Outcomes of Methotrexate-Associated T-Cell and NK/T-Cell Lymphoproliferative Disorders in Patients with a History of Rheumatological Disorders: A Retrospective Analysis of EBV-Association and Response to MTX Withdrawal

Introduction: Methotrexate (MTX)-associated lymphoproliferative disorders (LPD) are iatrogenic lymphoid neoplasms typically of B-cell lineage and often (50%) associated with the Epstein-Barr virus (EBV). Up to 60% of cases are reported to regress with MTX withdrawal. The relative frequency, clinical-pathological spectrum, EBV association, and outcome following MTX withdrawal in patients with LPD of T/NK-cell lineage are not well-known and no large series have been published.

Methods: We searched English language PubMed, Ovid and Scopus for keywords; methotrexate, T-cell lymphoma, lymphoproliferative disorder, NK/T cell lymphoma, EBV+ T-cell lymphoma, rheumatoid arthritis, and autoimmune. We reviewed each published case series and case report for unique cases. Case selection criteria included 1) pathologically proven diagnosis of T/NK-LPD, 2) ongoing MTX use at the time of diagnosis, and 3) withdrawal of MTX as initial intervention. Cases were defined as EBV+ (any positive staining for EBER-in situ hybridization (ISH) on tumor sample), EBV-, and EBVnr (not reported). No minimum follow-up was required, as long as the type of intervention(s) and outcome were reported. Clinical variables included: age, sex, EBV positivity, duration of RA, and duration of MTX use. Outcomes following MTX withdrawal included: 1) disease regression (as defined and reported by each paper) without need for additional therapy, 2) disease regression followed by additional therapy, 3) survival time at last follow up. Data analysis was performed using SAS 9.4.

Results: We found 40 cases of T/NK-LPD developing during MTX use. Two cases were reported twice and two were excluded based on lack of intervention outcomes, leaving 36 assessable cases (22 F, 14 M), 34 of which had rheumatoid arthritis (RA). Median age at diagnosis of T/NK-LPD was 65 years (21-85). For the subsets of cases with available data, median duration of RA (N=21) and median duration of MTX use (N=23) prior to T/NK-LPD diagnosis were 10 years (6 months-33 years) and 48 months (6-144 months), respectively. MTX doses ranged from 4 mg/wk to 15 mg/wk. Use of other concomitant immunosuppressive drugs was reported in only 5 cases (cyclosporine 2; hydroxychloroquine 2; infliximab 1). Diagnoses included: peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS, 9), angioimmunoblastic T-cell lymphoma (AITL, 7), cutaneous T-cell lymphoma (CTCL, 6), extranodal NK/T-cell lymphoma (ENKTL, 6), anaplastic large cell lymphoma (ALCL, 4), large granular lymphocytic leukemia (LGL, 3) and adult T-cell leukemia/lymphoma (ATLL, 1).

In total, 19 of 36 cases (53%) were EBV+ (6/6 ENKTL, 4/7 AITL, 4/9 PTCL-NOS, 3/6 CTCL ,1/3 LGL, 1/4 ALCL, 0/1 ATLL), 13 were EBV-, and 4 were EBVnr. Of the 19 EBV+ cases, 17 were initially treated with MTX withdrawal only and a sustained regression was observed in 12/17 cases (3 ENKTL, 3 CTCL, 2 AITL, 2 PTCL, NOS, 1 LGL, 1 ALCL). With a reported median follow-up of 18 months (3-48) none of the 12 patients had progression or required additional therapy. Two of the 17 patients (both AITL) had initial regression with MTX withdrawal, but then progressed and received chemotherapy. Two patients with ENKTL did not respond to MTX withdrawal alone. Disease regression following MTX withdrawal was also observed in 6 of 13 EBV- cases (2 AITL, 2 LGL, 1 PTCL, NOS and 1 CTCL). The median durations of RA and MTX use for EBV+ cases were longer than that for EBV negative cases (138 vs. 60 months and 69 vs. 24 months, respectively). Regressions with MTX withdrawal alone were more frequent in the 12/17 (71%) EBV+ lymphomas patients compared to 6/13 (46%) EBV- lymphomas.

Conclusions: We report a series of MTX-associated T/NK-LPD, mostly in patients with RA. MTX withdrawal maybe a reasonable first-line treatment option in MTX-associated T/NK-LPD in both the EBV+, and EBV- cases.