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Published in: Annals of Hematology 7/2018

01-07-2018 | Original Article

Association of bone marrow fibrosis with inferior survival outcomes in chronic myelomonocytic leukemia

Authors: Maliha Khan, Tariq Muzzafar, Hagop Kantarjian, Ifra Badar, Nicholas Short, Xuemei Wang, Kamal Chamoun, Preetesh Jain, Courtney DiNardo, Naveen Pemmaraju, Prithviraj Bose, Gautam Borthakur, Jorge Cortes, Srdan Verstovsek, Guillermo Garcia-Manero, Zeev Estrov

Published in: Annals of Hematology | Issue 7/2018

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Abstract

The impact of bone marrow fibrosis grade on the prognosis of patients with chronic myelomonocytic leukemia (CMML) remains controversial. Therefore, we examined the records of 82 patients diagnosed with CMML at our institution and summarized baseline characteristics and molecular profiles by subgroups of absent or mild (grades 0/1) and moderate (grade 2) fibrosis. Cox proportional hazards models were constructed to assess the prognostic significance of fibrosis grade. Grade 2 fibrosis was identified in 63 patients (76.8%), grade 1 in 16 patients (19.5%), and grade 0 in 3 patients (3.7%). Grade 2 fibrosis was associated with reduced hemoglobin levels (median 9.75 vs 11.0 g/dL in grade 0/1; p = 0.04) and increased percentages of ringed sideroblasts (7.5 vs 0%; p = 0.008). In multivariable analysis, grade 2 fibrosis was an independent predictor of poor overall survival (OS; 95% CI 1.32–6.35; HR 2.90; p = 0.008), but not event-free survival (EFS; 95% CI 0.62–2.67; HR 1.28; p = 0.50). Absolute neutrophil count (ANC) was found to impact OS (95% CI 1.01–1.09; HR 1.05; p = 0.009), while both ANC (95% CI 1.00–1.07; HR 1.04; p = 0.04) and peripheral blood blast percentage (95% CI 1.02–1.32; HR 1.16; p = 0.02) impacted EFS. These results implicate fibrosis grade is an important indicator of prognosis, with high-grade fibrosis predicting inferior survival. Given the prevalence of marrow fibrosis in CMML, fibrosis grading should be incorporated into prognostic assessment and therapeutic decision-making.
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Literature
1.
go back to reference Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. (2008) WHO classification of tumours of haematopoietic and lymphoid tissues. IARC: Lyon Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. (2008) WHO classification of tumours of haematopoietic and lymphoid tissues. IARC: Lyon
2.
go back to reference Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C (1982) Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51:189–199CrossRefPubMed Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C (1982) Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51:189–199CrossRefPubMed
3.
go back to reference Padron E, Komrokji R, List AF (2014) The clinical management of chronic myelomonocytic leukemia. Clin Adv Hematol Oncol 12(3):172–178PubMed Padron E, Komrokji R, List AF (2014) The clinical management of chronic myelomonocytic leukemia. Clin Adv Hematol Oncol 12(3):172–178PubMed
4.
go back to reference Verstovsek S, Manshouri T, Pilling D, Bueso-Ramos CE, Newberry KJ, Prijic S, Knez L, Bozinovic K, Harris DM, Spaeth EL, Post SM, Multani AS, Rampal RK, Ahn J, Levine RL, Creighton CJ, Kantarjian HM, Estrov Z (2016) Role of neoplastic monocyte-derived fibrocytes in primary myelofibrosis. J Exp Med 213(9):1723–1740CrossRefPubMedPubMedCentral Verstovsek S, Manshouri T, Pilling D, Bueso-Ramos CE, Newberry KJ, Prijic S, Knez L, Bozinovic K, Harris DM, Spaeth EL, Post SM, Multani AS, Rampal RK, Ahn J, Levine RL, Creighton CJ, Kantarjian HM, Estrov Z (2016) Role of neoplastic monocyte-derived fibrocytes in primary myelofibrosis. J Exp Med 213(9):1723–1740CrossRefPubMedPubMedCentral
5.
go back to reference Thiele J, Kvasnicka HM, Facchetti F, Franco V, van der Walt J, Orazi A (2005) European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica 90(8):1128–1132PubMed Thiele J, Kvasnicka HM, Facchetti F, Franco V, van der Walt J, Orazi A (2005) European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica 90(8):1128–1132PubMed
7.
go back to reference Hammond D, Jamali M, Wells RA, Zhang L, Mamedov A, Lenis M, Buckstein R (2016) Impact of bone marrow fibrosis in MDS patients treated with azacitidine. Blood 128:4339 Hammond D, Jamali M, Wells RA, Zhang L, Mamedov A, Lenis M, Buckstein R (2016) Impact of bone marrow fibrosis in MDS patients treated with azacitidine. Blood 128:4339
8.
go back to reference Santos FPS, Schlette E, Kantarjian H, Sargent R, Garcia-Manero G, Verstovsek S, Kadia T, Jabbour E, Pierce S, Borthakur G (2009) Myelodysplastic syndrome with fibrosis: experience of a single-institution with 139 patients. Blood 114:2775 Santos FPS, Schlette E, Kantarjian H, Sargent R, Garcia-Manero G, Verstovsek S, Kadia T, Jabbour E, Pierce S, Borthakur G (2009) Myelodysplastic syndrome with fibrosis: experience of a single-institution with 139 patients. Blood 114:2775
9.
go back to reference Tadmor T, Shvidel L, Aviv A, Ruchlemer R, Bairey O, Yuklea M, Herishanu Y, Braester A, Rahimi-Levene N, Vernea F, Ben-Ezra J, Bejar J, Polliack A, Israeli CLL Study Group (2013) Significance of bone marrow reticulin fibrosis in chronic lymphocytic leukemia at diagnosis: a study of 176 patients with prognostic implications. Cancer 119(10):1853–1859CrossRefPubMed Tadmor T, Shvidel L, Aviv A, Ruchlemer R, Bairey O, Yuklea M, Herishanu Y, Braester A, Rahimi-Levene N, Vernea F, Ben-Ezra J, Bejar J, Polliack A, Israeli CLL Study Group (2013) Significance of bone marrow reticulin fibrosis in chronic lymphocytic leukemia at diagnosis: a study of 176 patients with prognostic implications. Cancer 119(10):1853–1859CrossRefPubMed
10.
go back to reference Maschek H, Gutzmer R, Choritz H, Georgii A (1994) Life expectancy in primary myelodysplastic syndromes: a prognostic score based upon histopathology from bone marrow biopsies of 569 patients. Eur J Haematol, 1994;53:280–287 Maschek H, Gutzmer R, Choritz H, Georgii A (1994) Life expectancy in primary myelodysplastic syndromes: a prognostic score based upon histopathology from bone marrow biopsies of 569 patients. Eur J Haematol, 1994;53:280–287
11.
go back to reference Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079–2088PubMed Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079–2088PubMed
12.
go back to reference Malcovati L, Germing U, Kuendgen A, Della Porta MG, Pascutto C, Invernizzi R, Giagounidis A, Hildebrandt B, Bernasconi P, Knipp S, Strupp C, Lazzarino M, Aul C, Cazzola M (2007) Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J ClinOncol 25:3503–3510CrossRef Malcovati L, Germing U, Kuendgen A, Della Porta MG, Pascutto C, Invernizzi R, Giagounidis A, Hildebrandt B, Bernasconi P, Knipp S, Strupp C, Lazzarino M, Aul C, Cazzola M (2007) Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J ClinOncol 25:3503–3510CrossRef
13.
go back to reference Thiele J, Kvasnicka HM (2006) Grade of bone marrow fibrosis is associated with relevant hematological findings—a clinicopathological study on 865 patients with chronic idiopathic myelofibrosis. Ann Hematol 85(4):226–232CrossRefPubMed Thiele J, Kvasnicka HM (2006) Grade of bone marrow fibrosis is associated with relevant hematological findings—a clinicopathological study on 865 patients with chronic idiopathic myelofibrosis. Ann Hematol 85(4):226–232CrossRefPubMed
14.
go back to reference Rao DS, Shih MS, Mohini R (1993) Effect of serum parathyroid hormone and bone marrow fibrosis on the response to erythropoietin in uremia. N Engl J Med 328(3):171–175CrossRefPubMed Rao DS, Shih MS, Mohini R (1993) Effect of serum parathyroid hormone and bone marrow fibrosis on the response to erythropoietin in uremia. N Engl J Med 328(3):171–175CrossRefPubMed
15.
go back to reference Such E, Senent L, Nomdedeu B et al (2009) Chronic myelomonocytic leukemia (CMML) with more than 15% of ring sideroblasts in bone marrow: an overlapping disorder between CMML and refractory anemia with ring sideroblasts. Blood 114:290CrossRef Such E, Senent L, Nomdedeu B et al (2009) Chronic myelomonocytic leukemia (CMML) with more than 15% of ring sideroblasts in bone marrow: an overlapping disorder between CMML and refractory anemia with ring sideroblasts. Blood 114:290CrossRef
16.
go back to reference Hasegawa Y, Sakai N, Toyama M, Ninomiya H, Abe T (1990) Chronic myelomonocytic leukemia transformed from refractory anemia with ring sideroblasts with a rare abnormal chromosome, inv (12). RinshoKetsueki 31(1):75–79 Hasegawa Y, Sakai N, Toyama M, Ninomiya H, Abe T (1990) Chronic myelomonocytic leukemia transformed from refractory anemia with ring sideroblasts with a rare abnormal chromosome, inv (12). RinshoKetsueki 31(1):75–79
17.
go back to reference Schmitt-Graeff A, Thiele J, Zuk I, Kvasnicka HM (2002) Essential thrombocythemia with ringed sideroblasts: a heterogeneous spectrum of diseases, but not a distinct entity. Haematologica 87(4):392–399PubMed Schmitt-Graeff A, Thiele J, Zuk I, Kvasnicka HM (2002) Essential thrombocythemia with ringed sideroblasts: a heterogeneous spectrum of diseases, but not a distinct entity. Haematologica 87(4):392–399PubMed
18.
go back to reference Lambertenghi-Deliliers G, Orazi A, Luksch R, Annaloro C, Soligo D (1991) Myelodysplastic syndrome with increased marrow fibrosis: a distinct clinico-pathological entity. Br J Haemato l78(2):161–166CrossRef Lambertenghi-Deliliers G, Orazi A, Luksch R, Annaloro C, Soligo D (1991) Myelodysplastic syndrome with increased marrow fibrosis: a distinct clinico-pathological entity. Br J Haemato l78(2):161–166CrossRef
19.
go back to reference Scott BL, Storer BE, Greene JE, Hackman RC, Appelbaum FR, Deeg HJ (2007) Marrow fibrosis as a risk factor for posttransplantation outcome in patients with advanced myelodysplastic syndrome or acute myeloid leukemia with multilineage dysplasia. Biol Blood Marrow Transplant 13(3):345–354CrossRefPubMed Scott BL, Storer BE, Greene JE, Hackman RC, Appelbaum FR, Deeg HJ (2007) Marrow fibrosis as a risk factor for posttransplantation outcome in patients with advanced myelodysplastic syndrome or acute myeloid leukemia with multilineage dysplasia. Biol Blood Marrow Transplant 13(3):345–354CrossRefPubMed
20.
go back to reference Della Porta MG, Malcovati L, Boveri E, Travaglino E, Pietra D, Pascutto C, Passamonti F, Invernizzi R, Castello A, Magrini U, Lazzarino M, Cazzola M (2009) Clinical relevance of bone marrow fibrosis and CD34-positive cell clusters in primary myelodysplastic syndromes. J ClinOncol 27(5):754–762CrossRef Della Porta MG, Malcovati L, Boveri E, Travaglino E, Pietra D, Pascutto C, Passamonti F, Invernizzi R, Castello A, Magrini U, Lazzarino M, Cazzola M (2009) Clinical relevance of bone marrow fibrosis and CD34-positive cell clusters in primary myelodysplastic syndromes. J ClinOncol 27(5):754–762CrossRef
21.
go back to reference Campbell PJ, Bareford D, Erber WN, Wilkins BS, Wright P, Buck G, Wheatley K, Harrison CN, Green AR (2009) Reticulin accumulation in essential thrombocythemia: prognostic significance and relationship to therapy. J Clin Oncol 27(18):2991–2999CrossRefPubMedPubMedCentral Campbell PJ, Bareford D, Erber WN, Wilkins BS, Wright P, Buck G, Wheatley K, Harrison CN, Green AR (2009) Reticulin accumulation in essential thrombocythemia: prognostic significance and relationship to therapy. J Clin Oncol 27(18):2991–2999CrossRefPubMedPubMedCentral
22.
go back to reference Machherndl-Spandl S, Sega W, Bösmüller H, Germing U, Gruber CH, Nachtkamp K, Reinecke P, Sperr WR, Wimazal F, Müllauer L, Sotlar K, Horny HP, Tüchler H, Valent P, Krieger O (2014) Prognostic impact of blast cell counts in dysplastic bone marrow disorders (MDS and CMML I) with concomitant fibrosis. Ann Hematol 93(1):57–64CrossRefPubMed Machherndl-Spandl S, Sega W, Bösmüller H, Germing U, Gruber CH, Nachtkamp K, Reinecke P, Sperr WR, Wimazal F, Müllauer L, Sotlar K, Horny HP, Tüchler H, Valent P, Krieger O (2014) Prognostic impact of blast cell counts in dysplastic bone marrow disorders (MDS and CMML I) with concomitant fibrosis. Ann Hematol 93(1):57–64CrossRefPubMed
23.
go back to reference Padron E, Garcia-Manero G, Patnaik MM, Itzykson R, Lasho T, Nazha A, Rampal RK, Sanchez ME, Jabbour E, Al Ali NH, Thompson Z, Colla S, Fenaux P, Kantarjian HM, Killick S, Sekeres MA, List AF, Onida F, Komrokji RS, Tefferi A, Solary E (2015) An international data set for CMML validates prognostic scoring systems and demonstrates a need for novel prognostication strategies. Blood Cancer J 5:e333CrossRefPubMedPubMedCentral Padron E, Garcia-Manero G, Patnaik MM, Itzykson R, Lasho T, Nazha A, Rampal RK, Sanchez ME, Jabbour E, Al Ali NH, Thompson Z, Colla S, Fenaux P, Kantarjian HM, Killick S, Sekeres MA, List AF, Onida F, Komrokji RS, Tefferi A, Solary E (2015) An international data set for CMML validates prognostic scoring systems and demonstrates a need for novel prognostication strategies. Blood Cancer J 5:e333CrossRefPubMedPubMedCentral
24.
go back to reference Such E, Cervera J, Costa D, Solé F, Vallespí T, Luño E, Collado R, Calasanz MJ, Hernández-Rivas JM, Cigudosa JC, Nomdedeu B, Mallo M, Carbonell F, Bueno J, Ardanaz MT, Ramos F, Tormo M, Sancho-Tello R, del Cañizo C, Gómez V, Marco V, Xicoy B, Bonanad S, Pedro C, Bernal T, Sanz GF (2011) Cytogenetic risk stratification in chronic myelomonocytic leukemia. Haematologica 96(3):375–383CrossRefPubMed Such E, Cervera J, Costa D, Solé F, Vallespí T, Luño E, Collado R, Calasanz MJ, Hernández-Rivas JM, Cigudosa JC, Nomdedeu B, Mallo M, Carbonell F, Bueno J, Ardanaz MT, Ramos F, Tormo M, Sancho-Tello R, del Cañizo C, Gómez V, Marco V, Xicoy B, Bonanad S, Pedro C, Bernal T, Sanz GF (2011) Cytogenetic risk stratification in chronic myelomonocytic leukemia. Haematologica 96(3):375–383CrossRefPubMed
Metadata
Title
Association of bone marrow fibrosis with inferior survival outcomes in chronic myelomonocytic leukemia
Authors
Maliha Khan
Tariq Muzzafar
Hagop Kantarjian
Ifra Badar
Nicholas Short
Xuemei Wang
Kamal Chamoun
Preetesh Jain
Courtney DiNardo
Naveen Pemmaraju
Prithviraj Bose
Gautam Borthakur
Jorge Cortes
Srdan Verstovsek
Guillermo Garcia-Manero
Zeev Estrov
Publication date
01-07-2018
Publisher
Springer Berlin Heidelberg
Published in
Annals of Hematology / Issue 7/2018
Print ISSN: 0939-5555
Electronic ISSN: 1432-0584
DOI
https://doi.org/10.1007/s00277-018-3289-6

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