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Risk factors for post-HCT outcomes in CMML
JAK2), DNA methylation (DNMT3A, IDH1, IDH2, and TET2), transcription (RUNX1), epigenetic regulation (ASXL1, EZH2, and SETBP1), and splicing (SF3B1, SRSF2, U2AF1, and ZRSR2).9-11 TET2 and SRSF2 mutations are the most prevalent in CMML.12,13 Patients with MP-CMML have a higher propensity for alterations in signaling path- ways,14 whereas patients with MD-CMML predominantly have mutations associated with epigenetics.15 Recognition of associations between somatic mutations and clinical features has improved the risk stratification of CMML (molecular CMML Prognostic Scoring System, m-CPSS).16 Mutations in RUNX1, NRAS, SETBP1, and ASXL1 appear to be associated with unfavorable outcomes.16,17
Treatment of CMML with chemotherapy alone only infrequently results in prolonged remission. A randomized trial comparing oral etoposide and hydroxyurea showed superior survival with hydroxyurea.18 Treatment with hypomethylating agents results in less toxicity than asso- ciated with conventional chemotherapy; but again, remis- sions tend to be of short duration.19,20 The only therapeutic modality with proven curative potential is allogenic hematopoietic cell transplantation (HCT).21-27 Published data indicate that the major factors determining long-term relapse-free survival and overall survival are cytogenetic risk category, comorbidities, patient’s age and achieve- ment of complete remission.21,25-27 In the present study, we analyzed long-term outcomes after allogenic HCT for patients with CMML and, in a subcohort, carried out a comprehensive mutation analysis of 75 genes implicated in myeloid malignancies to define the relationship between somatic mutations and previously established risk factors.
Methods
Patients
Between May 1986 and September 2017, 129 patients with CMML underwent HCT at the Fred Hutchinson Cancer Research Center. All provided informed consent for enrollment in investiga- tional protocols and for long-term follow-up as required by the institutional review board of the Center. The characteristics of the patients and their diseases are summarized in Table 1. Patients were 7-74 (median, 55) years of age. The diagnosis and stratifica- tion of CMML, and determination of AML transformation were based on WHO 2016 criteria for all cases.1 The disease was also risk-categorized by cytogenetics,28 the MD Anderson Prognostic Score (MDAPS),6 the CMML-specific Prognostic Scoring System (CPSS),8 and the revised International Prognostic Scoring System (IPSS-R).29 The HCT Comorbidity Index (HCT-CI) scores were 0- 1 in 35 patients, 2-3 in 49 patients, and 4-11 in 45 patients.30
Donor and transplant characteristics
Donor and transplant characteristics are summarized in Table 2. All patients (and donors) were HLA genotyped, following institu- tional standards. Genotyping was carried out retrospectively in patients transplanted before the routine use of molecular typing. Donors for 42 patients (33%) were related (38 HLA-identical sib- lings, 4 HLA-mismatched family members), whereas 87 patients (67%) had unrelated donors (68 HLA-matched, 19 HLA mis- matched, including 2 cord blood transplants). The stem cell source was bone marrow in 34 (26%) patients, peripheral blood stem cells in 93 (72%) and cord blood in two. Reduced-intensity condi- tioning regimens were used in 19% of patients and high-intensity (myeloablative) regimens in 81% of patients. Graft-versus-host dis-
ease (GvHD) prophylaxis consisted of a calcineurin inhibitor- based regimen in all patients. The severity of any acute and chron- ic GvHD was assessed and the conditions were treated as described previously.31,32
Mutation analysis
Mutation analysis was performed on DNA from bone marrow mononuclear cells collected prior to transplantation in 52 patients. DNA was extracted using a DNeasy Blood & Tissue Kit (Qiagen, Valencia, CA, USA), following the manufacturer’s protocol. Next- generation sequencing libraries were prepared from 400 ng genomic DNA using the Archer VariantPlex Myeloid 75 gene
Table 1. Patient and disease characteristics.
Variable
Patients
Age (years)
Gender Male
Female
Diagnosis WHO
CMML-0
CMML-1
CMML-2
CMML-T* CMML-nonspecified
Subgroup
Myelodyplastic (MD) Myeloproliferative (MP) Indeterminate
Cytogenetic risk† Low
Intermediate High
Not available‡
CPSS Low
Intermediate-1 Intermediate-2 High
Not determined‡
MDAPS Low
Intermediate-1 Intermediate-2 High
Not determined‡
N. of patients %
129
85 65.9 44 34.1
21 16.3 31 24.0 38 29.5 37 28.7 2 1.6
88 68.2 40 31.0 1 0.8
72 55.8 22 17.1 30 23.3 5 3.9
1 0.8 16 12.4 74 57.4 30 23.3 8 6.2
29 22.5 34 26.4 46 35.7 15 11.6 5 3.9
7-74 (median, 55)
IPSS-R for myelodysplastic-CMML
Verylow 8 9.1
Low Intermediate High
Very high
Not determined‡
HCT-CI 0-1 2-3 ≥4
10 11.4 26 29.5 20 22.7 20 22.7 4 4.5
35 27.1 49 38.0 45 34.9
*Progressed to blasts ≥20% with a previous history of CMML.†According to Such E,et al.28 ‡Due to failed cell growth in cytogenetic study.WHO:World Health Organization; CMML; chronic myelomonocytic leukemia; CPSS: CMML Prognostic Scoring System; MDAPS, MD Anderson Prognostic Score; IPSS-R: Revised International Prognostic Scoring System; HCT-CI: Hematopoietic Cell Transplantation Comorbidity Index.
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