E2A-PBX1 fusion in adult acute lymphoblastic leukaemia: biological and clinical features

Molecular and cytogenetic studies performed in 305 adult acute lymphoblastic leukaemia (ALL) patients enrolled in the gimema (Gruppo Italiano Malattie EMatologiche dell'Adulto) multicentric protocols identified an E2A-PBX1 fusion and/or t(1;19) in 10 patients (3.3%). All had common ALL, were mostly CyIg+ and were CD34/CD13/CD33-. Nine patients achieved a complete remission (CR); five patients showed a haematological relapse after 7 months (median). Four patients are alive in first CR with a median follow-up of 29 months; three patients are molecularly negative. This abnormality is frequently associated with early treatment failure. E2A-PBX1+ adult ALL should be considered for intensified treatment strategies and monitoring of minimal residual disease.     

Progression from myelodysplastic syndrome to acute lymphoblastic leukaemia with Philadelphia chromosome and p190 BCR-ABL transcript

We describe a patient with Philadelphia chromosome (Ph¹)-positive acute lymphoblastic leukaemia (ALL) who developed it 2.5 years after being diagnosed with myelodysplastic syndrome (MDS). The patient initially had refractory anaemia (RA), but progressed to refractory anaemia with excess blasts (RAEB) 2 years later, that terminated in ALL. An immunophenotypic analysis of the lymphoblasts revealed CD10 and CD19 positive cells. The karyotype was normal 46,XY in RA phase, 46,XY,20q– during the RAEB phase, and 46,XY, t(9;22)(q34;q11), 20q– during the ALL phase. Furthermore, p190 BCR-ABL mRNA was detected in the ALL blasts. These findings indicate that this ALL arose from the MDS clone through multiple cytogenetic evolutions, the final event of which was the acquisition of p190 BCR-ABL type Ph¹     

Array-CGH reveals hidden gene dose changes in children with acute lymphoblastic leukaemia and a normal or failed karyotype by G-banding

A tiling path 33K BAC array was used to study 28 children with acute lymphoblastic leukaemia (ALL) who had normal or failed G-banded karyotypes. Twenty-two patients (79%) had a total of 135 copy number alterations (CNA) (69 gains and 66 losses); most of these patients showed CNA that were below the resolution of G-banding. Molecular cytogenetic and array comparative genomic hybridization results enabled the division of B-precursor ALL patients into five groups: high hyperdiploidy, intrachromosomal amplification of 21q, ETV6/RUNX1 rearrangement, others and no CNA. Apart from a shared deletion of 9p21.3, T-ALL patients had additional small CNA, with no region in common.     

Predicting relapse risk in childhood acute lymphoblastic leukaemia

Intensive multi‐agent chemotherapy regimens and the introduction of risk‐stratified therapy have substantially improved cure rates for children with acute lymphoblastic leukaemia (ALL). Current risk allocation schemas are imperfect, as some children are classified as lower‐risk and treated with less intensive therapy relapse, while others deemed higher‐risk are probably over‐treated. Most cooperative groups previously used morphological clearance of blasts in blood and marrow during the initial phases of chemotherapy as a primary factor for risk group allocation; however, this has largely been replaced by the detection of minimal residual disease (MRD). Other than age and white blood cell count (WBC) at presentation, many clinical variables previously used for risk group allocation are no longer prognostic, as MRD and the presence of sentinel genetic lesions are more reliable at predicting outcome. Currently, a number of sentinel genetic lesions are used by most cooperative groups for risk stratification; however, in the near future patients will probably be risk‐stratified using genomic signatures and clustering algorithms, rather than individual genetic alterations. This review will describe the clinical, biological, and response‐based features known to predict relapse risk in childhood ALL, including those currently used and those likely to be used in the near future to risk‐stratify therapy.     

Treatment of adults with BCR-ABL negative acute lymphoblastic leukaemia with a modified paediatric regimen

Between 2000 and 2006, 85 adult BCR-ABL negative acute lymphoblastic leukaemia (ALL) patients between 18 and 60 years of age were treated using a modified paediatric regimen, which included high doses of asparaginase delivered weekly for 30 weeks during intensification. The complete response rate with induction therapy was 89%, and decreased with increasing age, mainly due to higher induction mortality. All post-induction treatments were delivered on an outpatient basis. The most common complications during intensification were infections (47%), osteonecrosis (32%), venous thromboembolism (23%) and neuropathy (22%). At a median follow-up of 4 years, the 5-year overall survival (OS) and relapse-free survival (RFS) were 63% and 71%, respectively. Significant adverse predictors for OS were age >35 years, high white blood cell count, MLL rearrangement, allogeneic stem cell transplantation in first complete remission and <80% of the planned asparaginase dose delivered during intensification. Patients aged ≤35 years had a 3 year OS of 83%, as compared to 52% for patients aged >35 years. We conclude that the administration of this paediatric regimen is feasible and has considerable activity in adult ALL, particularly in younger patients. Effective delivery of asparaginase dosing appears to be important in achieving an optimal antileukaemic effect.     

Three distinct subgroups of hypodiploidy in acute lymphoblastic leukaemia

This study of children and adults with acute lymphoblastic leukaemia (ALL) is the largest series of patients with hypodiploidy (<46 chromosomes) yet reported. The incidence of 5% was independent of age. Patients were subdivided by the number of chromosomes; near-haploidy (23-29 chromosomes), low hypodiploidy (33-39 chromosomes) and high hypodiploidy (42-45 chromosomes). The near-haploid and low hypodiploid groups were characterized by their chromosomal gains and a doubled hyperdiploid population. Structural abnormalities were more frequent in the low hypodiploid group. Near-haploidy was restricted to children of median age 7 years (range 2-15) whereas low hypodiploidy occurred in an older group of median age 15 years (range 9-54). Patients with 42-45 chromosomes were characterized by complex karyotypes involving chromosomes 7, 9 and 12. The features shared by the few patients with 42-44 chromosomes and the large number with 45 justified their inclusion in the same group. Survival analysis showed a poor outcome for the near-haploid and low hypodiploid groups compared to those with 42-45 chromosomes. Thus cytogenetics, or at least a clear definition of the modal chromosome number, is essential at diagnosis in order to stratify patients with hypodiploidy into the appropriate risk group for treatment.     

Comparative genomic hybridization is a powerful tool, complementary to cytogenetics, to identify chromosomal abnormalities in childhood acute lymphoblastic leukaemia

Cytogenetics has a strong prognostic value in childhood acute lymphoblastic leukaemia (ALL), but results are often incomplete because of the poor chromosome morphology. To improve this analysis, we tested comparative genomic hybridization (CGH) for the detection of chromosomal imbalances. 72 children were retrospectively analysed using CGH. Only 53% of the patients had been fully banded by standard methods. With CGH, 36 patients retained a normal chromosomal profile and 36 had unbalanced abnormalities. No amplification was detected. Fluorescence in situ hybridization (FISH) with centromeric and unique sequence probes was used in those cases with discrepancies or unsuccessful karyotype to validate CGH results. CGH enabled clear identification of unbalanced chromosomal abnormalities, even in some cases which had a normal karyotype. In view of the strong prognostic value of hyperdiploidy in childhood ALL, CGH appears to be a powerful technique, complementary to conventional cytogenetics.     

Rescue of genomic information in adult acute lymphoblastic leukaemia (ALL) with normal/failed cytogenetics: a GIMEMA centralized biological study

Metaphase (M‐) and array (A‐) Comparative Genomic Hybridization (CGH) were used to investigate 40 cases of T‐ and 32 of B‐cell acute lymphoblastic leukaemia (ALL) with normal/failed cytogenetics. M‐CGH was performed in all cases and A–CGH in 10/12 T‐ALL cases with uncertain/normal M‐CGH results. M‐CGH was abnormal in 38/72 cases, with a total of 110 imbalances (60 gains, 50 losses). 25/40 patients with T‐ALL (62·5%) showed 77 imbalances, with at least 1 genomic imbalance and a mean of 3 aberrations/patient (range 1–12). 13/32 patients with B‐ALL (40·6%) presented 34 imbalances, with a mean of 2·6 imbalances (range 1–8). A‐CGH detected 4 more T‐ALL cases with genomic imbalances. A‐CGH identified NF1/17q11·2 deletion and interphase fluorescence in situ hybridization provided a 10·8% estimated overall incidence of NF1/17q11·2 deletion in T‐ALL. In all but one case (6/7) with NF1 deletion, denaturing high‐performance liquid chromatography and direct sequencing detected NOTCH1 gene mutations. Three or more imbalances in CGH‐positive cases were significantly associated with resistance to treatment and death during or after induction therapy. We suggest that the work‐up for ALL at diagnosis should include CGH investigations, particularly when cytogenetics is uninformative, because they may provide potentially valuable information with prognostic and therapeutic implications.