scholarly journals ETS Family Transcription Factor Fusions in Childhood AML: Distinct Expression Networks and Clinical Implications

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2356-2356
Author(s):  
Jenny L. Smith ◽  
Rhonda E. Ries ◽  
Yi-Cheng Wang ◽  
Amanda R. Leonti ◽  
Todd A. Alonzo ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Adverse Outcome ◽  
Transcriptional Networks ◽  
Clinical Implications ◽  
Cell Transplant ◽  
Minimal Set ◽  
Hematopoietic Stem ◽  
Bet Inhibitors ◽  
Ets Family

Abstract The ETS family of genes encode transcription factors (TFs) containing the ETS DNA binding domain, which have roles in cellular growth and development, including embryonic hematopoiesis. Dysregulation of these genes is associated with malignant transformation and tumorigenesis. In childhood acute myeloid leukemia (AML), the MNX1-ETV6 t(7;12)(q36;p13) and FUS-ERG t(16;21)(p11;q22) fusions are associated with adverse outcome. However, the biological and clinical implications of other ETS oncofusions in pediatric AML remain unknown. We identified 62 ETS gene fusions in 1,473 primary diagnostic AML samples (4.2%) using whole transcriptome RNA-sequencing and karyotype data. Four ETS family genes were identified to be involved in fusions with various partner genes: ETV6, ERG, FEV, and FLI1. Fusions with ETV6 were the most abundant (58%, 36/62) while FEV and FLI1 were the least; 21 fusion partners were identified where many function as TFs and co-activators (Figure 1A). MNX1-ETV6 (N=16) is enriched in infants (87.5% < 3 years, p < 0.001, Figure 1B), consistent with previous reports. ETV6 fusions with various partners (ETV6-Other, N=20) were likewise enriched in infants (50% < 3 years) and were significantly younger than patients without ETS fusions (median age: 3.0 vs 9.6 years, p = 0.025). FUS-ERG (N=10), HNRNPH1-ERG (N=8), and ETS fusions with various partners (ETS-Other, N=8) were primarily identified in patients 5-18 years old. Outcomes for patients with ETS fusions was determined after censoring for stem cell transplantation. Patients with ETS fusions as a collective group had adverse outcome with an EFS of 17.7% vs 39.9% (p = 0.047, Figure 1C), similar to high-risk cases in the reference group (22%), suggesting that patients with any ETS fusion may be considered high risk. Evaluation of outcomes by individual fusion groups at 3 years from diagnosis demonstrated an EFS of 0% for HNRNPH1-ERG, 18.0% for FUS-ERG, 14.2% for ETV6-Other, 20.8% for ETS-Other, and 28.4% for those with MNX1-ETV6. Twenty-one patients (37.5%) with ETS family fusions received stem cell transplant (SCT) in first complete remission, including HNRNPH1-ERG (N=5), FUS-ERG (N=3), ETV6-Other (N=5), ETS-Other (N=2), and MNX1-ETV6 (N=6). For these SCT recipients, OS at 3 years after transplant was 60.2%. We investigated whether ETS family fusions might have similar transcriptome profiles. Unsupervised uniform manifold approximation and projection (UMAP) on RNA-seq gene expression data followed by Leiden clustering found that individual fusions clustered in the same 3D space. More importantly, ETS fusion groups clustered closely to one another, indicating a shared transcriptional profile (Figure 1D, circle). Next, ETS fusion groups were each independently compared to the reference cohort (N=1421) using differential expression (DE) analysis. Intersection of DE genes revealed 17 overexpressed genes common to ETS fusions and 9/17 (52%) were also dysregulated when contrasting ETS cohorts to healthy normal marrows' transcriptome (N=68, Figure 1E). The minimal set of dysregulated genes included an adhesion molecule EDIL3, a prostaglandin (PG) enzyme HPGD, and a tyrosine phosphatase PTP4A3, which is strongly associated with progression in lymphoblastic leukemia and multiple myeloma. EDIL3 was reported to be overexpressed in MNX1-ETV6 and we found this molecule is a common feature of ETS fusions and their cellular dysregulation. The minimal set of 9 genes were further investigated using protein interaction networks defined from Pathway Commons v11. FUS-ERG and HNRNPH1-ERG both had significantly (adj. p < 0.001) activated HPGD networks; PG-E synthase and > 10 PG metabolism genes were upregulated. PG metabolism has important roles in regulating hematopoietic stem and progenitor (HSPC) functions and PG-E2 was shown to increase HSPC survival. ETV6-MXN1, ETV6-Other, and FUS-ERG had activated PTP4A3 networks and its expression was associated with sensitivity to BET inhibitors (BETi) in myeloma. They also exhibited increased activity of an ERG network with the overexpression of upstream regulators CBFA2T3 and GATA, and downstream targets like VWF and ZBTB16. Overall, we show that ETS fusions are uniformly high risk and share dysregulated cell adhesion (EDIL3) and transcriptional networks for ERG, HPGD, and PTP4A3, which provide opportunities for further research into the metabolome and therapeutics (BETi) in these fusions. Figure 1 Figure 1. Disclosures Shaw: T-Cell and/or Gene Therapy for Cancer: Patents & Royalties.

Tandem Autologous Stem Cell Transplants (auto-auto) with or without Maintenance Therapy Versus Single Autologous Transplant Followed by HLA-Matched Sibling Non- Myeloablative Allogeneic Stem Cell Transplant (auto-allo) for Patients (pts) with High Risk (HR) Multiple Myeloma (MM): Results From the Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) 0102 Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 526-526 ◽  
Author(s):  
Edward A Stadtmauer ◽  
Amrita Krishnan ◽  
Marcelo C Pasquini ◽  
Marian Ewell ◽  
Edwin P Alyea ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplant ◽  
Chronic Gvhd ◽  
Secondary Analysis ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Cell Transplant ◽  
Primary Analysis ◽  
Hematopoietic Stem

Abstract Abstract 526 The prognosis of patients with high-risk myeloma (HR MM) continues to be dismal, despite the early incorporation of novel agents. Early phase trials of allogeneic hematopoietic stem cell transplant (alloHCT) suggest the possibility of an immunologic graft-versus-myeloma effect that might favorably affect survival. Less toxic reduced-intensity HCT preparative regimens now allow more widespread use of alloHCT in the MM population. BMT CTN 0102 is a phase III multicenter clinical trial that biologically assigned patients to either melphalan 200mg/m2 (MEL 200) auto-auto without (obs) or with 1 year of thalidomide and dexamethosone (ThalDex), or an auto-allo approach using MEL 200 followed by alloHCT using 2 Gy total body irradiation. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine and mycophenolate mofetil. Patients were stratified by biological prognostic factors that were considered to be high risk at the time of the trial design: chromosome 13 deletions by metaphase karyotype and beta-2 microglobulin ≥4 mg/dl. The primary endpoint was 3-year progression free survival (PFS). Between December 2003 and March 2007, 710 patients from 43 US centers were enrolled, and 85 fulfilled the criteria of HR MM. Among them, 48 were assigned to auto-auto (24 Thal-Dex and 24 obs) and 37 to auto-allo. Groups differed in age (median 57 y and 51y, p=0.02) but were otherwise balanced. Compliance with second transplant was 65% for auto-auto and 78% for auto-allo. Compliance with ThalDex was poor, so the two auto-auto arms were pooled for the primary analysis. Three-year PFS was 33% (95% Confidence Interval (CI), 22–50%) and 40% (95% CI, 27–60%, p=0.74) and 3-year OS was 67% (95% CI, 54–82%) and 59% (95% CI, 49–78%, p=0.46) for auto-auto and auto-allo, respectively. Corresponding probabilities for 3-year progression/relapse was 53% and 33% (p=0.09), and 3 year treatment-related mortality was 8% and 20% (p=0.3). Among auto-allo patients, probabilities of grade 3–4 acute and chronic GVHD were 9% and 48%, respectively. Among the 59 (31 auto-auto, 28 auto-allo) patients who received second transplant, 3 year PFS was 35% and 46% (p=0.6). Disease response at day 56 after second transplant was 57% for very good partial response (VGPR) or better and 37% for complete response (CR) and near CR (nCR) in the auto-auto group; and 48% (VGPR or better) and 41% (CR+nCR) in the auto-allo group. In conclusion, this planned secondary analysis of a cohort of HR MM patients demonstrated equivalent 3-year PFS and OS for auto-auto and auto-allo in both intention-to-treat and as-treated analyses. However, trends in late PFS and time to progression/relapse suggest further follow-up is needed before final conclusions regarding the utility of auto-allo in this HR cohort can be made. Finally, this study shows the feasibility of an alloHCT approach for HR MM patients and may serve as a platform for future studies seeking to enhance graft-versus-myeloma effects. Disclosures: Stadtmauer: Celgene: Speakers Bureau. Krishnan:Celgene: Speakers Bureau. Qazilbash:Celgene: Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Giralt:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau.

Prognostic Factors and Outcomes in Allogeneic Hematopoietic Stem Cell Transplant Vs. Non-Transplant Chronic Lymphocytic Leukemia (CLL) Patients: A Comparative Analysis with the Leukemia/BMT Program of British Columbia (BC) and the BC Provincial CLL Database

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2549-2549 ◽  
Author(s):  
Sebastian J. Swic ◽  
Alexander G. T. MacPhail ◽  
Chinmay B. Dalal ◽  
Steven J.T. Huang ◽  
Alina S. Gerrie ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Hematopoietic Stem Cell ◽  
Conflicts Of Interest ◽  
Early Recognition ◽  
Lymphocytic Leukemia ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Long Term Outcome

Abstract Background: Chronic Lymphocytic Leukemia (CLL) patients (pts) have significant (sig) heterogeneity; survival ranges from decades to <5 years (yrs). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is promising treatment (tx) for high-risk pts. Ideally, predictive (pred) tools would allow clinicians to recognize such pts early, permitting transplant performance to maximize benefit and minimize procedure associated risk. Factors with significant (sig) pred capacity are not, however, entirely clarified. Moreover, limited studies compare CLL pts who have/have not received HSCT in terms of differences (diff) in characteristics (char) at diagnosis (dx), population (pop) composition and outcomes. This study evaluates pred factors for outcomes post allo-HSCT, and compares dx char between (bn) tx CLL pts who did /did not receive HSCT by evaluating a large pop-based CLL cohort (n= 1044) from the BC Provincial CLL Database (BCPCD). Methods: 102 CLL pts (71M, 31F) had consecutive allo-HSCT (01-91 to 03-13, L/BMT Program of BC). Median (med) age (range) at dx:HSCT was 50 (26-65):57 (32-68) yrs; med interval dx to HSCT 5.8 yrs (0.5 to 29). Most pts (78, 76%) received non-ablative therapy; (n=61 [60%] reduced-intensity fludarabine /busulfan [flu/bu] based [RIC], n=17 [17%] non-myeloablative flu-cyclophosphamide based [NMA]); 24 pts had myeloablative (MA) conditioning (CON). Donor status was 50% unrelated (UD) (51UD:51RD); 73M, 28 F. Results: With median (med) follow up (FU) (range) post allo-HSCT of 2 yrs (0.5-18); post dx of 9 yrs (1-38), 67 (50%) pts survive. 70 (69%) achieved CR post-HSCT a med of 187 (28-1274) days (d). 27 had CLL PROG a med of 339 (25-4367) d; 18 of 27 (67%) survive a med of 3 (0.5-18) yrs post HSCT. Factors pred OS post HSCT (KM p=; UVA HR=) (p<0.05) were: pre-HSCT FISH deletion 17p (del 17p) (0.005; 2.9), Dohner rank (0.02), HSCT specific comorbidity index (CoI) >3 vs. 0-2 (0.04; 2.5), HLA mismatched (MM) donor (0.03;2.3), pre-HSCT tx with alemtuzumab (alem) (0.005;3.0), CON (MA vs NMA or RIC) (0.046; 3.0), acute (A) graft vs host disease (GVHD) grade (g) 3-4 vs 0-2. (<0.001; 4.5), dn chim <90% (0.001; 5.2), abn FISH not clear post-HSCT (0.009; 2.6), yr of HSCT (pre- vs post-2010) (0.03; 3.13) and lack of CR post HSCT (<0.001; 10.5).The following sig pred for (OR; p=): >90% dn chim: no B symptoms at dx (2.5; 0.004), CON (RIC vs. NMA, (2.6; 0.006); clear FISH abn post-HSCT: CR post-HSCT (4.6; 0.004); CR post-HSCT: B symptoms at dx (0.4; 0.02), <=1 FISH abn (1.7; 0.045), rituximab (R) pre-HSCT (2.5; 0.001), clear FISH abn (2.5; 0.01), flu sensitivity (S) pre-HSCT (1.8; 0.03), S to last tx pre-HSCT (1.7; 0.03), CON (MA vs. RIC or NMA) (3.2; <0.001); PROG: Richter’s transformation ( Rich trans) pre-HSCT (3.5; 0.008), graft failure (3.3; 0.008), CoI >3 vs. 0-2 (6.9; 0.006), no R pre-HSCT (6.7; 0.01), CON (MA vs. NMA or RIC), (0.2; 0.03); NRM: pre-HSCT alem (2.7; 0.03), CoI >3 vs. 0-2 (2.7; 0.049), HLA MM (2.8; 0.01), CON (MA vs. rest) (3.0; 0.007), AGVHD g 3-4 vs. 0-2 (5.9; <0.001), FISH abn not clear (2.6; 0.04), and no CR (6.5; <0.001). Comparison bn allo-HSCT and BCPCD CLL pts showed sig diff at dx for Dohner FISH rank: more del 17p (23% vs.11%) and 11q (23% vs. 9%) in allo-HSCT pts (n=84 with pre-HSCT FISH); less +12 (13% vs. 17%), del 13q (24% vs.41%) or normal (22% vs 18%), p<0.001 than non-HSCT pts (n=952); Age at dx (med, range) was lower in HSCT (50, 26-65) vs non (62, 25-96), p<0.001; lymphocyte (lymph) count higher (14, 1-300 vs.11, 1-662, p=0.03), tx-free survival (TFS) from dx to 1st tx shorter at 0.75 (0-9.3) vs. 2.86 (0-20.6) yrs. Rich trans was more frequent in HSCT pts (8%) vs. non (3%), p=0.015.OS was sig better for HSCT pts (n=103) (med 17.6, SE 4.5, CI 95% 8.8-26) compared to non (n=494) (med 14.4, SE 1.1, CI 95% 12.1-16.6) (p=0.03). Conclusion: CLL allo-HSCT pts have sig diff than non including higher lymph at dx, shorter time to 1st tx, and higher risk FISH abn. 17p del remains high-risk with allo-HSCT. Pre-HSCT R increased post HSCT CR. Strategies to optimize post-HSCT CR and dn chim are important; these milestones are crucial to best outcome. PROG post-HSCT does not confer worse OS; rescue strategies are successful and deserve further study. Comparison of this large allo HSCT and pop-based BPCDB cohort indicate improved OS for allo-HSCT tx CLL pts vs. other, with a survival plateau. This data indicates early recognition of high-risk CLL patients for HSCT is likely to yield best long-term outcome. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals Clinical Outcomes of MDS Patients Who Were Allogeneic Hematopoietic Stem Cell Transplant Candidates but Did Not Proceed with Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2181-2181
Author(s):  
Rohan Gupta ◽  
Ibrahim Aldoss ◽  
Dongyun Yang ◽  
Sally Mokhtari ◽  
Samer K. Khaled ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Selection Bias ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
De Novo ◽  
Case Series ◽  
Cell Transplant ◽  
Consecutive Case ◽  
Hematopoietic Stem

Abstract Allogeneic hematopoietic stem cell transplant (alloHCT) remains the only potentially curative treatment for patients with myelodysplastic syndrome (MDS). However, this treatment is associated with significant risk of transplant-related mortality/morbidity such as graft-versus-host disease, infections, and regimen-related toxicities. Since there has been no "randomized" trial comparing between patients undergoing or not undergoing transplantation, the relative benefit of this treatment, particularly in elderly patients, is largely unknown. Retrospective comparative studies are significantly limited by the inherent selection bias of healthier/well-supported patients in the alloHCT group. Therefore, a critical knowledge gap exists regarding the survival outcome of MDS patients who are transplant eligible yet did not undergo alloHCT due to lack of suitable donors or other reasons. Herein, we retrospectively identified a consecutive case-series of 73 patients with MDS (excluding CMML), who were considered alloHCT candidates, based on initiation of an official donor search from 2005 to 2015, yet did not proceed with alloHCT. Median age at time of donor search was 60 years (range: 20-79) with the majority (63%) being male. Classifications of MDS were single or multi-lineage dysplasia (n=20), excess blast (n=39), MDS unclassified (n=6) or other/unknown classification (n=8). The cohort included 51 de novo MDS and 14 therapy-related MDS (t-MDS). Per International Prognostic Scoring System (IPSS) 29 patients (39.7%) were Intermediate (Int)-1, 14 (19.2%) were Int-2, and 23 (31.5%) were high risk at the time of donor search (Table 1). Reasons for no alloHCT were lack of donor (n=29), persistent/progressive disease (n=9), patient choice (n=13), or infections/complications after initiating the donor search (n=18). Treatments of these patients included chemotherapy (n=14), hypomethylating agents (n=61) and supportive care (n=23). Of the 73 patients, 15 (20.5%) had disease progression to acute leukemia at 1 year. There were 38 deaths with the median OS of 26.2 months (95%CI: 17.3-48.3 months). The 2-year probability of OS was 51% (95%CI: 36.7-62.9%). We next compared outcomes of these MDS patients who had a donor search without subsequent HCT to a consecutive case-series of MDS patients who underwent alloHCT from matched related and unrelated donors (cord blood and haploidentical transplants were excluded) during the same time period (n=276) at our center (Aldoss et al. Haematologica 2017). Patient demographics and MDS disease characteristics were similar between the two groups (Table 1). Median number of days from HLA typing to HCT were 168. By Kaplan-Meier method, OS (from the time of donor search) was significantly better for the alloHCT group (74% at 2-years) compared with non-HCT group (51% at 2-years), log-rank P<0.001 (Figure 1a). This survival benefit was primarily driven by the subgroup of patients with int-2/high risk IPSS. While the difference in the OS did not reach statistical significance in low/int-1 patients between HCT and non-HCT groups (OS probability at 2-years: 80% vs 68%, respectively, p= 0.182), the 2-year OS was significantly better (p<0.001) in the alloHCT group (67%, n=133) compared with non-HCT group (34%, n=37), when analysis was done in int-2 or high-risk patients. (Figure 1b) In an attempt to further assess the inherent selection bias, we analyzed and compared patients with no available donor (n=29, biologic assignment) with patients who did not receive HCT for other reasons (n=44). No statistically significant difference (p=0.13) was seen in the 2 year-OS (58% vs. 45%). In conclusion, using a unique cohort of patients who were referred for a donor search, our study in real-world practice demonstrates that transplant eligible MDS patients (at the time of donor search) who do not undergo alloHCT have worse survival outcomes compared to those undergoing transplantation. A prospective biologic assignment study is currently underway by the BMT CTN (#1102) to more definitively determine the impact and relative benefits of alloHCT in patients (≥50 years old) with Int2/high-risk de novo MDS. Disclosures Khaled: Alexion: Consultancy, Speakers Bureau; Daiichi: Consultancy; Juno: Other: Travel Funding. Salhotra:Kadmon Corporation, LLC: Consultancy. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Stein:Celgene: Speakers Bureau; Amgen Inc.: Speakers Bureau.

Nelarabine-Based Salvage Therapy in Adult Patients with T-Cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma (T-ALL/LL) Relapsing After Allogeneic Stem Cell Transplantation: A French Experience on Behalf of the Group for Research in Adult Lymphoblastic Leukemia (GRAAL),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4095-4095
Author(s):  
Edouard Forcade ◽  
Thibaut Leguay ◽  
Norbert Vey ◽  
Andre Baruchel ◽  
Jacques Delaunay ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
High Risk ◽  
Salvage Therapy ◽  
Acute Gvhd ◽  
Response Rate ◽  
Lymphoblastic Leukemia ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Hematopoietic Stem

Abstract Abstract 4095 Backgroud: The prognosis of patients with T-ALL/LL has been recently re-assessed, based on monitoring of minimal residual disease (MRD) levels and new insights in pathogenesis (NOTCH1 pathway mutations). To date, allogeneic hematopoietic stem cell transplant (HSCT) in first complete remission (CR) remains the standard option in patients identified with a high risk of relapse. In this context, patients relapsing after HSCT represent a very difficult challenge to get a second CR. Nelarabine, a pro-drug of Ara-G, has been associated with a high response rate in relapsing ALL (Gökbuget N et al., Blood 2011), but very few data are available on its efficacy and safety in the post-HSCT setting. Patients: Medical records of 11 T-ALL/LL patients who received nelarabine-based salvage therapy for a relapse after HSCT were retrospectively reviewed. These patients were treated with nelarabine alone (1,5g/m2/day (D) D1, D3, D5, every 28 days) (N=5) or nelarabine associated with hyperfractionated cyclophosphamide (HyperC; N=6). Results: Ten patients had T-ALL and one had T-LL. Median age was 23 years (14–62) at time of diagnosis. Ten patients underwent HSCT in first CR (median time between diagnosis and HSCT: 141 days). HSCT conditioning regimen was myeloablative for 7 patients including Total Body Irradiation for 6 of them (reduced intensity conditioning for 4 patients). Source of stem cells was hematopoietic peripheral blood stem cells in 6 patients, bone marrow in 4 patients and unrelated cord blood in one patient. Four patients received a transplant from an HLA matched sibling donor and 7 from an unrelated donor (HLA-matched 10/10 in 3 patients). GVHD prophylaxis consisted in ciclosporine for all patients, either associated with methotrexate for 8 patients, mycophenolate for 2 patients or alone for one patient. Eight patients presented grade I-II acute GVHD (no patient had grade III-IV). Two patients developed chronic GVHD (1 extensive). Relapse occurred with a median duration of 199 days (119–2099). Six patients were still under immunosuppressive agents, because of slow tapering off or context of GVHD, which was stopped quickly. One patient presented a relapse in the context of cGVHD. Of the 11 patients treated with nelarabine-based salvage therapy, 81% achieved hematological CR within a median delay of 48 days. At one year, disease-free and overall survivals were 56% and 90%, respectively. Eight patients received additional nelarabine consolidation cycles (median, 4 cycles) and 2 CR patients received Donor Lymphocytes Infusion (1 complete molecular CR). One patient presented acute GVHD following nelarabine-based first cycle, requiring immunosuppressive treatment. Main toxicity was neurological (Grade 2 according to National Cancer Institute Common Terminology Criteria for Adverse Events), with 2 patients presenting sensitive neuropathy and cerebellar ataxia. Conclusion: In patients with T-ALL/LL relapsing after allogeneic HSCT, nelarabine-based salvage therapy was well tolerated with 2 neurological complications grade 2 and one acute GVHD. Moreover, this treatment was associated with a very high (81%) response rate with some patients experiencing prolonged remission. Post-HSCT nelarabine maintenance might thus be a valuable option to investigate in high-risk patients, possibly driven by MRD detection. Assessing immune responses in this particular setting could also be of particular interest. Disclosures: Peffault de Latour: Alexion: Consultancy, Research Funding.

Feasibility and Outcome of Allogeneic Hematopoietic Stem-Cell Transplantation in High-Risk AML: Real-Life Perspective from a Single Institution

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4395-4395
Author(s):  
Marina Diaz-Beya ◽  
Miguel Angel Torrente ◽  
Alfonso Ardilla ◽  
Carles Serra ◽  
Nuria Martinez ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Median Time ◽  
De Novo ◽  
Conditioning Regimen ◽  
Real Life ◽  
Poor Performance Status ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Hematopoietic Stem

Abstract Introduction: Allogeneic stem cell transplant (alloHSCT) is the treatment of choice in patients with high-risk acute myeloid leukemia (AML). However, it is uncertain exactly how many of these patients actually undergo alloHSCT as planned initially. Moreover, the real efficacy of this therapeutic option remains controversial. Since few studies have addressed these questions, to shed light on these issues, we have analyzed the results of a policy of early donor search, the proportion of patients in which initially planned alloHSCT was performed, and the outcome of alloHSCT in our center. Patients and Methods: We included in the study 246 AML patients (median age, 51 years, 16-70; 51% males) considered fit for intensive chemotherapy, who were treated according to 3 consecutive protocols of the Spanish CETLAM cooperative group (CETLAM-99, CETLAM-2003, and CETLAM-2012). Patients were diagnosed between 2003 and 2013 in our center or referred to our center for alloHSCT; median follow-up of alive patients was 70.4 months (12.5-143.8). Indication of allloHSCT in CR1 was established according to the stratification risk of each protocol, based on AML origin (de novo vs. secondary), cytogenetics, number of courses to achieve CR, NPM1/FLT3-ITD/CEBPA mutational profile, and MRD status at end of consolidation. Statistical analyses were performed using R v3.1 and SPSS v20. The effect of alloHSCT was analyzed by Mantel-Byar test with SCT as a time-dependent covariable. Results: AlloSCT was planned in 167 (68%) patients deemed of high-risk and it was actually performed in 130 out of these high-risk AML patients (78%). Types of donor were: matched related donor (MRD), n=63; 7/8 or 8/8 matched unrelated donor (MUD), n=51 (HLA matching: 8/8 or 10/10= 32; 7/8 and 9/10, n=19); unrelated cord blood (UCB) n=14; and family haploidentical donor, n= 2. Status at SCT was first CR (CR1) in 63 patients (48%), ≥CR2 n=23 (18%), and non-CR AML in 44 patients (34%). The type of conditioning regimen was myeloablative in 66 (51%) of the patients. Ninety-eight patients out of 167 patients with an indication for alloHSCT, lacked a MRD (59%). An unrelated donor search was performed in 80 (82%) out of these 98 patients, and was successful in 54 (67.5%). An UCB unit was selected in 14 patients without a MUD in a timely fashion. The main reasons for not initiating an unrelated donor search were poor performance status (n=5), refractory disease (n=4), and age (n=4). Median time from start of search to finding of an adequate donor was 50 days, and median time from start of search to SCT was 131 days. The overall outcome of these 167 patients with an indication of alloHSCT was 2-year OS: 48±8% and 5-year LFS: 36%±8% with a markedly better outcome among patients in whom alloHSCT was finally performed (2-year OS: 57±8% vs. 11%±10%; Mantel Byar, p<0.0001). The beneficial effect of alloHSCT was maintained in the subset of patients in CR1 for whom alloHSCT was planned (2-year OS: 60±12%; vs. 33±16%; Mantel Byar p=0.001). Intere stingly, the outcome of patients with an indication of alloHSCT did not differ between patients with an HLA-identical sibling and patients in whom a donor search was started (2-year OS: 50±12%; vs. 52±11%; p=0.97), in an intention-to-treat analysis. Moreover, the outcome of alloHSCT did not vary among different donor sources (MRD, MUD, and alternative donors) (2-year OS from alloHSCT: 59%±14% vs. 61%±18% vs. 44%±30, p= 0.6). Conclusions: A policy of early search of MUD enabled alloHSCT to be performed in the majority of patients for whom it was planned. Performing of alloHSCT in patients improved outcome of this cohort of high-risk AML patients, compared to patients not achieving alloHSCT. An adequate MUD was identified in a two thirds of patients, and a similar outcome was found after alloHSCT for all donor sources (MRD, MUD, and alternative source) in this study. Disclosures Rosiñol: Celgene, Janssen: Honoraria.

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