Final Report of Combination of Sorafenib, Idarubicin, and Cytarabine for Initial Therapy in Younger Patients with Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1516-1516
Author(s):  
Cecilia Y Arana Yi ◽  
Jorge Cortes ◽  
Stefan Faderl ◽  
Guillermo Garcia-Manero ◽  
Marina Konopleva ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Salvage Therapy ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Long Term Outcome ◽  
Acute Myeloid

Abstract Abstract 1516 Background: Sorafenib is a potent inhibitor of FLT3 kinase with demonstrable clinical activity in patients with acute myeloid leukemia (AML) and FLT3-ITD mutation, but not those with FLT3-D835 mutation. Objectives: To determine the long term outcome of patients with AML treated with the combination of Sorafenib, cytarabine and idarubicin, and in particular those with FLT3-ITD mutation. Method: Between October 2007 to March 2010, 62 patients with newly diagnosed, previously untreated AML, were treated with Sorafenib 400 mg orally twice daily (BID) for 7 days, cytarabine 1.5 g/m2 by continuous intravenous (IV) infusion daily for 4 days (3 days if > 60 years of age), and idarubicin at 12 mg/m2 IV daily for 3 days on an IRB-approved clinical trial. After achieving remission, patients received up to 5 cycles of consolidation with sorafenib 400 mg BID continuously and abbreviated doses of cytarabine and idarubicin given at approximately one month intervals. Results: 62 patients were treated on the phase II portion of the study. Median age was 53 years (range, 18 – 66) and 12 (19%) patients were > 60 years. 23 (37%) had FLT3 mutations including 17 with FLT3-ITD, 4 with FLT3-D835, and 2 with both mutations. Cytogenetics was diploid in 36 (58%), chromosome 5 and 7 deletion in 4 (6%) and 1 (2%) respectively, complex in 8 (13%), miscellaneous in 13 (21%). Median white blood cell count (WBC) at diagnosis was 7.25 × 109/L (range, 0.6 – 225), and 28 (45%) patients had WBC > 10 × 109/L; among these, 12 (43 %) had FLT3-ITD. After induction, 49 (79 %) patients achieved CR and 5 (8%) CR with incomplete platelet recovery (CRp). 1 (2%) patient died before response assessment could be performed and 7 (11%) were non responders. Patients with FLT3-ITD were more likely to achieve a CR/CRp than patients without FLT3-ITD [18/19 (95%) patients vs. 36/43 (83%) patients, respectively (p=0.23)]. To date, 32 (59%) of the responders have relapsed including 10 of 18 (56%) patients with FLT3-ITD and 22 of 36 (61%) patients without FLT3-ITD (P=0.86). 35 patients received salvage therapy; 14 died after receiving salvage therapy, 11 achieved a second CR and 10 were refractory. After a median follow up of 40.6 months (range, 5.7 to 50 months), the median DFS and OS were 13 months and 29 months, respectively. Hematopoietic stem cell transplantation (HSCT) was performed in 34 (55 %) patients, including 23 in CR, and 11 with active disease. Stem cell source was from related donors in 15 (44%), unrelated donors in 9 (26%), cord blood in 7 (21%), and haploidentical donors in 3 (9%) patients. Overall, 35 (56%) patients have died; 16 (26%) had infectious complications, 12 (19%) multi-organ failure, 9 (15%) graft versus host disease, and 10 (16%) other causes with some patients having overlapping causes. Three-year disease free survival (DFS)(in patients achieving CR, n=54) and overall survival (OS) (n=62) were 34% and 47%, respectively (Figures 1 and 2). Conclusion: Combination of sorafenib, idarubicin and cytarabine is an effective regimen with durable responses in patients with newly diagnosed AML, particularly those with FLT3-ITD. Disclosures: Ravandi: Bayer: Research Funding; Onyx: Research Funding.

Hematopoietic Stem Cell Transplantation (HSCT) Benefits the Survival of Acute Myeloid Leukemia (AML) Patients with IDH1, NRAS and DNMT3A Mutations

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1981-1981
Author(s):  
Yang Xu ◽  
Zhen Yang ◽  
Hong Tian ◽  
Huiying Qiu ◽  
Aining Sun ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Newly Diagnosed ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Abstract 1981 Background: Gene mutations may serve as potential markers to extend the prognostic parameters in acute myeloid leukemia (AML) patients. In this study, we detected distribution of mutations in the nucleophosmin gene (NPM1), C-KIT, the fms-related tyrosine kinase 3 gene (FLT3), Isocitrate dehydrogenase gene 1 and 2 (IDH1, IDH2), the neuroblastoma RAS viral oncogene homolog (NRAS) and DNA methyltransferase 3A gene (DNMT3A) in 442 newly diagnosed AML patients (none-APL). Associations of gene mutations with clinical outcomes in these patients followed HSCT treatment or chemotherapy were further evaluated. Methods: Between February 2005 and December 2011, 442 newly diagnosed AML (none-APL) patients in our centre were retrospectively analyzed. There are 248 males and 194 females, and the median ages were 40 (16–60) years. 393 patients (88.9%) of patients were with single or normal karyotype and 49 patients (11.1%) were with complex abnormal karyotype. In addition to MICM examination, direct sequencing was employed to access the distribution of mutations in of FLT3-ITD (exon14), FLT3-TKD (exon 20), NPM1 (exon12), C-KIT (exon8, 17), IDH2 (exon 4), NRAS (exon1, 2), DNMT3A (exon23) of 445 AML patients. Complete remission (CR) was achieved in 258 patients (58.4%) followed the standard induction therapy, 128 patients received HSCT (Allo-HSCT: 121 vs. Auto-HSCT: 7) therapy after first remission or second remission while 258 patients received consolidation chemotherapy contained 4–6 cycles high dose Ara-C (HD-Ara-C). Overall survival (OS) and Event-free survival (EFS) were measured at last follow-up (censored), and Kaplan-Meier analysis was used to calculate the distribution of OS and EFS. Results: In 442 AML (None-APL) patients, 44 patients (9.7%) had C-KIT mutations, 97 patients (21.9%) had NPM1 mutations, 95 patients (21.5%) had FLT3-ITD mutations, 26 patients (5.9%) had FLT3-TKD mutations, 23 patients (5.2%) had IDH1 mutations, 48 patients (10.9%) had IDH2 mutations, 31 patients (7.0%) had DNMT3A mutations, and 40 patients (9.0%) had NRAS mutations. Using COX regression, we found that mutations in FLT3-ITD (HR:2.113; 95%CI: 1.1420 to 3.144),IDH1 (HR:3.023; 95%CI: 1.055 to 3.879), NRAS (HR:1.881; 95%CI: 1.021 to 2.945), and DNMT3A (HR: 2.394; 95%CI: 1.328 to 4.315) were independent unfavorable prognostic indicators of overall survival of AML patients. We further compared the outcomes of AML patients with such gene mutations followed different therapy (HSCT vs. HD Ara-C), and results shown that patients with mutations in IDH1, NRAS and DNMT3A received HSCT therapy had better survival. The median OS and EFS of patients with FLT3-ITD, IDH1, NRAS and DNMT3A in the two groups (HSCT vs. HD Ara-C) were as follows: IDH1 (OS: 35 months vs. 11 months, p=0.016; EFS: 34 months vs. 8 months, p=0.012), NRAS (OS: 27months vs. 8 months, p=0.008; EFS: 23 months vs. 4 months, p=0.049), DNMT3A (OS: 66 months vs. 19 months, p=0.008; EFS: 54 months vs. 13 months, p=0.002). Conclusions: Taken together, our data proved that mutant FLT3-ITD, IDH1, NRAS, and DNMT3A might serve as poor prognostic markers and hematopoietic stem cell transplantation as first-line treatment could favor the outcome of AML patients carrying IDH1, NRAS, and DNMT3A mutations. Disclosures: No relevant conflicts of interest to declare.

WT1 Monitoring of Minimal Residual Disease (MRD) in Patients with Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3695-3695 ◽  
Author(s):  
Michele Malagola ◽  
Crisitina Skert ◽  
Enrico Morello ◽  
Francesca Antoniazzi ◽  
Erika Borlenghi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Residual Disease ◽  
Newly Diagnosed ◽  
End Of Treatment ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Background: Although a complete remission (CR) can be achieved in 70-80% of newly diagnosed acute myeloid leukemia (AML) patients, relapses occur in up to the 50% of cases. Thus, minimal residual disease (MRD) monitoring is a major issue for early detection of patients at high-risk of treatment failure and relapse. Aim: to dynamically evaluate WT1 pan-leukemic molecular marker of MRD in patients with AML. Matherial and methods: 107 newly diagnosed AML patients consecutively treated between 2010 and 2013 were monitored with quantitative WT-1 from bone marrow (BM) and peripheral blood (PB) at baseline, after induction, after the first consolidation course, before allogeneic stem cell transplantation (allo-SCT), at the 3rd and the 6th month after transplantation Results: At diagnosis, 104/107 (97%) had increased PB and BM WT1 levels assessed according to the ELN assay. Eighty-eight out of 107 patients (82%) achieved a complete remission (CR) after induction, 30/88 (34%) relapsed during follow up and 24/107 (22%) were addressed to allogeneic stem cell transplantation (allo-SCT). By univariate analysis, PB-WT > 50x10^4/ABL and BM-WT1 > 250x10^4/ABL after induction (PB: p=0.02; BM: p=0.04), after consolidation (PB: p=0.003), at the end of treatment (PB and BM: p=0.001), at 3rd month of follow up (PB and BM: p=0.005) and at 6th month of follow up (PB: p=0.005) were associated with a reduced overall survival (OS). By multivariate analysis, a BM-WT1 > 250 x 10^4/ABL at the end of treatment was significantly associated with a reduced OS. In order to adapt the cut-off of WT1 in our series of patients, we considered WT1 levels as continuous variables and categorized them at approximately the 25th, 50th, and 75th percentile. A cut-off of PB-WT1 > 25x10^4/ABL and BM-WT1 > 125x10^4/ABL at the end of the treatment program was identified as correlated with reduced leukemia-free survival (LFS) and OS (p=0.001). Similarly, and restricting the analysis on the 24 patients allo-transplanted in CR, 8/11 (73%) with pre-transplant PB-WT1 ≥ 5 and 4/13 (31%) with PB-WT1 < 5 relapsed, respectively (p=0.04). The incidence of relapse was higher in AML patients with PB-WT1 ≥ 5 measured at 3rd (56% vs 38%; p=0.43) and 6th month (71% vs 20%; p=0.03) after allo-SCT. Interestingly, 5/5 (100%) patients with pre-transplant PB-WT1 ≥ 5 who never reduced this level at 3rd or 6th month after allo-SCT experienced a disease recurrence. Conclusions: our data, although retrospectively collected, show that WT1 monitoring may be useful to predict the relapse in AML patients. Acknowledgments: This work was supported in part by Banca di Credito Cooperativo di Pompiano e Franciacorta and Lions Club Bassa Bresciana Association. Disclosures Russo: Celgene: Research Funding; Gilead: Research Funding; Novartis: Consultancy.

scholarly journals A Phase II of Combination Daunorubicin and Cytarabine (Ara-C) and Nilotinib (TASIGNA) (DATA) in Patients Newly Diagnosed with Acute Myeloid Leukemia and KIT Expression: Final Results

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1443-1443
Author(s):  
Aref Al-Kali ◽  
Raoul Tibes ◽  
Jeanne Palmer ◽  
Hassan B. Alkhateeb ◽  
Mrinal M. Patnaik ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Liver Failure ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
White Blood Count ◽  
Newly Diagnosed ◽  
Relapse Rates ◽  
Acute Myeloid

Abstract Background: Acute myeloid leukemia (AML) is an aggressive blood cancer with a wide range of response and relapse rates using standard chemotherapy combining anthracycline plus cytarabine (7+3). The stem cell receptor tyrosine kinase KIT is expressed on more than 10% of blasts in 95% of relapsed AML cases and mediates leukemic proliferation and has anti-apoptotic effects (Domen and Weissman 2000). AML with high KIT expression is associated with poorer outcome (Del Poeta, Venditti et al 2003). Goals: To study the efficacy and safety of combination 7+3 and nilotinib in patients (pts) with AML and KIT expression. Primary goal is to determine the complete response (CR) rate; while secondary goals include 2-year overall survival (OS) and disease free survival (DFS) in addition to safety. Methods: A single arm, Phase II study, enrolled pts at Mayo Clinic (MN and AZ). Appropriate IRB was obtained and study was registered (NCT 01806571). Pts were enrolled if they were newly diagnosed with AML with KIT (CD117) expression of ≥ 20% on myeloblasts by flow cytometry. KIT mutations were allowed. Nilotinib 300 mg twice daily was given on days 4-14 of induction and consolidation; and continuous daily maintenance therapy for up to 2 years. Cytarabine 100 mg/m2/day continuous IV x7 days plus daunorubicin 60 mg/m2 IV daily x3 days were used for induction, while consolidation used standard cytarabine 3 gm/m2 twice daily days 1, 3, 5 for a total of 4 cycles. This is a Simon 1-stage design with a safety analysis after enrolling 12 pts, and an interim analysis after enrolling 18 out of 43 pts (Al-Kali, ASH 2015) recommended to continue study accrual. Results: i)- Demographics: Thirty four pts were enrolled from July 2013 to June 2017. Median age was 59 years (range 24-69) with 71% being male. Median laboratory findings include hemoglobin of 8.8 gm/dL, platelets of 56 x109/L, white blood count of 3.3 x109/L (0.4-125), and peripheral blood blasts 17 %(0-94%). Cytogenetics were normal in 43% of the pts and favorable cytogenetics were seen in 6%(inv 16). FLT3 gene testing was done on 26 pts and was positive in 13%. KIT gene sequencing (exon 8, 9, 10, 11, 17) revealed pathogenic mutation in 1/28 cases (4%). ii)- Clinical outcome Out of all 34 pts enrolled on the study, 18 (53%) achieved CR (or CR with incomplete platelet recovery) with a median CR duration of 21.8 months. Of 26 evaluable pts, the overall CR rate was 69%. 4 of the 18 pts (22%) who achieved remission needed a second induction. One pt died due to liver failure (had only one dose of nilotinib and toxicity was attributed to daunorubicin). 13 (38%) pts proceeded to allogeneic stem cell transplant (HSCT), 12 of whom are alive and none were able to initiate nilotinib maintenance. Only 6 (1 had HSCT) out of 34 (18%) pts relapsed after achieving CR. Median DFS was 45.8 months, while median OS was 42.4 months. 2-year DFS and OS were 58% and 72%, respectively. iii)- Safety Thirty four pts were evaluated for adverse events (AE). Fourteen pts had G4 non-hematological AEs, including fourteen G4 AEs related to infection, 2 with electrolyte imbalances, 1 heart failure, 1 elevated bilirubin, 1 elevated lipase, and 1 jejunal hemorrhage. One patient had G5 liver failure. Most common (>20%) G3 non-hematological AEs were febrile neutropenia (56%), hypophosphatemia (21%), elevated ALT (21%) and hypertension (21%). Conclusion: Combination daunorubicin and cytarabine with nilotinib (DATA) appears to be safe and effective. Final results show an acceptable safety profile with most common AE being infection. Thirty day mortality was low (3%). DATA regimen has comparable CR rates of 53% (intent to treat) and 69% in evaluable pts. Relapse rates were very low at 18% with durable responses and encouraging survival rates. Figure. Figure. Disclosures Al-Kali: Novartis: Research Funding. Tibes:Novartis: Research Funding. Palmer:Novartis: Research Funding.

scholarly journals The 17-Gene Leukemic Stemess Score Can Predict Treatment Outcomes Following Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3299-3299
Author(s):  
Dennis Dong Hwan Kim ◽  
Taehyung Kim ◽  
Tracy Murphy ◽  
Steven M Chan ◽  
Mark D. Minden ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Allogeneic Hct ◽  
Gvhd Prophylaxis ◽  
Acute Myeloid

Introduction: A 17-gene stemness score (LSC17 score) had been reported to determine the risk of therapy resistance in acute myeloid leukemia (Nature 2016), and this was replicated successfully in 5 independent cohorts (n=908). When the patients were stratified according to the median value of the LSC17 score, allogeneic hematopoietic stem cell transplantation (HCT) did not affect overall survival (OS) from initial diagnosis for either high- or low-score patients (p=0.2 for high and p=0.06 for low LSC17 score groups). In the present study, we aimed to further perform a subgroup analysis confined to the patients receiving allogeneic HCT and determine whether the LSC17 score at leukemia diagnosis was associated with treatment outcomes including OS, leukemia-free survival (LFS), non-relapse mortality (NRM), relapse incidence (RI), and acute/chronic GVHD following allogeneic HCT. Methods and patients: Out of 452 patients with available LSC17 scores, 123 patients were included into the final analysis who received allogeneic HCT using matched (n=104, 84.6%) or mismatched/haploidentical donors (n=19, 15.4%). 80 patients were from the previous study (Nature 2016), while 43 patients were a prospectively accrued cohort during 2016-2018. Patients and transplant characteristics were: male/female (n=61/62); median age, 51 (17-73); CR status prior to HCT, CR1 (n=93, 75.6%), CR2 (n=30, 24.4%); Conditioning regimen, reduced intensity/myeloablative conditioning (n=59, 48.0% vs n=64, 52.0%); GVHD prophylaxis using post-transplant cyclophosphamide (PTCy; n=45, 36.6%) or T cell depletion (n=62, 50.4%); Cytogenetic risk, favorable (n=10, 8.1%), intermediate (n=70, 56.9%), adverse (n=26, 21.1%), inconclusive or not done (n=17, 13.8%). The LSC17 score for each patient was measured in a diagnostic sample using a NanoString assay and compared to the high/low threshold of a reference AML cohort (Ng et al, Nature 2016 and unpublished data). Transplant outcomes were compared according to the LSC17 risk group for OS, LFS, NRM and RI. Univariate and multivariate analyses were conducted for OS and LFS using Cox's proportional hazard model or for NRM and RI using Fine-Gray model, respectively. The following variables were included in the model: the LSC17 score group (high vs low LSC17 score), chronic GVHD, CR status (CR2 vs CR1), Cytogenetic risk (adverse vs favorable/intermediate/inconclusive), GVHD prophylaxis (PTCy vs others, T-cell depletion vs others), Age (above 60 vs others), donor type (mismatched/haploidentical vs matched donors). Results: With a median follow-up duration of 22 months among survivors after HCT, 23 patients experienced relapse (n=23, 18.7%) while 63 deaths (51.2%) were noted. Out of 123 patients, 58 (47.1%) had a low LSC17 score and 65 (52.9%) had a high LSC17 score. There was no difference in the distribution of LSC17 scores between the group who received HCT (n=123; 0.479±0.026) vs not (n=229; 0.456±0.019; p=0.491). LFS survival was significantly better in the low LSC17 score group (51.5 vs 32.4% for 2-year LFS rate, p=0.0219), and there was a trend to higher OS rate in the low LSC17 group (48.1%) compared to the high LSC17 group at 2 years (34.2%, p=0.09). Furthermore, patients with a low LSC17 score had a significantly lower RI (14.9% vs 27.3% for 2-year relapse incidence, p=0.028). There is no difference of NRM between the groups (37.2% vs 38.2% at 2 years, p=0.647). Multivariate analysis confirmed that the high LSC17 score group was associated with worse LFS (HR 1.874 [1.080-3.249], p=0.025). However, it was not confirmed with respect to OS or relapse incidence. As expected, it was not associated with NRM. Conclusion: A low 17-gene stemness score is associated with better leukemia-free survival and lower relapse incidence after allogeneic HCT, and is suggested to be associated with OS. The high LSC17 score group may be considered for novel therapeutic strategies to reduce the risk of relapse after allogeneic HCT. Figure Disclosures Chan: Celgene: Honoraria, Research Funding; AbbVie Pharmaceuticals: Research Funding; Agios: Honoraria. Minden:Trillium Therapetuics: Other: licensing agreement. Michelis:CSL Behring: Other: Financial Support. Mattsson:Gilead: Honoraria; Celgene: Honoraria; Therakos: Honoraria. Wang:Pfizer AG Switzerland: Honoraria, Other: Travel and accommodation; Pfizer International: Honoraria, Other: Travel and accommodation; Trilium therapeutics: Other: licensing agreement, Research Funding; NanoString: Other: Travel and accommodation.

scholarly journals Adverse Prognosis in Acute Myeloid Leukemia with Abnormality Abn(3q): Does EVI1 Matter?

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1309-1309
Author(s):  
Theresa Kretschmann ◽  
Christoph Röllig ◽  
Brigitte Mohr ◽  
Michael Kramer ◽  
Matthias Stelljes ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chromosome 3 ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Cytogenetic Aberrations ◽  
The Impact ◽  
Acute Myeloid

Abstract Introduction: The ELN classification of cytogenetic aberrations in acute myeloid leukemia (AML) distinguishes favorable risk, intermediate risk I and II and adverserisk. The adverse-risk group contains patients (pts) with inv(3) and t(3;3). These pts have a significantly poorer outcome compared to other cytogenetic aberrations. The MRC classification considers both pts with inv(3) and t(3;3) as well as patients with other abn(3q) as adverse risk, but excludes t(3;5). Pts with inv(3) or t(3;3) have breakpoints located on the long arm of chromosome 3 at q21 and q26. As a result of these chromosomal modifications, an enhancer-protein is deregulated and the stem-cell regulator zinc finger protein EVI1 on 3q26 is over expressed. Other 3q aberrations do not involve EVI1. We conducted a comparative analysis on the impact of abn(3q) with likely EVI1 alteration versus abn(3q) without EVI1 involvement. Analyses were done both in the entire group of abn(3q) pts and in the subgroup of pts treated with allogeneic hematopoietic stem-cell transplantation (HSCT). Methods: We performed a retrospective analysis on 163 patients with an abnormality on the q arm of chromosome 3 (abn(3q)). These pts were treated between 1996 and 2009 in three multicenter studies by the German SAL study group (AML2003, AML96, AML60+). Pts with t(3;5) were excluded (n=11). The remaining 152 patients were divided into two groups. Group 1 (EVI1) contained 56 patients with a chromosomal aberration likely to alter EVI1, i.e. t(3;3), inv(3) and abn(3)(q26). Group 2 (noEVI1) comprised the remaining 96 patients displaying other abn(3q) aberrations. We compared groups for baseline characteristics, complete remission (CR), relapse-free survival (RFS) and overall survival (OS) in total and stratified for treatment. Results: Descriptive comparison of the groups (EVI1 vs noEVI1) revealed a significantly higher WBC count (14.3 vs 4.6 Gpt/l), PLT count (62 vs 47 Gpt/l) and -7 incidence (29% vs 16%) in the EVI1 group, whereas in the noEVI1 group, complex aberrations (25% vs 74%) and 17p alterations (0% vs 24%) occurred in a higher proportion of pts. CR rates (52% vs 47%), median RFS (7 vs 6 months) and median OS (6 vs 7 months) did not differ significantly between the two groups. In order to explore the clinical behavior of the different abn(3q) aberrations in relation to allogeneic HSCT, we compared EVI1 pts (n=21) versus noEVI1 pts (n=38) who received an allogeneic HSCT at any time during treatment. Patients with aberrant EVI1 were significantly younger (median age 44 vs 52 years), had a higher incidence of -7 (29% vs 13%), but less frequent karyotype complexity (10% vs 74%) or 17p alterations (0% vs 24%). More patients in the EVI1 group achieved a first CR before HSCT (95% vs 84%). Amongst CR pts, median RFS was slightly higher in the EVI1group (9 vs 6 months). In all abn(3q) pts with allogeneic HSCT, median OS was 30 months in the EVI1 group and only 12.5 months in the noEVI1 group. According to the log-rank test, this difference did not reach statistical significance (p=0.137). The advantage in mean OS for EVI1 patients is most likely due to the higher proportion of patients transplanted in CR while the accumulation of complex karyotypes in the noEVI1 group caused more primary resistant AML cases with a rapid progression even after allogeneic HSCT. Conclusions: Although AML development may be based on different molecularbiological mechanisms in patients with different abn(3q) aberrations depending on EVI1 alteration, the prognosis of the two groups is very similar. The most likely reason is the equal balance of favorable and adverse prognostic factors between the two groups such as age, karyotype complexity, 17p alteration and -7. Patients of both groups benefit from allogeneic HSCT to a similar extent. Confirmation of these results on larger data sets is desirable and under way. Disclosures Baldus: Novartis: Research Funding. Einsele:Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Thiede:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AgenDix GmBH: Equity Ownership.

Venetoclax and Posaconazole Plus Standard Dose Cytarabine or Azacytidine for Newly Diagnosed Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-41
Author(s):  
Tran-Der Tan ◽  
Lun-Wei Chiou
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Standard Dose ◽  
Newly Diagnosed ◽  
Hematopoietic Stem ◽  
Transplant Patients ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

Background: The present standard induction treatment for newly diagnosed acute myeloid leukemia (ND AML) is three days' daunorubicin or idarubicin plus seven days' cytarabine chemotherapy (3+7). Venetoclax plus azacytidine or low dose cytarabine is effective and better than azacitidine or low dose cytarabine alone for ND AML in VIALE A and VIALE C trials, respectively and the outcome by Venetoclax dose levels was not different between 400 mg, 800 mg, or 1200 mg a day. As a strong CYP3A inhibitor, posaconazole can increase serum level of Venetoclax and the dosage could be reduced to 75~100mg a day. Method: We treat ND AML patients with uninterrupted Venetoclax 100 mg plus posaconazole 300 mg daily and 7 days' standard dose of cytarabine (100 mg/m2/day) or 7 days' azacitidine (75 mg/m2/d), followed by 5 days' consolidation cytarabine (100 mg/m2/d) or another 7 days' azacitidine, and then followed by allogeneic hematopoietic stem cell transplantation. Results: Eight patients have enrolled the treatment including 7 underwent venetoclax/posaconazole/cytarabine and one venetoclax/posaconazole/azacitidine patients and four patients are secondary AML (one myeloma, one MDS, and 2 breast cancer patients). All patients were hematologic complete remission achieved in one month and 6 patients underwent allogeneic hematopoietic stem cell transplantation including one from matched sibling, two from matched unrelated, and three from haplo-identical donors (sons). Febrile neutropenia rates were similar to 3+7 treatment patients on historical comparison but shorter period of febrile illness. There was no grade II or higher adverse effect of oral mucosa and gastrointestinal tract as compared with conventional 3+7 therapy. Two out of six allo-transplant patients got leukemia relapse then salvage treatment ensued and the other 2 non-transplant and 4 allo-transplant patients are persisted in complete remission. Conclusion: Venetoclax plus posaconazole and standard dose cytarabine is a feasible choice of induction therapy in ND AML and high CR rate and transplant rate achieved and there was no detrimental effect upon the hematopoietic recovery during induction and transplant therapy. Figure Disclosures No relevant conflicts of interest to declare.

Autologous Hematopoietic Stem Cell Collection and Transplantation in Acute Myeloid Leukemia Patients in Second Remission after Treatment with Fractionated Gentuzumab Ozogamycin.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5211-5211
Author(s):  
Delphine Rea ◽  
Emmanuel Raffoux ◽  
Anne Laure Taksin ◽  
Adrienne De Labarthe ◽  
Nicolas Boissel ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Myeloid Leukemia ◽  
Autologous Transplantation ◽  
Normal Karyotype ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Acute Myeloid

Abstract Gemtuzumab ozogamicin (GO) at fractionated doses of 3 mg/m2 on days 1, 4 and 7 has recently shown efficacy with minimal liver toxicity and without veino occlusive disease (VOD) in patients with acute myeloid leukemia (AML) in first relapse. We report on autologous hematopoietic stem cell (HSC) collection and transplantation in 4 AML patients (median age 61; 54–64) in 2nd remission (CR2) after fractionated GO treatment uneligible for allogeneic HSC transplantation. Peripheral blood (PB)-HSC were collected by leukapheresis after mobilization with amsacrine + AraC (patients 1–3) or high dose AraC (patient 4) and subsequent G-CSF at 5 microgr/kg/day. In patient 1 (AML2 normal karyotype Flt3 wt), PB-HSC collection started at day 22 post-chemotherapy (CT) with a CD34 count of 13.4/microl and 2 cytapheresis were required to yield a total of 11.8×108 nucleated cells (NC)/kg, 3.7×106 CD34/kg and 6.9×104 CFU-GM/kg. In patient 2 (AML4, normal karyotype, Flt3 ITD), PB-HSC collection started at day 20 post-CT with a CD34 count of 8.2/microl and 3 cytapheresis were required to yield a total of 14.8×108 NC/kg, 3.1×106 CD34/kg and 33.7×104 CFU-GM/kg. In patient 3 (AML2 normal karyotype, Flt3 ITD), PB-HSC collection started at day 20 post-CT with a CD34 count of 30.2/microl and 2 cytapheresis were required to yield a total of 5.3×108 NC/kg, 6×106 CD34/kg and 42.5×104 CFU-GM/kg. PB-HSC from patient 3 were purged in vitro with mafosfamide, yielding final CN, CD34 and GM-CFU doses of respectively 4.9×108/kg, 5.2×106/kg and 0×104/kg. In patient 4 (AML1 normal karyotype, Flt3 wt), bone marrow (BM)-HSC were harvested and purged with mafosfamide. Prior purging, CN, CD34 and GM-CFU doses were respectively 1.7×108/kg, 6.7×106/kg and 16.1×104/kg. After purging, CN, CD34 and GM-CFU doses were respectively 0.36×108/kg, 3.6×106/kg and 0.1×104/kg. In patient 4, PB-HSC collection for rescue started at day 16 post-CT with a CD34 count of 27.4/microl and 1 cytapheresis was sufficient to yield a total of 1.8×108 NC/kg, 3.4×106 CD34/kg and 36.7×104 CFU-GM/kg. Autologous HSCT was performed after conditionning with busulfan and cyclophosphamide. Autologous grafts consisted in unpurged PB-HSC in patient 1 and 2, purged PB-HSC in patient 3 and purged BM-HSC in patient 4. All patients received continuous heparin infusion at 100U/kg/day as VOD prophylaxis. Extra hematological adverse events comprised grade 3–4 oral mucitis, grade 2–3 nausea and vomiting (n=4), grade 2–3 diarrhea (n=3), grade 1 liver enzyme elevation (n=4) and grade 1–3 cholestasis. Three patients presented fever of unknown origin, one showed gram-negative systemic infection and one showed clostridium difficile-associated diarrhea. No VOD was observed. Neutrophil recovery above 0.5/L occurred between day 25 and day 40. Platelet recovery above 20/L occurred at day 18 and day 300 in patients 2 and 4, and never occurred in patients 1 and 2. These latter relapsed 3 months after transplantation. Patients 3 and 4 are still in CR2, 7 and 21 months after transplantation. PB and BM collection after fractionated GO treatments for AML is feasible. After autologous transplantation, no VOD is observed but platelet recovery is severely impaired.

High Disease-Free and Overall Survival Rate Following Allogeneic Hematopoietic Stem Cell Transplantation for FLT3-Mutated Acute Myeloid Leukemia Even in Non-Remission Status

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2283-2283 ◽  
Author(s):  
Aya Nishida ◽  
Mitsuhiro Yuasa ◽  
Kosei Kageyama ◽  
Kazuya Ishiwata ◽  
Shinsuke Takagi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Poor Prognosis ◽  
Hematopoietic Stem ◽  
Remission Status ◽  
Disease Free ◽  
Acute Myeloid

Abstract [Background] FMS like tyrosine kinase 3 (FLT3) mutations occur in about 30% of patients with acute myeloid leukemia (AML). Patients with FLT3-mutated AML have a poor prognosis and are referred for early allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1). So far, there is still limited data available on allo-HSCT for FLT3-mutated AML in non-remission status. [Objective and method] To assess the clinical features and outcome of allo-HSCT for FLT3-mutated AML, we retrospectively analyzed patients underwent first allo-HSCT for FLT3-mutated AML excluding acute promyelocytic leukemia (FAB M3) from January 2011 to March 2016. [Result] During the study period, 332 patients received first allo-HSCT for AML in our institute. One hundred and thirty-eight were tested for the presence of FLT3-mutation and 35 showed positive results and were subjected to the analysis. The median follow-up day of survivors was 602 (101-1867). The median age of the patients was 55 years (range, 21-72). Twenty-one patients had de novo AML, 12 had AML with myelodysplasia related changes, and 2 had therapy related AML. Eighteen had normal karyotype, 4 had complex, and 13 had others. Seven were in remission (5 in CR1, and 2 in CR2), and 28 were in non-remission (8 in primary induction failure, 13 in relapse 1, and 7 in chemo naïve status). Twenty-nine patients used unrelated cord blood, 2 did unrelated bone marrow, and 4 did related peripheral blood stem cell as grafts. All but 1 received myeloablative pretransplant conditionings. At 2 years after transplantation, overall survival (OS), disease free survival (DFS), relapse rate (RR), and non-relapse mortality (NRM) of whole studied population were 65.9%, 50.2%, 28.4%, and 21.4%, respectively. Among those in non-remission before transplantation, OS, DFS, RR, and NRM at 2 years post-transplant were 62.2% (Figure 1A), 49.9%(Figure 1B), 24.3%, and 25.8%, respectively. Only younger age (<55 years) was the factor associated with better OS with statistical significance in multivariate analysis. [Conclusion] Our data indicated that allo-HSCT could overcome the poor prognosis of FLT3-mutated AML even for those in non-remission status, despite the profound chemo-resistant character of FLT3-mutated AML. Figure 1A Figure 1A. Figure 1B Figure 1B. Disclosures Izutsu: Abbvie: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Janssen Pharmaceutical K.K.: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria; Mundipharma KK: Research Funding.

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