Acute Myeloid Leukemia with rearrangements of CBFα or β (CBF-AML) are associated with a younger age and with a good prognosis when treated with intensive chemotherapy. CBF are infrequent in elderly ...patients (Appelbaum BJH 2006) and are associated with a better outcome as compared to other AMLs. Complete Remission (CR) rate and Event Free Survival (EFS) seemed to be lower than what was observed for younger patients. However, only limited data are available on the characteristics and outcome of CBF-AML in the elderly. We presents the results of a retrospective analysis of 150 patients with t(8;21) or inv(16) older than 60 years who received conventional induction chemotherapy in 17 centres of the french CBF AML intergroup (GOELAMS/ALFA groups). All patients received conventional anthracyclin + cytarabine induction therapy. Post-remission therapy consisted of low dose maintenance chemotherapy (87 patients 58%), intermediate or high dose cytarabine (47 patients, 31%) or Melphalan with autologous (SCT: 9 patients 6%). Median age was 67 years (range 60–82y). Inv(16) was found in 88 pts (58%) and t(8;21) in 62pts (42%). Additionnal chromosomal abnormalities were identified in 66 patients (44%) including 16 with trisomy 22 (11%) only in pts with Inv(16), 19 (13%) with loss of sex chromosome and 7 (5%) with del 9q mostly found in t(8;21). 132 patients achieved CR after 1 or 2 induction courses (88% CR rate), 3 pts had refractory diseasea and 15 died early (10%). 17 pts (11%) required ICU transfer during induction. Induction mortality was significantly related to poor performance status (p<0.001) and High WBC count at diagnosis(p=0.015). With a median follow-up of 17 months, Overall Survival (OS) and EFS were respectively 24 and 19 months. By multivariate analysis of factors influencing OS and LFS are presented in the Table. Outcome was favorable for Inv(16) patients (OS=27 months, EFS=22 months) compared to t(8;21) patients (OS=21 months, EFS=14 months). Interestingly, the benefit of intensive consolidation was limited to t(8;21) AML (EFS NR vs 11 months, p=0.002). No impact of age as a continuous variable could be demonstrated. After relapse, Median Overall survival was 5 months with a significantly better outcome in Inv(16) patients and if relapse was delayed (more than 12 months after CR1). No impact of age on outcome after relapse could be demonstrated. This large series of elderly patients with CBF-AML show that these patients must be offered standard induction which leads to high CR rate whatever the age. Nevertheless, the majority of them relapse with conventional post-remission treatment and the impact of intensive chemo seems limited. Alternative strategies of post-remission therapy are thus warranted including new cytotoxic drugs as well as targeted molecules.
VariableRR Overall survivalp=RR Event Free Survivalp=High WBC count2.56 1.464–4.4910.0012 1.104–3.5620.022ECOG (0–1 vs 2–4)5.12 2.878–9.112< 0.0012.76 1.457–5.2150.002Deletion 9q5.06 2.125–12.05< 0.0013.32 1.445–7.6290.005ICU admittance during induction5.18 2.744–9.764< 0.0012.86 1.216–6.7170.016use of High Dose Cytarabine0.373 0.196–0.7080.003NSNS
Transformation of Philadelphia (Ph)–negative myeloproliferative neoplasms (MPNs) to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) is associated with poor response to chemotherapy and ...short survival. Fifty-four patients with Ph-negative MPN (including 21 essential thrombocythemia ET, 21 polycythemia vera PV, 7 primary myelofibrosis, and 5 unclassified MPN) who had progressed to AML (n = 26) or MDS (n = 28) were treated with azacitidine in a patient-named program. Overall response rate was 52% (24% complete response CR, 11% partial response PR, 8% marrow CR or CR with incomplete recovery of cytopenias, 9% hematologic improvement) and median response duration was 9 months. Prognostic factors were for overall response the underlying MPN (71% vs 33% responses in ET and PV, respectively; P = .016); prognostic factors for CR achievement were the underlying MPN (14% CR for PV vs 43% for ET; P = .040) and World Health Organization classification at transformation (36% vs 12% CR in MDS and AML, respectively, P = .038). Recurrence of chronic phase features of the initial MPN was observed in 39% of the responders. Median overall survival was 11 months. Azacitidine gives encouraging results in Ph-negative MPN having progressed to AML or MDS, but response duration is short, and consolidation treatments have to be evaluated.
Abstract 3820
Poster Board III-756
AZA provides 50-60% responses and improves OS in higher-risk MDS (Lancet Oncol 2009) but prognostic factors of response and OS remain largely unknown.
An AZA ...compassionate program (ATU) was opened in France between Dec 2004 and Dec 2008 for higher risk MDS, and for AML not candidates or refractory to intensive chemotherapy (IC). We retrospectively analyzed the outcome of higher risk MDS (including RAEB-t) patients (pts) included in this program in the 42 centers with complete patient (pt) reporting, having received ≥ 1 cycle of AZA, and excluding those who had received prior allo SCT, IC, or a hypomethylating agent.
233 pts (M/F: 145/88) with a median age of 71y (range 20-91) were included. Diagnosis (WHO classification) was: RA±RS: 2, RCMD±RS: 7, RAEB-1: 48, RAEB-2: 123, and RAEB-t: 53; IPSS cytogenetic risk was favorable (fav) in 75 (32%), int (intermediate) in 35 (15%), and unfavorable (unfav) in 112 (48%) (failure in 11, 5%); IPSS was: int-2 in 133 (57%), high in 97 (42%), NA in 3 (1%). Median time since diagnosis was 5 months (range 0–209). 29 patients (12%) had previously received low dose Arac (LD AraC). 162 pts (70%) were RBC transfusion dependent, including 49% requiring ≥ 4 RBC units/8 weeks. Median follow-up was 13 months. Patients received a median of 5 cycles (range 1-26) of AZA, at FDA/EMEA-approved schedule (75 mg/m2/d x7d /4 week) in 70% patients and a less intensive schedule (5d/4w, or <75 mg/m2/d) in 30% patients, while 16% received concomitant valproic acid (VPA). First response was evaluated after 3-4 cycles. Best response (IWG 2006 criteria) was CR in 22 pts (9%), PR in 6 (3%), marrow CR (mCR) in 25 (11%), stable disease (SD) with HI in 34 (15% including HI-E ± HI-N/HI-P in 13, HI-P±HI-N in 17, and isolated HI-N in 4) leading to an overall response rate of 38%. Moreover, SD without HI was observed in 26%, progression in 26%, death before 4 cycles in 7% and AZA discontinuation before 4 cycles in 3%. Overall, HI-E was obtained in 48/162 anemic pts (23%). 38% of the responders progressed after a median time of 13 months (range 3-26), and 62% remained responders after a median time of 11 months (range 1-35). Median response duration was 10.2 months in CR pts, not reached in PR pts, 13 months in mCR pts, and 25 months in pts who achieved SD with HI. No pre-treatment characteristic including age, sex, time since diagnosis, WHO, karyotype, importance of cytopenias, BM or PB blast %, IPSS, RBC transfusion dependency, nor VPA addition was predictive of response, but pts with prior LD-AraC had a significant lower reponse rate (24% vs 50% in LD-AraC naive pts, p=0.01). Considering specific cytogenetic abnormalities, response rates were 42% in del5q/-5 (n=59), 38% in del7q/-7 (n=65), 38% in +8 (n=26), 39% in complex karyotype (n=67) and 49% in normal karyotype (n=57) (p=NS). 1 and 2-year OS were 57.9% and 29.7%, respectively, and median OS was 13.7 months. By univariate analysis, pre-treatment parameters negatively influencing OS were transfusion dependency, presence of PB blasts, cytogenetic risk (IPSS), and IPSS high risk. By multivariate analysis, OS was independently influenced by baseline transfusion dependency (≥4 RBC units/8 weeks; 1y-OS 57.5% vs 71.5%, p=0.01), presence of PB blasts (1y-OS 44.6 % vs 74.4%, p=0.02) and cytogenetics (1 y OS 78.2%, 55.8% and 46.4% for fav, int, and unfav, respectively (p=0.009)). In a landmark analysis of OS from first evaluation date, pts with CR, PR or SD with HI-E had improved OS compared to those with marrow CR or SD without HI-E (1-y OS: 71.5% vs 49.6%, p=0.03) and to those who progressed (1y OS=24.4% p=0.002). Overall Survival was significantly longer in pts who achieved HI-E (n=48; 1-y OS from evaluation: 65.4% vs 35.4%, p=0.003), but not in pts achieving HI-N (n=33, p=0.2) or marrow response (ie< 5% blasts with >50% decrease; n=47; p=NS), while reaching HI-P had a borderline favorable effect on OS (n=51, p=0.07).
No pre-treatment parameter (apart from prior LD-AraC treatment) predicted response to AZA. Regarding OS, presence of PB blasts, intermediate or unfavorable cytogenetics and transfusion dependency were associated with poorer survival. Improvement of anemia (and to a lesser extent of platelets) rather than BM blast reduction were associated with survival improvement. Whether other tests, including methylation profiles, may provide further information predicting response to AZA is being evaluated.
Fenaux:Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.
Abstract 843
AZA prolongs survival in higher-risk MDS including patients (pts) with 20-29 % marrow blasts, now considered WHO-AML ( Lancet Onc, 2009). However, no large AML cohorts (especially with ...'30% marrow blasts) treated upfront with AZA have been reported.
An AZA compassionate program (ATU) was initiated in France in Dec 2004 for higher risk MDS, and AML considered not candidates or refractory to intensive chemotherapy (IC). We retrospectively analyzed WHO AML pts having received at least 1 cycle of AZA in the 42 centers with complete pt reporting, excluding those previously treated by IC, allo SCT, low dose AraC or a hypomethylating agent.
138 pts were included between Dec 2004 and Dec 2008; M/F: 86/52; median age 73 years (y) (range 31-87), 117 pts (85%) were > 65 y and 54 (40%) >75y. 65 pts (47%) had prior WHO MDS and 30 pts (22%) therapy related (tAML). 44 pts (32%) had 20-29% marrow blasts. Median WBC was 3.0 G/L 0.8-111.5. Karyotype (MRC classification), was intermediate (int) in 60 pts,( including 38 normal (NK), and 7 isolated +8 ) adverse in 67 pts (including 42 -7/ del7q, 41 del5q/-5, 45 complex karyotype, two 3q26) and failed in 11 pts.
With a median follow-up of 11.3 months, pts received a median of 4.5 AZA cycles (range 1-26). Treatment was according to FDA-EMEA approved schedule for MDS in 95 pts (69%) and a less intensive schedule (5d/4w, or <75 mg/m2/d) in 31% pts, 29 pts (21%) received concomitant valproic acid (VPA).
First evaluation was made after 3 to 4 cycles. An overall AML response (ie according to AML-IWG criteria) was observed in 29 pts (21%) including 19 CR (14%), 3 CRp (2%) and 7 PR (5%) after a median of 3 cycles (1 – 11). An additional 25 pts (who had no CR, CRi or PR) achieved hematologic improvement (HI, according to MDS-IWG 2006 criteria). Neither any pretreatment characteristic including age, preceding MDS, tAML, karyotype, WBC, marrow blast %, combination with VPA were correlated with AML response. Median time to progression after AML response was 7.6 months
In the 138 pts, 1 y-OS was 40%, 2 y OS 18% and median OS 10.2 months. In univariate analysis, pre-treatment characteristics negatively influencing OS were higher WBC, adverse cytogenetics, higher absolute PB blasts and diagnosis of tAML. In multivariate analysis: higher WBC (p=0.018), and adverse cytogenetics (p=0.0006) retained prognostic significance for OS. In particular, pts with WBC >10 G/L (32 pts in our cohort) carried poorer prognosis ( 1 y OS of 27% vs 44% ,p=0.01); NK had better OS (1-y OS: 66%) than adverse cytogenetics (1-y OS: 30%, p=0.01) but also other “intermediate-risk” abnormalities (1-y OS: 30%, p=0.03).
Marrow blast % did not influence OS and survival, whatever the cut off chosen. In particular, pts with 20-29 % marrow blasts had 22% AML response and 1 y OS of 50%, compared to 21% and 1 y OS of 35%, respectively, in pts with >30% marrow blasts (p=NS and NS, respectively). Prior MDS also had no influence on survival.
Overall, 33 pts required hospitalization during treatment, mainly for neutropenic fever.
A landmark analysis at the time of evaluation showed that achievement of CR, CRi or PR was associated with improved OS (1y-OS 55% vs 31%,p=0.007). In pts with no AML-IWG response, however, achievement of HI also predicted better survival: 1 y-OS 55% vs 19 %, p=0.02.
In the 54 pts older than 75 y (ie pts generally considered unfit for IC), 12 (22%) had AML response including CR in 9 (17%) and 3 PR (5%). 1y-OS was 41 % vs 38% for younger pts (p=NS). Hospitalisation was needed in 31% of them vs 32% in younger pts (p=NS).
In this untreated cohort of generally older AML pts considered non candidates for intensive chemotherapy, response rate was 21% and 1 y OS 40%. Higher WBC counts and adverse karyotype were associated with poorer OS, but marrow blast %, whatever the threshold chosen, had no influence on outcome. Age above 75 y was associated with similar response and 1y OS. Finally, pts without AML IWG responses but with improved cytopenias also appeared to have improved survival.
Off Label Use: Azacytidine is approved by FDA and EMEA in the treatment of high risk MDS and AML up to 30% of bone marrow blast.. Fenaux:CELGENE: Research Funding; AMGEN: Research Funding.
Background: AZA significantly improves survival over conventional treatment in higher risk MDS, especially in case of −7/del 7q (ASH 2007, abst n°817). Del 5q is the most frequent cytogenetic abn in ...MDS. Lower risk MDS with del 5q respond dramatically to lenalidomide (LEN), but the response rate to LEN is lower in higher risk MDS and AML with del 5q, that still have a poor outcome (ASH 2007, abst n°820). We analyzed response to AZA in those pts.
Methods: A multicenter patient named treatment program of AZA (75mg/m2/d for 7 days every 28 days) for higher risk MDS and AML (ATU program) was started in France in 2004. The first 195 pts having completed ≥ 1 cycle included 38 pts with del 5q treated in 16 centers, who are analyzed here.
Results: Median age was 66y (range 45–82). M/F : 20/18, WHO at inclusion : AML in 14 pts (de novo : 8, post-MDS : 5, post-MPD : 1 ; first-line : 9, relapsing/refractory after intensive chemo : 5), MDS in 24 pts (RCMD-RS : 1; RAEB1 : 4; RAEB2 : 15; RAEBt : 1; CMML : 1; unclass : 2). Del 5q was isolated in 3/38 cases, and with 1 and > 1 additional abn in 4 and 31 cases resp.(31 complex karyotypes). 22/38 pts had concomitant −7/del 7q. In MDS pts, IPSS was int-2 in 5 and high in 19 pts, resp. 6 pts had received LEN without response. Pts received a median of 3 cycles of AZA (range 1–17). The overall response rate (ORR, including CR+ PR+ marrow CR) of pts with del 5q was 11% (4% PR, 7% marrow CR, but no CR). An additional 4% of MDS achieved only HI-E. ORR of del 5q pts was lower than that of pts without del 5q (11% vs 30%, p=0.04). In del 5q pts, the ORR was similar in pts with and without concomitant −7/del 7q (6 vs 13%, p=.56). On the other hand, the ORR was 19% in −7/del7q pts (n=48) and tended to be lower in the presence than in the absence of concomitant del 5q (7% vs 27% resp., p=.09). In the overall group of pts with complex karyotype (n=46), the ORR was 18%, and also tended to be negatively affected by presence of del 5q (9% vs 27%, p=0.2). After adjustment on risk factors in the ATU cohort (including WHO diagnosis and age), del 5q pts still had a poorer ORR (HR=0.26 0.07–0.91, p=0.035). Median survival after onset of AZA was 9 months in pts with del 5q vs 15 months in pts without del 5q (p=.007), and this difference was confirmed after adjustment on age and WHO diagnosis (HR=050 0.28–0.89, p=0.019). In pts with complex karyotype, there was a trend for lower OS in case of del 5q (median 10 m vs 7 m, p=0.25).
Conclusion: Those findings suggest that higher risk MDS and AML with del 5q have poorer response rates and survival to AZA as single agent than other high risk MDS and AML, possibly also including pts with complex karyotype without del 5q. Novel therapeutic strategies, combining for example AZA and other drugs, may be required in those pts.
5-Azacitidine, a cytidine analogue used as a hypomethylating agent, is one of the main drugs for the treatment of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) in the elderly. ...However, after administration, it exhibits several limitations, including restricted diffusion and cellular internalization due to its hydrophilicity, and a rapid enzymatic degradation by adenosine deaminase. The aim of this study was to improve the drug cell diffusion and protect it from metabolic degradation via the synthesis of amphiphilic prodrugs and their potential self-assembly. Azacitidine was conjugated to two different omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The carboxylic acid group of the omega-3 fatty acids was effectively conjugated to the amine group of the azacitidine base, yielding two amphiphilic prodrugs. Nanoprecipitation of the obtained prodrugs was performed and self-assemblies were successfully obtained for both prodrugs, with a mean diameter of 190 nm, a polydispersity index below 0.2 and a positive zeta potential. The formation of self-assemblies was confirmed using pyrene as a fluorescent dye, and the critical aggregation concentrations were determined: 400 µM for AzaEPA and 688 µM for AzaDHA. Additionally, the stability of the obtained self-assemblies was studied and after 5 days their final stable arrangement was reached. Additionally, cryo-TEM revealed that the self-assemblies attain a multilamellar vesicle supramolecular structure. Moreover, the obtained self-assemblies presented promising cytotoxicity on a leukemia human cell line, having a low IC
value, comparable to that of free azacitidine.
Next generation sequencing (NGS) investigates for somatic mutations. The utility of incorporating routine sequencing to guide diagnosis and therapeutic decisions remains challenging. We report an ...observational multicentric study that aimed to assess the impact of somatic mutations testing by NGS in a real-life setting of chronic myeloid malignancies (CMM). A total of 177 patients were enrolled, partitioned in two overlapping groups. In group A (N=94), the indication was to search for clonal hematopoiesis (CH), in a context of suspected myelodysplastic syndrome or myeloproliferative neoplasia. In group B (N=95), the theranostic impact of somatic mutations was studied. A panel of 34 genes was applied on DNA extracted from blood or bone marrow samples. Within group A, the detection of CH comforted the diagnosis of CMM for 31 patients while absence of CH ruled out the suspected diagnosis in 47 patients. Within group B, NGS identified prognostic somatic mutations in 32 patients, with a therapeutic impact in 18 cases. The use of NGS in daily practice was found here to be useful for an integrated final diagnosis in 83% of the patients through the presence or absence of somatic mutations. Moreover, exploration for somatic mutations had a prognostic impact that led to treatment modification in 19% of the cases. This study outlines the fact that adequate prescription of these new investigations may have a significant positive medico-economic impact by allowing appropriate management of the patients.
Background
Three different scoring systems have been developed to assess pre‐transplant comorbidity in allogeneic hematopoietic stem cell transplantation (Allo‐HSCT): the Hematopoietic Cell ...Transplantation‐Specific Comorbidity Index, the Comorbidity/Age index, and the Augmented Comorbidity/Age index. All were devised to predict overall survival (OS) and disease‐free survival (DFS) survivals and non‐relapse mortality (NRM) in patients receiving HLA‐matched Allo‐HSCT, but their performance has scarcely been studied in the haploidentical Allo‐HSCT setting with post‐transplant cyclophosphamide, a procedure in constant expansion worldwide.
Methods
To address this issue, their impact on survivals and NRM was examined in a cohort of 223 patients treated with haploidentical Allo‐HSCT in four different centers.
Results
With a median follow‐up of 35.6 months, 3‐year OS, DFS, and NRM were 48.1% ± 4%, 46.3% ± 4%, and 30.0% ± 3%, respectively. No impact was found for any of the three comorbidity scores in univariate analysis. In multivariate analyses, the only three factors associated with lower OS were DRI (p < 0.001), an older age of recipients (≥55 years old, p = 0.02) and of donors (≥40 years old, p = 0.005). Older donor age was also associated with lower DFS and higher NRM.
Conclusion
The comorbidity scores do not predict survivals nor NRM in haploidentical Allo‐HSCT with PTCY, suggesting that pre‐transplant comorbidities should not be a contra‐indication to this procedure.
Three different scoring systems have been developed to assess pre‐transplant comorbidity in allogeneic hematopoietic stem cell transplantation: the Hematopoietic Cell Transplantation‐Specific Comorbidity Index, the Comorbidity/Age index, and the Augmented Comorbidity/Age index, but their performance has scarcely been studied in the haploidentical stem cell transplantation setting with post‐transplant cyclophosphamide, a procedure in constant expansion worldwide. To address this issue, their impact was examined in a cohort of 223 patients from four French centers treated with haploidentical stem cell transplantation. No impact was found for any of the three comorbidity scores in this study, suggesting that pre‐transplant comorbidities should not be a contra‐indication to this procedure.
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