Poor Cytogenetics Research Articles

Real-World Outcome and Prognostic Factors in MDS Patients Treated with Azacitidine-A Retrospective Analysis.

Azacitidine (AZA) is recognized as a vital drug used in the therapy of myelodysplastic syndromes (MDS) due to its beneficial effect on survival and quality of life. Nevertheless, many patients fail to respond to AZA treatment, as prognostic factors still are not identified. The present retrospective analysis included 79 patients with MDS treated with AZA as first-line therapy in a real-life setting. The percentage of patients with good, intermediate, and poor cytogenetics was 46.8%, 11.4%, and 34.2%, respectively. The overall response rate (complete remission [CR], partial remission [PR], and hematological improvement [HI]) was 24%. The CR, PR, and HI rates were 13.9%, 2.5%, and 7.6%, respectively. Stable disease (SD) was documented in 40.5% of patients. The median overall survival (OS) and progression-free survival (PFS) were 17.6 and 14.96 months, respectively. Patients with ORR and SD had a significantly longer median OS (23.8 vs. 5.7 months, p = 0.0005) and PFS (19.8 vs. 3.5 months, p < 0.001) compared to patients who did not respond to AZA. In univariate analysis, only an unfavorable cytogenetic group was a prognostic factor of a lower response rate (p = 0.03). In a multivariate model, older age (p = 0.047), higher IPSS (International Prognostic Scoring System) risk (p = 0.014), and higher IPSS-R cytogenetic risk (p = 0.004) were independent factors of shorter OS. Independent prognostic factors for shorter PFS were age (p = 0.001), IPSS risk (p = 0.02), IPSS cytogenetic risk (p = 0.002), and serum ferritin level (p = 0.008). The safety profile of AZA was predictable and consistent with previous studies. In conclusion, our study confirms the efficacy and safety of AZA in a real-world population and identifies potential biomarkers for response and survival.

Reduced toxicity (FluBu3) versus myeloablative (BuCy) conditioning in acute myeloid leukemia patients who received first allogeneic hematopoietic stem cell transplantation in measurable residual disease-negative CR1.

In the present study, reduced toxicity (FluBu3) and myeloablative (BuCy) conditioning were compared in patients with AML who received first allogeneic HSCT in MRD-negative CR1. The study included 124 adult patients who underwent HSCT from an HLA-matched (8/8) sibling, unrelated, or 1-locus mismatched (7/8) unrelated donor (MMUD). The median age was 45 years and intermediate cytogenetics comprised majority (71.8%). The 2-year OS, RFS, CIR and NRM for BuCy (n = 78, 62.9%) and FluBu3 (n = 46, 37.1%) groups were 78.3% and 84.5% (p = 0.358), 78.0% and 76.3% (p = 0.806), 7.7% and 21.5% (p = 0.074) and 14.3% and 2.2% (p = 0.032), respectively. At the time of data cut-off, relapse and NRM were the main causes of HSCT failure in each of the FluBu3 and BuCy arms. Among patients, 75% of relapsed FluBu3 patients had high-risk features of either poor cytogenetics or FLT3-ITD mutation compared with 16.7% of BuCy patients. The majority of NRM in the BuCy group was due to GVHD (73%), half of whom received MMUD transplantation. To conclude, the FluBu3 reduced toxicity conditioning showed comparable post-transplant OS and RFS to BuCy and was associated with significantly reduced NRM that was offset by a trend towards higher risk of relapse even in MRD-negative CR1 population.

Effect of venetoclax plus chemotherapy on treatment-naive acute myeloid leukemia patients with moderate to poor cytogenetic profiles and the combination's influence on the expression of proteins of the anti-apoptoic family

Objective: This was an open-label observational assessment aimed to evaluate whether venetoclax (VEN) plus chemotherapy could enhance the therapeutic benefits for treatment-naive acute myeloid leukemia (AML) patients with adverse cytogenetic profiles. Methods: A total of 38 adult patients (including 11 patients with moderate risk stratification and 27 patients with high risk stratification) who were treated at the Affiliated Hospital of Inner Mongolia Medical University from April 2019 to May 2022 were enrolled in this study. Patients were randomized into two cohorts according to the random number method to receive single intensive chemotherapy (18/38) alone or VEN+intensive chemotherapy (20/38), respectively. The chemotherapy cohort received 2 cycles of induction chemotherapy (idarbicin or daunorubicin plus cytarabine), followed by 6 cycles of consolidation chemotherapy (cytarabine), while the treatment for the VEN + chemotherapy cohort consisted of the same chemotherapy as above plus oral VEN. Heparinized bone marrow samples were obtained from patients at enrollment de novo and post chemotherapy. The expressions of MCL-1 and BCL-2 were detected by Western blot analysis. Results: Patients with VEN+chemotherapy showed an objective response rate (ORR) of 90.0% (18/20), compared with 55.6% (10/18, P=0.012) of the chemotherapy group. Meanwhile, the VEN + chemotherapy cohort gained more benefits in progression-free survival (PFS) and overall survival (OS) than the chemotherapy cohort (mean PFS: 27.1 months versus 17.9 months, P=0.038; mean OS: 32.2 months versus 21.3 months, P=0.004). For patients with moderate risk stratification, there were no differences in the ORR and PFS between the chemotherapy cohort and the VEN + chemotherapy cohort: the ORR was 80.0% (4/5) versus 100% (6/6, P=0.251), and the PFS was 27.9 months versus 32.0 months (P=0.582). Moreover, the ORR was 85.7% (12/14) for the VEN+chemotherapy cohort and 46.2% (6/13) for the chemotherapy cohort in the high risk profile (P=0.029). The PFS of the VEN+chemotherapy cohort was superior to the chemotherapy cohort in the high risk profile (mean PFS: 23.7 months versus 11.1 months, P=0.002). Meanwhile, in the chemotherapy cohort, there were no difference in the PFS between FAB-M5 patients and non-FAB-M5 patients; the mean PFS was 20.0 months versus 15.5 months (P=0.298) for the two groups. Nevertheless, FAB-M5 patients were inferior to non-FAB-M5 patients in PFS in the VEN + chemotherapy arm (mean PFS: 19.6 months versus 30.2 months, P=0.031). The most frequent grade 4 hematological toxicities (therapy related) were leukopenia and thrombopenia. Grade 3/4 hematological adverse events in patients treated with VEN+chemotherapy were not increased compared with those who received chemotherapy. Western blot showed VEN continuously decreased the expression of BCL-2 proteins in both FAB-M5 and non-FAB-M5 patients, but obviously increased the expression of MCL-1 proteins only in FAB-M5 patients. Conclusions: VEN combined with intensive chemotherapy have yielded high ORR and survival advantages for de novo AML patients with poor cytogenetics profiles. The high-expression of MCL-1 may drive resistance to VEN.

Identification of a venetoclax-resistance prognostic signature base on 6-senescence genes and its clinical significance for acute myeloid leukemia

BackgroundSatisfactory responses can be obtained for acute myeloid leukemia (AML) treated by Venetoclax (VEN)-based therapy. However, there are still quite a few AML patients (AMLs) resistant to VEN, and it is critical to understand whether VEN-resistance is regulated by senescence.MethodsHere, we established and validated a signature for predicting AML prognosis based on VEN resistance-related senescence genes (VRSGs). In this study, 51 senescence genes were identified with VEN-resistance in AML. Using LASSO algorithms and multiple AML cohorts, a VEN-resistance senescence prognostic model (VRSP-M) was developed and validated based on 6-senescence genes.ResultsAccording to the median score of the signature, AMLs were classified into two subtypes. A worse prognosis and more adverse features occurred in the high-risk subtype, including older patients, non-de novo AML, poor cytogenetics, adverse risk of European LeukemiaNet (ELN) 2017 recommendation, and TP53 mutation. Patients in the high-risk subtype were mainly involved in monocyte differentiation, senescence, NADPH oxidases, and PD1 signaling pathway. The model’s risk score was significantly associated with VEN-resistance, immune features, and immunotherapy response in AML. In vitro, the IC50 values of ABT-199 (VEN) rose progressively with increasing expression of G6PD and BAG3 in AML cell lines.ConclusionsThe 6-senescence genes prognostic model has significant meaning for the prediction of VEN-resistance, guiding personalized molecularly targeted therapies, and improving AML prognosis.

A Simple Prediction Model of Outcomes after Allogeneic Hematopoietic Stem Cell Transplant (HCT) in Myelodysplastic Syndromes Using HCT-Comorbidity Index, Cytogenetic Risk, and Platelet Count

Introduction: Allogeneic hematopoietic stem cell transplant (HCT) is currently the only potentially curative option for patients (pts) with myelodysplastic syndromes (MDS). However, many pts relapse after HCT. While the International Prognostic Scoring System-Molecular (IPSS-M) is useful, next generation sequencing is not always available particularly in resource limited settings. Hence, we aimed to develop a prediction model utilizing readily available pt and HCT characteristics of post-HCT outcomes in pts with MDS treated with hypomethylating agent (HMA) therapy pre-HCT. Methods: Pts with MDS treated with HMA (azacitidine or decitabine) who received an HCT at Dana-Farber Cancer Institute from 01/2014-12/2020 were included. The primary outcome was progression free survival (PFS) post-HCT, defined as time from transplant to disease relapse or progression. Univariable analysis (UVA) and multivariable analysis (MVA) were used to identify predictors of PFS and build a model. Variables were pt age, sex, donor type (matched related donor (MRD) vs. matched unrelated donor (MUD) vs. 7/8 MUD vs. haploidentical), HCT-comorbidity index (HCT-CI), CMV status of donor/recipient, MDS subtype, graft versus host disease prophylaxis (GVHD ppx), HMA type, number of HMA cycles, conditioning intensity (myeloablative vs. reduced intensity), cell source (bone marrow vs. peripheral blood), response to HMA assessed by IWG 2023 criteria ( Zeidan Blood 2023), IPSS-Revised (IPSS-R) pre-HCT, and cytogenetic risk (very good, good, intermediate, poor, very poor) at diagnosis and pre-HCT. Results: A total of 148 pts with MDS received HMA and underwent subsequent HCT. Median age was 64 years (range 26-79) and 61.5% were men. Pts were treated with 7 days azacitidine (54.1%), 5 days decitabine (39.2%) and other schedules (6.7%) and received a median of 4 HMA cycles (range 1-20). Prior to HCT, IWG 2023 responses were: CR (15.5%), CRbi (14.9%), CRuni (19.6%), CRh (0.7%), PR (1.4%), HI (9.5%), and no response (38.5%). Most donors were MUD (60.8%) or MRD (18.2%), and most pts received reduced intensity conditioning (74.3%). GVHD ppx was tacrolimus (tac)/methotrexate (MTX) (54.7%), tac/MTX/sirolimus (19.6%), cyclophosphamide/mycophenolate mofetil/tac (15.5%), and other (10.1%). Median HCT-CI was 2 (range 0-13); 48.6% had HCT-CI ≥3. Median follow-up time among ongoing survivors was 48.3 months (range 5.5-101.3). The only statistically significant variables associated with post-HCT PFS in both UVA and MVA (with Cox MVA results shared here) were HCT-CI (≥4 vs. 0-3: HR 1.94, 95% CI 1.18-3.19, p=0.009), platelet count pre-HCT (platelets &amp;lt;40 vs. &amp;gt;70: HR 2.46, 95% CI 1.33-4.54, p=0.004; platelets 40-70 vs. &amp;gt;70: HR 1.84, 95% CI 1.02-3.32, p=0.044) and cytogenetic risk pre-HCT (very poor vs. other: HR 2.52, 95% CI 1.43-4.44, p=0.001). HCT-CI impacted non-relapse mortality (NRM) and not relapse whereas very poor cytogenetics impacted relapse and not NRM. A model predicting post-HCT outcomes was built with the following risk scores: HCT-CI: 0-3 (0), ≥4 (1.5); platelet count pre-HCT: &amp;gt;70 (0), 40-70 (1), &amp;lt;40 (2); cytogenetic risk pre-HCT: not very poor (0), very poor (2). Based on the sum risk score, patients were defined as low (0-1), intermediate (int) (1.5-2) or high (≥2.5) risk. The risk classification was significantly associated with post-HCT outcomes. Four-year post-HCT PFS was 68% (95% CI 56-78%), 36% (95% CI 22-51%) and 15% (95% CI 5-31%) for low, int and high risk, respectively (p&amp;lt;0.00001) ( Figure A). Accordingly, 4-year cumulative incidence of relapse was 23% (95% CI 14-33%) for low, 54% for int (95% CI 38-68%) and 62% for high (95%CI 39-78%) risk scores (p=0.00005). Four-year overall survival was 70% (95% CI 58-80%), 45% (95% CI 29-59%), and 19% (95% CI 7-36%) (p&amp;lt;0.00001), for the same respective risk groups ( Figure B). In contrast, NRM did not differ between risk categories (low: 9%, int: 10%, high: 23%; p=0.1). The predictability of this simple risk model (C-index: 0.72) was found to be superior to IPSS-R pre-HCT (C-index: 0.61) and IWG 2023 response pre-HCT (C-index: 0.617). Conclusion: We developed a simplified prognostic model of post-HCT outcomes for pts with MDS treated with HMA based on HCT-CI, platelet count, and cytogenetic risk post-HMA therapy and pre-HCT. We expect that this model will be particularly useful in resource-limited settings without easy access to next generation sequencing.

Characteristics and Outcomes of Younger Adult Patients (Pts) with Myelodysplastic Syndromes (MDS): A Multicenter Retrospective Study

Introduction: MDS are primarily diseases of the elderly, with median age at diagnosis of 72 years. Focused data on clinical and molecular characteristics, as well as outcomes, in younger pts under age 60 years are limited. We conducted this multicenter retrospective study to describe pt characteristics, cytogenetic and molecular profiles, treatment modalities, and outcomes in younger pts with MDS, including adolescent and young adults (AYA). Methods: The study included pts diagnosed with MDS between 2002-2023 at 7 academic centers. We compared baseline characteristics, treatment, and outcomes of AYA (18-39 years) and younger adult (YA) pts (40-59 years). Responses were assessed using the modified IWG 2006 response criteria which included complete remission (CR), marrow CR (mCR), and hematologic improvement (HI). Wilcoxon rank sum test and Fisher's exact (and Chi-square) test were used to compare pt and disease characteristics for continuous and categorical variables, respectively. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using log-rank test. Results: A total of 173 pts were identified (AYA, N=50; YA, N=123). Median age at diagnosis was 50 years (range, 18-59), with 51% females. Baseline characteristics are shown in Table 1. Therapy-related MDS (t-MDS) was observed in 40 pts (23%) with the remaining classified as de novo MDS (N=133; 77%). Inherited bone marrow failure syndromes were documented in 15 pts (9%), with Shwachman-Diamond Syndrome (N=4) and Fanconi anemia (N=4) being the most frequent. Using the WHO 2016 classification, the most common subtypes of MDS in both the AYA and YA cohorts were MDS with multilineage dysplasia (38% vs 19%), MDS with excess blasts-2 (MDS-EB) (24% vs 29%), and MDS-EB-1 (16% vs 20%). Similarly, using the WHO 2022 classification, the most common subtypes were MDS with low blasts (50% vs 21%), MDS with increased blasts-2 (MDS-IB-2) (24% vs 24%), and MDS-IB-1 (16% vs 18%). Stratifying pts using the IPSS-R cytogenetic (CG) risk group, the most common CG risk category identified was good CG (34% vs 52%, p=0.012). Poor/very poor CG were present in 34% and 37% of the AYA and YA groups, respectively. STAG2 and NRAS mutations occurred more frequently in the AYA pts compared to the YA group, while the YA cohort was enriched for the following mutations: TP53, DNMT3A, SF3B1, SRSF2, and TET2 (Figure 1). In the AYA population, 18 pts (38%) had very low/low, 10 (21%) intermediate, and 20 pts (42%) had high/very high risk MDS using IPSS-R. In the YA population, 32 pts (26%) had very low/low, 32 (26%) intermediate, and 57 pts (47%) had high/very high risk MDS using IPSS-R. Twenty-seven percent of pts with very low to intermediate-risk MDS using IPSS-R were upstaged to moderate high to very high-risk MDS using IPSS-M. The majority of pts (AYA: 75%; YA: 63%, p=0.5) were transfusion independent at baseline. Single-agent hypomethylating agents were the most frequently used frontline therapy, used in 17 AYA pts (34%) and 58 YA pts (48%), with more AYA pts receiving upfront allogeneic stem cell transplantation (Allo-SCT) compared to YA pts (28% vs 5%). After frontline therapy (Table 1), an additional 14 AYA (28%) and 52 YA (42%) pts received Allo-SCT. In pts with IPSS-R intermediate to very high-risk, response rates (HI+CR+mCR+mCR with HI) to frontline therapies were 46% and 54.5% in the AYA and YA groups, respectively. After median follow-up of 24 months [range, 1-218], median OS was numerically longer in the AYA versus YA group (155 vs 53 months, p=0.2). AML transformation occurred in 24% and 20% of the pts in the AYA and YA groups, respectively. Median OS was significantly longer in de novo compared to t-MDS pts (56 vs 27 months, p=0.03). Median OS among Allo-SCT compared to non-SCT pts were not reached vs 155 months ( p=0.9) in the AYA group and 53 vs 54 months ( p=0.4) in the YA group. IPSS-R (very low+low vs intermediate vs high+very high) was able to distinguish differences in OS in the YA (133 vs 53 vs 17 months, p=0.0002) and AYA (155 vs not reached vs 18 months, p=0.006) pts, with the exception of the intermediate-risk group in the AYA cohort. Conclusions: In this study, d e novoMDS was seen in the majority of younger pts with MDS (both AYA and YA). Mutations in STAG2 and NRAS were more common in the AYA pts, while YA pts had MDS more enriched for TP53, DNMT3A, TET2 and splicing mutations. This study is still ongoing with a plan to compare the abovementioned groups to older pts (≥60 years) with MDS.

Cluster of Differentiation 38 Protein Significantly Adds to the Prognostic Value of Cytogenetic Risk in Patients with Acute Myeloid Leukemia.

There is some controversy regarding the clinical significance of cluster of differentiation 38 (CD38) protein in acute myeloid leukemia (AML). We aimed to study the prognostic value of CD38 expression in relation to the standard cytogenetic risk stratification in AML patients. In this prospective study, adult patients with AML were diagnosed based on the finding of ≥ 20% blasts in the bone marrow and the flow cytometry. The control group was selected from normal bone marrow samples examined at the same period in the lab. The CD38 expression levels were assessed by immunophenotyping the bone marrow samples of the patients prior to therapy, as well as those from the controls. The subjects were N = 52 newly diagnosed adult AML patients, while n = 25 sex-and-age matched normal volunteers served as the control. The CD38 expression among AML patients ranged from 3.6% to 79.9%, significantly higher levels than in the control population (p =0.001). Positive CD38 expression was higher in AML patients with favorable cytogenetics when compared to those with intermediate and poor cytogenetics (75.0%, 57.1%, and 68.2%, respectively) (p =0.007). Median CD38 expression in AML patients was higher in the favorable cytogenetic group and lower in intermediate and poor cytogenetic groups, though lacking in significance (p =0.578). Patients with poor cytogenetic risk were associated with significantly shorter median overall survival when compared to favorable and intermediate cytogenetic risk (p =0.010). The expression of CD38 significantly adds to the prognostic value of cytogenetic risk stratification at diagnosis of AML patients.

Haploidentical vs matched unrelated donors for patients with ALL: donor age matters more than donor type.

Haploidentical hematopoietic cell transplantation (HCT) with posttransplant cyclophosphamide (PTCy) graft-versus-host-disease (GVHD) prophylaxis yields a similar overall survival (OS) to HLA-matched unrelated donor (MUD) HCT with conventional prophylaxis. Given the prognostic implications of donor age, we investigated the impact of donor age (younger [<35 years, n= 868] vs older [≥35 years, n= 418]) and donor type (haploidentical [n= 373] vs MUD [n= 913]) on OS in adult patients with acute lymphoblastic leukemia (ALL). Older donor age was independently associated with significantly poor OS, whereas donor type was not. Next, we directly compared the outcomes of a younger haploidentical donor (n= 187) vs an older MUD (n= 232). In this cohort, more patients in the haploidentical group had B-cell immunophenotype (89% vs 77%, respectively, P< .001), poor cytogenetics (61% vs 51%, respectively, P= .44), Philadelphia chromosome-negative (53% vs 48%, respectively, P= .38), received bone marrow graft (42% vs 16%, respectively, P< .001), and reduced-intensity conditioning (45% vs 23%, respectively, P< .001). In the multivariate analysis, the older MUD group was associated with a significantly higher risk of chronic GVHD, higher nonrelapse mortality (NRM), lower relapse, and poorer OS. Despite a higher risk of relapse, younger donor haploidentical HCT with PTCy prophylaxis may be preferred over older MUD HCT with conventional prophylaxis in patients with ALL due to lower NRM and better OS. Further analysis comparing the effect of donor age in haploidentical PTCy vs MUD PTCy is warranted.

A case of a Young Multiple Myeloma Patient With Poor Prognostic Cytogenetics

Multiple myeloma is a hematologic malignancy and a subtype of plasma cell dyscrasias, which accounts for 13% of all hematologic malignancies. It mainly affects older adults and is diagnosed in only 2% of the young population under the age of 40 years. This report presents a 33-year-old man diagnosed with Multiple myeloma with 4 poor prognostic specifications consisting of amplification of the 1q21, Translocation of t(4;14), deletion of the 6q21 and 13q14, along with decreased chromosome count to 44, X,-Y. Even though the combination of 4 poor prognostic cytogenetics in young patients is rare, he responded significantly to the Bortezomib regimen. He was selected as a candidate for bone marrow transplantation. The treatments get interrupted 2 days after the first session of the fifth cycle due to an undesirable COVID-19 infection. After 20 days, the symptoms return, and paraclinical findings show signs of MM relapse.

Reduced Toxicity FluBu3 Regimen Showed a Comparable Post-Transplant Outcomes to a Myeloablative BuCy Conditioing in Acute Myeloid Leukemia Patients Receiving First Allogeneic Hematopoietic Stem Cell Transplantation in MRD Negative CR1

Introduction: In a previous report, we found that post-transplant clinical outcomes were not significantly different between MAC (BuCy, CyTBI) and RIC (FluBu2TBI400) groups in AML CR1 with pre-transplant low WT1 expression. Based on this result, we expanded the use of conditioning regimen with reduced dose intensity for patients achieving deep response by minimal residual disease (MRD) assessment with available assays. FluBu3 regimen, consisting of fludarabine for 5 days (30mg/m2/day, D-6 to D-2) and busulfan for 3 days (3.2mg/kg/day, D-5 to D-3), was chosen and applied as reduced toxicity conditioning (RTC) in our institution since Jan 2017. Method: In this analysis, we compared MAC and RTC regimens; BuCy (busulfan 3.2 mg/kg/day for 4 days from D-7 to D-4 and cyclophosphamide 60 mg/kg/day for 2 days from D-3 to D-2) and FluBu3 protocols were used as MAC and RTC regimen, respectively. The inclusion criteria were set as follows: (1) adult (age ≥ 18 years) AML patients who were registered in a prospective cohort study; (2) receiving first allogeneic hematopoietic stem cell transplantation (HSCT) in CR1 between Aug 2017 and Nov 2021; (3) MRD negative at pre-transplant; (4) transplantation from either HLA-matched (8/8) sibling donor (MSD), matched unrelated donor (MUD) or 1-locus mismatched (7/8) unrelated donor (MMUD); (5) the use of either BuCy or FluBu3 conditioning. MRD negativity was defined by the absence of abnormalities in the following order; (i) <3 log reduction in RUNX1-RUNX1T1 and CBFB-MYH11, (ii) <4 log reduction of NPM1 level from diagnosis, and (iii) pre-transplant WT1 levels ≥ 250 copies for RUNX1-RUNX1T1, CBFB-MYH11, or NPM1 mutation negative AML. Peripheral blood was used as the source of stem cells in all patients, and the data was analyzed based on information available as of Jun 2022. Results: A total of 124 patients met the inclusion criteria, and 78 (62.9%) and 46 (37.1%) patients received BuCy and FluBu3 conditioning, respectively. The median age was 45 years and the patients with intermediate cytogenetics comprised the majority (71.8%). By the donor type, 64 (51.6%), 48 (38.7%) and 12 (9.7%) patients underwent MSD, MUD and MMUD transplantation. Between the two conditioning groups, patients receiving FluBu3 were older (median 39.5 vs 53 years, p<0.001) and significantly more patients in the FluBu3 group had received ATG (37.9% vs 93.5%, p<0.001). In each of the BuCy and FluBu3 groups, after median follow up of 39.5 and 53 months (p<0.001), the 2-year overall survival (OS) of 78.3% and 84.5% (p=0.358), relapse free survival (RFS) of 78.0% and 76.3% (p=0.806), cumulative incidence of relapse (CIR) of 7.7% and 21.5% (p=0.074) and non-relapse mortality (NRM) of 14.3% and 2.2% (p=0.0324) were observed. In addition, the probabilities of grade II-IV acute graft versus host disease (aGVHD) and cGVHD of moderated to severe at 2-year for BuCy and FluBu3 were 46.2% and 39.2% (p=0.306), and 59.5% and 36.0% (p=0.008), respectively. At the time of data cut-off, relapse was the main cause of HSCT failure in FluBu3 group (n=8) while NRM contributes most to HSCT failure in BuCy group (n=11). Six of 8 relapsed patients receiving FluBu3, compared to 1 out of 6 in BuCy group, had high-risk features of either poor cytogenetics or FLT3-ITD mutation. The majority of NRM in the BuCy group, 8 out of 11 cases, was due to GVHD and 4 of them received transplantation from MMUD. Conclusion: Among the AML patients in MRD negative CR1, the FluBu3 RTC regimen showed a comparable post-HSCT outcomes to a BuCy conditioing in terms of similar OS and RFS, while associated with significant reduced NRM that was offset by trend towards higher risk of relapse.

Amsa/ARA-C Followed By TBI 4 Gy or High Dose Chemotherapy Conditioning Regimens in Primary Refractory AML - Significantly Worse Outcomes in Younger Patients Conditioned with 4 Gy TBI

Background: Allogeneic stem cell transplantation (allo-SCT) plays a fundamental role in the management of acute myeloid leukemia (AML) and is generally recommended for patients with primary induction failure. The optimal conditioning regimen in preparation for SCT in this specific difficult contex has been the subject of continued controversy. Specifically, the role of total body irradiation (TBI) or chemotherapy (CT) as part of sequential conditioning, continues to be central to this debate. With improvement in CT delivery and the introduction of intravenous (IV) busulfan, the utilization of TBI has decreased in popularity. This is a retrospective, multi-center, registry-based, European Society of Blood and Marrow Transplantation (EBMT) study which aimed to compare the outcomes of allo-SCT with amsacrine (AMSA) /cytarabine (ARA-C) followed by TBI conditioning to CT-based conditioning and thus determine certain prognostic factors that could potentially aid in the decision to implement TBI into a patient's conditioning regimen in preparation for allo-SCT. Patients and Methods: For this analysis, we identified 466 adult patients (58.8% male, median age: 55 years, range: 18-75) with primary refractory AML (73.6% de novo) transplanted between the years 2001 and 2021 (median: 2013) from matched sibling donors (MSD) or matched unrelated donors (MUD: 59.2%), who had received AMSA and ARA-C conditioning followed by CT or TBI sequential conditioning. In patients with available cytogenetic data, 50% had intermediate cytogenetics and 50% had poor cytogenetics. Karnofsky score at the time of transplant was >90 in 57.8% of the patients. The majority (73.1%) received a combination cyclosporine (CSA) and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis and 92.7% underwent in vivo T-cell depletion. Results: Of the 466 eligible patients identified, 237 (50.8%) received sequential CT-based conditioning following high-dose AMSA/ARA-C with busulfan-fludarabine (BuFlu) or busulfan-cyclophosphamide-fludarabine (BuCyFlu) and 229 received sequential TBI-based conditioning following high-dose AMSA/ARA-C with a total of 4 Gy and cyclophosphamide-fludarabine (CyFlu). In univariate analysis, there was a significant difference in age between the two groups whereby patients receiving CT-based sequential conditioning were older (59.9 years vs 49.7 years, p<0.0001). Moreover, there was a significant difference in the proportions of MSD/MUD between the two groups with 67.9% being allografted from MUD in the CT group compared to 50.2% in the TBI group (p=0.0001). Given the significant interaction between age and conditioning (sequential TBI vs. CT), we stratified our sample by median age (<55 vs >= 55). In patients younger than 55 years, 2-year leukemia-free survival (LFS) was significantly higher in the CT group (51.9% vs 25.1%, p=0.002), as was overall survival (OS) (57.5% vs 38.3%, p=0.021). CT-based sequential conditioning was also associated with higher rates of grades II-IV and III-IV acute GVHD (38.1% vs 24.7%, p=0.02 and 19.8% vs 8.9%, p=0.022). In multivariate analysis, the use of TBI- vs CT-based sequential conditioning significantly influenced relapse (hazard ratio [HR] 1.98, p=0.018), non-relapse mortality (NRM: HR 2.7, p=0.038), LFS (HR 2.03, p=0.004), OS (HR 1.86 p=0.016) and acute GVHD II-IV (HR 0.45, p=0.014). Moreover, age (per 10 years) significantly impacted NRM (HR 2.42, p=0.0005), female to male donor impacted NRM (HR 2.41, p=0.032) and chronic GVHD incidence (HR 2.21, p=0.033) and in vivo T-cell depletion (TCD) impacted chronic GVHD (HR 0.32, p=0.03). In patients 55 years or older, there was no significant difference in post-allo-SCT outcome between patients who received TBI-based vs CT-based sequential conditioning. Conclusion: The above results highlight a significant difference in outcomes in AML patients receiving sequential TBI-based vs CT-based conditioning in preparation for allo-SCT according to age, whereby patients younger than 55 years had significantly worse outcomes after receiving TBI. This was not reflected in patients aged 55 years or more. Although only 4 Gy, these results emphasize the importance of age in the transplant physician's decision to incorporate TBI into conditioning regimens to optimize outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P355: MINI-HYPER-CVD PLUS INOTUZUMAB OZOGAMICIN, WITH OR WITHOUT BLINATUMOMAB, IN OLDER ADULTS WITH NEWLY DIAGNOSED B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA: UPDATES FROM A PHASE II TRIAL

Background: Blinatumomab (Blina) and inotuzumab ozogamicin (INO) improve the outcomes of patients (pts) with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). These drugs may allow for use of less chemotherapy and improve remission durations and overall survival (OS) in older pts with newly diagnosed B-ALL. Aims: To evaluate the combination of low-intensity chemotherapy and INO with or without Blina, in older pts with newly diagnosed B-ALL. Methods: Pts ≥60 years with newly diagnosed Philadelphia chromosome (Ph)-negative B-ALL were eligible to receive mini-hyper-CVD for up to 8 cycles. Initially, INO was given at 1.3-1.8mg/m2 on day (D) 3 of cycle 1 and 0.8-1.3mg/m2 on D3 of cycles 2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. POMP maintenance was given for up to 3 years. Starting with pt #50, the protocol was amended and INO was administered in fractionated doses with each of the 4 cycles of hyper-CVD (0.6 mg/m2 on D2 and 0.3 mg/m2 on D8 of cycle 1; 0.3 mg/m2 on D2 and 8 of cycles 2-4) followed by 4 cycles of blina. The cumulative doses of INO given before and after this amendment were 4.3 mg/m2 and 2.7 mg/m2, respectively. Maintenance was also amended to include 12 cycles of POMP and 4 cycles of blina (1 cycle of blina after every 3 cycles of POMP). Results: 80 pts have been treated with a median age of 68 years (range, 60-87); 30 pts (38%) were ≥70 years. 6 pts were in complete remission (CR) at enrollment and unevaluable for morphological response. Pt characteristics are summarized below (Figure 1A). The overall response rate (ORR) among 74 evaluable pts was 99% (CR, n=66; CRi, n=7). MRD negativity by flow cytometry was achieved in 61/76 pts (80%) after 1 cycle and 74/79 pts (94%) overall. The 30-day and 60-day mortality rates were 0% and 3%, respectively. Among 79 pts who achieved remission, 33 (42%) are still in ongoing remission without stem cell transplant (SCT), 31 (39%) died in remission, 11 (14%) relapsed without SCT, and 4 (5%) proceeded to SCT in first remission (1 of whom subsequently relapsed). Notably, 9 pts (11%) later developed MDS/AML, 7 of whom had a TP53 mutation. Overall, 6 pts (8%) developed VOD, 1 after allogeneic SCT. With a median follow-up of 55 months (range, 3-119), the 5-year continuous remission and OS rates were 76% and 47%, respectively (Figure 1B). Pts aged 60-69 years had better outcomes compared with pts ≥70 years (5-year OS rates: 59% vs 27%, respectively; P=0.04) and as did those without poor cytogenetics (i.e. complex, KMT2A-rearranged, low-hypodiploidy/near-triploidy) compared with poor cytogenetics (5-year OS rates: 54% and 25%, respectively; P=0.02). Deaths in remission were more frequent in pts ≥70 years compared with those 60-69 years (70% vs 35%; P=0.005). The 5-year OS rates for pts age 60-69 without poor-risk cytogenetics (n=37), age 60-69 with poor-risk cytogenetics (n=13), age ≥70 without poor-risk cytogenetics (n=24), and age ≥70 with poor-risk cytogenetics (n=6) were 69%, 39%, 36% and 0% respectively (Figure 1C). Presence of a TP53 mutation did not significantly impact OS (P=0.22). Image:Summary/Conclusion: Reduced-intensity chemotherapy plus INO, with or without blina, resulted in an ORR of 99% and a 5-year OS rate of 47% in older pts with newly diagnosed Ph-negative B-ALL. Outcomes were particularly favorable in those 60-69 years of age without poor-risk cytogenetics. Pts ≥70 years were at a higher risk of death in remission. A chemotherapy-free approach, with INO plus blina only, is therefore now being explored in this population.

Outcomes of patients with newly diagnosed acute myeloid leukemia (AML) and hyperleukocytosis.

e19029 Background: Hyperleukocytosis in AML is associated with inferior outcomes. Analyzing the factors associated with mortality in AML patients (pts) with a white blood cell count (WBC) ≥100 x 109/L can guide management and improve early mortality. Methods: We reviewed data from 129 pts with newly diagnosed AML presenting at our institution with WBC ≥100. Logistic regression models estimated odds ratios (OR) for 4-week mortality and Cox proportional hazard models estimated hazard ratios (HR) for overall survival (OS). Results: Median age was 65 years (range 23-86). 66% of pts had ECOG performance status (PS) &lt;2. Median WBC was 146 (range 100-687) and 78 pts had clinical leukostasis (CL) including renal failure in 31 pts (24%), new onset hypoxia in 29 pts (23%), headache in 19 pts (15%), chest pain in 9 pts (7%) and neurological symptoms in 3 pts (2%). 29 pts (22%) had poor cytogenetics. FLT3 and RAS pathway mutations were found in 63% and 27% of pts, respectively. Compared with pts without evidence of CL, pts with CL were less likely to have good PS (ECOG PS &lt;2, 58% vs 82%; P = 0.006), had higher 4-week (16% vs 2%; P = 0.015) and 8-week mortality (19% vs 6%; P = 0.038). Cytoreduction consisted of hydroxyurea in 124 pts (96%), cytarabine in 69 pts (54%) and leukapheresis in 31 pts (24%). Pts who underwent leukapheresis were less likely to receive cytarabine compared with pts who did not (35% vs 59%; P = 0.02); and tended to have more CL compared with pts who did not (74% vs 56%; P = 0.09). 30 pts had tumor lysis syndrome (TLS). TLS risk did not increase with WBC and was not associated with the cytoreductive modality used. 11 pts had intracranial hemorrhage (ICH): 9 pts (82%) with WBC ≥150 and 18% with WBC &lt;150 (P = 0.048). No association was observed between the incidence of ICH and the cytoreductive therapy. 4-week and 8-week mortality rates were 10% and 14%, respectively. After a median follow-up of 49.4 months [mos] (95% CI 26.2-72.6), median OS was 14.3 mos (95% CI 7-21.6), with 2-year OS of 40%. Median OS was 12.3 mos (95% CI 7.4-17.2) compared with 29 mos (95% CI 2.1-55.6) in pts with or without CL, respectively (P = 0.007). Median OS was 9.9 mos (95% CI 7.5-12.2) and 21.3 mos (95% CI 10.7-31.8) among those who did or did not undergo leukapheresis, respectively (P=0.003). Median OS was 42 mos (95% CI 14.2-69.8) compared with 8 ms (95% CI 6-10) in pts &lt; or ≥ 65 years. Conclusions: Older age, poor cytogenetics, TLS and DIC were associated with early mortality and inferior OS in pts with hyperleukocytosis. Careful monitoring of those pts with prompt cytoreduction and management of complications may help improve outcomes. [Table: see text]

Outcomes of second allogeneic stem cell transplantation and anti-relapse strategies in patients with relapsed/refractory acute myeloid leukemia: A unicentric retrospective analysis.

Second allogeneic stem cell transplantation (allo-SCT2) represents a rescue option for selected patients (pts) with relapsed/refractory (r/r) acute myeloid leukemia (AML). Still, relapse rates post-allo-SCT2 remain high and effective anti-relapse strategies and predictive biomarkers remain to be defined. We here analyzed a cohort of 41 AML patients (pts) undergoing allo-SCT2 in our center. Allo-SCT2 induced a third hematologic complete remission (CR) in 37 pts, at costs of a 36% non-relapse mortality rate. Furthermore, 19 pts eventually relapsed post allo-SCT2. Addressing relapse after allo-SCT2, 14 pts (74%) underwent cell-based anti-relapse strategies, including third allogeneic transplantation (allo-SCT3; 3/14), donor lymphocyte infusions (DLIs) combined with either 5-azacytidin and venetoclax (4/14) or chemotherapeutic agents (7/14). Notably, six of seven pts (86%) who received either allo-SCT3 or a combination therapy of DLIs, 5-azacytidine and venetoclax achieved CR despite poor cytogenetics post-allo-SCT2 (e.g., TP53). Finally, 11 of 41 pts were alive at the last follow-up (seven CR2, three CR3, one partial remission) resulting in estimated 2- and 5-year overall survival of 35% and 25%, respectively.

Age is no barrier for adults undergoing HCT for AML in CR1: contemporary CIBMTR analysis.

Acute Myeloid Leukemia (AML) has a median age at diagnosis of 67 years. The most common curative therapy remains an allogeneic hematopoietic stem cell transplantation (HCT), yet it is complicated by treatment-related mortality (TRM) and ongoing morbidity including graft versus host disease (GVHD) that may impact survival, particularly in older patients. We examined the outcomes and predictors of success in 1,321 patients aged 60 years and older receiving a HCT for AML in first complete remission (CR1) from 2007–2017 and reported to the CIBMTR. Outcomes were compared in three age cohorts (60–64; 65–69; 70+). With median follow-up of nearly 3 years, patients aged 60–64 had modestly, though significantly better OS, DFS and lower TRM than those either 65–69 or 70+; cohorts with similar outcomes. Three-year OS for the 3 cohorts was 49.4%, 42.3%, and 44.7% respectively (p=0.026). TRM was higher with increasing age, cord blood as graft source and HCT-CI score of ≥ 3. Conditioning intensity was not a significant predictor of OS in the 60–69 cohort with 3-year OS of 46% for RIC and 49% for MAC (p=0.38); MAC was rarely used over age 70. There was no difference in the relapse rate, incidence of Grade III/IV acute GVHD, or moderate-severe chronic GVHD across the age cohorts. After adjusting for other predictors, age had a small effect on OS and TRM. High-risk features including poor cytogenetics and measurable residual disease (MRD) prior to HCT were each significantly associated with relapse and accounted for most of the adverse impact on OS and DFS. Age did not influence the incidence of either acute or chronic GVHD; while graft type and associated GVHD prophylaxis were most important. These data suggest that age alone is not a barrier to successful HCT for AML in CR1 and should not exclude patients from HCT. Efforts should focus on minimizing residual disease and better donor selection.

Clinical, immunophenotypic, and cytogenetic characteristics of high-grade myelodysplastic syndromes with CD41-positive progenitor cells.

Patients with myelodysplastic syndromes (MDS) with progenitors expressing CD41 (CD41+ MDS) showed a poor prognosis in a previous study but their detailed characteristics remain unclear. One hundred thirty-seven subjects at our institution were diagnosed with excess blasts (EB)-1, EB-2, and acute myeloid leukemia with a low blast count (20%-30%). The immunophenotypes of progenitor cells in their bone marrow (BM) were determined by CD45-gating flow cytometry. A false-positive reaction to CD41 was eliminated by examining the flow cytometry data of lymphocytes and monocytes in addition to progenitors and by examining CD42b in histological sections. The characteristics were compared between CD41+ and CD41- MDS patients. Forty-three patients (31%) were CD41+. Additionally, 91% of the CD41+ MDS patients were very high-risk defined by the Revised International Prognostic Score System, which was higher than in patients with CD41- MDS (p=0.015). Approximately 60% of the CD41+ MDS patients had a monosomal karyotype and very poor cytogenetics, which was higher than in CD41- MDS patients (p < 0.001). Normal cytogenetics was less common in CD41+ patients (p=0.0016). Blasts with bleb formation were more abundant in CD41+ MDS patients (p=0.026). All CD41+ MDS patients were positive for CD13 and were mostly positive for CD33. The frequency of aberrant expression of other antigens on progenitors was similar between CD41+ and CD41- MDS patients. We determined clinical, immunophenotypic, and cytogenetic characteristics of CD41+ MDS patients. Further studies are needed to improve the survival of these patients.

Impact of Specific Adverse Cytogenetic Features on Outcomes after Allogeneic Hematopoietic Cell Transplantation in Myelodysplastic Syndrome with Very Poor Risk Cytogenetics: A Study from the Chronic Malignancies Working Party of EBMT

INTRODUCTIONMyelodysplastic Syndrome (MDS) is a heterogenous disease which is almost incurable without an allogeneic hematopoietic cell transplantation (allo-HCT). Within the revised international scoring system (R-IPSS), MDS with poor and very poor cytogenetics have a much worse outcome after allo-HCT. The very poor cytogenetic subgroup refers to patients harboring more than 3 abnormalities and is therefore a highly heterogenous group. We have shown in acute myeloid leukemia (AML) that beyond complex karyotype, specific adverse cytogenetic features such as 7q abnormalities (abn7q), 5q abnormalities (abn5q), 17p abnormalities (abn17p) and monosomal karyotype (MK) worsen the outcomes after allo-HCT. We have therefore retrospectively reviewed MDS with very poor cytogenetics and studied the impact of adverse cytogenetic features on outcomes after transplant. METHODSWe selected MDS patients who underwent allo-HCT between 2001 and 2018 from a matched related or unrelated donor, for whom a full cytogenetic report was available in the EBMT registry. We then stratified them according to the presence of abn7q, abn5q, abn17p, MK and the number of abnormalities (≤5, 6-9 and ≥10). Graft-versus-host disease (GvHD) and relapse-free survival (GRFS) was defined as survival without grade II-IV acute GvHD, extensive chronic GvHD or relapse. RESULTSA total of 154 patients were identified in the registry. One hundred twenty-three patients (81%) had MDS with excess of blasts and 4 (3%) had secondary AML. Median age was 59 years (interquartile range (IQR), 51-64) and the median follow-up was 38 months (95% confidence interval (CI), 34-60). The time from diagnosis to allo-HCT was a median of 6 months (IQR, 4-8). Two thirds of patients received a reduced-intensity conditioning regimen (N = 103, 67%) and 87 patients had a matched unrelated donor (57%). Almost all patients were in first complete remission at time of transplant (N= 149, 97%). Regarding specific cytogenetic features, 87 patients had abn7q (57%), 99 abn5q (64%), 59 abn17p (38%) and 120 MK (78%) with considerable overlap between groups.The 2-year overall survival (OS) and progression-free survival (PFS) was 34% (95% CI 26-42%) and 24% (95% CI 17-31%), respectively. The 2-year cumulative incidence of relapse and non-relapse mortality (NRM) was 59% (95% CI 51-67%) and 18% (95% CI 12-24%), respectively. The cumulative incidence of grade II-IV acute GvHD and chronic GvHD was 33% (95% CI 25-40%) and 44% (95% CI 36-53%) by day 100 and 2 years respectively. The 2-year GRFS was 12% (95% CI 6-17%). The presence of abn5q was associated with a significantly decreased PFS of 17% (95% CI 9-25%) versus 36% (95% CI 23-49%); p=0.05) and GRFS (6% (95% CI 1-11%) versus 23% (95% CI 11-34%); p=0.04). The presence of abn7q was associated with significantly increased NRM (25% (15-34%) versus 9% (2-16%); p=0.02) which did not translate into OS. There were no specific cytogenetic features that had an independent impact on the cumulative incidence of relapse, but age over 55 years did increase the relapse risk (<55: 45% (95% CI 31-59%); 55-65: 65% (95% CI 54-77%); >65: 66% (95% CI 50-83%); p=0.03). A continuous effect was also observed (per decade increase: HR=1.24, 95%CI 1.02-1.52; p=0.03). Patients with an interval of more than 6 months from diagnosis to allo-HCT had almost double the OS (45% (95% CI 32-58%)) compared to patients with an interval less than 6 months (27% (95% CI 17-37%); p=0.04), however a continuous effect was not observed. CONCLUSIONMDS with very poor cytogenetics according to R-IPSS is a very bad group with dismal outcomes after allo-HCT. Within this high-risk group, specific adverse cytogenetic features such as the number of abnormalities, abn7q, abn5q, abn17p or MK did not stratify outcomes further, except for abn5q which was associated with a decreased PFS. Our results might be explained in part by the low number patients and by the over-representation of adverse features within this cohort. Despite that, advancing age was associated with increased relapse. Whilst allo-HCT remains the best therapeutic option for this very high-risk patient group, efforts should focus on post-transplant preemptive intervention strategies to prevent relapse. DisclosuresByrne: Incyte: Honoraria. Schroeder: Celgene: Honoraria, Other: Travel support, Research Funding. Blaise: Jazz Pharmaceuticals: Honoraria. Hayden: Jansen, Takeda: Other: Travel, Accomodation, Expenses; Amgen: Honoraria. Scheid: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria; Roche: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria.

Clonal Dynamics of IDH1 Mutations in Acute Myeloid Leukemia

Introduction:Isocitrate dehydrogenase 1 (IDH1) gene is mutated in 7-14% of acute myeloid leukemia (AML) patients. IDH1 encodes for an enzyme that catalyzes the conversion of isocitrate to α- ketoglutarate. IDH1 mutation leads to accumulation of the oncometabolite 2-hydroxyglutarate. Clonal evolutionary dynamics of IDH1 mutations in AML have not been clearly characterized. The introduction of targeted small-molecule therapy, Ivosidenib, in AML treatment underscores the significance of understanding the topography of clonal dynamics in IDH1-mutated AML to optimize precision medicine.Methods:We analyzed ~6000 patients with next-generation sequencing (NGS) data and identified 107 patients with IDH1 mutated AML. Disease status was determined for each NGS test date by manual chart review. IDH1 mutation status was characterized during course of AML at diagnosis, remission, relapse, and with persistent disease. Cytogenic risk category was determined using ELN 2017 guidelines. Kaplan Meier survival analysis and log-rank test were used to determine significant differences in overall survival among patient groups.Results:Of the 107 total patients, 39 patients (36%) had AML with myelodysplastic-related changes (AML-MRC) and 39 patients (36%) had AML-NOS. The most frequently co-mutated genes were SRSF2, DNMT3A, ASXL1, RUNX1, NRAS, BCOR, STAG2, NPM1, JAK2, and FLT-3 in order of frequency. Of the total patients, 74 patients (69%) had good cytogenetics, 17 patients (16%) had intermediate cytogenetics, and 16 patients (15%) had poor/very poor cytogenetics. Among the patients with IDH1-mutated AML, 85 patients (79%) were IDH1-positive at initial diagnosis, while 22 patients (21%) were IDH1- negative at diagnosis and acquired the mutation later in disease course. Of those 22 patients, 18 patients gained the mutation in the setting of persistent disease, 3 patients at remission, and 1 patient at relapse. In those with persistent AML (n=42), 30 patients (71%) remained IDH1-positive while 12 patients (29%) lost the mutation. In those achieving remission (n=66), 12 patients (18%) who were IDH1-positive remained IDH1-positive while 51 patients (77%) cleared the mutation. In those with relapsed disease (n= 21), 17 patients (81%) with IDH1-positive AML remained IDH1-positive while 4 patients (19%) lost the mutation at relapse.There were no significant differences in median overall survival in patients who were positive or negative for IDH1 mutations at diagnosis, positive or negative with disease persistence, or among patients who remained IDH1-positive or lost the IDH1 mutation at disease relapse. Patients that were IDH1-positive at diagnosis were more likely to have poorer cytogenetics than patients who were IDH1-negative at diagnosis (p=0.0016).Conclusion:In summary, this study found that IDH1 mutations are unstable throughout the course of AML and periodic genetic testing of AML patients is necessary for optimizing precision medicine approaches. In disease remission, most patients (77%) cleared the IDH1 mutation. In the relapse setting, 81% of patients retained IDH1-positive status. Our study, the largest of its kind to our knowledge, shows that serial genomic profiling for the IDH1 mutation across disease course may be beneficial in helping to tailor targeted therapy for IDH1+ AML. DisclosuresSweet: Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sallman: Kite: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Intellia: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Incyte: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees. Hussaini: Adaptive: Consultancy, Honoraria, Speakers Bureau; Stemline: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy; Celegene: Consultancy; Decibio: Consultancy; Guidepoint: Consultancy; Bluprint Medicine: Consultancy.

Impact of Allogeneic Hematopoietic Cell Transplantation (HCT) As Consolidation Following CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy for Treatment of Relapsed Acute Lymphoblastic Leukemia (ALL)

Impact of Allogeneic Hematopoietic Cell Transplantation (HCT) As Consolidation Following CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy for Treatment of Relapsed Acute Lymphoblastic Leukemia (ALL)

Prognostic value of the revised International Prognostic Scoring System five-group cytogenetic abnormality classification for the outcome prediction of hematopoietic stem cell transplantation in pediatric myelodysplastic syndrome.

Cytogenetic abnormalities are a major risk factor for relapse after hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS). We aimed to evaluate the value of the five-group cytogenetic classification according to the revised International Prognostic Scoring System (R-IPSS) for predicting the outcome after HSCT in pediatric patients with MDS. We retrospectively analyzed the Japanese registration data of 242 pediatric patients with MDS. According to the R-IPSS classification, 112 (45.5%) patients had good, 55 (22.7%) had intermediate, 64 (26.4%) had poor, and 11 (4.6%) had very poor cytogenetics. The 5-year overall survival (5yOS) was 72%, 69%, 59%, and 30% in the good, intermediate, poor, and very poor cytogenetic subgroups (p = 0.026), respectively. The very good, good, and intermediate subgroups were grouped into a "standard" subgroup and reclassified into three subgroups (standard, poor, and very poor). Patients with very poor risk had worse 5yOS (hazard ratio 2.17, 95% confidence interval (CI) 1.02-4.61; p = 0.04) and a much higher 5yCIR (hazard ratio 2.52, 95% CI 1.05-6.04; p = 0.04) than those of patients in the standard group in the multivariate analysis, indicating that very poor risk cytogenetic characteristics independently predicted worse outcome after HSCT in pediatric patients with MDS.