Does Treatment for CLL Accelerate Myeloid Neoplasms?

The treatment of chronic lymphocytic leukemia (CLL) or CLL-like disease may accelerate the development of myeloid neoplasms, with the risk estimated to be 13 times higher in those with treatment than those without, according to a new study.

The study, published in the Journal of Clinical Pathology, may have implications for the treatment of CLL/CLL-like disease. CLL is the most common leukemia among adults in the Western world. Small lymphocytic lymphoma (SLL) is its nonleukemic variant, which can show up in the nodes, the spleen, or in tumors outside the bone marrow in the other tissues or organs. It usually has a slow course, with a median survival of more than 10 years. The introduction of more aggressive first-line drugs, including antimetabolites that mimic the structure of metabolic purines in combination with alkylating agents, has led to improved survival, particularly for myelodysplastic syndrome and acute myeloid leukemia.

The authors noted that it is well documented that the risk of secondary neoplasms in patients with other primary malignances is higher than in the general population. Some have theorized that the higher risk might be from the effects of chemotherapy or radiation, while those without prior treatment might simply be predisposed to developing the malignancies.

However, since myeloid neoplasms occur with some frequency in patients with CLL/CLL-like diseases who have not been treated, the authors said, that would have seemed to rule out the therapy causing the myeloid leukemia’s progression. The motivation for this study, therefore, was to better understand the development of myeloid neoplasms in this setting.

The authors compared the clinical and pathologic features of myeloid malignancies in 33 patients who had received treatment with 33 who had not. The cases with primary bone marrow involvement were selected from a 20-year period between 1999 and 2019. All patients with CLL/CLL-like disease diagnosed within 3 months preceding of identification of myeloid neoplasm were considered as cases “without treatment” regardless of whether treatment began in that timeframe or not.

The study showed that those who had been treated were younger (median age 65 vs 71); had a higher fraction of myelodysplastic syndrome (64% vs 36%; odds ratio [OR], 3.1; P <.05); a higher rate of adverse unbalanced changes to the structure and function of chromosomes, including complex changes,−5/5q- and/or −7/7q- (83% vs 28%; OR, 13.1; P <.001) and a shorter overall survival (median, 12 vs 44 months; P <.05).

The increase in risk may be based on the latency of myeloid progression of the leukemia and the cytogenetic profile, the authors said.

Twenty-three (70%) patients died of disease progression or complications among the 33 who were treated; 18 of 30 patients who had information available for analysis (60%) died in the group that was not treated (P <.02).

The authors said they believe their study of myeloid malignancies in the setting of CLL/CLL-like disease is the first to compare patients with prior treatment for neoplasms to those without. The study shows that the 2 categories of patients with myeloid neoplasms have distinct features in clinical presentation, spectrum of myeloid neoplasm, morphology, cytogenetic profile, and clinical outcome.

More sophisticated epidemiological studies are needed to understand why these differences exist, the authors said. Previous work has suggested that the combination of several agents including fludarabine and other agents, including cyclophosphamide, rituximab and/or other therapeutic agents could have a synergistic effect. In the current study, 80% of the patients had been treated with fludarabine and alkylating agents.

They suggested that fludarabine may enhance chromosomal aberrations and mutational events by promoting the activity of the alkylating agents. Another explanation would be that it facilitates myeloid leukemogenesis by preferential selection of a myeloid clone with a mutator phenotype.

The introduction of new drugs, such as Bruton’s tyrosine kinase inhibitors, PI3 kinase inhibitors, BCL2 inhibitors (venetoclax), immunomodulators, and chimeric antigen receptor T-cell therapy may affect the epidemiology of myeloid malignancies, the authors said.

Reference

Luedke C, Zhao Y, McCracken J, et al. Myeloid neoplasms in the setting of chronic lymphocytic leukaemia/chronic lymphocytic leukaemia-like disease: A clinicopathological study of 66 cases comparing cases with prior history of treatment to those without. J Clin Pathol. Published online: February 4, 2021. doi:10.1136/jclinpath-2020-207334