Page 17 - Haematologica May 2020

Editorials
A post-stem cell transplant risk score for Philadelphia-negative acute lymphoblastic leukemia
Dietger Niederwieser
University of Leipzig; Lithuanian University of Health Sciences, Kaunas, Lithuania and Aichi Medical University, School of Medicine, Nagakute, Japan
E-mail: DIETGER NIEDERWIESER - dietger@medizin.uni-leipzig.de doi:10.3324/haematol.2019.246322
Recent decades have seen major advances in under- standing the genetic basis of hematologic and non- hematologic malignancies. The discovery of the Philadelphia chromosome (Ph) in chronic myeloid leukemia was a key step forward.1,2 Since then, many recurrent chromosomal abnormalities, such as t(8,21) and t(15;17), have been found in acute leukemias, paving the way for identification of altered genes.3 These ongoing discoveries have provided and continue to provide major insights into the mechanisms by which key transcription factors and epigenetic modulators regulate normal hematopoiesis and, if dysregulated, promote leukemic transformation. To date, more than 200 balanced chro- mosomal rearrangements (translocations, insertions and inversions) defining biologically distinct subsets of acute leukemia have been identified. Chromosome analysis, together with molecular determinations, are now impor- tant components of routine clinical practice and essential for appropriate diagnosis. Cytogenetic findings have in addition been repeatedly shown to be among the most important and independent prognostic factors in both acute myeloid leukemia and acute lymphoblastic leukemia (ALL).4,5 For all these reasons, specific chromo- some alterations and their molecular counterparts have been included in the World Health Organization classifi- cation of hematologic malignancies and together with morphology, immunophenotype and clinical features are used to define distinct disease entities.6
The first comprehensive cytogenetic analysis showing biological and prognostic significance in adult ALL was performed at the Third International Workshop on Chromosomes in Leukemia in 1981.7 The frequency of abnormal karyotypes was shown to be slightly higher in adult than in pediatric ALL (60-69% vs. 58-64%, respec- tively) with t(9;22)(q34;q11) being the most frequent translocation.8 Less than 6% of children, but up to 40% of adults ≥40 years of age, with ALL harbor a Ph transloca- tion (Ph+) with or without additional alterations, which is a poor prognostic feature regardless of age. In contrast, less than 12% of adults, but 25% of children have high hyperdiploidy, a good prognostic feature.4
One of the hurdles to developing a more sophisticated cytogenetic profile is the overall incidence and, in particu- lar, the different subsets of Ph- adult ALL, each of which accounts for less than 10% of the total. Only sparse infor- mation is available on Ph- ALL patients. The most frequent Ph- chromosomal aberrations include t(4;11)(q21;q23)/KMT2A-AFFI (3-7%) involving the MLL gene, translocations t(8;14)(q24;q11) (2%) involving myc, t(1;19)(q23;p13)/TCF3-PBX1 (2-3%), t(10;14)(q24;q11) (2%), t(11;19)(q23;13.3) and structural abnormalities such as 9p, 6q, and 12p, 18, 19. Further cytogenetic changes
include the multiaberrant karyotype, monosomy 7, mono- somy 9, +8, del11 and low hypodiploidy, near triploidy and high hyperdiploidy. ALL study groups, including the Medical Research Council (MRC), Eastern Cooperative Oncology Group (ECOG), Southwest Oncology Group (SWOG), Northern Italy Leukemia Group (NILG), North UK and Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) categorize the cytogenetic alterations at diag- nosis into risk groups. Unfortunately, the representation of patients treated with hematopoietic stem cell transplanta- tion (SCT) is limited in these analyses. The largest study with patients undergoing allogeneic SCT was the MRC- ECOG study with 310 patients.9 Here, four risk categories were identified using the modified MRC-ECOG score (very high, high, intermediate and standard).10
In a study reported by Aleksandr Lazaryan et al. in this issue of Haematologica, the Acute Leukemia Working Committee of the Center for International Blood and Marrow Transplant Research (CIBMTR) investigated the usefulness of the MRC-ECOG score in a large cohort of patients after SCT (n=1731) all of whom were adults with Ph- ALL.11 While the standard- risk group had favorable outcomes compared to the intermediate-risk group, the adverse risk group was not clearly inferior using the mod- ified MRC-ECOG score. The analysis of relapse and post- transplant treatment failure revealed that t(8;14), mono- somy 7 and complex karyotype were the major important determinants. As a consequence, the authors propose, in addition to the modified MRC-ECOG score at diagnosis, the CIBMTR risk score for transplant, which does not include the t(4;11), t(1;19), t(17;19), t(5;14) and +8, but does include t(8;14), t(11;19), monosomy 7, del(7q), del(11q) and complex karyotype (Figure 1).
Previous studies on ALL patients after SCT have con- cluded that cytogenetics do not predict overall survival. The difference in respect to the current study might be explained by the high number of patients transplanted in advanced phase disease in addition to the high number of patients with Ph+ ALL included in one study.12 Another study found no difference in overall survival between patients with high risk [defined as t(4;11)(q21;q23), t(8;14)(q24;32), low hypodiploidy, complex karyotype] and standard-risk cytogenetics, most probably as a conse- quence of the low number of patients in the high-risk group.13 A different study identified t(4;11)/KMT2A-AFF1 and t(v;14q32)/IGH in Ph- patients, but censored patients at the time of SCT.14
A source of uncertainty in the current analysis is the lack of information on cytogenetic results at transplant.15 Furthermore, molecular information at diagnosis and min- imal residual disease might have influenced the results of this retrospective analysis. Despite these flaws, the results
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