Bone marrow fibrosis in patients with primary myelodysplastic syndromes has prognostic value using current therapies and new risk stratification systems

Abstract Background: Myelodysplastic syndromes (MDS) are malignant clinical disorders characterized by ineffective hematopoiesis, bone marrow dysplasia, peripheral cytopenias and a property to transform into acute myeloid leukemia (AML). Standard of care for MDS includes the hypomethylating agents (HMAs) (i.e. azacitidine, decitabine) to improve quality of life, decrease transfusion requirements and improve clinical outcome. However not all patients (pts) respond to HMAs and even in responding pts, cytopenias may persist. HMA-failure MDS has extremely poor prognosis and currently there are no approved therapeutic options for such pts who are often of advanced age with frequent comorbidities. Objectives: The dual primary objectives of this study evaluate the safety and efficacy of the second-generation thrombopoietin-receptor agonist (TPO-RA) eltrombopag (EPAG) for the treatment of MDS pts at the time of HMA-failure. Secondary objectives include incidence of transformation to AML and evaluation of bone marrow fibrosis during therapy. Methods: Eligible pts for this 2-arm phase 2 open-label clinical trial included adults with MDS after completing >4 HMA cycles with failure to achieve at least a partial response, or the presence of ongoing cytopenias per IWG criteria. Arm A includes eltrombopag monotherapy and Arm B includes eltrombopag with continuation of the HMA at the previous dosing schedule. The starting eltrombopag dose is 200mg orally daily, which can be increased to 300mg in the absence of toxicity. First response is assessed after 2 cycles with each cycle lasting 28 days. The primary efficacy endpoint was overall response rate based on the IWG-2006 criteria. Results: To date, 23 pts with a median age of 72 years (range 42-84 years) have been enrolled. Prior to study entry, pts had received a median of 6 (range 4-25) HMA cycles. Cytogenetics were diploid in 12 (53%), intermediate in 7 (30%), and high risk in 4 (17%) pts by IPSS. Median bone marrow blasts at study start was 3% (range 0-15%). Arm A has enrolled 7 pts with a median age of 74 years; Arm B has enrolled 16 pts with median age of 69 years. In Arm B, ongoing HMA therapy includes azacitidine in 7 (44%) and decitabine in 9 (56%). Nine (39%) pts increased to 300mg EPAG after median of 8 weeks on study. Median total cycles received on study is 5 (1-17); median OS has not been reached. Overall, 16 pts are response-evaluable; 7 pts discontinued prior to the first response assessment at 2 months (4 due to AEs including myalgias/fatigue (n=2), hyperbilirubinemia (n=1), and pneumonia (n=1), 2 per pt request and 1 for pt inability to comply with protocol requirements). Of the 16 response-evaluable pts, 3 (19%) in Arm B demonstrated platelet improvement, including one pt necessitating EPAG dose-reduction to 100mg due to platelet count exceeding 450 x10⁹/L with concomitant ANC recovery at 200mg EPAG dose level. An additional 8 (35%) pts have remained on study for a median of 5 cycles (2-17) with stable disease. Two pts discontinued therapy due to disease progression, including 1 (4%) that progressed to AML. The most common non-hematologic AEs regardless of attribution included hyperbilirubinemia (n=14, 61%), fatigue (n=13, 56%) myalgias (n=11, 48%), fever (7, 30%), dyspnea (7, 30%), nausea (6, 26%) and transaminitis (4, 17%). No significant increase in bone marrow fibrosis has been observed. Conclusion: Eltrombopag orally daily appears to be a safe and beneficial supportive adjunct for pts with MDS while receiving HMA-therapy or after HMA-failure due to persistent cytopenias. Treatment on this study continues and larger prospective clinical trials are needed to confirm these preliminary findings. Disclosures Off Label Use: Eltrombopag for the treatment of MDS-related cytopenias". Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. DiNardo:Novartis: Research Funding.

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Myelodysplastic syndromes with bone marrow fibrosis: a myelodysplastic disorder with proliferative features

Annals of Hematology ◽

10.1007/bf01698371 ◽

1991 ◽

Vol 63 (5) ◽

pp. 235-241 ◽

Cited By ~ 44

Author(s):

G. E. G. Verhoef ◽

C. De Wolf-Peeters ◽

A. Ferrant ◽

S. Deprez ◽

P. Meeus ◽

...

Keyword(s):

Bone Marrow ◽

Myelodysplastic Syndromes ◽

Bone Marrow Fibrosis ◽

Marrow Fibrosis

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The implication of identifying JAK2 V617F in myeloproliferative neoplasms and myelodysplastic syndromes with bone marrow fibrosis

Journal of Hematopathology ◽

10.1007/s12308-008-0014-8 ◽

2008 ◽

Vol 1 (2) ◽

pp. 111-117 ◽

Cited By ~ 10

Author(s):

Randall J. Olsen ◽

Cherie H. Dunphy ◽

Dennis P. O’Malley ◽

Lawrence Rice ◽

April A. Ewton ◽

...

Keyword(s):

Bone Marrow ◽

Myelodysplastic Syndromes ◽

Myeloproliferative Neoplasms ◽

Jak2 V617f ◽

Bone Marrow Fibrosis ◽

Marrow Fibrosis

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Myelodysplastic Syndromes with Bone Marrow Fibrosis: An Update

Annals of Laboratory Medicine ◽

10.3343/alm.2022.42.3.299 ◽

2022 ◽

Vol 42 (3) ◽

pp. 299-305

Author(s):

Akriti G. Jain ◽

Ling Zhang ◽

John M. Bennett ◽

Rami Komrokji

Keyword(s):

Bone Marrow ◽

Myelodysplastic Syndromes ◽

Bone Marrow Fibrosis ◽

Marrow Fibrosis

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Myelodysplastic syndromes with bone marrow fibrosis

Haematologica ◽

10.3324/haematol.2010.039875 ◽

2011 ◽

Vol 96 (2) ◽

pp. 180-183 ◽

Cited By ~ 24

Author(s):

M. G. Della Porta ◽

L. Malcovati

Keyword(s):

Bone Marrow ◽

Myelodysplastic Syndromes ◽

Bone Marrow Fibrosis ◽

Marrow Fibrosis

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P112 Prognostic impact of bone marrow fibrosis in myelodysplastic syndromes (MDS)

Leukemia Research ◽

10.1016/s0145-2126(07)70182-0 ◽

2007 ◽

Vol 31 ◽

pp. S100

Author(s):

S. Baghikar ◽

S. Braunstein ◽

P. Reinecke ◽

S. Knipp ◽

R. Haas ◽

...

Keyword(s):

Bone Marrow ◽

Myelodysplastic Syndromes ◽

Prognostic Impact ◽

Bone Marrow Fibrosis ◽

Marrow Fibrosis

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Genetic and Clinical Features of Chronic Myelmonocytic Leukemia with Fibrosis

Blood ◽

10.1182/blood-2019-128997 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5442-5442

Author(s):

Mohammad O Hussaini ◽

Jinming Song ◽

Andrew T Kuykendall ◽

David A Sallman ◽

Eric Padron ◽

...

Keyword(s):

Bone Marrow ◽

Risk Stratification ◽

Gene Panel ◽

World Health ◽

Pathology Report ◽

Monocyte Count ◽

Bone Marrow Fibrosis ◽

Worse Prognosis ◽

Marrow Fibrosis ◽

Severe Fibrosis

Introduction Chronic myelomonocytic leukemia (CMML) is an overlap syndrome with both myeloproliferative and myelodysplastic features. Clinical outcomes can be variable and risk stratification models such as GFM and Molecular Mayo Model (MMM) are useful. These models integrate age, WBC, anemia, thrombocytopenia, mutation status, monocyte count, and blast/promonocyte count, to segregate patients1. The presence of fibrosis in MDS (MF 2-3) is often associated with high grade disease, poor cytogenetics, and worse prognosis 2. The role of moderate to severe fibrosis in CMML (CMML-F) is not well studied. We investigated mutational landscape of CMML-F and whether CMML-F is associated with more aggressive disease thus warranting incorporation into risk models. Methods Total Cancer Care (TCC) and PathNet databases at Moffitt Cancer Center were queried for patients diagnosed with CMML between 2014 and 2017 with available Next Generation Sequencing (NGS) profiling (Genoptix 5-gene panel, Genoptix 21-gene panel, FoundationOne, Custom TrueSeq Myeloid). The cases were individually reviewed by a board-certified hematopathologist to confirm the diagnosis. The degree of reticulin fibrosis was manually collated from the pathology report and graded according to the World Health Organization (WHO) grading of bone marrow fibrosis (grade 0-3). Grade 1-2 or 2-3 fibrosis in the report were designated 1.5 and 2.5, respectively. CMML-F was defined as grade 2.5 or higher or collagen fibrosis. t-test and two tailed Fisher exact tests were performed for statistical analysis. Results Of 108 CMML patients (median age of 69.7 years), bone marrow fibrosis data was available for 91 individuals. The degree of fibrosis was as follows: Grade 0= 33, Grade 1= 34, Grade 1.5= 2, Grade 2= 15, Grade 2.5= 2, Grade 3=5 (of which 2 had collagen fibrosis). The CMML patients without fibrosis (MF<2.5) showed a longer median overall survival when compared to CMML-F (24.79 months versus 20.43 months; p=0.67), but it was not statistically significant. One of the 8 CMML-F patients had AML transformation (12.5%), similar to the 9 out of 82 CMML patients without fibrosis (11%). One of 2 patients (50%) with collagen fibrosis showed leukemic transformation, higher than the transformation rate in non-collagen fibrosis patients (11%; p=0.21). The most common mutations in CMML-F were: ASXL1 (25%), SRSF2 (25%), JAK2 (16.7%), and TET2 (16.7%). The most common mutations in non-CMML-F were: TET2 (60%), ASXL1 (45%), SRSF2 (38%), and RUNX1 (19%). Of note, TET2 mutations was less likely to occur in CMML-F (p=0.008). The average marrow blast percentage in CMML-F was 4.2% while in non-CMML-f was 8.6% (p=0.25). Conclusions: In this study we demonstrate that CMML-F is less likely to harbor TET2 mutations than CMML without fibrosis. However, unlike MDS, the presence of moderate-to-severe fibrosis does not correlate with worse prognosis in CMML. Large cohorts warranted to identify novel prognostic markers that could be incorporated into risk stratification schemas. Disclosures Kuykendall: Incyte: Honoraria, Speakers Bureau; Janssen: Consultancy; Abbvie: Honoraria; Celgene: Honoraria. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:JAZZ: Consultancy; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau.

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