as no, limited or extensive chronic GVHD according to standard criteria (Przepiorka D et. al. Bone Marrow Transplant 1995; Sullivan KM et. al. Semin Hematol 1991). Cumulative incidence of acute GVHD, chronic GVHD, non-relapse mortality (NRM) and overall survival (OS) were estimated by the Kaplan-Meier and comparison was done by a log- rank test. Risk factors associated with chronic GVHD after allo-HSCT were identified in a multivariable Cox regression model.Results: Within 1 year post-transplantation, 191 patients developed IFD (42 proven, 98 probable and 51 possible), including 39 patients with a history of IFD pre-transplantation. Of the 39 patients, 32 patients had stable IFD and 7 patients had active IFD at the time of their transplantation. The 1-year cumulative incidence of IFD was 25.3% ±1.7%. The cumulative incidence of grades II to IV acute GVHD at 100 days was 47.8% ± 4.4% in IFD group and 25.8% ±2.0% in non-IFD group, respectively (P < .001). The 2-year cumulative incidence of chronic GVHD and extensive chronic GVHD were significantly higher in patients with IFD compared to those without IFD (66.6% ± 5.0% versus 41.5% ± 2.4%, P < .001; 31.6% ± 4.8% versus 9.4% ± 1.4%, P < .001). Besides, patients with IFD also had higher 5-year NRM and lower 5-year OS compared to patients without IFD (29.2 ± 3.6% versus 10.9% ± 1.6%, P < .001 and 53.6 ± 3.8% versus 69.3% ± 2.2%, P < .001). Multivariate analyses showed that IFD was a significant risk factor for chronic GVHD, independent of other risk factors (hazard ratio [HR], 1.502; 95% confidence interval [CI], 1.127-2.001; P=0.005).Conclusions: The occurrence of IFD confers a high risk for acute GVHD and chronic GVHD development. This may provide new insights that allo-HSCT patients might benefit most from early and prolonged antifungal prophylaxis and immediate antifungal therapy. DisclosuresNo relevant conflicts of interest to declare.

Hematopoietic Cell Transplantation Outcomes among Medicaid and Privately Insured Patients with Sickle Cell Disease

Compared with privately insured patients, recipients of Medicaid have been reported to have worse outcomes in several clinical conditions and following various surgical and medical procedures. However, the relationship between health insurance status and allogeneic hematopoietic cell transplantation (alloHCT) outcomes among patients with sickle cell disease (SCD) is not well described. We sought to compare alloHCT outcomes between patients with SCD who underwent alloHCT while enrolled on Medicaid versus those who underwent alloHCT while covered by private health insurance. We conducted a retrospective multicenter study using data reported to the Center for International Blood and Marrow Transplant Research. US patients enrolled on Medicaid or private insurance who underwent a first alloHCT for SCD between 2008 and 2018 were eligible for this study. The primary outcome was event-free survival (EFS), defined as time to death or graft failure. Secondary outcomes included overall survival (OS), graft failure, acute graft-versus-host disease (GVHD), and chronic GVHD. Univariate analysis was performed using the Kaplan-Meier method for EFS and OS. The proportion of patients with graft failure, acute GVHD, and/or chronic GVHD was calculated using the cumulative incidence estimator to accommodate competing risks (ie, death). Cox regression was used to identify factors associated with EFS, OS, graft failure, and acute and chronic GVHD. A total of 399 patients (Medicaid, n=225; private insurance, n=174) were included in this study. The median duration of follow-up was 34 months (range, 1.0 to 134.7 months) for the Medicaid group and 38.7 months (range, 0.3 to 139.3 months) for the private insurance group. Compared with the patients with private insurance, those on Medicaid had a significantly lower 3-year EFS (75.4% [95% confidence interval (CI), 69.4% to 81%] versus 82.2% [95% CI, 76.9% to 87.8%]; P=.0279) and a significantly higher 3-year cumulative incidence of graft failure (17.2% [95% CI, 12.5% to 22.5%] versus 10.5% [95% CI, 6.4% to 15.4%]; P=.0372). There were no significant between-group differences in 3-year OS (P=.6337) or in the cumulative incidence of acute GVHD (P=.4556) or chronic GVHD (P=.6878). Cox regression analysis after adjusting for other significant variables showed that the patients enrolled on Medicaid had a lower EFS (hazard ratio [HR], 2.36; 95% CI, 1.44 to 3.85; P=.0006) and a higher cumulative incidence of graft failure (HR, 2.57; 95% CI, 1.43 to 4.60; P=.0015), with no significant between-group differences in OS (HR, 0.99; 95% CI, 0.47 to 2.07; P=.9765), acute GVHD (HR, 0.94; 95% CI, 0.59 to 1.49; P=.7905), or cGVHD (HR, 0.98; 95% CI, 0.65 to 1.48; P=.9331). That EFS is worse in patients on Medicaid compared with privately insured individuals following alloHCT for SCD provides the rationale for research to better understand the mechanisms by which insurance status impacts alloHCT outcomes among patients with SCD.