Bone Marrow Histologic and Cytogenetic Changes during Leukemic Transformation of Myelofibrosis with Myeloid Metaplasia.

BACKGROUND: Leukemic transformation (LT) eventually occurs in 10–30% of patients with myelofibrosis with myeloid metaplasia (MMM). Hoever, there is limited data regarding bone marrow histological and cytogenetic changes that accompany the process.

METHODS: The study population consisted of 67 consecutive patients with MMM in whom the diagnosis of LT was documented at our institution by bone marrow examination. Serial comparisons of both histological and cytogenetic changes were performed to monitor longitudinal changes accompanying disease progression.

RESULTS:

I. Bone marrow histologic changes during LT: All 67 patients displayed acute myeloid leukemia (AML) and all FAB subtypes except M3 were represented (most common were M7 at 25.4% and M0 at 22.4%). Median bone marrow myeloblast percentage was 43% (range 20–95) and cellularity 80% (range 5–95). However, only 37.5% and 30.3% had marked increases (> grade 2) in either reticulin fibrosis or osteosclerosis, respectively. Serial bone marrow comparisons (available in 33 patients at a median interval of 24.5 months (range; 2.1–110.4) after the diagnosis of MMM) demonstrated that LT was occasionally a focal process, but was always accompanied by a marked increase in myeloblasts. However, overall bone marrow cellularity changed by >15% in only 25% of the cases, none of the LT was associated with a > grade 1 change in reticulin fibrosis, and only 12% had an increase in osteosclerosis. On the other hand, LT was frequently associated with morphologic changes in megakaryocytes from large, round and clumped at the time of diagnosis of MMM to small, condensed and non-clumped at the time of LT.

II. Karyotypic changes of MMM to LT: Karyotypic analysis was available in 32 patients (48%) at the time of MMM (abnormal in 63%) and 56 patients (84%) at the time of LT (abnormal in 91%). At LT the majority of patients (n=34; 60.7%) displayed poor risk karyotypes with either complex karyotypes or single abnormalities of adverse prognostic significance. In contrast, only two patients (3.6%) manifested prognostically favorable karyotypes with a translocation or inversion involving one of the core binding factors (t(8;21)(q22;q22);Inv(16)(q22)). Twenty-eight patients had chromosome analysis performed both at diagnosis of MMM and at LT. At diagnosis of MMM, 20 patients had either normal chromosomes or a single chromosome anomaly while only 7 displayed a complex karyotype with 3 or more chromosome anomalies. However, at LT all twenty-eight patients had abnormal karyotypes, including 17 patients with markedly complex karyotypes and only 9 with simple clonal anomalies. The recurrent numeric and structural anomalies observed at transformation to AML most frequently involved chromosomes 5, 6, 7, 8, 17, 19 and 21. Additionally, amongst the 26/28 (93%) of patients whose karyotype changed from MMM to LT 11 patients (43%) displayed evolution of an existing clone, and 15 (57%) developed one or more additional abnormal clones.

CONCLUSIONS: The progression of MMM to LT is characterized by the emergence of new cytogenetic abnormalities as well as morphological changes in megakaryocytes. Unfortunately, the karyotypic profile that accompanies clonal evolution in MMM is often of the poor-risk category that undermines the value of aggressive chemotherapy in such patients. However, such therapy might be of value to the occasional patient with good-risk cytogenetic lesions.