Prognostic Scoring For Myelofibrosis

Background

Myelofibrosis (MF) is a chronic, rare, and fatal myeloproliferative neoplasm characterized by a progressive replacement of bone marrow with fibrous scar tissue. Secondary primary malignancies represent a major cause of morbidity and mortality in MF patients. The annual incidence of primary myelofibrosis (PMF) is about 1 case per 100,000 individuals.

Prognosis in PMF relies on clinical patient data, karyotyping and genetic mutations. The first prototype for prognosis scoring was the international prognostic scoring system (IPSS). IPSS was first produced in 2009 and was designed for application at the time of diagnosis. This IPSS was the result of data from 1054 consecutively diagnosed patients with PMF from 1980 to 2007. 4 risk groups were identified, with median survivals ranging from 23 years (high-risk) to 11.3 months (low-risk). Abnormal cytogenetic findings did not appear to affect patient outcomes. IPSS included five risk factors: age >65 years, hemoglobin <10 g/dl, leukocyte count >25 x 10⁹/L, circulating blasts ≥1% and constitutional symptoms. In 2010, DIPSS was adapted from IPSS, which allowed clinicians to use prognostic scoring at any time in the clinical course. Both IPSS and DIPSS (Dynamic IPSS) used the same five clinical risk factors to determine patient prognosis.

In 2011, DIPSS-plus was introduced, which was developed to account for the following IPSS/DIPSS-independent risk factors: thrombocytopenia, red cell transfusion need and karyotype. The inclusion of cytogenetic data boosted DIPSS-plus performance, most significantly for predicting leukemia-free survival. DIPSS-plus included the same five clinical variables used in previous iterations, but added three more DIPSS-independent risk factors: unfavorable karyotype (defined as the presence of complex karyotype or sole or two abnormalities that included +8, −7/7q−, i(17q), inv(3), −5/5q−, 12p− or 11q23 abnormalities), red cell transfusion need and platelet count <100x10⁹/L. DIPSS-plus low, intermediate-1, intermediate-2, and high-risk categories correspond to the presence of 0, 1, 2–3, and ≥4 of the above-mentioned eight risk factors, with respective median survivals of 15.4, 6.5, 2.9, and 1.3 years.

In an effort to improve upon DIPSS-plus, DIPSS-plus-independent-risk factors in PMF was developed, and it includes the absence of type 1/like CALR mutations, presence of high-risk mutations including ASXL1, SRSF2, U2AF1Q157, EZH2, and IDH1/2, very high-risk (VHR) karyotype, defined previously by the presence of monosomal karyotype or inv(3)/i(17q) abnormalities, but most recently refined to include single or multiple abnormalities of −7, i(17q), inv(3)/3q21, 12p−/12p11.2, 11q−/11q23, or other autosomal trisomies not including +8/+9 (e.g., +21, +19), degree of bone marrow fibrosis, monocytosis25, markedly elevated serum lactate dehydrogenase, nullizygosity for JAK2 46/1 haplotype, low JAK2V617F allele burden and increased serum levels of IL-8, IL-2R, free light chain and hepcidin.

Genetic Variables:

VHR karyotype (4 points)

'very high risk (VHR)'- single/multiple abnormalities of -7, i(17q), inv(3)/ 3q21, 12p-/12p11.2, 11q-/11q23, or other autosomal trisomies not including + 8/ + 9 (e.g., +21, +19) ¹

(check if present)

Unfavorable karyotype (3 points)

'Unfavorable karyotype is assigned to complex karyotype or sole or two abnormalities of +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p- or 11q23 rearrangement while all other scenarios, including normal karyotype, were considered 'favorable'. Unfavorable karyotype in PMF occurs in ~14% of patients and is associated with median survival of 2 years, compared to 5.2 years in its absence. ¹

(check if present)

HMR mutations

HMR - high molecular risk mutations include ASXL1, SRSF2, EZH2, IDH1, IDH2 and, in addition, for MIPSS70+ version 2.0, U2AF1Q157 ¹

0 HMR mutations
1 HMR mutation
≥2 HMR mutations

CALR type 1/like mutation (Absent)

CALR (Calreticulin) - Wild-type CALR is a multifunctional Ca2+ binding protein chaperone mostly localized In the endoplasmic reticulum ²

(check if present)

Clinical variables

Hemoglobin:

g/dL Male Female

Circulating blasts ≥2%

(check if present)

Constitutional symptoms such as fatigue, night sweats, fever?

(check if present)
Leukocytes > 25 x 10⁹/L

(check if present)
Platelets <100 x 10⁹/L

(check if present)

Bone marrow fibrosis grade ≥2

(check if present)

Include MIPSS analysis
(If yes, check any of the following high molecular risk mutations if present)

ASXL1 mutation
(check if present)

SRSF2 mutation
(check if present)

U2AF1Q157 mutation
(check if present)

Analysis

MIPSS70+ version 2.0

Genetic variables

VHR karyotype (4 points)
Unfavorable karyotype (3 points)

≥2 HMR mutations (3 points)
One HMR mutation (2 points)

Type 1/like CALR absent (2 points)

Clinical variables
Severe anemia (2 points) M: <9 g/dL F: <8 g/dL
Moderate anemia (1 point) M: 9-10.9 g/dL F: 8-9.9 g/dL

Circulating blasts ≥2% (1 point)

Constitutional symptoms (2 points)

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GIPSS (4-tiered)

Genetic variables

VHR karyotype (2 points)
Unfavorable karyotype (1 point)
Type 1/like CALR absent (1 point)

[High molecular risk mutations]
ASXL1 mutation (1 point)
SRSF2 mutation (1 point)
U2AF1Q157 mutation (1 point)
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MIPSS70

Genetic variables

One HMR mutation (1 point)
≥2 HMR mutations (2 points)

Type 1/like CALR absent (1 point)

Clinical variables
Hemoglobin < 10 g/dL (1 point)
Leukocytes > 25 × 10⁹/L (2 points)
Platelets <100 × 10⁹ /L (2 points)
Circulating blasts ≥2% (1 point)
Constitutional symptoms (1 point)
Bone marrow fibrosis grade ≥2 (1 point)

References

Tefferi, A., Nicolosi, M., Mudireddy, M. et al. Revised cytogenetic risk stratification in primary myelofibrosis: analysis based on 1002 informative patients. Leukemia 32, 1189–1199 (2018). https://doi.org/10.1038/s41375-018-0018-z
Tefferi A. Primary myelofibrosis: 2019 update on diagnosis, risk-stratification and management. Am J Hematol. 2018 Dec;93(12):1551-1560. doi: 10.1002/ajh.25230. Epub 2018 Oct 26. PMID: 30039550.
Tefferi, A., Guglielmelli, P., Pardanani, A. et al. Myelofibrosis Treatment Algorithm 2018. Blood Cancer Journal 8, 72 (2018). https://doi.org/10.1038/s41408-018-0109-0