Hematopoietic Stem Cell Transplantation In Complete Remission Research Articles

Survival after allogeneic transplantation according to pretransplant minimal residual disease and conditioning intensity in patients with acute myeloid leukemia.

The measurement of minimal residual disease (MRD) by multiparametric flow cytometry (MFC) before hematopoietic stem cell transplantation (HSCT) in patients with acute myeloid leukemia (AML) is a powerful prognostic factor. The interaction of pretransplant MRD and the conditioning intensity has not yet been clarified. The aim of this study is to analyze the transplant outcomes of patients with AML who underwent HSCT in complete remission (CR), comparing patients with positive MRD (MRD+) and negative MRD (MRD-) before HSCT, and the interaction between conditioning intensity and pre-HSCT MRD. We retrospectively analyzed the transplant outcomes of 118 patients with AML who underwent HSCT in CR in a single institution, comparing patients with MRD+ and MRD- before HSCT using a cutoff of 0.1% on MFC, and the interaction between conditioning intensity and pre-HSCT MRD. Patients with MRD+ before HSCT had a significantly worse 2-year (2y) event-free survival (EFS) (56.5% vs. 32.0%, p = 0.018) than MRD- patients, due to a higher cumulative incidence of relapse (CIR) at 2 years (49.0% vs. 18.0%, p = 0.002), with no differences in transplant-related mortality (TRM) (2y-TRM, 19.0% and 25.0%, respectively, p = 0.588). In the analysis stratified by conditioning intensity, in patients who received MAC, those with MRD- before HSCT had better EFS (p = 0.009) and overall survival (OS) (p = 0.070) due to lower CIR (p = 0.004) than MRD+ patients. On the other hand, the survival was similar in reduced intensity conditioning (RIC) patients regardless of the MRD status. Patients with MRD+ before HSCT have worse outcomes than MRD- patients. In patients who received MAC, MRD- patients have better EFS and OS due to lower CIR than MRD+ patients, probably because they represent a more chemo-sensitive group. However, among RIC patients, results were similar regardless of the MRD status.

Geriatric Nutritional Risk Index Is an Important Predictor of Survival in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Introduction:The body mass index (BMI) and geriatric nutritional risk index (GNRI) are nutrition-related risk assessment tool and has been used in various clinical settings. The relationship between BMI and the associated risk of hematopoietic stem cell transplantation (HSCT), such as relapse and non-relapse mortality (NRM), have been reported (Fuji S et al. BMT. 2014;49:1505). However, the relationship between GNRI and HSCT outcome remains inconclusive. We aimed to evaluate the association between GNRI and overall survival (OS), relapse, and NRM of patients who received allogenic HSCT for hematological malignancies. Methods:We retrospectively analyzed aged 16 years or older patients who underwent first allogeneic HSCT from January 2010 to December 2022 at the Jikei university hospital. The primary endpoints of this study was OS at 5 years. Secondary endpoints were NRM, the incidences of relapse, all-grade acute GVHD and chronic GVHD. Nutritional risk was evaluated both BMI and GNRI. Patients were classified into three groups based on pre-transplant BMI (underweight; BMI <18.5, overweight; BMI ≥25, and others as standard), and also classified into three groups based on pre-transplant GNRI (low-risk; GNRI>98, intermediate-risk; 92≤GNR≤98, and high-risk; GNR<92). GNRI was calculated as follows: (1.519 x serum albumin) + (41.7 x current body weight/ ideal body weight). Data on serum albumin level and body weight were collected at the beginning of conditioning regimen. Results:Two hundred and three patients who received allogeneic HSCT for hematological malignancies (acute myeloid leukemia; n=98, acute lymphoblastic leukemia; n=51, myelodysplastic syndrome; n=27, myeloproliferative neoplasms; n=8, chronic myeloid leukemia; n=18, and other leukemias; n=2) were evaluated. The median age was 52 years old (range 16-69). The median follow-up period of survivors was 1394 days (range 51-4420) after allogeneic HSCT. The donor sources consisted of 39 (19.2%) HLA-matched related donor, 50(24.6%) HLA-mismatched related donor, 26(12.8%) HLA-matched unrelated donor and 88(43.4%) HLA-mismatched unrelated donor. One hundred and nine patients (53.7%) received myeloablative conditioning regimens. Based on the BMI, underweight, standard, overweight were included 33 (16.3%), 139 (68.4%), and 31 (15.3%) patients, respectively. While, based on the GNRI, the low-risk, intermediate-risk and high-risk were divided into 105 (51.7%), 46 (22.8%), and 51 (25.2%) patients, respectively . The 5-year OS rates of standard, underweight, and overweight were 52.6%, 39.5%, and 62.1%, respectively (p=0.07). On the other hand, the 5-year OS of low-risk, intermediate-risk, and high-risk were 62.6%, 50.4%, and 33.2%, respectively (p=0.01). In addition, multivariate analysis showed high-risk group showed significantly lower OS (p=0.03). Five-year cumulative incidences (CI) of relapse in the standard, underweight, and overweight, were 46.4%, 45.4%, and 25.0%, respectively (p=0.11). However, multivariate analysis showed that CI of relapse ratio was significantly lower in overweight group (p=0.02). While, 5-year CI of relapse rates in the low-risk, intermediate-risk, and high-risk were 36.5%, 47.2%, and 52.5%, respectively (p=0.03). However, multivariate analysis showed that there were no significant differences in relapse among three risk groups (p=0.06). There were no significant differences in CI of NRM, acute GVHD and chronic GVHD either BMI or GNRI. Subgroup analysis in the patients who underwent HSCT in complete remission revealed that there was no significant difference in OS among the three BMI groups (p=0.11), as well as the three GNRI groups (p=0.06). For the patients in non-remission at the time of allogeneic HSCT, there was no significant difference in OS between the three groups in BMI; however, OS was shorter in the high-risk group in GNRI (p=0.01). Conclusions:In our study, OS of high-risk group defined by GNRI showed significantly poor , especially in non-remission patients. Although overweight defined by BMI did predict low CI of relapse, overweight did not predict OS. These results suggest that nutrition-related risk assessed by GNRI could be prognostic marker for survival in patients who received allogeneic HSCT.

A Phase II Study of Low-Intensity Chemotherapy (Mini-Hyper-CVD) and Ponatinib Followed By Blinatumomab and Ponatinib in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Background Patients with Philadelphia chromosome (Ph)-positive B-cell acute lymphoblastic leukemia (ALL) treated with Hyper-CVAD and ponatinib achieve deep responses and long-term overall survival (OS). We aim to investigate if a reduced intensity regimen of mini-Hyper-CVD (mini-HCVD) with sequential blinatumomab (blina) in combination with ponatinib may further improve outcomes while mitigating the toxicity of intensive chemotherapy and the need for hematopoietic stem cell transplantation (HSCT). Methods Patients age ≥18 years with newly diagnosed (ND) or relapsed/refractory (R/R) Ph-positive ALL, or chronic myeloid leukemia in lymphoid blast phase (CML-LBP) were eligible. Other inclusion criteria included adequate liver, renal and cardiac function, and ECOG performance status ≤2. Patients with baseline central nervous system (CNS) involvement were not excluded. All patients had BCR::ABL1 transcripts and fluorescence in situ hybridization (FISH) for t(9;22) done at baseline. Morphological analysis of FISH patterns was performed in ND patients to identify if the BCR::ABL1 signal was observed in myeloid cells (e.g., segmented neutrophils). Four cycles (C) of mini-HCVD alternating with methotrexate (MTX) + cytarabine were followed by blina 28µg/d given for four weeks every six weeks during C5-8. Patients received ponatinib 30mg daily initially, with a dose reduction to 15mg daily once in complete molecular remission (CMR). CMR was defined as undetectable BCR::ABL1 with an assay sensitivity of 0.01%. Rituximab was given for CD20-positive disease. Maintenance ponatinib, vincristine and prednisone for 15 cycles with blina + ponatinib every three cycles was given, followed by ponatinib for at least five years. All patients without CNS disease received 12 intrathecal injections of MTX or cytarabine. Results 20 patients (12 ND, 4 R/R, 4 CML-LBP) were treated between November 2019 and May 2023. Baseline characteristics are shown in Table 1. One patient with CML-LBP had received prior dasatinib while in chronic phase. The predominant BCR::ABL1 transcript was p190 in 7 (58%) ND patients. All patients achieved a complete remission (CR). Among patients in the ND, R/R, and CML-LBP cohorts, CMR was achieved in 10/12 (83%), 3/4 (75%), and 4/4 (100%) patients, respectively. In the ND cohort, six (50%) patients achieved CMR after C1 and eight (67%) after C3. Five (42%) ND patients had documented BCR::ABL1 signal in myeloid cells by FISH. Four of them achieved CMR, after C1, C3, C4 and C3 maintenance respectively. With a median follow-up of 25 months (range, 2-42), the 2-year continuous remission duration (CRD) and OS rates were 93% and 83% for the entire cohort (Figure 1), and 90% and 82% in the ND cohort, respectively. In the ND cohort, one (8%) patient had isolated CNS relapse (during C4 of maintenance with blina and ponatinib), three (25%) patients died (two in CR due to COVID-19 and one of HSCT complications), and eight (67%) patients are in remission without HSCT. No patients relapsed in the R/R cohort; one patient underwent HSCT, one patient died in CR from MTX-associated disseminated necrotizing leukoencephalopathy, and two patients are in remission without HSCT. None of the CML-LBP relapsed; one patient underwent HSCT in CR. Ponatinib dose was reduced in two patients prior to obtaining CMR (one had pancreatitis, one had cardiomyopathy). One patient switched from ponatinib to dasatinib due to a pulmonary embolism in C2. No patients required dose modification of blina. The 60-day mortality rate was 0%. Conclusion In patients with Ph-positive ALL, the combination of mini-HCVD and ponatinib followed by sequential blina and ponatinib yielded excellent outcomes with durable remissions. The toxicity profile was favorable and HSCT was avoided in most patients with ND disease. Longer follow-up is needed to confirm the durability of responses.

Outcome of hematopoietic stem cell transplantation in pediatric patients with acute lymphoblastic leukemia not in remission enrolled in JACLS ALL-02.

Hematopoietic stem cell transplantation (HSCT) is only indicated for acute lymphoblastic leukemia (ALL) patients for whom other treatments are unlikely to be curative. However, outcomes of patients not in complete remission (CR) at HSCT remain very poor. To improve the outcomes of patients receiving HSCT, it is important to obtain detailed clinical information about patients with ALL receiving HSCT in CR and not in CR. Patients enrolled in the Japan Association of Childhood Leukemia Study ALL-02 who underwent HSCT and were not in CR (non-CR patients, n = 55) were examined. The 1-year overall survival (OS) rate of non-CR patients was 27.3%. Compared with CR patients, non-CR patients experienced very early and early relapse significantly more frequently and had poorer prognostic factors. Most interestingly, high hyperdiploid (HHD) patients showed an excellent 1-year OS of 80%. In addition, long-term survival among surviving HHD patients was longer than 5years. All eight patients who survived after undergoing HSCT while not in CR were younger than 10years at initial diagnosis and were negative for central nervous system involvement. While limited, these results suggest that a subset of patients may benefit from HSCT while not in CR.

P574: CPX-351 COMBINED WITH HEMATOPOIETIC CELL TRANSPLANTATION WITH REGULATORY AND CONVENTIONAL T CELL IMMUNOTHERAPY FOR HIGH-RISK ACUTE MYELOID LEUKEMIA

Background: Patients with newly diagnosed acute myeloid leukemia with myelodysplasia-related changes (MRC-AML) or therapy-related AML (t-AML) have an extremely poor prognosis. CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin, improved significantly rates of remission and overall survival (Lancet JE et al, JCO 2018). Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative strategy for such patients, but incidence of post-transplant relapse is still unacceptably high. We developed a novel HSCT strategy that combines an age-adapted myeloablative irradiation-based conditioning regimen with regulatory and conventional T-cell adoptive immunotherapy (Treg/Tcon HSCT). HLA-haploidentical Treg/Tcon HSCT ensured low relapse rate (4%) and resulted in an unprecedented chronic graft versus host disease/relapse free survival (CRFS, 75%) in AML patients (Pierini et al., Blood Adv. 2021). Aims: We report preliminary outcomes of the combination therapy with CPX-351 and Treg/Tcon HSCT for MRC-AML and t-AML at our center. Methods: We included in the study all patients with MRC-AML or t-AML who were referred at our center from September 2019 to January 2022 and could be treated with CPX-351. Treg/Tcon HSCT consisted of a myeloablative conditioning regimen with total marrow/lymphoid irradiation, thiotepa, fludarabine and cyclophosphamide followed by an infusion of 2x106/Kg donor Tregs on day -4, 1x106/Kg Tcons on day -1 and a megadose (>6x106/Kg) of purified CD34+ hematopoietic progenitor cells on day 0. No pharmacological GvHD prophylaxis was given post-transplant (clinicaltrials.gov: #NCT03977103). Results: Seventeen patients with a median age of 57.5 years (46-72) were treated with CPX-351: 13 with newly diagnosed AML (11 MRC-AML and 2 t-AML) and 4 patients who relapsed after a previous HSCT and who acquired novel cytogenetic abnormalities (2 complex karyotypes, CK). 9/13 patients with newly diagnosed AML had karyotype abnormalities: 4 monosomy 7, 1 CK, 1 t(3;3), 1 isolated del(20q) and 2 (both t-AML) t(11;20) which resulted in NUP98-TOP1 fusion. Nine patients achieved complete remission (CR), 2 partial response (PR) and 2 had persistent disease. No patient experienced grade>3 extrahematologic toxicity. Ten/13 patients underwent a first HSCT (8 in CR, 2 in PR). Eight underwent Treg/Tcon HSCT (3 from HLA-matched, 5 from HLA-haploidentical donor), while 2 unmanipulated haploidentical HSCT followed by post-transplant cyclophosphamide (PT-Cy). All patients achieved full-donor engraftment. No patients experienced non-relapse mortality (NRM). Three/10 patients had a grade ≥ III acute GvHD; all of them are alive and off immunosuppressive therapy. At a median follow up of 16.2 months (range 9-29 months), 9/10 patients are alive and in CR with no chronic GvHD. No relapse occurred in the 8 patients who underwent Treg/Tcon HSCT, while one patient who underwent HSCT followed by PT-CY relapsed. The 4 patients who were treated after one previous HSCT received one single induction cycle with CPX-351, achieved CR and experienced no grade>3 extra-hematologic toxicity. All of them could undergo a second HSCT. NRM occurred in 1 patient (septic shock), while 3 patients are alive to date. Summary/Conclusion: CPX-351 allowed most of MRC-AML and t-AML patients to reach HSCT in CR despite high risk genetics and even when used in patients who relapsed after a 1st HSCT. Combination of CPX-351 with Treg-Tcon HSCT is safe and exert powerful antileukemic activity. Thus, it appears to be a promising strategy to ensure high rate of CRFS in very high-risk AML.

Impact of IDH1 and IDH2 mutation detection at diagnosis and in remission in patients with AML receiving allogeneic transplantation

AbstractSomatic mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) are common in acute myeloid leukemia (AML). The prognostic impact of the presence of IDH mutations may be influenced by the comutational status, the specific location of the mutation (ie, IDH1 R132, IDH2 R140, and IDH2 R172) at diagnosis, and the dynamics of the mutation burden during disease course. Even though many patients with IDH-mutated AML are consolidated by hematopoietic stem cell transplantation (HSCT), the underlying biology and prognostic consequences remain largely unknown. Here, we present a large analysis of 292 patients with AML who received HSCT in complete remission (CR) or CR with incomplete peripheral recovery (CRi), in which we assessed the IDH mutation status at diagnosis and HSCT as a potential marker for measurable residual disease (MRD). About a quarter of all patients were IDH-mutated at diagnosis. The diagnostic presence of IDH mutations in AML did not have a significant prognostic impact when consolidated with HSCT. However, IDH1 R132 and IDH2 R172 MRD positivity in remission at HSCT associated with an increased risk of relapse, while IDH2 R140 mutations did not. The IDH2 R140 variant allele frequency (VAF) at diagnosis was higher, clustering around 50%, and the mutation clearance at HSCT in morphologic remission was much lower compared with IDH1 R132 and IDH2 R172. In our cohort, IDH2 R140 mutations behaved more like a clonal hematopoiesis-related aberration, while IDH1 R132 and IDH2 R172 harbored AML disease-specific features.

Comparison of Prognostic Impact between the European Leukemia Net (ELN) 2017 Risk Classification and Pre-Transplant WT1 expression in Patients Receiving Allogeneic Transplantation for Acute Myeloid Leukemia (AML)

Background Although European Leukemia Net (ELN) risk classification was introduced in 2017 and has been applied as an important prediction tool for prognosis, there has been limited data on its value among the patients with allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the prognostic value of ENL 2017 criteria on post-HSCT outcomes and compared it with pre-HSCT measurable residual disease (MRD) status determined by Wilms tumor gene 1 (WT1) expression level.Methods: Patients who underwent HSCT and fulfilled following criteria were eligible in this current study: first HSCT in complete remission (CR) or CR with incomplete hematologic recovery and having bone marrow WT1 expression results before transplant. We found a total of 275 patients between Nov 2017 and July 2020, and we adopted the WT1 cut-off level of 250 copies per 10 4 ABL for defining MRD negative vs positive (Biol Blood Marrow Transplant. 2019;25:1925) .Results: Among 180 patients, , 110 (61%) and 70 (39%) patients were classified as a , intermediated (INT) and adverse (ADV) risk group by ELN 2017 classification. After a median follow-up of 18.3 months (range, 0.4 to 43.2 months), the Kaplan-Meier survival curve could not discriminate overall survival (OS), relapse free survival (RFS), or cumulative incidence of relapse (CIR) between the INT and ADV risk groups (p=0.2, p=0.68, p=0.061, respectively). On the other hand, we found that OS, RFS and CIR were unfavorable in MRD (+) group compared to either MRD negative INT or ADV risk group (35.8 % vs 59.1 % for OS, p=0.05; 24.7% vs 55.9% for RFS, p=0.002; 60.9% vs 20.4 % for CIR, p<0.001). We further divided the groups into 4 subgroups with incorporating pre-HSCT WT1 level: INT MRD(-), INT MRD(+), ADV MRD(-), and ADV MRD(+). Notably, the importance of MRD was more prominent in the INT risk group with showing significant differences in CIR between INT MRD(-) and INT MRD(+) group (p<0.001) in contrast to that observed between ADV MRD(-) and ADV MRD(+) groups (p=0.12). Among the 4 subgroups, patients of INT MRD(+) confers worst prognosis in regards to OS, RFS and CIR, which was even worse than those of ADV MRD(+) group.Conclusions: The ELN 2017 risk classification was not available to predict post-HSCT outcomes in INT and ADV risk group. We found that pre-HSCT MRD rather than ELN 2017 could more likely to predict post-HSCT relapse. The prognostic value of WT1 MRD was more prominent in ELN INT group compared to ADV group. A subset of INT patients had the worst prognosis if their pre-HSCT WT1 MRD remained positive, who they need additional therapeutic strategies to prevent relapse. [Display omitted] DisclosuresKim: Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; ILYANG: Research Funding; Takeda: Research Funding. Kim: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AIMS Biosciense: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AML-Hub: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; BMS & Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung Pharm Co.: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Consultancy, Honoraria; LG Chem: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Pintherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Speakers Bureau; SL VaxiGen: Consultancy, Honoraria; VigenCell: Consultancy, Honoraria.

Real-Life Experience of Sorafenib Maintenance after Allogeneic Hematopoietic Stem Cell Transplantation for FLT3-ITD AML Reveals High Rates of Toxicity-Related Treatment Interruption

Introduction: FLT3-Internal Tandem Duplication (FLT3-ITD) mutations of the gene encoding the FLT3 tyrosine kinase receptor are found in 25-30% of AML patients and are associated with a poor prognosis despite intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). FLT3 tyrosine kinase inhibitors (TKI) significantly improve survival of FLT3 mutated AML patients in large prospective trials (Stone, NEJM 2017; doi:10.1056/NEJMoa1614359). Post-HSCT maintenance with sorafenib - a broad-spectrum TKI with strong activity against FLT3 - was recently shown to reduce the risk of relapse and improve survival in the phase II SORMAIN trial (Burchert, JCO 2020; doi: 10.1200/JCO.19.03345). Importantly, clinical trials reported a low rate of toxicities requiring sorafenib discontinuation (Chen et al, BBMT 2014;doi: 10.1016/j.bbmt.2014.09.007; Burchert et al., J Clin Oncol. 2020; doi: 10.1200/JCO.19.03345). The aim of our single-center retrospective analysis was to evaluate the real-life experience in patients treated with post-allogeneic HSCT sorafenib maintenance therapy for FLT3-ITD AML with a particular focus on tolerability and toxicity-related treatment interruption. Methods: We conducted a single-center retrospective study on 33 FLT3-ITD AML patients undergoing allogeneic HSCT in complete remission between 2013 and 2020, including 20 patients who received sorafenib maintenance and 13 who did not. Sorafenib was started at hematologic reconstitution at 200 mg BID and increased at 400 mg BID after a week in case of good tolerance. Treatment was maintained until two years if tolerated. In case of toxicity, the drug was either reduced to 200mg BID, or stopped. Among the 13 patients in the untreated group, 8 were transplanted between 2013 and 2016 before we started to routinely use sorafenib maintenance, and 5 were transplanted in 2017 or later. Among the latter, sorafenib maintenance was not started because of aGVHD and insufficient hematologic reconstitution (n=3), low-allelic ratio of FLT3-ITD (n=1), early death due to PTLD (n=1). Results: In the sorafenib group (n=20), median time from transplant to sorafenib initiation was 68 days (range 40-213). Overall, 16 patients (80%) experienced toxicities leading to dose reduction (4 patients, 20%) or interruption (12 patients, 60%). In these patients, the average time on sorafenib before toxicity occurrence was 98 days (range 1-717; only one patient stopped treatment after 1 day because of severe diarrhea). Most common toxicities were skin (7, grade II), gastrointestinal (5, grade II), and hematologic (5, grade II and III). One patient experienced uveitis (grade III) and pneumonia (grade IV), both resolutive after sorafenib interruption. One patient experienced severe hypertension (grade III), 1 had hepatitis (grade III) and another one a PRESS syndrome (grade IV) possibly related to sorafenib. Other causes of sorafenib interruption included FLT3-ITD negative relapse in 1 patient, relapse in 1 patient, and end of scheduled maintenance in 1 patient. Among the 12 patients who interrupted sorafenib because of toxicities, 3 patients were re-challenged with good tolerance in 2 cases, while 7 were switched to midostaurine. Among these 7, 4 completed the 2-y treatment and 3 interrupted midostaurine because of toxicities (2 patients experienced digestive intolerance and 1 pneumonia). The average time of sorafenib exposure in the whole sorafenib group was 180 days (range 1-765). Importantly, the analysis of patients' outcome confirmed the previously reported positive impact of sorafenib maintenance on overall survival (Figure 1B) despite high rates of treatment interruption. Conclusion: Our real-life analysis reveals higher rates of toxicity-related interruption of sorafenib maintenance after allogeneic HSCT than previously reported in clinical trials. Interestingly, our results confirm the favorable impact of sorafenib maintenance on clinical outcome despite a high rate of toxicity-related treatment interruption, suggesting the feasibility of switching to other maintenance approaches in case of low tolerability. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: sorafenib as a maintenance treatment to prevent FLT3-ITD mutated AML reccurence after allogeneic transplantation

Significance of minimal residual disease monitoring by real-time quantitative polymerase chain reaction in core binding factor acute myeloid leukemia for transplantation outcomes.

Despite the well-defined role of minimal residual disease (MRD) monitoring by real-time quantitative polymerase chain reaction (RT-PCR) for RUNX1/RUNX1T1 and CBFB-MYH11 transcripts in core binding factor (CBF) acute myeloid leukemia (AML) after intensive chemotherapy, there has been a paucity of data assessing the utility of MRD monitoring at and after allogeneic hematopoietic stem cell transplantation (HSCT). Patients with CBF AML who underwent HSCT in complete remission (first or second) from January 2007 through December 2018 were included in this analysis. MRD by polymerase chain reaction at HSCT was assessed in 50 of 76 patients, and 44 (88%) had evidence of MRD (MRDpos). MRDpos patients had 3-year overall survival (OS) and leukemia-free survival (LFS) rates of 69.3% and 66.3%, respectively. Six MRD-negative patients had 3-year OS and LFS rates of 100% and 100%, respectively. Thirty-five of the 70 evaluable patients (50%) had a day +100 MRD assessment by RT-PCR, and 14 (40%) were MRDpos. The presence of MRD by RT-PCR on day +100 was not associated with lower estimates of LFS (75% vs 82.2%; P=.3) but was associated with a higher relapse incidence, although the difference did not reach statistical significance (27.6% vs 9.7%; P=.2). Durable complete remissions can be achieved in patients with CBF AML with HSCT even if they are MRDpos by RT-PCRat HSCT. The clinical impact of frequent MRD monitoring for identifying a group at high risk for early relapse and then for determining the best time point for therapeutic interventions to prevent impending relapse warrants investigation in prospectively designed clinical trials.

High BAALC copy numbers in peripheral blood prior to allogeneic transplantation predict early relapse in acute myeloid leukemia patients.

High BAALC expression levels at acute myeloid leukemia diagnosis have been linked to adverse outcomes. Recent data indicate that high BAALC expression levels may also be used as marker for residual disease following acute myeloid leukemia treatment. Allogeneic hematopoietic stem cell transplantation (HSCT) offers a curative treatment for acute myeloid leukemia patients. However, disease recurrence remains a major clinical challenge and identification of high-risk patients prior to HSCT is crucial to improve outcomes. We performed absolute quantification of BAALC copy numbers in peripheral blood prior (median 7 days) to HSCT in complete remission (CR) or CR with incomplete peripheral recovery in 82 acute myeloid leukemia patients using digital droplet PCR (ddPCR) technology. An optimal cut-off of 0.14 BAALC/ABL1 copy numbers was determined and applied to define patients with high or low BAALC/ABL1 copy numbers. High pre-HSCT BAALC/ABL1 copy numbers significantly associated with higher cumulative incidence of relapse and shorter overall survival in univariable and multivariable models. Patients with high pre-HSCT BAALC/ABL1 copy numbers were more likely to experience relapse within 100 days after HSCT. Evaluation of pre-HSCT BAALC/ABL1 copy numbers in peripheral blood by ddPCR represents a feasible and rapid way to identify acute myeloid leukemia patients at high risk of early relapse after HSCT. The prognostic impact was also observed independently of other known clinical, genetic, and molecular prognosticators. In the future, prospective studies should evaluate whether acute myeloid leukemia patients with high pre-HSCT BAALC/ABL1 copy numbers benefit from additional treatment before or early intervention after HSCT.

High Expression of ZBTB7A at Diagnosis Associated with Inferior Outcome in Acute Myeloid Leukemia Patients Receiving Hematopoietic Stem Cell Transplantation

Introduction: The transcription factor ZBTB7A regulates early differentiation of hematopoietic progenitors & has been associated with oncogenic as well as oncosuppressive functions. While it was shown that ectopic overexpression of Zbtb7a in immature lymphocytes leads to the development of an aggressive T-cell lymphoblastic leukemia, high ZBTB7A expression in cytogenetically normal acute myeloid leukemia (CN-AML) is associated with improved outcomes. Furthermore, recently a leukemogenic cooperation between RUNX1/RUNX1T1 &ZBTB7A mutations in t(8;21)-associated AML was suggested.Here, we further evaluated the complex role of ZBTB7A expression in hematopoietic malignancies by assessing its potential prognostic impact in AML pts undergoing hematopoietic stem cell transplantation (HSCT) after non-myeloablative conditioning (NMA).Methods: We analyzed bone marrow (BM) at diagnosis of 140 pts (median age 63 years [y], range 37-75y) treated at our institution between 2000 & 2015. All pts received NMA conditioning (3x30mg/m2 Fludarabine on days -4 to -1 & 2Gy total body irradiation) followed by HSCT in complete remission with (CR; n=111; 79.3%) or without peripheral hematological recovery (CRi; n=29; 20.7%). Median follow-up for pts alive was 3.5y.Our cohort included pts with CN-AML (n=62, 44.3%), complex karyotype (n=17; P=12.1%) & other cytogenetic abnormalities (n=61; 43.6%). At diagnosis mutations in the genes CEBPA, DNMT3A, IDH1, IDH2, NPM1 & the presence of FLT3-ITD were determined. In diagnostic BM cytogenetics were analyzed using standard techniques for banding & fluorescence in-situ hybridization & the expression of common surface markers was analyzed using flow cytometry. The expression of ZBTB7A was assessed using quantitative RT-PCR & normalized to ABL1 as internal control. As a cut-off the third quartile of normalized gene expression was identified to group high & low ZBTB7A expressers.Results: At diagnosis pts with a high ZBTB7A expression more often had a complex karyotype (P=.02) & were less likely to have core-binding factor AML by trend (P=.18). Additionally, high ZBTB7A levels associated with significantly fewer blasts in peripheral blood (P=.008) & BM (P=.02). The BM mononuclear cells in high ZBTB7A expressers were to a smaller extent positive for myeloid markers (CD38 P=.03; CD33 P=.11; CD13 P=.13) & exhibited a higher percentage of erythroid (Glycophorin A P=.03) as well as monocytic (CD11b P=.04; CD14 P=.01) surface markers. We did not find any statistical associations between ZBTB7A levels & the mutation status of NPM1, CEBPA, IDH1, DNMT3A or the presence of FLT3-ITD. Yet, there was a trend for more IDH2 mutations in the group of high ZBTB7A expressers (P=.18).At diagnosis a high expression of ZBTB7A associated with a significantly higher cumulative incidence of relapse (CIR; P=.002, Figure 1A). This finding also translated into a significantly shorter overall survival (OS; P=.01; Figure 1B) for AML pts with high ZBTB7A levels at diagnosis. When we restricted our analyses to CN-AML, high ZBTB7A expression remained a negative prognostic factor by trend (CIR P=.16; OS P=.11).Conclusion: Expression of ZBTB7A associated with distinct biological features & surface marker pattern in AML. This underlines the results of recent studies which identified ZBTB7A as a novel player in leukemogenesis. However, our findings are in contrast with the previously shown favorable prognostic impact of high ZBTB7A levels in a CN-AML cohort mainly treated with chemotherapy. In contract all pts included in our studies were consolidated with NMA-HSCT. Since this treatment regimen is mainly based on the graft versus leukemia effect a high ZBTB7A expression could potentially interfere with the immunological recognition of the AML blasts resulting in a reduced response to NMA-HSCT.Consequently, future functional studies & clinical trials should aim at further characterize the complex role of ZBTB7A in AML. [Display omitted] DisclosuresPoenisch:Mundipharma: Research Funding.

The Impact of Antithymocyte Globulin (ATG) Dose in Allogeneic Hematopoietic Stem Cell Transplantation with HLA Mismatched Donors

Background: Antithymocyte globulin (ATG) is usually included in conditioning regimens in hematopoietic stem cell transplantation (HSCT) from HLA mismatched donors to reduce the incidence of graft versus host disease (GVHD) and rejection. In this study, we intended to assess the clinical impact of ATG dose in HSCT from HLA mismatched donors.Patients and Methods: We retrospectively analyzed 268 consecutive patients with acute myeloid leukemia (n=159), acute lymphoblastic leukemia (n=49) or myelodysplastic syndrome (n=60) receiving busulfan based conditioning and HSCT with HLA mismatched sibling, unrelated, or haplo-identical family donors in five centers of Korea between 2005 and 2015.Results: The median age was 44.5 (range, 15-75) years. Fourty-two patients were treated with myeloablative conditioning and 226 patients with reduced intensity conditioning regimen. ATG at a total dose of 0 (n=31), 2.5-7.5 mg/kg (n = 16), 9 mg/kg (n = 164) or 12mg/kg (n=57) was given to patients according to protocol. 140 patients received HSCT in complete remission and 73 patients in relapse or refractory status. The median follow up duration for surviving patients was 33.8 (range, 2.0-100.6) months. The 3-year overall survival (OS) and event free survival (EFS) rate for all patients was 44.7% and 39.2% There was no significant difference of OS according to ATG dose (P=0.153), but ATG dose of 2.5-7.5mg/kg was significantly associated with better EFS than 0, 9 mg/kg, or 12mg/kg of ATG groups (79.1% vs. 45.4%, 38.9%, and 31.7%, respectively, P=0.038) (Table 1). In addition, ATG dose significantly affected on relapse (P=0.046). The relapse incidence in patients receiving 2.5-7.5 mg/kg of ATG was lower compared to those given 0, 9, or 12 mg/kg of ATG (6.7% for 2.5-7.5mg/kg of ATG group vs. 29.5%, 34.0%, and 46.9% for 0, 9, and 12 m/kg of ATG groups, respectively). The incidences of acute GVHD grades II-IV were 32.6%, 25.0%, 29.4% and 24.6% in patients receiving 0. 2.5-7.5, 9, and 12 mg/kg of ATG, respectively. The incidence of extensive chronic GVHD tended to be lower according to the increase of ATG dose (36.8%, 34.5%, 27.4%, and 21.1% for 0. 2.5-7.5, 9, and 12 mg/kg of ATG dose, respectively).In multivariate analysis, ATG dose of 9 mg/kg (P=0.023) and 12 mg/kg (P=0.036) was associated with shorter EFS compared to 2.5-7.5 mg/kg of ATG.Conclusion: 9mg/kg of ATG dose or more in HLA mismatched busulfan based HSCT with HLA mismatch donors increased the risk for relapse and reduced the EFS. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

CD123 redirected multiple virus-specific T cells for acute myeloid leukemia

Hematopoietic stem cell transplantation (HSCT) has been increasingly used as a curative treatment for acute myeloid leukemia (AML). However, relapse rates after HSCT in complete remission (CR) are reported between 30% and 70%. In addition, numerous studies suggested that secondary viral infection from a variety of viruses including Epstein-Barr virus (EBV), adenovirus (Adv), and cytomegalovirus (CMV) are among the most common causes of death post-HSCT. Currently, chimeric antigen receptor (CAR)-based T cells have been developed to treat AML in clinical studies, while virus-specific cytotoxic T cells (VST) have been proven to be able to effectively prevent or treat viral infection after HSCT. Thus it would be desirable to develop T cells with the ability of simultaneously targeting AML relapse and viral infection. In this article, we now describe the generation of VST cells that are engineered to express CAR for a specific AML cell-surface antigen CD123 (CD123-CAR-VST). Using Dendritic cells (DCs) pulsed with EBV, Adv, and CMV peptides as sources of viral antigens, we generated VST from A2 donor peripheral mononuclear cells (PBMC). VST were then transduced with retroviral vector encoding CD123-CAR to generate CD123-CAR-VST. We demonstrated that CD123-CAR-VST recognized EBV, Adv, and CMV epitopes and had HLA-restricted virus-specific cytotoxic effector function against EBV target. In addition, CD123-CAR-VST retained the specificity against CD123-positive AML cell lines such as MOLM13 and THP-1 in vitro. Thus our results suggested that CD123-CAR-VST might be a valuable candidate to simultaneously prevent or treat relapse and viral infection in AML HSCT recipients.

Randomized Phase II Study of Two Schedules of Flavopiridol (Alvocidib, F) Given as Timed Sequential Therapy (TST) Wtih Ara-C and Mitoxantrone (FLAM) for Adults with Newly Diagnosed, Poor-Risk Acute Myelogenous Leukemia (AML)

AbstractAbstract 186Acute Myeloid Leukemia - Therapy, excluding Transplantation: Pediatric and Adult AML TherapyF is a protein bound, cytotoxic, cyclin dependent kinase inhibitor. A prior Phase II trial of TST with FLAM, with F given by one hour bolus daily × 3 for adults with newly-diagnosed AML with poor-risk features demonstrated that the complete remission (CR) rate was 30/45 (67%) with median overall survival (OS) and disease-free survival (DFS) for CR patients being 12.6 and 13.3 months, respectively. We now compare FLAM using bolus F (50 mg/m2 daily × 3; Arm A) vs. FLAM using F given by pharmacologically-derived “hybrid” schedule (30 mg/m2 bolus over 30 min followed by 40 mg/m2 in a 4 hr infusion daily × 3; Arm B) in 70 newly-diagnosed AML patients (pts) with poor-risk features. Results: Pt demographics are presented below.Age# < 50Secondary AMLAdverse GeneticsMDS/MPDt-AMLSingleComplexFlt3ARM A (n = 36)59ü(24–78)31956133Total 24/36 = 67%Total 22/36 = 61%ARM B (n = 34)58ü(20–73)51698105Total 25/34 = 74%Total 23/34 = 68%Grade > 3 tumor lysis occurred in 4/70 (6%) with 1 death (A), 1 transient hemodialysis (A), 1 transient hyperkalemia (B), and 1 discontinuation of therapy (B). Four pts (6%) died from regimen toxicity before day 60 (1 A, 3 B). Median time for ANC >500/uL was Day 33 (range 22–71), and platelets > 50,000/uL Day 30 (21-80) for both arms. CR rate in Arm A is 23/36 (64%) including 16/24 (67%) with prior MDS and 13/19 (68%) with adverse cytogenetics and 3/3 (100%) with FLT3-ITD. CR rate in Arm B is 24/34 (71%) including 16/24 (67%) with prior MDS, 12/18 (67%) with adverse cytogenetics, and 4/5 (80%) with FLT3-ITD. As of 7/1/10, 20/23 Arm A CR pts have received chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HCT) in CR: 15/23 (65%) of these pts remain alive and in continuous CR for up to 14+ months, 2 relapsed 4 months post-HCT, and 2 died (1 FLAM consolidation, 1 HCT). Similarly, 20/24 Arm B CR pts have received chemotherapy and/or HCT in CR: 12/20 (60%) remain alive and in continuous CR for up to 18+ months. Of Arm B pts receiving FLAM consolidation, 1 relapsed at 2 months, 1 died at 8 months of cardiac failure, and 2 died during therapy. Three were unable to receive a second cycle and 1 refused. Overall, 51/70 (73%) of all pts and 40/47 (85%) of CR pts are alive 2+ - 19+ months after FLAM. Conclusions: TST with FLAM induces CR in >60% of newly diagnosed, poor-risk AML pts, including those with prior MDS and adverse genetics. There does not appear to be major difference in toxicity or responses between the two F schedules (bolus vs. “hybrid” bolus-infusion). Thus far, allogeneic HCT has been successfully undertaken in 21/47 (45%) of first CR patients, median age 57 (20-64), with 2 early relapses and 1 death from GVHD. Bolus F may be easier to administer than hybrid F and is therefore recommended for further study in newly diagnosed AML pts. These salutary results of FLAM in poor-risk pts will now be evaluated broadly in adults with AML and compared to traditional cytotoxic chemotherapy induction regimens. Disclosures:No relevant conflicts of interest to declare.