Grade II-IV GVHD Research Articles

Anti-T-lymphocyte globulin (ATLG) compared to post-transplant cyclophosphamide as GvHD prophylaxis in ALL patients undergoing allogeneic stem cell transplantation

We retrospectively analyzed high-risk ALL patients in CR1 receiving total body irradiation based conditioning regimen with ATLG (n = 74) or PTCy (n = 73) for GVHD prophylaxis. The 3-year OS and LFS were similar in both groups: 65 and 60% in the ATLG group and 64 and 67% in the PTCy group (p = 0.9 and 0.5, respectively). CIR and NRM rate at three years was 12 and 21% after PTCy and 19 and 20% after ATLG (p = 0.4 and p = 0.9, respectively). Acute GvHD grades II-IV and grades III/IV at 100 days was 46 and 19% after PTCy and 33 and 10% after ATLG (p = 0.08 and p = 0.9, respectively). Chronic GvHD of all grade at two years was higher after PTCy: 55% versus 26% (p < 0.001). Based on the propensity score matching (PSM) analysis, aGvHD grades II-IV was trending higher in the PTCy group compared to the ATLG group (p = 0.07). In contrast to the PSM analysis, on multivariate analysis the receipt of PTCy compared with ATLG was associated with a reduced CIR (p = 0.026). Our retrospective single-center analysis shows a lower incidence of acute and chronic GvHD while displaying similar LFS and OS after ATLG compared to PTCy in TBI based allogeneic stem cell transplantation for high-risk ALL.

Sequential Conditioning Does Not Improve Outcomes of Allogeneic Stemcell Transplantation in CMML Patients

Background: Allogeneic stem cell transplantation (SCT) is potentially curative therapy for patients with CMML. Data on optimal allo-SCT conditioning in CMML Patients is scarce. Methods: This retrospective study from the Department of Stem Cell Transplantation at the University Medical Center Hamburg, Germany, compared allo-SCT outcomes in CMML patients across three conditioning regimes: Thiotepa-Busulfan (TB), Sequential FLAMSA-Busulfan Fludarabine (FLAMSA-FB), and Treosulfan-Fludarabine (Treo-Flu). TB consisted of Thiotapa ( 5mg/Kg; a total dose of 10mg/Kg) on day -6 and -5 and Busulfan (3.2mg/Kg; total dose 6.4mg/Kg or 9.6mg/Kg) on days -4 and -3 or -4 to -2. FLAMSA-FB regimen consists of fludarabine (30 mg/m 2 ; total dose 120 mg/m 2 ), amsacrine (100 mg/m 2 ; total dose 400 mg/m 2 ), and cytarabine (1 g/m 2 ; total dose 4 g/m 2 ) therapy from days -11 to minus -8, followed by a three-day interval without therapy and Busulfan from day -4 to -2 with a total dose of 6.4mg/Kg and Fludarabine on day -4 and -3 (30 mg/m 2, total dose 60mg/m 2 ).Treo-Flu regimen consisted of Treosulfan (12 g/m 2 , total dose 36 mg/m 2 ) on days-6 to -4 and fludarabine (30 mg/m 2 ; total dose 150 mg/m 2 ) on days -6 to -2. Results Sixty-nine consecutive patients with CMML who underwent allo-SCT between the years 2006-2022. Twenty-two received TB, 27 received FLAMSA-FB, and 20 received Treo-Flu conditioning. Transplant sources included matched related donors (MRD, 8 patients), mismatched related donors (MMRD, 8 from TB), matched unrelated donors (MUD, 31), and mismatched unrelated donors (MMUD, 23) with significant group variations (p&amp;lt;0.001). Most Patients received ATLG for GVHD prophylaxis (TB 68%, FLAMSA-FB 93%, Treo-Flu 85%, p=0.08). Regarding CPSS-mol scores, the TB group exhibited a significantly higher proportion of high (46%) and intermediate-2 scores (32%) than FLAMSA-FB (11% high, 7% intermediate-2) and Treo-Flu (40% high, 20% intermediate-2) (p=0.001). One TB patient experienced primary graft failure, but engraftment times were comparable across groups. Although not statistically significant (p=0.07), the TB group showed a trend towards improved 3-year OS rates (84%) compared to FLAMSA-FB (37%) and Treo-Flu (49%). The TB group also displayed significantly higher 3-year PFS rates (79%) compared to FLAMSA-FB and Treo-Flu (both 30%), (p=0.03). (Figure 1) No significant differences were observed in 3-year non-relapse mortality (NRM) across the TB (17%), FLAMSA-FB (30%), and Treo-Flu (26%) groups (p=0.7). Interestingly, no TB patients relapsed at 3 years, contrasting with the FLAMSA-FB (41%) and Treo-Flu groups (43%, p=0.02). Lastly, cumulative incidences of acute GVHD grade II-IV (TB 41%, FLAMSA-FB 35%, Treo-Flu 30%, p=0.75) and all-grade chronic GVHD (TB 50%, FLAMSA-FB 65%, Treo-Flu 40%, p=0.35) were similar across groups. Conclusion Our study suggests that sequential conditioning with FLAMSA-FB does not improve Transplant outcomes in patients undergoing allo-SCT for CMML.

Role of Splenic Irradiation Prior to Transplant for Myelofibrosis: A Global Collaboration

JAK inhibitors and novel agents have shown promising reduction of spleen size in newly diagnosed myelofibrosis. However, not all patients will respond or they eventually progress at some point. Despite hematopoietic cell transplantation (HCT) being the only curative treatment option to date, splenomegaly prior to HCT remains a particular challenge. On the other hand, numbers of patients eligible for HCT continue to increase worldwide, and thus management of splenomegaly becomes more and more relevant. One approach to reduce spleen size prior to HCT could be splenic irradiation. However, evidence on its role remains scarce. We took advantage of a global collaboration between European, US, and Latin American centers to investigate the role of splenic irradiation as part of the HCT platform for patients with myelofibrosis. Radiation therapy had to be given within 3 months prior to or be part of conditioning therapy for HSCT. Detailed information on irradiation as well as post-HCT safety profiles was collected in addition to usual patient-, disease-, and transplant-related variables. This global collaborative study included 52 patients, of whom 71% had primary myelofibrosis, 17% post polycythemia vera and 12% post essential thrombocythemia myelofibrosis. Median age at HCT was 60 years (range, 32-76). Risk category according to DIPSS prior to irradiation was intermediate-1 in 20%, intermediate-2 in 52%, and high in 28%. Driver mutation status was JAK2 in 44%, CALR in 40%, MPL in 4%, and triple negative in 12%. Four patients had portal vein thrombosis before irradiation. Ruxolitinib before irradiation was received by 76% and 4% received fedratinib. Reduced intensity conditioning HCT was received by 73% and 85% were matched related or matched unrelated donor transplants. Median time from irradiation to HCT was 2 weeks (range, 0.9-12 weeks) and median spleen size prior to irradiation was 23 cm (range, 14-35). Spleen size was measured by ultrasound in 70%, CT scan in 20%, and physical examination in 10%. Median total irradiation dose was 7 Gy (range, 3-12), fractionated in a median of 5 administrations (range, 2-12). Splenic irradiation resulted in a significant spleen reduction prior to HCT but was also associated with significant reduction in platelet and leukocyte counts ( Table). Spleen size did not correlate with blood counts prior or after irradiation. Higher platelet count prior to irradiation correlated with higher counts after irradiation (r=0.83; P&amp;lt;0.001). There was no correlation between irradiation dose and post-irradiation hematological toxicities. Only 1 patient had non-hematological adverse events (tumor lysis syndrome). Neutrophil engraftment was achieved by 90% within a median of 18 days after HCT and platelet engraftment was achieved by 81% within a median of 38 days. Median follow-up of the total cohort was 2.7 years and 3-year overall survival was 66% (95% CI, 52-80%; Figure). Non-relapse mortality was 27% (95% CI, 15-39%) and cumulative incidence of relapse was 11% (95% CI, 2-20%; Figure). Incidence of acute GVHD grade II-IV and chronic GVHD was 25% and 38%, respectively. Increased spleen size (as continuous variable) prior to irradiation was associated with worse outcome (P=0.05), showing 3-year survival of 73% for spleen ≤25cm vs 42% for &amp;gt;25cm, and non-relapse mortality of 58% vs 14%, respectively (P=0.02). No effect of spleen size after irradiation on outcomes was observed. All 4 patients with portal vein thrombosis died (2-year survival 25%). A multivariable model showed that larger spleen size before irradiation, lower hemoglobin levels, CALR/MPL-unmuated driver mutation genotype, and presence of portal vein thrombosis were significantly associated with worse survival ( Table). This first international and largest study to date on splenic irradiation as part of the HCT algorithm for patients with myelofibrosis and splenomegaly showed a significant impact of spleen size on overall survival and non-relapse mortality, while relapse rates were low. In addition, lower hemoglobin levels and presence of portal vein thrombosis at time of irradiation predicted worse outcomes.

Post-Transplant Cyclophosphamide (PTCY) Compared to ATG in Patients with Myelodysplastic Neoplasms Allografted with an Unrelated Donor: A Registry Study of the Chronic Malignancies Working Party of the EBMT

Background Prospective randomized trials have reported a benefit for ATG-based GVHD prophylaxis in the setting of allogeneic hematopoietic stem cell transplantation (alloHSCT) with an unrelated donor (UD). However, the best GVHD prophylaxis has been recently challenged by the use of PTCY, first in haplo-identical transplant and then in HLA mismatched or matched unrelated transplantation. We here present the outcomes of PTCY vs ATG as GVHD prophylaxis in MDS patients from the EBMT registry transplanted with an unrelated donor. Method A total of 969 patients transplanted from 2012 to 2019 in 92 participating centers, receiving either PTCY or ATG, were included in this study. The primary outcomes were progression free survival (PFS) and overall survival (OS). Competing risks analyses were performed to analyze non-relapse mortality (NRM) with competing event relapse, and acute GvHD grade II-IV, chronic GvHD and neutrophil engraftment with competing events relapse and death. Cox proportional hazards regression with a predefined covariate constellation (age, IPSS-R cytogenetics, donor HLA matching, age, hypomethylating agents (HMA) prior to transplantation, comorbidity score and MDS classification (MDS with or without excess blast, EB) was used to obtain adjusted effect estimates of ATG compared to PTCY for OS and PFS. Results Overall, 214 patients received PTCY and 755 received ATG as GVHD prophylaxis for UD alloHSCT. Patients of the ATG group were older (60.1 year-old [IQR: 50.6-65.2] vs 57.2 year-old [IQR: 46.4-61.1], p=0.008). Disease characteristics were similar in both group: there were a total of 583 MDS with EB at diagnosis, 510 MDS-EB at transplantation, and 207 patients transformed into AML. Among patients with available data for IPSS-R at MDS diagnosis (n=760) 44 (5.8%) were Very Low, 114 (15%) Low, 209 (27.5%) Intermediate, 232 (30.5%) High and 161 (21.2%) Very High. Patients of the PTCY group received more frequently HMA before transplantation (72.4% vs 57.3%, p=0.001) and were preferentially transplanted from an HLA mismatched 9/10 donor (37.9% vs 21.6%, p&amp;lt;0.001). Conditioning regimen was more frequently myeloablative in the PTCY group (55.4% vs 38.7%, p&amp;lt;0.001). Neutrophil engraftment at 28 days was significantly better with ATG (93% vs 84%, p&amp;lt;0.001). With a median follow-up of 4.4 (95% CI 4.2 - 4.8) years, five-year OS was 57% (49-64) with PCTY and 49% (95% 46-53%) in ATG group, p=0.127. Five-year cumulative incidence of relapse was similar in both groups (22%, 95%CI 16-29 in PTCY vs 25%, 95%CI 22-28 in ATG; p=0.28). Notably, 5-year PFS was marginally higher for PTCY with 52% (95%CI 44-59) vs 44% (95%CI 40-48) for ATG, p=0.075, whereas 5-year NRM was 26% (95% CI 20-32%) vs 31% (95% CI 27-34) in PTCY and ATG, respectively, p=0.28. Grade II-IV acute GVHD incidence was lower using PTCY (22% [95% CI 17-28%] vs 30% [95% CI 26-33%]), p=0.035 while there was no difference for chronic GVHD (36% (29-43% with PTCY vs 38% (34-41%) in ATG at 5 years). Multivariable analyses confirmed a better OS and PFS for PTCY, with a HR of ATG of 1.34 (95% CI 1.02-1.76), p=0.04, and a better PFS for PTCY with a HR for ATG of 1.31 (95%CI 1.01-1.69) (Table 1). There was no apparent interaction between GvHD prophylaxis and IPSS-R or HLA matching, suggesting an effect exclusive to the type of GVHD prophylaxis used. Conclusion: This EBMT registry study suggests that MDS patients who received a transplant from an unrelated donor had a better OS and PFS using PTCY compared to ATG. This confirms that PTCY instead of ATG in this setting is a valid option.

Bone Marrow Quality Index: A Predictor of Acute Graft-versus-Host Disease in Hematopoietic Stem Cell Transplantation for Thalassemia

Bone marrow continues to be the preferred source of stem cells in allogenic transplantations for non-malignant disorders. Granulocyte-colony stimulating factor (G-CSF)-primed bone marrow (BM) is associated with low rates of acute GVHD and allows reduced collection volumes while ensuring speedy engraftment. However, variability in bone marrow harvest quality is a concern. This report analyses the utility of a novel indicator - Bone Marrow Quality Index (BMQI), which is a ratio of marrow cell count to peripheral blood cell counts, to predict acute GVHD. We analysed 184 consecutive first matched related donor bone marrow transplants for thalassemia using G-CSF-primed bone marrow over 6 years from March-2017 to April-2023 across 2 centres in India. Bone Marrow Quality Index (BMQI) was defined as the ratio of WBC count of G-CSF primed bone marrow to Peripheral WBC count within 24 hours of harvest. EBMT criteria were used for grading GVHD. Log-rank test was used to assess the impact of BMQI on GVHD. Chi-squared test was used to compare categorical data and Wilcoxon test was used to compare the numeric data. Cox proportional-hazards model was used to investigate the association of BMQI vis-à-vis other factors on acute GVHD. Of the 184 patients, 19 had a BMQI <0.9 and 18 between 0.9 and 1. The remaining 147 had BMQI >1. The proportion of patients with acute GVHD grade II-IV was 37%, 22% and 12% respectively for patients who received BMQI <0.9, 0.9-1 and >1 (p= 0.018). Patients who received BMQI <0.9 had a 3.1 times higher chance (95% CI being 0.9 to 10.6) of developing aGVHD II-IV and in those with BMQI 0.9-1 this was 2 times (95% CI being 0.5 to 6.6) higher. BMQI was the significant predictor associated with GVHD hazard (p=0.014). BMQI seems to be the most relevant and controllable predictor of acute GVHD. BMQI is a novel, informative, and very simple indicator which could influence GVHD prophylaxis decision-making. Our indicator is accurately measurable, inexpensive, precise, and timely; further it does not involve any sophisticated equipment, thus may be widely applicable. Prior knowledge of poor marrow quality may help intensify prophylaxis and monitoring for acute GVHD besides triggering review of collection procedures.

Hematopoietic cell transplantation for telomere biology diseases: A retrospective single-center cohort study.

Telomere biology diseases (TBD) result from defective telomere maintenance, leading to bone marrow failure. The only curative treatment for aplastic anemia related to TBD is a hematopoietic cell transplant (HCT). Although reduced-intensity conditioning (RIC) regimens decrease transplant-related mortality, non-hematological phenotypes represent a major challenge and are associated with poor long-term follow-up outcomes. To describe the outcome of TBD patients transplanted for marrow failure. This is a retrospective, single-center study describing the outcomes of 32 consecutive transplants on 29 patients between 1993 and 2019. The median age at transplantation was 14 years (range, 3-30 years). Most patients received a RIC regimen (n = 28) and bone marrow (BM) from an unrelated donor (n = 16). Four patients received a haploidentical transplant. Chimerism was available for 27 patients with a median time to neutrophil recovery of 20 days (13-36 days). Primary graft failure occurred in one patient, whereas second graft failure occurred in two. Acute GVHD grade II-IV and moderate to severe chronic GVHD occurred in 22% of patients at risk. Fourteen patients were alive after HCT at the last follow-up (median, 6 years; 1.4-19 years). The 5-year overall survival was better after matched sibling donor (MSD) transplantation compared to other hematopoietic stem cell sources (88.9% vs. 47.7%; p = .05; CI = 95%). Overall, 15 patients died after HCT, most of them (n = 11) after the first year of transplant, due to non-hematological disease progression or complication of chronic GVHD. Hematopoietic cell transplantation is a potentially curative treatment option for TBD, nonetheless the poor outcome reflects the progression of non-hematologic disease manifestations, which should be considered when transplantation is indicated.

Abatacept/Tacrolimus or Abatacept/Tacrolimus/Post-Transplant Cyclophosphamide Are Safe and Highly Effective in Preventing Graft-Versus-Host Disease in Matched or Mismatched Donor Peripheral Blood Stem Cell Transplantation

Background: Abatacept blocks CD28-CD80/86 axis and prevents T-cell co-stimulation. In early studies, abatacept has shown promising results when added to methotrexate and tacrolimus in matched and mismatched donor SCT. Further promising results have been demonstrated with a combination of post-transplant cyclophosphamide (PTCy), abatacept, and a short course of tacrolimus to improve the results of GvHD prevention in the setting of haploidentical SCT. Based on this data we initiated a phase Ib-II clinical trial of the efficacy and toxicity of the Abatacept/Tacrolimus/PTCy combination for patients who received HLA-mismatched grafts and Abatacept/Tacrolimus combination for patients who received HLA-matched grafts. Aim: assess the frequency of acute and chronic GVHD grade II-IV. Patients received G-CSF mobilized peripheral blood grafts from related and unrelated donors. GvHD prevention consisted of PTCy 50mg/kg IV on day +3 and +4, abatacept 10mg/kg IV on day -1, +5, +14 and +28 and tacrolimus. Tacrolimus was started on day -1 at 0.02 mg/kg/day by continuous IV and adjusted thereafter to maintain a trough level of 5-12 ng/mL. Tacrolimus taper was planned to begin on day +90 and complete by day +120 in the absence of GvHD. All patients received standard supportive care including acyclovir and co-trimoxazole until CD4-count >200 cells/muL, posaconazole/voriconazole until day +60, and if CMV positive by serology, ganciclovir 5 mg/kg per day until day +100. G-CSF was administered routinely until neutrophil engraftment. From Oct 2020 to Jul 2022, 51 patients were enrolled. The median age was 44 years (23-64) M/F 49%/51%. Diagnosis: AML 23,5% (12/51), B-NHL 17,6% (9/51), HD 17,6% (9/51), ALL 15,6% (8/51), MDS 9,8% (5/51), MF 5,9% (3/51), CLL 4% (2/51), MM 4% (2/51), AA 2% (1/51). Disease status before conditioning: 30/51 had CR, 15/51 - PR, 6/51- active disease. Conditioning regimens: Treo/Flu for AML, ALL, MDS and MF (28/51, 55%), Benda/Flu for B-NHL, HD, CLL and MM (22/51, 43%), Flu/Cy/ATG for AA (1/51, 2%). RIC/MAC: 65%/35%. 29,4% (15/51) of patients received cryopreserved products. Median times to ANC and platelet engraftment were 15 (8-60) and 18 days. 2 patients had primary graft failure (absence of engraftment > 28 days, non-response MDS before SCT and B-NHL, both 5/10, both older than 60). In both cases, a second HSCT was performed from the same donors. In the first case (non-response MDS), repeated HSCT without any effect and the patient died, in the second case, there was graft engraftment with the restoration of blood parameters. 1 patient (ETP ALL, mismatched related donor 5/10) had poor graft function. Transfusion of purified CD34+ cells (Miltenyi Biotec) from the same donor was accompanied by restoration of hematopoiesis. With a median follow-up was 154 days (25-641) with 34 patients having >120 days, 23 >180 days, and 7 >365 days of follow-up, 13,7% (7/51) patients developed acute GvHD grade II-IV (mostly skin, gut, liver). 9,8% (5/51) of patients developed chronic GvHD grade II-IV (skin, lungs, mucous eyes, liver, joints). 47% (24/51) completed tacrolimus taper by day +120. 3 patients switched from tacrolimus to sirolimus and one to prednisone due to intolerance or toxicity. 3 patients with MF received ruxolitinib from day +30 as a treatment for MF (no signs of GVHD of any grade). All patients with GvHD grade II-IV received systemic steroids. 7 patients received ruxolitinib, 3 - MMF, 4 - rituximab, 1 - daratumumab, 2 - ibrutinib, 1 - acalabrutinib and 2 - imatinib. CMV activation rate was 35,3%. There were 1 case of BK virus and 1 case of JC virus (patient with HD after aGVHD and cGVHD). 2 patients developed thrombotic microangiopathy (one received tacrolimus, one did not). During the observation period, 25,5% (13/51) patients died: 3 due to COVID-19, 4 due to relapse/progression, 3 from infectious complications (2 sepsis and 1 PML due to JCPyV), 1 from non-engraftment, and 1 due to uncontrolled AIHA. Summary: our preliminary results suggest that Abatacept/Tacrolimus +- PTCy is feasible and seems to offer very promising outcomes with low rates of acute and chronic GvHD grade II-VI. Based on this and previous trials we need a phase III clinical trial to evaluate abatacept. In our practice, abatacept-based immunosuppressive therapy has become routine. Additional reducing mortality is possible due to the widespread use of anti-covid antibodies and the exclusion of patients with a lack of response to disease therapy.

Registry Data Indicate a Meaningful Chance for Successful Pregnancies after Allogeneic Stem Cell Transplantation: Results from the German Stem Cell Transplant Registry (DRST)

Background Long-term survival following allogeneic hematopoietic cell transplantation (alloHCT) has improved significantly over the last decades. Beyond curation, return to a normal social life, including family planning, represents an important goal especially for young adult cancer survivors. However, alloHCT recipients are at high risk for infertility due to precedent chemotherapy, total body irradiation, transplant-related morbidity and long-term immunosuppressive medication. Nevertheless, spontaneous pregnancies following alloHCT were reported occasionally. Systematic studies on fertility preservation and pregnancies after alloHCT are very rare and do not cover the most recent era of transplantation. To fill this gap, we conducted a national multicenter study to investigate the pregnancy rate after alloHCT and their outcomes and to analyze potential risk factors in female transplant recipients. Methods Retrospectively, we evaluated data on disease and transplant characteristics from all women of childbearing age (18-40 years), who received an alloHCT in Germany between 2003 and 2018. Data were retrieved from the German Registry for Stem Cell Transplantation (DRST). Follow-up data were introduced into a competing risk model in order to calculate rates of pregnancies and first live birth per person-year after alloHCT. "First live birth” and "death w/o prior live birth” were considered as competing risks. Cumulative hazards were estimated with the Nelson-Aalen estimator. To perform a risk factor analysis for the expected incidence rate we used multivariable Poisson regression. In addition, we performed structured guideline interviews with those women who consented in providing detailed information about conception, course of pregnancy, and children's health. Results In total, 2,654 women met the eligibility criteria and 74 pregnancies were reported in 50 women. Pregnancies were reported at a median of 4.7 years (0.7-14.7 years) following alloHCT. Women who conceived pregnancy had a median age of 24 years (range 18 to 34) at alloHCT. Underlying diseases were AML/MDS in 19 patients, bone marrow failure syndromes in 17 patients, Lymphoma/ALL in 8 patients, and CML in 6 patients. Most patients underwent non-myeloablative or RIC (NMA/RIC) conditioning (76%). Total body irradiation (TBI) was part of the conditioning regimen in 12 patients (24%) of whom 4 patients received a cumulative TBI dose ≥8 Gray. Notably, acute GVHD grade II-IV had been reported in 11 women and chronic GvHD in 14 women. Factors associated with a better chance of pregnancy were younger age at alloHCT (p<0.001), TBI with <8 Gray (p<0.020), NMA/RIC conditioning (p= 0.032) and non-malignant transplant indications such as hemoglobinopathy/bone marrow failure syndrome (p=0.006). Fifty-three of 74 pregnancies resulted in live births. Based on competing risk analyses this translated into an annual rate of 0.45% (95% CI: 0.31 to 0.59 %) first-livebirths after alloHCT. This rate is 6 times lower than the corresponding first-birth rate of 3% for german women between 18 and 40 years of age. Detailed informations on conception and outcomes were obtained for 52 pregnancies. Forty out of 52 (77%) pregnancies occurred spontaneously, while assisted reproductive technologies (ART) were used in the remaining women. Techniques that resulted in successful pregnancies were: IVF (n=2), ICSI (n=2), ovarian tissue cryopreservation (n=2), oocyte donation (n=6). Preterm deliveries (29%) and low birth weight (21%) were higher as compared to reference data for the general population. Conclusions Our data strongly indicate that female alloHCT survivors should be educated about the realistic possibility to become pregnant after HCT. Lower age at alloHCT (<35 years), non-myeloablative or reduced-intensity conditioning, cumulative doses of TBI <8 Gray and non-malignant transplant indications increase the chances to preserve fertility. Interdisciplinary fertility counseling before alloHCT is essential to inform about the possibilities of assisted reproductive technologies. Nevertheless, the chances for spontaneous pregnancies should not be underestimated, and patients should be aware of this to avoid unexpected or unwanted pregnancies. Further research is needed to better understand and tailor procedural choices for conditioning regimens with respect to fertility preservation.

Outcomes with Post-Transplant Cyclophosphamide for Graft Versus Host Disease Prophylaxis after Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

Background: Graft versus Host Disease (GVHD) is a common complication of allogeneic hematopoietic stem cell transplant (HSCT). In this condition, the donated stem cells attack the recipient cells, leading to life-threatening consequences. One of the methods of preventing GVHD is by using post-transplantation cyclophosphamide (PTCy). PTCy has proven to have minimum toxicities to the body and, at the same time, has a high success rate in mitigating the rate of rejection and reducing the incidence of GVHD by acting as a potent immunosuppressant on both B and T cell lymphocytes in the host and donor's cells. This systematic review and meta-analysis was conducted to observe the effect of using PTCy for GVHD prophylaxis after HSCT. Methodology: Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on PubMed, Cochrane Library, and ClinicalTrials.gov through September 2021. We used MeSH terms and keywords for "Cyclophosphamide" AND "stem cell transplantation" AND "GVHD." No filters or publication time limits were applied to the search. A total of 17 studies were included after the screening of 1145 records and excluding duplicates, reviews, and non-relevant articles. Quality evaluation was done using the NIH quality assessment tool, and inter-study variance was calculated using Der Simonian-Laird Estimator. Pooled analysis was done using the 'meta' package (Schwarzer et al.R programming language) and proportions with 95% confidence intervals (CI) were computed. Results: A total of 5649 patients from 17 studies were included in this meta-analysis. (Table 1) The median age of patients was 49 (18-80) years, and 24.8% (1402/5649) were males. The median duration of follow-up was 23 (1-158.4) months. The donor type was haploidentical 70% (3258/4650), matched unrelated donor (MUD) 16% (761/4650), matched related donor (MRD) 13% (580/4650), and mismatched unrelated donor (MMUR) 1% (49/4650). The conditioning was myeloablative (MAC) in 53% (1461/2734) and reduced intensity (RIC) in 47% (1273/2734) of the patients. The pooled median overall survival (OS) reported at two years was 59% (95%CI 0.53-0.64, I 2 =66%, p=0.02, n=2843) while the pooled relapse rate (RR) was 29% (95%CI 0.11-0.51, I 2 =92%, p <0.01, n=303). The pooled incidence of acute GvHD grade II-IV and grade III-IV was 26% (95%CI 0.19-0.35, I 2 =80%, p <0.01, n=859) and 12% (95%CI 0.04-0.32, I 2 =94%, p<0.01, n=562), respectively. The pooled incidence of chronic GVHD was 17% (95%CI 0.11-0.26, I 2 =90%, p<0.01, n=819) with pooled incidence of extensive chronic GVHD of 9% (95%CI 0.05-0.19, I 2 =83%, p<0.01, n=697) as reported by seven included studies. The pooled incidence for non-relapse mortality (NRM) was 16% (95%CI 0.09-0.24, I 2 =83%, p< 0.01, n=769). Conclusion: Post-transplant Cyclophosphamide is an effective treatment option for graft versus host disease prophylaxis after allogeneic hematopoietic stem cell transplantation with an acceptable toxicity profile. However, further randomized trials are needed to consolidate these findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Final Clinical Outcomes from a Phase 2 Trial of Posoleucel, an Off-the-Shelf, Multivirus-Specific T-Cell Therapy, for the Prevention of Clinically Significant Viral Infections Post-HCT

Background: Allogeneic hematopoietic cell transplant (allo-HCT) recipients are highly susceptible to reactivation of double-stranded DNA viruses. Approximately 70% of high-risk allo-HCT recipients develop clinically significant infections (CSI, defined as viremia + treatment or end organ disease). We present results from a phase 2 trial evaluating the safety and efficacy of posoleucel, a partially HLA-matched, off-the-shelf, multivirus-specific T cell investigational product, for preventing CSIs due to adenovirus (AdV), BK virus (BKV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), or JC virus (JCV). Methods: This open-label trial enrolled high-risk allo-HCT recipients, including those with grafts from haploidentical, umbilical cord blood, mismatched unrelated donors, and matched unrelated donors with lymphocytes <180/mm3 as well as recipients who underwent T cell depletion. To be eligible, patients had to be engrafted and within 15-49 days of allo-HCT. Those with grade ≥3 GVHD and those requiring steroids (>0.5 mg/kg/day prednisone equivalent) at enrollment were ineligible. Patients received up to 7 infusions of posoleucel once every 14 days and were tested weekly for viremia using quantitative PCR assays. The primary endpoint was the number of CSIs due to AdV, BKV, CMV, EBV, HHV-6, or JCV by week 14. IFN-γ ELISpot analysis was performed for each targeted virus on serial peripheral blood samples to assess functional T cell immune reconstitution and determine the frequency of circulating virus-specific T cells detected over time. To evaluate the persistence and potential contribution of posoleucel to antiviral immune reconstitution, T-cell receptor (TCR) β immunosequencing was performed at selected timepoints. TCR sequences unique to posoleucel were identified computationally and used to track in vivo persistence in serial samples. Results: Twenty-six patients were dosed. Posoleucel dosing began a median of 42 days after allo-HCT. Twenty (77%) patients had viral DNA detected in blood (reactivation) from one or more viruses, 13 (50%) had 2 or more viral reactivations, and 7 (27%) had 3 or more viral reactivations in the 14 weeks after the initiation of posoleucel dosing (Figure). However, by week 14, only 3 patients (12%) had CSIs (2 CMV viremia requiring treatment and 1 EBV-post-transplant lymphoproliferative disorder). No patient had a CSI with more than 1 virus. Nine patients (35%) experienced adverse events that were possibly or probably related to treatment. Eight patients (31%) had serious adverse events (SAEs), 2 of which were judged to be possibly related to treatment (skin and pulmonary GVHD) and 1 probably related to treatment (allergic reaction). Overall, 8 patients (31%) had acute GVHD Grade II-IV. One patient (4%) discontinued posoleucel due to a treatment-emergent SAE of chronic pulmonary GVHD. No patient experienced cytokine release syndrome. TCR sequencing data (N=12) indicated that posoleucel was detectable in vivo during the dosing phase of the study and for up to 12 weeks after the last infusion, with polyclonal VSTs detected in all 12 patients. Six of the 7 patients with available ELISpot data demonstrated IFN-γ-producing virus-specific T cell responses coincident with viral replication. The confirmed persistence of posoleucel and expansion of IFN-γ-producing virus-specific T cells directed against reactivating viruses, suggests a contribution of posoleucel to functional immune reconstitution. Conclusion: Results from this open-label phase 2 trial show that high-risk allo-HCT patients who received posoleucel had lower than expected rates of clinically significant viral infections from the 6 targeted viruses despite the observed and expected low-level viral reactivations throughout the study. Repeat dosing of posoleucel was generally safe and well tolerated. Posoleucel VSTs were detected in vivo for up to 26 weeks, and reconstituting T cells demonstrated functional specificity for multiple viruses. A placebo-controlled global phase 3 trial evaluating the safety and tolerability of posoleucel for the prevention of clinically significant AdV, BKV, CMV, EBV, HHV-6, and JCV infections is ongoing (NCT05305040). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Allogeneic Hematopoietic Cell Transplantation in Patients with Therapy-Related Myeloid Neoplasm Following Treatment for Lymphoma: A Study of the Chronic Malignancies Working Party of the EBMT

Introduction: Therapy-related myeloid neoplasms (t-MNs) represent group of myeloid neoplasms arising after treatment for an antecedent cancer or autoimmune disease and historically present a dismal prognosis. Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for t-MN. The Chronic Malignancies Working Party of EBMT previously reported outcomes for t-MN following breast cancer treatment demonstrating comparable outcomes to de novo disease and the crucial role of oncological surveillance due to risk of relapse of primary cancer. In this retrospective registry-based study, we analyzed the outcomes and complications of patients with t- MN arising secondary to lymphoma treatment who underwent allo-HCT. Methods: Patients ≥18 years old receiving a first allo-HCT for t-MN [either therapy-related Myelodysplastic syndrome (t-MDS) or t-Acute myeloid leukemia (t-AML)] between 2006 and 2017 were included in this analysis. Both t-MN arising after completion of treatment for Hodgkin and Non-Hodgkin Lymphoma were included. Results: In the EBMT registry, we identified 378 patients from 47 centers. t-MDS was the indication for allo-HCT in 222 (59%) and t-AML in 156 patients (41%), respectively, with a median age at allo-HCT of 58 years and males representing 62% of cases. Most of the patients were previously treated for Follicular Lymphoma (22%), followed by Hodgkin's Lymphoma (22%) and Diffuse large B-cell Lymphoma (16%). Autologous HCT was a prior line of therapy in 38% of cases, and at the time of allo-HCT 15% of lymphomas were not in complete remission (CR). For t-MN, CR was recorded at the time of allo-HCT in 46% of cases, with a Karnofsky status >80 in 66%. The conditioning regimen was reduced intensity in 70% of patients, 22% received TBI and 65% received T-cell depletion. Stem cell source was peripheral blood in 90% of cases. Donor was matched related (MRD) in 26%, matched unrelated (MUD) in 46%, mismatched related (MMRD) in 4% of cases, and mismatched unrelated (MMUD) in 20% of cases, respectively. Median follow-up was 72 months, and the 5-year overall survival (OS) was 32%. In univariate analysis, OS was worse for patients transplanted for t-MDS (26 vs 41% for t-MDS vs t-AML, p=.032), not being in remission for t-MN at the time of allo-HCT (24% vs 38% for CR vs 34% for untreated, p=.013), and patients with a longer interval from lymphoma diagnosis to allo-HCT (23% for >10 years vs 37% for 5-10 years vs 36% <5 years, p=.028). Five-year t-MN progression-free survival (PFS) was 28%: patients with active t-MN at allo-HCT presented with lower PFS (33% vs 20% for CR vs 31% for untreated, p=.003) as did patients with t-MDS (22% vs 36% for t-AML, p=.022). t-MN Relapse incidence (RI) and Non-relapse mortality (NRM) at 5 years were 35% and 37%, respectively. Uncontrolled t-MN was associated with higher RI (42% vs 35% for CR vs 25% for untreated, p=.025); having an MRD was associated with a worse RI (48%, 33%, 25%, 31% for MRD, MUD, MMRD, and MMUD, p=.009), but to a significantly lower NRM (21%, 35%, 47%, 52% for MRD, MUD, MMRD, and MMUD, p<0.001). A higher NRM was observed in patients older than 60 years (44% for >60 years vs 34% for 50-60 years vs 27% for <50 years, p=.034) and in those with heavily pretreated lymphoma, (32% for 1st CR vs 40% for 2nd CR vs 61% for ≥3rd CR vs 45% for not in CR, p=.028). Acute grade II-IV GVHD occurred in 33% of patients (14% grade III-IV), with a 12-months incidence of chronic GVHD of 32% (18% of extensive grade). By 5 years post allo-HCT, the relapse incidence of lymphoma was 3% at 60 months, while the rate of secondary malignancies was 8%. On multivariable analysis, compared to t-MN in CR, uncontrolled t-MN was associated with significantly worse OS, PFS, and NRM. Age was correlated with better OS, PFS, and higher NRM (all p-values<0.04). MRD was associated with higher RI (p=.03) and worse NRM (p=.02). Conclusions: This analysis shows encouraging results for patients treated with allo-HCT for t-MN arising secondary to lymphoma treatment, however significant rates of NRM and relapse remain of concern. Lymphoma recurrence represents a rare event, but when considered together with the relatively high rate of secondary malignancies (8%) necessitates vigilance. Of note, our cohort was exposed to conventional chemotherapeutic agents for lymphoma treatment, and further efforts should explore supplementary variables in addition to the impact of novel therapies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparison of outcomes for HLA-matched sibling and haplo-identical donors in Myelodysplastic syndromes: report from the chronic malignancies working party of EBMT

Myelodysplastic syndromes (MDS) are the second common indication for an Allo-HCT. We compared the outcomes of 1414 matched sibling (MSD) with 415 haplo-identical donors (HD) transplanted with post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis between 2014 and 2017. The median age at transplant with MSD was 58 and 61 years for HD. The median time to neutrophil engraftment was longer for HD being 20 vs 16 days for MSD (p < 0.001). Two-year overall survival (OS) and PFS (progression free survival) with MSD were significantly better at 58% compared with 50%, p ≤ 0.001, and 51% vs 47%, p = 0.029, with a HD. Relapse at 2 years was lower with a HD 23% than with MSD 29% (p = 0.016). Non relapse mortality (NRM) was higher with HD in the first 6 months post-transplant [HR 2.59 (1.5–4.48) p < 0.001] and was also higher at 2 years being 30% for HD and 20% for MSD, p ≤ 0.001. The incidence of acute GVHD grade II-IV and III–IV at 100 days was comparable for MSD and HD, however, chronic GVHD at 2 years was significantly higher with MSD being 44% vs 32% for HD (p < 0.001). After multivariable analysis, OS and primary graft failure were significantly worse for HD particularly before 6 months [HR 1.93(1.24–3.0)], and HR [3.5(1.5–8.1)]. The median age of HD 37 (IQR 30–47) years was significantly lower than sibling donors 56 (IQR 49–62 years) p < 0.001. However, there was no effect on NRM, relapse or PFS. This data set suggests that a MSD donor remains the preferred choice in MDS over a haplo donor. Transplants with haploidentical donors result in satisfactory long-term outcome, justifying it’s use when no better donor is available.

Impact of donor kinship on non-T-cell depleted haploidentical stem cell transplantation with post transplantation cyclophosphamide for acute leukemia: From the ALWP of the EBMT.

Non-T-cell depleted haploidentical hematopoietic cell transplantation (Haplo-HCT) is a unique transplantation setting in which several donors are available. We assessed the impact of donor kinship on outcome of Haplo-HCT with post-transplantation cyclophosphamide in a cohort of 717 acute leukemia patients. We compared sibling with parent donors in patients ≤45 years, and child with sibling donors in patients >45 years. Donor kinship was not associated with worse outcomes in multivariate analysis. For patients ≤45 years, the hazard ratio (HR) for leukemia-free survival (LFS), overall survival (OS), relapse incidence (RI), and chronic graft-versus-host disease (cGVHD) was 0.87 (p = 0.75), 1.19 (p = 0.7), 0.52 (p = 0.19), and 0.99 (p = 0.97) for parents versus siblings, respectively, and for patients >45 years the HR was 0.93 (p = 0.8), 0.98 (p = 0.94), 1.3 (p = 0.53), and 0.98 (p = 0.95) for children versus siblings, respectively. Univariate incidence of acute GVHD grade II-IV was significantly higher in patients transplanted from siblings versus children (p = 0.002). Factors associated with inferior outcome were advanced disease and earlier transplant. In patients ≤45 years, acute lymphocytic leukemia and peripheral blood stem cell graft were additional prognostic factors for OS. We did not find a significant impact of donor kinship on transplantation outcome when analyzing by age group (≤45 and >45 years).

Myeloablative conditioning with thiotepa-busulfan-fludarabine does not improve the outcome of patients transplanted with active leukemia: final results of the GITMO prospective trial GANDALF-01

The outcome of refractory/relapsed (R/R) acute leukemias is still dismal and their treatment represents an unmet clinical need. However, allogeneic transplantation (allo-HSCT) remains the only potentially curative approach in this setting. A prospective study (GANDALF-01, NCT01814488; EUDRACT:2012-004008-37) on transplantation with alternative donors had been run by GITMO using a homogeneous myeloablative conditioning regimen with busulfan, thiotepa and fludarabine while GVHD prophylaxis was stratified by donor type. The study enrolled 101 patients; 90 found an alternative donor and 87 ultimately underwent allo-HSCT. Two-year overall survival of the entire and of the transplant population (primary endpoint) were 19% and 22%, without significant differences according to disease, donor type and disease history (relapsed vs refractory patients). Two-year progression-free survival was 19% and 17% respectively. The cumulative incidences of relapse and non-relapse mortality were 49% and 33% at two years. Acute grade II-IV and chronic GVHD occurred in 23 and 10 patients. Dose intensification with a myeloablative two-alkylating regimen as sole strategy for transplanting R/R acute leukemia does seem neither to improve the outcome nor to control disease relapse. A pre-planned relapse prevention should be included in the transplant strategy in this patient population.

Hematologic Recovery after Allogeneic Transplantation: Risk Factors and Its IMPACT on Transplant Related Mortality

Introduction. Hematologic recovery is often not satisfactory in patients undergoing an allogeneic stem cell transplantation (HSCT). A significant proportion have been reported to have low peripheral blood counts, despite full donor chimerism. This condition can be related to several factors including: number of CD34+ cells infused , stem cell source, underlying disease, conditioning regimen, GvHD and viral infections. Recently transplant platforms have changed, including the use of haploidentical transplants and modified GvHD prophylaxis.Aim of the study: to investigate factors associated with hematological recovery following an allogeneic HSCT in current transplant years.Methods: We included 1311 patients, with hematological diseases, undergoing an allogeneic HSCT, between year 2000 and 2020, in two transplant center: Genova and Roma. The main diagnoses were acute leukemia (54%), lymphoproliferative disorders (13%) , myelodysplastic syndromes (9%) and myelofibrosis (9%). 1108 patients aged <60 years and 203 aged >60 years. Platelet counts were taken as a surrogate marker of hematologic recovery.Results: We first ran a multiple regression analysis on factors influencing platelet counts between 50 and 100 days post-transplant. These factors were patients age >60 years, GvHD grade II-IV, non sibling donor and a diagnosis of myelofibrosis.Platelet recovery at different time points, up to over 4 years post-transplant, is shown in Figure 1a in patients stratified according to an age cut off of 60 years. Patients younger than 60 years showed significantly improved platelet recovery , at each time point, when compared to patients over 60 years ; the difference persisted beyond 4 years. There was no difference in platelet recovery in patients aged 18-40 and 41-60. Donor age and year of transplant had no effect on platelet recovery. Figure 1b shows platelet recovery according to risk factors (age, GvHD, myelofibrosis, non sib donor).Transplant related mortality (TRM). We then asked whether low platelet counts predicted TRM. Patients with a platelets count higher than 20 and 50x10^9 on days 50-100 post-HSCT, showed a reduced transplant related mortality (TRM) as compared to patients with a lower platelet count (13%vs 39%: p<0.000001; 11% vs31%, p<0.000001) (Figure 1 c,d).Conclusions: Platelet recovery post-HSCT seems to be strongly influenced by patient's age, together with GvHD, a diagnosis of myelofibrosis and donor type. Slow recovery in older patients remains statistically significant beyond 4 years after HSCT. Hematologic recovery after HSCT has not improved over the past 2 decades. Low platelet counts are a strong risk factor for mortality after allogeneic HSCT. Clinical trials with TPO agonists post HSCT are warranted to assess whether hematologic recovery can be improved, and whether this will translate in reduced mortality. [Display omitted] DisclosuresSica: Pfizer: Honoraria. Laurenti: AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Roche: Honoraria, Research Funding; Gilead: Honoraria; BeiGene: Honoraria. Metafuni: Jazz: Other: Invited Clinical case presentation at meeting. Angelucci: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene BSM: Honoraria, Other: DMC; Blue Bird Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini-Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: steering commitee, Speakers Bureau; Vertex Pharmaceuticals: Honoraria, Other: DMC; Crispr therapeutics: Honoraria, Other: DMC; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees.

The Impact of Age in Allogeneic Stem Cell Transplantation with Thiotepa Busulfan and Fludarabine (TBF) for Myelofibrosis : A Retrospective Analysis

Allogeneic hematopoietic stem-cell transplantation (HSCT) currently remains the only curative therapy for intermediate or high risk disease.myelofibrosis (MF). We are reporting 56 patients (pts) who underwent an allogeneic HSCT in our Centre between 2016 and 2020, and assessed factors predictive of outcome.The median age was 59 years (36-72). Most patients (72%) were JAK2+ and had int2-high DIPSS (92%). The conditioning regimen consisted of thiotepa, busulfan , fludarabine (TBF). All pts received thiotepa 10 mg/kg and fludarabine 150 mg/m^2. The dose of busulfan was adjusted considering the age and the comorbidity score. One pt received 3 days of busulfan (total dose 9.6 mg/kg); 47 received 2 days (total dose 6.4 mg/kg) and 8 received one day of busulfan iv (3.2 mg/kg). Donor was an identical sibling in 13 pt, haploidentical in 18, matched unrelated donor (UD) in 18 and a mismatchedUD in 7. Thus we had 31 HLA matched and 25 HLA mismatched grafts. Fortytwo patients received post-transplant cyclophosphamide (PTCy)-based GVHD (Graft versus host disease ) prophylaxis with cyclosporine and mycophenolate mofetil , and 14 patients received a standard GvHD prophylaxis (CSA+MTX+ATG).The 2 year survival (OS) was 73 % and disease free survival (DFS) was 66 % and the cumulative incidence (CI) of TRM was 23% and of relapse 11%.The incidence of acute GvHD grade II-IV was 22% in HLA matched and 50% in HLA mismatched pts (p=0.022), grade III-IV was 6% and 25% respectively (p=0.042) . The incidence of moderate-severe chronic GvHD was 25% in HLA matched and 36% in HLA mismatched grafts (p=0.36). HLA had a major impact on survival : 85% vs 49% survival for matched vs mismatched patients (p=0.01). Patients age >60 years had a major impact on outcome, with a 2 year survival of 51% vs 88% in patients over (n=24) or under 60 years of age (n=32) (p=0.007; the DFS was 46 % and 80% respectively and the CI of TRM was 42% vs 9% (p=0.003).As to the total dose of busulfan, we found 26% TRM in patients receiving busulfan for 2 days (total doe 6.4 mg/kg) (n=47) and 0% in older patients receiving 1 day only (total dose 3.2 mg/kg) (n=8) ; relapse rate was 10% and 20% respectively.In multivariate cox analysis including age, spleen size ,DIPSS score, number of transfusion received and donor type, only HLA matching influenced the incidence of acute GvHD; transfusion burden and age plays a role in NRM and OS; DIPSS predicts relapse .In conclusion: older patients with MF have a high NRM and need to be prepared with a milder conditioning regimen. DisclosuresLaurenti: Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria; BeiGene: Honoraria. Sica: Pfizer: Honoraria.

Outcome of Human Umbilical Cord Blood Stem Cell Transplantation (CBT) for Acute Myeloid Leukemia in Patients Achieving First Complete Remission after One Versus Two Induction Courses: A Study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

Background: Achieving a first complete remission (CR1) is an important prognostic factor for transplantation outcome. However, there are no data in the setting of cord blood transplantation (CBT) indicating whether the number of induction courses (1 or 2) needed to achieve CR1, is of prognostic significance. As CBT is advantageous for acute myelogenous leukemia (AML) patients (pts) with positive pre transplant measurable residual disease (MRD) (Milano F, NEJM 2016), it is conceivable that in the CBT setting, no difference in transplantation outcome will be observed between pts achieving CR1 after 1 or 2 inductions.Methods: Using the European Society for Blood and Marrow Transplantation (EBMT)/Acute Leukemia Working Party (ALWP) registry, we compared transplantation outcomes of adult pts aged ≥18 years with AML that underwent CBT in 2005-2020 in CR1, achieved following 1 versus (vs) 2 induction courses. Multivariate analysis (MVA) adjusting for differences between the induction groups was performed using a Cox's proportional-hazards regression model for main outcomes.Results: Three hundred and twenty-five pts were included comprising 243 (75%) with 1 and 82 (25%) with 2 induction chemotherapy courses. Median (range) follow-up was 65.4 (57.4-73.5) and 51.0 (34.8-61.5) months, respectively (p=0.6). Median age was 49.4 (19.0-70.9) and 52.1 (19.2-71.5) years (p=0.8), respectively. For patients with 1 and 2 induction courses, respectively, 49.4% and 57.3% were male, 225 (92.6%) and 78 (95.1%) pts had de novo AML, and 18 (7.4%) and 4 (4.9%) had secondary AML (p=0.6). Pts with 1 and 2 induction courses, respectively, were classified by cytogenetic risk as follows: intermediate, 62.0% and 79.2%, adverse, 33.2% and 19.5%, and favorable, 4.8% and 1.3% (p=0.02) (missing data~25%). The FLT3-ITD mutation was harbored by 33.7% and 32.3% of the pts (p=0.8), respectively (missing data ~6%). Conditioning was myeloablative (MAC) in 43.0% and 36.6% and reduced intensity (RIC) in 57.0% and 63.4%, respectively (p=0.31). Karnofsky performance score (KPS) was > 90 in 74.7% and 71% of the pts, respectively (p=0.5). The most frequent anti-graft-versus-host disease (GVHD) prophylaxis was cyclosporin A (CSA) and mycophenolate mofetil (MMF) in 75.6% and 82.5 %, or CSA with or without steroids in 16.1 % and 11.2%, respectively. Anti-thymocyte globulin (ATG) was administered to 32.9% and 25.6% of the CBT recipients, respectively (p=0.2). Engraftment rates were lower for pts achieving CR1 after 1 vs 2 induction courses (91.3% and 98.8% p=0.02) with corresponding day 60 absolute neutrophil count (ANC) > 0.5 x 10 9/L in 89.6% vs 96.3% of the pts (p=0.03).Day 180 incidence of acute GVHD grades II-IV was similar in both induction groups, 38.3% and 37.2% (p=0.8), as was 2-year total chronic GVHD, 23.4% and 27.5 %, respectively (p=0.6). In univariate analysis, the 2–year non-relapse mortality (NRM), relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were similar between patients achieving CR1 with 1 vs 2 induction courses with 22.6% vs 23.6% (p=0.87) 25.1% vs 30.4% (p=0.4), 52.3% vs 46.0% (p=0.3), 58.6% vs 50.0% (p=0.2), and 44% vs 44.1% (p=0.66), respectively. Similarly in MVA, there was no significant association between 2 courses of induction and NRM (hazard ratio (HR) = 1.1; 95% CI, 0.6-1.8, p=0.7), RI (HR = 1.4; 95% CI, 0.9-2.3, p=0.1), LFS (HR = 1.3; 95% CI, 0.9-1.8, p=0.2), OS (HR = 1.3; 95% CI, 0.9-1.9, p=0.1), and GRFS (HR = 1.1; 95% CI, 0.8-1.5, p=0.5).Conclusions: In CBT recipients, we did not find any significant differences in outcomes in patients achieving CR1 after one or two induction courses. Notably, engraftment was better in patients receiving two courses of induction chemotherapy. [Display omitted] DisclosuresLabopin: Jazz Pharmaceuticals: Honoraria. Forcade: Novartis: Other: travel grant. Sierra: Amgen: Other: Educational grant; Roche: Other: Educational grant; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Other: Educational grant; Jazz Pharmaceuticals: Research Funding; Janssen: Other: Educational grant; Novartis: Honoraria, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria; BMS Celgene: Honoraria, Research Funding. Byrne: Incyte: Honoraria. Blaise: Jazz Pharmaceuticals: Honoraria. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

Sequential Fludarabine, Ara-C, Etoposide (FLAV) Followed By Fludarabine/ Busulfan Reduced Toxicity Conditioning Is Safe and Effective Salvage for Adult Patients with Refractory Acute Myeloid Leukemia and High Risk Myelodysplasia

BackgroundA significant proportion of patients with acute myeloid leukemia (AML) will either be refractory to initial chemotherapy or will suffer refractory relapse. The role of allogeneic transplantation (SCT) in active disease is contentious. There is a growing body of literature that sequential chemotherapy, pioneered by the German FLAMSA regimen, followed by RIC SCT is a safe and efficacious modality in these patients, and there have been numerous modifications of this regimen, especially as amsacrineis not widely available. Fludarabine, cytarabineand and etoposide (VP16) (FLAV) have been reported as an effective salvage regimen. Here we report on single center outcomes of a variation of the FLAMSA regimen, substituting amsacrine for etoposide with mainly myeloablative conditioning.MethodsPatients were offered this regimen if fit for allogenic HSCT and had AML which is refractory to two cycles of chemotherapy or refractory to one cycle and considered at high risk for complication with second cycles. Patients with MDS received this regimens if eligible for transplant with high or very high risk cytogenetics. All patients received cytoreductive chemotherapy consisted of fludarabine 30mg/m2/day x 4 days, Cytarabine 2g/m2/day x 4 days, etoposide 100mg/m2/day x 3days, commenced simultaneously. After 3 days of rest, conditioning chemotherapy consisted of fludarabine 30mg/m2 x 2 days and and IV busulfan 0.8mg/m2 q 6 hours; the number of busulfan doses varied between 8 - 12, depending on patient comorbidity. All patients received 2 doses of ATG at 2.5mg/m2/day on day -3 and -2. All patients received GCSF mobilized peripheral blood hematopoietic cells. Post-transplant GVHD prophylaxis consist of CsA and MMF. CsA was tapered from day+60 and stopped at day +90 in the absence of GVHD. MMF was discontinued between day +30 and day +40. Donor lymphocyte infusions were collected for planned prophylactic DLI.ResultsTwenty six patients received FLAV-SCT between March 2014 and July 2019. The median age was 38 (14-60); 16 (62%) female. Overall 12 (46%) pts had de novo AML, 10 (39%) pts had secondary or therapy related AML and 4 (15%) pts had MDS. Fourteen (54%) pts had adverse risk cytogenetics include 8 (31%) pts had complex or monosomal karyotype. Patients' characteristics are summarized in Table 1.All patients had active disease prior to FLAV-SCT. The median time for ANC and platelet engraftment was 14 (10 - 42) days and 17 (10 - 52) days respectively. Day 30 assessment shows CR in 16 (61%) pts and CR/CRi in 17 (65%) pts. Outcomes are summarized in Table 2. Three patients (12%) developed veno-occlusive disease. Acute GVHD grade II-IV and III-IV occurred in 9 (35%) pts and 2 (8%) pts respectively. Three (12%) patients developed chronic GVHD. Cumulative incidence of NRM at 100 days and 2 years was 8% and 12% respectively. The median OS for all pts was 5.2 months with 2 years rate of 32% (15 - 50). Among responders, the median OS and RFS were 19.2 months and 8.7 months, 2y-OS and RFS were 47% and 25%, respectively (Figure 1).ConclusionOur result demonstrates that transplant is an effective therapeutic modality in this very high risk refractory AML/MDS patients. Sequential chemotherapy (FLAV) followed by SCT with busulfan at myeloablative dose is tolerable with an acceptable toxicities and encouraging results. [Display omitted] DisclosuresChaudhri: Novartis: Honoraria; Abbvie: Honoraria; Astra Zeneca: Honoraria. Alzahrani: King Faisal Specialist Hospital and Research Centre: Current Employment; Novartis: Consultancy, Honoraria; Bayer: Consultancy, Honoraria, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau.

Posttransplant Cyclophosphamide-Based Haploidentical Vs Matched Unrelated Donor Peripheral Blood Hematopoietic Stem Cell Transplantation Using Myeloablative Targeted Busulfan-Based Conditioning for Pediatric Acute Leukemia

Haploidentical related donor (HRD) is a common alternative donor strategy used when matched sibling or unrelated donors are not available for hematopoietic stem cell transplantation (HSCT). Post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis is an attractive option when performing a HRD HSCT because of its promising outcomes and easy application. However, there have been no studies comparing HRD HSCT with PTCy and MUD HSCT with antithymocyte globulin, using similar busulfan-based myeloablative conditioning regimen in pediatric acute leukemia. Herein, we compared the outcomes in children and adolescents with acute leukemia after HRD HSCT with PTCy (n=35) and matched unrelated donor (MUD) HSCT (n=45) after targeted busulfan-based myeloablative conditioning using intensive pharmacokinetic monitoring. The median follow-up times of the HRD and MUD groups were 3.7 and 4.6 years. No engraftment failure was observed. The cumulative incidence of GVHD grades II-IV (34.3% versus 48.9%, p=0.142), grades III-IV (2.9% vs. 8.9%, p=0.272), extensive chronic GVHD (11.4% vs. 18.3%, p=0.417), relapse (25.6% vs. 28.0%, p=0.832), and non-relapse mortality (0% vs. 2.2%, p=0.420) were not significantly different. The 3-year severe chronic GVHD-free/relapse-free, leukemia-free and overall survival rates in the HRD and MUD groups were 62.9±8.7% versus 49.8±7.6% (p=0.318), 74.4±8.0% versus 67.5±7.2% (p=0.585), and 88.6±5.4% versus 83.7±5.7% (p=0.968), respectively. In subgroup analyses of patients with acute lymphoblastic leukemia and acute myeloid leukemia, there were no significant differences in outcomes between the groups. Our results demonstrated that HRD HSCT with PTCy using a targeted busulfan-based myeloablative conditioning shows outcomes similar to those of MUD HSCT. HRD HSCT with PTCy could be considered for pediatric acute leukemia patients who lack an HLA-matched donor. DisclosuresKang: Cartexell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding.

OUTCOMES OF ALLOGENEIC SC TRANSPLANT IN HEMATOLOGICAL MALIGNANCY PATIENTS USING BUSULFAN 3 (9.6 MG/KG) BASED CONDITIONING REGIMEN

To study the outcomes of allo-HCT in patients with hematological malignancy who received BU3 (9.6 mg/kg) based conditioning from matched related or unrelated donors. A retrospective analysis of KFSHRC- BMT Database, we identified 65 patients who received Allo-HCT between October 2005 and December 2019 at King Faisal Specialist Hospital & Research Center. The patients received SCT from full HLA matched related or unrelated donors. We excluded Mismatched MUD, Cord & Haplo-identical Stem Cell sources. We identified 47 AML (72.3%), 8 MDS (12.3%), 8 Myelofibrosis (12.3%) & 2 CML (3.1%) patients. Acute GvHD grade II-IV and III-IV occurred in 29% and 14% respectively. Chronic GvHD occurred in 55% and was extensive in 24% of patients. With Median follow-up 60.5 months, 2 years and 5 years OS were 58.5 % and 44.1% respectively. The 2 years and 5 years DFS were 52.9% and 44.5% respectively. Cumulative incidence of relapse and NRM at 2- years were 29.5% and 17.4% respectively. Day +100 TRM were 10.7% Allogeneic SCT using BU3 based regimen appears feasible to use in patients who are not suitable for fully myeloablative (BU4) regimen. TRM, DFS & OS rate were comparable to reports from studies using BU4 based regimen, warranting prospective studies in these patients.