Influence of Cytogenetics on the Outcome of Patients With High-Risk Myelodysplastic Syndrome Including Deletion 5q Treated With Azacitidine With or Without Lenalidomide

Abstract

In myelodysplastic syndromes (MDS), cytogenetic characteristics of the malignant bone marrow cells influence the clinical course. The aim of this study was to evaluate whether cytogenetics is useful to predict outcome and response in patients with del(5q) under azacitidine (AZA) ± lenalidomide (LEN) therapy. We therefore performed comprehensive cytogenetic analyses in MDS patients with del(5q) treated within the randomized phase II trial NMDSG10B. Seventy-two patients were enrolled in the study and 46 patients (64%) had sufficient cytogenetics at inclusion and response evaluation. Karyotyping was significantly more sensitive during follow-up to detect del(5q) compared to FISH, 34 patients (97%) versus 27 patients (77%) (p = 0.027). The overall response rate (ORR) did not differ between the 11 patients with < 3 aberrations (median 1 aberration) and the 59 patients with ≥ 3 aberrations (median 7 aberrations, range 3-16), while ≥ 3 aberrations were associated with shorter overall survival (OS), 9.9 months versus 25.2 months (p = 0.004). OS was significantly shorter in patients with unbalanced translocation of 5q than patients with del (5)(q14q34), 8.4 months versus 21.1 months (p = 0.004). Both complex karyotype and multi-hit TP53 alterations were more frequent in patients with unbalanced translocations of 5q versus del (5)(q14q34), 98% and 88% versus 67% and 47% (each p = < 0.001). Most patients with cytogenetic progression had multi-hit TP53 alterations at inclusion. Cytogenetic progression occurred at a similar frequency in the AZA arm and in the AZA + LEN arm. In summary, this study in homogenously treated MDS patients with different abnormalities of 5q demonstrates the influence of cytogenetics on treatment results. Trial Registration: EudraCT number: 2011-001639-21; ClinicalTrials.gov identifier: NCT01556477.

Keywords: TP53; azacitidine; deletion 5q; high‐risk myelodysplastic syndrome; lenalidomide; outcome.

FIGURE 1

(A) Karyogram after fluorescence R‐banding showing a complex aberrant karyotype. (B) mFISH of the same patient detecting cryptic aberrations. (C) Telomere length measurement of the same metaphase with T/C‐FISH.

FIGURE 2

Treatment responses according to the number of chromosome aberrations and karyotype complexity as analyzed by χ ²‐ or Fisher's exact tests. (A) Influence of grade of complexity on treatment response. Complex karyotype was categorized as three to four aberrations and five or more aberrations. The number of aberrations were not significantly associated with CR, mCR, HI, or no response. (B) Influence of grade complexity at inclusion on cytogenetic response. Complex karyotype was categorized as three to four aberrations and five or more aberrations. No statistically significant differences were observed in the different cohorts. CCyR = cytogenetic complete remission; CR = complete remission; HI = hematologic improvement; mCR = marrow complete remission; NoCyR = no cytogenetic response; PCyR = partial cytogenetic response.

FIGURE 3

Overall survival according to the type of chromosome 5 abnormality and karyotype complexity as analyzed by Kaplan–Meier; p‐values derived from log‐rank tests. Number of patients in parentheses. (A) Survival in patients with del (5)(q14q34) versus unbalanced translocations of 5q deletion (log‐rank p = 0.004). (B) Survival according to the number of aberrations at inclusion, less than 3 aberrations versus complex karyotype (log‐rank p = 0.004).

FIGURE 4

Telomere length measurement at inclusion and final assessment. (A) Median telomere lengths (kilobases) of patients at study entry: nonresponders, patients who responded, and age‐matched control. (B) Median telomere lengths (kilobases) of patients at final assessment: nonresponders, patients who responded, and age‐matched control. (C) Comparison of median telomere lengths of patients at study entry and final assessment: nonresponders and patients who responded.