Incidence of Transformation to Large Cell Lymphoma and to Second Malignancies in Symptomatic Patients with Waldenstrom’s Macroglobulinemia (WM) Treated with Cladribine (2-CdA) Combination Induction Therapy
Authors: Rakkhit Ronjay , Delasalle Kay B , Gavino Maria B. , Thomas Sheeba K. , Dimopoulos Meletios A , Hagemeister Fredrick B. , Rodriguez Maria Alma , McLaughlin Peter , Alexanian Raymond , Weber Donna M. 
Published: April 2020

Abstract
Waldenstrom’s macroglobulinemia (WM) is an incurable malignancy characterized by malignant proliferation of lymphoplasmacytoid cells that produce a monoclonal IgM. Treatment of this disorder with nucleoside analogues like 2-CdA and fludarabine have resulted in excellent response rates and subsequent median survivals of approximately 8–9 years for previously untreated patients at our center. We, and others, have previously questioned the impact of initial treatment of Waldenstrom’s Macroglobulinemia on the risk of development of second malignancy and transformation (TR) to aggressive NHL (Non-Hodgkin’s Lymphoma). The objective of this analysis was to determine the incidence of transformation to large cell lymphoma and second malignancies in patients (pts) treated with 2-CdA either alone or in combination for induction therapy of patients with symptomatic WM. We performed a retrospective analysis of 111 consecutive, previously untreated patients with symptomatic WM who were treated with using 2 consecutive 4–6-week courses of either 2-CdA alone or in combination with other agents including prednisone (pred), cyclophosphamide (Cy), and rituximab (Rit) between January 1991 – July 2005. Patients received either 2-CdA 0.1 mg/kg by continuous infusion (CI) over 24 hours (hrs) × 7 days (n=16), an identical program with prednisone 60 mg/m2/d po for 7 days (n=22), 2-CdA 1.5 mg/m2 by subcutaneous injection (SC) q8 hrs × 7d + Cy 40 mg/m2 p.o. b.i.d. × 7d (n= 38), or identical 2-CdA (SC) + Cy + Rit 375 mg/m2 by intravenous infusion (IV) weekly × 4 weeks (n=35). Among 111 pts, 23 (21%) had either transformation to large cell lymphoma or development of a second malignancy within a median of 55 months. Ten patients (9%) had transformation to large cell lymphoma after treatment with 2-CdA alone (3 pts), 2-CdA/pred (1 pts), 2-CdA/Cy (3 pts) and 2CdA/Cy/Rit(3 pts). The median time to development of transformation to large cell lymphoma was 37 months (1mo – 110 mo) and 4 pts had transformation of disease within 13 months. An additional 13 pts (12%) developed other second malignancies including breast cancer (ca) (2pts), renal cell ca (2 pts), Basal cell ca of skin (2 pts), Hodgkin’s lymphomas (2 pts), cervical ca (1 pt), ovarian ca (1 pt), colorectal ca (1 pt), mesothelioma (1 pt), head/neck squamous cell ca (1 pt), vascular sarcoma (1 pt), bladder ca (1 pt) and prostate ca (1 pt), AML (1 pt) after treatment with 2-CdA (5 pts), 2-CdA/pred (1 pt), 2-CdA/Cy (4 pts), and 2CdA/Cy/Rit (3 pts). The median time to development of a second malignancy was 85.5 months and there did not appear to be any significant trend towards development of any particular secondary malignancy. While 2-CdA based induction regimens for WM provide excellent cause-specific survival for WM, this analysis suggests that the incidence of large cell transformation and second malignancies is pronounced among this group of patients with Waldenstrom’s Macroglobulinemia. Whether this rate of transformation/second malignancy is related to treatment with nucleoside analogues, or due to the natural progression of disease in patients with long survival after treatment with 2-CdA regimens remains unclear. We are currently extending the retrospective analysis to include a similar historic cohort of patients treated with alkylating agents and will provide updated data regarding both groups of patients at the time of presentation.