TREATMENT OF MOLECULAR RELAPSE IN PATIENTS WITH ACUTE MYELOID LEUKEMIA

Background:

Evidence for beneficial effect of minimal residual disease (MRD) monitoring and early intervention (=pre-emptive therapy) in non-APL acute myeloid leukemia (AML) pts. are very limited.

Aims:

To assess usefulness, efficacy and toxicity of various treatment regiments in the therapy of molecular relapse in non-APL AML patients.

Methods:

We have performed a retrospective analysis of molecular relapses in AML pts. with molecular target and its treatments. RQ-PCR was used for the MRD monitoring. Molecular relapse was defined as confirmed reappearance of the fusion transcript or mutated gene detection or its 10-fold increase in pts. with persistent positivity and corresponding bone marrow cytology, immunophenotype and cytogenetic analysis remained negative.

Results:

In the study period 1/1/2003 – 1/2/2013 we have treated 38 molecular relapses in 21 pts.. Median follow up was 35,5 months (range 12-121 months). The median time from the end of initial AML therapy to the first molecular relapse was 5 months (range 1,0-29,0 months) – 4,0 months (range 1,0-14,0 months) for RUNX1/RUNXT1 positive pts.;  2,1 months (range 2,0-14,0 months) for CBFB/MYH11 positive pts.;  13,5 months (range 5,0-29,0 months) for patients with MLL fusion abnormalities; 4,0 months (range 2,0-4,0 months) for patients with NPM1 mutation.

The frequency of  treatment regimens and their efficacy in the first molecular relapse (n=21) was as follows: conventional chemotherapy (“5+2” like regimens) (CHT) – 19,0% (n=4), clofarabine (CLO) – 42,8% (n=9), gentuzumab ozogamicine (GO) – 14,3% (n=3),  immunomodulation after allogeneic hematopoietic stem cell transplantation (IMMUNO) – 19,0% (n=4), and low dose ARA-C (LD-ARAC) – 4,8% (n=1). The overall response rate (RR = CMoR + PMoR) to pre-emptive therapy of the first molecular relapses was 66,6 % (14/21) (47,6% CMoR+ 19,0% PMoR) - CLO – 77,8%RR (55,6% CMoR + 22,2% PMoR); CHT – 100% RR (50% CMoR + 50% PMoR); IMMUNO – 50% RR (CMoR); GO - 33.3% RR (CMoR); LD-ARAC - 0% RR.

In the follow up period 69,2% (n=9) of responding pts. revealed the second molecular relapse with median 7,0 months (range 1,0-19,0 months). Moreover, in 15,9% (n=2) hematological relapse occurred without foregoing molecular relapse with median 3,5 months (range 3,0-4,0 months). The second molecular relapse was pre-emptively treated in 9 patient with RR 66,6% (n=6) (CR+PR).

However, again in 4/6 (66,6%) of successfully treated pts. with the second molecular relapse,  subsequent molecular relapses occurred with median 9,5 months (range 4,0 – 16 months) and were again treated with RR 25% (n=1).

At any time during treatment 61,9% of patients underwent allogeneic HSCT.

Overall, only 3 pre-emptively treated patients did not revealed any further hematological or molecular relapse during the observational period (2/3 pts. underwent allogeneic HSCT)

6/21 (28,6%) of patients with molecular relapse survived during the study period (all with initial or subsequent molecular response) with OS 68 months, compare to OS of 17 months in 15/21 (71,4%) of pts that expired during the follow up period.

Summary / Conclusion:

Our study has shown feasibility of MRD monitoring and pre-emptive strategy using molecular targets in non-APL AML pts. Different pre-emptive treatment strategies led to response in 66,6% of molecular relapses with the highest frequency of CMoR when CLO was used. Even pre-emptive therapy enables us to obtain time for preparing allogeneic  HSCT (performed in 2/3 of patients), majority of patients relapsed again in follow up period. However, our data showed that this approach (even in limited number of patients with initial or subsequent response) could provide prolongation of overall survival.

Keywords: Acute myeloid leukemia, Molecular relapse, Therapy

Abstrakta v časopise Haematologica 2013, Suppl1

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