Impact of cytogenetic abnormalities in adults with Ph-negative B-cell precursor acute lymphoblastic leukemia

Abstract

Multiple cytogenetic subgroups have been described in adult Philadelphia chromosome (Ph)-negative B-cell precursor (BCP) acute lymphoblastic leukemia (ALL), often comprising small numbers of patients. In this study, we aimed to reassess the prognostic value of cytogenetic abnormalities in a large series of 617 adult patients with Ph-negative BCP-ALL (median age, 38 years), treated in the intensified Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/2005 trials. Combined data from karyotype, DNA index, fluorescence in situ hybridization, and polymerase chain reaction screening for relevant abnormalities were centrally reviewed and were informative in 542 cases (88%), allowing classification in 10 exclusive primary cytogenetic subgroups and in secondary subgroups, including complex and monosomal karyotypes. Prognostic analyses focused on cumulative incidence of failure (including primary refractoriness and relapse), event-free survival, and overall survival. Only 2 subgroups, namely t(4;11)/ and 14q32/ translocations, displayed a significantly worse outcome in this context, still observed after adjustment for age and after censoring patients who received allogeneic stem cell transplantation (SCT) in first remission at SCT time. A worse outcome was also observed in patients with low hypodiploidy/near triploidy, but this was likely related to their higher age and worse tolerance to therapy. The other cytogenetic abnormalities, including complex and monosomal karyotypes, had no prognostic value in these intensive protocols designed for adult patients up to the age of 60 years.

The poor prognosis of low hypodiploidy in adults with B‐cell precursor acute lymphoblastic leukaemia is restricted to older adults and elderly patients

“…KMT2A gene rearrangements and hypodiploidy are the two cytogenetic subtypes with the poorest outcomes in B‐cell precursor ALL (BCP‐ALL), with hypodiploidy being further categorized into high‐hypodiploidy (40–45 chromosomes), low‐hypodiploidy/near triploidy (30–39/60–78 chromosomes) and near‐haploidy (<30 chromosomes) (Harrison et al , ; Holmfeldt et al , ). Previous reports have demonstrated that patients with <40 chromosomes have an adverse prognosis, although the modal number of chromosomes associated with disease progression remains a matter of debate (Raimondi et al , ; Harrison et al , ; Moorman et al , ; Nachman et al , ; Mehta et al , ; Issa et al , ; Lafage‐Pochitaloff et al , ). The poor outcome associated with hypodiploidy has also been attributed to the older age of the patients with this cytogenetic subtype (Moorman et al , ; Lafage‐Pochitaloff et al , ).…”

“…Previous reports have demonstrated that patients with <40 chromosomes have an adverse prognosis, although the modal number of chromosomes associated with disease progression remains a matter of debate (Raimondi et al , ; Harrison et al , ; Moorman et al , ; Nachman et al , ; Mehta et al , ; Issa et al , ; Lafage‐Pochitaloff et al , ). The poor outcome associated with hypodiploidy has also been attributed to the older age of the patients with this cytogenetic subtype (Moorman et al , ; Lafage‐Pochitaloff et al , ). In turn, it is well known that minimal residual disease (MRD) can overcome most of the prognostic factors in ALL, and it has been suggested that MRD‐negative children with hypodiploid BCP‐ALL do not have a poor outcome (Mullighan et al , ).…”

“…Low‐hypodiploidy has been considered a poor prognostic subtype of BCP‐ALL at all ages, even in patients treated within MRD‐based protocols (Issa et al , ; Lafage‐Pochitaloff et al , ). However, the low incidence of this cytogenetic abnormality hampers full establishment of its prognostic significance.…”

How to prophylax against invasive fungal infections in adult ALL? An unmet need

“…ALL is the predominant leukaemia in paediatrics where chemotherapy treatments are highly curative . However, the diagnosis of ALL in adults typically portrays inferior survival as the disease is frequently associated with complex karyotype abnormalities and resistance to chemotherapy . These patients typically undergo highly intensive induction and consolidative chemotherapy programmes, with therapy lasting 2‐3 years.…”

Targeting the phosphatidylinositol 3‐kinase/Akt/mechanistic target of rapamycin signaling pathway in B‐lineage acute lymphoblastic leukemia: An update

“…As to adults, they have CR rates of about 85%, however their 5‐year survival rate is 40% overall and approximately 7% for patients who experience relapse (Fielding et al, ; Goldstone et al, ). Indeed, adults are at a higher risk of relapse due to disease factors present at diagnosis, including the Philadelphia chromosome (Ph) formed upon the t(9;22) reciprocal translocation that fuses the breakpoint cluster region (Bcr) gene with the Abelson tyrosine kinase (Abl) (Lafage‐Pochitaloff et al, ). The incidence of Ph + B‐ALL increases with age and occurs in up to 50% of B‐ALL diagnosed in individuals ≥50 year old (Pui & Evans, ).…”