Blastic Transformation in Mexican Population With Chronic Myelomonocytic Leukemia

Accepted Manuscript Blastic Transformation in Mexican Population with Chronic Myelomonocytic Leukemia Alfonso Rivera Duarte, Alejandra Armengol Alonso, Elena Sandoval Cartagena, Elena Tuna Aguilar PII:

S2152-2650(17)30820-0

DOI:

10.1016/j.clml.2017.06.029

Reference:

CLML 963

To appear in:

Clinical Lymphoma, Myeloma and Leukemia

Received Date: 26 May 2017 Accepted Date: 19 June 2017

Please cite this article as: Rivera Duarte A, Armengol Alonso A, Sandoval Cartagena E, Tuna Aguilar E, Blastic Transformation in Mexican Population with Chronic Myelomonocytic Leukemia, Clinical Lymphoma, Myeloma and Leukemia (2017), doi: 10.1016/j.clml.2017.06.029. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT BLASTIC TRANSFORMATION IN MEXICAN POPULATION WITH CHRONIC MYELOMONOCYTIC LEUKEMIA Alfonso Rivera Duarte1, Alejandra Armengol Alonso1, Elena Sandoval Cartagena2, Elena Tuna Aguilar1 1 Department Hematology-Oncology Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. 2 Universidad Anahuac México Norte.

RI PT

Corresponding author: Alfonso Rivera Duarte, [email protected] Authors address: Belisario Dominguez, seccion XVI, PC 14080, Mexico City.

AC C

EP

TE D

M AN U

SC

Background: Chronic myelomonocytic leukemia (CMML) is the most aggressive of chronic leukemias, with a short overall survival and a high transformation rate to acute leukemia. We investigated factors related to blastic transformation in Mexican population treated in a tertiary referral center. Methods: Records of patients diagnosed with CMML between 2000-2015 were reviewed; patients with incomplete data were excluded. IBM SPSS Statics 21.0 software was used to perform statistical analysis. Findings: 54 patients were included, with a median age of 71 years and an overall survival of 16 months. The rate of blastic transformation found was 33% (18 patients), with a time to progression of 9 (0-87) months. Comparing patients who didn’t underwent blastic transformation to those who did, those who progressed to acute leukemia tend to be younger (58 vs. 71 years, p=0.001), had a higher peripheral blood blast count (≥2% vs. 0%, p= 0·003), and where more likely to have immature myeloid precursors circulating in peripheral blood (94% vs. 64%, p=0.02). In multivariate analysis, age continued to be a statistically significant factor to progression (HR 0.97, 95% IC = 0·929-0·987). Interpretation: Mexican patients with CMML that progressed to overt acute leukemia were considerably younger, with a higher tumor burden and short overall survival. In this population, it is important to consider a more aggressive treatment at diagnosis, focusing in high dose chemotherapy and hematopoietic stem cell transplantation in a short term. Funding: None

INTRODUCTION

Chronic myelomonocytic leukemia (CMML) is a clonal, hematopoietic stem cell malignant disorder, characterized by overlapping features of both myeloprolifetative neoplasm and myelodisplasic syndrome (MDS). According to the 2016 WHO Classification the main characteristics are (1) persistent peripheral blood (PB) monocytosis (> 1 X 109/L) that account for more than 10% of the white cell blood differential count, (2) absence of Philadelphia chromosome, (3) absence of PDGFRA (Platelet derived growing factor receptorα) or PDGFRB (Platelet derived growing factor receptor-β) gene rearrangements (4) less than 20% blast and promonocytes in PB and bone marrow (BM), and (5) dysplasia involving one or more myeloid lineages. According to the newest WHO revision, this disease is further sub-classified into CMML-0 (<2% PB blast and

1

ACCEPTED MANUSCRIPT <5% BM blast), and CMML-1 (2-4% PB blast and 5-9% BM blast), and CMML-2 (5-19% PB blast and 10-19% BM blast or presence of Auer rods). 1,2 CMML is a rare disease of the old, with a median presentation age that ranges between 71-75 years, with a male predilection, and an annual incidence of 0.3 cases for 100,000 habitants. 3,4 Information regarding incidence in Latin America is unknown.

RI PT

CMML is considered the most aggressive of the chronic leukemias. The reported median overall survival is 30 months, being one of the main causes of death the underlying transformation risk to acute myeloid leukemia (AML), which occurs in 15-29% of cases. 5–9

M AN U

SC

Factors identified to be related with increased transformation risk to AML are; ASLX1 mutations, 10 high risk cytogenetic alterations (complex karyotype, alterations in chromosome 7, and chromosome 8 trisomy), 11 age older >65, CMML-2 subtype, high blast count in BM, hemoglobin <10 g/dL, absolute monocyte count > 10 X 109/L, platelet count <100 X 109/L, red blood cell transfusion dependency, and immature myeloid circulating cells (IMC). 12–15

EP

TE D

All of these factors have been identified in various prognostic score models, even tough they are validated, some inconsistencies are found in different populations. As an example, the MD Anderson prognostic score (MDAPS) is specific for CMML, 13 and had identified lower hemoglobin, presence of IMC and absolute lymphocytosis as a risk factor for shorter overall survival, however, when applying the prognosis system in an external different cohort, the IMC had no prognostic impact. 16 The presence of mutations has also been matter of discussion; the Myelodysplastic French Group incorporated the ASLX1 into their prognostic model due to the statistical significance for overall survival and AML free survival. 4 The Mayo Clinic did not include mutations into their survival prognostic model due to the lack impact in OS and LFS. 12

AC C

To the date, information regarding blastic transformation in Mexican population with CMML has not been published, particularly identification of factors related to blastic transformation. The aim of this study is to identify factors related to blastic transformation in Mexican population with CMML attended in a third level hospital teaching center. MATERIALS AND METHODS Patients In this retrospective analysis, all patients >18 years with CMML diagnosed and treated at our institution between January 2000 and December 2015 were included. Records were analyzed and clinical and laboratory data collected at time of diagnosis and at time of progression and/or death. Progression to AML was confirmed by bone marrow aspiration.

2

ACCEPTED MANUSCRIPT Patients with inconsistent information were excluded from the analysis. The diagnosis of CMML and the sub-classifications of CMML were revisited to be in accordance with the 2016 revision to the World Health Organization Classification of Myeloid Neoplasms and Acute leukemia.1 Each patient prognosis was stratified according to the Spanish cytogenetic risk classification system and the Mayo Clinic prognostic model. 11,12

RI PT

Variables for the risk factors analysis included age, sex, hemoglobin, absolute leucocyte, neutrophil, lymphocyte, monocyte and, platelets count, circulating blast in PB, blast in BM, IMC, lactate dehydrogenase, WHO sub-categories (CMML-1 and CMML-2), cytogenetic abnormalities, and the prognostic scores previously mentioned.

SC

Treatment data were collected at diagnosis and at progression if occurred, which included supportive care (transfusion, hydroxiurea, erythropoiesis stimulating agents) and aggressive chemotherapy (cytarabine, anthracyclens and VP-16).

M AN U

For those patients who progressed to acute myeloid leukemia, response to induction chemotherapy was graded according to the International Working Group criteria. 16 In order to try to find a relationship between patient’s background and progression to acute leukemia, epidemiological information such as exposure to benzene, tobacco, pesticides, and wood-burning stoves was collected.

TE D

This study received institutional ethics board review approval.

AC C

EP

Differences in the distribution of continuous variables were analyzed with MannWhitney; nominal variables were compared using X2-test. Leukemia-free survival (LFS) was calculated from the date of CMML diagnosis to the time of leukemia transformation. Overall survival (OS) was calculated from the time of CMML diagnosis to the date of death or last contact. OS and LFS curves were constructed by Kaplan-Meier method and compared by the log-rank test. For multivariable analysis the Cox proportional hazard regression model was used. P value less than 0.05 were considered statistical significant. SPSS package, version 21, software (IBM Corp, Armonk, NY) was used for statistical analysis.

RESULTS

54 patients with diagnosis of CMML seen at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, met the eligibility criteria and were included in the present study. With a median age of 71 years (range 23-86), 34 (63%) were males. According to the WHO sub-classification, 34 (63%) patients were CMML-0, 9(16·7%) CMML-1, and 11(20·3%) were CMML-2. Valid cytogenetic information was available in 47 (87%) of patients, of which 17 (36%) had abnormal karyotype, of those, 7 (13%) had complex karyotype and 3 (5·6%) had abnormalities of chromosome 7.

3

ACCEPTED MANUSCRIPT Table I includes whole group information. Of the 54 patients at diagnosis, 36 (66%) were treated with supportive measures only and six (11%) with chemotherapy, while ten (18·5%) patients required no treatment at all.

RI PT

For the whole group, with a median follow up of 13.5 (IQR 4-45·5) months, the leukemia-free survival was 49% at 2 years. During the follow up, 18 (33.3%) patients suffered progression to acute myeloid leukemia. The median time to blastic transformation was 9 months (IQR4-45·5), nine (50%) of the patients who underwent blastic transformation were women; the median age at progression was 58 years, and 72% were younger than 65 years. Figure I show the LFS according to the age group.

TE D

M AN U

SC

When comparing information at diagnosis between the eighteen patients with blastic transformation and the thirty six without progression, the univariate analysis revealed that the former were younger (P=0·001), with heavier leukemic burden noted as higher peripheral blood blast count (P=0.003), and as expected, higher percentage of type 2 CMML (P=0·006), also with higher percentage of circulating immature myeloid cells in peripheral blood (P=0·026). In the multivariate analysis, younger age p=0·006, HR 0·957; 95% (CI 0·9290·987), blast count in peripheral blood p= <0.001, HR 1·27; 95% (CI 1·1271·442), and WHO sub classification p=<0·001, HR 4.848; 95% (CI 2.256-10.417) remained statistical significant. Table II shows characteristics of patients who progress to acute leukemia.

EP

From the 18 patients with blastic transformation; 11 had available cytogenetic, and in five (45%) a change in karyotype was documented at progression; four patients acquired additional chromosomal alterations consistent with complex karyotype and the other one had alterations in chromosome 7. Of the patients with AML progression, 17(94%) had treatment requirements at CMML diagnosis; however, none of the treatments offered had the ability to impact CMML natural history.

AC C

Due to comorbidities, poor performance status or patients/family will, 11 patients received palliative care only, and seven (38·9%) were offered to receive intensive induction chemotherapy with curative intention, six received combination of anthracyclines and cytarabine (7+3), while the other one received a combination of mitoxantrone and cytarabine. None of the seven patients achieve complete remission despite re-inductions with alternative regimens. Because of poor survival and lack of response, none of the patients were considered candidates to allogeneic stem cell transplantation. The overall survival of the whole group was 13 months, 12 months for those who underwent blastic transformation and 23 for those who died at chronic stage disease. The overall survival in the group after blastic transformation was particularly poor, with a median overall survival of 1·4 months.

4

ACCEPTED MANUSCRIPT Figure II show the comparison of overall survival in both groups.

RI PT

When comparing the outcomes of the 54 patients according to prognostic models used in this study, the Spanish cytogenetic classification system could not discriminate between those who progressed from those who did not, however, the Mayo Clinic prognostic model was able to separate the groups, for low, intermediate and high risk, with a LFS at two years of 71, 63 and 37% respectively. Figure III shows the LFS according to Mayo Clinic prognostic model.

SC

Epidemiological data collected showed that 27 (50%) patients had previous exposition to wood-burning stoves, 7(13%) to benzene, 10(18·5%) to agrochemical toxics, and 16(29·5%) were active smokers, none of these parameters gave additional information of statistical significance to the risk of progression analysis. DISCUSSION

M AN U

Blastic transformation is ominous in patients with CMML, often reported from 15-29%4–9,17, in our study the progression to AML occurred in 33%, slightly higher than previously reported.

TE D

Factors related to blastic transformation are well known, and are consistently related to shorted leukemia free survival. In our study neither cytogenetic abnormalities, 18,19,20 female sex, 21 transfusion dependency, hemoglobin, platelet, neutrophil, lymphocyte and absolute monocyte count were found to be statistically significant to predict higher progression risk to AML .12-15

EP

Of the different prognostic scores used, only the Mayo Clinic prognostic model was able to clearly differentiate between the three risk groups; for those with a high-risk classification, the LFS at 2 years was 37%.

AC C

Age older than 65 years is often reported to be related to shortened overall survival and almost always present in prognostic scoring systems as an adverse condition, interestingly in a large Mayo Clinic retrospective study, the median age of blastic transformation was 66 years, 21 in our analysis the median age was 58 years, and of these patients, 72% were younger than 65 years. As striking these results are, they were not totally a surprise. For unknown reasons, the median age of patients with chronic hematologic malignancies are lower in the population attended at our institution compared with the median age at presentation reported in larger international cohorts. As an example, the median age of presentation of chronic myeloid leukemia in our center is 37 years,22 almost 15 years earlier than expected; in MDS, the patients median age at our institution is 56 years.23 The reason of why this shift in epidemiology data is not known, in order to try to find an explanation, we conducted an epidemiological sub-analysis, we focus on background and possible toxic expositions earlier in life, however a positive correlation was not found. Other possible explanation could be the population bias in Latin America, and particularly in Mexico were

5

ACCEPTED MANUSCRIPT the age pyramid is different from the demographic distribution seen in developed countries. In Mexico, the base of the pyramid is much more wider as a consequence of younger population, and in industrialized regions of the world an invers phenomenon is seen.

RI PT

Other factors related to AML in the current study like blast count in PB, IMC, and CMML subtypes are indicative of high tumor burden, just age and blast count continued to be statistically significant in the multivariate analysis, they were also reported previously. 21

M AN U

SC

The rate of complete remission after intensive induction chemotherapy in secondary AML was 0%, reflecting chemoresistance and the highly aggressive nature of CMML. In the Patnaik analysis at the Mayo Clinic, the rate of blastic transformation was also addressed, the percentage of progressed patients that achieve a complete remission was 30%, and long survival was possible in 8% of that population. 21 The reason of chemoresistance in our patients in unknown, the chemotherapy used at our institution was the standard induction treatment described for AML, of notice, hypomethylating agents were not used. Survival was also shorter than previously reported; in our study we found an overall survival of 13 months, compared to a expected median survival of 30 months reported elsewhere,24,25 this difference could be in part to the highly percentage of blastic transformation, but also the patients who did not progress to AML had an overall survival of just 23 months.

TE D

The limitations of our study are the retrospective nature and the lack of mutational analysis in our patients.

EP

Further larger studies are needed in order to correctly address and try to explain the differences in the reported ages at progression in patients with CMML and other hematological malignancies.

AC C

CMML is an orphan disease, so far, at our center the treatment of CMML had been watch and wait and cytoreductive therapy with non impact in the disease natural history,26–30 however, due to the highly aggressive behavior and chemoresistance at progression, a more aggressive treatment at diagnosis should be address particularly in young patients, fit and candidate for stem cell transplantation, so far, the only curative option in patients with CMML.31–34 This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

6

AC C

EP

TE D

M AN U

Variables Age in years; median (range) Age <65 years n (%) Men n (%) Hemoglobin g/dL; median (range) Leucocytes X 109/L; median (range) Absolute neutrophil X 109/L; median (range) Absolute lymphocytes X 109/L; median (range) Absolute monocytes X 109/L; median (range) Total platelets X 109/L; median (range) Blast PB %; median (range) Blast BM %; median (range) Morphologic subtype WHO; n (%) CMML-0 CMML-1 CMML-2 LDH mg/dl; median (range) Immature myeloid cells %; n (range) Spanish cytogenetic abnormalities n=47 (%) High risk Intermediate risk Low risk Mayo Clinic prognostic score High risk Intermediate risk Low risk Treatment at diagnosis n (%) HU ARA-C EPO VP-16 Other None RBC transfusion dependency

SC

TABLES AND FIGURES

RI PT

ACCEPTED MANUSCRIPT

n=54 patients 71·7 (23-86) 20 (37) 34 (63) 9·9 (4·2-15·8) 12·57 (12·57-180·6) 5·309 (0·120-37·0) 1·782 (0·132-19·01) 3·010(1·012-89·0) 100 (15-558·0) 0 (0-18) 1 (0-17) 34 (63) 9 (16·7) 11 (20·3) 230 (85-1010) 41 (75·9) 10 (21·3) 7 (14.9) 30 (63·8) 35 (64·8) 13 (24·1) 6(11·1) 35 (64·8) 1 (1·9) 1 (1·9) 5 (9·3) 2 (3·6) 10 (18·5) 33 (61·1)

7

ACCEPTED MANUSCRIPT

Without progression AML n=36 patients 71·7 (37-86) 7 (19·4) 34 (94·4) 10·1 (4·2-15·8) 12·57 (2·37-180) 518 (0·230-37.0) 1·747 (0·132-19·01)

58·1 (23-86) 13 (72) 9(50) 8·2 (4·8-14·6) 12·6 (1·5-85·8) 5.836 (0·12-33.019) 1·982 (0·20-19·01)

0·001 <0·001 NS NS NS NS

2·680 (1·012-89·0) 93 (15-558·0)

3·096 (1·050-35·6) 115 (4·0-494)

NS

0 (1-2) 0 (0-17)

2 (0-18) 2 (2-12)

28 (77·8) 4 (11·1) 4 (11·1) 230 (85-1010)

6 (33·3) 5 (27·8) 7 (38·9) 278 (146-412)

0·006

24 (66·7)

17 (94·4)

0·026

7 (23·3) 3 (10) 20 (66·7)

3 (17·8) 4 (23·5) 10(58·8)

NS

22 (61·1) 9 (25) 5 (13·9)

13 (72·2) 4 (22·2) 1 (5·6)

M AN U

Age in years Median (range) Age <65 years n (%) Men n (%) Hemoglobin g/dL; median (range) Leucocytes X 109/L; median (range) Absolute neutrophil count X 109/L; median (range) Absolute lymphocyte count X 109/L; median (range)

AC C

EP

TE D

Absolute monocytes count X 109/L; median (range) Total platelets X 109/L; median (range) Blast PB %; median (range) Blast BM %; median (range) Morphologic subtype WHO; n (%) CMML-0 CMML-1 CMML-2 LDH mg/dl; median (range) Immature myeloid circulating cells n (%) Spanish cytogenetic abnormalities n=47(%) High risk Intermediate risk Low risk Mayo Clinic prognostic model n (%) High risk Intermediate risk Low risk

p

Progression AML n=18

SC

Variables

RI PT

Table I: Characteristics of whole cohort.

NS

NS 0·003 NS

NS

NS

8

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

Treatment at diagnosis n (%) 14 (77·8) 21 (58·3) HU 1 (5·6) 0 ARA-C NS 2 (11·1) 3 (8·3) EPO 0 2 (5·6) VP-16 1 (5·6) 9 (25) Other None RBC transfusion dependency 29 (55·6) 13 (72·2) NS Table II: Characteristics at diagnosis of patients who progress to AML compared to those who did not

Numbers at risk Age ≤65 Age >65

20 34

9 18

5 17

5 14

2 12

2 10

1 7

4

2

Figure I shows the LFS according to the age group.

9

36 18

19 12

19 3

EP

Numbers at risk Without AML progression With AML progression

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

17 2

14

12

8

4

2

AC C

Figure II shows the comparison of overall survival in both groups, the difference by logrank was P=0·01

10

6 13 35

6 10 11

6 8 8

6 5 8

4 4 6

4 2 6

4 1 3

1 1 2

1 1

EP

Numbers at risk Low risk Intermediate risk High risk

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

Figure III shows the LFS according to the Mayo Clinic prognostic score, the difference P=0·035.

11

ACCEPTED MANUSCRIPT BIBLIOGRAPHY

AC C

EP

TE D

M AN U

SC

RI PT

1. Arber D, Orazi A, Hasserjian R, Borowitz M, Beau M Le, Bloomfield CD, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. 2016;127(20):2391–406. 2. Swerdlow S, Campo E, Harris N, et al. WHO classification of Tumors of Haematopoietic and Lymphoid Tissues, IARC Press, Lyon 2008. 3. Rollison D, Howlader N, Smith MT, Strom SS, Merritt WD, Ries LA, et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the Un. Program. Blood. 2008;112:45–52. 4. Itzykson R, Kosmider O, Renneville A, Gelsi-Boyer V, Meggendorfer M, et al. Prognostic score including gene mutations in chronic Myelomonocytic Leukemia. J Clin Oncol. 2013;31:2428–2436. 5. Patnaik M, Parikh SA, Hanson CA, Tefferi A. Chronic myelomonocytic leukaemia: A concise clinical and pathophysiological review. Br J Haematol. 2014;165:273–286. 6. Benton CB, Nazha A, Pemmaraju N, Garcia-Manero G. Chronic myelomonocytic leukemia: Forefront of the field in 2015. Crit Rev Oncol Hematol. 2015;95:222–242. 7. Such E, Germing U, Malcovati L, Cervera J, Kuendgen A, Della Porta M, Nomdedeu B. et al. Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia. Blood. 2013;121:3005–3015. 8. Breccia M, Latagliata R, Mengarelli A, Biondo F, Mandelli F, Alimena G. Prognostic factors in myelodysplastic and myeloproliferative types of chronic myelomonocytic leukemia: A retrospective analysis of 83 patients from a single institution. Haematologica. 2004;88:866–868. 9. Nösslinger T, Reisner R, Grüner H, Tüchler H, Nowotny H, Pittermann E, et al. Dysplastic versus proliferative CMML--a retrospective analysis of 91 patients from a single institution. Leuk Res. 2001;25:741–747. 10. Patnaik M, Itzykson R, Lasho T, Kosmider O, Finke C, Hanson C, et al. ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients. Leukemia . 2014;28:2206–2212. 11. Such E, Cervera J, Costa D, Sol F, Vallesp T, Luo E, et al. Cytogenetic risk stratification in chronic myelomonocytic leukemia. Haematologica. 2011;96:375–383. 12. Patnaik MM, Padron E, LaBorde RR, et al. Mayo prognostic model for WHO-defined chronic myelomonocytic leukemia: ASXL1 and spliceosome component mutations and outcomes. Leukemia 2013; 27:1504–1510. 13. Kantarjian H, O'Brien S, Ravandi F, et al. Proposal for a new risk model in myelodysplastic syndrome that accounts for events not considered in the original International Prognostic Scoring System. Cancer 2008; 113:1351.

12

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

14. Elena C, Gallì A, Such E, et al. Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia. Blood 2016; 128:1408–1417. 15. Calvo X, Nomdedeu M, Santacruz R, Martínez N, Costa D, Pereira A, et al. Comparison of three prognostic scoring systems in a series of 146 cases of chronic myelomonocytic leukemia (CMML): MD Anderson prognostic score (MDAPS), CMML-specific prognostic scoring system (CPSS) and Mayo prognostic model. A detailed review of prognostic factor in CMML Leuk Res. 2015;39:1146–1153. 16. Cheson B, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. Revised Recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2003;21:4642–4649. 17. Germing U. New Response parameters in chronic myelomonocytic leukemia. Blood. 2002;100:731–732. 18. Patnaik M, Tefferi A. Cytogenetic and molecular abnormalities in chronic myelomonocytic leukemia. Blood Cancer Journal 2016; 6, e393. 19. Tang G, Zhang L, Fu B, Hu J, Lu X, Hu S, et al. Cytogenetic risk stratification of 417 patients with chronic myelomonocytic leukemia from a single institution. Am J Hematol. 2014;89:813–818. 20. Wassie EA, Itzykson R, Lasho TL, Kosmider O, Finke CM, Hanson CA, et al. Molecular and prognostic correlates of cytogenetic abnormalities in chronic myelomonocytic leukemia: A Mayo Clinic-French Consortium Study. Am J Hematol. 2014;89:1111–1115. 21. Patnaik MM, Wassie EA, Lasho TL, Hanson CA, Ketterling R, Tefferi A. Blast transformation in chronic myelomonocytic leukemia: Risk factors, genetic features, survival, and treatment outcome. Am J Hematol. 2015;90:411–416. 22. Aguayo A, Garcia-Alvarez E, Cazares-Ordonez Y, Crespo-Solis E, MartinezBanos D, Guadarrama-Beltran E, Cervera-Ceballos EE, Lopez-Karpovitch X. Chronic Myeloid Leukemia: A Clinicoepidemiologic and Therapeutic Description of a Single Institution in Mexico City. Clinical Leukemia. 2008;2:261–266. 23. Zamora E, Lopez X. Hematologic response predictor factors in adults with myelodysplastic syndromes (SMD) treated with cyclosporin A (CSA). Gaceta Médica de México. 2015; 151:345–353. 24. Selimoglu-Buet D, Solary E. Chronic Myelomonocytic Leukemia Prognostic Classification and Management: Evidence Base and Current Practice. Curr Hematol Malig Rep. 2014;9:301–310. 25. Patnaik MM, Tefferi A, Lanier WL, Jopke TL, Sankey KD, Smith NM. Chronic Myelomonocytic Leukemia: Focus on Clinical Practice. Mayo Clin Proc. 2016;91:259–272. 26. Malcovati L, Hellström-Lindberg E, Bowen D, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood.2013;122:2943–2964. 27. Onida F, Barosi G, Leone G, Malcovati L, Morra E, Santini V, et al. Management recommendations for chronic myelomonocytic leukemia:

13

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

consensus statements from the SIE, SIES, GITMO groups. Haematologica. 2013 ;98:1344–1352 28. Wattel E, Guerci A, Hecquet B, et al. A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia. Groupe Français des Myélodysplasies and European CMML Group. Blood 1996; 88:2480– 2487. 29. Braun T, Itzykson R, Renneville A, et al. Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial. Blood 2011; 118:3824–3831 30. Adès L, Sekeres MA, Wolfromm A, et al. Predictive factors of response and survival among chronic myelomonocytic leukemia patients treated with azacitidine. Leuk Res 2013; 37:609–613. 31. Zang DY, Deeg HJ, Gooley T, et al. Treatment of chronic myelomonocytic leukaemia by allogeneic marrow transplantation. Br J Haematol 2000; 110:217–222. 32. Park S, Labopin M, Yakoub-Agha I, et al. Allogeneic stem cell transplantation for chronic myelomonocytic leukemia: a report from the Société Française de Greffe de Moelle et de Thérapie Cellulaire. Eur J Haematol 2013; 90:355–364. 33. Krishnamurthy P, Lim ZY, Nagi W, et al. Allogeneic haematopoietic SCT for chronic myelomonocytic leukaemia: a single-centre experience. Bone Marrow Transplant 2010; 45:1502–1507. 34. Kröger N, Zabelina T, Guardiola P, et al. Allogeneic stem cell transplantation of adult chronic myelomonocytic leukaemia. A report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 2002; 118:67–73.

14