AN URGENT NEED EXISTS FOR BROADER DISEASE CONTROL IN MYELOFIBROSIS1

MF

Myelofibrosis (MF) is a rare type of blood cancer characterized by a dysregulated bone marrow microenvironment, resulting in progressive fibrosis and impaired hematopoiesis2‑4

The aggressive and heterogeneous nature of many hematologic malignancies complicates treatment and can result in poor survival.5,6

Explore the unmet need in myelofibrosis with Dr Andrew Kuykendall

So, oftentimes, patients with myelofibrosis present with enlarged spleens or these things we call constitutional symptoms.

So, fever, chills, night sweats, bone pain, weight loss.

These are inflammatory symptoms, and both the spleen and the symptoms are critically tied.

Oftentimes, patients have both of these to some extent, and these associate with a poor quality of life and decreased overall survival.

The other concern that we have is ultimately patients may deal with other changes in their blood counts, and so they may notice that their white blood cell count is elevated with hemoglobin being low.

So, if you have moderate to marked fibrosis, patients have a much different prognosis than if they have minimal to mild fibrosis.

Additionally, the more scar tissue in fibrosis you get actually probably influences the ability to have normal erythropoiesis.

And so, oftentimes this fibrosis level is linked to the degree of anemia, the need for transfusions.

So, when you think about myelofibrosis, I think you can consider this and really focus in on 4 different hallmarks of the disease: splenomegaly or spleen enlargement, constitutional symptoms, anemia, and bone marrow fibrosis.

Certainly, the first 3 when we talk about symptoms, spleen, and anemia, these are often reasons that the patients present to the clinic.

And then bone marrow fibrosis is something that’s inherently linked to the disease.

Historically, we’ve had JAK inhibitors, which have been approved for the indication of myelofibrosis, and they’re very effective at attacking the splenomegaly and the constitutional symptoms.

I think that one thing we know is that patients who receive JAK inhibitor therapy don’t typically do so for an extended period of time.

Half of patients will be off of a JAK inhibitor at about 3 years. This is what long-term follow-up with some of these critical studies has shown us.

And we know that outcomes after JAK inhibitor therapy discontinuation are quite poor.

So, we need to be thinking about how do we extend the durability of our responses with these agents and get patients to stay on therapy with controllable disease for a longer period of time?

So, as we mentioned, bone marrow fibrosis is a hallmark of the disease. I think that this is diagnostically linked to myelofibrosis.

It’s something we know we have to look at when we’re looking at clinical trials if we want to achieve disease modification.

As you get more fibrosis, more scar tissue in the marrow, it becomes more of an inhospitable environment to have normal hematopoiesis, and that’s where we start to see a link with more anemia, more difficulty in making red blood cells.

I think if we truly think we’re getting rid of the disease we would expect bone marrow fibrosis to change.

What JAK inhibitors are able to do is reduce spleen volume and improve symptoms.

And they do this pretty much for all patients; however, there are some limitations to JAK inhibitors.

I would say first and foremost these do not get rid of the underlying disease, so when we look at the bone marrow oftentimes we still see disease that’s there.

We still see a hypercellular marrow, megakaryocytic atypia, and the mutations that drive the disease are usually still present, right? They may shift in how often they're there, but they're usually still present.

So, we’re not having a lot of disease response and, unfortunately, we’re not talking about complete or partial responses when we use JAK inhibitors.

We’re talking about clinical improvements.

Overall, the limitations to me are lack of a disease-modifying effect, the fact that it actually worsens other cytopenias and the inability to give it to some patients that have preexisting cytopenias, and overall a lack of duration or durability as far as treatment goes.

And so I think those are the things we are looking to improve when we’re trying to treat our myelofibrosis patients in a better way.

References:

  1. Al-Ali HK, Griesshammer M, le Coutre P, et al. Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: a snapshot of 1144 patients in the JUMP trial. Haematologica. 2016;101(9):1065-1073. doi:10.3324/haematol.2016.143677
  2. Mesa R, Su Y, Woolfson A, et al. Development of a symptom assessment in patients with myelofibrosis: qualitative study findings. Health Qual Life Outcomes. 2019;17(1):61. doi:10.1186/s12955-019-1121-1
  3. Guglielmelli P, Rotunno G, Pacilli A, et al. Prognostic impact of bone marrow fibrosis in primary myelofibrosis. A study of the AGIMM group on 490 patients. Am J Hematol. 2016;91(9):918-922. doi:10.1002/ajh.24442
  4. Lacout C, Pisani DF, Tulliez M, et al. JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis. Blood. 2006;108(5):1652-1660. doi:10.1182/blood-2006-02-002030
  5. Takenaka K, Shimoda K, Akashi K. Recent advances in the diagnosis and management of primary myelofibrosis. Korean J Intern Med. 2018;33:679-690. doi:/10.3904/kjim.2018.033
  6. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Myeloproliferative Neoplasms V.3.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed October 1, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org
  7. 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
  8. Scherber R, Mesa R. Management of challenging myelofibrosis after JAK inhibitor failure and/or progression. Blood Rev. 2020;42:100716. doi:10.1016/j.blre.2020.100716
  9. Pemmaraju N, Verstovsek S, Mesa R, et al. Defining disease modification in myelofibrosis in the era of targeted therapy. Cancer. 2022;128:2420-2432. doi:10.1002/cncr.34205
  10. Wilkins BS, Radia D, Woodley C, Farhi SE, Keohane C, Harrison CN. Resolution of bone marrow fibrosis in a patient receiving JAK1/JAK2 inhibitor treatment with ruxolitinib. Haematologica. 2013;98(12):1872-1876. doi:10.3324/haematol.2013.095109
  11. Vachhani P, Verstovsek S, Bose P. Disease modification in myelofibrosis: an elusive goal? J Clin Oncol. 2022;40(11):1147-1154. doi:10.1200/JCO.21.02246
  12. Kleppe M, Koche R, Zou L, et al. Dual targeting of oncogenic activation and inflammatory signaling increases therapeutic efficacy in myeloproliferative neoplasms. Cancer Cell. 2018;33(1):29-43. doi:10.1016/j.ccell.2017.11.009
  13. 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
  14. Jiang Q, Jamieson C. BET'ing on dual JAK/BET inhibition as a therapeutic strategy for myeloproliferative neoplasms. Cancer Cell. 2018;33(1):3-5. doi:10.1016/j.ccell.2017.12.007
  15. Ross D, Babon J, Tvorogov D, et al. Persistence of myelofibrosis treated with ruxolitinib: biology and clinical implications. Haematologica. 2011;106(5):1244-1253. doi:10.3324/haematol.2020.262691
  16. Copher R, Kee A, Gerds A. Treatment patterns, health care resource utilization, and cost in patients with myelofibrosis in the United States. Oncologist. 2022;27(3):228-235. doi:10.1093/oncolo/oyab058
  17. Naymagon L, Mascarenhas J. Myelofibrosis-related anemia: current and emerging therapeutic strategies. Hemasphere. 2017;1(1):e1. doi:10.1097/HS9.0000000000000001
  18. Bose P, Verstovsek S. JAK inhibition for the treatment of myelofibrosis: limitations and future perspectives. Hemasphere. 2020;4:4(e424). doi:10.1097/HS9.0000000000000424
  19. Mascarenhas J, Gerds A, Verstovsek S. Paradigm shift: combination BET and JAK inhibition in myelofibrosis. Leukemia. 2021;35(12):3361-3363. doi:10.1038/s41375-021-01405-z
  20. Hilton J, Cristea M, Postel-Vinay S, et al. BMS-986158, a small molecule inhibitor of the bromodomain and extraterminal domain proteins, in patients with selected advanced solid tumors: results from phase 1/2a trial. Cancers. 2022;14:4079. doi:10.3390/cancers14174079

At diagnosis, approximately 90% of patients with MF have intermediate- or high-risk disease, which are both associated with more advanced disease features7

The median overall survival

for patients with intermediate-1, intermediate-2, or high-risk myelofibrosis is
~6.5, ~2.9, and ~1.3 years, respectively.7

Patients with myelofibrosis often present clinically with 4 main hallmarks that are associated with poor quality of life and short survival8,9:

Significant symptom burden, including fatigue, fever, and bone pain

Several studies have shown a correlation between inflammation and perceived symptoms of MPNs such as MF. Elevated levels of inflammatory cytokines have been linked to cancer-related fatigue, fever, and night sweats.10

Anemia, arising due to changes in the bone marrow microenvironment

Anemia in MF is multifactorial in nature and complex to address. Impaired hematopoiesis can lead to anemia, which in turn can be linked to other symptoms.11,12

Splenomegaly due to splenic extramedullary hematopoiesis (EMH)

Splenomegaly can cause abdominal pain and early satiety with the depth and durability of spleen response to the current standard of treatment correlating with overall survival.13,14

Impairment of the bone marrow microenvironment, including bone marrow fibrosis

The proliferation of clustering atypical megakaryocytes and inflammatory cytokines within the bone marrow is also a key indicator of MF and contributes significantly to disease progression.12,15-17

In myelofibrosis, aberrant activation of pro-fibrotic pathways impairs the body's hematopoietic system15

Megakaryocyte.

1. Dysregulated genetic signaling

BET-mediated elevation in NF-κB target gene expression occurs, along with mutations in the JAK/STAT signaling pathway in hematopoietic cells17,18

Abnormal megakaryocytes clustering.

2. Megakaryocyte clustering

Abnormal morphology occurs, characterized as atypical megakaryocytes presenting in tight clusters12,17

Cytokines released from a megakaryocyte.

3. Excessive cytokine release

Clonally expanded megakaryocyte clustering in the bone marrow triggers excessive cytokine release17,18

Bone marrow fibrosis.

4. Impairment of the bone marrow microenvironment

Abnormal cytokine production impairs the bone marrow microenvironment, which leads to bone marrow fibrosis and anemia12,17

Extramedullary hematopoiesis in the spleen.

5. Extramedullary hematopoiesis

Bone marrow fibrosis leads to extramedullary hematopoiesis where blood cells are made outside of the bone marrow in the spleen, leading to splenomegaly and constitutional symptoms9,19

Bone marrow fibrosis is a key indicator of disease progression, with higher-grade bone marrow fibrosis correlating to4:

  • Low hemoglobin counts
  • Increased spleen volume
  • Higher risk assessment scores (eg, IPSS/DIPSS)

Higher-grade (>1) bone marrow fibrosis has been linked to more advanced disease, severe anemia, and reduced survival.4,20,21

An unmet need exists for an agent that can support deeper and more
durable responses in combination with JAK inhibition.11,18,19

Dig deeper into the drivers of MF progression

BET POTENTIAL

BET=bromodomain and extraterminal domain, DIPSS=Dynamic International Prognostic Scoring System, IPSS=International Prognostic Scoring System, JAK=Janus kinase, MPN=myeloproliferative neoplasm, STAT=signal transducer and activator of transcription, WHO=World Health Organization.

References:

  1. Copher R, Kee A, Gerds A. Treatment patterns, health care resource utilization, and cost in patients with myelofibrosis in the United States. Oncologist. 2022;27(3):228‑238. doi:10.1093/oncolo/oyab058
  2. Luker GD, Nguyen HM, Hoff BA, et al. A pilot study of quantitative MRI parametric response mapping of bone marrow fat for treatment assessment in myelofibrosis. Tomography. 2016;2(1):67‑78. doi:10.18383/j.tom.2016.00115
  3. 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
  4. Guglielmelli P, Rotunno G, Pacilli A, et al. Prognostic impact of bone marrow fibrosis in primary myelofibrosis. A study of the AGIMM group on 490 patients. Am J Hematol. 2016;91(9):918‑922. doi:10.1002/ajh.24442
  5. Tefferi A. Primary myelofibrosis: 2019 update on diagnosis, risk‑stratification and management. Am J Hematol. 2018;93(12):1551‑1560. doi:10.1002/ajh.25230
  6. Mascarenhas J, Gleitz HFE, Chifotides HT, et al. Biological drivers of clinical phenotype in myelofibrosis. Leukemia. 2023;37(2):255‑264. doi:10.1038/s41375‑022‑01767‑y
  7. Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refined dynamic international prognostic scoring system for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol. 2011:29(4):392‑397. doi:10.1200/JCO.2010.32.2446
  8. Al‑Ali HK, Griesshammer M, le Coutre P, et al. Safety and efficacy of ruxolitinib in an open‑label, multicenter, single‑arm phase 3b expanded‑access study in patients with myelofibrosis: a snapshot of 1144 patients in the JUMP trial. Haematologica. 2016;101(9):1065‑1073. doi:10.3324/haematol.2016.143677
  9. Abdelouahab H, Zhang Y, Wittner M, et al. CXCL12/CXCR4 pathway is activated by oncogenic JAK2 in a PI3K‑dependent manner. Oncotarget. 2016;8(33):54082‑54095. doi:10.18632/oncotarget.10789
  10. Mendez Luque LF, Blackmon AL, Ramanathan G, Fleischman AG. Key role of inflammation in myeloproliferative neoplasms: instigator of disease initiation, progression, and symptoms. Curr Hematol Malig Rep. 2019;14(3):145‑153. doi:10.1007/s11899‑019‑00508‑w
  11. Naymagon L, Mascarenhas J. Myelofibrosis‑related anemia: current and emerging therapeutic strategies. Hemasphere. 2017;1(1):e1. doi:10.1097/HS9.0000000000000001
  12. Lacout C, Pisani DF, Tulliez M, Gachelin FM, Vainchenker W, Villeval JL. JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis. Blood. 2006;108(5):1652‑1660. doi:10.1182/blood‑2006‑02‑002030
  13. Vachhani P, Verstovsek S, Bose P. Disease modification in myelofibrosis: an elusive goal? J Clin Oncol. 2022;40(11):1147‑1154. doi:10.1200/JCO.21.02246
  14. Yoon J, Pettit K. Improving symptom burden and quality of life in patients with myelofibrosis: current strategies and future directions. Expert Rev Hematol. 2021;14(7):607‑619. doi:10.1080/17474086.2021.1944096
  15. Psaila B, Wang G, Rodriguez‑Meira A, et al. Single‑cell analyses reveal megakaryocyte‑biased hematopoiesis in myelofibrosis and identify mutant clone‑specific targets. Mol Cell. 2020;78(3):477‑492.e8. doi:10.1016/j.molcel.2020.04.008
  16. Ciurea SO, Merchant D, Mahmud N, et al. Pivotal contributions of megakaryocytes to the biology of idiopathic myelofibrosis. Blood. 2007;110(3):986‑993. doi:10.1182/blood‑2006‑12‑064626
  17. Wilkins BS, Radia D, Woodley C, Farhi SE, Keohan C, Harrison CN. Resolution of bone marrow fibrosis in a patient receiving JAK1/JAK2 inhibitor treatment with ruxolitinib. Haematologica. 2013;98(12):1872‑1876. doi:10.3324/haematol.2013.095109
  18. Kleppe M, Koche R, Zou L, et al. Dual targeting of oncogenic activation and inflammatory signaling increases therapeutic efficacy in myeloproliferative neoplasms. Cancer Cell. 2018;33(1):29‑43.e7. doi:10.1016/j.ccell.2017.11.009
  19. 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
  20. Lekovic D, Gotic M, Perunicic‑Jovanovic M, et al. Contribution of comorbidities and grade of bone marrow fibrosis to the prognosis of survival in patients with primary myelofibrosis. Med Oncol. 2014;31(3):869. doi:10.1007/s12032‑014‑0869‑8
  21. Nazha A, Estrov Z, Cortes J, Bueso‑Ramos CE, Kantarjian H, Verstovsek S. Prognostic implications and clinical characteristics associated with bone marrow fibrosis in patients with myelofibrosis. Leuk Lymphoma. 2013;54(11):2537‑2539. doi:10.3109/10428194.2013.769537