PS981 LONG TERM AML SURVIVORS HAVE INCREASED MORTALITY AND HIGH PREVALENCE OF CLONAL HEMATOPOIESIS
Authors: Ilani N. Chapal , Niemeyer E. , Cohen N. Mendelson , Moskovitz Y. , Oron B. , Mitchell A. , Minden M.D. , Tanay A. , Balicer R. , Biezuner T. , Cilloni D. , Metzeler K. , Ofran Y. , Kaushansky N. , Slush L. 
Published: June 2019

Background:

Acute myeloid leukemia (AML) is defined by the accumulation of immature blasts in the bone marrow (BM) resulting, if left untreated, in acute BM failure. While AML presents in an acute form, it is clear today that most AML cases are preceded by a long phase of age related clonal hematopoiesis (ARCH) with almost no symptoms. The clinical and molecular trajectories of AML both before and after diagnosis are highly predictable. Recent studies identified the high risk individuals destined to evolve from ARCH to AML based on blood counts parameters (mainly red cell distribution width (RDW)) and molecular attributes such as clone size and the number of ARCH defining events. Most AML patients will achieve complete remission after induction chemotherapy, however most will relapse within a median time of 11 months despite post remission consolidation or bone marrow transplantation (BMT). A small fraction of AML patients will maintain at long term remission (LTR).

Aims:

The course of AML from ARCH to relapse is well characterized both clinically and molecularly, however, this information is missing for long term AML survivors, specifically for AML patients who did not receive BMT. The fact that AML has a long chronic history before its acute presentation might suggest that a recovery from the acute phase will not necessary result in resetting the hematopoietic system but rather to turn it back to its chronic phase before AML presentation.

Methods:

To answer the question whether preleukemic events are still present at LTR and what important clinical implications it might have, we studied morbidity, mortality and molecular structure among two unique LTR cohorts. One cohort is the electronic health records (HER) of 4.2 million individuals covering over 15 years of follow up and include 61 LTR survivors who did not undergo BMT (LTSnoBMT). The second cohort which contains molecular data, included analysis of genetic variation in 30 LTR cases at diagnosis and LTR, and was compared to a group of lymphoid malignancies patients at remission.

Results:

We found that the mortality among LTSnoBMT 10 years after diagnosis was 20%>50% higher in comparison to controls. In addition, several lab results were different between the LTSnoBMT and controls including higher red cell distribution width (RDW) among older (>55) LTSnoBMT. Recent studies found a correlation between high RDW and mortality among individuals carrying age related clonal hematopoiesis (ARCH) mutations. We also found that ARCH defining events were significantly more prevalent among LTSnoBMT in comparison to controls (63% vs 37% p = 0.039). Furthermore of the ARCH defining events among the LTSnoBMT 62% were recurrent AML variants as oppose to 21% among the controls (p = 0.002). Of the recurrent mutations IDH1/2 were the most common mutations and 2 out of 7 IDH1/2 cases experienced a late relapse (Figure 1).

Summary/Conclusion:

Altogether, even after the sustainable eradication of the malignant clone, the hematopoietic system/microenvironment does not normalize (abnormal blood counts, high prevalence of ARCH and higher mortality).

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These results suggest that AML at LTR is a unique situation and that this group of patients are not fully recovered and should be further studied and treated.