Post Allogeneic Transplantation Research Articles

Letermovir as secondary prophylaxis of cytomegalovirus infection after allogeneic hematopoietic cell transplantation: A single center experience.

Letermovir, a novel anti-cytomegalovirus (CMV) agent acts by inhibiting the viral terminase complex and is approved for primary prophylaxis in CMV seropositive patients post allogeneic hematopoietic cell transplantation (HCT). The favorable efficacy and safety profile make it an attractive option for use as secondary prophylaxis in patients at high-risk for CMV reactivation. In this study, we report the efficacy and safety of letermovir secondary prophylaxis after at least one treated episode of CMV reactivation in a cohort of 39 high-risk patients. Thirty two (82%) patients received anti-thymocyte globulin (ATG), 27 (69%) received a combination of ATG and post-transplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis. Twenty one patients (54%) received CMV seronegative grafts. In addition, 18 (46%) patients had HLA mismatched unrelated or haploidentical donors while 18 (46%) had active GVHD requiring immunosuppression at the time of commencing secondary prophylaxis. Letermovir was initiated at a median of 47 days (range, 41-56) after HCT and was administered for a median duration of 77 days (range, 46-90). A single breakthrough CMV reactivation was noted in this high-risk cohort. Four additional episodes of CMV reactivation occurred at a median of 28 days (range, 23-59 days) after discontinuation of secondary prophylaxis. The drug was well tolerated and 77% of the cohort completed the planned duration of secondary prophylaxis. None of the patients discontinued treatment due to treatment-related adverse effects. In conclusion, letermovir is effective and well tolerated and may be considered for secondary prophylaxis in patients at high risk for CMV reactivation. Prospective studies are required to validate these findings.

Bone marrow findings post allogeneic transplant for myeloproliferative neoplasms and chronic myelomonocytic leukemia with increased fibrosis.

Allogeneic hematopoietic stem cell transplant for myeloid neoplasms with increased fibrosis is uncommon; morphologic features posttransplant can be concerning for persistent disease. In this retrospective study, we identified 22 patients transplanted for myeloproliferative neoplasms or chronic myelomonocytic leukemia with fibrosis at our institution, and reviewed slides from pretransplant and posttransplant bone marrow biopsies. Clinical features and results of molecular, chimerism, and cytogenetic studies were retrieved from the medical record. Pretransplant bone marrow biopsies commonly exhibited hypercellularity, atypical megakaryocytes, and reticulin fibrosis. At day 100, 36% of biopsies had reticulin grade >MF1 and 33% of those tested had positive molecular studies, with no significant associations between day 100 marrow characteristics and molecular profile or peripheral count recovery times. In the 1 year posttransplant biopsies (n = 12), 7 of 9 had negative molecular studies; of these, none had reticulin grade >MF1, 1 had trichrome 1+, 2 had atypical megakaryocytes, and 1 was hypercellular. Supporting recent literature, our study indicates that persistent day 100 reticulin fibrosis/collagen deposition does not show an association with day 100 molecular status. Our study additionally provides data for 12 patients with 1 year posttransplant marrow biopsies, with the majority of those lacking either increased fibrosis or molecular evidence of persistent disease.

Incidence, management and outcome of Hepatic Veno-Occlusive disease /Sinusoidal Obstruction Syndrome after hematopoietic stem cell transplant in Thalassemia major patients: A prospective study of Pakistani BMT.

Hepatic Veno occlusive disease (VOD), also known as sinusoidal obstruction syndrome (VOD/SOS), is a post-transplant life threatening complication. In this study, we aimed to discuss the incidence, management and outcome of VOD in post allogenic transplant patients of beta thalassemia major (BTM). A prospective study was conducted in Armed Forces Bone Marrow Transplant Center, between 2001-2022. A total of 385 fully Human Leucocyte Antigen (HLA) matched BTM patients, with Ursodeoxycholic acid for prophylaxis, were included in the study. Incidence of VOD was calculated through cumulative incidence estimates. Chi square test and Mann Whitney test were used to compare discrete and continuous variables respectively. VOD was diagnosed and graded according to European Society for Blood and Marrow Transplantation EBMT Pediatric diagnostic criteria. Risk factors for VOD were grouped as recipient, transplant and donor related. Univariate analysis was performed by log-rank test. All patients who developed VOD were managed primarily with fluid restriction and strict input output monitoring. Statistical analyses were performed using SPSS v 25.0. Out of 385 transplant patients, forty developed VOD. Median time from date of transplant till onset of VOD was 14 days (range 6-30). Cumulative incidence of all grade VOD was 10.39% (95% CI, 7-14). Eleven out of 40 patients who developed VOD died. Cumulative incidence of Transplant related mortality (TRM) for patients with and VOD was 20.5% (95% CI, 16.6-25.1) vs 27.5% (95% CI, 16.1-42) (p value 0.318) respectively. Among risk factors, age of recipient and fibrosis (p value of 0.04 and 0.000 respectively) were found to be significantly associated with VOD. Careful selection of transplant candidates before transplant can help reduce the incidence of VOD.

Somatic and Germline HLA Determinants of Immune Surveillance and Escape in Myelodysplastic Syndromes

While the contribution of canonical myeloid genetic drivers to myelodysplastic syndromes/neoplasms (MDS) pathobiology is well established, other genetic events operative under special circumstances, and by itself not constituting intrinsic drivers, may affect the disease course. These include genetic defects conveying resistance to specific therapies, clonally restricted DNA repair alterations favoring the accumulation of additional mutations, and/or lesions facilitating the resistance to inflammation or immune escape. Here, we focus on this latter aspect as it may shed light on the pressure exerted by immune tumor surveillance or acquired resistance to cancer immune therapies, a field that has lagged in myeloid neoplasia as compared to the dramatic changes obtained in solid tumors. We hypothesize that during MDS ontogeny and leukemia evolution a spectrum of immunological mechanisms may shape the oncogenic landscape and facilitate the emergence of clones with diverse immunogenic potential as targets, leading to selective immunotherapeutic liabilities. We accrued a clinically and molecularly well annotated cohort of 101 MDS patients at various stages of the disease spectrum [N=51 low risk (LR)-MDS, N=32 high risk (HR)-MDS, N=18 secondary AML-sAML)]. This cohort included specific clinical sub-entities wherein the contribution of immune forces appears to be a prominent feature i.e., hypocellular MDS (hMDS, N=9) or MDS with co-occurring T large granular lymphocytosis (LGL) (N=5). By combining human leukocyte antigen (HLA) and T cell receptor (TCR) immunosequencing at disease onset, we leveraged our bioinformatics expertise to impute HLA mutations and losses, HLA evolutionary divergence (HED), and characteristics of T cell repertoires. The median age of the whole cohort was 71.2 years (IQR: 63.4-77.7), and median bone marrow (BM) blast count was 3% (1-11%). Cytogenetics revealed normal karyotype in 41 patients (40%), while complex karyotype was observed in 21 (20%) and partial or complete loss of chromosome 7 in 10 cases (10%). Comparisons with a cohort of 784 ethnicity-matched healthy individuals (HC), showed no differences in terms of locus-specific HED configurations. However, when HED scores were analyzed across the disease spectrum, we observed a heterogeneous distribution in MDS patients for the HLA-C locus, with higher values in hypoplastic and LGL-associated MDS as compared to HR diseases (p= 0.0068) and sAML (p= 0.0409). The screening for immune evasion highlighted the presence of both somatic mutations and losses in the HLA region in 14 patients, with both type of alterations found in 1 case. Of those, 6 patients (20% LGL-MDS, 5% LR-MDS and 17% sAML) harbored HLA mutations (in HLA-A, B, C and DPB1 loci), whereas HLA losses were observed in 9 patients (22% hMDS, 5% LR-MDS, 10% HR MDS, 11% sAML) almost exclusively in class II alleles (chiefly DPB1, DRB1 and DPA1). When exploring the degree of immunocompetence by TCR immunosequencing as a proxy, we found a higher degree of diversity (imputed via inverse Simpson index) as compared to healthy controls (p=1.5e-07), possibly in relationship to diverse T cell responses across the disease spectrum. However, no difference between MDS sub-entities was found. Of interest is that the maximal productive frequency (an indicator of the degree of T cell expansion) was higher in patients with hMDS and LGL-associated MDS as compared to HR-MDS (p=0.0079). Finally, inter-sample comparisons of shared clonotypes showed a high degree of overlap with regards to TCR repertoires among MDS as compared to healthy subjects. Our data emphasize the adaptive immune-molecular network underpinning MDS development. HLA constellations and their interactions with TCR repertoires may create selective immune pressure. Somatic HLA aberrations may serve as a marker of ongoing immune pressure and correspond to oligoclonal T-cell expansions and variations in TCR diversity. While virtually no HLA mutations have been previously found in AML/MDS, we show a relatively higher frequency of HLA aberrations in hMDS and MDS-LGL, immunologically stressed scenarios reminiscent of aplastic anemia and post-allogenic transplant AML/MDS cases, whereby respectively 36% 1 and 38% 2 of patients harbored HLA lesions as a mean of escape from cytotoxic lymphocytes or allogeneic Graft-vs-Leukemia reactions.

Bisantrene in Combination with Fludarabine and Clofarabine As Salvage Therapy for Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML)- an Open-Label, Phase II, Study

Background: Bisantrene (Bis), is a topoisomerase-II inhibitor with anthracycline-like activity, lower cardiotoxicity, and activity in patients (pts) with relapsed (rel)/primary refractory (PR) acute myeloid leukemia (AML) (Am J Hematol, 2021). Bis was also found to synergize with the cytotoxic purine nucleoside analogs clofarabine (Clo) and fludarabine (Flu) in vitro (J Clin Exp Oncol, 2021). We now conducted a phase II study combining Bis with Clo and Flu in pts with Rel/PR AML (NCT04989335). Methods: This was a phase II open-label single-center study with 2 stages: a stage with 3+3 dose escalation to assess the safety and provide phase 2 dose (RP2D, 4 vs 5 days) of infusion (i.v.) with up to 12 pts and an expansion phase with up to 17 pts (Simon 2-stage design 9+8) to assess the primary efficacy and confirm the safety of f Bis/Clo/Flu combination pts with Rel/PR AML. Flu (10 mg/m 2) was administered i.v. over 1 hour (h), followed by a 1-h infusion of Clo (30 mg/m 2), and then a 2-h infusion of Bis at 250 mg/m 2, with a 1-hour break for 4 days. The primary endpoint was achieving a partial response (PR). Efficacy was assessed by bone marrow (BM) examination 21 - 30 days post-therapy. Safety included treatment-emergent adverse events (TEAEs), all-cause mortality, and cardiac monitoring with ECG and troponins Toxicity was assessed as per Common Terminology Criteria for Adverse Events (CTCAE v5.0). Interim analysis was planned after the first 12 pts. Results: 20 pts were included from August 2021. The median age was 48 (19-69) years and 55% were male.14 pts had de novo AML and 5 had secondary AML, 11 pts were in rel, while 9 had PR disease. Median lines of therapy were 4(3-9), 12 with ≤ 4 and 8 >4 lines of therapy. All pts were refractory to the last line of therapy.15 pts (75%) were in relapse post allogeneic transplantation (HSCT). 5 (25%) pts had active extramedullary disease (EMD, 1 with CNS involvement). Median bone marrow blasts pre-Bis/Clo/Flu treatment was 50%. Cytogenetic was normal in 10 (50%) of the pts, 5 had a complex karyotype, 2 MLL rearrangements, 1 t8; 21 and 2 pts had other chromosomal abnormalities. The maximum tolerated dose of the Bis/Clo/Flu combination was 4 days of infusion due to grade 3 liver toxicity in 2 pts and 1 pt that died from sepsis in the first stage of the study. Overall 10 pts developed liver toxicity with elevated liver enzymes and bilirubin in 9 of them (grade 1-4 pts; grade 2-3 pts and grade 3-3 pts). Liver toxicity was transient and resolved in all pts. Two pts had treatment interruption due to liver toxicity. 4 pts had grade I renal toxicity, 7 had mild fluid retention, and 18 developed neutropenic fever of which 10 pts had verified bacteremia. Five pts had pneumonia, 4 invasive fungal infections, and 2 sepsis (1/2 died).1 additional pt died from cerebral venous sinus thrombosis. Overall 5 pts died early and could not be evaluated for response. Clinical-relevant cardiac toxicity was not observed in any of the pts and no one developed ECG changes Transient grade 1 elevation of troponin levels was observed in 4 pts. Six pts responded (CR-5, PR-1) 3 with EMD, however, responses were short-lived and lasted up to 3 months. Five pts (responding-4, active disease-1, being the second transplant in 4) underwent HSCT 1-3 months post-Bis/Clo/Flu with reduced /intermediate intensity conditioning. Stem cell donors were haploidentical-2, matched unrelated -1, and matched sibling-2, respectively. Three pts died: one from graft versus host disease and the other from relapse within 4 months post-transplant and the third from sepsis 2 years post-HSCT. Two of the transplanted pts are in complete remission with a 2-month follow-up. Conclusions : In this Phase II study in a very advanced group of relapsed refractory AML ptsresistant to multiple previous lines of chemotherapy including transplantation and with a median of 50% blasts at study initiation, Bis/Clo/Flu combination therapy was found to be safe and well tolerated without cardiac toxicity or tumor lysis syndrome. The maximum length of Bis/Clo/Flu administration was 4 days due to rapidly reversible liver toxicity, and transaminitis. As expected in this highly pretreated population, the infection rates were high. Six /15 evaluable pts (40%) respond, enabling an HSCT in 5 of them. These rather impressive results in such a heavily pretreated population support further studies of Bisantrene-based combinations, including those with venetoclax or hypomethylating agents.

Relapse Incidence Post Unrelated Allogeneic Stem Cell Transplantation with Post-Transplant Cyclophosphamide (PTCy) Versus Conventional Anti-Graft Versus Host Disease Prophylaxis in Patients with Acute Myeloid Leukemia: A Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Background: Recently, the BMT CTN 1703 phase III study compared post-transplant cyclophosphamide with tacrolimus with mycophenolate mofetil (PTCy/TAC/MMF) to TAC /methotrexate (MTX) as graft- versus-host disease (GVHD) prophylaxis post allogeneic transplantation (HSCT), demonstrating a lower incidence of severe acute (a) GVHD and chronic (c) GVHD and better GVHD-free, relapse-free survival (GRFS). The control arm did not include anti-thymocyte globulin (ATG), used in many centers for GVHD prophylaxis. Methods: The study aim was to compare PTCy with TAC or cyclosporine A (CSA) and MMF (PTCy/TAC or CSA & MMF) to ATG combined with TAC and MTX (ATG/TAC/MTX) in acute myeloid leukemia (AML) patients (pts) undergoing HSCT from matched siblings (MSD) or 9-10/10 unrelated donor (UD) in first complete remission (CR1). Statistical tests included a multivariate analysis (MVA) adjusting for potential confounding factors using a Cox proportional-hazards regression model for main outcomes. Results: 6050 pts met the inclusion criteria, 402 received PTCy/TAC or CSA & MMF and 5648 received ATG/TAC/MTX as GVHD prophylaxis. Median follow-up was 23.4 (IQR, 20.3-24.9) and 41.8 (IQR, 39.6-43.3) months (p<0.0001). The median year of the transplant was 2018 (2010-2020) and 2016 (2007-2020) (p<0.0001). Pts in the PTCy/TAC or CSA & MMF group were younger, with a median age of 48.7 (range 18-5.6) versus 51.5 (8-77.8) years (p=0.024). The diagnosis was de novo AML in 84.1% vs 85.3% and secondary (s) AML in 15.9% vs. 14.7% (p=0.49). The cytogenetic risk was categorized as intermediate (70.9% vs. 67.1%), adverse (22.2% vs. 25.7 %), and favorable (6.9% vs. 7.2%) for pts in the PTCy/TAC or CSA & MMF and ATG/TAC/MTX groups, respectively (p=0.35) (data missing for 2214 pts). Karnofsky performance status (KPS) did not differ between the groups. There was a higher frequency of pt cytomegalovirus (CMV) seropositivity and female (F) donor to male (M) pt combination in the PTCy/TAC or CSA & MMF versus the ATG/TAC/MTX groups, 77.8% vs. 71.8% (p=0.009) and 18.4% vs. 14.4% (p=0.029), respectively. More pts in the PTCy/TAC or CSA & MMF group received reduced intensity conditioning (RIC) 51.5% versus 41.1% in the ATG/TAC/MMT group, respectively (p<0001). Day 60 neutrophil engraftment (ANC >0.5 x 10 9/L) was 98.7% vs. 98.6% (p=0.84). Day 180 incidence of a GVHD grade II-IV and III-IV was 21.2% vs. 20.4% (p=0.92) and 8.1% vs. 6% (p=0.1), in pts receiving PTCy/TAC or CSA & MMF versus the ATG/Tac/MTX GVHD prophylaxis, respectively. The 2-year (y) total and extensive chronic (c) GVHD were 33.7% vs. 30% (p=0.09) and 10.7 % vs. 11.2% (p=0.81), respectively. GVHD was the cause of death in 11.6% vs. 13.9% of pts who died. In the MVA, both aGVHD (grade II-IV or III-IV) and cGVHD (total or extensive) did not differ between the groups with hazard ratios (HRs) =1.15 (95% CI 0.86-1.53, p=0.35), HR=0.87 (95% CI 0.56-1.34, p=0.52), HR=0.91 (95% CI 0.7-1.18, p=0. 47 and HR=1.51 (95% CI 0.96-2.36, p=0.074). Two-y NRM was significantly lower in pts that received PTCy/TAC or CSA & MMF versus ATG/TAC/MTX for GVHD prophylaxis, HR=1.57 (95% CI 1.07-2.3, p=0.022). Other HSCT outcome parameters did not differ between the groups. The HR for 2-y RI was 0.99 (95% CI 0.77-127, p=0. 93). The HRs for 2-y leukemia-free survival (LFS), overall survival (OS), and GRFS were HR=1.15 (95% CI 0.94-1.42, p<0.18), HR=1.18 (95% CI 0.94-1.49, p=0.16) and HR=1.12 (95% CI 0.93-1.36, p=0.22), respectively. Donor type and conditioning regimen were poor prognostic factors for grade II-IV, III-IV aGVHD, and total and extensive cGVHD. For cGVHD, additional poor prognostic factors were F donor to M pt combination and pt CMV seropositivity. Poor prognostic factors for LFS, OS, and GRFS were 9/10 UD, age (by 10 y), sAML, adverse-risk cytogenetics, lower KPS, and pt CMV seropositivity. For NRM, factors were the same apart from cytogenetics risk which was not a prognostic factor. In addition, time from diagnosis to HSCT was a prognostic factor for NRM and RI. Other poor prognostic factors for RI were lower KPS and pt CMV seropositivity. Conclusions: In this registry-based retrospective analysis, comparing PTCy in combination with TAC or CSA and MMF to ATG in combination with TAC and MTX as GVHD prophylaxis, we observed a similar incidence and severity of both aGVHD and cGVHD. NRM was significantly lower with the PTCy-based GVHD prophylaxis, while all other transplant outcome parameters were similar.

Prediction of Sinusoidal Obstructive Syndrome after Allogeneic Stem Cell Transplantation Using Liver Stiffness Measurement By Fibroscan

Background: Sinusoidal Obstructive Syndrome/ Veno-Occlusive Disease (SOS/VOD) is a potentially life-threatening complication post allogeneic transplantation (HSCT) with an incidence of ~ 10% in adults. The sensitivity of SOS symptoms (hyperbilirubinemia ≥2 mg/dl, weight gain>5%, painful hepatomegaly and ascites) is good, but the specificity is relatively low because other conditions such as infections, GvHD, and exacerbation of previous liver disease may cause similar symptoms. Transient elastography (TE) using FibroScan has been implemented as a non-invasive assessment of post-sinusoidal portal hypertension (PHTN) one of the hallmarks of SOS. We aimed to assess TE's applicability in predicting and diagnosis of SOS. Methods: This single-center study was conducted between January 2021 and June 2023. Twenty-seven patients (pts) underwent TE, 11 before HSCT (group 1) due to high risk of developing SOS in order to guide subsequent treatment, and 17 after HSCT (group 2) (1 pt was in both groups) due to an elevation of bilirubin ≥2 mg/dl. SOS was defined using the EBMT criteria. Results: Eleven pts were included in the 1 st group (M 5, F 6). The median age was 43 (22-65) years. 7 pts had acute myelogenous leukemia (AML) -4/7 secondary AML (sAML), and 4 pts had myelofibrosis (MF). 5/7 AML pts received a median of 4 (2-5) lines of chemotherapy before HSCT; 2/4 sAML pts got azacytidine/ venetoclax and all 4 MF pts received Ruxolitinib before HSCT. Two pts had chemotherapy for antecedent malignancy. Donors were HLA-matched siblings (n=5), matched unrelated (n=2), or haploidentical (n=4). Risk factors for developing VOD included: active disease (n=9), multiple lines of chemotherapy (n=7), elevated serum ferritin (n=5), splenomegaly (n=5 including 1 pt with overt PHTN), severe liver toxicity during previous treatment (n=4), age ≥60 (n=3), second transplantation (n=3), pre-existing liver disease including fatty liver (n=3, including 1 pt with liver cirrhosis), severe obesity (n=2), prior treatment with GO (n=2), baseline liver enzymes elevation (n=2), and alcohol abuse(n=1). The conditioning regimen included total body irradiation (n=1), busulphan (BU) alone (n=5), or double alkylating agents (DAC, n=5), respectively. Four patients had myeloablative conditioning (MAC). Most pts had several risk factors for VOD median 5 (3-8). This group had a median liver stiffness measurement (LSM) of 10.1 kPa (range, 3.3-28.3). In 6/11 pts with LSM ≥7.2 kPa, the conditioning was modified; Treosulfan was given instead of BU (n=3), non-DAC instead of DAC protocol (n=3), reduced intensity instead of MAC (n=4), methotrexate was omitted (n=2). One pt received Defibrotide prophylaxis. With these modifications only 2 pts developed SOS (1 died). The second group included 17 pts (M 10, F 7), median age 49 (32-62) years with AML/myelodysplastic syndrome (n=7), acute lymphoblastic leukemia (n=5), MF (n=4), and lymphoma (n=1). Ten had MAC, and 5 had DAC. Five had active disease at HSCT. Three had prior liver disease. All pts had bilirubin elevation ≥2 mg/dl after HSCT but only 10 fulfilled additional criteria for the diagnosis of SOS based on the EBMT criteria. Pts who developed SOS had significantly higher LSM compared to those who did not; 10.7 kPa (IQR, 7.5-25.2) versus 5.9 kPa (IQR, 5.1-7.4), respectively (p=0.007) (Figure 1A). There was a positive correlation between the diagnosis of SOS and LSM levels, with a correlation coefficient of 0.6 (p= 0.04) as determined by the Spearman correlation test. LSM was able to diagnose SOS with an AUC of 0.89 (p=0.008) (Figure 1B). The cut-off value for SOS diagnosis was 7.5 kPa, with a sensitivity of 80% and specificity of 88%. Pts with severe VOD were treated with defibrotide and none of them died .of VOD. Conclusions: Pts with a high risk for VOD may have a high baseline LSM. In these pts, modifying the planned conditioning and GVHD prophylaxis regimens to less hepato-toxic ones may reduce the incidence of subsequent VOD. LSM elevation after HSCT should increase awareness of SOS, while pts with hyperbilirubinemia and low LSM usually suffered from other causes of liver toxicity. High LSM could support the diagnosis of VOD in borderline cases. Therefore, LSM may be an additional diagnostic tool in diagnosing SOS after HSCT, but more studies are needed to confirm these findings.

Modified Endothelial Activation and Stress Index (mEASIX) Score and Immune Effector Cell Associated Haematotoxicity (ICAHT) Following Varnimcabtagene Autoleucel (IMN-003A), a CD19-Directed Chimeric Antigen Receptor T (CAR-T) Cell Therapy, in the Phase-2 Study (IMAGINE)

Background: Varnimcabtagene autoleucel (IMN-003A) is an anti-CD19 CAR-T cell immunotherapy for patients (pts) with relapsed refractory B cell malignancies (RR BCM) in first-in-India Industry Phase 2 IMAGINE study, administered in a fractionated (10%/30%/60%) infusion protocol. Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) are commonly associated adverse events with CAR-T cell therapy. The modified Endothelial Activation and Stress Index (mEASIX) score [lactate dehydrogenase (LDH) (U/L) × CRP (mg/dL) / platelets (PLT) (10 9 cells/L)] is a prognostic predictor of outcomes for patients in post-allogeneic transplant setting. Elevated LDH and low PLT levels have been associated with severe ICANS, and high IL-6 level is a recognized marker for CRS. Immune Effector Cell Associated Hemato-Toxicity (ICAHT) represents the most common toxicity after CAR-T cell therapy. CAR-HEMATOTOX score is used to risk stratify patients for cytopenia. This abstract reviews the mEASIX score and ICAHT for pts in the IMAGINE study, prognostic value of mEASIX for CRS, ICANS and responses, and correlation of ICAHT score with outcomes. Methods: mEASIX scores were calculated for each pt at lymphodepletion (LD), D0, D+1 and D+4. CRS and ICANS were graded as per American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Pts were monitored for ICAHT post CAR-T infusion and risk stratified using CAR-HEMATOTOX score. ICAHT was graded using CTCAE v5.0. Appropriate statistical tools were used for analysis. Results: Twenty-four RR BCM pts (12 B-ALL; 12 B-NHL) were treated with var-cel in this study. Overall response rate (ORR) was 91.7% (22/24) at D+28 (B-ALL 91.7%; B-NHL 91.7%) and 80.9% (17/21) at D+90 (B-ALL 80%; B-NHL 81.8%). AESIs reported were CRS (Grade [G] 1 62.5%; G3+ 4.2%; overall 66.7%); ICANS (G1 4.2%; G3+ 0%; overall 4.2%); neutropenia (G3+ 91.7%; overall 100%); anemia (G3+ 29.2%; overall 95.8%); and thrombocytopenia (G3+ 20.8%; overall 91.7%). CRS median onset was D+5 and duration 3 days. No G3+ ICANS was reported. Treatment related mortality was 4.2% (n=1/24, CRS); 3 pts died of disease progression. The mEASIX score at LD, D0, D+1 and D+4 and its correlation with CRS, ICANS and responses is shown in Table 1. At D+1, mEASIX score <1 was predictive for responses (entire cohort, p=0.05; OR 15.0). At D+4, mEASIX score >1 was nearing statistical significance (p=0.07) for CRS (all grades; OR 6.0). However, mEASIX score at other timepoints was not predictive for CRS, ICANS or responses. The incidence of ICAHT was 100% (all grades; n=24), 100% neutropenia (G3+ 91.7%); 95.8% (n=23) anemia (G3+ 29.2%) and 91.7% (n=22) thrombocytopenia (G3+ 20.8%). The median time (range) to resolution of anemia, neutropenia and thrombocytopenia was 90 (11-270), 17.5 (1-181) and 9 (1-181) days respectively. Classical, biphasic and prolonged cytopenia pattern was seen for Neutropenia in 6, 2 and 16 pts respectively; for Anemia in 2, 0 and 21 patients respectively and for Thrombocytopenia in 4, 1 and 17 patients respectively. Overall, all patients, except two, were pancytopenic during their treatment course. Figure 1 shows the temporal course of var-cel mediated haematotoxicity (ICAHT). Two pts (8.3%) each received red cells, platelets, G-CSF and romiplostim; majority did not need supportive treatment. CAR-HEMATOTOX score was low risk in 18 pts and high risk in 6 pts. There was no statistical correlation between low risk (18 pts) and high risk (6 pts) with responses (17 pts, p=0.92) or with relapse / disease progression (9 pts, p=0.21). Conclusions: This is the first-in-India industry study evaluating mEASIX and ICAHT in patients treated with CAR-T cell therapy. mEASIX score <1 was predictive of responses at D+1 and score >1 at D+4 was mildly predictive of CRS. All patients developed ICAHT but only a small number of patients needed supportive treatment. Overall, var-cel was well tolerated with manageable cytopenia. The CAR-HEMATOTOX score was not predictive of relapse / disease progression in the IMAGINE study. mEASIX score may be used as an early predictor of CRS for permissive use of Tocilizumab before onset of severe symptoms. The ICAHT profile was heterogeneous, probably reflective of hematopoietic reserve, lines of treatment and downstream immune responses. The predictive role of mEASIX score and ICAHT profile in a real-world setting needs further study.

Post-Transplant Cyclophosphamide, Tacrolimus or Cyclosporine a and Mycophenolate Mofetil Compared to Anti-Thymocyte Globulin tacrolimus or Cyclosporine a and Methotrexate Combinations As Graft- versus -Host Disease Prophylaxis Post Allogeneic Stem Cell Transplantation from Sibling and Unrelated Donors in Patients with Acute Myeloid Leukemia: a Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow

Background: Recently, the BMT CTN 1703 phase III study compared post-transplant cyclophosphamide with tacrolimus with mycophenolate mofetil (PTCy/TAC/MMF) to TAC /methotrexate (MTX) as graft- versus-host disease (GVHD) prophylaxis post allogeneic transplantation (HSCT), demonstrating a lower incidence of severe acute (a) GVHD and chronic (c) GVHD and better GVHD-free, relapse-free survival (GRFS). The control arm did not include anti-thymocyte globulin (ATG), used in many centers for GVHD prophylaxis. Methods: The study aim was to compare PTCy with TAC or cyclosporine A (CSA) and MMF (PTCy/TAC or CSA & MMF) to ATG combined with TAC or CSA and MTX (ATG/TAC or CSA & MTX) in acute myeloid leukemia (AML) patients (pts) undergoing HSCT from matched siblings (MSD) or 9-10/10 unrelated donor (UD) in first complete remission (CR1). Statistical tests included a multivariate analysis (MVA) adjusting for potential confounding factors using a Cox proportional-hazards regression model for main outcomes. . Results: 6050 pts met the inclusion criteria, 402 received PTCy/TAC or CSA & MMF and 5648 received ATG/TAC or CSA & MTX as GVHD prophylaxis. Median follow-up was 23.4 (IQR, 20.3-24.9) and 41.8 (IQR, 39.6-43.3) months (p<0.0001). The median year of the transplant was 2018 (2010-2020) and 2016 (2007-2020) (p<0.0001). Pts in the PTCy/TAC or CSA & MMF group were younger, with a median age of 48.7 (range 18-5.6) versus 51.5 (8-77.8) years (p=0.024). The diagnosis was de novo AML in 84.1% vs 85.3% and secondary (s) AML in 15.9% vs. 14.7% (p=0.49). The cytogenetic risk was categorized as intermediate (70.9% vs. 67.1%), adverse (22.2% vs. 25.7 %), and favorable (6.9% vs. 7.2%) for pts in the PTCy/TAC or CSA & MMF and ATG/TAC or CSA & MTX groups, respectively (p=0.35) (data missing for 2214 pts). Karnofsky performance status (KPS) did not differ between the groups. There was a higher frequency of pt cytomegalovirus (CMV) seropositivity and female (F) donor to male (M) pt combination in the PTCy/TAC or CSA & MMF group, 77.8% vs. 71.8% (p=0.009) and 18.4% vs. 14.4% (p=0.029). More pts in the PTCy/TAC or CSA & MMF group received reduced intensity conditioning (RIC) 51.5% versus 41.1% in the ATG/TAC or CSA & MTX group, respectively (p<0001). Day 60 neutrophil engraftment (ANC >0.5 x 10 9/L) was 98.7% vs. 98.6% (p=0.84). Day 180 incidence of a GVHD grade II-IV and III-IV was 21.2% vs. 20.4% (p=0.92) and 8.1% vs. 6% (p=0.1), in pts receiving PTCy/TAC or CSA & MMF versus the ATG/TAC or CSA & MTX GVHD prophylaxis, respectively. The 2-year (y) total and extensive chronic (c) GVHD were 33.7% vs. 30% (p=0.09) and 10.7 % vs. 11.2% (p=0.81), respectively. GVHD was the cause of death in 11.6% vs. 13.9% of pts who died. In the MVA, both aGVHD (grade II-IV or III-IV) and cGVHD (total or extensive) did not differ between the groups with hazard ratios (HRs) =1.15 (95% CI 0.86-1.53, p=0.35), HR=0.87 (95% CI 0.56-1.34, p=0.52), HR=0.91 (95% CI 0.7-1.18, p=0. 47 and HR=1.51 (95% CI 0.96-2.36, p=0.074). Two-y NRM was significantly lower in pts that received PTCy/TAC or CSA & MMF versus ATG/TAC or CSA & MTX for GVHD prophylaxis, HR=1.57 (95% CI 1.07-2.3, p=0.022). Other HSCT outcome parameters did not differ between the groups. The HR for 2-y RI was 0.99 (95% CI 0.77-127, p=0. 93). The HRs for 2-y leukemia-free survival (LFS), overall survival (OS), and GRFS were HR=1.15 (95% CI 0.94-1.42, p<0.18), HR=1.18 (95% CI 0.94-1.49, p=0.16) and HR=1.12 (95% CI 0.93-1.36, p=0.22), respectively. Donor type and conditioning regimen were poor prognostic factors for grade II-IV, III-IV aGVHD, and total and extensive cGVHD. For cGVHD, additional poor prognostic factors were F donor to M pt combination and pt CMV seropositivity. Poor prognostic factors for LFS, OS, and GRFS were 9/10 UD, age (by 10 y), sAML, adverse-risk cytogenetics, lower KPS, and pt CMV seropositivity. For NRM, factors were the same apart from cytogenetics risk which was not a prognostic factor. In addition, time from diagnosis to HSCT was a prognostic factor for NRM and RI. Other poor prognostic factors for RI were lower KPS and pt CMV seropositivity. Conclusions: In this registry-based retrospective analysis, comparing PTCy in combination with TAC or CSA and MMF to ATG in combination with TAC or CSA and MTX as GVHD prophylaxis, we observed a similar incidence and severity of both aGVHD and cGVHD. NRM was significantly lower with the PTCy-based GVHD prophylaxis, while all other transplant outcome parameters were similar.

Survival advantage of treosulfan plus fludarabine (FT14) compared to busulfan plus fludarabine (FB4) in active acute myeloid leukemia post allogeneic transplantation: an analysis from the European Society for Blood and Marrow Transplantation (EBMT) Acute Leukemia Working Party (ALWP).

We compared FT14 (fludarabine 150-160 mg/m2, treosulfan 42 g/m2) versus FB4 (fludarabine 150-160 mg/m2, busulfan 12.8 mg/kg) in acute myeloid leukemia (AML) transplanted at primary refractory/relapsed disease. We retrospectively studied: (a) adults diagnosed with AML, (b) recipients of first allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated/sibling donor (2010-2020), (c) HSCT with primary refractory/relapsed disease, (d) conditioning regimen with FT14 or FB4. We studied 346 patients, 113 transplanted with FT14, and 233 with FΒ4. FT14 patients were significantly older, more frequently had an unrelated donor and had received a lower dose of fludarabine. Cumulative incidence (CI) of acute graft-versus-host disease (GVHD) grade III-IV and extensive chronic GVHD was similar. With a median follow-up of 28.7 months, 2-year CI of relapse was 43.4% in FT14 versus 53.2% in FB4, while non-relapse mortality (NRM) was respectively 20.8% versus 22.6%. This led to 2-year leukemia-free survival (LFS) of 35.8% for FT14 versus 24.2% in FB4, and overall survival (OS) of 44.4% versus 34%. Adverse cytogenetics and conditioning regimen independently predicted CI of relapse. Furthermore, conditioning regimen was the only independent predictor of LFS, OS, and GVHD-free/relapse-free survival. Therefore, our real-world multicenter study suggests that FT14 is associated with better outcomes in primary refractory/relapsed AML.

Diagnostic performance of natural language processing in detection of acute cancer VTE.

e19062 Background: The annual incidence of venous thromboembolism (VTE) is roughly 50-fold increased post allogeneic hematopoietic cell transplant (HSCT). Timely detection of VTE events has a significant impact on morbidity and mortality from these events. Manual chart review is commonly used for detection of VTE events; however, this is labor intensive and often not feasible. The International Classification of Diseases, 10th revision (ICD-10) has attempted to codify VTE more easily but has high false positive and false negative rates. Natural language processing (NLP) algorithms have been designed to improve detection of VTE events in electronic medical record systems over the past several years. This study aims to compare the accuracy of our institution’s NLP algorithm to the ICD-10 in detecting extremity VTE/pulmonary embolism (PE) events in hematopoietic stem cell transplant (HSCT) patients. Methods: This study was a retrospective analysis of adult patients who had allogeneic HSCT at MD Anderson between 2016-2020. Patient charts were assessed by three different methods for acute VTE events within 100 days of HSCT (index date). ICD-10 codes and our institution’s NLP algorithm were used separately to identify these VTE events. Afterwards, manual chart review was performed for confirmation. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for the ICD-10, NLP, and the NLP+ICD combination. Results: A total of 1,391 patient charts were analyzed in our study. There were 129 (9.3%) VTE events detected via manual chart review. Three methodologies were used for comparison: the NLP algorithm alone, the ICD code alone, and detection by NLP or ICD. The NLP algorithm alone had the best specificity (98.9%) and PPV (89.4%) of the three methods. The ICD-10 code had a statistically significant decrease in ability to detect acute VTE events compared to the NLP (p<0.001) (Table). Of the 19 VTE events not identified by NLP, all were found in radiology or vascular laboratory reports. Conclusions: Our study shows the overall superior performance of the NLP algorithm, as it had higher sensitivity, specificity, PPV, and NPV compared to the ICD-10, as well as a better specificity and PPV compared to the combination of both methods. Future refinement of the NLP algorithm and combination with other detection methodologies will allow for more accurate detection of VTE in large cohorts. [Table: see text]

CD34 Stem Cell Boost in Pediatric Allogeneic Stem Cell Transplant Recipients: A Case Series and Review of Literature

Patients with poor graft function (PGF) or declining donor chimerism (DC) post allogeneic hematopoietic cell transplantation (HCT) may benefit from a CD34-selected stem cell boost (SCB). We retrospectively studied outcomes of fourteen pediatric patients (PGF: 12 and declining DC: 2), with a median age of 12.8 (range 0.08–20.6) years at HCT, who received a SCB. Primary and secondary endpoints included resolution of PGF or improvement in DC (≥ 15% increase), overall survival (OS) and transplant-related mortality (TRM), respectively. The median CD34 dose infused was 7.47 × 106/kg (range 3.51 × 106–3.39 × 107/kg). Among patients with PGF who survived ≥ 3 months post-SCB (n = 8), we observed a non-significant decrease in the cumulative median number of red cell transfusions, platelet transfusions, and GCSF but not intravenous immunoglobulin doses in the 3 months before and after SCB. Overall response rate (ORR) was 50%, with 29% complete and 21% partial responses. ORR was better in recipients who received lymphodepletion (LD) pre-SCB versus none (75% versus 40%; p = 0.56). The incidence of acute and chronic graft-versus-host-disease was 7% and 14%, respectively. The 1-year OS was 50% (95% CI 23–72%) and TRM was 29% (95% CI 8–58%). SCB was effective in half of our cohort with possible benefit of LD pre-SCB.

Antiviral therapy defiant mixed viral retinitis post hematopoietic allogeneic stem cell transplant

Cytomegalovirus (CMV) retinitis is an uncommon presentation post allogeneic transplant and can be vision-threatening. Our case demonstrates the occurrence of polymerase chain reaction (PCR) proven mixed viral retinitis (cytomegalovirus and varicella zoster virus) post allogeneic stem cell transplant despite multiple prophylactic antiviral therapies, including letermovir, and in the documented absence of CMV DNAemia. A 21-year-old female with acute myeloid leukemia presented with mixed viral retinitis (cytomegalovirus and varicella zoster virus) post allogenic transplant. This presentation occurred despite ongoing standard prophylaxis for both of these viruses, as well as following two courses of treatment for CMV viremia, with a documented negative CMV PCR in the blood prior to the presentation with retinitis. The patient was treated with intravenous ganciclovir and subsequently transitioned to oral valganciclovir with durable resolution of the retinitis. We report a rare case of mixed viral retinitis occurring despite multiple antiviral prophylaxes including letermovir and with PCR-documented absence of preceding CMV viremia, in a post-allogeneic stem cell transplant patient, with PCR of the aqueous fluid demonstrating two viral populations. With very little existing literature on either mixed viral retinitis or CMV retinitis during letermovir prophylaxis, this case expands the literature on both topics. CMV retinitis is an uncommon potentially vision threatening presentation post hematopoietic stem cell transplant, and can occur due to early CMV reactivation, low CD4 count, and delayed CD4 lymphocyte recovery. Letermovir has poor CNS and retinal penetration. This case highlights the need for more research on secondary prophylaxis with letermovir.

Impact of age on hospitalization and outcomes post allogeneic hematopoietic cell transplantation outcome, a single center experience.

The outcomes of allogeneic hematopoietic cell transplantation (HCT) in older patients are not well defined. We retrospectively analyzed the outcomes of 332 patients, with the median age of 65years (range, 60-76), between 2014 and 2019. We categorized them to 3 age groups (G): G1, 60-65years (n = 175); G2, > 65-70years (n = 127); and G3, > 70years (n = 30). The median length of hospitalization during the initial HCT period was 30days, with a significant difference when stratified by age (p = 0.049). Overall, 183 (58.7%) patients were re-hospitalized within the first 6months post HCT, and 60 (21.6%) in the second 6-month period. The 2-year OS was 56% in G1, 53% in G2, and 34% in G3 (p = 0.05). The 2-year event-free survival (EFS) was 54% for G1, 49% for G2, and 31% for G3 (p = 0.04). Non-relapse mortality (NRM) at 2years was 25% in G1, 36% in G2, and 52% in G3 (p = 0.008). In multivariable analysis, patients aged 60-65years had significantly better EFS (p = 0.04) and had a trend toward lower NRM (p = 0.05) than those aged > 70years. Re-admission in the first 6months post HCT had a significant impact on OS, EFS, and NRM. HCT-specific comorbidity index > 3 had significantly affected NRM. Finally, age had a significant influence on length of hospitalization during HCT. In conclusion, patients aged > 70years have an inferior EFS and higher NRM. This likely related to higher rate of re-admissions due to infectious complications (84%).

Long-Term Kinetics of Serum Galactomannan during Treatment of Complicated Invasive Pulmonary Aspergillosis

Several studies have evaluated the serum galactomannan (GM) antigen assay in pediatric patients, and there is convincing evidence for its usefulness as a diagnostic tool for invasive Aspergillus infections in patients with acute leukemias or post allogeneic hematopoietic cell transplantation (HCT). Less is known about the utility of the assay in monitoring responses to treatment in patients with established invasive aspergillosis (IA). Here, we present the long-term kinetics of serum galactomannan in two severely immunocompromised adolescents with invasive pulmonary aspergillosis (IPA) who were cured after complicated clinical courses. We also review the utility of the GM antigen assay in serum as a prognostic tool around the time of diagnosis of IA and as a biomarker to monitor disease activity in patients with established IA and assess responses to systemic antifungal therapy.

Long-Term Outcomes of a Clinical Trial of Molecular and Functional Drug Screening for Individualized Therapy in Relapsed and Refractory (R/R) Acute Leukemia (AL)

Background. Outcome of patients (pts) with R/R AL is dismal. While traditional precision medicine basket trials have assigned treatment based on targeted inhibitors for certain mutations, this approach has limited use for pts without such mutations or with co-occurring mutations. In contrast, we developed a clinical trial for which treatment was assigned based on molecular characteristics and functional drug testing. Patient cell samples were analyzed for 194 recurring mutations and by high throughput screening (HTS) for a custom panel of drugs and drug combinations to comprehensively select the best treatment for each individual patient. Here we report the final analysis and long-term outcomes of this individualized approach. (NCT02551718) Methods. Eligibility criteria included diagnosis of AL, relapsed or refractory to at least 2 lines of treatment, ECOG <4 and adequate organ function. Blood/bone marrow (BM) and/or fluid or tissue involved by leukemic blasts was subjected to cell enrichment using magnetic beads, then assayed for drug sensitivity using the CLIA approved Cancer Drug Sensitivity Test (CDST) performed at the University of Washington Quellos High Throughput Core (method described in Lee et al. Nat Commun 2018), mutations by MyAML®, RNAseq and single cell mutation analysis (MissionBio). The HTS included 170 drugs and drug combinations, both FDA-approved and investigational. Drug recommendations were provided by the study to the patient's physician based on the lowest IC50, percentile rankings compared to other tested patients, no history of failed prior use, and insurance authorization. The patient's physician made the final decision about treatment. Results. 60 pts were enrolled: 51 acute myeloid leukemia (AML), 7 acute lymphoblastic leukemia (ALL), 1 undifferentiated, 1 mixed phenotype. The median age was 58 years (range 22-82). For AML pts, ELN 2017 was favorable, intermediate and adverse in 8 (16%), 14 (28%) and 28 (56%) pts, respectively. Median prior lines of therapy were 4 (range 1-8); 15 pts (25%) had primary induction failure and 23 pts (40%) had relapsed post allogeneic transplant, 10 in the first 100 days (d). For those who had relapsed disease, median duration of 1st CR was 6.8 months (range 0.5-52.6). Final HTS test results were obtained within 5 d (4-13), and each patient exhibited a unique pattern of drug response (Figure 1). 35 patients were treated with a single drug (N=12) or combination (2-4 agents; N=23) recommended by the trial. 25 of the patients did not complete treatment on this study because of transition to supportive care (6), treatment with other therapy (10), travel out of state to local care (4), participation on another trial (CAR-T cell-2, investigational agent-2), and pneumonia (1). 30 patients had at least 1 mutation for which targeted inhibitors [FLT3 (11), KIT (2), IDH1/2 (7), NRAS/KRAS (20), ABL1 (3), JAK2 (1)] were available, and seven patients received one. Additionally, 35 pts (4 had more than 1) had a mutation that could now be considered for investigational therapy, including TP53 (12), NPM1 (8), KMT2A rearrangement (4), WT1 (10), or spliceosome mutation (5). Median follow up duration was 2.7 months (range 0.3-36.3). Of 27 pts for whom a post-treatment BM was performed, overall response rate was 33% including 2 complete remission (CR), 1 CR with incomplete count recovery (CRi) and 6 partial remissions (PRs). Of 22 pts with circulating blasts, 21 (95%) exhibited decline with chosen regimen, and 7 (31.8%) exhibited resolution. Median overall survival (OS) for those receiving assay guided therapy was 135 days (d) (95%CI 79-213), compared to 34 d (95%CI 26-63) for enrolled patients not treated on study with corresponding 100 day-OS of 57% (95%CI 39-72%) and 24% (95%CI 10-42), respectively (P<0.001) (Figure 2). Median survival post consent was 109 d (95%CI 79-341) for the subset of post-allogeneic transplant relapsed pts who then received assay guided therapy vs. 30 d (95%CI 8-92) for the those not treated on this trial (P 0.003). Assay guided therapy can decrease risk of death by 83% after adjusted by age, sex, type of leukemia, cytogenetic risk, number of lines of previous treatment (HR 0.17, 95%CI 0.08-0.35, P <0.001) for this group of pts with extensive prior therapy. Conclusion. Genomic analysis and functional screening of enriched leukemia cells can comprehensively predict in vivo efficacy and individualize optimal treatment for patients with R/R AL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Influence of Conditioning Regimen Intensity on Outcomes Post-Allogeneic Transplantation for AML in Complete Morphological Remission

Introduction: Acute myelogenous leukemia (AML) is a major indication for allogeneic hematopoietic cell transplantation (alloHCT). Myeloablative (MAC) regimens are preferred for their intensity, however, reduced intensity conditioning regimens (RIC) have been increasingly used to permit older patients and patients with comorbidities to undergo transplant. The literature is conflicting regarding the comparison of outcomes between RIC and MAC patients. While MAC regimens are associated with less relapse, non-relapse mortality (NRM) is higher. RIC regimens on the other hand, demonstrate less NRM but higher relapse rates. We sought to compare RIC vs MAC regimens at our centre for alloHCT of AML in complete remission (CR). Methods: We retrospectively analyzed the outcomes of 451 patients that underwent alloHCT for AML at the Princess Margaret Cancer Centre (PMCC) with either RIC or MAC using various donors between the years 2015-2020. Primary endpoint was 2-year overall survival (OS), secondary endpoints included cumulative incidence of relapse (CIR), cumulative NRM, and GVHD free/relapse free survival (GRFS). Conditioning regimen intensity was determined as defined by Bacigalupo et al (BBMT 2009). Of the total cohort 331 patients received RIC and 121 MAC. Among MAC regimens, 59% received FLU(4)Bu(4) (Fludarabine 140mg/m2 + Busulfan 12.8mg/m2). Among RIC patients 71% received Flu(4)Bu(2)TBI(200) (Fludarabine 140mg/m2+ Busulfan 6.4 mg/m2 + TBI 200cGy). Results: Median age at transplant was 48 years (range: 19-67) for MAC recipients and 61 (range: 18-75) for RIC recipients (p<0.001). Other patient characteristics are described in Table 1. For the entire cohort at 2 years, the incidence of NRM was 19.1% for MAC (95% CI: 12.4-26.8) and 22.5% for RIC (95% CI: 18.1-27.1) (p=0.44). Two-year CIR was 19.8% (95% CI: 12.9-27.8) for MAC recipients and 24.5% (95% CI: 20.0-29.4) for RIC recipients (p=0.15). Two-year OS was 61% and 53% for MAC and RIC, respectively (p=0.02). Acute GVHD occurred in 58.3% of MAC recipients versus 46.8% of RIC recipients. Chronic GVHD occurred in 43.3% of the MAC recipients versus 38% of the RIC recipients. At two years GRFS was 40.8% (95% CI: 35.4-46.1) for MAC and 33.7% (95% CI: 25.0-42.6) for RIC, p=0.30. When examining the Disease Risk Index (DRI) for the entire cohort, OS for high risk was 43.3% (95% CI: 32.5-53.5) vs 66.6% (95% CI: 61-71) and 64% (95% CI: 38-80) for intermediate risk and low risk respectively, p<0.001. A propensity score (PS) matched analysis was done matching patients for age, HLA matching (mismatched vs full match), DRI (low, intermediate, high risk) and in vivo T cell depletion (yes vs no). Two-year OS was 67% for the MAC recipients (95% CI: 57-76) and 66% for the RIC recipients (95% CI: 56-75), p=0.95 (Figure 1a). NRM for MAC was 22% (95% CI: 14-30) versus 14% (95% CI: 8-22) for RIC, p=0.19. CIR at 2 years was 18.5% for MAC (95% CI 11-27) and 24.3% for RIC (95% CI: 16-33), p=0.22. GRFS at 2 years was 36% (95% CI: 26.4-45.7) for MAC and 48.3% (95% CI: 38-58) for RIC recipients, p=0.17. In the subgroup analysis examining matched related donor (MRD) recipients in particular, the OS at 2 years was for MAC 83.6% (95% CI: 66.8-91.3) vs 57.3% (95% CI: 45.1-67.7) for RIC, p=0.006 (Figure 1b) Two-year NRM was 10.3% for MAC vs 23.4% for the RIC group, p=0.14. CIR at 2 years was 12.2% for MAC vs 23.4% for RIC in the MRD setting, p=0.11. Conclusions: Our study shows that in the MRD setting there is a statistically significant improved survival, especially in patients with low and intermediate DRI scores. In other donor settings, there is no significant difference in outcomes between patients that undergo alloHCT with MAC vs RIC regimens. MAC conditioning regimens should continue to be the preferred choice of intensity for patients that may tolerate it. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Early Results of MT-401 (Zedenoleucel) in Post-Transplant MRD+ aml Patients

Background: Measurable residual disease (MRD) testing has become more prevalent in AML. MRD positivity is associated with increased relapse risk and shorter survival in AML, and currently, there no approved therapies for these patients. Zedenoleucel (also known as MT-401) is a non-genetically modified allogeneic multi-tumor associated antigen (mTAA)-specific T cell therapy with selectivity to multiple tumor antigens, specifically preferentially expressed antigen in melanoma (PRAME), Wilms' tumor 1 (WT1), New York esophageal 1 (NY-ESO-1) and Survivin. An ongoing Phase 1 dose-escalation study (ADSPAM) conducted by Baylor College of Medicine (BCM) shows acceptable safety and tolerability at doses up to 200 x 106 cells administered post-HSCT in the adjuvant, as well as relapsed/refractory setting. There are promising preliminary clinical results with mTAA-specific T cell therapy targeting these same tumor antigens (Lulla et al., 2021). Objective: To determine whether MRD+ patients post-allogeneic transplant can be treated safely and effectively with multiTAA-specific T cells (MT-401/zedenoleucel) Methods: A multicenter Phase 2 study (ARTEMIS) evaluating the safety, tolerability and efficacy of zedenoleucel in patients with AML, including MRD+ patients, post-HSCT is ongoing. The study explores this therapy in patients with no active disease [in complete remission (CR) and MRD-] or in patients with active disease (frank relapse or MRD+). Patients may receive up to 3 consecutive infusions of zedenoleucel as a monotherapy (50-200 × 106 cells every 2 weeks) at weeks 0, 2 and 4 during the Intervention Period, and enter Follow-up at Week 8. Primary endpoints include various safety measurements. Efficacy evaluations occur at weeks 8, 12, 18, 24, 48 and yearly for 4 years using ELN recommendations for standard AML response criteria. MRD testing was done by flow cytometry or molecular testing (e.g. RT-PCR). Results: No concerning safety signals arose, including any dose-limiting toxicities in safety lead-in patients. The MRD+ patients had a variety of genetic mutations/abnormalities. One patient with NPM1 mutation converted from MRD+ to MRD- at week 8 evaluation. Another patient with RUNX1 genetic abnormality showed a decrease in MRD by PCR from a starting baseline of 0.8093% to resolution via peripheral blood at approximately 32 weeks post-treatment with MT-401. T cell composition of the product consisted of 71% CD4+ and 24% CD8+ T cells. T cell receptor (TCR) analysis identified 3,117 antigen-specific clones (881 Survivin, 783 NY-ESO-1, 750 PRAME, 709 WT1). Immune monitoring of this patient using biomarker analysis showed T cell specificity not only for the targeted antigens but also for non-targeted antigens over time, thereby demonstrating epitope spreading. Interestingly, the tumor antigen composition by RNASeq identified an antigen expression profile that changes over time and inversely correlates with the presence of antigen-specific T cells, demonstrating the interplay of tumor cell immunogenicity and antigen-specific T cells. Conclusions: The preliminary ARTEMIS results showed that administration of MT-401 converted MRD+ patients to MRD- indicating that early intervention with MT-401 administration at MRD+ stage in post-transplant AML can be beneficial.

CT-282 Case Report: Successful Management of Severe Veno-Occlusive Disease after Allogeneic Stem Cell Transplantation Using a Transjugular Intrahepatic Portosystemic Shunt

Veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (VOD/SOS), of the liver is a complication of allogeneic bone marrow or peripheral stem cell transplantation and is known to be an unpredictable, life-threatening complication with high mortality. We report here a case of a 24-year-old male patient who was diagnosed in 2019 at Gustave Roussy institute with AML. The patient was treated with the AML protocol 3+7 in December 2019 with a complete cytologic response and a positive MRD. Leukemia relapse was observed in September 2020, treated by gemtuzumab ozogomycin and cytarabine with a negative MRD. A successful allogeneic bone marrow transplantation from an HLA-matched pheno-identical related donor was conducted on December 22, 2020, using a myeloablative conditioning regimen. The patient was always controlled by a daily blood test and controlled blood transfusions, and a weekly repeated Doppler ultrasound examination did not indicate a high-risk profile of VOD. However, 12 days post transplant, the patient's condition deteriorated with the appearance of abdominal ascites, weight gain of 6 kg (per base 76 kg), and liver cytolysis with ASAT 72 UI/L, ALAT 86 UI/L, and normal bilirubin. Worsening cytolysis was observed, with ASAT 659 UI/L, ALAT 557 UI/L, and normal bilirubin. A Doppler ultrasound found 5 positive criteria of VOD (hepatomegaly, portal dilation, enlargement of the gall bladder wall, splenomegaly, ascites, decrease in the diameter of the subhepatic veins). Defibrotide was initiated. The patient's condition worsened and was refractory to medical therapy. Transjugular intrahepatic portosystemic shunting (TIPS) was performed 13 days after transplantation without technical complications in any case. The median hepatic venous pressure gradient prior to the procedure was 20 mmHg with a drop to 12 mmHg. An abdominal CT scan showed an under hepatic hematoma with hemorrhagic syndrome. Ascites puncture with abdominal drain installation was done. In summary, following TIPS, the patient showed clinical improvement, and VOD resolved subsequently with a complete remission post allogeneic transplant.

AML-109 Preliminary Results of MT-401 in Post-Transplant Measurable Residual Disease Positive (MRD+) Acute Myeloid Leukemia (AML) Patients

Measurable residual disease (MRD) testing has become more prevalent in AML. MRD positivity is associated with increased relapse risk and shorter survival in AML and, currently, there are no approved therapies for these patients. To determine whether MRD+ patients post-allogeneic transplant can be treated safely and effectively with multi-tumor-associated antigen (mTAA)-specific T cells (MT-401/zedenoleucel) Design: A multicenter Phase 2 study (ARTEMIS) evaluating the safety and efficacy of MT-401 in patients with AML post-transplant is ongoing and includes patients with MRD+ disease. Three MRD+ AML patients were enrolled and treated in the ARTEMIS study. MRD testing was done by flow cytometry or molecular testing (e.g., RT-PCR). Patients received up to 3 consecutive infusions of MT-401 as a monotherapy (50-200×106 cells every 2 weeks) at weeks 0, 2, and 4 during the Intervention Period, and entered Follow-up starting at Week 8 for up to 5 years. The primary endpoint includes various safety measurements and incidence of dose-limiting toxicities (DLTs). The secondary endpoint was efficacy evaluations using ELN recommendations for standard AML response criteria. No DLTs were observed. The MRD+ patient had a variety of genetic mutations/abnormalities. One patient with NPM1 mutation converted from MRD+ to MRD- at week 8 evaluation. Another patient with RUNX1 genetic abnormality showed a decrease in MRD by PCR from a starting baseline of 0.8093% to resolution via peripheral blood at approximately 32 weeks post-treatment with MT-401. T cell receptor (TCR) analysis identified 3,117 antigen-specific clones (881 Survivin, 783 NY-ESO-1, 750 PRAME, 709 WT1). Immune monitoring of this patient showed T cell specificity not only for the targeted antigens but also for non-targeted antigens over time, thereby demonstrating epitope spreading. Interestingly, the tumor antigen composition by RNASeq identified an antigen expression profile that changes over time and inversely correlates with the presence of antigen-specific T cells, demonstrating the interplay of tumor cell immunogenicity and antigen-specific T cells. The lead-in portion of the ARTEMIS results showed that administration of MT-401 converted MRD+ patients to MRD-indicating that early intervention with MT-401 administration at MRD+ stage in post-transplant AML can be beneficial.