Clofarabine, Etoposide and Mitoxantrone In the Therapy of Relapsed and Refractory Acute Myelogenous Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4353-4353
Author(s):  
W. Christopher Ehmann ◽  
Sulfikar Ibrahim ◽  
Witold Rybka ◽  
David F. Claxton
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Treatment Options ◽  
Single Agent ◽  
Myelogenous Leukemia ◽  
Dose Finding ◽  
High Dose ◽  
Phase 2 ◽  
Patients Âgés ◽  
Treatment Regimens ◽  
Acute Myelogenous

Abstract Abstract 4353 Currrent therapy for acute myelogenous leukemia depends on the activity of cytosine arabinoside (ara-C). The development of regimens without this agent would potentially provide non-crossresistant treatment options for these disorders. Clofarabine, a novel agent showing significant single agent activity in AML, provides a platform for potentially effective treatment independent of ara-C. We treated 10 patients ages 30–67 (median 51) with relapsed or refractory AML with a phase I dose finding protocol employing a three drug combination based on clofarabine. The objectives were to define a maximally tolerated and recommended phase 2 dose and identify early phase 2 activity. Seven patients (70%) were refractory to 1 or 2 treatment regimens immediately prior to enrollment, the other 3 pts (30%) were relapsed following a remission. All patients had relapsed following or were refractory to standard 7+3 chemotherapy and 7/10 had received intermediate or high dose cytarabine within <52 weeks of enrollment. Patients received clofarabine 20mg/m2 (Dose level 1 – DL1 – 4 patients treated) or 25mg/m2 (DL2 – 6 patients) days 2–6, etoposide 100mg/m2 days 1–5, and mitoxantrone 8mg/m2 days 1–3. Treatment emergent non-hematological toxicities included mucositis (4 patients, ≤ grade 2) and diarrhea (2 patients, ≤ grade 3). Two out of 6 patients (33%) at DL2 failed to recover absolute neutrophils (ANC) to 500/mcL by Day 42, and this was judged a potentially treatment related toxicity given lack of residual leukemia in day 14 marrows. Seven of 9 (78%) day 14 marrows were markedly hypocellular or aplastic, and two showed residual leukemia. Four out of 10 patients (40%) showed complete remission (CR – 2 patients) or remission with incomplete hematopoietic recovery (CRi – 2 patients). Three patients survive in remission 34, 98, and 236 days from enrollment. We conclude that the clofarabine, etoposide and mitoxantrone combination has acceptable toxicity and is an active regimen for significantly pretreated acute myelogenous leukemia. The total response rate compares favorably with other AML salvage regimens. As there has been delayed myeloid recovery at higher doses, we are pursuing DL1. The activity of this regimen is potentially non-crossresistant with ara-C, therefore larger studies are justified. Currently, patients are enrolling in an expanded cohort at the recommend phase 2 dose. Disclosures: Claxton: Genzyme: Research Funding. Off Label Use: Clofarabine for AML therapy.

High-dose cytosine arabinoside in the treatment of acute myelogenous leukemia: contributions to outcome of clinical and laboratory attributes.

1987 ◽  
Vol 5 (4) ◽  
pp. 532-543 ◽  
Author(s):  
J E Curtis ◽  
H A Messner ◽  
M D Minden ◽  
S Minkin ◽  
E A McCulloch
Keyword(s):  
Cytosine Arabinoside ◽  
Acute Myelogenous Leukemia ◽  
Single Agent ◽  
Myelogenous Leukemia ◽  
Remission Induction ◽  
High Dose ◽  
Cell Renewal ◽  
Previous Trial ◽  
Self Renewal ◽  
Acute Myelogenous

High-dose cytosine arabinoside (HDAra-C) has been used for remission induction, and in conventional doses for maintenance in a trial of single-agent therapy in 43 previously untreated patients with acute myelogenous leukemia (AML). Rationale for the trial was provided by the observed decrease in leukemic blast cell self-renewal in culture following exposure to Ara-C. Compared with a previous trial of 57 patients treated with multidrug therapy, single-drug Ara-C was associated with a significantly improved complete remission rate (P = .010), although the survival time was not increased. All patients with low self-renewal responded to HDAra-C in contrast to the previous trial where some patients with this phenotype failed remission induction. The clinical observations are consistent with the view that the antileukemic effect of Ara-C has some specificity for cellular events required for self-renewal of blast cells. Exposure in vivo to Ara-C was associated with an increase in blast stem cell renewal at relapse, indicating that maintenance with other drugs should be tested. The study demonstrates the importance of biological attributes in design and analysis of clinical trials.

scholarly journals Phase II Trial of Vorinostat With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome

2012 ◽  
Vol 30 (18) ◽  
pp. 2204-2210 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Francesco Paolo Tambaro ◽  
Nebiyou B. Bekele ◽  
Hui Yang ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Acute Myelogenous Leukemia ◽  
Single Agent ◽  
Complete Response ◽  
Myelogenous Leukemia ◽  
Platelet Recovery ◽  
Free Survival ◽  
Binding Factor ◽  
Deacetylase Inhibitor ◽  
Acute Myelogenous

Purpose To evaluate the safety and efficacy of the combination of the histone deacetylase inhibitor vorinostat with idarubicin and ara-C (cytarabine) in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Patients and Methods Patients with previously untreated AML or higher-risk MDS age 15 to 65 years with appropriate organ function and no core-binding factor abnormality were candidates. Induction therapy was vorinostat 500 mg orally three times a day (days 1 to 3), idarubin 12 mg/m2 intravenously (IV) daily × 3 (days 4 to 6), and cytarabine 1.5 g/m2 IV as a continuous infusion daily for 3 or 4 days (days 4 to 7). Patients in remission could be treated with five cycles of consolidation therapy and up to 12 months of maintenance therapy with single-agent vorinostat. The study was designed to stop early if either excess toxicity or low probability of median event-free survival (EFS) of more than 28 weeks was likely. Results After a three-patient run-in phase, 75 patients were treated. Median age was 52 years (range, 19 to 65 years), 29 patients (39%) were cytogenetically normal, and 11 (15%) had FLT-3 internal tandem duplication (ITD). No excess vorinostat-related toxicity was observed. Induction mortality was 4%. EFS was 47 weeks (range, 3 to 134 weeks), and overall survival was 82 weeks (range, 3 to 134 weeks). Overall response rate (ORR) was 85%, including 76% complete response (CR) and 9% in CR with incomplete platelet recovery. ORR was 93% in diploid patients and 100% in FLT-3 ITD patients. Levels of NRF2 and CYBB were associated with longer survival. Conclusion The combination of vorinostat with idarubicin and cytarabine is safe and active in AML.

Marrow irradiation with high-dose 153Samarium-EDTMP followed by chemotherapy and hematopoietic stem cell infusion for acute myelogenous leukemia

2006 ◽  
Vol 47 (8) ◽  
pp. 1583-1592 ◽  
Author(s):  
Vilmarie Rodriguez ◽  
Peter M. Anderson ◽  
Mark R. Litzow ◽  
Linda Erlandson ◽  
Barbara A. Trotz ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Acute Myelogenous

Loss of the Y Chromosome: An Age-Related or Clonal Phenomenon in Acute Myelogenous Leukemia/Myelodysplastic Syndrome?

2008 ◽  
Vol 132 (8) ◽  
pp. 1329-1332
Author(s):  
Anna K. Wong ◽  
Belle Fang ◽  
Ling Zhang ◽  
Xiuqing Guo ◽  
Stephen Lee ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
Y Chromosome ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Related Phenomenon ◽  
Patients Âgés ◽  
Age Related ◽  
Acute Myelogenous ◽  
Bone Marrow Analysis

Abstract Context.—The clinical association between loss of the Y chromosome and acute myelogenous leukemia and myelodysplastic syndrome (AML/MDS) has been debated because both phenomena are related to aging. A prior publication suggests that loss of the Y chromosome in more than 75% of cells may indicate a clonal phenomenon that could be a marker for hematologic disease. Objective.—To evaluate the relationship between loss of the Y chromosome and AML/MDS. Design.—A retrospective review of cytogenetic reports of 2896 male patients ascertained from 1996 to 2007 was performed. Results were stratified based on the percentage of cells missing the Y chromosome and were correlated with patients' ages and bone marrow biopsy reports through logistic regression analysis with adjustment for age. Results.—Loss of the Y chromosome was found in 142 patients. Of these, 16 patients demonstrated myeloid disease, with 2 cases of AML and 14 cases of MDS. An increased incidence (P &lt; .05) of AML/MDS was seen only in the group composed of 8 patients with complete loss of the Y chromosome in all karyotyped cells (1 case of AML and 7 cases of MDS). Conclusion.—Loss of the Y chromosome appears to be primarily an age-related phenomenon. However, in individuals in which all cells on cytogenetic analysis showed loss of the Y chromosome, there was a statistically significant increase in AML/MDS, suggesting that the absence of any normal-dividing cells in a bone marrow analysis may be indicative of AML/MDS.

Response to salvage therapy and survival after relapse in acute myelogenous leukemia.

1989 ◽  
Vol 7 (8) ◽  
pp. 1071-1080 ◽  
Author(s):  
M J Keating ◽  
H Kantarjian ◽  
T L Smith ◽  
E Estey ◽  
R Walters ◽  
...  
Keyword(s):  
Salvage Therapy ◽  
Acute Myelogenous Leukemia ◽  
Specific Treatment ◽  
Lactic Dehydrogenase ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Salvage Regimen ◽  
Conventional Dose ◽  
Acute Myelogenous ◽  
Probability Of Response

The response to and survival following first salvage therapy regimens for 243 patients with acute myelogenous leukemia (AML) treated between 1974 and 1985 were evaluated. Eighty (33%) patients obtained a complete remission (CR), 24% died prior to achieving a response, and 43% were resistant on their first salvage regimen. The median survival was 18 weeks. Five percent overall and 16% of the CR patients are predicted to survive for more than 5 years. The factor most strongly associated with response and survival was the duration of the initial remission with 49 of 82 (60%) patients whose initial CR duration was at least 1 year in duration obtaining a second CR v 31 of 161 (19%) for patients with a shorter remission (P less than .01). Age, liver function, serum lactic dehydrogenase (LDH), karyotype, and the proportion of blasts plus promyelocytes present at the time of starting salvage therapy were strongly associated with probability of response and survival. Multivariate analysis was used to develop logistic regression and proportional hazard models to predict probability of response and survival, respectively. The major regimens used were conventional-dose cytarabine (ara-C) (combined with anthracyclines or amsacrine), high-dose ara-C, rubidazone, amsacrine (AMSA), other anthracyclines, and autologous or allogeneic transplant programs. After allowing for the prognostic factors in the models, specific treatment regimens were not strongly associated with prognosis.

Does cranial irradiation reduce the risk for bone marrow relapse in acute myelogenous leukemia? Unexpected results of the Childhood Acute Myelogenous Leukemia Study BFM-87.

1993 ◽  
Vol 11 (2) ◽  
pp. 279-286 ◽  
Author(s):  
U Creutzig ◽  
J Ritter ◽  
M Zimmermann ◽  
G Schellong
Keyword(s):  
Bone Marrow ◽  
Acute Myelogenous Leukemia ◽  
Cranial Irradiation ◽  
Low Risk ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Number Of Patients ◽  
Acute Myelogenous ◽  
Wbc Count ◽  
Group B

PURPOSE One of the goals of study AMA-BFM-87 was to test prospectively in acute myelogenous leukemia (AML) patients if cranial irradiation could be replaced by late intensification therapy with high-dose cytarabine (Ara-C) and etoposide (VP-16). PATIENTS AND METHODS Patients with a low risk of CNS relapses (ie, no initial CNS disease, WBC count at diagnosis < or = 70.000/microL) were randomized for irradiation (group A, 31 patients). In 25 patients (group B), randomization was refused. As interim results showed no increase of CNS relapses in nonirradiated patients, prophylactic irradiation was discontinued after 2 1/2 years to prevent unnecessary CNS toxicity. Forty-four patients (group C) entered the study after randomization had been stopped. RESULTS In all patients with a low risk of CNS recurrences (n = 100), a significantly higher probability of relapse-free interval (pRFI) of 5 years was found in irradiated patients (pRFI = .78) compared with nonirradiated patients (pRFI = .41) (P = .007). Moreover, a slightly higher incidence of CNS relapses was observed in nonirradiated patients. Due to the small number of patients, this was not observed when randomized patients only were analyzed. In accordance with these findings, the favorable outcome of low-risk patients in the preceding study, AML-BFM-83 (pRFI > .80), could only be reproduced in study AML-BFM-87 in patients who had received cranial irradiation. CONCLUSION These results indicate that cranial irradiation should be an integral part of the treatment of all AML patients not undergoing bone marrow transplantation. Residual blasts in the CNS may escape systemic chemotherapy and lead to recurrence of the initial disease not only in the CNS, but also in the bone marrow.

Synergy between high-dose cytarabine and asparaginase in the treatment of adults with refractory and relapsed acute myelogenous leukemia--a Cancer and Leukemia Group B Study.

1988 ◽  
Vol 6 (3) ◽  
pp. 499-508 ◽  
Author(s):  
R L Capizzi ◽  
R Davis ◽  
B Powell ◽  
J Cuttner ◽  
R R Ellison ◽  
...  
Keyword(s):  
Median Time ◽  
Acute Myelogenous Leukemia ◽  
Standard Dose ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Time To Failure ◽  
Cutaneous Toxicity ◽  
High Dose Cytarabine ◽  
Acute Myelogenous ◽  
Refractory Aml

One hundred ninety-five adult patients with refractory or first relapse acute myelogenous leukemia (AML) were randomly assigned to receive high-dose cytarabine (HiDAC), 3 g/m2 as a three-hour intravenous (IV) infusion every 12 hours for four doses, followed by 6,000 IU/m2 asparaginase (ASNase) administered at hour 42, or HiDAC without ASNase. Treatment was repeated on day 8. The median patient age was 52 years. There was an overall superior complete remission (CR) rate for HiDAC/ASNase (40%) v HiDAC (24%), P = .02. Subset analysis according to prior response and age showed the following CR rates: 54% from HiDAC/ASNase treatment of refractory AML in patients less than 60 years, and 31% in patients greater than 60 years; CR from HiDAC in the same refractory groups were 18% (less than 60) and 0% (greater than 60); 37% from HiDAC/ASNase treatment of relapsed AML in patients less than 60 years, and 43% in patients greater than 60 years; CRs from HiDAC in the same relapsed groups were 33% (less than 60) and 21% (greater than 60). Toxicity in the two treatment arms was comparable and consisted primarily of leukopenia, thrombocytopenia, mild hepatic dysfunction, diarrhea, conjunctivitis and serositis, and hyperglycemia. There was only one case of transient cerebellar toxicity and no cutaneous toxicity. Median time to full hematologic recovery was 5 weeks. There was an overall survival benefit for patients treated with HiDAC/ASNase (19.6 weeks) compared with HiDAC (15.9 weeks), P = .046, primarily attributable to effects in refractory patients. Median time to failure for refractory patients who achieved CR was 38.5 weeks with HiDAC/ASNase, and 13.3 weeks for those treated with HiDAC. For relapsed patients in CR from HiDAC/ASNase the median time to failure was 17.7 weeks and 18.3 weeks for HiDAC. The overall 42% CR rate from HiDAC/ASNase v 12% from HiDAC in patients with refractory AML indicates that HiDAC/ASNase is not cross-resistant with standard-dose cytarabine (SDAC) and anthracyclines. We conclude that HiDAC/ASNase has substantial activity in poor-prognosis AML and that this combination warrants further trials in earlier stage disease.

scholarly journals Mitoxantrone and high-dose cytosine arabinoside in refractory acute myelogenous leukemia

Cancer ◽  
1988 ◽  
Vol 62 (4) ◽  
pp. 677-682 ◽  
Author(s):  
Ronald S. Walters ◽  
Hagop M. Kantarjian ◽  
Michael J. Keating ◽  
William K. Plunkett ◽  
Elihu H. Estey ◽  
...  
Keyword(s):  
Cytosine Arabinoside ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Acute Myelogenous
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