Excess Coincidences of Hematopoietic Neoplasms

Abstract Introduction: In recent years diagnostic advances, novel therapies and improved supportive care have led to growing life expectancy of patients suffering from hematologic neoplasms. Hence, the coincidence of different neoplasms may be observed more frequently challenging both clinicians as well as patients to select the most appropriate treatment approach. However, studies on this topic are rare and the issues of common etiologic factors, epidemiology, or pathogenic mechanisms are unclear yet. Aim: Compare expected and observed frequencies of coincidences of hematologic neoplasms and determine the types of coincidences. Material and Methods: Patients with co-occurring neoplasms were identified by cytomorphology, immunophenotyping, cytogenetics, and molecular genetics based on peripheral blood and bone marrow samples sent to our laboratory for diagnostic purposes (11/2011-03/2015, 3.3 yrs). Therapy-related coincidences were excluded. The ratio of the number of observed to expected coincidences was derived from published epidemiologic data (WHO, ELN, SEER). We report on coincidences of different entities distinguished by WHO criteria: acute lymphoblastic (ALL), myeloid (AML), and undifferentiated (AUL) leukemia, chronic myeloid leukemia (CML), monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia (MBL/CLL), myelodysplastic syndrome (MDS), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), monoclonal gammopathy of undetermined significance/multiple myeloma (MGUS/MM), myeloproliferative neoplasms (MPN), and mature B- and T-cell neoplasms (B-NHL, T-NHL). Analysis of B-NHL sub-categories was performed for hairy cell leukemia (HCL) as well as for follicular (FL), lymphoplasmacytic (LPL), mantle cell (MCL), and marginal zone (MZL) lymphoma. Results: Coincidences of neoplasms were detected in 828 of 46,906 patients (2%, 804 with two and 24 with three neoplasms, respectively) affecting 1% of patients diagnosed with ALL (10/981), 1% in AML (58/5,464), 29% in AUL (5/17), 1% in CML (16/1,655), 6% in MBL/CLL (382/6,811), 4% in MDS (255/6,289), 2% in MDS/MPN (40/2,716), 4% in MGUS/MM (390/9,289), 0.6% MPN (63/9,748), 8% in B-NHL (393/4,712, including 50 cases of HCL, 16 FL, 99 LPL, 26 MCL, and 112 MZL), and 8% in T-NHL (36/277). Out of theoretically possible 120 coincidences of two respective neoplasms 77 (64%) in fact were observed. MBL/CLL and MGUS/MM, respectively, co-occurred with each category. The most frequent coincidences were B-NHL with MBL/CLL (n=148), MDS with MGUS/MM (n=119), and B-NHL with MGUS/MM (n=116). Relating observed and expected frequencies corrected for prevalence and incidence revealed that coincidences were more abundantly diagnosed than statistically expected. For ALL, the highest rate was observed for coincidence with MZL (0.3/0.004, observed/expected cases p.a.), for AML with LPL (0.6/0.003), for AUL with LPL (0.3/1e-05), for CML with AUL (0.3/0.001), for MBL/CLL with LPL (11.2/0.004), for MDS with LPL (2.1/0.004), for MDS/MPN with LPL (0.9/0.002), for MGUS/MM with LPL (13/0.006), for MPN with LPL (0.6/0.006), for B-NHL with MBL/CLL (44.8/0.1), for T-NHL with HZL (1.8/0.0003), for FL with LPL (0.3/0.0005), for HZL with LPL (0.3/7e-05), for LPL with HZL (0.6/0.0003), for MCL with LPL (0.6/0.0001), and for MZL with LPL (1.2/0.0002). Table 1 lists the enrichments of all coincidences. Conclusions: The epidemiology of coincidences is notoriously difficult to study, in particular for rare entities, e.g. AUL. However, we revealed a surprisingly broad spectrum of abundant coincidences and demonstrated that their frequency is substantially higher than expected. These differences are likely due to common causal, etiologic or pathogenic mechanisms that are shared between neoplasms. Common pathways pivotal for the pathogenesis of LPL and CLL, i.e. BTK-dependent BCR signaling which can be inhibited by Ibrutinib achieving excellent response rates, were already identified. The LPL + MBL/CLL coincidence was highly enriched and additional coincidences were identified. Future studies entangling the underlying mechanisms are needed. The demonstrated excess coincidences raise the question whether more abundant preventive screenings could translate into earlier detection, more therapeutic options, and finally increased survival of affected patients. Figure 1. Figure 1. Disclosures Rose: MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.