Disease characteristics and outcomes of acute myeloid leukemia in germline RUNX1 deficiency (Familial Platelet Disorder with associated Myeloid Malignancy)

Abstract

Familial Platelet Disorder with associated Myeloid Malignancy (FPDMM, FPD/AML, RUNX1-FPD), caused by monoallelic deleterious germline RUNX1 variants, is characterized by bleeding diathesis and predisposition for hematologic malignancies, particularly myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Clinical data on FPDMM-associated AML (FPDMM-AML) are limited, complicating evidence-based clinical decision-making. Here, we present retrospective genetic and clinical data of the largest cohort of FPDMM patients reported to date. We describe 159 European patients (from 94 families) of whom 134 were evaluable for the development of malignant disease. Sixty developed a hematologic malignancy (44.8%), most frequently AML (36/134, 26.9%) or MDS (18/134, 13.4%). Somatic alterations of RUNX1 by gene mutation (48%) and chromosome 21 aberrations (14.3%) were the most common somatic genetic aberrations in FPDMM-AML, followed by FLT3-ITD mutations (24.1%). Somatic RUNX1 and FLT3-ITD mutations were not detected in FPDMM-associated MDS, suggesting important contributions to leukemic transformation. Remission-induction chemotherapy resulted in complete remission in 80% of FPDMM-AML patients with a 5-year overall survival (OS) of 50.4%. Survival outcome was non-inferior compared to a large cohort of newly diagnosed adult RUNX1-mutated AML (5-year OS 36.6%, p = 0.5), with relatively infrequent concurrent adverse risk somatic aberrations (ASXL1 mutation, monosomal karyotype, monosomy 5/del 5q) in FPDMM-AML. Collectively, data support the notion that step-wise leukemic evolution in FPDMM is associated with distinct genetic events and indicate that a substantial subset of FPDMM-AML patients achieves prolonged survival with conventional AML treatment, including allogeneic stem cell transplant. These findings are anticipated to inform personalized clinical decision-making in this rare disorder.

Figure 1

Description and classification of germline variants. (A) Graphical representation of germline variants identified in the cohort. Depicted is the RUNX1C isoform (NM_001754). SNVs and indels are indicated above the transcript; color indicates variant type, arrow indicates variant location, number indicates the number of patients in whom the variant was found. CNVs are indicated below the transcript; color indicates variant type, line indicates part of the transcript that is affected, number indicates the number of patients in whom the variant was found. A dotted line preceding exon 1 indicates (partial) deletion of the untranslated region. ## indicates likely benign variant, # indicates variants of uncertain significance, unlabeled variants were classified as pathogenic or likely pathogenic. (B) Classification of all variants and unique variants (i.e., without duplicates) per updated MMVCEP RUNX1 classification guidelines., (C) Distribution of pathogenicity classes in germline variant types. CNV, copy number variant; indels, insertion & deletions; LB, likely benign; LP, likely pathogenic; P, pathogenic; RHD, runt homology domain, SNV, single nucleotide variant; TAD, transactivation domain; VUS, variant of uncertain significance.

Figure 2

Cohort selection and demographics. (A) Consort diagram depicting cohort selection after germline RUNX1 variant curation. (B) Table describing cohort demographics. (C) Age at identification of germline RUNX1 variant for all patients and specifically for index patients (i.e., first identified patient within a family). Each dot represents a patient and the median age is depicted by a line. Missing data for all patients n = 19/159 and for index patients n = 14/91. B, benign, LB, likely benign; LP, likely pathogenic; P, pathogenic; VUS, variant of uncertain significance.

Figure 3

Hematologic malignancies and correlations with germline variant types. (A) Occurrence of (presenting) hematologic malignancy in 134 evaluable patients. Asterisks indicate the transformation of disease as specified in the legend. (B) Distribution of germline variant types in patients that developed a hematological malignancy compared to patients that did not. (C) Age of onset of hematologic malignancies, with dots representing individual patients and horizontal lines indicating median ages. Missing data n = 4 (1 AML, 2 MDS, 1 Other). (D) Age of primary AML onset in patients grouped per germline variant types, with dots representing individual patients and horizontal lines indicating median ages. Missing data n = 1 (CNV). AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; CNV, copy number variant; MDS, myelodysplastic syndrome; MDS>sAML, MDS transformed into secondary AML; n.s., not significant; PMF, primary myelofibrosis; PMF > MDS = PMF transformed into MDS; T‐ALL, T‐cell acute lymphoblastic leukemia; *, the transformation of malignant disease as specified in panel A; #, patients with a variant of uncertain significance.

Figure 4

Somatic cytogenetic and molecular aberrations in FPDMM‐associated AML and MDS. (A) Somatic cytogenetic and molecular aberrations per FPDMM patient that developed AML (FPDMM‐AML) or MDS (FPDMM‐MDS). Each column represents a patient. Above patient ID, rows represent patient characteristics, with cytogenetic findings in the top row (displayed as composite karyotypes). Below patient ID, each row represents a gene. Identified somatic mutations are depicted as filled cells with a number indicating the number of different mutations found in a patient in a single gene. Dark gray cells indicate a gene was not included in the analysis; light gray cells indicate missing data. Below genes, sequencing technique and additional FLT3 fragment analysis are indicated. (B) Comparison of somatic mutations between FPDMM‐AML and RUNX1‐mutated AML patients in HOVON data. * Number of cases in which a specific gene was included in mutational analysis, differed per gene. NF1 was not included in this analysis due to the low number of analyses (n = 8). (C) Comparison of cytogenetic aberrations between FPDMM‐AML and RUNX1‐mutated AML patients in HOVON data. ck2022, complex karyotype according to ELN2022; CN‐LOH, copy‐neutral loss ofheterozygosity; mk, monosomal karyotype; RUNX1m, RUNX1‐mutated.

Figure 5

Treatment and outcome of FPDMM‐associated AML. (A) Remission induction treatment in FPDMM‐associated AML (FPDMM‐AML) patients and response to intensive remission chemotherapy (IC). (B) Age of FPDMM‐AML patients who achieved CR(i) compared to patients who did not achieve CR(i) after initial remission induction treatment. Missing data n = 1. (C) Consolidation treatment in FPDMM‐AML patients. (D) Proportions of FPDMM‐AML patients and HOVON RUNX1‐mutated AML patients that achieve CR(i) after IC. (E) Overall survival of all FPDMM‐AML patients compared to all HOVON patients with RUNX1‐mutated AML. (F) Overall survival of a subset of FPDMM‐AML patients (i.e., age at AML diagnosis between 18 and 65, treated with high‐intensity chemotherapy remission induction therapy) compared to a propensity score matched cohort of HOVON patients with RUNX1‐mutated AML. allo‐SCT, allogeneic stem cell transplant; CB, cord blood; CR(i), complete remission (with incomplete recovery); HMA, hypomethylating agent; IC, intensive induction chemotherapy; MUD, matched unrelated donor; RUNX1m, RUNX1‐mutated; Sib, sibling.