Mycophenolate Mofetil and Thrombopoietin Receptor Agonists in the Treatment of Refractory Thrombocytopenia in Patients with Autoimmune Lymphoproliferative Syndrome

Abstract 2218

Autoimmune lymphoproliferative syndrome (ALPS), often due to an inherited defect in the FAS gene, presents with chronic non-malignant lymphadenopathy, splenomegaly, and autoimmune cytopenias (Oliveira JB et al. “Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop”. Blood. 2010 Oct 7;116(14):e35-40). Thrombocytopenia has been noted in approximately 23% of ALPS patients. These patients, especially those with massive splenomegaly and hypersplenism, are often refractory to standard dose short-term corticosteroid regimens and intravenous immunoglobulins (IVIG). Mycophenolate mofetil (MMF) has been used for persistent thrombocytopenia as a steroid sparing long-term measure in 40 out of 245 ALPS patients in our cohort. The median age at initiation of MMF was 10.5 years (range 7 months to 43 years) with an average follow-up of 3.8 years on MMF (range 3 months to 11 years). Here we share our experience over the last 7 months related to the use of thrombopoietin receptor agonists in 3 ALPS patients who have persistent, severe, MMF-refractory thrombocytopenia (platelets <10,000/uL) (Figure).

Patient 1 is a 21 year old man with ALPS-FAS and splenomegaly who has been on MMF for 2 years. He presented with monthly episodes of thrombocytopenia requiring high dose corticosteroids and IVIG followed by four weeks of rituximab and daily prednisone without any durable improvement in his thrombocytopenia. He was started on eltrombopag 50mg daily and was able to taper off prednisone in one month with sustained stable platelet count. Three months after starting eltrombopag, he was able to survive surgical intervention for a spontaneous pneumothorax while on eltrombopag and MMF.

Patient 2 is an 18 year old woman with ALPS-FAS and surgical asplenia who has been on MMF for approximately 7 years. She began having significant, symptomatic thrombocytopenia refractory to high-dose corticosteroids with transient responses to IVIG. She was started on eltrombopag 50mg daily with MMF and initially responded. However, when MMF was discontinued her platelet count plummeted. Despite reinitiating MMF, her platelet counts never recovered on eltrombopag and she continued to require monthly IVIG. She was eventually switched to romiplostim, and was incrementally increased to the maximum dose of 10mcg/kg/week. Her platelet counts continue to fluctuate, but she has not required any IVIG in over one month.

Patient 3 is a 19 year old man with ALPS-U and surgical asplenia who has been on MMF for the last 9 years. During the past year he has had episodes of symptomatic thrombocytopenia requiring monthly courses of high dose corticosteroids and IVIG. After initiation of eltrombopag, he had a significant rise in his platelet counts. However, upon discontinuation of MMF, his platelet counts plummeted. MMF was restarted and he was trialed on multiple, different eltrombopag dosing regimens leading to supratherapeutic responses with platelet counts over 1,000,000/uL. Eltrombopag was held during these periods to allow for the significant thrombocytosis to resolve, but withholding eltrombopag led to platelet counts to eventually fall precipitously. Furthermore, he also developed severe headaches due to MMF and MMF had to be discontinued. After multiple dosing regimens, he eventually maintained a stable platelet count on eltrombopag 50mg daily for 5 days alternating with eltrombopag 25mg for 2 days without the concomitant use of MMF.

Recently, there has been increasing evidence supporting the use of thrombopoietin receptor agonists in the treatment of refractory immune thrombocytopenia. MMF continues to be well tolerated as a long-term corticosteroid sparing drug for patients with ALPS complicated by chronic, refractory thrombocytopenia. Our preliminary experience suggests that there may be a role for thrombopoietin receptor agonists, most likely in combination with an immunosuppressive agent such as MMF, in the treatment of refractory thrombocytopenia in patients with ALPS. However, schedule and duration of therapy with this class of drugs needs further long term evaluation.

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