Refractory primary autoimmune myelofibrosis treated with ruxolitinib
Authors: Salman Otoukesh, Joo Y. Song, Mona Mojtahedzadeh, Sally Mokhtari, Guido Marcucci, Vinod Pullarkat, Haris Ali
Journal: American Journal of Hematology (2021)

Autoimmune myelofibrosis (AIMF) is a rare non-clonal entity characterized by bone marrow fibrosis and autoimmune phenomena.1, 2 Cytokines elaborated by bone marrow-lymphocytes appear to be the cause of marrow fibrosis in AIMF.1 Autoimmune myelofibrosis can be classified as primary (P-AIMF) when it occurs without an established underline autoimmune disease or secondary (S-AIMF) when it occurs in the setting of an established autoimmune disease like systemic lupus erythematosus, rheumatoid arthritis or Sjögren disease).1, 3 The lymphoid aggregates in the marrow characteristic of AIMF are implicated as the source of the inflammatory cytokines – including interferon-gamma, interleukin-8, IL-2, IL-17, transforming growth factor beta, and lipocalin-2 that lead to marrow fibrosis. Pullarkat et al. initially defined P-AIMF by the following criteria: (1) grade 3–4 fibrosis in the marrow, (2) lack of clustered or atypical megakaryocytes, (3) lack of myeloid, erythroid dysplasia, eosinophilia, or basophilia, (4) lymphocyte infiltration of the bone marrow, (5) lack of osteosclerosis, (6) absent or mild splenomegaly, (7) presence of autoantibodies, and (8) absence of disorder known to cause MF.1 A lack of mutations associated with myeloproliferative neoplasms can be added to these criteria. Since the underlying pathophysiology of AIMF is immune mediated, it is crucial to differentiate it from primary myelofibrosis, a myeloproliferative neoplasm. Note, AIMF is generally very responsive to steroids and immunosuppression. Some cases can be steroid refractory and pose a challenge due to severe cytopenias. We report a case of transfusion dependent P-AIMF, refractory to multiple lines of treatments who was treated successfully with the JAK inhibitor ruxolitinib with regression of fibrosis in the marrow. A previously healthy 61-year-old Latina female presented with severe fatigue and was found to be profoundly anemic with hemoglobin of 7 g/dl. Complete blood counts (CBC) were otherwise normal: WBC of 6.5 × 109/l (neutrophils 3.5 × 109/l, lymphocytes 2.2 × 109/l), MCV of 86.3 fl, and platelet count of 149 × 109/l. Laboratory studies were consistent with hypoproliferative anemia. Further laboratory studies showed kappa light chain of 44.7 mg/l (normal range: 3.3–19.4 mg/l), lambda light chain of 27.5 mg/l (normal range: 5.7–26.3 mg/l), kappa/lambda ratio at 1.63 (normal range: 0.26–1.65), Serum protein electrophoresis showed no abnormal M-spike. Serum Immunoglobin levels were normal and T-cell receptor gamma gene rearrangement was not detected. Antinuclear antibodies were not detected. Direct antiglobulin test was positive for IgG and negative for C3. There was no clinical/laboratory evidence of hemolysis. Physical examination was unremarkable except for anemia. Bone marrow biopsy in July 2018 showed a hypercellular marrow with left shifted erythroid precursors and marked myelofibrosis (MF 3/3), interstitial lymphoid aggregates, and adequate stainable iron with no ring sideroblasts. There was no dysplasia to support diagnosis of myelodysplastic syndrome, nor any megakaryocytic atypia or clustering suggestive of primary MF. Cytogenetics was normal. Peripheral blood smear showed decreased red blood cells without tear-drop erythrocytes or leukoerythroblastosis. A diagnosis of AIMF was made based on established criteria of reticulin fibrosis with no clustering of atypical megakaryocytes, lack of dysplasia in erythroid or myeloid series, no eosinophilia or basophilia, presence of reactive lymphoid aggregates in the bone marrow, lack of osteosclerosis, absence of splenomegaly, presence of autoantibodies (positive direct antiglobulin test), and absence of another underlying disorder causing marrow fibrosis.6 Patient was red cell transfusion dependent at presentation. She was initially treated with prednisone at 1 mg/kg daily for 3 months with no clinical response in terms of red cell transfusion dependency. Her treatment was then changed to weekly rituximab, again with no clinical response after 4 weeks of therapy. She then received danazol followed by cyclosporine for 3 months without a clinical response and remained transfusion dependent with resultant iron overload for which she was placed on deferasirox. Follow up BM biopsy on March 2019 showed a hypercellular bone marrow (80% cellularity) (Figure 1(A)) with marked reticulin fibrosis (MF 3/3) (Figure 1(B)), focal collagen fibrosis (Figure 1(B), inset), myeloid hyperplasia with decreased megakaryocytes. Next generation sequencing (NGS) using a 73 gene panel (including CALR, JAK1/2/3, MPL and other common myeloid mutations) did not detect any genetic alterations. Ruxolitinib (10 mg twice daily) administration was started in March 2019, which resulted in transfusion independence since July 2019. A CBC in January 2020 showed WBC: 6100/μl, HGB: 11.1 g/dl, HCT: 31.9%, MCV: 113.8 fL, RDW: 12.8%, and platelet count: 247 000/μl. The WBC differential count was normal. A subsequent bone marrow biopsy showed a normocellular bone marrow (40%) (Figure 1(C)) and mild reticulin fibrosis (MF 1/3) (Figure 1(D)). As of April 2021, patient has remained on ruxolitinib and has been tolerating it well. Herein, we described for the first time, a remarkable response to the JAK inhibitor, ruxolitinib, in a patient with steroid refractory P-AIMF, who was also refractory to other immunosuppressive agents including anti-CD20 antibody (rituximab), danazol, and cyclosporine. This response could be attributed to the immunosuppressive effect of ruxolitinib, particularly its effect on T-cells. The pathophysiology of P-AIMF is not entirely clear; however, it is postulated that the infiltrating bone marrow lymphocytes produce abnormal fibrogenic cytokines, leading to marrow fibrosis. In patients with P-AIMF, inflammatory cytokines including transforming growth factor beta (TGF-β) and interleukin-8 (IL-8) were found to be significantly increased.4 Autoreactive T cells probably contribute to this process as well and in mouse models, depletion of CD8+ T cells, while the CD4+ T cells number remained unchanged, successfully inhibited autoimmunity and reversed accumulation of fibroblasts and/or reticulin fibrosis.5 Although autoimmune phenomena have been described in primary MF as well as myelodysplasic syndromes, our patient did not have any features of primary MF or any clonal abnormality by cytogenetic analysis or genetic mutations by next generation sequencing. Corticosteroids are usually the initial line of treatment for patients with AIMF, with high response rates including improvement of cytopenia and transfusion independency, in most cases even before resolution of marrow fibrosis. For steroid refractory patients, other immunosuppressive agents including cyclosporine, cyclophosphamide, intravenous gamma globulin, azathioprine, and growth factors have been used as the second line treatments resulting in varying response rates for cytopenia and fibrosis regression.1, 3, 6, 7 Even with the resolution of cytopenia after successful corticosteroid or other immunosuppressive therapy, fibrotic changes might not regress in many cases, indicating that pro-inflammatory cytokines might alter hematopoiesis in ways other than by inducing fibrosis. In our patient, after 4 months of treatment with ruxolitinib, cytopenias resolved completely and the patient became transfusion independent and her marrow fibrosis improved from severe (MF 3/3) to mild (MF 1/3) (Figure 1). Ruxolitinib is a JAK1/2 inhibitor, approved for management of primary MF, through inhibition of JAK/STAT pathway. Interestingly, ruxolitinib improves constitutional/cytokine mediated symptoms of primary MF showing its inhibitory effect on inflammatory cytokines. The JAK–STAT pathway has a crucial role at intracellular cytokine signaling in both B and T lymphoid cells and regulation of both innate and adaptive immune response (JAK1/2).8 Successful targeting of this pathway has shown efficacy in many autoimmune disorders with high levels of pro-inflammatory cytokines (TNF-a and IL-6) including psoriasis, rheumatoid arthritis, and ankylosing spondylitis.8, 9 In patients with primary MF, ruxolitinib administration is often associated with myelosuppression and worsening of anemia. However, in patients with AIMF, anemia might be mainly related to cytokine mediated suppression of erythropoiesis. The difference in anemia pathogenesis between the two disease is likely why ruxolitinib administration in our patient did not result in worsening of anemia. On the other hand, it led to both improvement of anemia as well as fairly rapid decrease in marrow fibrosis thereby demonstrating its potential effectiveness as a therapy for AIMF. In summary, P-AIMF is a very rare disease which needs to be distinguished from the PMF. Although response rate to steroids is high, ruxolitinib should be considered in steroid refractory cases. This study was supported by intramural funds from City of Hope National Medical Center. H.A.: speakers bureau and advisory board for Incyte. G.M.: speakers' bureau for AbbVie and Novartis, advisory board with Janssen. V.P.: speakers Bureau for Jazz, Amgen, Novartis, AbbVie, advisory board for AbbVie and Jazz Pharmaceuticals. The rest of the authors declare no conflict of interest. The data that support the finding of this letter are available from the corresponding author upon reasonable request.