Leukemic Diffuse Large B-Cell Lymphoma in a Patient With Myeloproliferative Disorder

Abstract

Essential thrombocythemia is well-known to transform to other myeloid disorders, such as leukemia; however, the risk for development of lymphoma is not as well studied. This case report discusses a 76-year-old man with a history of prefibrotic post-essential thrombocythemia myelofibrosis on ruxolitinib, who developed anemia, thrombocytopenia, and leukocytosis with peripheral blasts. Results of a bone marrow biopsy and PET and CT scans revealed stage IV leukemic diffuse large B-cell lymphoma. Several days after cessation of ruxolitinib, the patient developed fevers, hypotension, and low-grade disseminated intravascular coagulation, and subsequently developed spontaneous tumor lysis syndrome, which resulted in death. This case is unique in several aspects: it highlights the rare possibility of lymphomatous transformation of myeloproliferative disorders, an unusual presentation of lymphoma masquerading as leukemia, and the possibility of ruxolitinib withdrawal syndrome. Additionally, this case serves as a reminder that the use of novel therapies should be adopted after a thorough assessment of long-term risks, including those associated with abrupt withdrawal.

Myeloproliferative and lymphoproliferative disorders: State of the art

“…Notably, lymphomas developed in the Austrian cohort shared some common phenotypic and genotypic features; they were all negative for the JAK2 V617F mutation (that was present in their MPN counterpart), developed from a preexisting B‐cell clone detectable at early stages of MPN and showed extranodal involvement and high MYC and BCL2 expression, thus resembling those lymphoproliferative diseases occurring in immunocompromised hosts. Consistently, two previous published reports described a similar, aggressive clinical picture …”

“…Consistently, two previous published reports described a similar, aggressive clinical picture. 73,74 It is intriguing that the authors could recapitulate both the development of myeloid hyperplasia (corresponding to the MPN phase) and the occurrence of an aggressive B-cell neoplasm through STAT1 knock out mice, which is basically an immunodeficiency model with significant impairment of interferon-dependent biological responses. 75 To focus on the question of the relationship of JAK inhibitor treatment and lymphoid neoplasms in patients with MPN, Pemmaraju et al performed a large database review of 2583 patients with MPN.…”

Accumulation of JAK activation loop phosphorylation is linked to type I JAK inhibitor withdrawal syndrome in myelofibrosis

“…These results suggest that there are fundamental differences in the nature of JAK activation in CALR-mutated cells compared to JAK2-mutated cells. We performed an extensive search of medical literature and adverse drug reaction databases and were unable to find any reports of withdrawal syndrome in CALR-mutated patients (9,17,(19)(20)(21)24). Analysis of 10 published cases of severe ruxolitinib withdrawal syndrome (table S2) showed a high frequency of JAK2 mutant cases (100%) compared to expected mutation frequencies ( 2 2 × 2 contingency table, P = 0.0203).…”

Mechanisms Underlying the Anti-inflammatory and Immunosuppressive Activity of Ruxolitinib

“…An increased risk of lymphoma during treatment with ruxolitinib or discontinuation of ruxolitinib has been suggested by sporadic reports (46, 47). Recently, four cases of aggressive lymphoma were reported during treatment among 69 MPNs patients receiving ruxolitinib (5.8% rate of lymphoma development) (22).…”