Treatment of advanced stage methotrexate-associated lymphoproliferative disorders (MTX-LPDs) with methotrexate discontinuation

Abstract

We present two cases of patient’s with long-standing autoimmune diseases being treated with immunosuppressants that developed aggressive lymphoproliferative disorders. Immunosuppressants have a well-known association with disorders. Sustained regression of these lymphoproliferative disorders occurred with simple discontinuation of these immunosuppressive agents.

Background

This demonstrates the possibility of conservative management for methotrexate-associated lymphoproliferative disorders (MTX-LPDs) which might negate the need for more toxic and/or harmful treatment options.

Case presentation

Case 1: A 63-year-old man with a medical history of psoriatic arthritis and HTN presented with fevers and night sweats. He was diagnosed with psoriatic arthritis in the mid-1990s and had been well controlled on MTX 15 mg weekly since. He also took folic acid supplements and losartan for his HTN. He was a former smoker with a 50 pack-year history and quit smoking in 1993. He drank alcohol (EtOH) socially and denied use of illicit drugs. He had a family history of psoriasis and type 2 diabetes mellitus in his father and rheumatic fever in his mother. He had no known family history of cancer. On 23 November 2010, a chest CT was done and revealed nodules in the right upper lobe (6×5 mm) and right middle lobe pleura (5 mm), multiple enlarged lymph nodes (<1.5 cm) and ground glass changes (figure 1). CT/Positron Emission Tomography (PET) fusion scan showed mild metabolic activity in borderline mediastinal node and precarinal regions on the right (samples of these lymph nodes were biopsied to provide tissue diagnosis). Endobronchial ultrasound-guided transbronchial needle aspiration of subcarinal level 7 and right hilar level 10 lymph nodes were performed and sent for flow cytometry and immunophenotyping. Immunophenotyping showed a population of monoclonal B cells, most of which expressed CD5, CD19, CD20 and weak intensity monoclonal kappa. These findings were consistent with B-Cell small lymphocytic lymphoma (SLL)/chronic lymphocytic leukaemia (CLL). Staging revealed that his disease was stage IV (two pulmonary lymph nodes and minimal bone marrow involvement). After diagnosis of stage IV, SLL/CLL MTX was stopped. After discontinuation of MTX, he was continually monitored for signs or symptoms of disease recurrence. His LPD, although at an advanced stage when discovered, was completely stable once MTX was stopped (figure 2). His stage IV SLL/CLL has continued to remain stable without chemotherapy or radiation therapy (XRT).

Figure 1.

Case 1: CT chest (23 November 2010) hilar lymph node (prior to cessation of MTX). MTX, methotrexate.

Figure 2.

Case 1: CT chest (8 March 2011) hilar lymph node (following cessation of MTX). MTX, methotrexate.

Case 2: A 54-year-old man with a medical history of biopsy-proven dermatomyositis presented to the hospital with pleuritic chest pain. He was diagnosed with dermatomyositis in 2005. He had been on both MTX and azathioprine as well as high doses of prednisone since that time, but his disease had been difficult to control. He had never smoked cigarettes, drank alcohol or used illicit drugs. He had a family history of HTN and coronary artery disease in his father. A CT angiogram of the patient’s chest was done in late October 2010 for chest pain and it showed acute pulmonary embolism (PE). The patient was started on Coumadin for his PE. The CT angiogram also showed nodules in the soft-tissue of both axillae, soft-tissue of the back (mostly on the left side) and right ileum. One and half month later, follow-up CT of the chest/abdomen/pelvis showed a mass in the anterior pole of the right kidney with ill-defined borders (4.7×2.8 cm), a mass in the mid-pole of the left kidney (2.7×1.7 cm), a mass in the left pararenal fascia (3.1×2.4 cm), a mass in the anterior mediastinal soft-tissue (new since 31 October 2010; 2.3×2.4 cm), a mass engulfing the internal mammary artery (new since 31 October 2010; 5.8×2.3 cm) and a mass at the medial border of the spleen (new since 31 October 2010; 3.5×1.3 cm) (figures 3 and 4). After imaging was performed, MTX and azathioprine were stopped. At that time, biopsy of the anterior mediastinal mass was performed. Limited tissue for immunohistochemical (IHC) staining made definitive diagnosis difficult, but biopsies were suspicious for necrotic large cell lymphoma. Bone marrow biopsy and aspirate as well as fine-needle aspiration of right shoulder mass were then performed. IHC staining of these biopsies were positive for CD2, CD3, CD4, CD5, CD7, CD8 and CD45. These findings were consistent with T-cell lymphoma. CT neck/chest on 18 January 2011 showed interval decrease in multiple previously described masses. Decrease in mass size occurred with simply discontinuing immunosuppressive treatments (MTX and azathioprine) (figures 5 and 6). Hydroxychloroquine, prednisone and rituximab were started to control the patient’s dermatomyositis symptoms. The patient did not respond well to rituximab, so this was replaced with intravenous immunoglobulin. Subsequent CT scans performed for maintenance monitoring showed continued improvement of masses off immunosuppressive medications. The patient continued to require high doses of steroids (>20 mg daily). Repeat MRIs showed persistent inflammation. He was evaluated at National Institutes of Health (NIH) for a second opinion. Due to continued requirement of high-dose steroids and his worsening clinical condition, the patient was restarted on MTX in May 2017. No signs of disease recurrence have been observed to date.

Figure 3.

Case 2 CT chest (16 December 2010) left internal mammary artery mass (prior to cessation of MTX). MTX, methotrexate.

Figure 4.

Case 2: CT chest (16 December 2010) anterior mediastinal mass (prior to cessation of MTX). MTX, methotrexate.

Figure 5.

Case 2: CT chest (18 January 2011) left internal mammary artery mass (following cessation of MTX). MTX, methotrexate.

Figure 6.

Case 2: CT chest (18 January 2011) anterior mediastinal mass (following cessation of MTX). MTX, methotrexate.

Outcome and follow-up

Monitoring in both cases was performed by the patient’s haematology/oncology physicians. Both patients follow-up imaging studies continue to remain stable to this day despite never having received chemotherapy or XRT. The only treatment required for these advanced stage lymphomas was discontinuation of immunosuppressive treatment (MTX in both cases).

Discussion

Immunosuppressive agents (especially MTX) have a well-known association with LPDs.^1–3 Improvement or regression of MTX-LPD lesions occurs in 30%–59% of patients following discontinuation of MTX.^{1 2 4} This improvement following discontinuation of these immunosuppressive agents is further proof of the association between these medications and LPDs^{2 5} Complete remission seems to occur relatively shortly (average of 1 month) after MTX discontinuation.⁶ Partial remission takes longer to appreciate (average of 2–3 months) after MTX is stopped.^6–8 Patients with Epstein-Barr Virus (EBV) positive LPD have higher incidence of spontaneous regression and complete remission after MTX withdrawal alone than those with other histological types of LPD.^{6 8 9} Unfortunately, in our cases EBV testing was not done. Some cases, however, also require chemotherapy and/or XRT in addition to discontinuation of the immunosuppressive agent. The cases that require chemotherapy and/or XRT are those with disease progression despite withdrawal of the offending immunosuppressive agent or those with relapse after regression.⁸ The chemotherapy regimen of choice for classical Hodgkin lymphoma type of LPD is adriamycin, bleomycin, vinblastine and dacarbazine.⁹ Chemotherapy regimens for non-Hodgkin’s lymphoma LPDs include rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone or rituximab, cyclophosphamide, pirarubicin, vincristine and prednisolone with or without XRT.^{8 9}

There appears to be no way to predict which patients will improve with simple withdrawal of immunosuppression and which will require additional treatment modalities.⁴ There seems to be no reliably reproducible responses among the various histological types of MTX-LPD.1 4 9 10 Despite varying histopathological types and clinical stages, there is generally no overall difference in survival rates between LPD types.⁹ Five-year overall survival rate for MTX-LPD is 80%.⁸

While there are no guidelines on how to treat MTX-LPD cases, discontinuation of the offending immunosuppressive agent is imperative.^{1 11} After discontinuation of MTX, close observation can be used to determine whether additional treatment is necessary.^{2 11} Morbidity and mortality resulting from treatment complications is a significant reason to consider MTX withdrawal and observation as first line in these cases.¹¹

While it has been shown that remission is possible after withdrawal of MTX, the literature does not report any cases where patients have been rechallenged with the offending drug. It may be possible in certain selective patients to rechallenge with MTX if no other alternatives are available. These patients need to be followed even more closely for any signs of LPD development.

Learning points.

• Immunosuppressive treatments (especially methotrexate, MTX) for rheumatological diseases have a long association with lymphoproliferative disorders (LPDs).

• Discontinuation of immunosuppressive treatment is the first step following discovery of MTX-LPD.

• Spontaneous regression or disease stability (despite stage at time of discovery) of MTX-LPD is possible following withdrawal of immunosuppressive agents.

• Close observation of disease is necessary after withdrawal of immunosuppressive agents to determine the possible need for additional treatment.

• It may be possible to rechallenge selective patients without recurrence of LPD.