Risk-Adapted Therapy of Adult Acute Myeloid Leukemia (AML): Safety and Efficacy of Repetitive HD-ARA-C Courses with Low-Dose Autologous Blood Stem Cell Support.
Authors: Intermesoli Tamara , Oldani Elena , Micò Caterina , Guerini Vittoria , Salvi Anna , Ruggeri Emanuela , Rossi Andrea , Giussani Ursula , Bellavita Piero , Rambaldi Alessandro , Barbui Tiziano , Bassan Renato 
Published: April 2020

In adult AML, effective postremission consolidation is obtained with HD-ARA-C and either autologous or allogeneic stem cell transplantation (SCT). HD-ARA-C is highly myelotoxic, causing remissional deaths and nonlethal toxicity that often precludes the administration of repetitive courses especially in older patients. We are evaluating a risk-oriented strategy that specifically considers the use of multiple, stem cell-supported HD-ARA-C courses.

After double induction (ICE/IC or ICE/sequential HD-ARA-C-I when primary resistance is documented), ARA-C 1 g/m2/bd is given on dd 1–4, followed by G-CSF to collect autologous CD34+ blood stem cells. Then, patients with high risk cytogenetics, i.e. -5/del(5q), -7, t(11q23), t(9;22), abn 3q, 9q, 11q, 20q, 21q, 17p, iso(17q), t(3;5), t(6;9), or &gt;3 unrelated clonal anomalies, and those with intermediate risk cytogenetics (normal or not known, non-high, non-favourable) plus any additional risk feature (WBC &gt;50, MDS/secondary, late CR, FLT-3 mutation, hepatosplenomegaly, FAB M0,6,7) are grouped together in the high-risk (HR) category and are preferentially submitted to an allogeneic SCT. In the remaining cases, i.e. the standard-risk (SR) group, three HD-ARA-C-based cycles (2 g/m2/bd on dd 1–5, plus idarubicin) are planned, each one followed by the reinfusion of 1–2x106/kg CD34+ cells on day 6, and by G-CSF; HR patients unable to undergo SCT are transferred to HD-ARA-C, and those with an insufficient CD34+ cell yield are given one-two courses with intermediate-dose ARA-C.

Ninety-one unselected patients (males 46) aged 17–68 years (median 50 years, 38 &gt;55 years) with either de novo or secondary/MDS-related (23%) non-M3 AML (cytogenetics: favourable 10, intermediate 13, normal 45, unfavourable 15, unknown 8) are thus far evaluable: 67 HR and 24 SR. CR rate was 76% (96% in SR, 69% in HR). Stem cell harvest was successful in 43/58 (74%). So far, SCT was performed in 16 HR cases, while 89 HD-ARA-C courses were administered to 34 other patients (16 SR and 18 HR), with a median intercycle time of 39 days (only 17% &gt;45 days), a median duration of neutropenia &lt;0.5 and thrombocytopenia &lt;20 of 9 and 6 days, respectively, and no toxic death while pancytopenic/in-hospital (vs. 8% in historical, unsupported HD-ARA-C-treated cohort). By treatment intention, median overall survival is 21 mos. (37% at 4 years, 57% in SR and 30% in HR), and median DFS is 25 mos. (43% at 4 years, 56% in SR and 36% in HR). DFS is 57% and 19% in HR patients with (n=21) and without (n=25) HLA/DR identical family-related/unrelated donor, respectively (P=0.01).

In conclusion low-dose autologous CD34+ cell rescue (plus G-CSF) may sensibly limit HD-ARAC-related toxicity in unselected adults with AML, up to an age of 68 years in this study, allowing an effective increase in dose intensity. This translated into a DFS rate &gt;50% at 4 years in the SR group (mainly cases with normal/intermediate risk cytogenetics without additional risk factors), whereas an allo-SCT was more beneficial to the HR group. These results document the role of blood stem cell-supported, repetitive HD-ARA-C courses, particularly in intermediate-risk patients and/or those aged &gt;55 years or with contraindications to allogeneic SCT.