A simplified prognostic score is presented based on the multivariate analysis of 138 refractory/relapsed acute myeloid leukaemia (AML) patients (median age 55 years, range: 19-70) receiving a combination of intensive chemotherapy þ Gemtuzumab as salvage regimen. Overall, 2-year event-free survival (EFS) and overall survival (OS) were 29±4% and 36 ± 4%, respectively. Disease status (relapse o12 months, including refractory patients), FLT3-ITD-positive status and high-risk cytogenetics were the three strongest independent adverse prognostic factors for OS and EFS in this series. We then defined three subgroups with striking different outcomes at 2 years: no adverse factor (favourable, N ¼ 36): OS 58%, EFS 45%; one adverse factor (intermediate, N ¼ 54): OS 37%, EFS 31%; two or three adverse factors (poor, N ¼ 43): OS 12%, EFS 12% (Po10 À4 , P ¼ 0.001). This new simplified Leukemia Prognostic Scoring System was then validated on an independent cohort of 111 refractory/relapsed AML patients. This new simplified prognostic score, using three clinical and biological parameters routinely applied, allow to discriminate around two third of the patients who should benefit from a salvage intensive regimen in the setting of refractory/relapsed AML patients. The other one third of the patients should receive investigational therapy.

Adult and child B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) differ in terms of incidence and prognosis. These disparities are mainly due to the molecular abnormalities associated with these two clinical entities. A genome-wide analysis using oligo SNP arrays recently demonstrated that PAX5 (paired-box domain 5) is the main target of somatic mutations in childhood BCP-ALL being altered in 38.9% of the cases. We report here the most extensive analysis of alterations of PAX5 coding sequence in 117 adult BCP-ALL patients in the unique clinical protocol GRAALL-2003/GRAAPH-2003. Our study demonstrates that PAX5 is mutated in 34% of adult BCP-ALL, mutations being partial or complete deletion, partial or complete amplification, point mutation or fusion gene. PAX5 alterations are heterogeneous consisting in complete loss in 17%, focal deletions in 10%, point mutations in 7% and translocations in 1% of the cases. PAX5 complete loss and PAX5 point mutations differ. PAX5 complete loss seems to be a secondary event and is significantly associated with BCR-ABL1 or TCF3-PBX1 fusion genes and a lower white blood cell count. Leukemia (2009Leukemia ( ) 23, 1989Leukemia ( -1998 doi:10.1038/leu.2009; published online 9 July 2009 Keywords: BCP-ALL; oncogenesis; BCR-ABL1; PAX5; TCF3-PBX1 Introduction PAX5 (paired-box domain 5) is the guardian of the B-cell identity as stated in a recent review. 1 This transcription factor belongs to the family of paired-box domain transcription factors. 2 Its expression is initiated during early stages of B-cell differentiation beginning at the pro-B stage, 3 and is turned off to allow terminal B-cell differentiation. 4 The Pax5 homozygous deletion in murine models leads to the trans-or de-differentiation of B-cells into several other hematopoietic cell lineages. [5][6][7] PAX5 is thus involved both in the maintenance of B-cell identity and in the control of terminal B-cell differentiation.Deregulations and mutations of key differentiation factors are frequently found in lymphomas and leukemias. Translocations associated with hematologic malignancies involving PAX5 exemplify PAX5 dual function. On one hand, the t(9;14)(p13;q32) translocation brings the potent enhancer of the IGH gene close to the PAX5 promoter leading to an aberrant expression of a normal PAX5 protein. 8,9 This translocation is recurrent in small plasmacytoid B-cell lymphocytic lymphomas and diffuse large B-cell lymphomas. 10 It emphasizes the importance of PAX5 downregulation during terminal B-cell differentiation. 9 On the other hand, PAX5 translocations have also been associated with a block of early B-cell differentiation because the PAX5-ETV6 chimeric protein, product of the dic(9;12)(p13;p13), is associated with B-cell progenitor acute lymphoblastic leukemia (BCP-ALL). 11 Additional PAX5 fusion partner genes have been identified as HIPK1 (chromosomal band 1p13), 12-14 LOC392027 (7p12.1), 15 AUTS2 (7q11.1), 13 POM121 (7q11), 14 ELN (7q11), 16 JAK2 (9p24), 14 SLCO1B3 (12p12), 15 DACH1 (13q21), 14 PML (15q24), 17 ZNF5...

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Minimal residual disease (MRD) quantification is widely used for therapeutic stratification in pediatric acute lymphoblastic leukemia (ALL). A robust, reproducible, sensitivity of at least 0.01% has been achieved for IG/TCR clonal rearrangements using allele-specific quantitative PCR (IG/TCR-QPCR) within the EuroMRD consortium. Whether multiparameter flow cytometry (MFC) can reach such inter-center performance in ALL MRD monitoring remains unclear. In a multicenter study, MRD was measured prospectively on 598 follow-up bone marrow samples from 102 high-risk children and 136 adult ALL patients, using IG/TCR-QPCR and 4/5 color MFC. At diagnosis, all 238 patients (100%) had at least one suitable MRD marker with 0.01% sensitivity, including 205/238 samples (86%) by using IG/TCR-QPCR and 223/238 samples (94%) by using MFC. QPCR and MFC were evaluable in 495/598 (83%) samples. Qualitative results (<0.01% or ≥0.01%) concurred in 96% of samples and overall positivity (including <0.01% and nonquantifiable positivity) was concurrent in 84%. MRD values ≥0.01% correlated highly (r(2)=0.87) and 69% clustered within half-a-log(10). QPCR and MFC can therefore be comparable if properly standardized, and are highly complementary. MFC strategies will benefit from a concerted approach, as does molecular MRD monitoring, and will contribute significantly to the achievement of 100% MRD informativity in adult and pediatric ALL.

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