Molecular Predictors of Outcome in Patients with MDS and AML Following MDS after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 912-912 ◽  
Author(s):  
Michael Heuser ◽  
Christian Koenecke ◽  
Razif Gabdoulline ◽  
Patrick Löffeld ◽  
Vera Dobbernack ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cell ◽  
High Risk ◽  
Complete Remission ◽  
Research Funding ◽  
Prognostic Impact ◽  
Complex Karyotype ◽  
Hematopoietic Stem ◽  
Signal Transducers ◽  
Active Disease

Introduction: The landscape of molecular aberrations in patients with myelodysplastic syndromes (MDS) has been well characterized and has identified ASXL1, BCOR, CUX1, IDH1, IDH2, SRSF2, RUNX1, U2AF1, TP53 and others as negative prognostic markers for overall survival (OS). We comprehensively investigated the prognostic impact of genetic aberrations in the context of allogeneic hematopoietic stem cell transplantation (alloHSCT) in a large cohort of patients with high risk MDS or secondary AML following MDS (sAML). Patients and Methods: 308 Patients with a diagnosis of MDS (47.4%) or sAML (52.6%) who received an alloHSCT at four German university medical centers and for whom genomic DNA was available at a time with active disease before transplantation were evaluated for the presence of mutations in 54 genes by Illumina high-throughput sequencing. Results: At least one mutation was identified in 82% of our patients with a median number of 2 mutations per patient. The most frequently mutated genes were ASXL1 (24.4%), DNMT3A, (23.1%), RUNX1 (16.9%), TET2 (16.9%), STAG2 (12%), TP53 (11.7%), and SRSF2 (11%) in agreement with previous reports. Mutation frequencies were similar between MDS and sAML patients for all mutated genes except SRSF2, TET2 and WT1, which were more frequently mutated in sAML. We grouped the mutated genes into functional classes and found that patients most frequently had mutations in modifiers of DNA methylation (42.2%), followed by chromatin modifiers (41.5%), splicing genes (31.1%), transcription factors (30.8%), signal transducers (28.8%) and tumor suppressors (14.6%). Mean variant allele frequencies were highest in modifiers of DNA methylation (33.2%), while signal transducers had the lowest allele frequency (20.4%). We next assessed the prognostic impact of gene classes and individual genes on outcome of patients after alloHSCT. Median follow up from transplantation was 4.15 years. Median patient age at time of HSCT was 58 years (range 19-75). 76 patients (25%) werein complete remission and 232 patients (75%) had active disease before transplantation. Low, intermediate, and high risk cytogenetics according to IPSS were found in 116 (38%), 59 (19%), and 115 (37%) patients, respectively. Matched and mismatched related donor HSCT was performed in 71 and 4 patients, respectively (23.1 and 1.3%), and matched and mismatched unrelated donor HSCT in 171 and 62 patients, respectively (55.5 and 20.1%). The six functional gene classes had no prognostic impact on survival, cumulative incidence of relapse and non-relapse mortality. We therefore evaluated the prognostic impact of individual gene mutations, of aberrations of chromosomes 3, 5, 7, 8, 17, 20 or a complex karyotype, and of transplant characteristics on OS. Parameters with significant impact on OS in univariate analysis were included in a multivariate cox proportional hazards model. Significant predictors of OS in multivariate analysis were mutations in PTPN11 (HR 3.1, present in 2.3% of pts.), IDH2 (HR 2.6, present in 4.2%), PHF6 (HR 2.2, present in 4.9%), NRAS (HR 1.8, present in 7.5%), presence of a complex karyotype (HR 1.8, present in 16.6%), transplantation from haploidentical donor (HR 5.5), RAEB/sAML not in complete remission before transplantation compared to untreated RA/RARS or RAEB/sAML and treated RAEB/sAML in remission (HR 2.0), GvHD prophylaxis other than calcineurin inhibitor with methotrexate or mycophenolate mofetil (HR 1.7) and female sex of the donor (HR 1.7). TP53 mutations lost their unfavorable prognostic impact when complex karyotype was added to the multivariate model. Competing risk analysis for cumulative incidence of relapse and non-relapse mortality showed that IDH2 and NRAS mutations and a complex karyotype were significantly associated with higher risk for relapse while PTPN11 and PHF6 mutations predicted for a higher incidence of non-relapse mortality. Importantly, a negative prognostic impact of ASXL1, BCOR, CUX1, IDH1, SRSF2, RUNX1 and U2AF1 seen previously in MDS patients not undergoing alloHSCT was not found in the transplant setting, suggesting that alloHSCT may overcome the unfavorable effect of these mutations. Conclusion: By extensive genetic characterisation of 308 MDS or sAML patients undergoing alloHSCT we identified mutations in IDH2, NRAS and complex karyotype as predictors of relapse and reduced OS and provide a matrix to refine risk prediction for allogeneic HSCT. Disclosures Heuser: Karyopharm: Research Funding. Platzbecker:Boehringer: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Thiede:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AgenDix GmBH: Equity Ownership.

scholarly journals Prognostic Impact of Nutritional Status at Diagnosis and Weight Changes in Acute Myeloid Leukemia Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-33
Author(s):  
Dominic Brauer ◽  
Donata Backhaus ◽  
Vladan Vucinic ◽  
Dietger Niederwieser ◽  
Uwe Platzbecker ◽  
...  
Keyword(s):  
Weight Loss ◽  
High Risk ◽  
Nutritional Status ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Normal Weight ◽  
Prognostic Impact ◽  
Weight Changes ◽  
Hematopoietic Stem ◽  
Active Disease

Introduction: Overweight & obesity represent prognostic factors for survival in multiple cancer entities, but the association between body mass index (BMI) & survival is not consistent across all cancer types. In acute myeloid leukemia (AML) data on the prognostic impact of diagnostic nutritional status remain inconsistent & in patients (pts) with hematologic malignancies, obesity prior to hematopoietic stem cell transplantation (HSCT) has been linked to inferior outcomes. Therefore, obesity has been included as one risk factor into the hematopoietic cell transplant comorbidity index (HCT-CI), which predicts non-relapse mortality (NRM) & overall survival (OS) in older HSCT pts. Additionally, AML pts often suffer from weight loss during therapy, which might also impair survival. Here we investigated the prognostic impact of the nutritional status at diagnosis & weight changes during therapy in AML pts receiving a HSCT. Methods: We analyzed 662 AML pts who underwent allogeneic HSCT (median age 59.4, range 16.3-74.9 years) in complete remission (CR, 68%), CR with incomplete peripheral recovery (CRi, 14%) or active disease (18%) after non-myeloablative (59%), reduced intensity (15%) or myeloablative (26%) conditioning. Donors were matched related (20%), matched unrelated (59%), mismatched (19%) or haploidentical (2%). Comorbidities were assessed by the HCT-CI. The body mass index (BMI; kg/m2) at diagnosis, prior to HSCT & the BMI difference (∆BMI = BMIHSCT - BMIDx) were evaluated. For ∆BMI a cut-point of -2 was determined applying the R package "OptimalCutpoints" & divided pts into two groups with unchanged/increased BMI (∆BMI ≤-2, 57%) & decreased BMI (∆BMI >-2, 43%). AML disease risk was assessed according to European LeukemiaNet (ELN) 2017 classification & was 25% favorable, 30% intermediate & 45% adverse. Median follow up after HSCT was 3.1 years. Results: The median BMI at AML diagnosis was significantly higher than at HSCT (median 25.8 vs 24.7 kg/m2, P<.001). According to WHO classification, at diagnosis vs HSCT 39% vs 53% of pts were under-/normal weight (BMI <25 kg/m2), 42% vs 35% were overweight (BMI 25-29.9 kg/m2)& 20% vs 12% were obese (BMI ≥30 kg/m2). Pts with ∆BMI >-2 were older (P=.002) & more likely to have de novo AML (P<.001) but did not vary regarding HCT-CI (P=.19) or pre-HSCT remission status (P=.99). Compared to non-obese pts, obese pts at diagnosis had higher NRM (P=.05) & shorter OS (P=.004, Figure 1A, B), while no significant prognostic impact was found for BMI at HSCT (NRM P=.15, OS P=.10). Weight loss (∆BMI >-2) between diagnosis & HSCT was a strong predictor for higher NRM (P=.006) & shorter OS (P<.001, Figure 1C, D). In multivariate analyses, ∆BMI >-2 remained significant for higher NRM (Hazard ratio 1.23, P=.008) after adjustment for donor type & for shorter OS (Odds ratio 0.82, P=.001) after adjustment for ELN risk, age & remission status at HSCT. Analyzing the three ELN risk groups separately, the prognostic impact of ∆BMI >-2 was particularly seen in ELN favorable (NRM P=.09, OS P=.02) & intermediate (NRM P=.02, OS P=.002) but not in ELN adverse risk pts (NRM P=.41, OS P=.20). ∆BMI >-2 was also a significant prognostic factor in pts transplanted in CR/CRi (NRM P=.01, OS P<.001) but not in the high-risk population of pts transplanted with active disease (NRM P=.15, OS P=.10). When we analyzed the prognostic impact of weight changes depending on the BMI category at diagnosis, we observed that weight loss (∆BMI >-2) had a prognostic impact in under-/normal weight (NRM P=.08, OS P=.007) & overweight (NRM P=.10, OS P=0.09), but not in obese pts (NRM P=.81, OS P=.70). Conclusion: Obesity at diagnosis & weight loss (∆BMI >-2) associated with adverse outcomes due to higher NRM in AML pts undergoing HSCT. The prognostic impact of weight loss between diagnosis & HSCT represented a strong, potentially modifiable & independent risk factor & was particularly seen in non-high-risk pts. In high-risk pts with ELN adverse risk or with active disease at HSCT, weight loss did not impact outcomes, most likely due to the aggressive phenotype of the underlying AML. The data indicates that nutritional dynamics in AML pts destined for HSCT should be monitored & supportive therapy adjusted accordingly to improve outcomes. Disclosures Vucinic: Celgene: Honoraria. Niederwieser:Novartis: Speakers Bureau; Cellectis: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Daiichi: Research Funding. Platzbecker:Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Jentzsch:Novartis: Honoraria; JAZZ Pharmaceuticals: Honoraria. Schwind:Pfizer: Honoraria; Novartis: Honoraria, Research Funding; JAZZ Pharmaceuticals: Honoraria.

Prognostic Impact of Different High Risk Features in Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukemia in First Complete Remission.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2303-2303
Author(s):  
Theis Terwey ◽  
Philipp Hemmati ◽  
Gero Massenkeil ◽  
Bernd Dörken ◽  
Renate Arnold
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Complete Remission ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Prognostic Impact ◽  
Very High ◽  
First Complete Remission

Abstract Abstract 2303 Poster Board II-280 Introduction: In acute lymphoblastic leukemia (ALL) specific clinical and biological features confer high relapse risk and inferior overall survival (OS) after treatment with conventional chemotherapy alone. The differential prognostic impact of these high risk features after treatment with allogeneic hematopoietic stem cell transplantation (HCT) has not been well studied. Patients and Methods: 79 adult ALL patients in first complete remission (CR) received allogeneic HCT at our center between 1995 and 2008. All patients were high or very high risk according to German Multicenter Study Group for Adult ALL (GMALL) criteria. Median age was 36 years (range: 17-68). Patients received high-dose conditioning consisting of 12 Gy total body irradiation ± etoposide ± cyclophosphamide (n=69, 87%) or reduced intensity conditioning (RIC) consisting of fludarabine/busulfan/ATG (n=10, 13%) and HSCT from related (n=34, 43%) or unrelated (n=45, 57%) donors. Bone marrow (n=17, 22%) or peripheral blood stem cells (n=62, 78%) were given. Graft-versus-host-disease prophylaxis was CSA/MTX for high-dose conditioning or CSA/MMF for RIC. Results: Patients were classified as high risk or very high risk due to Philadelphia chromosome-positive disease (Ph+) (n=30, 38%), leukocytosis>30/nl at diagnosis in B-ALL (n=25, 23%), late response to induction therapy in B-ALL (>week 4) (n=13, 16%), early or mature T-ALL (n=13, 16%), pro-B-ALL/t(4;11) (n=8, 10%), persistence of minimal residual disease (MRD) (>week 16) (n=8, 10%) or complex aberrant karyotype (n=6, 8%). 57 patients (72%) presented with one high risk feature, whereas 20 patients (25%) and 2 patients (3%) presented with two or three features, respectively. Currently, after a median follow-up of 56 months (7-169) 49 patients (62%) remain alive. Projected OS of the whole cohort at 1, 2 and 5 years was 78%, 70% and 55% and leukemia-free survival was 77%, 66% and 55%. Cumulative incidence of non-relapse mortality (NRM) and relapse mortality (RM) at 5 years was 23% and 18%, respectively. In multivariate Cox regression analysis, a non-significant trend for inferior OS was seen for patients with early or mature T-ALL (hazard ratio (HR): 2.03 (95%CI: 0.92-4.52), p=0.082), whereas no differential effect on OS, NRM or RM was seen for any other high risk feature (Table 1). In additional analyses, inferior OS (HR 1.81 (95%CI: 1.02-3.29), p=0.043) and increased RM (HR 2.17 (95%CI 1.16-4.05), p=0.015) was observed for patients with more than one high risk feature. Conclusions: In summary, this single center study on allogeneic HCT in high risk ALL found a negative prognostic trend for early or mature T cell immunophenotype. No differential prognostic impact on OS, NRM and RM was seen for other high risk features as defined by GMALL criteria, however this conclusion is limited by the low patient number in some of the subgroups. Overall survival for the whole cohort was 55% at 5 years, with inferior OS and higher RM being observed in patients with more than one high risk feature. Disclosures: No relevant conflicts of interest to declare.

Treatment with Anti-CD19 BiTE® Blinatumomab in Adult Patients with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (r/r ALL) Post-Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 861-861 ◽  
Author(s):  
Anthony Selwyn Stein ◽  
Max S. Topp ◽  
Hagop M Kantarjian ◽  
Nicola Goekbuget ◽  
Ralf C Bargou ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Salvage Therapy ◽  
Research Funding ◽  
Employment Equity ◽  
Hematopoietic Stem ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Current therapies for patients with r/r ALL who have had prior allogeneic hematopoietic stem cell transplantation (alloHSCT) have very poor outcomes. Improvements in the therapeutic options available for adult r/r ALL are required. Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct that redirects cytotoxic T cells to lyse CD19-positive B cells. The aim of the present analysis was to characterize a subset of patients with r/r ALL and prior alloHSCT before treatment with blinatumomab from a large confirmatory open-label, single-arm, multicenter phase 2 study (Topp MS et al Lancet Oncol 2015;16(1):57-66). Methods: Eligible patients (≥18 years) had Philadelphia chromosome-negative r/r ALL with 1 of the following negative prognostic factors: primary refractory, first relapse within 12 months of first remission, relapse within 12 months of alloHSCT, or second or greater salvage. Patients with active acute or chronic graft-versus-host disease (GvHD) were excluded. Patients were required to stop all immunosuppressive GvHD therapy within 2 weeks before starting blinatumomab. A total of 189 patients were enrolled and received blinatumomab by continuous intravenous infusion (4 weeks on/2 weeks off) for up to 5 cycles. The primary endpoint was complete remission or complete remission with partial hematologic recovery (CR/CRh) within the first 2 cycles. Secondary endpoints included overall survival (OS), relapse-free survival (RFS), and adverse events (AEs). Results: 64 (34%) patients had received alloHSCT before study enrollment; 10 patients had 2 prior alloHSCTs. Donor types primarily included 29 (45%) matched sibling and 31 (48%) unrelated, with 34 (59%) patients receiving myeloablative conditioning regimens (donor chimerism data were unavailable). Among those with prior alloHSCT, median age (range) was 32 (19-74) years. At baseline, 23 (36%) patients had 1 prior relapse, 24 (38%) had 2 prior relapses, and 17 (27%) had ≥3 prior relapses; 28 (44%) patients had relapsed post-alloHSCT. Of the 55 patients who had received previous salvage therapy, 38 (69%) had received salvage therapy after last alloHSCT and prior to blinatumomab. Median time (range) between the last alloHSCT and subsequent relapse was 6 (1-33) months. Median time from last prior alloHSCT to first dose of blinatumomab was 10 (3-40) months. Nineteen (30%) patients had a history of GvHD, and 42 (66%) had ≥50% bone marrow blasts at start of treatment as assessed by a central laboratory. Patients received blinatumomab for a median of 2 (1-5) cycles. Efficacy data are presented in Table 1. Overall, 45% (29/64; 95% confidence interval [CI], 33-58) of patients achieved CR/CRh within the first 2 cycles, with similar rates of remission also observed in the alloHSCT-naïve (42%; 52/125) group. With a median follow-up of 8.8 months, median (95% CI) OS was 8.4 (4.2-9.4) months for the 64 patients with prior alloHSCT treated with blinatumomab. Of the 29 responders (CR, n=18 and CRh, n=11), 22 (76%) had a minimal residual disease (MRD) response and 19 (66%) achieved a complete MRD response. Median RFS (95% CI) was 6.1 (5.0-7.7) months. 9/29 (31%) responders subsequently underwent another alloHSCT. In total, 56 (88%) patients had grade ≥3 treatment-emergent AEs, with the most frequent including neutropenia (22%), febrile neutropenia (20%), anemia (17%), and thrombocytopenia (14%). Six patients reported treatment-emergent GvHD (two grade ≥ 3) during blinatumomab treatment, 3 of whom had GvHD in skin. Eight patients had fatal treatment-emergent AEs, which included 1 due to gastrointestinal hemorrhage, 1 due to respiratory failure, and 6 due to infection/infestation; 1 of these (candida infection) was considered to be possibly related to treatment by the investigator. Of the subjects who had treatment-emergent fatal AEs, none were in remission at the time of death. Summary: In this heavily pretreated group of patients with r/r ALL and prior alloHSCT, single-agent blinatumomab was able to induce a CR/CRh rate of 45%, with an AE profile consistent with that previously reported. Post-alloHSCT patients who had relapsed performed equally as well as those without prior alloHSCT. To prolong remission in this poor outcome patient group, the addition of other immunotherapies to the treatment regimen may be considered for future investigations. Disclosures Stein: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Research Funding. Topp:Astra: Consultancy; Regeneron: Consultancy; Affimed: Consultancy, Research Funding; Roche: Consultancy, Other: Travel Support; Jazz: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria, Other: Travel Support. Goekbuget:Erytech: Consultancy; Gilead Sciences: Consultancy; Kite: Consultancy; Mundipharma: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bayer: Equity Ownership; Sanofi: Equity Ownership; GlaxoSmithKline: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Eusapharma/Jazz: Consultancy, Honoraria, Research Funding; Medac: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; SigmaTau: Consultancy, Honoraria, Research Funding. Bargou:Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Patents & Royalties: Patent for blinatumomab; University of Wuerzburg, Germany: Employment; GEMoaB GmbH: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Rambaldi:Roche: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Celgene: Research Funding; Pierre Fabre: Honoraria. Zhang:Amgen: Employment, Equity Ownership. Zimmerman:Amgen: Employment, Equity Ownership. Forman:Mustang: Research Funding; Amgen: Consultancy.

scholarly journals Clinical Relevance of Morphologic and Molecular Complete Remission in AML Patients Undergoing Reduced Intensity or Non-Myeloablative Conditioning

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-29
Author(s):  
Madlen Jentzsch ◽  
Dominic Brauer ◽  
Juliane Grimm ◽  
Marius Bill ◽  
Donata Backhaus ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Risk Stratification ◽  
Genetic Risk ◽  
Research Funding ◽  
Myeloablative Conditioning ◽  
Remission Status ◽  
Active Disease ◽  
Reduced Intensity

Introduction: For most acute myeloid leukemia (AML) patients (pts) an allogeneic stem cell transplantation (HSCT) offers the best chance for relapse-free long-term survival. Evaluation of measurable residual disease (MRD) at HSCT allows risk stratification additionally to genetic risk at diagnosis. Pts with active AML or with positive MRD status (MRD+) pre-HSCT have similar and dismal outcomes following myeloablative conditioning. Reduced intensity (ric) or non-myeloablative (nma) conditioning regimes have been developed to allow HSCT also in AML pts with higher age or comorbidities. Here, we analyzed and compared the clinical relevance of morphologic and MRD-based remission status in AML pts prior to nma- or ric-HSCT. Methods: We analyzed 345 AML pts who received an allogeneic peripheral blood HSCT at a median age of 63 (range 21-77) years with active disease (34%), or in first (49%) or second (17%) complete remission (CR, 87% of pts in remission) or CR with incomplete peripheral recovery (CRi, 13% of pts in remission) after nma (75%) or ric (25%) conditioning. Donors were HLA matched related (11%), matched unrelated (67%), antigen mismatched unrelated (21%) or haploidentical related (1%). At diagnosis, cytogenetics and the mutation status of CEBPA, NPM1 and presence of FLT3-ITD were assessed. Using a next-generation targeted amplicon sequencing approach we analyzed a panel comprising 54 recurrently mutated genes in myeloid malignancies on the MiSeq platform (Illumina). Pre-HSCT morphologic remission status as well as MRD status in pts in morphologic CR/CRi based on NPM1 mutations, BAALC, MN1 and WT1 expression were evaluated. MRD+ pts were defined by being positive for any of the analyzed markers. Median follow up after HSCT was 2.2 years. Results: Pts transplanted with active disease differed from pts in remission with or without MRD pre-HSCT: they were less likely to have de novo AML (P=.02 & P=.09, respectively) and had higher genetic risk including a higher frequency of an abnormal (P=.001 & P<.001, respectively), a complex (P=.06 & P=.04, respectively) or a monosomal karyotype (P<.001 & P=.003, respectively), a lower frequency of NPM1 mutations (P<.001 & P<.001, respectively) and worse ELN genetic risk (P<.001 & P<.001, respectively). They were also more likely to receive ric-HSCT (P<.001 & P<.001) because pts with active AML were frequently transplanted after FLAMSA conditioning. Pre-HSCT MRD- pts only differed from pre-HSCT MRD+ pts regarding a lower white blood count (P=.006) and lower circulating blasts at diagnosis (P=.05) while the proportion of pts transplanted in CR or CRi did not differ between MRD- and MRD+ AML pts. Also the number of applied chemotherapy cycles prior to HSCT did not differ between the three pts groups. Pre-HSCT MRD- pts had a significantly lower cumulative incidence of relapse/progression (CIR) compared to both MRD+ pts (P<.001) and pts transplanted with active disease (P<.001) while CIR did not differ between MRD+ pts and pts transplanted with active disease (P=.24, Figure 1A). Pre-HSCT MRD- pts had longer overall survival (OS) than pre-HSCT+ pts (P=.04) who again had longer OS than pts transplanted with active disease (P=.01, Figure 1B). In multivariate analyses, the MRD corrected remission status prior to HSCT remained a significant factor for CIR (Hazard Ratio 1.65, Confidence interval [CI] 1.31-2.06) after adjustment for ELN risk and for OS (Odds Ratio 0.63, CI 0.49-0.84) after adjustment for ELN risk, hemoglobin and platelet count at diagnosis. Conclusion: AML pts transplanted with active disease showed a variety of high-risk diagnostic parameters compared to pre-HSCT MRD- or MRD+ pts, as secondary disease and adverse genetic risk. In contrast, pre-HSCT MRD- and MRD+ pts could not be discriminated by high risk factors at diagnosis, underlining the importance of a dynamic risk stratification during remission. Both pts with active disease or a MRD+ status in CR/CRi prior to nma- or ric-HSCT showed dismal outcomes with higher CIR and shorter OS than MRD- pts. However, while CIR was comparable in pts with molecular or morphologic detectable disease, OS was worst in pts transplanted with active disease, indicating that MRD+ pts might still be salvageable after suffering relapse and able to achieve long-term outcomes. Figure Disclosures Jentzsch: JAZZ Pharmaceuticals: Honoraria; Novartis: Honoraria. Platzbecker:AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Schwind:Pfizer: Honoraria; JAZZ Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding.

scholarly journals Prognostic Value of Cpss Cytogenetic Risk Classification in Patients with CMML after Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Multicenter Study of the Chronic Malignancies Working Party of the EBMT

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2182-2182
Author(s):  
Christian Koenecke ◽  
Dirk-Jan Eikema ◽  
Sheree Hazelaar ◽  
Dietrich W. Beelen ◽  
Victoria Potter ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct

Abstract Introduction: The only curative treatment approach for patients with Chronic Myelomonocytic Leukemia (CMML) is allogeneic hematopoietic stem cell transplantation (HSCT), but disease relapse after transplantation is a major concern. Predictors for disease outcome after HSCT are limited. However, unfavorable cytogenetic abnormalities have been shown to serve as predictors for relapse after transplantation. The aim of this large multicentric, international study was to retrospectively determine the impact of cytogenetic information according to the CMML-specific prognostic scoring system (CPSS) on outcome after allogeneic HSCT. Patients and Methods: Patients were selected from the EBMT database who had received a first allogeneic HSCT for the treatment of CMML between 2000 and 2015. 268 centers participated into this study. In total, 1503 patients were included. Impact of CPSS-cytogenetic classification was analyzed regarding overall survival (OS) and cumulative incidence of relapse and non-relapse mortality after HSCT (gray test). Results: 488 female (32.5%) and 1013 male (67.5%) patients were included to the study. Median age at HSCT was 57.6 years (range 0.3-75.4). At time of HSCT, only 422 (28.1%) patients were in complete remission, whereas 1004 (66.8%) had active disease (77 missing). Matched related donor HSCT was performed in 35.7% of the patients, matched unrelated donor HSCT in 57.6%, mismatched related in 3.3% and mismatched unrelated in 3.4%. Bone marrow (12.6%), peripheral blood (84.3%), or both (0.3%) served as the stem cell graft. Cord blood was used as a graft in 2.8%. Myeloablative preparative regimens wereused in 223 patients (15.0%), and less intensive regimens were given to 1268 patients (85.0%). Median survival of patients included into this study was 52.2 months. 637 patients had sufficient cytogenetic information according to CPSS (866 missing), complete relapse information was available in 1385 patients. 143 patients could be categorized into CPSS-high, 85 in intermediate and 375 in low risk cytogenetics, respectively. In univariate analysis high risk CPSS cytogenetic information was found to be strongly associated with OS (low 38% (32-44%), intermediate 41% (30-53%), high 26% (18-34%)), and higher cumulative incidence of relapse (low 40% (35-46%), intermediate 42% (30-54%), high 48% (39-56%)), but not with non relapse mortality (low 28% (23-33%), intermediate 25% (16-35%), high 30% (22-38%)) at 60 months (Figure 1). Conclusion: In this international, multicentric analysis we show that CMML patients with high-risk cytogenetics had significantly worse OS after HSCT than patients with intermediate or low risk cytogenetics according to CPSS. New therapeutic strategies to prevent relapse after HSCT in CMML patients with high-risk cytogenetics are needed. Disclosures Koenecke: Amgen: Consultancy; abbvie: Consultancy; BMS: Consultancy; Roche: Consultancy. Beelen:Medac: Consultancy, Other: Travel Support. Finke:Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding. Niederwieser:Novartis: Research Funding; Miltenyi: Speakers Bureau. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Kobbe:Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding.

scholarly journals Clinical Significance of Mutations and Copy Number Lesions on Prognosis of Patients with MDS after Unrelated Bone Marrow Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1971-1971
Author(s):  
Tetsuichi Yoshizato ◽  
Yoshiko Atsuta ◽  
Yusuke Shiozawa ◽  
Kenichi Yoshida ◽  
Yasuhito Nannya ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multivariate Analysis ◽  
Stem Cell ◽  
Bone Marrow Transplantation ◽  
Stem Cell Transplantation ◽  
Copy Number ◽  
Research Funding ◽  
Complex Karyotype ◽  
Clinical Factors ◽  
Hematopoietic Stem

Abstract Background: Myelodysplastic syndromes (MDS) are a group of heterogeneous disorders of hematopoietic stem cells, characterized by defective hematopoiesis and dysplasia of multiple blood lineages. Patients with MDS could achieve complete remission only by allogeneic hematopoietic stem cell transplantation (HSCT). However, because of its high mortality and morbidity, long-term survival is accomplished only in the half of the patients, underscoring the importance of accurate prognostication before the therapeutic choice. For this purpose, several systems, such as the International Prognostic Scoring System, are being successfully applied to predicting patients' clinical outcomes. Advanced molecular diagnostics of recent years might further improve the prediction. Nevertheless, originally established based on the data from patients who are untreated or only supportively treated, existing systems may not always be applied properly to the prediction of outcomes of the patients who are treated by HSCT. Methods: We enrolled 790 patients with MDS who were treated by unrelated bone marrow transplantation between 2006 and 2013 through the Japan Marrow Donor Program. Oncogenic variants and copy number alterations were identified by targeted-capture sequencing of peripheral blood-derived DNA using RNA baits designed for 69 known or putative driver genes in myeloid neoplasms and 1,674 single nucleotide polymorphisms. Results: The median age at HSCT and observation period were 51 years old (16-66) and 1106 days (48-6018), respectively. At the time of transplant, 29%, 34%, 24%, and 5.2% of the cases were diagnosed as low-risk MDS, high-risk MDS, secondary acute myeloid leukemia, and myelodysplastic / myeloproliferative neoplasms, respectively, while the disease subtype was unknown for the remaining 8.2% of the cases. Mutations were observed in 73% of the patients, where U2AF1 was most frequently mutated (13.8%), followed by RUNX1 (12.9%), ASXL1 (12.8%), TP53 (12.4%), and NRAS (7.1%). The mean number of mutations was 2.0 per patient with a mean allelic burden of 43.8%. Sequencing data were successfully used for sensitive detection of CNVs and copy-neutral loss-of-heterozygosity (LOH) (or uniparental disomy; UPD). Among the most frequent lesions were 7q LOH, complex karyotype-like CNVs as defined by 3 or more CNVs excluding UPD in targeted sequencing), 5q LOH, trisomy 8, and 17p LOH, observed in 15.5%, 12.9%, 10.1%, 7.0%, and 6.8% of the patients, respectively. Mutations in TP53, CBL, and EZH2 significantly co-occurred with LOH in 17p, 11q, and 7q, with odds ratios of 190, 75.5, and 11.7, respectively. On the basis of these findings, we combined frequently identified LOH lesions with associated mutations for further analyses of survival. In univariate analysis of overall survival (OS), 9 lesions were significantly associated with shorter OS; TP53 mutation and/or 17p LOH (TP53 / 17p LOH) (HR 2.76, P = 1.6 x 10-14), CSNK1A1 / 5q LOH (HR 2.66, P = 2.13 x 10-12), CBL / 11q LOH (HR 2.42, P = 3.88 x 10-7), EZH2 / 7q LOH (HR 2.29, P = 1.46 x 10-12), NRAS mutations (HR 1.86, P = 2.0 x10-4), ETV6 / 12p LOH (HR 1.83, P = 2.84 x 10-5), 1q gain (HR 1.73, P = 0.0037), 20p LOH (HR 1.57, P = 0.030), and FLT3 mutations (HR 1.53, P = 0.027). The number of these unfavorable lesions significantly correlated with OS (P=8.9 x 10-16). Specifically, those with at least one mutation showed a significantly shorter OS, compared to those with none of these mutations (HR 2.54, P<2.0 x 10-16). TP53 / 17p LOH was the most unfavorable among the 9 lesions by multivariate analysis (HR 1.97, P=1.6 x 10-14). Multivariate analysis with clinical factors revealed that the presence of at least 1 of the 9 lesions was independently associated with poor OS (HR 2.05, P<2.0 x 10-16), together with well-known clinical factors negatively affecting OS, including red blood cell transfusion before HSCT (HR 1.93, P=0.0036), 3 or more grade of the performance status at HSCT (HR 1.92, P=1.6 x 10-4), and older age (HR 1.69, P=2.0 x 10-4). The presence of at least one lesion negatively affected OS irrespective of the presence of complex karyotype-like CNVs. Conclusions: The present study highlights the clinical significance of somatic mutations and CNVs in MDS cases treated by HSCT. Our findings suggest that the novel set of lesions identified in this study could be successfully used for the prediction of outcome in MDS in the setting of stem cell transplantation. Disclosures Kataoka: Yakult: Honoraria; Kyowa Hakko Kirin: Honoraria; Boehringer Ingelheim: Honoraria. Kanda:Otsuka Pharmaceutical: Honoraria, Research Funding. Makishima:The Yasuda Medical Foundation: Research Funding. Ogawa:Takeda Pharmaceuticals: Consultancy, Research Funding; Sumitomo Dainippon Pharma: Research Funding; Kan research institute: Consultancy, Research Funding.

scholarly journals Outcomes of HMA and Venetoclax in Relapsed AML Post-Allogenic Hematopoietic Stem Cell Transplant

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Osama Diab ◽  
Haitham Abdelhakim ◽  
Joseph P. McGuirk ◽  
Tara Lin
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Complete Remission ◽  
Hematopoietic Stem Cell ◽  
Research Funding ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Pharmaceutical Research ◽  
Cell Transplant ◽  
Hematopoietic Stem

Background: There is no standard of care treatment for Acute Myeloid Leukemia (AML) in relapse post-allogeneic hematopoietic stem cell transplant (post-HSCT), with overall 5-year survival about 5-10%. Venetoclax (Ven) is a novel BCL2 inhibitor approved by the FDA for treatment of newly diagnosed AML in combination with hypomethylating agents (HMA) or low dose cytarabine for patients unfit for intensive induction. However, data in relapsed/refractory AML are limited, especially in the post-HSCT setting. In this retrospective study, we reviewed outcomes of patients with AML relapse post-HSCT who received Ven in combination with HMA in a single center. Methods: Charts of 17 patients who had AML relapse post-HSCT treated with combination of Ven and HMA between November 2018 - March 2020 at the University of Kansas Medical Center were reviewed. We utilized descriptive statistics for baseline characteristics and outcomes, and Kaplan-Meier log-rank test for calculating overall survival. Results Seventeen patients received Ven+HMA for AML relapse post-HSCT in our center. At the time of SCT, patients were in first complete remission (CR) (n=15); second CR (n=1) and primary failure induction (1). Median age was 62 at time of relapse (31-71) years, and 8 patients were female (47%). 9 patients (53%) had adverse risk AML (ELN 2017) 8 of them were in CR1 and 1 with primary induction failure. Common mutations included DNMT3a, ASLX-1, TET2 (3); TP53 (2); IDH1/2 (2); NPM1/FLT3 (1); NPM1/IDH2 (1); NPM1 (1 transplanted in CR2); FLT3 (1). 2/17 had received Ven+HMA prior to SCT; 4 patients received HMA alone prior to SCT. 11 patients (65%) were naïve to either Ven or HMA prior to relapse. Median time to relapse was 181 (44-851) days post-HSCT. 9 (53%) patients received Azacitidine+Ven and 8 (47%) received Decitabine+Ven. HMA+Ven was the first line of therapy post-HSCT relapse in 14 patients. 2 had donor lymphocyte infusion (DLI) after either MEC or dacogen but relapsed prior to Ven+HMA. 1 had IDH (2) inhibitor. Patients received median of 2 (1-10) cycles of HMA+Ven. Six (35%) patients achieved complete remission/complete remission with incomplete hematologic recovery (CR/CRi), and 2/6 patients had negative measurable residual disease by multiparameter flow cytometry. Median overall survival was 361 days from relapse (Figure 1). 3/14 patients received subsequent DLI with Ven+HMA. Disease progression was the most common cause of death in 8/9 of patients who died during the follow up period. Most common side effects included neutropenic fever (n=8, 47%) and acute graft versus host disease (aGVHD) (n=5, 30%). 2/5 developed new aGVHD on HMA+Ven with no prior history of aGVHD. However, aGVHD was mainly grade I-II and responsive to therapy. Discussion HMA+Venetoclax demonstrates potential activity in patients with AML relapse post-HSCT with a CR/CRi rate of 35%, comparable to other salvage therapies. There were no unexpected side effect in this high-risk population. Larger studies are needed to confirm efficacy and toxicity in this setting. Disclosures McGuirk: Pluristem Ltd: Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Bellicum Pharmaceutical: Research Funding; Allo Vir: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding. Lin:Aptevo: Research Funding; Abbvie: Research Funding; Bio-Path Holdings: Research Funding; Celgene: Research Funding; Gilead Sciences: Research Funding; Incyte: Research Funding; Jazz: Research Funding; Mateon Therapeutics: Research Funding; Ono Pharmaceutical: Research Funding; Pfizer: Research Funding; Prescient Therapeutics: Research Funding; Seattle Genetics: Research Funding; Tolero Pharmaceuticals: Research Funding; Trovagene: Research Funding; Genetech-Roche: Research Funding; Celyad: Research Funding; Astellas Pharma: Research Funding.

scholarly journals Allogeneic Hematopoietic Stem Cell Transplantation, Especially Haploidentical, May Improve Long-term Survival for Children With High-risk T-cell Acute Lymphoblastic Leukemia in First Complete Remission

2021 ◽  
Author(s):  
Yongzhan Zhang ◽  
Lu Bai ◽  
Xiao-jun Huang ◽  
Ai-dong Lu ◽  
Yu Wang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Hematopoietic Stem Cell Transplantation ◽  
Complete Remission ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Cell Acute Lymphoblastic Leukemia ◽  
First Complete Remission

Abstract Purpose The role of hematopoietic stem cell transplantation (HSCT) for children with high-risk (HR) T- cell acute lymphoblastic leukemia (T-ALL) in first complete remission (CR1) is still under critical discussion. This study explored the hierarchical criteria, prognostic factors of childhood T-ALL, and the role of HSCT, especially haplo-HSCT, for children with HR T-ALL in CR1. Methods Seventy-four pediatric T-ALL patients were included in this study and stratified into low-risk chemotherapy cohort (n=16), high-risk chemotherapy cohort (n=31) and high-risk transplant cohort (n=24). Results Patient prognosis in the high-risk chemotherapy cohort was significantly inferior to the low-risk chemotherapy cohort (5-year overall survival (OS): 51.2%±10% vs. 100%, P = 0.003; 5-year event-free survival (EFS): 48.4%±9.8% vs. 93.8%±6.1%, P = 0.01; 5-year cumulative incidence of relapse (CIR): 45.5%±0.8% vs. 6.3%±0.4%, P = 0.043). The 5-year OS, EFS, and CIR of the high-risk transplant cohort were 77.0%±8.3%, 77.0%±8.3%, and 11.9%±0.4%, respectively. When compared to the high-risk chemotherapy cohort, the P values were 0.084, 0.041, and 0.011, respectively. Minimal residual disease (MRD) re-emergence, initial white blood cell (WBC) count, and age≥10 years were independent risk factors for prognosis. ConclusionsHSCT, especially haplo-HSCT, might effectively improve the survival outcomes for HR childhood T-ALL in CR1.

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