Efficacy and Safety of FLAG-Ida As Frontline Therapy in a Pediatric AML Population: A Single Institution Experience

Abstract Children with acute myeloid leukemia (AML) are commonly treated using a daunorubicin-cytarabine ±etoposide (DA/ADE) backbone as developed by the Medical Research Council (MRC) AML 12 trial and since adopted by the Children's Oncology Group (COG). This regimen is an anthracycline-intensive regimen, incorporating mitoxantrone in the consolidation phase, with a stated cumulative cardiotoxic exposure of ~444 mg/m 2 doxorubicin equivalents, though recent data suggests mitoxantrone is more cardiotoxic than previously considered (~10x more cardiotoxic than doxorubicin instead of 3x). The MRC AML15 trial randomized DA/ADE versus fludarabine-cytarabine-idarubicin (FLAG-Ida) and found superior event-free survival (EFS) from FLAG-Ida, with fewer cycles of intensive chemotherapy (4 vs 5), and less than half the cardiotoxic exposure, potentially reducing acute and long-term morbidity. Experience with FLAG-Ida as frontline therapy in children with de novo AML is limited. Following MRC 15, minimal residual disease (MRD) monitoring has become standard of care for risk stratification in AML, but MRD data for the FLAG-Ida regimen in children has not yet been reported. We collected data from 30 pediatric patients (age 0.3-20.0 years) with newly diagnosed de novo AML (no preceding myelodysplastic syndrome, secondary AML, or prior malignancy) and no underlying genetic disease (e.g., Trisomy 21, Fanconi Anemia, Kostmann Syndrome, Shwachman-Diamond Syndrome) treated at our institution with MRC 15-style FLAG-Ida between 2014 and 2021 (Table 1). Each case was characterized by cytogenetics, chromosomal microarray analysis (since 2015, in 29/30), and a proprietary molecular testing panel (since 2017, in 21/30); AML risk category was assigned at diagnosis using the contemporary COG classification (AAML1831). Following Induction I and II, MRD was measured in each patient by multiparameter flow cytometry using a 'difference from normal' approach (MRD+ defined by contemporary COG threshold, MRD≥0.05%). Patients with poor disease response (MRD+) or high-risk cytogenetics proceeded to hematopoietic stem cell transplantation (HSCT) in first remission. Patients routinely received antimicrobial prophylaxis with sulfamethoxazole-trimethoprim, an azole or echinocandin, and levofloxacin. The study was approved by the Institutional Review Board. Following Induction I, 28/30 (93%) patients were MRD negative, and 30/30 (100%) patients following Induction II. Only 1/20 (5%) patients without high-risk AML required HSCT for slow-responding disease; 1/30 (3%) patients were unable to proceed to consolidation (prolonged myelosuppression). No patient developed treatment-related mortality (TRM) during pre-HSCT chemotherapy (2 subsequent to HSCT). Cardiac evaluation in surviving patients was normal (LVSF>28%) post-therapy in 23/24 (96%). Median survival for patients alive at last follow-up was 2.3 years with overall 3-year EFS and overall survival (OS) of 73±9% and 80±8%, respectively (Figure 1A). Survival for patients in the low-risk subset is depicted (Figure 1B, 1C); all low-risk patients were alive at last follow-up. FLAG-Ida was well tolerated and effective in our pediatric AML population with no TRM, excellent early disease response by MRD, and encouraging albeit early EFS and OS. This compares favorably with the adult MRC AML 15 experience as well as with the COG DA/ADE regimen, particularly for MRD response (in AAML0531, ~30% patients were MRD+ following Induction I [Brodersen et al 2020]). These data support our continued use of FLAG-Ida in pediatric AML alone or in combination with targeted and/or molecular therapies. Further study of FLAG-Ida as frontline therapy in children with AML is warranted. Figure 1 Figure 1. Disclosures Gaynon: Takeda pharmaceuticals: Other: member of DSMC committee. Orgel: Jazz Pharmaceuticals: Consultancy.

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Prognostic Value of Molecular Markers for Guiding Post-Remission Therapy in Patients with De Novo Acute Myeloid Leukemia (AML) and Intermediate-Risk Cytogenetics

Blood ◽

10.1182/blood.v112.11.2522.2522 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2522-2522

Author(s):

Marta Pratcorona ◽

Mireia Camós ◽

Montserrat Torrebadell ◽

Maria Rozman ◽

Ana Carrió ◽

...

Keyword(s):

High Risk ◽

Prognostic Value ◽

De Novo ◽

Low Risk ◽

High Dose ◽

Intermediate Risk ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Molecular Features ◽

Mutational Status

Abstract The heterogeneous prognosis of patients with intermediate-risk cytogenetics AML (AML-IR) can be partially clarified by screening of NPM1 mutations (NPMmut) and internal tandem duplication of FLT3 (FLT3-ITD). Nonetheless, additional factors might influence the prognostic effect of these molecular lesions, such as the FLT3-ITD mutant level. Moreover, the optimal post-remission strategy might differ depending on the underlying molecular lesion. In this regard, we analyzed the outcome, according to NPM1 and FLT3 mutations and post-remission therapy given, of a series of patients diagnosed with de novo AML-IR in a single institution who received intensive chemotherapy. Patients were treated following 4 sequential protocols of CETLAM group during the period 1994–2006, consisting of 1 or 2 cycles of standard induction chemotherapy and 1 course of high-dose cytarabine-based consolidation therapy. Thereafter, patients underwent hematopoietic stem cell transplantation (HSCT) according to donor availability and presumed risk (protocols LAM 99 & 2003). NPM1 mutations and FLT3-ITD were screened in diagnostic DNA by PCR amplification followed by Genescan analysis. The ratio between FLT3-ITD and wildtype FLT3 alleles (ITD/wt ratio) was calculated using the area under the peak of corresponding alleles. Overall, 134 patients (51% male; median age, 53; range: 17–70) with AML-IR (normal karyotype, 66%) were studied. NPM1mut and FLT3-ITD were found in 45% and 37% of patients, respectively, with a median ITD/wt ratio of 0.59 (0.045–5.5). After induction regimen, 109 patients (81%) achieved complete response (CR). The only variables predictive of a favorable response were NPMmut (90% vs. 75%; p=0.01) and age <60 (85% vs. 72.5%; p=0.05). After a median follow-up of 69 months, relapse risk (RR) at 5 years was 54% (±5%). RR was higher in patients presenting with hyperleukocytosis (>50 × 109/L), NPMwt, and FLT3-ITD. Interestingly, the prognostic value of FLT3-ITD depended on the relative mutant level, and detection of FLT3-ITD with a low ITD/wt ratio (i.e.,<0.3) did not increase the risk conferred by underlying NPM1 mutational status. In accordance, a composite variable based on NPMmut and quantitative FLT3-ITD was created defining 2 prognostic categories: a low-risk group (LOWmol), constituted by patients with NPMmut and either absence of FLT3-ITD or low ITD/wt ratio, and a high-risk subset (HIGHmol), defined by the absence of NPMmut and/or high ITD/wt ratio. This molecular stratification showed independent prognostic value for RR (5-year RR: 24%±10% vs. 81%±7 in LOWmol vs. HIGHmol patients, respectively; p<0.001), and survival (OS; relative risk: 2.8, 95% CI:1.6-5, p<0.001; figure Moreover, the effect of post-remission therapy varied in both molecular-defined subgroups. Thus, among patients with an age ≤60, 5-year survival in LOWmol patients with a planned autologous HSCT (autoHSCT) was 83%±9%, not differing significantly from that of patients undergoing allogeneic HSCT (intention-to-treat analysis; figure On the other hand, 5-year OS of HIGHmol patients who underwent allogeneic HSCT in first CR was 73%±13, which compared favorably with other post-remission strategies (5-yr OS: 27%±7%; p=0.019). In conclusion, in patients with intermediate-risk AML, the combined assessment of NPM1 mutations and quantitative estimation of FLT3-ITD allows the distinction of 2 categories of patients with different prognosis. Thus, whereas autoHSCT arises as an effective postremission therapy in patients harboring low-risk molecular features, allogeneic HSCT in first CR seems to overcome adverse prognosis of patients with high-risk disease. Nonetheless, the validity of this molecularly-based therapeutic algorithm warrants confirmation in other studies. Figure Figure

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Allogeneic Hematopoietic Stem Cell Transplantation (allo HSCT) in Patients with IPSS Low or Intermediate-1 Myelodysplastic Syndrome (MDS): A Prospective Multicenter Phase II Study Based on Donor Availability By the GFM & SFGM-TC "MDS-ALLO-Risk"

Blood ◽

10.1182/blood-2021-146846 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1842-1842

Author(s):

Marie Sebert ◽

Cendrine Chaffaut ◽

Sylvain Thepot ◽

Corentin Orvain ◽

Thomas Cluzeau ◽

...

Keyword(s):

High Risk ◽

Lower Risk ◽

Research Funding ◽

Low Risk ◽

Donor Group ◽

Hematopoietic Stem ◽

The Past ◽

Group A ◽

Group B

Abstract Background: Allo HSCT is a potentially curative treatment in MDS which, in higher risk (IPSS high and int 2) MDS demonstrated an overall survival (OS) advantage over conventional treatment (especially HMAs) in retrospective (Koreth et al., JCO 2013) and prospective (Robin et al. leukemia 2015) studies. Retrospective studies, on the other hand, suggested no OS advantage for allo HSCT in lower risk MDS (IPSS low and int 1), except possibly in the "poorest" lower risk MDS subsets, as classified by the WPSS (Alessandrino et al. AMJH 2013) However, about 25% of lower risk MDS patients are reclassified as higher risk by the R-IPSS and a proportion of other lower risk MDS can also harbor some higher risk features that compromise their outcome. MDS-ALLO-RISK trial (clinicaltrial.gov NCT02757989), was designed to assess outcome of lower risk MDS patients with some high-risk features after HLA-matched donor HSCT. Method: The primary objective of this study was to demonstrate an OS improvement in lower risk MDS patients with some high risk features with a donor compared with those without a donor (with a 3 year OS of 70% versus 40%, respectively) . Inclusion criteria were: IPSS low or int1 MDS with at least one of the following characteristics: 1) R-IPSS intermediate or higher 2) RBC transfusion dependent anemia and failure to two or more treatments (including EPO, Lenalidomide or HMA ); 3) platelets < 20 G/L requiring transfusions 4) ANC < 0.5 G/L with severe infection 5) no contra indication to allo HSCT 6) age <70 years 7) HLA identical donor (sibling or 10/10 unrelated) 105 inclusions were planned: 62 in group with a donor (group A) and 43 in group without a donor (group B). Recruitment began in June 2016 and stopped in March 2021 due to futility on the interim analysis. Median follow-up was 20 months. Data cut off analysis was June 2021. Results: 79 patients were included, 64 in group A and 15 in group B. Median age was 62.4 (IQR: 58-65) years in group A and 66 (IQR: 60.5-68) years in group B. Patients in group A were more frequently males (73 vs 40%, p=0.029), WHO was CMML in 8 (10%), MDS-SLD in 5 (8%), MDS-MLD in 9 (11%), MDS-EB1 in 41 (52%), MDS-RS in 12 (15%), unclassified in 4 (6%) without significant differences between the two groups. IPSS /IPSS-R was similar in both groups: IPSS low in 10% (11% in group A and 7% in group B) and Int-1 in 90%. IPSS-R: very low risk (6% vs 0%); low risk (25% vs 27%); intermediate (50% vs 47%); high (19% vs 27%); no very high risk. Among the 64 patients with a donor, 58 (92%) received HSCT, 2 died before HSCT; 2 had progressive disease and 2 are planned for HSCT. Transplanted patients received reduced intensity conditioning regimen with busulfan 6.4mg/kg, fludarabine 150mg/m2 and ATG (rabbit antithymocyte globulin therapy, grafalon®) 30mg/kg and cyclosporine-mycophenolate mofetil as GVHD prophylaxis. In group A, 21/64 had died, including 13 died from a non-relapse cause. In group B, 4/15 patients had died, 3 from MDS progression and one from CNS bleeding. Three-year OS was 60% (95%CI: 46.9-76.8) in group A and 64.2% (41.3-99.6) in group B (p=NS). At the time of analysis, 20 and 5 patients had progressed/relapsed in group A and B respectively. with a cumulative incidence of relapse/progression (from inclusion) of 27.4% (IC95%: 15;39.8) in group A and 41.7% (IC95%:9.2;74.2) in group B (p=0.71). Among the 58 transplanted patients, 11 (19%) died without disease progression, including one death from a solid tumor. 3 years non-relapse mortality in transplanted patients was 23.4% (IC95%:9.7;37). 3 years Incidence of grade 2 to 4 acute GVHD was 40.8% and 3 years chronic GVHD was 24.9%. Conclusion: In this, to our knowledge, first prospective study in IPSS lower risk patients with some unfavorable clinical or biological features, HLA identical donor (sibling or 10/10 unrelated) HSCT yielded a 3-year OS of 60%. Non relapse mortality was however 23%, and OS somewhat lower than expected (70% at 3 years) and similar to that observed in patients without a donor. Long-term follow-up is needed to better define subgroups of IPSS lower risk MDS that may benefit from allo HSCT. Disclosures Sebert: Abbvie: Consultancy; BMS: Consultancy. Cluzeau: Pfizer: Other: travel, accommodations, expenses; Astellas: Speakers Bureau; Amgen: Speakers Bureau; Agios: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Speakers Bureau; Takeda: Other: travel, accommodations, expenses; Jazz Pharma: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau. Loschi: AbbVie: Ended employment in the past 24 months, Honoraria; CELGENE/BMS: Honoraria; Gilead: Ended employment in the past 24 months, Honoraria; Novartis: Ended employment in the past 24 months, Honoraria; Servier: Ended employment in the past 24 months, Honoraria; MSD: Honoraria. Huynh: Jazz Pharmaceuticals: Honoraria. Ades: ABBVIE: Honoraria; NOVARTIS: Honoraria; CELGENE/BMS: Honoraria; CELGENE: Research Funding; JAZZ: Honoraria, Research Funding; TAKEDA: Honoraria. Fenaux: JAZZ: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Robin: NEOVII MEDAC NOVARTIS: Research Funding.

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Crebbp Alterations Are Associated with a Poor Prognosis in De Novo AML

Blood ◽

10.1182/blood-2021-154052 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3451-3451

Author(s):

Adam J. Lamble ◽

Robert B. Gerbing ◽

Jenny L. Smith ◽

Rhonda E. Ries ◽

Edward A. Kolb ◽

...

Keyword(s):

High Risk ◽

Poor Prognosis ◽

De Novo ◽

Conflicts Of Interest ◽

Prognostic Significance ◽

Cell Transplant ◽

Single Nucleotide Variants ◽

Phase 3 ◽

Hematopoietic Stem ◽

De Novo Aml

Abstract Introduction: The translocation, t(8;16)(p11;p13), results in the fusion between KAT6A and CREBBP and has been associated with a poor prognosis in both pediatric and adult acute myeloid leukemia (AML). This lesion has therefore been re-classified as high risk on the active Phase 3 Children's Oncology Group (COG) trial for de novo AML, AAML1831 (NCT04293562). Less is known about the prognostic significance of CREBBP sequence variants. Methods: CREBBP variant status was determined in patients with AML enrolled on 4 successive COG trials for de novo pediatric AML (NCT00003790, NCT00070174, NCT01407757, NCT01371981). Fusions involving CREBBP were prospectively obtained via conventional cytogenetics and retrospectively confirmed via RNAseq. Insertions and deletions (indels) leading to frameshift mutations and single nucleotide variants (SNVs) were retrospectively interrogated via next generation sequencing. Results: Of 2216 patients (age: 0-29.8 years), 55 (2.5%) patients had an alteration involving CREBBP. Sixteen (29%) of these were a fusion involving CREBBP (CREBBP/fus), with KAT6A being the most common translocation partner (n=15) and the remaining translocation involving ANK1. The remaining 39 patients (71%) had a CREBBP mutation (CREBBP/mut), including 19 with an indel (CREBBP/indel) leading to a frameshift mutation and 20 with a SNV (CREBBP/SNV). We compared clinical and biologic characteristics between the three cohorts. CREBBP/fus patients were significantly younger than CREBBP/indel and CREBBP/SNV patients (median ages of 2.6 vs. 7.8 vs. 11.9 years; p=0.027). There was a higher prevalence of t(8;21)/RUNX1-RUNX1T1 in CREBBP/indel patients compared to CREBBP/SNV patients (42.1% vs. 5%; p=0.008). In contrast, CREBBP/SNV patients were more likely to be associated with a normal karyotype (40% vs. 5.3%; p=0.02). There was a similar prevalence of co-occurring high-risk lesions in CREBBP/indel (n=5; CBFA2T3-GLIS2, KMT2A-AFF1, KMT2A-MLLT4, MLLT10-PICALM, NUP98-HOXA9) and CREBBP/SNV (n=7; DEK-NUP214, ETV6-FOXO1, FUS-ERG, NUP98-NSD1, ETV6-MNX1, FLT3-ITDx2) patients. There was otherwise no difference between presenting WBC count, FLT3-ITD, NPM1, CEBPA, remission rates or MRD status after Induction 1 therapy. Patients with any CREBBP alteration had a significantly worse 5-year event free survival (EFS) compared to patients without (25.9% vs. 45.2%; p=0.002) and this inferior EFS overlaps with contemporarily defined high-risk patients (Figure 1a). Evaluation of outcomes based on type of alteration demonstrated a similar 5-year EFS of 33.3% and 23.1% between CREBBP/fus and CREBBP/mut patients, respectively (Figure 1b; p=0.832). This poor EFS was maintained in the CREBBP/indel patients with a co-occurring t(8;21) (n=8, 5-year EFS 12.5%). When patients with co-occurring high-risk lesions were excluded from analysis, the remaining CREBBP/mut (n=27) patients maintained their poor EFS (29.6%). Despite their poor EFS, CREBBP/mut patients had an analogous overall survival (OS) to non-CREBBP patients (57.4% vs. 62.3%; p=0.499, Figure 1c), demonstrating that these patients could be successfully salvaged following relapse. In contrast, all patients with CREBBP/fus that relapsed subsequently died from their disease (OS 33.3%). Conclusions: In a large study of CREBBP alterations in pediatric patients with de novo AML, we show that these patients have a dismal EFS, regardless of alteration type. Further, despite enrichment of t(8;21), the favorable prognosis typically conferred by this alteration was abrogated by the co-occurrence of CREBBP/indel. Similarly, by excluding patients with co-occurring high-risk lesions from analysis, we show that these poor outcomes persist in a cohort of patients that would otherwise be considered low risk. Translocations between CREBBP and KAT6A in patients over 90 days of age are considered high risk on the active COG phase 3 trial. Given the inferior EFS and high salvage rates associated with other CREBBP alterations, intensification of upfront treatment, including hematopoietic stem cell transplant, should be considered in this population. The authors would like to acknowledge Astellas Pharma Global Development, Inc. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Outcome of Myelodysplastic Syndrome in Veterans Treated with 5-Azacitidine and Decitabine

Blood ◽

10.1182/blood.v118.21.5055.5055 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5055-5055

Author(s):

Kanza S Abbas ◽

Ang Li ◽

Gustavo A. Rivero ◽

Premal D Lulla ◽

Alka Mulchandani ◽

...

Keyword(s):

High Risk ◽

Myelodysplastic Syndrome ◽

Research Funding ◽

De Novo ◽

Dose Range ◽

Low Risk ◽

Myelogenous Leukemia ◽

End Point ◽

Hypomethylating Agent ◽

De Novo Aml

Abstract Abstract 5055 Background: Myelodysplastic syndrome (MDS) represents a heterogenous disorder characterized by ineffective hematopoiesis and propensity to evolution to acute myelogenous leukemia (AML). Azanucleosides like 5-azacitidine (AZA) and decitabine-5-aza-2'-deoxycytidine (DAC) improve survival (Fenaux, 2008; Silverman, 2002 and Steensma, 2009). In this retrospective study, we aimed to evaluate: (1) clinical outcomes in Veterans (pts) diagnosed with MDS and treated with either 5-AZA or DAC and (2) survival outcomes according to number of cycles received of either hypomethylating agent. Design: After obtaining IRB approval, data was collected from the Michael E. DeBakey VA Medical Center cancer registry and pharmacy records between January 1, 2000 and June 1, 2011. For analysis, pts were included in the study if they were ≥18 years (y), had morphological evidence of MDS per bone marrow examination at the time of diagnosis and were treated with either hypomethylating agent (but not both) as first-line therapy for 2 cycles or more. Pts with de-novo AML prior to treatment were excluded. Pts received AZA at 75 mg/m2/day (d) (dose range, 50–75 mg/m2/d) (d 1–7) or DAC at 20 mg/m2/d (dose range, 15–20 mg/m2/d) (d1-5) at four weeks interval. The primary end-point was Overall Response Rate (ORR) which included Complete Response (CR), Partial Response (PR) and Hematological Improvement (HI) according to IWG 2006. Secondary end-point was Overall Survival (OS) per treatment group. Results: We identified 39 pts who underwent treatment with azanucleosides. 18 pts were excluded either because of de-novo AML diagnosis at presentation, they had received < 2 cycles of treatment, or had received > 2 cycles of both agents, 11, 5, and 2 pts, respectively. Demographics are depicted in table 1. 21 pts were available for analysis, from which 2/21 (10%) and 19/21 (90%) were female and male, respectively. Median age was 66 y (range, 55–78 y) and 63 y (range, 56–78 y) for pts treated with AZA vs. DAC (P=0.458). 9/21 (43%), 5/21 (24%), 7/21 (33%) pts had good, intermediate and poor-risk karyotypes. 13/21 (62%) and 8/21 (38%) pts received AZA and DAC, respectively. ORR was 15% vs. 38%, for AZA vs. DAC (P=0.618). Per IPSS score, 52% and 48 % of the pts were high-risk (high and Int-2) and low-risk (Int-1 and low), respectively. ORR was 30% vs. 18%, for low-risk vs. high-risk pts (P=0.635). OS was superior in low-risk compared to high-risk pts (394d vs. 214d, P=0.029, Figure 1). Pts who responded to therapy (CR+ PR +HI), had superior OS compared to pts with stable or progressive disease (411d vs. 194d, P= 0.01). There was no statistical difference in OS between different age groups. OS in pts receiving ≥4 or <4 cycles of treatment was 486d vs. 187d for AZA-treated pts (P=0.005) and 411d vs. 174d for DAC group (P=0.04). Leukemia transformation was seen in 5 vs. 2 pts treated with AZA and DAC. For this subset, Time to Leukemia transformation (TTL) was 102d vs. DAC 272d (P=0.65). Conclusions: In our study, therapy with AZA and DAC was associated with ORR comparable to historical data of about 25%. OS was superior in pts receiving ≥4 cycles of treatment of either regimen. Despite the small number of pts and retrospective nature of our study, our data suggest that TTL is similar for both agents. Prospective studies, in veteran pts, evaluating efficacy of AZA vs. DAC are needed. Disclosures: Off Label Use: Use of azacytidine and decitabine for low risk MDS. Yellapragada:Bristol Myers Sqibb: Research Funding; Celgene: Research Funding.

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Myc and Bcl2 Overexpression and Traslocation Assessed By Immunohystochemistry (IHC) and FISH: Retrospective Analysis in a Series of De Novo DLBCL Homogeneously Treated with Rituximab-CHOP

Blood ◽

10.1182/blood.v128.22.5305.5305 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5305-5305

Author(s):

Chiara Ciochetto ◽

Maria Stella Scalzo ◽

Barbara Botto ◽

Alessia Castellino ◽

Annalisa Chiappella ◽

...

Keyword(s):

High Risk ◽

Retrospective Analysis ◽

Board Of Directors ◽

Poor Prognosis ◽

De Novo ◽

B Cell Lymphoma ◽

Low Risk ◽

Advisory Committees ◽

Bcl6 Expression

Abstract Introduction: MYC and BCL2 overexpression assessed by IHC and rearrangement detected by FISH are important prognostic factor in Diffuse Large B-Cell Lymphoma (DLBCL). Double Hit Lymphoma (DHL) patients have a poor prognosis with conventional therapy and Double expressor Lymphoma (DE) have worse outcome compared with conventional DLBCL although data are controversial. Aimed at a better knowledge of this issue, we performed a retrospective analysis to determine prevalence and outcome of Single Hit Lymphoma (SHL), DHL and DE in patients with de-novo DLBCL treated with Rituximab and CHOP. Methods: de novo DLBCL treated with R-CHOP between January 2003 and December 2013 were included in the study. BCL2 and BCL6 expression were evaluated by IHC at diagnosis while MYC expression was retrospectively investigated with Tissue Micro Arrays (TMA) technique; cases were considered positive for MYC, BCL2 or BCL6 expression by IHC if >40%, >40% or >25% of cells stained positive, respectively. FISH analysis for MYC and BCL2 rearrangements were performed with dual color break apart probes on TMA. PFS and OS were estimated with Kaplan-Meier method and compared between groups with the Cox model. We further evaluated in this series the IHC score proposed by Botto et al. (Blood 2014 124:2964) in DLBCL. The score was based on the assessment in IHC of the expression of MYC, BCL2 and BCL6. The three variable contributed with different risk in the multivariate analysis and an IHC sum additive score of 0-5 was calculated proportionally to the coefficient estimated (coefficient [Log hazard ratio] 0.92 for MYC+, 0.73 for BCL2+ and 0.48 for BCL6-), assigning an individual risk of 2 points for MYC or BCL2 positivity and 1 point for BCL6 negativity. Patients were stratified in three different risk groups; Low risk (0-1 point), Intermediate risk (2 points) and High risk (≥3 points). Results: Of a total of299 DLBCL screened, 267 were evaluable for survival analysis; median age was 65 years (range 20-90). 154 patients had complete immunohystochemical data and 101 were fully investigated by IHC and FISH. No significant differences in clinical presentation or in the outcome were seen between patients with or without available histologic tissue for IHC and FISH. Among 154 patients with complete IHC data we found 12 (8%) DLBCL without expression (DLBCL), 96 (62%) Single expressor (SE), 46 DE (30%). With a median follow up of 60 months, 5-year PFS rates were: DLBCL 90%, SE 60% and DE 43% respectively (fig 1) (HR 8.25 (95% CI: 1.12 -60.99) p 0.039); 5ys OS rates were 91%, 68% and 57% respectively (HR 5.72 (95% CI: 0.77 - 42.82) p 0.08). Applying the prognostic model (adjusted for IPI and age) defined in our previous pilot study we recorded 12/154 patients with low risk score, 61/154 with intermediate and 81/154 patients in high risk group. 5y-PFS rates were 91% vs 67% vs 45% (p=0.014) respectively (HR 1.74 (95% CI: 1.12 -2.69) p 0.014). Among 101 patients investigated by FISH we recorded 10 SHL (10%) and 8 DHL (8%). Clinical characteristics were superimposable among DLBCL, SHL and DHL with a prevalence of non GCB phenotype in DE group (56%). Among 101 patients fully investigated for FISH and IHC, 38 patients had MYC overexpression by IHC; 11 of them had also a MYC translocation. We found 3 cases with MYC rearrangement without protein overexpression. With a median follow up of 60 months PFS in DLBCL, SHL and DHL was 65%, 58% and 25% respectively (fig. 2); 5 ys OS was 70%, 77% and 25% respectively. The worse prognosis of DHL was statistically significant with an HR of 3.3 (95% CI: 1.37- 7.94, p 0.008) in terms of PFS and 3.9 (95% CI:1.59- 9.52 p 0.003) in terms of OS. Conclusion: Our data confirmed that our IHC prognostic score based on MYC, BCL2 and BCL6 expression, is a simple, reproducible and valid prognostic assessment that identify three groups with a different outcome in a large cohort of DLBCL. Moreover these data confirm intermediate prognosis for patients with DE lymphoma and poor prognosis of DHL treated with conventional chemoimmunotherapy. Figure 1 PFS in patients with complete IHC data Figure 1. PFS in patients with complete IHC data Figure 2 PFS in patients with complete FISH data Figure 2. PFS in patients with complete FISH data Disclosures Chiappella: Roche: Speakers Bureau; Celgene: Speakers Bureau; Janssen-Cilag: Speakers Bureau; Teva: Speakers Bureau; Pfizer: Speakers Bureau; Amgen: Speakers Bureau. Cavallo:Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Honoraria. Vitolo:Celgene: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Impact of Allogeneic Hematopoietic Stem Cell Transplantation in First Complete Remission and Additional Cytogenetic Aberrations at Diagnosis on Prognosis in 1256 Pediatric Patients with KMT2A-Rearranged Acute Myeloid Leukemia: A Retrospective Study By the I-BFM-SG

Blood ◽

10.1182/blood-2021-148041 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2360-2360

Author(s):

Romy E. Van Weelderen ◽

Kim Klein ◽

Christine J. Harrison ◽

Hester A. De Groot-Kruseman ◽

Jonas Abrahamsson ◽

...

Keyword(s):

High Risk ◽

Myeloid Leukemia ◽

Multivariate Analyses ◽

Cox Model ◽

Univariate Analysis ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Cytogenetic Aberrations ◽

Pediatric Aml

Abstract Introduction KMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML) is a heterogeneous genetic subgroup with a frequency of about 25% in children with AML. At the 62 nd ASH annual meeting last year, we reported on the differences in outcome of various KMT2A subgroups based on translocation partner and the significance of minimal residual disease (MRD) status during and after induction as a follow-up study of Balgobind et al., Blood 2009. The impact of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) and the presence of additional cytogenetic aberrations (ACAs) on prognosis have not yet been described for our cohort. Methods Data on allo-HSCT in CR1 and the presence of ACAs of 1256 KMT2A-r de novo pediatric AML patients from 15 AML study groups affiliated with the I-BFM Study Group, diagnosed between 2005 and 2016, were retrospectively collected and studied. Karyotypes were reviewed and classified by two of the authors (RW&CH). Based on translocation partners, patients were classified to the KMT2A high-risk subgroup (6q27, 10p11.2, 10p12, 4q21, and 19p13.3) or non-high-risk subgroup (9p22, 19p13, 19p13.1, 1q21, Xq24, 17q21, 1p32, and 17q12). These two categories have been used to estimate a Cox model. Patients with unknown translocation partners were excluded from these analyses (n=126). Flow cytometry MRD levels at the end of induction course 1 (EOI1) and 2 (EOI2) <0.1% were considered negative, and levels ≥0.1% positive. Kaplan-Meier's methodology was used to estimate disease-free survival (DFS) and overall survival (OS). DFS was calculated from EOI1 for patients in CR to date of relapse or death/last follow-up. OS was calculated from the time of diagnosis to date of death/last follow-up. Two-sided P-values of ≤ .01 were considered statistically significant. Covariates with P-values ≤ .05 in univariate analyses were included in multivariate analyses; allo-HSCT in CR1 was included as a time-dependent covariate in the Cox model. MRD status at EOI2 was excluded from multivariate analyses as therapy could have been adjusted to the MRD status and the number of MRD positive patients was small. Results Of 1256 pediatric patients with KMT2A-r AML, data on HSCT in CR1 and ACAs were available for 1186 (94.4%) and 1204 patients (95.9%), respectively; 211 (17.8%) patients received HSCT in CR1 and ACAs were present in 601 (49.9%) patients. Compared with the KMT2A non-high-risk subgroup, patients in the KMT2A high-risk subgroup underwent HSCT in CR1 more often (23.8% vs 15.0%; P < .001). ACAs were borderline significantly more common in the KMT2A high-risk subgroup (54.1% vs 46.4%; P = .015). Univariate analysis of the probability of DFS (Table 1) showed that the KMT2A high-risk subgroup (HR 2.1; 95% CI, 1.7-2.5), age ≥10 years (HR 1.4; 95% CI, 1.2-1.7), and MRD ≥0.1 at EOI1 (HR 1.5; 95% CI, 1.1-1.9) were associated with DFS. HSCT in CR1 was a borderline significant prognostic factor (HR 0.7; 95% CI, 0.6-0.9). In a multivariate analysis for DFS (n=515) (Table 1), the KMT2A high-risk subgroup (HR 2.0; 95% CI, 1.6-2.6), MRD ≥0.1 at EOI1 (HR 1.7; 95% CI, 1.2-2.3), and HSCT in CR1 (HR 0.6; 95% CI, 0.4-0.9) were associated with DFS. Univariate analysis of the probability of OS (Table 1) showed that the KMT2A high-risk subgroup (HR 1.8; 95% CI, 1.5-2.2), age ≥10 years (HR 1.6; 95% CI 1.3-2.0), WBC ≥100 x10 9/L (HR 1.4; 95% CI, 1.1-1.7), the presence of ACAs (HR 1.4; 95% CI, 1.2-1.7), and MRD ≥0.1 at EOI1 (HR 2.1; 95% CI, 1.6-2.7) were associated with OS. HSCT in CR1 was not associated with OS. The effect of HSCT in CR1 was not significantly different between the KMT2A high-risk and non-high-risk subgroups. In a multivariate analysis for OS (n=557) (Table 1), the KMT2A high-risk subgroup (HR 1.9; 95% CI, 1.4-2.5), age ≥10 years (HR 1.5; 95% CI, 1.1-1.9), the presence of ACAs (HR 1.6; 95% CI, 1.2-2.1), and MRD positivity at EOI1 (HR 1.9; 95% CI, 1.4-2.5) were associated with OS. Conclusions In this cohort of KMT2A-r pediatric AML patients, the presence of ACAs at diagnosis was independently associated with inferior OS, but not with DFS. This may be due to the exclusion of refractory patients in DFS analysis, who were significantly more common in the group of patients with ACAs. Analysis has yet to be performed to distinguish karyotype complexity. In addition, allo-HSCT in CR1 was an independent predictor of improved DFS, but was not a prognostic factor for OS. Figure 1 Figure 1. Disclosures Abrahamsson: wedish Children´s Cancer Foundation. Research grants and 50% senior research position for clinical research on pediatric leukemia: Research Funding. Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau.

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Expression of C-Type Lectin-Like Molecule-1 (CLL-1) on Stem Cells Might Discriminate De Novo Acute Myeloid Leukemia from Acute Myeloid Leukemia Originating from Myelodysplastic Syndromes

Blood ◽

10.1182/blood.v112.11.2697.2697 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2697-2697

Author(s):

Theresia M Westers ◽

Monique Terwijn ◽

Canan Alhan ◽

Yvonne FCM van der Veeken ◽

Claudia Cali ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

High Risk ◽

Myeloid Leukemia ◽

De Novo ◽

Low Risk ◽

Cell Compartment ◽

Stem Cell Compartment ◽

De Novo Aml ◽

Acute Myeloid

Abstract It is generally accepted that myelodysplastic syndromes (MDS) most often originate in a multipotent, myelorestricted progenitor population, although primary transformation may occur at the hematopoietic stem cell level. MDS can be classified into low risk and high risk with evolution to acute myeloid leukemia (AML) predominantly in the latter cases. In AML, survival of leukemia-initiating cells, often referred to as leukemic stem cells, after chemotherapy is thought to lead to minimal residual disease and relapse. Hence, in de novo AML a larger size of the stem cell compartment is predictive for poor survival. [Van Rhenen et al.,Clin Cancer Res 2005,11] The monoclonal antibody against the cell surface antigen C-type lectin-like molecule-1, CLL-1, together with lineage infidelity markers enables discrimination of normal and malignant stem cells. [Van Rhenen et al.,Blood 2007,110; Van Rhenen et al.,Leukemia 2007,21] It could be hypothesized that CLL-1 and aberrant marker expression on MDS stem cells together with size of the stem cell compartment may predict leukemic evolution. Therefore, stem cells, defined as CD45dimCD34+CD38−, were analyzed for expression of CLL-1 and aberrant lineage markers in bone marrow samples from 88 MDS patients classified by WHO as 16 RA w/o RS, 42 RCMD w/o RS, 3 MDS-U, 5 hypoplastic MDS, 6 MDS/MPD and CMML, 15 RAEB-1 and 2, 20 AML patients with a known MDS history and 26 healthy controls. Analysis of the CD34+CD38− frequency in all MDS patients and normal controls revealed no significant differences (median 0.0061% vs. 0.0074%, respectively), whereas the frequency of CD34+CD38− cells was 17-fold higher in high risk MDS (RAEB-1 and 2, median: 0.076%) as compared to low risk MDS (median: 0.0046%, p<0.001). Similar as in AML, stem cells were significantly more prevalent within the blast cell fraction (CD45dimSSCint/low) of high risk MDS as compared to low risk MDS (median 0.77% and 0.25%, respectively), reflecting the differences in clinical course in these patients (p=0.040). Regarding CLL-1 expression, a reliable number of stem cells (>20) could be tested in 11/15 high risk RAEB-1 and 2 cases and in 16/73 of the remaining low risk MDS cases. In these cases, median CLL-1 expression on the CD34+CD38− cells was 1.6% (range 0–50) in low risk and 2.0% (range 0–27) in high risk MDS. Median CLL-1 expression on stem cells was 0.0% (range 0–4.7) in normal controls. Nevertheless, expression of lineage infidelity markers, such as CD5, CD7 and CD56, on CD34+CD38− stem cells in MDS strongly suggests that a considerable part of these stem cells is malignant (median 35% in 7/16 patients tested). Our data show that CLL-1 is virtually absent on stem cells in MDS. Remarkably, median CLL-1 expression on stem cells in AML cases that evolved from MDS (7%, range 0–53, n=9) was manifold lower than in de novo AML (median 45% when excluding non de novo AML [Van Rhenen et al.,Blood 2007,110], p=0.034). Detailed analysis of CLL-1 expression in AML had already revealed that CLL-1 expression increases with differentiation (CD34− > CD34+CD38− > CD34+CD38+). [Bakker et al.,Cancer Res 2004,64;Van Rhenen et al.,Blood 2007,110] Thus, our data suggest that the CD34+CD38− cells in high risk MDS and AML with antecedent MDS are more immature than in most de novo AML, which might explain poor prognosis of AML cases with MDS history. To conclude, our data indicate that CLL-1 is a specific marker of de novo AML, while CLL-1-negative AML may have been evolved from a MDS pre-phase that is further characterized by an increasing size of the stem cell compartment upon progression towards AML.

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Hematopoietic Cell Kinase (HCK) Is Involved in Myelodysplastic Syndromes and Acute Leukemia Pathophysiology By Modulating PI3K Pathway and Enhancing Erythroid Differentiation

Blood ◽

10.1182/blood.v124.21.1891.1891 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1891-1891

Author(s):

Fernanda Marconi Roversi ◽

Fernando V Pericole ◽

João Agostinho Machado-Neto ◽

Ana Leda Longhini ◽

Adriana Silva Santos Duarte ◽

...

Keyword(s):

High Risk ◽

Actin Polymerization ◽

De Novo ◽

Specific Inhibitor ◽

Erythroid Differentiation ◽

Pi3k Pathway ◽

Low Risk ◽

Healthy Donors ◽

Cd34 Cells ◽

De Novo Aml

Abstract Introduction: Src family non-receptor tyrosine kinase regulates diverse cellular responses mainly by activating PI3K signaling, an important pathway that contributes to many cancers pathology. HCK, a Src family member, is restricted expressed in hematopoietic cells; however, high levels of HCK have been reported in solid tumors and hematologic neoplasms and have been associated with a worse prognosis. Identification of unbalanced pathways and upregulated proteins and a better knowledge of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) pathogenesis could help identify potential druggable targets and new prognostic biomarkers. The clinical and biological role of HCK in MDS and AML pathophysiology has not yet been elucidated and may be a novel therapeutic approach. Aims : To evaluate HCK expression in hematopoietic stem cells (HSC/CD34+) and in total bone marrow (BM) cells from healthy donors and MDS and AML patients. We further attempted to analyze the HCK knockdown and drug inhibition on differentiation, proliferation, apoptosis and migration in HSC/CD34+ and in a panel of human leukemia cell lines (KG1a, U937, HL60, P39). Materials and Methods : A total of 34 healthy donors and 139 patients at diagnosis (MDS=75 [low-risk=46, high-risk=29], AML with Myelodysplastic related changes (AML-MRC)=21 and de novo AML=43), were included in the study. HCK gene and protein expression was analyzed by qPCR and Western blot. Results are expressed as median (minimum–maximum) after appropriate statistical analysis. For functional analysis, HCK was inhibited with specific lentiviral vector system in HSC/CD34+ (isolated from umbilical cord blood units and BM), KG1a, U937, HL60 and P39 cells. Apoptosis was evaluated by Annexin-V/PI, cell growth by CellTiter assay, migration by Transwell, CXCR4 expression and actin polymerization by flow cytometry. We also verified the effects of a HCK specific inhibitor, ASN05260065, kindly provided by ASINEX and Dr Maurizzio Bottas. Results : HCK mRNA were significantly increased in HSC/CD34+ from patients with MDS (4.87 [0.03-14.75]; P=.003) and AML (8.36 [0.70-24.47]; P=.003) compared to healthy donors (1.19 [0.06-3.02]). When patients were stratified according to WHO classification, HCK expression was significantly higher in low-risk MDS compared to high-risk and AML-MRC (8.10 [2.30–14.75] vs 3.22 [0.03–6.33] and 1.02 [0.70–2.78], P<.001). Similar results were found in BM cells: HCK transcripts were significantly increased in MDS compared to healthy donors, and in low-risk compared to high-risk MDS (P<.0001). Interestingly, 5 of 5 MDS patients showed a significant decrease in HCK expression after disease progression. Also, a negative correlation was observed between BM blast percentage and HCK expression in MDS patients. In HSC/CD34+ cells, BFU-E colony number was significantly lower after HCK inhibition. HCK depletion reduced cell death in HSC/CD34+, P39 and KG1a cells and diminished proliferation in KG1a and U937 cells. Moreover, HCK knockdown decreased the phosphorylation of AKT, mTOR (PI3K pathway members) and ERK and treatment of HCK silenced cells with PI3K inhibitors had no synergic effect. Confirming the HCK lentivirus silencing results, HCK specific inhibitor treatment downregulated PI3K and ERK signaling. In addition, HCK inhibition significantly reduced migration towards CXCL12 chemoattractive stimuli by regulating CXCR4 expression and F-actin polymerization. Attempts have been made to transduct CD34+ from low-risk MDS patients however more than 80% cells were apoptotic and impossible to perform further assays. Conclusions : HCK is overexpressed in HSC/CD34+ and BM cells from MDS, mainly in low-risk MDS, and de novo AML. During MDS progression, HCK expression reduction correlates with increasing blast percentage and could indicate less dependence on microenvironment. HCK inhibition reduced BFU-E colony formation and our previous results showed that HCK expression increases during erythroid differentiation of non-transduced low-risk MDS CD34+ cells. Thus, HCK seems to play a role as a downstream effector in erythropoietin (Epo) signaling which could explain the higher HCK expression in low-risk MDS. Besides, HCK is an upstream regulator of PI3K and MAPK pathway that enhances cell apoptosis, survival and proliferation. Our study described new insights to the role of HCK in Epo/PI3K signaling and in leukemogenesis. Disclosures No relevant conflicts of interest to declare.

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Prognostic Factors in Primary Chronic Myelofibrosis in Patients Aged Less Than 70 Years: A Report on 207 Patients with the Description of a Scoring System and Its Validation on 100 Other Patients.

Blood ◽

10.1182/blood.v104.11.1524.1524 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1524-1524 ◽

Cited By ~ 1

Author(s):

Tetsuya E. Tanimoto ◽

Kazuya Shimoda ◽

Takuhiro Yamaguchi ◽

Takashi Okamura ◽

Hideaki Mizoguchi ◽

...

Keyword(s):

Prognostic Factors ◽

High Risk ◽

Risk Group ◽

Survival Rates ◽

High Risk Group ◽

Low Risk ◽

Data Set ◽

Hematopoietic Stem ◽

External Data

Abstract Primary chronic myelofibrosis (PCMF) is a rare myeloproliferative disorder among young individuals. Conventional therapies are often ineffective and only palliative. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) using myeloablative or reduced-intensity conditioning offers the only possible curative treatment. However, the course of PCMF is highly variable from only a few months to more than a decade. To identify PCMF patients for allo-HSCT candidates, we analyzed a Japanese cohort aged less than 70 years and established a new prognostic system based on simple clinical parameters. In a training series, we used 207 patients with complete data, whose diagnoses were made over a period of 10 years (1988 to 1997) (Okamura T et al. Int J Hematol 2001). Patients who received allo-HSCT were not included. Using the Cox proportional hazard regression model, four initial variables were independently associated with shorter survival: Male sex (hazard ratio [HR], 2.26; 95% confidence interval [C.I.], 1.35–3.46), Hemoglobin < 10 g/dL (HR, 3.01; 95% C.I., 1.83–4.93), the presence of constitutional symptoms (fever, sweats and weight loss) (HR, 2.33; 95% C.I., 1.33–4.06), and circulating blasts ≥ 1% (HR, 1.53; 95% C.I., 1.00–2.33). Based on the above criteria, two groups were identified; a low-risk goup with up to one adverse prognostic factor and a high-risk group with two or more adverse prognostic factors. With the median follow-up time of 83 months, the median survival was 292 months in the low-risk group, and 66 months in the high-risk group, respectively (P <.0001, Figure). An external data set of 100 patients who diagnosed after 1999 was used for validation. The 4 prognostic systems separated the validation series in groups with significantly different survival rates despite the median follow-up time of 12 months. A simple prognostic model using the combination of sex, Hb level, constitutional symptoms and circulating blasts was developed and validated. This model might help to select patients with PCMF for treatment and to evaluate therapeutic results including allo-HSCT. Figure Figure

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Poor Outcome after Allogeneic Hematopoietic Stem Cell Transplantation for De Novo AML with Chromosome 7 Abnormalities: A Report for the ALWP of the European Group for Blood and Marrow Transplantation.

Blood ◽

10.1182/blood.v110.11.325.325 ◽

2007 ◽

Vol 110 (11) ◽

pp. 325-325

Author(s):

Agnes Buzyn ◽

Myriam Labopin ◽

Jurgen Finke ◽

Tapani Ruutu ◽

G. Ehninger ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

De Novo ◽

Conditioning Regimen ◽

Chromosome 7 ◽

Partial Deletion ◽

Hematopoietic Stem ◽

Monosomy 7 ◽

Advanced Phase ◽

De Novo Aml

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for many acute myeloid leukemia (AML) patients, especially those with high-risk features. However, for the latter, cure rates remain disappointing due to relapse and transplant related mortality. Since high-risk AML defines a heterogeneous group of patients, the aim of this study was to evaluate specifically the impact of chromosome 7 abnormalities on the outcome of patients transplanted for AML. From 1982 to 2005, 159 de novo AML patients were reported in the EBMT registry with a chromosome 7 abnormality. Median age was 40 years (16–67). FAB subtypes were various: 20 M0, 34 M1, 34 M2, 30 M4, 10 M5, 6 M6, 9 M7, 16 missing. Monosomy 7 was present in 86 patients (54%) either isolated (n=71) or associated to a complex karyotype (n=15), whereas 46% had partial deletion. HSCT was performed in complete remission (CR1) in 85 patients (53%) and for an advanced phase for 69 (43%) defined as either primary refractory (n=49) or progressive (n= 20). The donor was a match sibling (n=88), unrelated donor (MUD) (n=42), or mismatched UD (n=29). The conditioning regimen was myeloablative for 123 patients (77%), containing TBI for 82. Stem cell source was peripheral blood for 97 patients (61%). T cell depletion was performed for 54% of the transplants either in vivo (n=60) or in vitro (n=26). The median follow up of the cohort is 47 months. A GvHD grade II-IV occurred in 47 patients (30%) and III/IV in 28 patients (18%). Among 132 patients alive at day 100, 38% developed chronic GvHD. At time of analysis only 42 patients are alive. The main cause of death is relapse (57%). The univariate analysis shows that the probability of OS at 5 years is 43% for patients transplanted in CR as compared to 11% for advanced phase patients (p<0,0001), and is only 17% for patients with a monosomy 7 compared to 29% for patients with a partial deletion (p=0,007). The survival of patients with AML FAB subtypes M5, 6 or 7 is only 8% compared to 24% for other subtypes (p=0,03). The year of transplant, T cell depletion, type of donor, conditioning regimen, cell source, and patients age have no influence on survival. In the multivariate analysis, CR at transplant (p= 0,005) and partial deletion of chromosome 7 (p=0,02) are the only two factors associated with a better 5 years OS. In conclusion, patients with abnormalities of the chromosome 7 and specially those with monosomy 7 represent a very high risk group of AML patients after HSCT, mostly because of the relapse risk, suggesting a very poor graft-versus-leukemia (GvL) effect in this disease which does not seem to be improved by the use of an UD. Thus, new approaches attempting to decrease the relapse rate of de novo AML with chromosome 7 abnormalities after HSCT are urgently needed.

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