Further exploration is needed to uncover solutions that are able to control both symptoms and THE UNDERLYING DISEASE1,2
Goals for managing symptoms of myelofibrosis and underlying disease could include1-6:
Sustained
reduction of
SPLEEN VOLUME
Reversal of
BONE MARROW FIBROSIS
Improved
SYMPTOM RESPONSES
Reduced
VARIANT ALLELE FREQUENCY (VAF)
ANEMIA RESPONSE
for longer transfusion-free periods
Improved
OVERALL SURVIVAL
For patients with MF, the most important treatment goal was to slow or delay the progression of their condition (US MPN Landmark survey)7
- Other important goals for patients included better quality of life, healthy blood counts, and symptom improvement7
A CLOSER LOOK AT SOME POTENTIAL MANAGEMENT GOALS:
Sustained reduction of spleen volume
JAK inhibition typically achieves SVR ≥35% in ~40% of patients at 24 weeks8,9
The majority may not sustain SVR10
~70% did not sustain SVR at ~3 years
(Landmark clinical trial)10
Anemia response for longer transfusion-free periods
All patients with MF are at risk of developing anemia3
At diagnosis, nearly 40% of patients with MF have hemoglobin (Hb) levels <10 g/dL and nearly one-quarter are already RBC transfusion dependent3
In some patients, durable anemia response could help mitigate symptoms or allow for longer transfusion-free periods, improving quality of life3,11
Reversal of bone marrow fibrosis (BMF)
BMF is a key diagnostic feature (2008 WHO criteria) of MF12
In a long-term follow-up, reduced BMF* with JAK inhibition was correlated with:
Increased SVR13
Decreased leukoerythroblastosis13
Targeting the malignant stem cell may disrupt the downstream signaling that contributes to BMF2,5,14
Reduced variant allele frequency (VAF)15-18
VAF refers to the allelic burden in mutations such as JAK2 V617F that are present in myelofibrosis and other MPNs15-17
In some studies, reductions have been shown to be associated with improvements in clinical response, such as a reduction in spleen volume18
The heterogeneity of MF—including treatment experiences and response definitions—is variable and lacks clinical consensus19
Rethinking the ways we look at myelofibrosis and disease progression can help management of the disease evolve5,20,21
AbbVie is committed to ongoing research in myelofibrosis.
*Measured by grade of reticulin and collagen deposition.13
JAK=Janus kinase; JAK/STAT=Janus kinase signal transducer and activator of transcription; MF=myelofibrosis; MPN=myeloproliferative neoplasm; RBC=red blood cell; SVR=spleen volume reduction; WHO=World Health Organization.
References: 1. Pettit K, Odenike O. Novel therapies for myelofibrosis. Curr Hematol Malig Rep. 2017;12(6):611-624. doi:10.1007/s11899-017-0403-0 2. Schieber M, Crispino JD, Stein B. Myelofibrosis in 2019: moving beyond JAK2 inhibition. Blood Cancer J. 2019;9(9):74. doi:10.1038/s41408-019-0236-2 3. Naymagon L, Mascarenhas J. Myelofibrosis-related anemia: current and emerging therapeutic strategies. HemaSphere. 2017;1(1):e1. doi:10.1097/HS9.0000000000000001 4. Tefferi A, Guglielmelli P, Pardanani A, Vannucchi AM. Myelofibrosis treatment algorithm 2018. Blood Cancer J. 2018;8(8):72. doi:10.1038/s41408-018-0109-0 5. Kramann R, Schneider RK. The identification of fibrosis-driving myofibroblast precursors reveals new therapeutic avenues in myelofibrosis. Blood. 2018;131(19):2111-2119. doi:10.1182/blood-2018-02-834820 6. Tefferi A, Lasho TL, Jimma T, et al. One thousand patients with primary myelofibrosis: the Mayo Clinic experience. Mayo Clin Proc. 2012;87(1):25-33. doi:10.1016/j.mayocp.2011.11.001 7. Mesa RA, Miller CB, Thyne M, et al. Myeloproliferative neoplasms (MPNs) have a significant impact on patients’ overall health and productivity: the MPN Landmark survey. BMC Cancer. 2016;16:167. doi:10.1186/s12885-016-2208-2 8. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. doi:10.1056/NEJMoa1110557 9. Pardanani A, Claire Harrison, Cortes JE, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol. 2015;1(5):643-651. doi:10.1001/jamaoncol.2015.1590 10. Verstovsek S, Mesa RA, Gotlib J, et al. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017;10(1):55. doi:10.1186/s13045-017-0417-z 11. Mughal TI, Vaddi K, Sarlis NJ, Verstovsek S. Myelofibrosis-associated complications: pathogenesis, clinical manifestations, and effects on outcomes. Int J Gen Med. 2014;7:89-101. doi:10.2147/IJGM.S51800 12. Zahr AA, Salama ME, Carreau N, et al. Bone marrow fibrosis in myelofibrosis: pathogenesis, prognosis and targeted strategies. Haematologica. 2016;101(6):660-671. doi:10.3324/haematol.2015.141283 13. Kvasnicka HM, Thiele J, Bueso-Ramos CE, et al. Long-term effects of ruxolitinib versus best available therapy on bone marrow fibrosis in patients with myelofibrosis. J Hematol Oncol. 2018;11(1):42. doi:10.1186/s13045-018-0585-5 14. Santos FPS, Verstovsek S. Therapy with JAK2 inhibitors for myeloproliferative neoplasms. Hematol Oncol Clin North Am. 2012;26(5):1083-1099. doi:10.1016/j.hoc.2012.07.008 15. Vannucchi AM, Pieri L, Guglielmelli P. JAK2 allele burden in the myeloproliferative neoplasms: effects on phenotype, prognosis and change with treatment. Ther Adv Hematol. 2011;2(1):21-32. doi:10.1177/2040620710394474 16. Harrison CN, McLornan DP. Current treatment algorithm for the management of patients with myelofibrosis, JAK inhibitors, and beyond. Hematology Am Soc Hematol Educ Program. 2017;2017(1):489-497. doi:10.1182/asheducation-2017.1.489 17. Hasselbalch HC. The role of cytokines in the initiation and progression of myelofibrosis. Cytokine Growth Factor Rev. 2013;24(2):133-145. doi:10.1016/j.cytogfr.2013.01.004 18. Pemmaraju N, Verstovsek S, Mesa R. Defining disease modification in myelofibrosis in the era of targeted therapy. Cancer. 2022;128(13):2420-2432. doi:10.1002/cncr.34205 19. Harrison CN, Schaap N, Mesa RA. Management of myelofibrosis after ruxolitinib failure. Ann Hematol. 2020;99(6):1177-1191. doi:10.1007/s00277-020-04002-9 20. Rubert J, Qian Z, Andraos R, Guthy DA, Radimerski T. Bim and Mcl-1 exert key roles in regulating JAK2V617F cell survival. BMC Cancer. 2011;11:24. doi:10.1186/1471-2407-11-24 21. Tremblay D, Mascarenhas J. Next generation therapeutics for the treatment of myelofibrosis. Cells. 2021;10(5):1034. doi:10.3390/cells10051034
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