Combined Myeloid and Lymphoid Malignancies in 13 Elderly Patients

Myeloid malignancies such as myelodysplasia (MDS) often evolve from age related clonal hematopoiesis (CH) with progression of variant allele frequencies. The Philadelphia negative myeloproliferative neoplasms (MPN) polythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are associated with mutations in JAK2, CALR, or MPL. Multiple myeloma (MM) and monoclonal gammopathies (MGUS) are felt to be age related, and the malignant cell is of lymphoid origin. Burkitt's Lymphoma is associated with EBV exposure and dysregulation of c-myc. However the etiology of most lymphoproliferative disorders (LPD) is not defined, but immune dysregulation may be causative. The combination of myeloid and lymphoid malignancies are not recognized to be a common occurrence; however within a three year period 13 patients with combined myeloid and lymphoid malignancies were detected in a single community practice.

DATA

Five patients had combined myeloid and lymphoid malignancies diagnosed concurrently. Three had a lymphoid disorder and then developed a myeloid disorder. Five had a myeloid disorder followed by a lymphoid disorder. Three patients had multiple myeloma (MM) and two had MGUS. Initially all patients responded to standard therapies, One patient at 87 years died from end stage renal disease likely related to her myeloma. Another patient with CLL and PV died at 92 years from an epithelial malignancy.

Concurrent diagnoses Age at diagnosis (years)

• CLL ET 76

• MGUS MDS 77

• MM MDS 78

• MM MDS (RSBA) 85

5) DLBCL MF. 60

LPD/MM followed by a Age at initial diagnosis (years) and time to second diagnosis

myeloid disorder.

1) MZL MF 58 15 months

2) MM ET 83 7 months

3) CLL PV 86 4 years

Myeloid disorder

followed by a LPD/MGUS

• MDS DLBCL 76 3 months

• MDS MGUS 78 30 months

• TP CLL 15 60 years

• ET MyF 77 65 months

• ET CLL 60 15 years

(CLL chronic lymphocytic leukemia, DLBCL diffuse large B cell lymphoma, MF myelofibrosis, MyF mycosis fungoides, MZL mantle zone lymphoma, RSBA ringed sideroblastic anemia, TP inherited thrombocytopenia)

JAK2 mutations were found in three of the four ET patients and in the one PV patient. One MF patient and one ET patient were negative for the JAK2 and CALR mutations. The mutation status of the other MF patient was not known. At diagnosis the patient with inherited thrombocytopenia was suspected to have a myeloid disorder.

Combined myeloid and lymphoid malignancies is not well defined and is a seemingly uncommon event. Yet an Italian study demonstrated that MPN patients with JAK2 mutations have a 2.8-3.4 fold increased risk of developing a LPD compared with an age matched population (1). The linkage is unclear.

Immune senescence may be important for the development of LPD observed in the elderly. Also long term latency of many years between the JAK2V617F mutation acquisition and MPN presentation has been documented (2).

The occurrence of both myeloid disorders and LPD is not well recognized. Future studies may provide insights into the mechanisms underlying these disorders. Increasing genetic complexity and immune senescence associated with aging likely plays a major role.

The limitations of this study are its small size, single community investigator, retrospective clinical nature, and the lack of gene sequencing and other molecular studies in most if not all of the patients.

This observation was noted over three years in a single community practice which strongly implies that combined occurrence may be more common than recognized and suggests that further investigation is warranted.

Boxer none, Denes none

References

1. Rumi E, Passamonti F, Elena C, et al. Increased risk of lymphoid neoplasm in patients with myeloproliferative neoplasm:a study of 1,915 patients. Haematologica. 2011;96(3):454-458.

2. Williams N, Lee J, Mitchell E, et al. Life histories of myeloproliferative neoplasms inferred from phylogenies. Nature. 2022;602(7895):162-168.

No relevant conflicts of interest to declare.