The effect of salvage therapy on the response and survival outcomes of AML patients with induction failure

Acute Myeloid Leuekmia (AML) patients who fail to respond to standard induction chemotherapy have a poor prognosis. Additionally, outcome of Allogenic Hematopoietic Cell Transplantation (allo-HCT) is poor if there is no response achieved during the induction phase before transplant¹. Effective salvage therapy before allo-HCT may improve the outcome of AML patients, hence the rationale for this study.

Mohammed Wattad from the Kliniken Essen Sud, Essen, Germany and colleagues retrospectively studied the impact of salvage therapy regimens in combination with or without allo-HCT transplantation on the response and survival outcomes of AML patients who experienced induction failure from five prospective trials by the German-Austrian AML Study group (AMLSG). The results from the study were published ahead of print in Leukemia on 19^th January 2017.

The AMLSG evaluated different dose-intensified salvage regimens in a sequential phase 2 design in 3,324 AML patients between 1993 to 2009. 1,025/3,324 AML patients with induction failure were qualified for inclusion in this study. Patients received either intensive salvage regimen (n = 875, median age = 55 years) or a non-intensive palliative treatment (n =150, median age = 68 years).

In patients receiving intensive salvage regimen (n = 875) after induction failure, salvage therapy regimen consisted of either 7 + 3 – based salvage therapy (n = 59) or High-Dose cytarabine (HA) alone (n = 150) or combined with mitoxantrone and All-Trans Retinoic Acid (A-HAM, n = 247) or with gemtuzumab ozogamicin (GO-A-HAM, n = 140), and other intensive regimens (n = 165). 87 patients received allo-HCT without prior chemotherapy (direct allo- HCT).

The key results of the study are:

• In patients receiving intensive salvage chemotherapy, favorable Complete Response (CR)/ Complete Response of Incomplete Hematological Recovery (CRi) was associated with GO-HAM treatment; Odds Ratio (OR) = 1.93, P = 0.002
• Unfavorable prognostic factors associated with CR/CRi include age (OR = 0.75; P< 0.0001) and unfavorable cytogenetics (OR =0.62, P = 0.006) 
• 5- year Overall Survival (OS) in patients receiving allo-HCT either at CR (n = 193), directly (n = 87) or with refractory disease (n =192) were 48%, 36% and 25% respectively; P < 0.0001
• Patients transplanted with refractory disease after salvage therapy had a lower OS compared to direct allo-HCT patients (P = 0.01) or at CR (P < 0.0001)
• Possibility to perform allo-HCT and achievement of CR/CRi from salvage therapy before allo-HCT were significantly associated with OS outcome; HR = 0.33, P < 0.0001 and HR = 0.59, P < 0.0001 respectively 
• Unfavorable cytogenetics (HR = 1.80, P < 0.0001), FMS-like Tyrosine Kinase 3 – Internal Tandem Duplication (FLT3-ITD) (HR = 1.47, P = 0.0007) and mutated IDH1 (HR =1.37, P = 0.03 respectively) were significant unfavourable factors for OS
• Patients with a high allelic ratio (n = 41) of FMS-like Tyrosine Kinase 3 – Internal Tandem Duplication (FLT3-ITD) had a significantly lower OS compared to patients with low allelic ratio of FLT3-ITD

In summary, direct allo-HCT or intensive salvage therapy using GO-A-HAM followed by allo-HCT results in a favourable outcome for AML patients. The authors concluded by suggesting that these regimens could be therapeutic options for AML patients with induction failures.

Abstract

We evaluated the impact of salvage regimens and allogeneic hematopoietic cell transplantation (allo-HCT) in acute myeloid leukemia (AML) with induction failure. Between 1993 and 2009, 3324 patients with newly diagnosed AML were accrued in 5 prospective treatment trials of the German-Austrian AML Study Group. After first induction therapy with idarubicin, cytarabine and etoposide (ICE), 845 patients had refractory disease. Additionally, 180 patients although responding to first induction relapsed after second induction therapy. 875 of 1025 patients (median age 55 years) with induction failure received intensive salvage therapy: 7+3-based (n=59), high-dose cytarabine (HA) combined with mitoxantrone (n=150), with all-trans retinoic acid (n=247), with gemtuzumab ozogamicin (GO-A-HAM) (n=140),, other intensive regimens (n=165), experimental treatment (n=27), direct allo-HCT (n=87). In patients receiving intensive salvage chemotherapy (n=761), response (CR/CRi) was associated with GO-A-HAM treatment (OR [odds ratio], 1.93; P=0.002), high-risk cytogenetics (OR, 0.62; P=0.006) and age (OR for a 10 years difference, 0.75; P<0.0001). Better survival probabilities were seen in an extended Cox regression model with time dependent co-variables in patients responding to salvage therapy (P<0.0001) and having the possibility to perform an allo-HCT (P<0.0001). FLT3-ITD, mutated IDH1 and adverse cytogenetics were unfavorable factors for survival.