Outcome and Clinical Characteristics of Clonal and Malignant Myeloid Transformation in Inherited Bone Marrow Failure Syndromes

Inherited bone marrow failure syndromes (IBMFSs) are a group of rare, genetic disorders with a risk of clonal and malignant myeloid transformation including clonal marrow cytogenetic abnormalities, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The clinical characteristics and outcome of IBMFS-related clonal and malignant myeloid transformation are unclear, particularly in cases of early transformation such as isolated clonal marrow cytogenetic abnormalities.

The aims of this study were to determine the risk and clinical outcome of IBMFS-related clonal and malignant myeloid transformation using data from the Canadian Inherited Marrow Failure Registry (CIMFR).

The CIMFR is a multicenter collaborative study which is intended to enroll all patients with IBMFSs in Canada. The registry was approved by the Institutional Ethics Board of all the participating institutions, and includes 15 of 16 pediatric tertiary care centers across all provinces in Canada. We estimate that these centers care for >95% of the eligible pediatric IBMFS population in Canada. The CIMFR is population-based as >90% of the patients in this study are from centers who enrolled >80% of the patients in their institutions. Clonal and malignant myeloid transformation was defined as having either clonal marrow cytogenetic abnormalities or prominent bi-lineage morphologic dysplasia or increased percentage of marrow blasts (≥5%) or a combination of the above.

Among 327 IBMFS patients enrolled on the CIMFR, 45 (13.8%) developed clonal and malignant myeloid transformation. In these 45 patients, the three most common IBMFS diagnoses were Fanconi anemia (31.1%), Shwachman-Diamond syndrome (20.0%) and unclassifiable IBMFSs (28.9%). Clonal marrow cytogenetic abnormalities were identified in 38/45 (84.4%) patients, while 5/45 (11.1%) patients had constitutional cytogenetic changes, 1/45 patients had AML with no cytogenetic abnormalities and 1/45 patients had no cytogenetic abnormalities. Two out of the 5 patients with constitutional cytogenetic abnormalities developed a clonal marrow cytogenetic abnormality later in their disease course. The most common clonal marrow cytogenetic abnormality was monosomy 7, which was found in 14/38 (36.8%) patients. Cytology in the majority of patients 20/45 (44.4%) was consistent with refractory cytopenia. Eight out of the 45 patients developed AML and 2 of these patients had monosomy 7. Twenty-two out of 45 (48.9%) patients with clonal and malignant myeloid transformation underwent hematopoietic stem cell transplantation due to severe cytopenia, excess blasts or leukemia. Fourteen out of the 22 (63.6%) transplanted patients are alive at last follow-up. Out of 8 patients who had AML, 3 received transplant and are alive at last follow-up. The 5 remaining AML patients died; 3 while awaiting transplant, 1 did not achieve remission and 1 refused transplant. Overall mortality in the group of patients with clonal and malignant myeloid transformation was 15/45 (33.3%) at a median follow-up of 10 months from diagnosis with clonal and malignant myeloid transformation. Overall mortality in those 282 patients on CIMFR without clonal and malignant myeloid transformation is 6.4%.

Despite short-term follow-up of patients on the CIMFR, a relatively high prevalence of clonal and malignant myeloid transformation was found. Clonal marrow cytogenetic abnormalities are associated with a high risk of progression into advanced MDS or AML and death.

No relevant conflicts of interest to declare.