Prefibrotisk Myelofibros Björn Andréasson

Hb <13g/dL for men or <12 for women This algorithm is able to identify the vast majority of true MF patients and true ET patients Parameters’ thresholds N Positives Specificity (includes True MF patients) Sensitivity (excludes True ET patients) “MF suspicion” bucket Hb <13g/dL for men or <12 for women 536 46 92% (422 / 457) 14% (11 / 79) WBC ≥13x109/L 56 91% (417 / 457) 20% (16 / 79) “High likelihood of true ET” WBC <7x109/L 104 22% (99/ 457) 94% (74 / 79) LDH < 200mU/mL 428 (101 / 457) (72 / 79) A B Source: Sensitivity and specificity for Hb, WBC and LDH threshold from Carobbio et al. 2012

Leukemic Transformation This is key, as the patient outcomes for the two diseases are significantly different Overall Survival ET patients MF patients p value Median Survival 21.76 years 14.44 years 0.0002 Rate at 10 years 89% 76% Rate at 15 years 80% 59% Leukemic Transformation ET patients MF patients p value Rate at 10 years 0.7% 5.8% 0.0012 Rate at 15 years 2.1% 11.7% ET patients MF patients Source: Barbui et al. July 2011/ 10.1200/JCO.2010.34.5298, Journal of clinical oncology; 1,104 patients previously diagnosed as having ET Study eligibility criteria included availability of treatment-naive BM specimens obtained within 1 year of diagnosis, all bone marrows subsequently underwent a central re-review.

Prefibrotic Primary Myelofibrosis (PrePMF) criteria Arber 2016 Major criteria 1. Megakaryocytic proliferation and atypia, without reticulin fibrosis >grade 1*, accompanied by increased age-adjusted bone marrow cellularity, granulocytic proliferation, and often decreased erythropoiesis 2. Not meeting the WHO criteria for BCR-ABL positive CML, PV, ET, MDS, or other myeloid neoplasms 3. Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence of another clonal marker,† or absence of minor reactive bone marrow reticulin fibrosis‡ Minor criteria Presence of at least 1 of the following, confirmed in 2 consecutive determinations: a. Anemia not attributed to a comorbid condition b. Leukocytosis >11 x 109/L c. Palpable splenomegaly d. S-LDH increased to above upper normal limit of institutional reference range Diagnosis of prePMF requires meeting all 3 major criteria, and at least 1 minor criterion

Diagnostic work-up in prefibrotic myelofibrosis

MF-0 MF-1

Survival according to stage of PMF % S u r v i a l Years after diagnosis n=178 PMF-0 n=139 n=128 n=281 PMF-3 PMF-2 PMF-1 20 40 60 80 100 2 4 6 8 10 12 14