The prognostic relevance of serum lactate dehydrogenase and mild bone marrow reticulin fibrosis in essential thrombocythemia

Transcription

1 Received: 3 February 2017 Revised: 13 February 2017 Accepted: 14 February 2017 DOI: /ajh RESEARCH ARTICLE The prognostic relevance of serum lactate dehydrogenase and mild bone marrow reticulin fibrosis in essential thrombocythemia Mythri Mudireddy 1 Daniela Barraco 1 Curtis A. Hanson 2 Animesh Pardanani 1 Naseema Gangat 1 Ayalew Tefferi 1 1 Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota; 2 Division of Hematopathology, Department of Laboratory Medicine, Mayo Clinic, Rochester, Minnesota Correspondence Ayalew Tefferi, Division of Hematology, Department of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN tefferi.ayalew@mayo.edu Abstract The 2016 World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms (MPN) underscore the prognostically-relevant distinction between essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (pre-pmf). In addition, leukocytosis has been identified as an important prognostic marker in otherwise WHO-defined ET. However, controversy remains regarding the objectivity of morphologic criteria in distinguishing ET from pre-pmf and the precise prognostic cutoff values for leukocytosis. Serum lactate dehydrogenase (LDH) level might be a biologically more accurate measure of leukocyte turnover and a more sensitive marker of pre-pmf, in otherwise WHO-defined ET. In the current study of 183 consecutive patients with WHO-defined ET, the presence of grade 1 bone marrow (BM) fibrosis did not affect presenting clinical or laboratory features; in contrast, increased serum LDH at diagnosis was associated with leukocytosis (p 5.002), thrombocytosis (p <.001), palpable splenomegaly (p 5.03) and higher international prognostic score (IPSET) (p 5.002); serum LDH did not correlate with BM fibrosis, JAK2/CALR/ MPL or TET2/ASXL1 mutations. In univariate analysis, risk factors for survival included age 60 years (p 5.002; HR 10.2, 95% CI ), male sex (p 5.02; HR 3.2, 95% CI ), leukocyte count /L (p 5.007; HR 4.7, 95% CI ), and increased serum LDH (p 5.002; HR 3.7, 95% CI ), but not BM fibrosis (p 5.17). In multivariable analysis, age, sex and serum LDH remained significant; serum LDH also remained significant, in the context of IPSET (p 5.003) and in patients with leukocytosis (p 5.003). We conclude that serum LDH level carries an independent prognostic value for survival in ET and might represent a biologically more accurate surrogate for leukocytosis. 1 INTRODUCTION Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm (MPN) characterized by proliferation of enlarged and mature megakaryocytes, without significant abnormalities in granulopoiesis or erythropoiesis. 1 The 2016 World Health Organization (WHO) diagnostic criteria for ET include platelet count of /L, demonstration of JAK2, MPL, or CALR mutations, and exclusion of other myeloid neoplasms and causes of reactive thrombocytosis. 1 The distribution of JAK2, CALR, andmpl mutations in ET are 55, 25, and 3%, respectively; approximately 17% are triple-negative. 2 Clinical course of patients with ET may be complicated by arterial or venous thrombosis and, in the long term by fibrotic and leukemic transformations. 3 ET shares certain bone marrow histological, clinical phenotype, and molecular markers, with early/prefibrotic primary myelofibrosis (pre-pmf). 2,4 In a landmark study of 1104 patients with presumed ET, the International Working Group for MPN Research and Treatment (IWG-MRT) identified 180 (16%) patients in whom the diagnosis was revised into pre-pmf, after a central pathologic review. 5 More importantly, the study showed significantly worse overall (OS), leukemia-free (LFS) and myelofibrosis-free (MFFS) survival in patients with pre-pmf, compared to those with WHO-defined ET. 5 This prognostically-relevant distinction between pre-pmf and ET has since been endorsed by both the 2008 and 2016 WHO documents. 1,6 In a subsequent study of the 891 patients with WHO-defined ET, the IWG-MRT identified advanced age 454 VC 2017 Wiley Periodicals, Inc. wileyonlinelibrary.com/journal/ajh Am J Hematol. 2017;92:

2 MUDIREDDY ET AL. 455 (60 years), leukocytosis ( /L) and history of thrombosis as risk factors for inferior survival. 7 The above-mentioned two IWG-MRT studies have established the prognostic importance of prefibrotic morphology and leukocytosis in ET. However, controversy remains regarding the objectivity of megakaryocyte morphology in distinguishing ET from pre-pmf 5,8 14 and the precise cutoff values for leukocytosis. 5,11,15,16 Accordingly, we hypothesized that serum LDH level might be a biologically more accurate measure of leukocyte turnover as well as a more sensitive marker of pre-pmf, and therefore explored its independent prognostic relevance in the current study. 2 METHODS The current study was approved by the institutional review board of the Mayo Clinic (Rochester, MN, USA). Study patients were selected from our institutional database of MPN with diagnosis of ET fulfilling the 2008 WHO criteria. 6 The degree of BM reticulin fibrosis was based on real life BM reports at the time of initial diagnosis from Mayo clinic hematopathologists in accordance with the European consensus scoring system. 17 Patients with BM fibrosis grade 2 were excluded from study, in order to further minimize the inadvertent inclusion of patients with pre-pmf. Serum LDH (institutional reference range: U/L) levels were obtained at the time of diagnosis or within 12 months of diagnosis in the absence of any treatment. Screening for JAK2, CALR, MPL, ASXL1, and TET2 mutations was performed according to previously described methods. 18,19 Statistical analyses considered clinical and laboratory data collected at the time of diagnosis or referral to the Mayo Clinic. Differences in the distribution of continuous variables between categories were analyzed by Mann Whitney test. Patient groups with nominal variables were compared by v 2 test. OS was calculated from the date of diagnosis to the date of death (uncensored) or last contact (censored). Thrombosis-free survival (TFS), MFFS, and LFS were calculated from the date of diagnosis to the date of development of thrombotic complication, progression into myelofibrosis, and leukemic transformation (uncensored), respectively, or last contact/date of death (censored). Survival curves were prepared by the Kaplan-Meier method and compared by the log-rank test. The Cox proportional hazard regression model was applied for multivariable survival analysis. p values <0.05 were considered significant. The Stat View (SAS Institute, Cary, NC) statistical package was used for all calculations. 3 RESULTS 3.1 Patient characteristics A total of 183 patients (57% females) with median age of 59 years met the above-outlined criteria and were all evaluable for the degree of BM reticulin fibrosis. Median levels of hemoglobin, platelets, and leukocytes for the 183 study patients were 14 g/dl, /L and /L, respectively. Palpable splenomegaly was reported in 15% patients and 12% displayed leukoerythroblastosis (LES) defined by the presence of at least 1% immature myeloid cells or nucleated red blood cells, in the peripheral blood smear. Driver mutational status was JAK2 in 72%, CALR 17%, MPL 2%, and triple-negative in 9%. Thrombosis history at diagnosis was obtained from 13% of the patients and 12% experienced at least one thrombotic event after the time of diagnosis. Risk stratification according to the International Prognostic Scoring System for ET (IPSET) 7 was 19% high, 43% intermediate and 38% low. Grading of BM reticulin fibrosis was documented in all 183 study patients: 113 (62%) were assigned grade 0 and 70 (38%) grade 1. Serum LDH information at the time of diagnosis was available in 110 patients (median value 194 U/L) and increased in 31 (28%) patients. Mutational status for TET2 and ASXL1 was available in 77 patients with mutational frequencies of 8% each. 3.2 Clinical and laboratory correlates for BM reticulin fibrosis, grade 1 Table 1 provides a comparative illustration of clinical and laboratory features of 183 patients with ET stratified by grade 0 or grade 1 BM fibrosis. We found no significant difference between patients with or without BM fibrosis in terms of various clinical and laboratory findings at diagnosis, including age (p 5.91), sex (p 5.94), hemoglobin level (p 5.96), leukocyte count (p 5.18), leukocytosis /L (p 5.48), platelet count (p 5.34), driver mutational status (p 5.84), presence of LES (p 5.43), presence of palpable splenomegaly (p 5.57), thrombosis history (p 5.92), or serum LDH (p 5.36). 3.3 Clinical and laboratory correlates for increased serum LDH level Table 2 provides a comparative illustration of clinical and laboratory features of 110 patients with ET stratified by increased or normal serum LDH. We found a direct correlation of increased serum LDH with increased leukocyte count (p 5.002), leukocytosis /L (p 5.01), increased platelet count (p <.001), presence of palpable splenomegaly (p 5.03) and higher IPSET score (p 5.002). There were no significant correlations with age (p 5.56), sex (p 5.56), hemoglobin level (p 5.9), presence of LES (p 5.11), driver mutational status (p 5.4), TET2/ASXL1 mutations or thrombosis history (p 5.07). 3.4 Survival analysis After a median follow-up of 91 months (range months), 42 (23%) deaths, 2 (1%) leukemic transformations, 7 (4%) fibrotic progressions, and 22 (12%) thrombotic events were documented. In univariate analysis, the following were found to adversely affect OS: age 60 years (p 5.002; HR 10.2, 95% CI ), male sex (p 5.02; HR 3.2, 95% CI ), leukocyte count /L (p 5.007; HR 4.7, 95% CI ), and increased serum LDH (Figure 1A; p 5.002; HR 3.7, 95% CI ). Survival was not affected by BM reticulin fibrosis (Figure 1B; p 5.13), thrombosis history (p 5.66), platelet count (p 5.24), hemoglobin level (p 5.5), leukocyte count /L (p 5.09), presence of palpable splenomegaly (p 5.6), or driver mutational status (p 5.4). In multivariable analysis of survival, age, sex, and serum LDH

3 456 MUDIREDDY ET AL. TABLE 1 Presenting clinical and laboratory features of 183 patients with World Health Organization (WHO)-defined essential thrombocythemia, stratified by the presence or absence of grade 1 bone marrow reticulin fibrosis Variables All patients (n 5 183) Patients with bone marrow fibrosis, grade 1 (n 5 70, 38%) Patients without bone marrow fibrosis, grade 0 (n 5 113, 62%) P value Age in years; median (range) 59 (15-88) 59 (15-88) 59 (17-86) 0.91 Age 60 years; n (%) 89 (49%) 33 (47%) 56 (50%) 0.75 Females; n (%) 104 (57%) 40 (57%) 64 (57%) 0.94 Hemoglobin, g/dl; median (range) 14 ( ) 14 ( ) 14 ( ) 0.96 Leukocytes, /L; median (range) 8.5 ( ) 9.3 ( ) 8.2 ( ) 0.18 Leukocytes /L; n (%) 47 (26%) 20 (29%) 27 (24%) 0.48 Leukocytes /L; n (%) 17 (9%) 8 (11%) 9 (8%) 0.43 Platelets, /L; median (range) 812 ( ) 813 ( ) 811 ( ) 0.34 Platelets >1, /L; n (%) 51 (28%) 18 (26%) 33 (29%) 0.6 Driver mutation status 0.84 JAK2 mutated; n (%) 131 (72%) 51 (73%) 80 (71%) CALR mutated; n (%) 31 (17%) 12 (17%) 19 (17%) MPL mutated; n (%) 4 (2%) 2 (3%) 2 (2%) Triple negative; n (%) 17 (9%) 5 (7%) 12 (11%) ASXL1 and TET2 mutations N evaluable (8%) 2 (7%) 4 (9%) 0.8 ASXL1 mutated; n (%) 6 (8%) 2 (7%) 4 (9%) 0.8 TET2 mutated; n (%) Leukoerthroblastosis present; n (%) N evaluable Serum LDH level; median U/L (range) N evaluable Increased serum LDH; n (%) N evaluable Palpable splenomegaly at diagnosis; n (%) 19 (12%) 9 (14%) 10 (10%) ( ) 198 ( ) 191 ( ) (28%) 11 (30%) 20 (28%) (15%) 9 (13%) 18 (16%) 0.57 IPSET 0.5 Low; n (%) 69 (38%) 24 (34%) 45 (40%) Intermediate; n (%) 79 (43%) 34 (49%) 45 (40%) High; n (%) 35 (19%) 12 (17%) 23 (20) Thrombosis at or before diagnosis; n (%) 23 (13%) 9 (13%) 14 (12%) 0.92 JAK2, Janus kinase 2; CALR, calreticulin; MPL, MPL proto-oncogene; ASXL1, additional sex combs 1; TET2, ten-eleven translocation 2; IPSET, International Prognostic Score for Essential Thrombocythemia; MF, myelofibrosis; LDH, lactate dehydrogenase. level remained significant (p , p 5.02, p 5.02, respectively); serum LDH level also remained significant for survival, in the context of IPSET (p 5.003; HR 4.4, 95% CI ), as well as in patients with leukocytosis, analyzed separately (Figure 2A,B; p 5.17 and p 5.003, respectively). The number of informative cases with leukemic (n 5 2) or fibrotic (n 5 7) were too small to allow valid statistical analysis for LFS or MFFS, whereas increased serum LDH did not appear to influence TFS (p 5.58). 4 DISCUSSION The key finding in the current study was the identification of serum LDH as an independent prognostic factor in WHO-defined ET. Prior studies have shown that serum LDH may be increased in ET, but none have systematically evaluated its prognostic impact. This is a practically appealing observation because the particular laboratory test is widely available and inexpensive. The current study also suggested

4 MUDIREDDY ET AL. 457 TABLE 2 Presenting clinical and laboratory features of 110 patients with World Health Organization (WHO)-defined essential thrombocythemia, stratified by the presence or absence of increased serum lactate dehydrogenase Variables All patients (n 5 110) Patients with normal LDH (n 5 79, 72%) Patients with increased LDH (n 5 31, 28%) P value Age at diagnosis in years; median (range) 59 (15-87) 59 (18-87) 63 (15-85) 0.56 Age 60 years; n (%) 53 (48%) 34 (43%) 19 (61%) 0.08 Females; n (%) 65 (59%) 48 (61%) 17 (55%) 0.56 Hemoglobin, g/dl;median (range) 14.1 ( ) 14.1 ( ) 14.1 ( ) 0.9 Leukocytes, /L;median (range) 8.3 ( ) 7.8 ( ) 10 ( ) Leukocytes /L; n (%) 25 (23%) 13 (16%) 12 (39%) Leukocytes /L; n (%) 7 (6%) 3 (4%) 4 (13%) 0.08 Platelets, /L; median (range) 802 ( ) 765 ( ) 1063 ( ) Platelets >1, /L; n (%) 32 (29%) 15 (19%) 17 (55%) Driver mutation status 0.4 JAK2 mutated; n (%) 84 (76%) 62 (78%) 22 (71%) CALR mutated; n (%) 14 (13%) 8 (10%) 6 (19%) MPL mutated; n (%) 3 (3%) 3 (4%) 0 (0%) Triple negative; n (%) 9 (8%) 6 (8%) 3 (10%) ASXL1 and TET2 mutations N evaluable (8%) 2 (5%) 2 (15%) 0.2 ASXL1 mutated; n (%) 4 (8%) 3 (8%) 1 (8%) - TET2 mutated; n (%) Leukoerythroblastosis present; n (%) N evaluable (12%) 7 (9%) 6 (20%) 0.11 Palpable splenomegaly at diagnosis; n (%) 13 (12%) 6 (8%) 7 (23%) IPSET Low; n (%) 44 (40%) 35 (44%) 9 (29%) Intermediate; n (%) 46 (42%) 36 (46%) 10 (32%) High; n (%) 20 (18%) 8 (10%) 12 (39%) Thrombosis at or before diagnosis; n (%) 12 (11%) 6 (8%) 6 (19%) 0.07 Bone marrow reticulin fibrosis; n (%) 0.9 Grade 0 72 (65%) 52 (66%) 20 (65%) Grade 1 38 (35%) 27 (34%) 11 (35%) JAK2, Janus kinase 2; CALR, calreticulin; MPL, MPL proto-oncogene; ASXL1, additional sex combs 1; TET2, ten-eleven translocation 2; IPSET, International Prognostic Score for Essential Thrombocythemia; MF, myelofibrosis. that serum LDH might supersede leukocyte count in its prognostic value and this might be related to its property as a biologically more accurate measure of cell turnover; in the current study, serum LDH was the only independent risk factor for survival, other than age and sex, and its prognostic effect was shown to be independent of leukocyte count and most apparent in patients with leukocytosis. It is also possible that increased serum LDH is a more sensitive marker of occult pre-pmf. Consistent with the latter contention, a study from the IWG-MRT that included 536 patients in the test cohort and 321 patients in a validation cohort examined the discriminatory power of several laboratory parameters, including serum LDH, and found the latter to have the best performance in distinguishing pre-pmf from WHO-defined ET. 25 The observations in the current study carry the potential to significantly affect current models of prognostication in ET and possibly other MPN. At present, risk stratification for survival in ET is according

5 458 MUDIREDDY ET AL. FIGURE 1 (A) Overall survival in 110 patients with World Health Organization-defined essential thrombocythemia, stratified by the presence or absence of increased serum lactate dehydrogenase (LDH). (B) Overall survival in 183 patients with World Health Organization-defined essential thrombocythemia, stratified by the presence or absence of grade 1 of bone marrow reticulin fibrosis to the IPSET, which utilizes advanced age, leukocytosis, and history of thrombosis as adverse variables; 7 of note, driver mutational status has not been shown to affect OS in ET although JAK2/MPL mutated patients are at increased risk of thrombosis whereas MPL mutations might increase the risk of fibrotic progression. 2,26 The current study introduces sex and serum LDH as independent risk factors whose inclusion in future prognostic models might undermine the prognostic contribution from leukocytosis or thrombosis. At the same time, we are acutely aware of possible confounding of LDH-based risk stratification by co-morbidities that might be associated with increased LDH, such as liver disease. It is, therefore, important to consider the current findings as being preliminary and in need of validation by additional studies that are designed to offset potential test limitations. Future studies should also include adequate numbers of informative cases with leukemic and fibrotic progressions, as well as thrombotic events, in order to assess LDH impact on such events, in the context of previously identified risk factors for thrombosis (advanced age, presence of JAK2V617F and MPL, and history of thrombosis), 2,15 leukemic transformation (thrombosis history, platelets >1 million/ll, leukocytosis, age >60 years) 5,16,27 and fibrotic progression (anemia, age >60 years, male sex, increased BM reticulin fibrosis, presence of MPL mutation, and elevated serum LDH) Unlike the case with serum LDH, and mostly consistent with previous observations, 31,32 the presence of mild BM reticulin fibrosis was of limited value in predicting survival in the current study. This observation is similar to polycythemia vera (PV) studies performed by our group and the IWG-MRT, in which mild BM fibrosis has no impact on OS. 28,30 Previous reports have shown that reticulin grade at diagnosis was correlated with increased leukocyte count, platelet count, arterial thrombosis, major hemorrhage and higher risk of fibrotic transformation. 31,32 These observations were not reproduced in the current study but this might be related to the small sample size, especially in terms of informative cases. Serum LDH was not fractionated into isoenzymes for the current study. However, a prior study has shown increased LDH3 in ET patients suggesting the value of LDH isoenzyme fractionation. 20 Regardless, the systematic inclusion of serum LDH in future studies should help clarify not only its independent prognostic role but also its prognostic interaction with bone marrow fibrosis. FIGURE 2 (A) Effect of serum lactate dehydrogenase (LDH) on overall survival in 136 World Health Organization-defined essential thrombocythemia patients with normal white blood cell count. (B) Effect of serum lactate dehydrogenase (LDH) on overall survival in 47 World Health Organization-defined essential thrombocythemia patients with leukocytosis /L

6 MUDIREDDY ET AL. 459 REFERENCES [1] Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127: [2] Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol. 2017;92: [3] Tefferi A, Pardanani A. Myeloproliferative neoplasms: A contemporary review. JAMA Oncol. 2015;1: [4] Barosi G, Rosti V, Bonetti E, et al. Evidence that prefibrotic myelofibrosis is aligned along a clinical and biological continuum featuring primary myelofibrosis. PloS One. 2012;7. [5] Barbui T, Thiele J, Passamonti F, et al. Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: An international study. J Clin Oncol. 2011;29: [6] Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes. Blood. 2009;114: [7] Passamonti F, Thiele J, Girodon F, et al. A prognostic model to predict survival in 867 World Health Organization-defined essential thrombocythemia at diagnosis: A study by the International Working Group on Myelofibrosis Research and Treatment. Blood. 2012; 120: [8] Barbui T, Thiele J, Vannucchi AM, et al. Myeloproliferative neoplasms: Morphology and clinical practice. Am J Hematol. 2016;91: [9] Tefferi A. Primary myelofibrosis: 2014 update on diagnosis, riskstratification, and management. Am J Hematol. 2014;89: [10] Barbui T, Thiele J, Vannucchi AM, et al. Rationale for revision and proposed changes of the WHO diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis. Blood Cancer J. 2015;5:e337. [11] Thiele J, Kvasnicka HM, Mullauer L, et al. Essential thrombocythemia versus early primary myelofibrosis: A multicenter study to validate the WHO classification. Blood. 2011;117: [12] Marcinek J, Plank L, Szepe P, et al. Fibrosis identified in the bone marrow biopsies of patients with essential thrombocythemia: Its incidence and significance for the differential diagnostic considerations. Cesk Patol. 2008;44: [13] Wilkins BS, Erber WN, Bareford D, et al. Bone marrow pathology in essential thrombocythemia: Interobserver reliability and utility for identifying disease subtypes. Blood. 2008;111: [14] Brousseau M, Parot-Schinkel E, Moles MP, et al. Practical application and clinical impact of the WHO histopathological criteria on bone marrow biopsy for the diagnosis of essential thrombocythemia versus prefibrotic primary myelofibrosis. Histopathology. 2010;56: [15] Barbui T, Vannucchi AM, Buxhofer-Ausch V, et al. Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHOdefined essential thrombocythemia. Blood Cancer J. 2015;5:e369. [16] Gangat N, Wolanskyj AP, McClure RF, et al. Risk stratification for survival and leukemic transformation in essential thrombocythemia: A single institutional study of 605 patients. Leukemia. 2007;21: [17] Thiele J, Kvasnicka HM, Facchetti F, et al. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica. 2005;90: [18] Vannucchi AM, Lasho TL, Guglielmelli P, et al. Mutations and prognosis in primary myelofibrosis. Leukemia. 2013;27: [19] Tefferi A, Wassie EA, Lasho TL, et al. Calreticulin mutations and long-term survival in essential thrombocythemia. Leukemia. 2014; 28: [20] Mazzotta S, Guerranti R, Gozzetti A, et al. Increased serum lactate dehydrogenase isoenzymes in Ph-negative chronic myeloproliferative diseases: a metabolic adaptation? Hematology. 2006;11: [21] Hoffbrand AV, Kremenchuzky S, Butterworth PJ, et al. Serum lactic dehydrogenase activity and folate deficiency in myelosclerosis and other haematological diseases. Br Med J. 1966;1: [22] Woodliff HJ, Lynch W. Serum lactic dehydrogenase activity in myeloproliferative and lymphoproliferative disorders. Med J Aust. 1967;1: [23] Budman DR, Lackner H, Berczeller P, et al. The diagnostic value of the serum lactic dehydrogenase determination in the evaluation of unexplained thrombocytosis. Am J Clin Pathol. 1981;75: [24] Carcamo C, Pallares E, Rubi J, et al. Lactate dehydrogenase isoenzymes in patients with essential thrombocythemia. Thromb Res. 1993;70: [25] Carobbio A, Finazzi G, Thiele J, et al. Blood tests may predict early primary myelofibrosis in patients presenting with essential thrombocythemia. Am J Hematol. 2012;87: [26] Haider M, Elala YC, Gangat N, et al. MPL mutations and palpable splenomegaly are independent risk factors for fibrotic progression in essential thrombocythemia. Blood Cancer J. 2016;6:e487. [27] Passamonti F, Rumi E, Arcaini L, et al. Prognostic factors for thrombosis, myelofibrosis, and leukemia in essential thrombocythemia: A study of 605 patients. Haematologica. 2008;93: [28] Barbui T, Thiele J, Passamonti F, et al. Initial bone marrow reticulin fibrosis in polycythemia vera exerts an impact on clinical outcome. Blood. 2012;119: [29] Alvarez-Larran A, Cervantes F, Bellosillo B, et al. Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients. Leukemia. 2007;21: [30] Barraco D, Cerquozzi S, Hanson CA, Ketterling RP, et al. Prognostic impact of bone marrow fibrosis in polycythemia vera: Validation of the IWG-MRT study and additional observations. Blood Cancer J [31] Campbell PJ, Bareford D, Erber WN, et al. Reticulin accumulation in essential thrombocythemia: Prognostic significance and relationship to therapy. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27: [32] Abdulkarim K, Ridell B, Johansson P, et al. The impact of peripheral blood values and bone marrow findings on prognosis for patients with essential thrombocythemia and polycythemia vera. Eur J Haematol. 2011;86: How to cite this article: Mudireddy M, Barraco D, Hanson CA, Pardanani A, Gangat N, Tefferi A. The prognostic relevance of serum lactate dehydrogenase and mild bone marrow reticulin fibrosis in essential thrombocythemia. Am J Hematol. 2017;92: