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    • Aside from this report only

    2019-06-11

    Aside from this report, only two other studies of dexrazoxane use in adult AML patients have been published. In a series of seven patients with AML, Lemez and Maresova reported that the administration of dexrazoxane 30min before daunorubicin (dose 8-13x higher than daunorubicin) or mitoxantrone (dose 40-60x higher than mitoxantrone) allowed them to give cumulative anthracycline doses in the range of 550–1300mg/m2 of daunorubicin without signs of cardiac toxicity [24]. Complete remission was achieved in all patients with relapsed AML treated with high dose cytarabine, anthracycline, and dexrazoxane. However, almost all of these patients were significantly younger (ages 21–58, median 35 years) than our cases (ages 55–71, median 61.5 years), and all had much higher baseline LVEF (62–70%) than our patients (LVEF 40–50%). In another study, Woodlock and colleagues safely administered dexrazoxane to two AML patients: prior to mitoxantrone in a 70 year old patient with ischemic MK2 inhibitor disease (LVEF 30%), and prior to idarubicin in a 43 year old patient with concurrent myocardial infarction (LVEF 70%) [11]. Both patients had preserved LVEF after therapy but died shortly thereafter. Dexrazoxane was not thought to be the culprit agent. Strategies to mitigate the cardiac toxicities of anthracycline therapy are urgently needed to allow for the safe administration of effective, intensive chemotherapy regimens in adult AML patients. A recent cooperative group trial demonstrated that higher daunorubicin doses (90mg/m2 vs. 45mg/m2) during induction therapy improved clinical outcomes for AML patients across cytogenetic and molecular subgroups [25]. In another large multicenter study, higher-dose daunorubicin (90mg/m2 vs. 45mg/m2) improved complete remission rate (52% vs. 35%, p<0.001) in adults over the age of 60 years and overall survival (38% vs. 23%, p<0.001) for those aged 60–65 years [26]. Older individuals who constitute the majority of new diagnoses are at particular risk for cardiotoxic complications. Based on our clinical experience and the current data, we believe that the use of dexrazoxane as standard cardioprotection during intensive chemotherapy should be further investigated in large randomized controlled clinical trials. Until such high-quality evidence emerges, we would suggest strongly considering dexrazoxane in adults with known significant cardiac comorbidities and/or who are fit for intensive anthracycline-containing therapy but are approaching or have crossed their lifetime cumulative dose of anthracycline. Dexrazoxane should be administered intravenously 15min before every dose of mitoxantrone/idarubicin (50:1 dexrazoxane: anthracycline) or daunorubicin (10:1 dexrazoxane: daunorubicin). It is important to note that dexrazoxane is renally eliminated and therefore would require a 50% dose reduction in the setting of renal insufficiency. Other approaches to limit cardiotoxicity in such patients should also be utilized when possible. These include concomitant beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and statins, all of which have previously been shown in various studies to improve a variety of cardiac outcomes in patients receiving anthracyclines [27]. Of note, in patients with metastatic breast cancer, liposomal doxorubicin conferred similar efficacy but significantly less cardiotoxicity than standard doxorubicin [28]. It remains to be seen whether CPX-351, a new liposomal formulation of cytarabine: daunorubicin which has shown improvement in response and overall survival in older patients with secondary AML, represents a safer, less cardiotoxic, induction choice than standard 7+3 [29].
    Conclusion
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    Introduction High risk MDS and AML are heterogeneous myeloid malignancies and usually have a very poor prognosis. Advanced age and co-morbidities often make the patients unsuitable candidates for intensive chemotherapy or allogeneic stem cell transplantation (allo-SCT) [1]. New less toxic treatments that improve response rates and extend survival are needed for such patients. In this phase I study, we sought to determine safety and efficacy of sequential therapy with low-dose clofarabine and lenalidomide in high risk MDS and AML. Both clofarabine lenalidomide have partial efficacy as single agents for MDS and AML [2,3]. Although the immunomodulatory effects of lenalidomide are well described [4,5], little is known about the effect of clofarabine on cellular immunity. We hypothesized that the lymphocyte depleting effect of clofarabine would create a favorable immunological microenvironment for subsequent lenalidomide therapy promoting T cell and NK cell reconstitution. Here we report cellular immune profiles of the four cases receiving sequential clofarabine and lenalidomide for high risk MDS and AML.