Clofarabine, high-dose cytarabine and liposomal daunorubicin in pediatric relapsed/refractory acute myeloid leukemia: a phase IB study

Eijkelenburg, Natasha K. A. van; Rasche, Mareike; Ghazaly, Essam; Dworzak, Michael; Klingebiel, Thomas; Rössig, Claudia; Leverger, Guy; Starý, Jan; Bont, Eveline S.J.M. de; Chiţu, Dana; Bertrand, Yves; Brethon, Benoît; Strahm, Brigitte; Sluis, Inge M. van der; Kaspers, Gertjan J. L.; Reinhardt, Dirk; Zwaan, C. Michel

doi:10.3324/haematol.2017.187153

Cited by 27 publications

(28 citation statements)

References 35 publications

(46 reference statements)

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“…After relapse, the majority of children was treated with an SCT. Outcome seemed better in these patients compared to chemotherapy only, with OS-rates comparable to other recent studies [23,24]. However, conclusions cannot easily be drawn, since SCT is mostly performed in children achieving CR2 and in relatively good state [25,26].…”

Section: Discussionsupporting

confidence: 64%

Pediatric relapsed acute myeloid leukemia: a systematic review

Hoffman

Schoonmade

Kaspers

2020

Expert Review of Anticancer Therapy

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Introduction: Pediatric relapsed acute myeloid leukemia (AML) remains lethal in the majority of cases, despite intensive therapy. Randomized trials are largely lacking, and the main issues of optimal therapy and prognostic factors remain unclear. Area covered: This systematic review includes all literature evaluating treatment outcome after first relapse. We searched databases PubMed and Embase.com. Twelve out of six thousand articles were ultimately included, based on age of the population (<21 years), relapsed AML, and information on clinical outcome (second complete remission (CR2), disease-free survival (DFS), event-free survival (EFS) and overall survival (OS)). There was only one randomized clinical trial reported. This review shows that there is no standard treatment for relapsed AML in children, and that outcome varies for CR2 and (2-to 10-year) OS rates, mean 64% (range, 50-75%), and 31% (16-43%), respectively. Children treated with chemotherapy only in first complete remission (CR1) tend to have better outcome after relapse than children receiving allo-SCT in CR1. Allo-SCT seems to be the most effective consolidation therapy in children achieving CR2, after relapse. Duration of CR1 was the most frequently reported statistically significant prognostic factor. Through randomized clinical trials, better knowledge of prognostic factors enabling risk-stratified treatment, and of more effective and less toxic therapies, should contribute to better clinical outcome for children with relapsed AML. Expert opinion: Outcome of pediatric relapsed AML has improved to OS rates up to 40%. However, there is a lack of knowledge on (independent) prognostic factors, optimal reinduction chemotherapy, timing of allo-SCT, and late effects. International collaboration should enable large, randomized clinical trials addressing these issues.

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Section: Discussionsupporting

confidence: 64%

Pediatric relapsed acute myeloid leukemia: a systematic review

Hoffman

Schoonmade

Kaspers

2020

Expert Review of Anticancer Therapy

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“…One patient had a residual blast count of 60% and received asparaginase and methotrexate chemotherapy without efficacy. Another patient displayed partial failure with blast count decreasing from 15% to 6% and received subsequent clofarabin, daunoxome, cytarabine chemotherapy, according to a phase I study, 11 associated with ponatinib because of Fms‐like tyrosine kinase 3‐internal tandem duplication (FLT3‐ITD), allowing to finally achieve CR and undergo HSCT (Supporting Information 2).…”

Section: Resultsmentioning

confidence: 99%

Association of fludarabin, cytarabine, and fractioned gemtuzumab followed by hematopoietic stem cell transplantation for first‐line refractory acute myeloid leukemia in children: A single‐center experience

Penel‐Page

Pleşa

Girard

et al. 2020

Pediatric Blood & Cancer

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Context: Acute myeloid leukemia (AML) is a rare disease in children, with only 50% to 60% eventfree survival. Among patients with AML, 10% do not respond to first-line chemotherapy. There is no recommendation concerning second-line treatments. Gemtuzumab ozogamicin (GO) is a monoclonal antibody targeting CD33, linked to calicheamicin. We report the efficacy and tolerance of a salvage regimen of fludarabin, cytarabine, and GO (FLA-GO) in patients refractory to first-line treatment.Methods: Eight patients (median age 14.5 years), who had more than 2% minimal residual disease (MRD) by flow cytometry (MRD flow), received gemtuzumab 3 mg/m 2 on days 1, 4, 7, associated with cytarabine 2000 mg/m 2 and fludarabin 30 mg/m 2 on days 1 to 5.Results: Six patients achieved complete remission (CR) (blast count morphology ≤5 × 10 −2 , CR-MRD flow <1 × 10 −3 for four patients). Five patients received a second course. We observed 11 episodes of febrile neutropenia, including 6 septicemias without complication. There was no fungal infection or toxic death. Two patients received granulocyte colony stimulating factor.One patient had partial platelet recovery; one, prolonged pancytopenia. All patients received hematopoietic stem cell transplantation (HSCT). We observed five mild-to-severe sinusoidal obstruction syndromes during HSCT procedures, particularly in patients who did not receive defibrotide prophylaxis. At the date of last contact (median follow-up: 58 months; range: 22-78), six patients were in continuous CR with negative MRD. Two patients died of post-HSCT relapse. Conclusion:FLA-GO is a good salvage regimen for pediatric refractory AML, with significant but acceptable toxicity. HSCT is mandatory to achieve sustained CR in these patients.

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“…Therapeutic options for pediatric relapsed/refractory acute myeloid leukemia (AML) are limited, and clinical trials of new agents are slow to be developed 1 . Accordingly, two‐year relapse‐free and overall survival rates for these patients, even with current chemotherapeutic regimens and hematopoietic stem cell transplant (HSCT), are only 25%‐30% 2‐4 …”

Section: Introductionmentioning

confidence: 99%

Single‐center pediatric experience with venetoclax and azacitidine as treatment for myelodysplastic syndrome and acute myeloid leukemia

Winters

Maloney

Treece

et al. 2020

Pediatric Blood & Cancer

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Background The BCL‐2 inhibitor venetoclax (ven) has revolutionized the treatment of acute myeloid leukemia (AML) in elderly adults, leading to its recent FDA approval for this population in combination regimens. Although extensive data exist for adult myeloid malignancies, there are limited preclinical data on the efficacy and/or dosing of venetoclax for pediatric myelodysplastic syndrome (MDS) or AML and thus little information to guide use of this regimen in pediatric patients. Our objective was to describe our single‐center experience with venetoclax in combination with the hypomethylating agent 5‐azacitidine (aza) in pediatric patients with MDS or AML. Procedure We conducted a retrospective chart review of patients treated at Children's Hospital Colorado prior to March 2020 with at least one cycle of ven/aza. Patients were included if between the ages of 1 and 25 years with a diagnosis of high‐grade MDS or AML. AML patients had relapsed or primary refractory disease or were deemed poor candidates for standard chemotherapy. Results Eight patients received ven/aza, two for high‐grade MDS and six for AML. Ven/aza was well tolerated by all patients. The most common adverse events seen with this regimen were gastrointestinal and hematologic. Morphologic responses were seen in six patients including both patients with MDS. All four AML responders became minimal residual disease negative. Three responders have thus far proceeded to allogeneic hematopoietic stem cell transplant following ven/aza. Conclusions Our clinical experience suggests that ven/aza is a safe and promising regimen that should be further explored with late‐phase clinical trials.

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Clofarabine, high-dose cytarabine and liposomal daunorubicin in pediatric relapsed/refractory acute myeloid leukemia: a phase IB study

Cited by 27 publications

References 35 publications

Pediatric relapsed acute myeloid leukemia: a systematic review

Pediatric relapsed acute myeloid leukemia: a systematic review

Association of fludarabin, cytarabine, and fractioned gemtuzumab followed by hematopoietic stem cell transplantation for first‐line refractory acute myeloid leukemia in children: A single‐center experience

Single‐center pediatric experience with venetoclax and azacitidine as treatment for myelodysplastic syndrome and acute myeloid leukemia

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