Efficacy and Toxicity Of Decitabine Versus CHG Priming Regimen In Patients With Higher Risk Myelodysplastic Syndrome

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2789-2789 ◽  
Author(s):  
Lingyun Wu ◽  
Xiao Li ◽  
Feng Xu ◽  
Chunkang Chang ◽  
Qi He ◽  
...  
Keyword(s):  
Overall Survival ◽  
Myelodysplastic Syndrome ◽  
Low Dose ◽  
Conflicts Of Interest ◽  
International Prognostic Scoring System ◽  
Overall Response ◽  
Clinical Responses ◽  
Myelomonocytic Leukemia ◽  
Low Dose Cytarabine ◽  
Count Recovery

Abstract Objectives Decitabine has been approved for the treatment of myelodysplastic syndrome (MDS). CHG regimen (low-dose cytarabine and homoharringtonine in combination with granulocyte colony-stimulating factor (G-CSF)) has been reported to be effective in higher risk MDS patients. The comparative efficacy of these 2 forms of treatment in MDS is unknown. The objective of the current study was to compare the efficacy and toxicity of decitabine and CHG regimen in higher risk MDS. Methods We compared lower intensity decitabine with CHG regimen in higher risk MDS (International Prognostic Scoring System (IPSS) intermediate- or high-risk or chronic myelomonocytic leukemia (CMML)). Decitabine was given 20 mg/m2 intravenously over 1 hour daily for 5 days. CHG chemotherapy consisted of an intravenous continuous infusion of low-dose cytarabine (25 mg/d) (days 1–14) and homoharringtonine (1 mg/d) (days 1–14) in combination with G-CSF (300 μg/d) by subcutaneous injection from day 0 until peripheral neutrophil count recovery to 2.0× 109/L. The complete remission (CR), overall response (OR), overall survival and toxicity was compared between the two groups. Results A total of 132 patients with higher risk MDS were enrolled in this study, 70 cases in decitabine group and 62 cases in CHG group. The CR rate was 25.7% with decitabine, compared to 32.3% with CHG regimen (p=0.538). The overall response rate (including CR, partial remission (PR), marrow CR and hematological improvement (HI)) between the two groups was also not significantly different (68.6% with decitabine and 58.1% with CHG regimen) (p = 0.209). Overall survival was not significantly different between the two groups (median survival: 18.2 months in decitabine group vs 15.3 months in CHG group; p=0.176). Grade 4 neutropenia occurred more frequently with decitabine (58.3 %) than with CHG regimen (32.3 %) (p = 0.004). Grade 4 thrombocytopenia was also more frequently with decitabine (61.4 %) than with CHG regimen (38.7 %) (p = 0.009). Conclusions Both decitabine and CHG regimens were effective in treating patients with higher risk MDS. The two regimens did not differ in terms of clinical responses. However, decitabine showed severer hematological toxicities than CHG regimen. This trial was registered at www.clinicaltrials.gov as ChiCTR-ONC-11001501. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Very Low-Dose Decitabine Is Effective in Treating Intermediate or High Risk Myelodysplastic Syndrome

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5536-5536
Author(s):  
Hongmin Li ◽  
Liru Wang ◽  
Yue Wu ◽  
Li Su ◽  
Hong Zhao ◽  
...  
Keyword(s):  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Low Dose ◽  
Conflicts Of Interest ◽  
Peripheral Blood Cell ◽  
Chi Square ◽  
Exact Test ◽  
Overall Response ◽  
Cell Counts ◽  
Blast Cells

Abstract Background: As an available hypomethylating agent, decitabine has significantly improved the outcome of patients with myelodysplastic syndrome (MDS). Nowadays the regular recommendation dose of decitabine is 20 mg/m2/d for five consecutive days with relatively high incidence of treatment related morbidities and costs. In this study, we aim to explore the efficacy and safety of very low-dose decitabine in the treatment of patients with MDS. Methods: The clinical data of twenty-nine newly diagnosed consecutive MDS patients with IPSS intermediate-1-risk or above from fourteen hospitals in Beijing between Nov. 2015 to May. 2016 were collected retrospectively. Twenty-four patients received decitabine monotherapy (decitabine 7mg/m2/d for 7 days, repeated every 4 weeks), five patients received decitabine combined with decreased dose of CAG (Acla 10mg, d1-7; cytarabine 10mg q12h, d1-8; G-CSF150ug q12h, d1-14, repeated every 4-6 weeks). The overall response (ORR), complete remission (CR), partial response (PR) and hematologic improvement (HI) rate was evaluated. The safety profile and the treatment cost were documented. Factors affecting the efficacy were also analyzed in the end using the chi-square test or Fisher's exact test for categorical data and the Wilcoxon rank-sum test or the Student's t test for continuous data. Results: Of the twenty-nine patients, twenty-one were males and eight were females. The median age was 63 years (36~85 years). Two patients (6.9%) were diagnosed as MDS-RCUD, three (10.3%) as MDS-RCMD, ten (34.5%) as MDS-RAEB1, and fourteen (48.3%) as MDS-RAEB2. At the end of follow-up time, the medium course was 2 (range 1-11 courses). Nine patients (31%) finished one course, seven patients (24.1%) finished two courses, five patients (17.2%) finished three courses, eight patients (27.4%) finished four or more courses. Ten patients achieved CR (34.5%), eight (27.6%) PR, one (3.4%) HI, eight (27.6%) stable disease (SD), two (6.8%) progress disease (PD) or death. The overall response rate (ORR) was 65.5%. Infection and bleeding rate were recorded in 44.9% of the courses, respectively, with 21.7% severe infections and 11.6% severe bleedings. Other side effects were rare and mild including unstable angina pectoris, vomiting, low serum albumin etc. (less than 2%). Two patients died, one died of cerebral hemorrhage within 30 days, and the other died of disease progression after 4 courses of treatment. The median cost of each course of treatment was 7.3 (1.4~28.4), 3.9(1.4~8.9), 3.1 (1.3~10.9), 2.6 (1.2~5.7) thousand dollars respectively. Nineteen patients who achieved at least HI (responders) were compared with the rest ten patients who did not benefit from the treatment (non-responders). Only difference in age (67.3±11.8 years for responders vs 56.1±11.9 years for non-responders, p=0.023) and proportion of bone marrow blast cells (10.8±4.9% for responders vs 5.8±5.3% for non-responders, p=0.016) was found between responders and non-responders, whereas no other differences were noticed between the two groups either in sex ratio (M:F 2.2:1 vs 4:1, p=0.675), high ECOG percentage (57.9% vs 20%, p=0.114), peripheral blood cell counts (hemoglobin 71 g/L vs 66 g/L, p=0.522; neutrophils 0.71 vs 0.6 × 109/L, p=0.426; or platelet 33 vs 75 × 109/L, p=0.218), percentage of adverse prognostic karyotypes (26.3% vs10% , P =0.633), or percent of intermediate -2 or high risk IPSS ( 68.4% vs 40%, p=0.236). Conclusions: Verylow-dose decitabine alone or combined with decreased dose CAG regimen showed relatively good efficacy, well-tolerance and low medical cost in the treatment of intermediate or high risk MDS. Elderly patients or patients with a higher proportion of blast cells may be the better candidates for this regimen. Disclosures No relevant conflicts of interest to declare.

Comprehensive Mutational Screening Of 5-Azacitidne Treated Myelodysplastic Syndrome (MDS) Patients Fails To Identify a Specific Mutational Profile Predicting Response To Therapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2792-2792 ◽  
Author(s):  
Austin G. Kulasekararaj ◽  
Azim M Mohamedali ◽  
Alexander E Smith ◽  
Syed A Mian ◽  
Nazia Matto ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Tp53 Mutation ◽  
Low Dose ◽  
Overall Response Rate ◽  
Response Rate ◽  
Univariate Analysis ◽  
Mutation Status ◽  
Tp53 Mutations ◽  
Overall Response ◽  
Low Dose Cytarabine

Abstract Introduction 5-azacitdine (aza) treatment in myelodysplastic syndrome (MDS) induces a response rate of 40-45% and prognostic factors for response and survival remain still largely unknown. Presence of mutant TET2 has been shown to predict better response to aza and the recently described French Azacitidine prognostic score segregates patients into 3 groups with varying median overall survival. Although a plethora of somatic mutations have been described in MDS, none has been consistently shown to be prognostically important in the context of response to hypomethylating agent(s). Patients and methods To identify the mutation signature associated with aza response, we undertook screening of 24 myeloid genes (splicing, epigenetic, transcription factors, STAG2, TP53) in 66 MDS patients treated with aza at our institution over a period of 2004-2012. Mutation analysis was done by deep (454 FLX) and Sanger sequencing. SNP-6 karyotyping was also performed in a subset to correlate with mutation status. Responses were assessed as per the international working group for MDS criteria. The median age was 67 years (range 36–87 years), median number of courses 7(range 2–42), 79% of patients belonged to int-2/high risk IPSS category. WHO category subtypes were; RA/RARS-2; RCMD-9; RAEB-39; s-AML (evolved from pre-existing MDS) -5, therapy related myeloid neoplasm (t-MDS/t-AML) -8 and CMML-3.IPSS cytogenetic subgroups were, good risk: 22, intermediate: 7, and poor risk: 37. One fourth of patients had received prior therapy, with only two receiving low dose cytarabine. Median time from diagnosis to aza treatment was 8.6 months. The overall response rate (ORR) to Aza was 47% (31/66) with complete response (CR) 17%, partial response (PR) 11%, marrow CR (mCR) 12% and stable disease with hematological improvement (SD-HI) 7%. Results Candidate mutations were seen in 82% (54/66) of patients, with the more than half harboring ≥2 mutations each. The most frequently (≥5 %) mutated genes being ASXL1 (29%), TP53 (23%), TET2 (14%), DNMT3A (12%), SRSF2 (12%), EZH2 (11%), NRAS (8%), U2AF1 (8%), IDH2 (8%), RUNX1 (8%), CCBL (6%) and FLT3-ITD (5%). On univariate analysis presence of EZH2 mutations predicted for a better ORR compared to wild type EZH2 (21% vs. 3%, p<0.04). TET2 mutations did not confer a better response (13% vs. 14%, p=0.1). None of other mutations predicted response. In multivariate logistic regression analysis, only shorter duration of disease (< than 8 months) predicted a better response (p=0.33,HR 0.29,CI 0.07-0.9). Patients with any mutation had a worse outcome compared to patients with no mutations (p=0.03, med OS 12.4 vs. 20.2 months). TP53 mutations were detected and quantified by high throughput sequencing in poor risk IPSS cytogenetic group (15/37) and were absent in patients with normal cytogenetics and isolated chromosome 7 abnormalities. Sequential samples were available in 9 patients and changes in clone sizes were correlative of treatment response, with 3 patients achieving cytogenetic response with concurrent reduction in clone size but the responses were transient. The TP53 mutation status correlated strongly with finding aberration of chromosome 17p by SNP array and positive p53 antibody staining on bone marrow trephine. On univariate analysis, TP53 mutations had an adverse impact on OS (P=0.0001, med OS 9.7 vs. 20.2 months). Age, IPSS cytogenetic risk group, WHO subtypes, overall response rate (ORR),progression to AML, TP53 mutation status and presence of EZH2 ,ASXLI,TET2,DNMT3A, SRSF2,NRAS mutations were used as co-variables in multivariate analysis.TP53 mutation status (HR=7.9(3.9-17.8), p=0.0001) and DNMT3A mutations (HR=2.5 (1.03-6.2), p=0.04) were established as independent prognostic variables influencing OS. Additionally, ORR to aza treatment imparts a better survival advantage (HR=0.3 (0.16-0.57),p=0.0001) Conclusion This study shows that gene mutations are frequent in all cytogenetic subgroups of MDS. TET2 mutations did not predict response to aza contrary to published reports, which could be due to differences especially as low dose cytarabine was infrequently used in our cohort. TP53 mutations do not correlate with response rate but imparts a dismal prognosis. In conclusion, although we have screened comprehensively we do not identify a mutational profile predictive of response to azacitdine. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Korszakváltás a gyermekkori szerzett csontvelő-elégtelenséggel járó kórképek kezelésében Magyarországon

2018 ◽  
Vol 159 (42) ◽  
pp. 1710-1719
Author(s):  
Krisztián Kállay ◽  
Judit Csomor ◽  
Emma Ádám ◽  
Csaba Bödör ◽  
Csaba Kassa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Survival Rate ◽  
Myelodysplastic Syndrome ◽  
Aplastic Anemia ◽  
Severe Aplastic Anemia ◽  
Juvenile Myelomonocytic Leukemia ◽  
Reduced Intensity Conditioning ◽  
Myelomonocytic Leukemia ◽  
Reduced Intensity

Abstract: Introduction: Acquired bone marrow failures are rare but fatal diseases in childhood. Since 2013, Hungary has been participating as a full member in the work of the European Working Group on uniform diagnostics and therapy in patients with acquired bone marrow failure syndromes. Hypocellular refractory cytopenia of childhood has been emphasized as a frequent entity, transplanted by reduced intensity conditioning with excellent outcomes. Aim: To analyse and compare the results of treatment before and after our joining. Method: A total of 55 patients have been treated in the 8 centres of the Hungarian Pediatric Oncology Network during 5 years between 2013 and 2017 (severe aplastic anemia: 9, myelodysplastic syndrome: 41, juvenile myelomonocytic leukemia: 5 patients). Allogeneic hematopoietic stem cell transplantation was performed in severe aplastic anemia in 7 cases, while antithymocyte globulin was administered in one case and one patient died before diagnosis. In patients with myelodysplastic syndromes, watch and wait strategy was applied in 4, while transplantation in 37 cases. Reduced intensity conditioning was used in 54 percent of these cases. Transplantation was the treatment of choice in all 5 patients with juvenile myelomonocytic leukemia. Results: In the whole patient cohort, the time from diagnosis to treatment was median 92 (3–393) days, while in severe aplastic anemia median 28 (3–327) days only. Grade II–IV acute graft versus host disease occurred in 22.6%, grade III–IV in 6.8% and chronic in 11.2%. All the patients treated with severe aplastic anemia are alive and in complete remission (100%). The overall estimated survival rate is 85.1% in myelodysplastic syndrome, while 75% in juvenile myelomonocytic leukemia. The median follow-up was 30.4 (1.1–62.5) months. There was a remarkable increase in overall survival comparing the data before (1992–2012) and after (2013) joining the international group, 70% vs. 100% (p = 0.133) in severe aplastic anemia and 31.3% vs. 85.1% (p = 0.000026) in myelodysplastic syndrome. Conclusion: Due to a change in the paradigm of the conditioning regimen in hypocellular refractory cytopenia of childhood, the overall survival rate has significantly increased. Orv Hetil. 2018; 159(42): 1710–1719.

scholarly journals Mutational Characteristics and Changing Pattern from Idiopathic Cytopenia of Undetermined Significance to High-Risk Myelodysplastic Syndrome Stratified By IPSS-R

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3009-3009
Author(s):  
Eun-Ji Choi ◽  
Young-Uk Cho ◽  
Seongsoo Jang ◽  
Chan-jeoung Park ◽  
Han-Seung Park ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Rna Splicing ◽  
Conflicts Of Interest ◽  
Low Risk ◽  
International Prognostic Scoring System ◽  
Intermediate Risk ◽  
Sequencing Data ◽  
Undetermined Significance

Background: Unexplained cytopenia comprises a spectrum of hematological diseases from idiopathic cytopenia of undetermined significance (ICUS) to myelodysplastic syndrome (MDS). Revised International Prognostic Scoring System (IPSS-R) is the standard tool to assess risk in MDS. Here, we investigated the occurrence, characteristics, and changing pattern of mutations in patients with ICUS and MDS stratified by IPSS-R score. Methods: A total of 211 patients were enrolled: 73 with ICUS and 138 with MDS. We analyzed the sequencing data of a targeted gene panel assay covering 141 genes using the MiSeqDx platform (Illumina). The lower limit of variant allele frequency (VAF) was set to 2.0% of mutant allele reads. Bone marrow components were assessed for the revised diagnosis according to the 2016 WHO classification. Lower-risk (LR) MDS was defined as those cases with very low- or low-risk MDS according to the IPSS-R. Higher-risk (HR) MDS was defined as those cases with high- or very high-risk MDS according to the IPSS-R. Results: Patients with ICUS were classified as very low-risk (39.7%), low-risk (54.8%), and intermediate-risk (5.5%) according to the IPSS-R. Patients with MDS were classified as LR (35.5%), intermediate-risk (30.4%), and HR (34.1%). In the ICUS, 28 (38.4%) patients carried at least one mutation in the recurrently mutated genes in MDS (MDS mutation). The most commonly mutated genes were DNMT3A (11.0%), followed by TET2 (9.6%), BCOR (4.1%), and U2AF1, SRSF2, IDH1 and ETV6 (2.7% for each). IPSS-R classification was not associated with mutational VAF and the number of mutations in ICUS. In the 49 LR MDS, 28 (57.1%) patients carried at least one MDS mutation. The most commonly mutated genes were SF3B1 (20.4%), followed by TET2 (12.2%), U2AF1 (10.2%), DNMT3A (10.2%), ASXL1 (10.2%), and BCOR (6.1%). Higher VAF and number of mutations were observed in LR MDS compared to ICUS patients. In the 42 intermediate-risk MDS, 27 (64.3%) patients carried at least one MDS mutation. The most commonly mutated genes were ASXL1 (23.8%), followed by TET2 (21.4%), RUNX1 (16.7%), U2AF1 (14.3%), DNMT3A (14.3%), SF3B1 (9.5%), and SRSF2, BCOR, STAG2 and CBL (7.1% for each). In the 47 HR MDS, 36 (76.6%) patients carried at least one MDS mutation. The most commonly mutated genes were TET2 (25.5%), followed by DNMT3A (14.9%), TP53 (14.9%), RUNX1 (12.8%), U2AF1 (10.6%), ASXL1 (10.6%), and SRSF2 and KRAS (6.4% for each). As the disease progressed, VAF and number of the MDS mutations gradually increased, and mutations involving RNA splicing, histone modification, transcription factor or p53 pathway had a trend for increasing frequency. Specifically, ASXL1, TP53, and RUNX1 mutations were the most striking features in patients with advanced stage of the disease. Cohesin mutations were not detected in ICUS, whereas these mutations were detected at a relatively high frequency in HR MDS. Our data were summarized in Table 1. Conclusions: We demonstrate that on disease progression, MDS mutations are increased in number as well as are expanded in size. Furthermore, a subset of mutations tends to be enriched for intermediate- to HR MDS. The results of this study can aid both diagnostic and prognostic stratification in patients with unexpected cytopenia. In particular, characterization of MDS mutations can be useful in refining bone marrow diagnosis in challenging situations such as distinguishing LR MDS from ICUS. Disclosures No relevant conflicts of interest to declare.

scholarly journals Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome

Leukemia ◽  
2018 ◽  
Vol 33 (2) ◽  
pp. 379-389 ◽  
Author(s):  
Jorge E. Cortes ◽  
Florian H. Heidel ◽  
Andrzej Hellmann ◽  
Walter Fiedler ◽  
B. Douglas Smith ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Newly Diagnosed ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia In Patients up to Age 75: Comparison of Survival In Patients with An Available Donor Compared to Patients without a Donor

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2381-2381
Author(s):  
Teresa Field ◽  
Janelle Perkins ◽  
Taiga Nishihori ◽  
Joseph Pidala ◽  
Hugo F. Fernandez ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Analysis ◽  
Myelodysplastic Syndrome ◽  
Cell Transplantation ◽  
Research Funding ◽  
Chronic Myelomonocytic Leukemia ◽  
No Donor ◽  
Hematopoietic Stem ◽  
Myelomonocytic Leukemia

Abstract Abstract 2381 Allogeneic hematopoietic cell transplantation (HCT) remains the only curative treatment strategy for patients with Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML). Recent reduction of the transplant related toxicity has permitted the expansion of empiric age limitations for HCT up to 75 years. There has been limited comparative data on HCT focusing on donor availability in patients with MDS/CMML. Between January 2004 and September 2009, a total of 255 new patients (NP) with a diagnosis of MDS or CMML were evaluated for HCT at Moffitt Cancer Center. This report describes the outcomes of these patients with emphasis on donor availability. Donor Search Results: Of the 255 NP, 58 did not undergo a donor search. Reasons for not proceeding were as follows: Medicare declined coverage due to age >65 (18), waiting as have low risk disease (15), patient declined (6), patient seen as second opinion only (7) and patient was not eligible for HCT (12). These patients were not included in the survival analysis. Of the 197 patients who had a donor search initiated, a sibling (SIB) matched unrelated (MUD) or single HLA antigen/allele mismatch (mMUD) unrelated adult donor was found in 173 patients. A suitable adult donor was not identified in the remaining 24 patients. To mitigate bias due to factors giving a survival advantage to patients who were stable enough to survive the donor and proceed to HCT, the survival analysis included only those patients alive 90 days after the donor search was initiated. We have been able to identify donors within this time frame for 99% of the patients who ever found one, although time to transplant is longer. At the 90 days landmark, there were 164 patient in the Donor cohort, and 19 patients in the No Donor cohort. Donor Cohort: The median age was 56.6 yrs (18.5 – 73.5). Ninety-seven patients (59%) were older than 55 yrs and 26 (16%) were above 65 yrs. At the time of the transplant consult, IPSS risk was Low (10), Int-1 (44), Int-2 (48), High (25), AML (21), CMML (13), or not evaluable (NE) (3). Donors included SIB (60), MUD (75) and mMUD (29). Median follow-up of surviving patients is 27.7months (7.2 – 70.7). No Donor Cohort: Median age was 57.4 yrs (32.6 – 68.1) with 12 patients (63%) older than 55 yrs and 3 (16%) patients older than 65 years of age. IPSS at initiation of the donor search was Int-1 (5), Int-2 (6), High (5), AML (1) and CMML (2). Median follow-up is 9.2 months (1.4 – 61.5). Of the 19 patients with no donor, 3 patients received an umbilical cord blood HCT elsewhere and were analyzed by intent to treat. Outcomes: Patients with a donor had significantly improved overall survival from time of donor search vs. patients with no donor (P=0.007) with 2 year OS of 48% vs. 23%, respectively. Median survival for the donor group was 22.2 months [95% CI 14.7 – 35.7] vs. 10.1 months for those without a donor [95% CI 2.3 – 14.7]. Transplant: Of the 164 patients with a donor, 121 (74%) patients received the planned allogenic transplants. The 2-year overall survival (OS) after transplantation is similar for SIB (51%), MUD (39%) or mMUD (68%) transplant recipients (P=0.4), and also similar by age below or above 55 years (P=0.7). These data demonstrate that most patients with MDS or CMML can have a suitable donor identified and proceed to HCT. Overall survival is significantly improved for those patients who have a suitable sibling or unrelated donor. Disclosures: Lancet: Eisai: Consultancy; Celgene: Honoraria. Alsina: Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. List: Celgene: Research Funding.

Frontline Therapy for Older Patients (pts) with Acute Myeloid Leukemia (AML): Clofarabine Plus Low-Dose Cytarabine Induction Followed by Prolonged Consolidation with Clofarabine Plus Low-Dose Cytarabine Alternating with Decitabine

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 336-336 ◽  
Author(s):  
Stefan Faderl ◽  
Farhad Ravandi ◽  
Guillermo Garcia-Manero ◽  
Xuelin Huang ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Median Overall Survival ◽  
Low Dose ◽  
Response Rates ◽  
Newly Diagnosed ◽  
Secondary Aml ◽  
Prolonged Consolidation ◽  
Low Dose Cytarabine

Abstract Abstract 336 Standard therapy (e.g. “3+7”) of newly diagnosed older pts (≥ 60 yrs) with AML is characterized by low response rates, short response durations, and substantial toxicities. New approaches are therefore actively explored in clinical trials. Clofarabine is a second generation deoxyadenosine nucleoside analogue with activity in older pts with frontline AML and presence of unfavorable prognostic factors. In our experience, the combination of clofarabine with low-dose cytarabine achieved higher response rates at no increase of toxicity compared with clofarabine alone (Faderl S et al. Blood 2008). Based on the initial experience, we have designed a combination of lower-dose clofarabine plus low-dose cytarabine induction followed by a prolonged consolidation of these drugs alternating with decitabine to improve survival and maintain the high response rates from the earlier study. Pts were eligible if ≥ 60 yrs of age with newly diagnosed AML. Pts were excluded for ECOG PS > 2, creatinine > 1.5 mg/dL, cardiac ejection fraction < 40%, and prior therapy with clofarabine or decitabine. Induction therapy consisted of clofarabine 20mg/m2 i.v daily × 5 days plus cytarabine 20mg s.c. twice daily × 10 days. Responding pts could receive up to 17 courses of consolidation therapy of clofarabine plus cytarabine (over 3 and 7 days, respectively) during courses 1–2, 6–8, 12–14 alternating with decitabine 20mg/m2 i.v. daily for 5 days during courses 3–5, 9–11, and 15–17. All pts received antibiotic prophylaxis with levofloxacin, valacyclovir and itraconazole (or equivalent). Fifty-nine pts have been accrued with a median age of 70 yrs (range 60–81), of whom 17 pts (29%) were ≥ 75 yrs. Eleven pts (19%) had a PS of 2. Seven pts (12%) had a WBC of > 20,000/mcl at diagnosis. Thirty pts (51%) had abnormal cytogenetics. Molecular profile: FLT3/ITD 5 pts (9%), FLT3/D835 2 (4), NPM1 6 (13), Ras 2 (4). Thirteen pts (22%) had prior MDS (4 pts prior azacitidine; 2 pts prior lenalidomide) and 17 pts (29%) had secondary AML (Hx of prior chemo and/or XRT). Of 57 pts evaluable for response, 35 (61%) achieved CR and 4 (7%) CRp for an ORR of 68%. Six pts (11%) required more than one course to response. The ORR for pts with diploid vs abnormal cytogenetics was 79% vs 57%; for pts with prior MDS 46% vs 82% for pts with neither MDS nor secondary AML. All 7 pts with a FLT3 mutation responded. With a median follow up of 11.6 months (1.1-20.2+), 16 pts relapsed. Responses (CR) are ongoing in 19 pts. Median CR duration is 14.1 mos (1.8-16.4). Six pts (10%) died on study. Only one pt suffered an early death ≤ 28 days from induction (C1D26). Deaths were due to myelosuppression-associated infectious complications. Median overall survival for all 59 pts was 18.1 mos (0.8-20.2+). Median overall survival for responding patients has not been reached. The median number of consolidation cycles received by pts in CR/CRp was 4 (0-14). Fifteen of these pts have so far received at least 6 consolidation cycles. Most toxicities were ≤ grade 2 and included rash (64%), nausea (61%), transaminase elevations (58%), bilirubinemia (51%), diarrhea (32%), mucositis, creatinine evelations, and headache (12% each). Among toxicities > grade 2, transaminase elevations (14%) and bilirubinemia (5%) were most frequent. One pt (65 yr old female) experienced renal failure and pulmonary edema shortly following start of the induction. Myelosuppression and neutropenic fever were common, but prolonged myelosuppression in responders was rare. In summary, clofarabine plus low-dose cytarabine achieves high response rates with a manageable toxicity profile and low induction mortality in pts ≥ age 60 with previously untreated AML. Longer follow up and comparisons with conventional therapy will help establish whether or not this combination also has a survival advantage. Disclosures: Faderl: Genzyme: Honoraria, Research Funding; Eisai: Research Funding. Off Label Use: clofarabine and decitabine in AML. Kantarjian:Genzyme: Research Funding; Eisai: Research Funding.

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