scholarly journals Acute Myeloid Leukemia Patients in Complete Remission with Positive Measurable Residual Disease Prior to Allogeneic Transplant Have Worse Outcomes, Similar to Active Disease Regardless of Conditioning Regimen Intensity and Post-Transplant Cyclophosphamide Administration

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4907-4907
Author(s):  
Pavan Tenneti ◽  
Jiaxian He ◽  
Brittany Knick Ragon ◽  
Nilay A. Shah ◽  
Jing Ai ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Peripheral Blood Stem Cell ◽  
Residual Disease ◽  
Conditioning Regimen ◽  
Single Institution ◽  
Gvhd Prophylaxis ◽  
Active Disease ◽  
Measurable Residual Disease

Abstract Introduction Allogenic hematopoietic cell transplant (HCT) for acute myeloid leukemia (AML) is a curative option in patients with intermediate/high risk disease who achieve morphologic complete remission (CR) after induction chemotherapy. Patients in CR but with positive measurable residual disease (pMRD) prior to HCT had high relapse risk(RR) (67% vs 65%) and low 3 year overall survival (OS) (26% vs 23%),similar to those with active disease in a single institution study (Araki et.al; Volume 34, Feb 1,2016, JCO). However, this study included only patients who received myeloablative conditioning (MAC) and included both peripheral blood and marrow grafts. A single institution retrospective study showed that use of MAC compared to reduced intensity conditioning (RIC) improved 3 year RR(19% v 67%; P < .001) and OS( 61% v 43%; P = .02) in patients with pMRD/CR(determined by molecular analysis of limited gene mutational panel)(Hourigan et.al. Volume 38, April 20,2020, JCO). We analyzed a cohort of AML patients that underwent either MAC or RIC followed by peripheral blood stem cell grafts and post-transplant cyclophosphamide (PTCy) based GVHD prevention regimen at our institution to determine the effect of pMRD on transplant outcomes. Methods: To evaluate the impact of pMRD on transplant outcomes, we analyzed AML patients who underwent HCT at Levine Cancer Institute between June 2014 and April 2020 with MRD testing performed within 1 month prior to HCT. MRD testing was performed at University of Washington by using multiparametric flow cytometry (MPC). The overall sensitivity of the assay is conservatively estimated as 0.1%. In our institution, all patients received MAC (Bu/Flu) or RIC (Bu/Flu or Flu/Cy/TBI) regimens followed by peripheral blood stem cell grafts and identical PTCy-based GVHD prophylaxis regimens that included tacrolimus and mycophenolate. Patient and transplant related characteristics were presented via descriptive statistics. Corresponding P-values were determined using Fisher's exact test for categorical variables and nonparametric Mann-Whitney U test for continuous variables. Relapse-free survival (RFS) and OS were estimated using the Kaplan Meier method. All statistical tests were two sided, and a P-value < 0.05 was considered statistically significant. Results From June 2014 to April 2020, 105 patients with AML underwent HCT. Eighty-three patients with MRD results were included in the final analysis - 52 (63%) with negative MRD (nMRD)/CR, 16 (19%) with pMRD/ CR and 15 (18%) with active disease (no CR). Baseline characteristics were similar except for presence of significantly greater number of high risk patients, based on ASTCT disease classification in the active disease group compared to pMRD/CR and nMRD/CR cohorts( 87% vs 19% vs 0%, P =< 0.001). Median follow up for the entire cohort was 32.7 months. RFS was superior in patients with nMRD/ CR compared to pMRD/ CR or active disease (56.4% vs 19.4% vs 35%, P= 0.005). In addition, OS was superior in nMRD/ CR compared to pMRD/CR or active disease (56.7% vs 35.2% vs 40%, P= 0.014). The use of MAC compared to RIC did not improve RFS (0% vs 32%, P= 0.018) and OS (0% vs 44%, P= 0.071) in pMRD/CR cohort. The use of MAC or RIC did not significantly impact RFS (69% vs 52%, P=0.729) or OS (61% vs 53%, P=0.739) in nMRD/CR patients. Conclusion: Our study validates the previous data that prognosis of patients with pMRD/CR (determined by MPC) prior to HCT is not significantly better than those having active disease. The outcomes were poor regardless of conditioning regimen intensity and PTCy based GVHD prophylaxis used at our institution. These patients might benefit from additional chemotherapy or targeted treatments to achieve nMRD prior to HCT and/or maintenance therapy post HCT. Patients with nMRD/CR disease had similar outcomes with MAC or RIC. This finding suggests that less aggressive conditioning regimens incorporating PTCy could be considered in a subset of patients with nMRD/CR, thereby sparing them from complications associated with MAC. Prospective trials are needed to further study these findings. Figure 1 Figure 1. Disclosures Copelan: Amgen: Consultancy. Grunwald: Astellas: Consultancy; Karius: Consultancy; PER: Other; Gilead: Consultancy; Incyte: Consultancy, Research Funding; Amgen: Consultancy; PRIME: Other; Daiichi Sankyo: Consultancy; Bristol Myers Squibb: Consultancy; AbbVie: Consultancy; Trovagene: Consultancy; Stemline: Consultancy; Pfizer: Consultancy; Janssen: Research Funding; Blueprint Medicines: Consultancy; Sierra Oncology: Consultancy; Med Learning Group: Other; Cardinal Health: Consultancy; MDEdge: Other; Agios: Consultancy.

scholarly journals Venetoclax and Azacitidine for Older Newly Diagnosed Patients with Acute Myeloid Leukemia: A Single-Institution Pilot Study Using Measurable Residual Disease to Guide Therapy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2638-2638 ◽  
Author(s):  
Amanda Winters ◽  
Jonathan A Gutman ◽  
Enkhtsetseg Purev ◽  
Brett M. Stevens ◽  
Shanshan Pei ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Residual Disease ◽  
Refractory Disease ◽  
Advisory Committees ◽  
Ras Pathway ◽  
Measurable Residual Disease ◽  
Count Recovery

Background: Venetoclax (ven) was approved for older untreated acute myeloid leukemia (AML) patients due to high response rates and durable remissions. As a participating site in the dose escalation study, we observed deeper/more durable responses in some who received >400mg ven. We also noted 16/33 discontinued azacitidine (aza) after achieving a response; 9 relapsed and 7 remained in long term remission on ven only. Based on these observations, we designed a study that hypothesized: A)Higher initial doses of ven would allow deeper/more durable responses, and B)Multi modality high sensitivity measurable residual disease (MRD) testing could identify patients able to discontinue aza and remain on maintenance ven. Methods: This is an ongoing phase 2 study (NCT03466294) of 42 untreated AML patients ≥60 who decline/are ineligible for induction. Patients have adequate organ function and white blood cell counts <25x109/L (hydrea permitted). In cycle 1, patients receive aza 75mg/m2 on days (d) 1-7 and ven, escalated from 100 to 200 to 400 to 600mg on d 1-4. Ven continues at 600mg d 5-28 and bone marrow biopsies (BMBXs) are performed on d 8 and 28. Patients who achieve morphologic remission without count recovery have up to 14 days off therapy before subsequent cycles, with growth factor support; "upgraded" responses are recorded if count recovery occurs. Non responders discontinue or receive up to two additional cycles of aza and ven 600mg. Responders who remain MRD+ by multiparameter flow cytometry (MPFC, Hematologics) and/or digital droplet PCR (ddPCR) for as many identifiable diagnostic genes as possible also receive up to 2 additional cycles of aza and ven 600mg. MRD+ responders after 3 cycles continue aza and ven 400mg until toxicity/progression. Patients who experience MRD- responses at any time stop aza and continue ven 400mg daily (Fig 1). Results: 30 patients enrolled between May 2018 and July 2019; median age is 71 (60-88), 10% evolved from MDS and 10% and 73% had intermediate and unfavorable risk disease by ELN, respectively (Table 1). 732 adverse events (AEs) occurred; 46 (6%) were serious, the most common were neutropenic fever (37%) and pneumonia (13%). The most common >grade 2 related AEs were leukopenia (53%), thrombocytopenia (44%) and neutropenia (35%); there were no related grade 5 AEs. The overall response rate was 70% (21/30; CR=19, MLFS=2). Median number of cycles to achieve best response was 1. Significant blast reductions were seen on day 8; of the 28 with interpretable day 8 BMBXs, 10 achieved MLFS on day 8. 4 completed ≥1 cycle and were refractory. An additional 4 did not complete cycle 1: 1 died of disease and 3 elected to come off therapy (all subsequently died of disease). Four (19%) responders relapsed, after a median 180 days (27-279). With median follow up of 214 days, median response duration has not been reached. 10 patients died, after a median 65 days (29-256); 1/30 died within 30 days. Median overall survival has not been reached. Of the 26 who completed ≥1 cycle, 19 were MRD- by MPFC, including 18/19 who achieved CR. Of these 26, 3 were not monitored by ddPCR: for 2 patients this was due to the absence of detectable baseline mutations and for 1 patient it was due to refractory disease. The remaining 23 had ddPCR monitoring; 3 became MRD- by this modality (Fig 2). All 3 were also MRD- by MPFC and per protocol discontinued aza and initiated ven maintenance (Fig 1). MRD negativity by both parameters occurred after cycles 1, 2 and 3, respectively. One MRD- patient relapsed after 216 days; two remain in remission after 301 and 124 days. An additional 4 who achieved MRD+ responses discontinued aza at their insistence (and in violation of the protocol); 1 relapsed after 279 days, and 3 remain in ongoing remission. Univariate predictors of refractory disease were FAB M0/M1 (OR 0.070, p=0.02) and RAS pathway mutations (OR 14.25, p=0.02). Conclusions: Higher initial doses of ven are tolerated in this population. Blast reduction occurs quickly in many patients (day 8), for this low intensity regimen. Response rates are consistent with lower doses of ven. Very deep responses, as measured by highly sensitive MRD methods (MPFC and ddPCR are capable of sensitivity up to 0.02%), are attainable. Longer follow up time will determine if higher ven doses and MRD-driven decisions related to continuation of aza result in more durable responses. Increased maturation of blasts and RAS pathway mutations are predictors for refractory disease. Disclosures Lyle: Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo Incyte: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Pollyea:Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Diachii Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia: Is It Time to Move Toward a Minimal Residual Disease-Based Definition of Complete Remission?

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2571-2571
Author(s):  
Daisuke Araki ◽  
Brent L Wood ◽  
Megan Othus ◽  
Jerald P. Radich ◽  
Anna B. Halpern ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Treatment Algorithms ◽  
Free Survival ◽  
Hazard Ratios ◽  
Minimal Residual ◽  
Active Disease

Abstract Background: Treatment algorithms for allogeneic hematopoietic cell transplantation (HCT) typically consider patients with acute myeloid leukemia (AML) in morphologic complete remission (CR) separately from those with active disease (i.e. ≥5% marrow blasts by morphology), implying distinct outcomes for these two groups. However, it is well recognized that the presence of minimal residual disease (MRD) at the time of transplantation is associated with adverse post-HCT outcomes for patients in morphologic CR. This well established effect of pre-HCT MRD prompted us to compare outcomes in patients in MRDpos CR to those with active AML who underwent myeloablative allogeneic HCT at our institution. Patients and Methods: We retrospectively studied 359 consecutive adults with AML who underwent myeloablative allogeneic HCT from a peripheral blood or bone marrow donor between 2006 and 2014. Pre-HCT disease staging included 10-color multiparametric flow cytometry (MFC) on bone marrow aspirates in all patients. MRD was identified as a cell population showing deviation from normal antigen expression patterns compared with normal or regenerating marrow. Any level of residual disease was considered MRDpos. Results: Three hundred and eleven patients (87%) were in morphologic CR at the time of transplantation, with 76 (21%) in MRDpos CR and 235 (66%) in MRDneg CR. 48 patients (13%) had active disease (7 untreated newly diagnosed AML, 16 untreated relapsed AML, and 25 refractory or relapsed AML who failed salvage therapies). Patients with MRDpos CR or active AML more often had adverse-risk cytogenetics (P=0.001) and secondary leukemias (P<0.001) than MRDneg CR patients. Patients with active AML also more often had incomplete blood count recovery before HCT than patients in morphologic CR (P<0.001). Three-year relapse estimates were 67% in MRDpos morphologic CR patients and 65% in patients with active AML, contrasted to 22% in MRDneg CR patients. Three-year overall survival estimates were 26%, 23%, and 73% in these three groups, respectively. After multivariable adjustment for age, cytogenetic risk, type of AML (de novo vs. secondary AML), pre-HCT karyotype (normalized vs. not), and pre-HCT peripheral blood counts (recovered vs. not), MRDneg CR status remained statistically significantly associated with longer overall and progression-free survival as well as lower risk of relapse compared to being in MRDpos morphologic CR or having active disease, with very similar outcomes between the latter two groups. Specifically, compared to MRDneg CR patients, the hazard ratios (95% confidence interval) for MRDpos CR patients and those with active disease were 3.68 (2.51-5.40) and 4.39 (2.56-7.53) (both P <0.001) for overall survival; for progression-free survival, corresponding hazard ratios were 4.37 (3.02-6.30) and 5.29 (3.18-8.80) (both P <0.001), whereas for risk of relapse, these estimates were 4.16 (2.68-6.44) and 4.86 (2.49-9.49) (both P <0.001), respectively. Conclusion: Outcomes for adults transplanted with morphologically detectable disease closely resemble those of MRDpos CR patients, with a cumulative relapse risk of ~65% and survival estimates of 20-25% at 3 years. This similarity held up after accounting for numerous other prognostic covariates. The resemblance in outcomes between patients with MRDpos morphologic CR and those with active disease at the time of HCT support the use of treatment algorithms that use MRD-based rather than morphology-based disease assessments. Disclosures Radich: Novartis: Consultancy, Research Funding; Incyte: Consultancy; Gilliad: Consultancy; Ariad: Consultancy. Walter:AstraZeneca, Inc.: Consultancy; Covagen AG: Consultancy; Pfizer, Inc.: Consultancy; Seattle Genetics, Inc.: Research Funding; Amgen, Inc.: Research Funding; Amphivena Therapeutics, Inc.: Consultancy, Research Funding.

scholarly journals A Prospective Phase 2 Study of Venetoclax and Low Dose Ara-C (VALDAC) to Target Rising Molecular Measurable Residual Disease and Early Relapse in Acute Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1261-1261
Author(s):  
Ing S Tiong ◽  
Sun Loo ◽  
Emad Uddin Abro ◽  
Devendra Hiwase ◽  
Shaun Fleming ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Residual Disease ◽  
Phase 2 ◽  
Advisory Committees ◽  
Early Relapse ◽  
Phase 2 Study ◽  
Measurable Residual Disease ◽  
Acute Myeloid

Abstract Introduction Rising molecular measurable residual disease (MRD) is an arbiter of clinical relapse in acute myeloid leukemia (AML). Venetoclax (VEN) is active against IDH and NPM1 mutant (mt) AML as monotherapy (Konopleva et al, 2016 and Chua et al, 2020) and can yield MRD negative remission when combined with low dose ara-C (LDAC) in patients unfit for intensive chemotherapy (DiNardo and Tiong et al, 2020). In a retrospective study, we showed that VEN in combination with hypomethylating agents or LDAC could erase rising NPM1mt MRD in 6/7 cases (Tiong et al, 2020). We now present a prospective phase 2 study of VEN and LDAC in patients with molecular MRD failure or oligoblastic AML relapse. Methods This multicenter phase 2 study stratified patients into oligoblastic relapse (marrow blasts 5-15%; Group A), or molecular MRD failure (Group B) as defined by the European LeukemiaNet (ELN) recommendations (failure confirmed by 2 interval samples) (Schuurhuis et al, 2018). Patients received VEN 600 mg (days 1-28) and LDAC 20 mg/m 2 (days 1-10). Primary objectives were morphologic or MRD response (≥1 log reduction) in groups A and B, respectively. Key secondary objectives were allogeneic hematopoietic cell transplantation (allo-HCT) realization and relapse-free (RFS) and overall survival (OS). The study had Alfred Health ethics approval (196/19). NPM1mt and other fusion transcript levels (per 10 5 ABL) from bone marrow were analyzed by RT-qPCR, IDH1 and IDH2 by Bio-Rad TM droplet digital PCR. Results The study enrolled 32 patients, with 29 evaluable (cut-off date 15/7/21). The median age of the study population was 62 years; 79% had intermediate cytogenetic risk, 66% NPM1mt, 11% FLT3-ITD and 37% IDH1/IDH2 mt. Most received prior intensive chemotherapy (93%) and 2 (7%) allo-HCT in first remission. Median interval from AML diagnosis to study entry was 12.6 months (Table 1). After a median follow-up of 7.9 months, patients had received a median of 3 cycles (range 1-14) of VEN-LDAC, with 13 patients ongoing. The main reasons for treatment cessation were allo-HCT (n=10; 34%) or donor lymphocyte infusion (n=2; 7%), treatment failure (n=3) or an adverse event (n=1). Hematologic complete/incomplete response (CR/CRi) among 11 patients with oligoblastic relapse (group A) was 73% and included: CR (n=5, 45%) or CRi (n=3, 27%), with an additional patient with morphologic leukemia-free state and 2 patients with stable disease. Overall, across both groups, median RFS and OS were not reached, estimated at 78% and 91% at 1 year, respectively. Among 18 patients with molecular MRD failure (group B) treated with VEN+LDAC, molecular response (≥1 log reduction) was achieved in 72%, and the RFS and OS were estimated at 83% and 87% at 1 year, respectively. Analysis of a sub-group of patients with NPM1mt (n=18); 6 and 12 from Groups A and B, respectively revealed the median NPM1mt transcript level at study entry to be 8985 copies (IQR 826, 94,431). A molecular response was achieved in 14 (78%) patients, including 9 (50%) with complete molecular remission (CR MRD-), with most responses achieved within 2 cycles of therapy (Figure B). Treatment with VEN-LDAC was generally well tolerated, with 15 serious adverse events reported within the first 2 cycles, including infection (n=6; 19%) and febrile neutropenia (n=3; 9%). Only one subject discontinued treatment due to stroke. Conclusions In this prospective study, in patients with first oligoblastic relapse or MRD failure, VEN in combination with LDAC induced a high rate of molecular MRD remission that was rapidly achieved, resulting in a high rate of survival at 12-months (&gt;90%) and with low toxicity. Follow-up is ongoing to determine the durability of response. Treatment of patients with MRD or early clinical failure may represent an attractive clinical trial setting for investigation of novel, non-intensive AML therapies. This approach will be investigated in a future multi-arm, precision-based platform trial called INTERCEPT (Investigating Novel Therapy to Target Early Relapse and Clonal Evolution as Pre-emptive Therapy in AML). Figure 1 Figure 1. Disclosures Tiong: Servier: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Pfizer: Consultancy. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Fleming: Amgen Inc: Research Funding. Bajel: Amgen: Speakers Bureau; Abbvie, Amgen, Novartis, Pfizer: Honoraria. Fong: Amgen, BMS: Speakers Bureau; Amgen: Research Funding; AbbVie, Amgen, Novartis, Pfizer, Astellas: Honoraria. Wei: Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Macrogenics: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: This presentation will discuss the use of venetoclax in targeting measurable residual disease and early relapse of acute myeloid leukemia.

scholarly journals Comparison of Acute Myeloid Leukemia Measurable Residual Disease Detection By Flow Cytometry in Peripheral Blood and Bone Marrow

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2729-2729
Author(s):  
Colin D. Godwin ◽  
Yi Zhou ◽  
Megan Othus ◽  
Carole M. Shaw ◽  
Kelda M. Gardner ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Correlation Coefficient ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Residual Disease ◽  
Spearman Correlation ◽  
Advisory Committees ◽  
Measurable Residual Disease ◽  
Acute Myeloid

BACKGROUND: The current recommendation against the need for bone marrow aspiration (BMA) in routine follow-of persons with acute myeloid leukemia (AML) in remission preceded the recognition that multiparameter flow cytometry (MFC) is a sensitive and specific means to detect imminent morphologic relapse. Given this recognition, we wondered whether BMA is now necessary, or if concordance between MFC results in peripheral blood (PB) and BMA is such as to make BMA unnecessary, at least for evaluation of measurable residual disease (MRD) by MFC. Previous studies have demonstrated a strong correlation between disease detection by MFC in PB and BMA. Here we examined 724 paired PB and BMA samples from 482 patients to further examine the concordance between PB and BMA blast detection by MFC, particularly among patients in morphologic remission. PATIENTS AND METHODS: We included adults in our institutional AML database, covering 2008-2018. Our Hematopathology database was queried to identify PB and BMA MFC sample pairs with samples considered "paired" if measured within one week of each other. If an individual had multiple pairs, all were included unless otherwise specified. Ten-color MFC was performed routinely on BMA aspirates with a panel of three antibody combinations, with the same antibody combinations applied to PB samples. When identified, the abnormal population was quantified as a percentage of the total CD45+ white cell events. Any level of residual disease was considered positive. Complete remission (CR) and relapse were defined according to the European LeukemiaNet 2017 classification. Relationship between PB and BMA blast % was measured using Spearman's Rank-Order Correlation. Relationship between PB and BMA samples identified as positive or negative is illustrated using 2 X 2 tables (Table 1). RESULTS: Considering all 724 sample pairs, the Spearman correlation coefficient between PB and BMA blast percentage was 0.93, and was 0.91 considering only the first sample pair for each individual patient (n= 482). 315 sample pairs were positive by PB, 97% of which were also positive by BMA while 95% of 409 pairs negative by PB were also negative by BMA. Similar results were seen considering only a patient's first pair. Restricting analysis to patients with pairs obtained between the dates of CR and relapse, the Spearman correlation coefficient was 0.82 with 91% of 35 cases positive in PB also positive in BMA; 93% of 114 pairs negative in PB were also negative in marrow. As a complementary means to compare pairs when AML burden was low, we examined only pairs where the BMA MFC showed <5% blasts. Here, the Spearman correlation coefficient between PB and BMA blasts was 0.83. 90% of 70 positive PB cases were also positive by BMA while 95% of 295 negative PB cases were also negative by BMA. Examining pairs taken from patients in morphologic remission immediately prior to undergoing hematopoietic cell transplant yielded a Spearman correlation coefficient of 0.92, with all 9 PB positive cases also being positive in BMA and 96% of PB negative cases being negative in BMA. CONCLUSIONS: This is the largest cohort of AML PB and BMA sample pairs analyzed by MFC to-date. The percentages of blasts measured in PB and BMA are strongly correlated. In the 365 pairs from patients with MRD-level disease, the predictive value of PB MFC positivity for BMA positivity was 90% (63/70) while the predictive value PB MFC negativity for BMA negativity was 95%. Disclosures Othus: Glycomimetics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Gardner:Abbvie: Speakers Bureau. Walter:BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding; Argenx BVBA: Consultancy; Aptevo Therapeutics: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Astellas: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership.

scholarly journals Loss of Plasmacytoid Dendritic Cell Differentiation Is Highly Predictive for Persistent Measurable Residual Disease and Poor Outcomes in Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1523-1523
Author(s):  
Wenbin Xiao ◽  
Aaron D Goldberg ◽  
Christopher Famulare ◽  
Sean Delvin ◽  
Minal Patel ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Residual Disease ◽  
Advisory Board ◽  
Post Induction ◽  
Equity Ownership ◽  
Poor Outcomes ◽  
Measurable Residual Disease ◽  
Acute Myeloid

Abstract Background Measurable residual disease (MRD) is associated with inferior outcomes in patients with acute myeloid leukemia (AML). MRD monitoring enhances risk stratification and may guide therapeutic intervention. Post-induction MRD is frequently cleared with further therapy and the clearance may lead to better outcomes. In contrast, persistent MRD is associated with poor outcomes. At present it is not possible to predict which patients are likely to clear MRD with further therapy. Here we report a simple, objective, widely applicable and quantitative MFC approach using the ratio of blast/PDC to predict persistent MRD and poor outcomes in AML. Patients and Methods A cohort of 136 adult patients with a confirmed diagnosis of AML by WHO criteria who underwent standard induction therapy at a single center between 4/2014 and 9/2017 was initially included. 69 patients achieved complete morphologic remission (36 MRD-neg. and 33 MRD-pos.). MRD status was assessed by MFC using a different from normal (DfN) approach. PDC were quantified as the percent of total WBC by flow cytometry based on low side scatter, moderate CD45, CD303, bright CD123 and HLA-DR expression. Results The proportion of PDC was markedly decreased in patients with AML (≥20% blasts) (N=136) with a median of 0.016% (interquartile range IQR: 0.0019%-0.071%, Figure 1A), more than 10-fold lower than observed in normal controls (median 0.23%, IQR 0.17%-0.34%) (N=20). While there was no difference between MRD-neg. and normal control groups (median 0.31%, IQR: 0.17%-0.49%; vs. 0.28%, IQR: 0.17%-0.34%), MRD-pos. group had significantly reduced PDC proportion compared to the control (median 0.074%, IQR: 0.022%-0.33%, Wilcoxon rank sum, p=0.019). In an attempt to achieve better separation and to eliminate possible effects of hemodilution, the ratio of blast/PDC was calculated by using the proportions of blasts and PDCs out of total WBCs as quantitated by flow cytometry. A cut-off threshold of the blast/PDC ratio of 10 was chosen to separate each group (Figure 1B). Importantly, a ratio cut-off of 10 had a corresponding specificity of 97.4% for predicting MRD positivity status. MRD positivity was significantly associated with inferior overall survival (OS) and relapse-free survival (RFS) in our study cohort (OS HR 4.11 (95% CI: 1.30-13.03), p=0.016; RFS HR 4.20 (95% CI: 1.49-11.82), p=0.007, Figure 1C and D). The 2-year cumulative incidence of relapse in the MRD-neg. group compared to MRD-pos. group was 10% (95% CI: 2-24%) vs. 37% (95% CI: 18-56%, p=0.014). Importantly, blast/PDC ratio ≥10 was also strongly associated with inferior OS and RFS (OS HR 3.12 (95% CI: 1.13-8.60), p= 0.028; RFS HR 4.05 (95% CI: 1.63-10.11), p=0.003, Figure 1E and F), which is similar in magnitude to MRD positivity. Furthermore, MRD-pos. patients with blast/PDC ratio <10 had 4 times higher MRD clearance rate than MRD-pos. patients with a ratio ≥10 (6/11, 55% vs 2/17, 12%, Fisher exactp=0.02). Conclusion We have established an objective and quantitative MFC method to risk stratify post induction AML patients by risk for relapse, MRD clearance and likelihood of survival. Loss of PDC correlates with residual leukemia, is highly specific for MRD positivity in post-induction patients, and strongly predicts poorer overall survival and higher likelihood of relapse. Loss of PDC also predicts persistent MRD in post-induction MRD-pos. patients despite further therapy, suggesting that MRD-pos. patients with normal PDC may benefit from further therapy prior to transplant, while MRD-pos. patients with loss of PDC may not. Figure 1. Figure 1. Disclosures Goldberg: AROG: Research Funding; Pfizer: Research Funding; Celgene: Consultancy. Geyer:Dava Oncology: Honoraria. Levine:Isoplexis: Equity Ownership; C4 Therapeutics: Equity Ownership; Gilead: Honoraria; Qiagen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Prelude: Research Funding; Imago: Equity Ownership; Roche: Consultancy, Research Funding; Loxo: Consultancy, Equity Ownership; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Epizyme: Patents & Royalties; Janssen: Consultancy, Honoraria. Tallman:BioSight: Other: Advisory board; AROG: Research Funding; AbbVie: Research Funding; Cellerant: Research Funding; ADC Therapeutics: Research Funding; Orsenix: Other: Advisory board; Daiichi-Sankyo: Other: Advisory board.

scholarly journals Clonal Hematopoiesis and Its Implications for Flow Cytometric Assessment of Measurable Residual Disease in Patients with NPM1-mutated Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 38-39
Author(s):  
Sanam Loghavi ◽  
Courtney D. DiNardo ◽  
Koichi Takahashi ◽  
Rashmi Kanagal-Shamanna ◽  
Tomoyuki Tanaka ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Residual Disease ◽  
Advisory Committees ◽  
Clonal Hematopoiesis ◽  
Hla Dr ◽  
Measurable Residual Disease ◽  
Acute Myeloid ◽  
Myeloid Progenitors

INTRODUCTION: NPM1 mutations (NPM1mut) occur in ∼30% of acute myeloid leukemia (AML) and frequently co-occur with mutations in other genes including those attributed to clonal hematopoiesis (CH) including DNMT3A and TET2, among others. CH mutations may persist beyond attaining NPM1mut-negative remission. Persistent CH may be associated with immunophenotypic alterations in myeloid progenitors detected by flow cytometry (FC) which poses an interpretive challenge in assessment of measurable residual disease (MRD) by FC. The aim of this study was to characterize the immunophenotypic alterations associated with persistent CH in the setting of NPM1mut clearance and to determine their possible clinical or biologic significance. METHODS: The cohort included 67 consecutive patients (pts) with NPM1mut AML treated at our institution between 01/2017 and 11/2019. FC assessment for MRD was performed an eight-color panel using FACSCanto II instruments (BD Biosciences, San Diego, CA) with a sensitivity of 10-3 to 10-4. Whole bone marrow (BM) DNA was interrogated for mutations with an 81-gene myeloid next-generation sequencing (NGS) panel using an Illumina MiSeq sequencer (Illumina, Inc., San Diego, CA, USA) with a sensitivity: 1% variant allelic frequency (VAF). RESULTS: Pts included 26 men and 41 women with a median age of 64 (range, 19-84) years with newly diagnosed NPM1mut AML. AML blasts had the following immunophenotype at baseline: promyelocytic-like phenotype (CD34-, CD117+, HLA-DR-) in 18 (27%), aberrant myeloid CD34-/CD117+/HLA-DR+ in 15 (22%), aberrant myeloid CD34+ in 13 (19%), myelomonocytic in 11 (16%), and monocytic in 10 (15%) cases. All pts had additional co-mutations at baseline (Fig 1). The most frequently co-mutated genes were DNMT3A (58%) FLT3 (51%), TET2 (27%), IDH2 (24%), PTPN11 (19%), IDH1 (18%), NRAS (16%), and SRSF2 (12%). Pts were treated with intensive (35;52%) and non-intensive induction regimens (32; 48%) (Fig 1); 22 (33%) received an allogeneic hematopoietic stem cell transplant as post-remission consolidation. We compared FC and NGS results in follow-up samples in pts achieving NPM1mut negative remission with adequate data available for comparison (n=50). 13 (26%) pts cleared all mutations whereas 37 (74%) had persistent CH. The most common mutations in the setting of residual CH involved DNMT3A (70%), TET2 (27%), IDH2 (19%) and IDH1 (11%). Among 37 pts with residual CH, 19 (51%) had no phenotypic alterations detected by FC while 17 (49%) had myeloid progenitors with alterations in intensity of antigen expression (increased CD13, CD123, CD117 and/or decreased CD38) or deviation from normal maturation but not diagnostic for AML MRD (herein referred to as pre-leukemic (PL) phenotype); 1 sample was MRD+ by FC. Mutation VAF of ≥5% was significantly more common (p=0.008) in cases with FC PL+ (100%) vs cases with normal FC phenotype (63%). IDH2 and SRSF2 mutation were exclusively observed in PL+CH+ cases with the former being statistically significant when compared with the FC-normal group (p=0.016). PL phenotype by FC did not correlate with intensity of induction therapy (41% treated with intensive regimens vs 59% non-intensive). The CH+/PL+ cohort had more pts ≥60 yrs old (67%) but the difference was not significant. There was no significant association between PL+ and residual mutation count. Presence of PL+ phenotype was not associated with a shorter relapse-free survival (RFS) (median not reached for both groups). CONCLUSIONS: Post-remission clonal hematopoiesis in the setting of NPM1mut clearance is common, and may result in immunophenotypic changes in myeloid progenitors, posing interpretive challenges for MRD assessment by FC. These alterations may be attributable to specific CH characteristics, such as IDH2 and SRSF2 mutations and VAF, but are not associated with a shorter RFS and thus should not be interpreted as residual AML or considered a high-risk attribute. Additional studies in other AML subtypes are warranted to further delineate these changes and their clinical significance. Figure 1 Disclosures DiNardo: Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Takeda: Honoraria; Jazz: Honoraria; ImmuneOnc: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Syros: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; MedImmune: Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Short:AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding; Amgen: Honoraria; Astellas: Research Funding. Kadia:JAZZ: Honoraria, Research Funding; Ascentage: Research Funding; Astra Zeneca: Research Funding; Incyte: Research Funding; Celgene: Research Funding; Novartis: Honoraria; Cyclacel: Research Funding; Genentech: Honoraria, Research Funding; Amgen: Research Funding; Abbvie: Honoraria, Research Funding; Cellenkos: Research Funding; Pulmotec: Research Funding; Astellas: Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Konopleva:Sanofi: Research Funding; Eli Lilly: Research Funding; AstraZeneca: Research Funding; Rafael Pharmaceutical: Research Funding; Amgen: Consultancy; F. Hoffmann La-Roche: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Kisoji: Consultancy; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Ascentage: Research Funding; Calithera: Research Funding; Forty-Seven: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Cellectis: Research Funding; Agios: Research Funding; Ablynx: Research Funding. Kantarjian:Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria; Ascentage: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Ravandi:Macrogenics: Research Funding; Celgene: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding.

scholarly journals Clearance of Somatic Gene Mutations in Patients with Acute Myeloid Leukemia Prior to Allogeneic Hematopoietic Cell Transplantation (HCT) Predicts Outcome

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4621-4621
Author(s):  
Onyee Chan ◽  
Chetasi Talati ◽  
Hannah Asghari ◽  
Nelli Bejanyan ◽  
Hany Elmariah ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Conditioning Regimen ◽  
Gene Mutations ◽  
Advisory Committees ◽  
Somatic Gene ◽  
Line Of Therapy

Background: In recent years, genomic studies have uncovered a number of driver gene mutations in acute myeloid leukemia (AML). There is great interest in leveraging residual disease detection methods including next-generation sequencing (NGS) to predict outcomes, especially in the setting of allogeneic hematopoietic cell transplantation (HCT). One study showed measurable minimal residual disease (MRD) at the time of HCT increases the risk of relapse in patients who received a reduced-intensity conditioning (RIC) regimen (Hourigan et al. 2019). In this study, we evaluate the prognostic impact of somatic mutation clearance using NGS prior to HCT in patients with AML. Methods: We identified a total of 139 patients with AML who underwent HCT at the Moffitt Cancer Center (2013-2018). Using European LeukemiaNet (ELN) criteria, patients were included if at the time of HCT they were adverse risk in complete remission (CR)1, intermediate risk in CR1, favorable risk in CR1 if indication for transplant present, or favorable risk in CR2 with at least one time point when NGS was performed before and after HCT. We utilized clinical data captured by BMT Research and Analysis Information Network (BRAIN). Molecular testing via NGS included 54-gene TruSight Myeloid panel tested on Illumina sequencers with a lower limit of detection of 5%. Positive persistent detectable disease (PDD) was defined as presence of detectable mutations on NGS at HCT. Univariate and multivariate analyses were conducted using log-rank and Cox regression, respectively. Kaplan-Meier analysis was used to estimate overall survival (OS) and relapse free survival (RFS) from the time of diagnosis. Cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were calculated by the Fine and Gray model. Results: Of the 139 patients (74 males/65 females), 59% were PDD positive at HCT and 41% PDD negative at HCT. Median age at HCT was 59 years. More patients were in ELN-defined adverse risk (46.8%) in comparison to intermediate risk (35.3%) or favorable risk (18%). In both cohorts, majority of the patients had 1 line of therapy prior to HCT. Overall, 57.6% of patients received myeloablative conditioning regimen (MAC) with the remaining receiving RIC. More patients received MAC in both PDD positive at HCT and PPD negative at HCT groups (Table 1). There were 35 patients (25.2%) who relapsed after HCT, and 17 had NGS available at diagnosis, at the time of HCT, and at relapse. The mutation frequencies and changes over time are shown in Figure 1. Univariate analysis showed inferior OS in patients who are PDD positive at HCT compared to PDD negative at HCT (HR 1.98, 95% CI 1.06-3.72, p=0.032). After adjusting for ELN risk and PDD status, the patients who received more than 1 line of therapy prior to HCT had significantly worse OS (p=0.005). Patients with negative PDD at HCT had a significantly better OS at 2-year compared to PDD positive at HCT patients, 78.7% vs. 62.4% (p=0.029) with a median follow up of 29.9 months (Figure 2A). The RFS at 2-year were 72.6% for PDD negative at HCT patients and 51.8% for PDD positive at HCT patients (p=0.090). There was no difference in NRM or CIR between these two groups (p=0.605 and p=0.136, respectively). Further subgroup analysis did not find a significant difference between PDD status and different types of conditioning regimen (Figure 2B). Conclusions: In this study, we report that clearance of somatic gene mutations in AML patients prior to HCT confers better outcomes compared to those with measurable PDD at HCT. There is a survival advantage in patients who received fewer lines of treatment prior to HCT. Larger cohort and greater depth of NGS coverage is needed to better clarify the impact of conditioning regimen in this population. Disclosures Talati: Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Honoraria; Agios: Honoraria. Bejanyan:Kiadis Pharma: Other: advisory board. Komrokji:JAZZ: Consultancy; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau. Kuykendall:Janssen: Consultancy; Incyte: Honoraria, Speakers Bureau; Abbvie: Honoraria; Celgene: Honoraria. Lancet:Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding. Sallman:Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Research Funding; Incyte: Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau. Sweet:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Pfizer: Consultancy; Incyte: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy; Jazz: Speakers Bureau.

Prospective Phase II Multicenter Study of Conditioning with Treosulfan, Fludarabine and Low-Dose (2 Gy) Total Body Irradiation Followed by Hematopoietic Cell Transplantation From Related or Unrelated Donors for Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 963-963 ◽  
Author(s):  
Boglarka Gyurkocza ◽  
Jonathan Gutman ◽  
Eneida R. Nemecek ◽  
Eileen Sickle ◽  
Merav Bar ◽  
...  
Keyword(s):  
High Risk ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Low Dose ◽  
Residual Disease ◽  
Conditioning Regimen ◽  
Intermediate Risk ◽  
Free Survival ◽  
Off Label ◽  
Relapse Rates

Abstract Abstract 963 Background: We showed previously that a transplant conditioning regimen of treosulfan combined with fludarabine was associated with low non-relapse mortality (NRM) and a high probability of survival in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) with low or intermediate risk cytogenetics (Nemecek et al, BBMT 2011). Relapse rates were high, however, in patients with high-risk cytogenetics, which resulted in a 2-year relapse-free survival of 39% in this group. Objective: The objective of the present study was to reduce the relapse incidence and improve overall survival (OS) in patients with high-risk AML or MDS by adding low-dose TBI (2 Gy) to the treosulfan plus fludarabine regimen. Patients and methods: Ninety-six patients with AML (n=60) or MDS (n=36) were enrolled. Patients were 60 years of age or younger (median age: 50 years) and had high-risk MDS, unfavorable or intermediate-risk AML in first complete remission (CR) or any AML beyond first CR. Cytogenetic risk in AML was stratified using the Southwest Oncology Group criteria, while the World Health Organization-based Prognostic Scoring System was used in patients with MDS. Patients received intravenous (IV) treosulfan, 14 g/m2/day on days -6 to -4, IV fludarabine 30 mg/m2/day on days -6 to -2, and 2 Gy TBI on day 0, followed by infusion of marrow (n=11) or peripheral blood stem cells (n=85) from related (n=27) or unrelated (n=69) donors. Donors were single HLA allele-level mismatched in 9 patients and HLA-matched at the allele level in 87 patients. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate (10 mg/m2 on days +1, +3, +6 and +11 post-HCT) and tacrolimus (days –1 to +180). Results: All evaluable patients engrafted. With a median follow-up of 12.8 (range, 0.2 – 34.7) months in surviving patients, the estimated 2-year progression-free survival and OS were 59% and 68%, respectively. The cumulative incidences of relapse or progression and NRM at 2 years were 30% and 11%, respectively (Figure 1). The incidences of grade II (grades III-IV) acute and extensive chronic GVHD at 2 years were 48% (11%) and 40%, respectively. Relapse occurred in 39% of patients with AML and 18% of patients with MDS (Figure 2A). OS was 61% among patients with AML and 79% in patients with MDS (Figure 2B). In univariate analyses, cytogenetic risk status did not impact relapse for the entire cohort nor for patients with AML or MDS analyzed separately (Figures 3A and 3B). As a result, 2-year OS rates were similar in patients with favorable/intermediate and unfavorable cytogenetic risk AML (64% and 57%, respectively) or in good/intermediate and poor risk MDS (88% and 71%, respectively). Patients with AML with minimal residual disease (MRD; n=10) or in refractory relapse (n=4) at the time of HCT, had higher relapse rates (87% vs. 25%) and lower OS (25% vs. 81%) at 2 years than patients in remission without MRD at the time of HCT. Conclusions: In summary, treosulfan, in combination with fludarabine and low-dose TBI was an effective conditioning regimen for allogeneic HCT in patients with AML (in CR at the time of HCT) or MDS. Relapse and OS rates in patients with high-risk cytogenetics did not differ significantly from those in patients with low or intermediate risk karyotypes. The relapse rate was particularly low in patients with MDS, including those with high risk cytogenetics, and further trials with treosulfan-based regimens are warranted. For patients with AML who have residual disease at HCT novel regimens need to be developed. The data suggest that in patients with AML high risk as defined by cytogenetics had a different impact on outcome than high risk as defined by other parameters, such as tumor burden. Disclosures: Gyurkocza: medac GmbH, Hamburg, Germany: Research Funding. Off Label Use: Off-label usage of treosulfan, fludarabine, methotrexate and tacrolimus will be discussed. Sickle:medac GmbH, Hamburg, Germany: Research Funding. Baumgart:medac GmbH, Hamburg, Germany: Employment. Deeg:medac GmbH, Hamburg, Germany: Research Funding.

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