Novel Therapeutic Approach Yields Excellent Results in Minimally Differentiated Acute Myeloid Leukemia (AML-M0): Time To Think out of the Box.

Abstract

Background: AML M0 has dismal complete remission (CR) rates (<50% in most series) and poor long term survival with conventional combination chemotherapy (CT). Thus it is considered a candidate for allogenic bone marrow transplantation (BMT) in first remission and also for other novel therapeutic approaches. There is increasing recognition of angiogenesis as a pathogenic and prognostic factor in AML. The objective of our study was to evaluate the efficacy of low-dose oral metronomic CT in patients with AML-M0. Materials and methods: Eleven patients fulfilling the diagnostic criteria for AML-M0 and ineligible for standard CT and/or BMT were accrued in this pilot protocol between June 1998 and Feb 2005. The treatment consisted of Prednisolone 40 mg/m2/d, Etoposide 50 mg/m2/d and 6-TG 40 mg/m2/d (PET), given orally on out-patient basis continuously for 21 days every month. Post-induction high dose Ara-C (HD-Ara-C) was given whenever possible. Results: The median age was 17 yrs (range 1.5 to 52); 9 were males and 2 females. The median leukocyte count at presentation was 15.4 x 109/L (range 0.9 to 142) and platelet count was 62 x 109/L (range 21 to 442). CD56 and CD7 were positive in 3/5 and 8/11 of those evaluated. Cytogenetic studies were done in 7 patients. Ten of the eleven patients received at least 1 cycle of PET CT of which 9 (90%) achieved CR. The eleventh patient received only 1 week of CT before being lost to follow up, however by then she had already cleared all blasts (57%) in the peripheral blood. Importantly the whole induction was given on out patient basis with only 2 patients requiring admission. There was minimal to nil blood, platelet and antibiotic support required during the entire Induction therapy. Four of them received HD-Ara-C after achieving CR; two of them died in remission at 6 and 11 months. The other two are alive in CR at 36 months and 14 months. Others who could not get HD-Ara-C because of socio-economic reasons were continued on PET or ET chemotherapy for up to maximum of 12 cycles. The median overall survival was 20 months for those who continued treatment. So far no relapses are noted in those who received PET x 2 followed by HD-Ara-C. Conclusions: The dramatic remission rates, excellent tolerability, minimal cost and morbidity with this protocol provide proof of principle that metronomic approach may be a superior alternative to conventional induction chemotherapy in the treatment of AML-M0. Additionally, incorporation of HD-Ara-C consolidation and metronomic maintenance may improve the long term outcome of this disease with dismal prognosis.

SIOP PODC adapted risk stratification and treatment guidelines: Recommendations for acute myeloid leukemia in resource‐limited settings

“…This regimen has been reported by the Tata Memorial Hospital, Mumbai, India 31,32 (G. Narula, personal communication). It includes a combination of oral etoposide, 6‐thioguanine (6‐TG), and prednisolone as follows: (a) etoposide at 50 mg/m 2 orally once a day for 21 days, if oral preparation is unavailable, replace with intravenous (i.v.)…”

“…Patients in such settings may have increased TRM if standard chemotherapy is administered upfront. However, the evidence supporting a metronomic approach to upfront chemotherapy in children with AML is limited 31,32 . In addition, there is concern regarding the development of resistance to chemotherapeutic drugs with the administration of low‐dose chemotherapy.…”

“…However, the evidence supporting a metronomic approach to upfront chemotherapy in children with AML is limited. 31,32 In addition, there is concern regarding the development of resistance to chemotherapeutic drugs with the administration of low-dose chemotherapy. Nevertheless, it is anticipated that, in a level 2 setting, beginning treatment with inexpensive, low-intensity chemotherapy will result in reduced TRM and an overall improvement in survival.…”

“…It is recommended to administer at least one cycle of either of the two options for the prephase chemotherapy before the start of induction course 1. Up to three cycles of prephase chemotherapy may be administered, based on an assessment of the clinical condition and socioeconomic circumstances of the patient.Prephase chemotherapy: Option 1-PrET regimen (Recommendation 2 C)This regimen has been reported by the Tata Memorial Hospital, Mumbai, India31,32 (G. Narula, personal communication). It includes a combination of oral etoposide, 6-thioguanine (6-TG), and prednisolone as follows: (a) etoposide at 50 mg/m 2 orally once a day for 21 days, if oral preparation is unavailable, replace with intravenous (i.v.)…”

Efficacy and Safety of Metronomic Chemotherapy Versus Palliative Hydroxyurea in Unfit Acute Myeloid Leukemia Patients: A Multicenter, Open-Label Randomized Controlled Trial

“…However, the main mechanism of the regimen in treating hematologic malignancies including AML is assumed to be the inhibition of tumor angiogenesis (Padró et al, 2000). Few observational studies and one case report had revealed favorable survival outcome of using metronomic chemotherapy in AML patients (Banavali et al, 2005;Tandon et al, 2013;Kapoor et al, 2016). To our knowledge, this study is the first randomized controlled trial to directly examine the efficacy and safety outcomes of metronomic chemotherapy in unfit AML patients.…”