Clinical, cytogenetic, and molecular characteristics of patients with both chronic lymphocytic leukemia and myeloproliferative neoplasm Free

Introduction: Chronic lymphocytic leukemia (CLL) and myeloproliferative neoplasms (MPN) have a higher rate of co-occurrence than expected. When co-occurring, they are traditionally thought to be clonally unrelated with distinct hematopoietic lineages, although some reports suggest a subset of co-occurring CLL and MPN may arise from a common hematopoietic progenitor cell. Data describing patients with both CLL and MPN in the era of modern treatment and next generation sequencing (NGS) is sparse. Here, we report clinical characteristics and cytogenetic/molecular alterations in patients with both CLL and MPN followed at our institution.

Methods: Patients with both CLL and MPN who were seen at the Icahn School of Medicine at Mount Sinai between the years of 2010 to 2025 were identified. Electronic medical records were reviewed to obtain clinical characteristics, treatment history, outcomes, and molecular/ cytogenetic data for each patient.

Results: 15 patients met our inclusion criteria; 60% were male, and the median age at diagnosis of first hematologic malignancy was 60. The median time of follow up from first diagnosis was 11.7 years (rage: 3.7-21.5). 6 patients (40%) had antecedent MPN, 5 (33%) had antecedent CLL, and 4 (27%) were synchronously diagnosed. 80% were alive at last follow up. All patients who died had antecedent MPN; 1 patient died due to refractory marginal zone lymphoma, 1 patient died due to Richters transformation, and 1 patient died due to myelofibrosis.

7 patients (47%) had essential thrombocythemia (ET), 4 (27%) had primary myelofibrosis (PMF), and 4 (27%) had polycythemia vera (PV). In 5 patients with antecedent CLL, 20% had ET, 40% had PV, and 40% had PMF. In 6 patients with antecedent MPN, 50% had ET, 33% had PV, and 17% had PMF. In 4 patients who were synchronously diagnosed, 75% had ET and 25% had PMF. 4 patients (40%) with PV or ET had progression to myelofibrosis.

8 patients (53%) received CLL-directed therapy, and 10 patients (67%) received MPN-directed therapy. 4 patients (27%) received concurrent CLL- and MPN-directed therapy. Of 5 patients with antecedent CLL, 4 (80%) received BTK inhibitor therapy and 2 (40%) received chemo-immunotherapy prior to MPN diagnosis. Of 6 patients with antecedent MPN, 2 (33%) received hydroxyurea and 2 (33%) received ruxolitinib prior to CLL diagnosis.

With regards to cytogenetics, 10 (67%) had del13q14 (100% of patients with antecedent CLL and 33% of patients with antecedent MPN). Of those with del13q14, 9 (90%) had del13q14.3 and 1 had del13q14.2. 4 patients (27%) had del11q22.3 (40% of patients with antecedent CLL, 17% of patients with antecedent MPN). 20% had del17p.13 patients (87%) had an abnormal karyotype. 8 patients had testing for IGHV mutation status; 6 patients (75%) had mutated IGHV.

AJAK2 V617F mutation was detected in 80% of patients and a canonical CALR mutation was detected in 20% of patients. 87% underwent commercial NGS testing on peripheral blood or bone marrow samples. Of patients who underwent commercial NGS testing, 77% had mutations in genes other than JAK2/CALR. The most frequently mutated genes were TET2 (in 31% of all patients, 50% of patients with antecedent CLL, and 17% of patients with antecedent MPN), TP53 (in 15% of all patients, 0% of patients with antecedent CLL, and 33% in patients with antecedent MPN), XPO1 (in 15% of all patients, 50% in patients with antecedent CLL, and 0% in patients with antecedent MPN),and ATM (15% in all patients, 25% in patients with antecedent CLL, and 17% in patients with antecedent MPN). Pathogenic alterations in ZRSR2, ASXL1, RB1, RPS15, POT1, CHEK2, NOTCH1, EP300, CUX1, DNMT3A, PAX5, SRSF2, SF3B1, and CTCF were also observed.

Conclusions: In this retrospective analysis of 15 patients with co-occurring CLL and MPN, we report clinical characteristics, outcomes, and cytogenetic/molecular alterations. With a median follow-up of over 10 years, overall survival was 80%; progressive hematologic malignancies were the cause of death for all patients who died. Almost all patients had commercial NGS panels available; of those, over 75% of patients harbored pathogenic alterations in genes other than JAK2/CALR, with the most common being alterations in TET2, TP53, XPO1, and ATM. Further analysis of the molecular characteristics of the MPN and CLL cellular compartments is warranted to investigate the clonal relationship between MPN and CLL cells in patients with both diseases.