Low efficacy and high mortality associated with clofarabine treatment of relapsed/refractory acute myeloid leukemia and myelodysplastic syndromes

Roberts, Daniel A.; Wadleigh, Martha; McDonnell, Anne; DeAngelo, Daniel J.; Stone, Richard; Steensma, David P.

doi:10.1016/j.leukres.2014.11.031

Cited by 14 publications

(11 citation statements)

References 26 publications

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“…Among the most used courses, the best results have been obtained with fludarabine‐based courses (such as FLAG and FLAG‐IDA), cytarabine alone or combined with anthracycline, and etoposide‐containing courses, which can obtain a complete remission in the 40–55% of PIF‐AML cases . These results are very similar to those obtained with clofarabine and cytarabine combinations (35–55% complete remission rate), and probably for this reason, clofarabine, a more expensive drug than fludarabine, did not replace fludarabine as salvage chemotherapy in the clinical practice .…”

Section: Discussionsupporting

confidence: 53%

Multicentre survey to explore current survival of patients with acute myeloid leukaemia who failed induction chemotherapy

Lazzarotto

Candoni

Nadali

et al. 2015

European J of Haematology

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Treatment options of PIF-AML still are limited and the prognosis, even recently, remains extremely poor. This survey shows that PIF-AML is still rarely cured without Allo-SCT and confirms the importance of initiating an urgent unrelated donor search in cases without a matched sibling donor. Moreover, the outcome of Allo-SCT is better in patients who achieve a good AML debulking before transplant. To reach this goal, new predictive scores and new protocols of salvage therapy (with target drugs or combinations) need to be explored urgently in PIF-AML.

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Section: Discussionsupporting

confidence: 53%

Multicentre survey to explore current survival of patients with acute myeloid leukaemia who failed induction chemotherapy

Lazzarotto

Candoni

Nadali

et al. 2015

European J of Haematology

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“…52 Standard-dose clofarabine used after HMA failure in patients with advanced MDS showed excessive toxicity. 53 Low-dose chemotherapy The use of subcutaneous low-dose cytarabine after HMA failure does not have any advantage over supportive care, 10 with absence of response and OS of 7.4 months. Combination of cytarabine with experimental agents has not shown encouraging results.…”

Section: Management Of Hma Failuresmentioning

confidence: 99%

How I treat MDS after hypomethylating agent failure

Santini

2019

Blood

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Hypomethylating agents (HMA) azacitidine and decitabine are standard of care for myelodysplastic syndrome (MDS). Response to these agents occurs in ∼50% of treated patients, and duration of response, although variable, is transient. Prediction of response to HMAs is possible with clinical and molecular parameters, but alternative approved treatments are not available, and in the case of HMA failure, there are no standard therapeutic opportunities. It is important to develop a reasoned choice of therapy after HMA failure. This choice should be based on evaluation of type of resistance (primary vs secondary, progression of disease [acute leukemia or higher risk MDS] vs absence of hematological improvement) as well as on molecular and cytogenetic characteristics reassessed at the moment of HMA failure. Rescue strategies may include stem-cell transplantation, which remains the only curative option, and chemotherapy, both of which are feasible in only a minority of cases, and experimental agents. Patients experiencing HMA failure should be recruited to clinical experimental trials as often as possible. Several novel agents with different mechanisms of action are currently being tested in this setting. Drugs targeting molecular alterations (IDH2 mutations, spliceosome gene mutations) or altered signaling pathways (BCL2 inhibitors) seem to be the most promising.

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“…Median OS was 3 months for the entire cohort, with a small subgroup taken to transplant that had a median OS of 18 months. Unfortunately, the 30-day mortality or induction death rate was equally as high as the response rate at 21 % with 70-80 % experiencing a documented infection or febrile neutropenia, respectively [38]. The ORR for the 30 patients that had previously received HMAs was poor: only 4 patients responded to clofarabine (ORR 17 %); most patients who had received HMAs were given clofarabine alone (n=19) as opposed to combination therapy with cytarabine.…”

Section: Clofarabinementioning

confidence: 99%

Outlook and Management of Patients with Myelodysplastic Syndromes Failed by Hypomethylating Agents

Roberts

Steensma

2015

Curr Hematol Malig Rep

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The DNA hypomethylating agents (HMAs) azacitidine and decitabine are currently the most frequently administered disease-modifying therapies for patients with higher-risk myelodysplastic syndromes (MDS). However, azacitidine and decitabine are not curative, the median response duration is 11-15 months, and only 10-20 % of patients experience complete hematologic and cytogenetic response. Moreover, once an HMA fails the patient, the prognosis is poor, with a median survival of less than 6 months unless the patient undergoes hematopoietic stem cell transplantation (HSCT). Recent insights into the genetic basis of MDS have enhanced biological understanding and prognostication accuracy, but these developments have not yet led to regulatory approval of new therapies. While there are multiple potential approaches to patients with MDS for whom HMAs have failed, including supportive care alone, cytotoxic therapy, lenalidomide, histone deacetylase inhibitors, and HSCT, favorable responses to these approaches are limited and new therapies are greatly needed. Here, we review clinical and biological data about the population of patients failed by HMAs, evaluate currently available approaches to patients in this clinical situation, and discuss prospects for development of novel active agents.

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Low efficacy and high mortality associated with clofarabine treatment of relapsed/refractory acute myeloid leukemia and myelodysplastic syndromes

Cited by 14 publications

References 26 publications

Multicentre survey to explore current survival of patients with acute myeloid leukaemia who failed induction chemotherapy

Multicentre survey to explore current survival of patients with acute myeloid leukaemia who failed induction chemotherapy

How I treat MDS after hypomethylating agent failure

Outlook and Management of Patients with Myelodysplastic Syndromes Failed by Hypomethylating Agents

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