Fludarabine, Melphalan, and Alemtuzumab Conditioning in Adults With Standard-Risk Advanced Acute Myeloid Leukemia and Myelodysplastic Syndrome

Purpose This prospective phase II study evaluated toxicity, relapse rate, progression-free survival, and overall survival after allogeneic transplantation and conditioning with fludarabine, melphalan, and alemtuzumab in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Patients and Methods Fifty-two consecutive adults with AML and MDS were enrolled onto the study. Median age was 52 years (range, 17 to 71 years) and the majority of patients had high-risk disease, comorbidities, and/or modest reduction in performance status. Fifty-six percent of patients had unrelated or mismatched related donors. Results After a median follow-up of 18 months (range, 2 to 34 months), 1-year survival was 48% (95% CI, 34% to 61%), progression-free survival was 38% (95% CI, 25% to 52%), relapse rate was 27% (95% CI, 15% to 40%), and treatment-related mortality was 33% (95% CI, 20% to 46%). The cumulative probability of extensive chronic graft-versus-host disease (GVHD) was only 18% (95% CI, 8% to 40%); extensive chronic GVHD was only observed in recipients of unrelated donor transplants. Performance score and disease status were the major predictors of outcome. High-risk disease (ie, active AML or MDS with > 5% blasts) or even modest decreases in performance status were associated with poor outcomes. Patients with standard-risk leukemia (first or second complete remission) or MDS (< 5% blasts) had excellent outcomes despite unfavorable disease characteristics. Conclusion Fludarabine and melphalan combined with in vivo alemtuzumab is a promising transplantation regimen for patients with AML or MDS and low tumor burden. For patients with active disease, this regimen provides at best modest palliation. Despite a low incidence of GVHD, transplantation is still associated with considerable nonrelapse mortality in patients with decreased performance status.

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Safety and Efficacy of Bendamustine and Idarubicin in Combination Therapy for Patients Age ≥50 with Untreated Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome – Results From a Phase I/II Adaptive Design Study.

Blood ◽

10.1182/blood.v120.21.2622.2622 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2622-2622

Author(s):

Mazyar Shadman ◽

Jack M. Lionberger ◽

Raya Mawad ◽

Ravinder K Sandhu ◽

Carol Dean ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myelodysplastic Syndrome ◽

Myeloid Leukemia ◽

Posterior Probability ◽

Performance Status ◽

Outpatient Setting ◽

Ecog Performance Status ◽

Grade 3 ◽

Acute Myeloid

Abstract Abstract 2622 Background: Acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS with 10–19% blasts) are associated with higher mortality in the elderly population. This poor outcome is in part attributed to therapy resistance and therefore, using combinations of agents with different mechanisms of action may improve outcomes. The nitrogen mustard Bendamustine combines unique alkylating characteristics with putative anti-metabolite activity while Idarubicin inhibits DNA and RNA synthesis by intercalation between DNA base pairs. In this single-arm adaptive phase I/II dose-escalation trial, we assessed increasing doses of Bendamustine in combination with a uniform dose of Idarubicin. We used a Bayesian approach to determine whether there was a dose of Bendamustine which, together with Idarubicin can provide a complete response (CR) rate of at least 40%, with minimal (<30%) grade 3–4 extramedullary toxicity in untreated AML or high-risk MDS patients age > 50. Methods: Eligible patients were age 350 with untreated AML or high-risk MDS, had an ECOG performance status <3 and creatinine and bilirubin each less <2.0. Patients received 1 of 3 doses of Bendamustine (45, 60 or 75 mg/m2 daily days 1–5) together with Idarubicin (12 mg/m2 days 1–2). Response was assessed according to the International Working Group (IWG) criteria (Cheson et. al., JCO, 2003) and non-hematologic toxicities according to the NCI CTCAE v.3. After each cohort of 3 patients at a given dose had been evaluated for toxicity and response, Bayesian posterior probabilities based on the data and non-informative prior probabilities were computed. If no Bendamustine dose was associated with a >95% posterior probability of both grade 3–4 extramedullary toxicity <30% (between the 1/6 and 2/6 of the conventional 3+3) and CR rate >40%, the study stopped. Otherwise, the study would continue at the highest dose that met the above criteria until 45 patients had been treated. Treatments were administered in the outpatient setting and patients were admitted to the hospital only if medically indicated. Results: Between October 2010 and May 2012, 39 patients were treated per protocol. The median age was 73 (range, 56–82). Patients had ECOG performance status of 1 (92%), or 2 (7%). AML patients comprised majority of the cases (34/39; 87%). Among AML patients, 35% (12/34) had primary AML, 47% (16/34) had AHD (antecedent hematologic disorders) and 18% (6/34) had secondary AML with a prior history of chemotherapy or radiation. None of the patients had favorable-risk cytogenetic (CG) and 19 (49%) had poor-risk CG including 9 patients (23%) with monosomal karyotype. None of the patients with normal CG had favorable molecular markers. Treatment was given in 1, 2, and 3 cycles in 25 (64%), 7 (18%) and 7(18%) patients, respectively. The number of patients in each cohort and the treatment efficacy and toxicity is reported in the table below. The MTD (maximum tolerated dose) was established at 60 mg/m2 of Bendamustine as two grade 3 toxicities were seen at the dose of 75 mg/m2 (congestive heart failure and mucositis in one patient each). Patients were treated as outpatients but hospitalization was required in 90% of the patients (35/39; 90%). The leading cause of admission was febrile neutropenia (26/35; 74%) followed by fungal infections (4/35; 11%). Conclusion: The combination of Bendamustine (60 mg/m2 (for 5 days) with Idarubicin (12 mg/m2 for 2 days) can be delivered in the outpatient setting and had a <95% posterior probability of >30% toxicity. However, the posterior probability of a CR rate >40% was also <95%, suggesting that continued exploration of new therapeutic combinations is warranted in elderly patients with AML or high-grade MDS. Disclosures: Off Label Use: Bendamustine is indicated for the treatment of CLL and indolent non-Hodgkin's lymphoma. In our study we are using Bendamustine to treat AML.

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Impact of Adding Melphalan to Fludarabine and a Myeloablative Dose of Intravenous Busulfan for Patients Who Received Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-125470 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 254-254

Author(s):

Yoshimitsu Shimomura ◽

Masahiko Hara ◽

Hisashi Yamamoto ◽

Tatsuo Ichinohe ◽

Takahiro Fukuda ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Propensity Score ◽

Myeloid Leukemia ◽

Research Funding ◽

Conditioning Regimen ◽

Allogeneic Hsct ◽

High Risk Disease ◽

Standard Risk ◽

Acute Myeloid

Introduction Fludarabine and a myeloablative dose of intravenous busulfan with or without total body irradiation (Flu/Bu4) is a widely accepted myeloablative conditioning regimen with reduced toxicity for allogeneic hematopoietic stem cell transplantation (HSCT) that has been able to expand the indications for allogeneic HSCT while maintaining the intensity. However, relapse is a major concern especially in patients with high-risk hematological malignancies. Accordingly, a novel conditioning regimen that included Flu/Bu4 plus melphalan (Flu/Bu4/Mel) was used, with excellent outcomes, i.e., the 2-year overall survival (OS) was 54.9% in patients with non-remission acute myeloid leukemia. However, no study has compared Flu/Bu4/Mel and other conditioning regimens. Therefore, this multicenter retrospective observational study aimed to investigate the impact of adding melphalan to Flu/Bu4 by comparing patients who received Flu/Bu4/Mel and those who received Flu/Bu4. Methods The present study included 2394 adult patients who received Flu/Bu4/Mel (n=581) or Flu/Bu4 (n=1813) between January 2010 and December 2016 at the Japan Society of Hematopoietic Cell Transplantation. High-risk disease was defined as incomplete remission in patients with acute myeloid leukemia and acute lymphoblastic leukemia as well as refractory anemia with excess blast transformation in patients with myelodysplastic syndrome; standard risk disease was defined as stable disease or disease progression in patients with malignant lymphoma before HSCT. We set the primary endpoint as the 5-year OS, evaluated by using the log-rank test. To compare the impact of the conditioning regimen on the primary endpoint, we used a multivariable Cox proportional hazards model. The following adjusted covariates were selected clinically based on previous studies: age, sex, disease, disease status at HSCT, hematopoietic cell transplant comorbidity index (HCT-CI), donor source, acute graft versus host disease prophylaxis, and years of HSCT. In addition, we performed propensity score matched analysis to minimize the potential treatment selection bias because the baseline characteristics of patients and disease could have influenced the selection of the conditioning regimen. Propensity score matching with a 1:1 ratio was performed by using the nearest neighbor-matching method with a caliper width fixed at 0.01. In addition, detailed analysis was performed by dividing patients into the high-risk and standard risk groups because the initial single-center retrospective studies mainly enrolled patients with high-risk disease. Results A total of 2394 patients were enrolled and analyzed: 581 patients received Flu/Bu4/Mel and 1813 patients received Flu/Bu4. The median age was 60 years (interquartile range, 53-63 years) and 1489 patients (62.2%) were men. The clinical characteristics of patients treated with Flu/Bu4/Mel and those treated with Flu/Bu4 were different. The Flu/Bu4/Mel group included more patients who were young, had acute myeloid leukemia and malignant lymphoma, had high-risk disease, had higher HCT-CI, received cord blood transplantation, received tacrolimus-based acute graft versus host disease prophylaxis, and had undergone transplantation recently. Regarding the primary endpoint, the 5-year OS after allogeneic HSCT was 33.7% (95% confidence interval [CI]: 27.5-40.1%) in the Flu/Bu4/Mel group vs 35.4% (95% CI: 32.7-38.1%) in the Flu/Bu4 group (p=0.794). The adjusted hazard ratio was 0.73 (95% CI: 0.62-0.85) for the Flu/Bu4/Mel group compared to the Flu/Bu4 group (p<0.001). After propensity score matching, the 5-year OS after allogeneic HSCT was 35.1% (95% CI: 28.0-42.2%) in the Flu/Bu4/Mel group vs 28.1% (95% CI: 22.4-34.0%) in the Flu/Bu4 group (p=0.008; Figure). On detailed subgroup analysis, among patients with high-risk disease, the 5-year OS was 29.5% (95% CI: 23.0-36.4%) in the Flu/Bu4/Mel group vs 20.8% (95% CI: 17.3-24.6%) in the Flu/Bu4 group (p<0.001), while among standard-risk patients, it was 46.3% (95% CI: 35.6-56.2%) in the Flu/Bu4/Mel group vs 43.8% (95% CI: 40.3-47.4%) in the Flu/Bu4 group (p=0.745; P for interaction: 0.010). Conclusion The results showed that Flu/Bu4/Mel resulted in superior 5-year OS compared to Flu/Bu4, with an adjusted hazard ratio of 0.73. In addition, patients with high-risk disease showed better survival benefit with Flu/Bu4/Mel treatment. Figure Disclosures Ichinohe: Astellas Pharma: Research Funding; Chugai Pharmaceutical Co.: Research Funding; CSL Behring: Research Funding; Eisai Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Pfizer: Research Funding; Nippon Shinyaku Co.: Research Funding; MSD: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Takeda Pharmaceutical Co.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; JCR Pharmaceuticals: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria. Atsuta:CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria.

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Improved Treatment Results in High-Risk Pediatric Acute Myeloid Leukemia Patients After Intensification With High-Dose Cytarabine and Mitoxantrone: Results of Study Acute Myeloid Leukemia–Berlin-Frankfurt-Münster 93

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.10.2705 ◽

2001 ◽

Vol 19 (10) ◽

pp. 2705-2713 ◽

Cited By ~ 143

Author(s):

U. Creutzig ◽

J. Ritter ◽

M. Zimmermann ◽

D. Reinhardt ◽

J. Hermann ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myeloid Leukemia ◽

Rank Test ◽

High Dose ◽

Free Survival ◽

Log Rank Test ◽

Risk Patients ◽

Standard Risk ◽

Acute Myeloid

PURPOSE: To improve outcome in high-risk patients, high-dose cytarabine and mitoxantrone (HAM) was introduced into the treatment of children with acute myelogenous leukemia (AML) in study AML-BFM 93. Patients were randomized to HAM as either the second or third therapy block, for the purpose of evaluation of efficacy and toxicity. PATIENTS AND METHODS: A total of 471 children with de novo AML were entered onto the trial; 161 were at standard risk and 310 were at high risk. After the randomized induction (daunorubicin v idarubicin), further therapy, with the exception of HAM, was identical in the two risk groups and also comparable to that in study Acute Myeloid Leukemia–Berlin-Frankfurt-Münster (AML-BFM) 87. RESULTS: Overall, 387 (82%) of 471 patients achieved complete remission, and 5-year survival, event-free survival (EFS), and disease-free survival rates were 60%, 51%, and 62%, respectively. Idarubicin induction resulted in a significantly better blast cell reduction in the bone marrow on day 15. Estimated survival and probability of EFS were superior in study AML-BFM 93 compared with study AML-BFM 87 (P = .01, log-rank test). This improvement, however, was restricted to the 310 high-risk patients (remission rate and probability of 5-year EFS in study AML-BFM 93 v study AML-BFM 87: 78% v 68%, P = .007; and 44% v 31%, P = .01, log-rank test). Probability of 5-year EFS among standard-risk patients in study AML-BFM 93 was similar to that in study AML-BFM 87 (65% v 63%, P = not significant). Whether HAM was placed as the second or third therapy block was of minor importance. However, patients who received the less intensive daunorubicin treatment during induction benefited from early HAM. CONCLUSION: Improved treatment results in children with high-risk AML in study AML-BFM 93 must be attributed mainly to the introduction of HAM.

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