• Specific pathophysiologic mechanism is not well understood
• Few studies have addressed this question; hypotheses include
  • Fibrosis likely driven by overproduction of cytokines
    • Predominant source of cytokines is hypothesized to relate to lymphoid aggregates (Clin Adv Hematol Oncol 2018;16:619)
  • CD8+ T lymphocytes and IFN gamma have been implicated as having pathogenic roles in a mouse model of primary biliary cholangitis with myelofibrosis (J Autoimmun 2018:89:101)
  • IFN gamma signaling through JAK-STAT pathway may play a role
    • Overactivation of the JAK-STAT pathway has been associated with multiple autoimmune disorders and malignancies (J Allergy Clin Immunol 2021;147:814)
    • Case reports of refractory pAIMF that were responsive to JAK inhibitors (Am J Hematol 2021;96:E283)
  • Most hypotheses are extrapolated from studies of other neoplastic myelofibrotic disorders
    • Megakaryocytes, platelets and monocytes have been shown to play a role in other etiologies of myelofibrosis (e.g., thrombopoietin associated myelofibrosis, hairy cell leukemia, primary myelofibrosis) via cytokines possibly including PDGF, calmodulin, TGF beta, VEGF and basic fibroblast growth factor (Br J Haematol 2007;139:351, N Engl J Med 2000;342:1255)
      • Specific roles of these cytokines in AIMF have not yet been shown
    • Increased levels of IFN gamma, TGF beta and IL8 have been associated with cases of primary myelofibrosis (PMF) with autoimmune features (e.g., cases of PMF with positive mitogen stimulated DAT or serologic markers of autoimmunity)
      • Unclear if this represents mechanistic overlap between the 2 entities (Leuk Res 2013;37:1509)

• Overall good prognosis (Acta Haematol 2017;138:129)
  • ~85% of cases with clinical follow up had at least partial symptomatic improvement after treatment (Eur J Haematol 2023;111:706)
• Few reports of long term follow up available (Acta Haematol 2017;138:129, Eur J Haematol 2023;111:706)
• Cases of relapse have been reported (Haematologica 2021;106:871, Pediatr Blood Cancer 2022;69:e29762)
• Factors associated with treatment resistance are unknown

• Insufficient data on optimal indications and efficacy of different treatment regimens (Haematologica 2021;106:871)
  • Adequate prospective trials are difficult due to rarity of AIMF (Eur J Haematol 2023;111:706)
• Usually responds to glucocorticoids
  • Most cases with post treatment biopsy data report diminished or reversed marrow fibrosis (Eur J Haematol 2023;111:706)
• Other immunomodulators are sometimes used, alone or with glucocorticoids
  • E.g., hydroxychloroquine, mycophenolate, intravenous immunoglobulin, rituximab and others (Eur J Haematol 2023;111:706)
• Ruxolitinib reportedly used in few case reports (Leuk Lymphoma 2023;64:1723, Am J Hematol 2021;96:E283)
• Treatment may aim to control underlying autoimmune disorder (Pediatr Blood Cancer 2023;70:e30144)

Contributed by Ria Vergara-Lluri, M.D.

Contributed by Ria Vergara-Lluri, M.D.

A 47 year old woman presents with fatigue, joint pains and pallor. Laboratory workup is notable for severe anemia, thrombocytopenia and a serum ANA titer of 1:40. A bone marrow biopsy is obtained and shows marked hypercellularity with scattered nonparatrabecular lymphoid aggregates (images above) as well as myelofibrosis highlighted by reticulin staining (not shown). Which of the following findings would be typical for a diagnosis of autoimmune myelofibrosis (AIMF)?

1. Increased numbers of megakaryocytes in dense clusters
2. MPL mutation on next generation sequencing (NGS) myeloid panel
3. Palpable splenomegaly
4. Response to glucocorticoids
5. Severe reticulin fibrosis (MF grade 3)

D. Response to glucocorticoids. Autoimmune myelofibrosis (AIMF) is a nonneoplastic condition that may be responsive to a course of glucocorticoids. Overall, the diagnosis of AIMF requires careful correlation of the patient's clinical information with the histopathologic findings on bone marrow biopsy. By morphology, AIMF is associated with a hypercellular marrow (typically with erythroid and megakaryocytic hyperplasias), benign lymphoid aggregates (e.g., nonparatrabecular, polyclonal lymphocytes), polytypic plasmacytosis and without overt features of dysplasia.

Answer E is incorrect because myelofibrosis in AIMF is usually mild to moderate, although rare cases of AIMF have been associated with severe reticulin fibrosis and this finding alone would not be inconsistent with the diagnosis. Answer C is incorrect because palpable splenomegaly is quite uncommon in AIMF, though not exclusionary. Answer B is incorrect because the presence of a pathogenic mutation in MPL ought to prompt assessment favoring neoplasia. The absence of somatic mutations on next generation sequencing panels for myeloid malignancies (e.g., JAK2, CALR and MPL) can be an essential part of the diagnostic work up of AIMF. Answer A is incorrect because while it is typical to see increased numbers of megakaryocytes in AIMF, dense clusters of megakaryocytes (which are very likely to also display cytologic atypia) would be highly unusual for (and morphologically inconsistent with) AIMF. This observation strongly favors a myeloid neoplasm (such as primary myelofibrosis) and should trigger a thorough work up to demonstrate clonality (e.g., karyotype, NGS testing).

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Reference: Autoimmune myelofibrosis (AIMF)

A 37 year old woman with no significant medical history was admitted to the hospital for acute onset of fevers and severe fatigue. Her vital signs and physical examination were significant only for fever and tachycardia; there is no palpable hepatosplenomegaly.

• Imaging studies showed no organomegaly or lymphadenopathy
• Laboratory studies were remarkable for WBC 3.1 x 10⁹/L, Hb 8.0 g/dL, Plt 39 x 10³/uL, ANA titer of 1:80 and a negative DAT
• Peripheral blood smear showed cytopenias without leukoerythroblastosis
• Remainder of the infectious, autoimmune and neoplastic workup was negative
• Bone marrow biopsy displayed a markedly hypercellular marrow with erythroid and megakaryocytic hyperplasias, scattered nonparatrabecular lymphoid aggregates, no overt dysplasia or excess blasts and mild polytypic plasmacytosis (< 10%)
• Reticulin staining revealed moderate reticulin fibrosis (MF2; image shown above)
• Normal karyotype was reported while next generation sequencing (NGS) myeloid panels for somatic mutations were negative

She received a course of glucocorticoids and achieved complete hematologic response and was discharged from the hospital. Rheumatology consultation revealed no established autoimmune disorder. She is being closely monitored by the hematology clinical service. A repeat biopsy performed 1 year after her hospital admission showed similar findings, though decreased reticulin fibrosis is observed (MF1). Which of the following is the most appropriate diagnosis at this time?

1. Myelofibrosis, secondary to polycythemia vera
2. Primary autoimmune myelofibrosis
3. Primary myelofibrosis, overt stage
4. Primary myelofibrosis, prefibrotic stage

B. Primary autoimmune myelofibrosis. Autoimmune myelofibrosis (AIMF) is a nonneoplastic condition that may occur in the presence of another predefined autoimmune disorder (secondary AIMF) or in the presence of nonspecific autoantibodies / symptoms not meeting criteria for another established autoimmune disorder (primary AIMF).

Secondary AIMF has been described in association with many autoimmune disorders, including systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, autoimmune hemolytic anemia and others. In this vignette, over the course of close clinical follow up, no specific autoimmune, infectious / inflammatory or other hematologic disorder could be established. Furthermore, her favorable response to glucocorticoids and mild decrease in reticulin fibrosis on repeat biopsy is typical of AIMF. Thus, a diagnosis of primary AIMF may be suggested at this time and is the most appropriate choice of those listed here, after careful consideration of the bone marrow findings in the context of clinical information and disease course. Alternate causes of myelofibrosis (including, for example, exposure to drugs, infectious causes, myeloproliferative neoplasm (MPN) or post-MPN myelofibrosis) must be ruled out. Answer A is incorrect because in this case, the patient described has no significant medical history nor evidence of neoplastic progression, making post-MPN myelofibrosis unlikely. Answers C and D are incorrect because the vignette describes a characteristic combination of morphologic and genetic findings that would be seen with AIMF, including the absence of somatic mutations on next generation sequencing panels for myeloid malignancies (e.g., JAK2, CALR and MPL), which can be an essential part of the diagnostic work up.

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Reference: Autoimmune myelofibrosis (AIMF)