Prognostic cytogenetic markers in childhood acute lymphoblastic leukemia: Cases from Mansoura Egypt

The objective of the work was to evaluate children with acute lymphoblastic leukemia (ALL) showing resistance to immediate induction chemotherapy in relation to conventional and advanced cytogenetic analysis. The study was conducted on 63 ALL children (40 males and 23 females) with age range 4.5 months–16 years (mean = 7.76 years). They included 37 cases who attained a true remission and 26 complicated by failure of remission, early relapse or death. They were subjected to history, clinical examination and investigations including CBC, BM examination, karyotyping, FISH for translocations and flowcytometry for immunophenotyping and minimal residual disease diagnosis.

Cases aged <5 years; male sex with organomegaly had better remission although statistically insignificant. Initially low HB <8 gm/dl, high WBCs and platelet counts >50.000/mm³ also showed better but non-significant remission rates. Most of our cases were L₂ with better remission compared to other immunophenotypes. About 40 informative karyotypes were subdivided into 15 hypodiploid, 10 pseudodiploid, 8 normal diploid and 7 hyperdiploid cases; the best remission rates were noticed among the most frequent ploidy patterns. Chromosomes 9, 11 and 22 were the most frequently involved by structural aberrations followed by chromosomes 5, 12 and 17. Resistance was noted with aberrations not encountered among remission group; deletions involving chromosomes 2p, 3q, 10p and 12q; translocations involving chromosome 5; trisomies of chromosomes 16 and 21; monosomies of 5 and X and inversions of 5 and 11. Our conclusions were that cytogenetic and molecular characterizations of childhood ALL could add prognostic criteria for proper therapy allocation.     

Prognostic cytogenetic markers in childhood acute lymphoblastic leukemia: Cases from Mansoura,Egypt

Objective: To evaluate children with acute lymphoblastic leukemia (ALL) showing resistance to immediate induction chemotherapy in relation to conventional and advanced cytogenetic analysis.

Subjects and methods: This work was conducted on 63 ALL children (40 males and 23 females) with age range 4.5 months–16 years (mean = 7.76 years). They included 37 cases who attained true remission and 26 complicated by failure of remission, early relapse or death. They were subjected to history, clinical examination and investigations including CBC, BM examination, karyotyping, FISH for translocations and flow cytometry for immunophenotyping and minimal residual disease diagnosis.

Results: Cases aged <5 years; male sex with organomegaly had better remission although statistically insignificant. Initially low Hb < 8 gm/dl, high WBCs and platelet counts > 50,000/mm³ also showed better but non-significant remission rates. Most of our cases were L ₂ with better remission compared to other immunophenotypes. Forty informative karyotypes were subdivided into 15 hypodiploid, 10 pseudodiploid, 8 normal diploid and 7 hyperdiploid cases; the best remission rates were noticed among the most frequent ploidy patterns. Chromosomes 9, 11 and 22 were the most frequently involved by structural aberrations followed by chromosomes 5, 12 and 17. Resistance was noted with aberrations not encountered among remission group; deletions involving chromosomes 2p, 3q, 10p and 12q; translocations involving chromosome 5; trisomies of chromosomes 16 and 21; monosomies of 5 and X and inversions of 5 and 11.

Conclusions: Cytogenetic and molecular characterizations of childhood ALL may add prognostic criteria for optimal therapy allocation.     

Prognostic significance of cell surface markers in childhood acute lymphoblastic leukaemia

Examination of surface markers on leukaemic blasts from 51 children with ALL revealed that ALL is a heterogeneous disease. The majority (68 X) of patients with ALL lack surface markers (null leukaemia); 28% could be classed as T cell as they form rosettes with sheep RBC and 4% have been shown to possess surface immunoglobulins and hence are classed as B cells. The children with null cell leukaemia have a better prognosis than T and B cell types.     

Prognostic significance of cell surface markers in childhood acute lymphoblastic leukaemia.

Examination of surface markers on leukaemic blasts from 51 children with ALL revealed that ALL is a heterogeneous disease. The majority (68%) of patients with ALL lack surface markers (null leukaemia); 28% could be classed as T cell as they form rosettes with sheep RBC and 4% have been shown to possess surface immunoglobulins and hence are classed as B cells. The children with null cell leukaemia have a better prognosis than T and B cell types.     

Prognostic importance of blast cell DNA content in childhood acute lymphoblastic leukemia

Using flow cytometric techniques, we determined the pretreatment distribution of DNA content in propidium iodide-stained leukemic blasts from 205 children with "standard-risk" acute lymphoblastic leukemia (ALL). Risk assignment was based on an initial WBC count less than 100 X 10(9)/L, no thymic mass, no meningeal leukemia, and lymphoblasts lacking sheep erythrocyte receptors or surface immunoglobulin. A single aneuploid leukemic line was detected in 74 cases (36.1%): 70 hyperdiploid and four hypodiploid. For hyperdiploid cases, the DNA index (DI, or ratio of the DNA content of leukemic v normal G0/G1 cells) ranged from 1.06 to 2.0 (median, 1.20). A secondary leukemic line with hyperdiploid cellular DNA content was identified in 21 cases with diploid primary lines. Children whose primary leukemic line showed a DI greater than or equal to 1.16 (n = 57) had significantly better responses to treatment than did those with either a diploid DI (n = 130; P = .002) or values in the range of 1.01 to 1.15 (n = 14; P = .001). The relative risk of failure for hyperdiploid cases with DI greater than or equal to 1.16, corresponding to greater than or equal to 53 chromosomes, was one-third that of the other two groups. Treatment responses of patients with both diploid and hyperdiploid lines were identical to those associated with single diploid lines, but significantly worse than those associated with single hyperdiploid lines with DI greater than or equal to 1.16 (P = .016). The most favorable prognostic variables selected by a Cox proportional hazards model were: DI greater than or equal to 1.16 (P = .001), white race (P = .022), WBC less than or equal to 25 X 10(9)/L (P = .032), age between 2 and 9 years (P = .075), and hemoglobin less than 7.0 g/dL (P = .094). DNA index greater than or equal to 1.16 retained its significant prognostic impact even after adjustment for other variables (P = .001). With the combination of DI greater than or equal to 1.16 and WBC less than or equal to 25 X 10(9)/L, one can identify a group of children with ALL who have a low probability of relapse when treated with current therapy. If they remain disease-free after longer follow-up, it may be advisable to treat them with less intensive, hence less toxic, chemotherapy than patients with higher WBC counts or lower DI values.     

Clinical and cytogenetic features in childhood acute lymphoblastic leukemia with 1; 19 translocation

We studied the clinical and cytogenetic features of 14 acute lymphoblastic leukemia (ALL) patients with 1; 19 translocation. Ten patients had poor prognostic factors such as age over 10 years, hyperleukocytosis over 5 X 10(4)/microliters or high serum lactic dehydrogenase levels over 5,000 IU/l. Two patients had relapsed within 12 months after the onset, but their 5-year survival rate was 84.6%. Cytogenetically, 6 of 14 patients had multiple subclones. Two had the clones with hyperdiploidy greater than 50 chromosomes, which was known to be one of the favorable prognostic factors in childhood ALL. These findings show ALL children with 1; 19 translocation have a more favorable outcome in spite of some high-risk features than hitherto been thought.     

Prognostic significance of CD20 expression in childhood B-cell precursor acute lymphoblastic leukemia

CD20 expression is associated with inferior survival in adults with acute lymphoblastic leukemia (ALL). We analyzed the prognostic impact of CD20 expression in 353 children with B-cell precursor ALL treated in 3 consecutive St Jude Total Therapy studies. CD20 expression (> 20%) was found in 169 patients (48%) and was more frequent in patients between 1 and 10 years of age than in those younger than 1 or older than 10 years (P = .001). None of 14 patients with MLL-AF4 expressed CD20. There was no association between CD20 expression and E2A-PBX, TEL-AML1, ploidy, white blood cell count at diagnosis, or sex. In contrast to the experience in adult ALL, our patients with CD20 expression tended to have a better treatment outcome than those without the expression: 5-year event-free survival 84% +/- 2.9% versus 78% +/- 3.1% (P = .08). These data suggest that CD20 expression is not associated with inferior outcome in pediatric patients treated with contemporary regimens.     

Prognostic factors in adult acute lymphoblastic leukemia

The prognosis of patients with acute lymphoblastic leukemia (ALL), treated with modern chemotherapeutic regimens, is dependent on a number of variables. The major prognostic factors for survival in adult ALL are age, cytogenetic abnormalities, immunologic subtype, white blood cell (WBC) count, and time to achieve complete remission (CR). Determination of these factors is crucial for adapting post remission therapy in adult ALL. Indeed, risk-adapted strategies based on those biologic and clinical features are currently being applied to improve survival. In this review, we report the different prognostic factors described in adult ALL and discuss the controversies in current adult ALL management in relation with these different features. The data reported are derived from the medical literature and from the experience of the authors. Prognostic factors appear to be time-dependent. This emphasizes their determination according to the phase of treatment. The use of time-segmented multivariate analysis able to distinguish prognostic factors associated with the induction phase and those associated with the post-induction phase of treatment seems suitable to define accurately prognostic models.     

Prognostic factors in childhood T-cell acute lymphoblastic leukemia: a Pediatric Oncology Group study.

Two hundred fifty-three children with newly diagnosed T-cell acute lymphoblastic leukemia (ALL), who were treated uniformly with modified LSA2L2 therapy, were evaluated using univariate and recursive partition analyses to define clinical or biologic features associated with risk of treatment failure. Overall event-free survival (EFS) at 4 years was 43% (SE = 4%). Factors examined included white blood cell (WBC) level, age, gender, race (black v other), presence of a mediastinal mass, hepatomegaly, splenomegaly, marked lymphadenopathy, hemoglobin level, platelet count, blast cell expression of antigens such as the common acute lymphoblastic leukemia antigen (CALLA, CD10), HLA-DR, and T-cell-associated antigens (CD3, CD4, CD8, CD7, CD5, and THY). Univariate analysis showed that age less than or equal to 5 or less than or equal to 7 years, WBC level less than 10, less than 25, less than 50 or less than 100 x 10(3)/microL, and blast cell expression of CD4, CD8, or CALLA were associated with significantly better EFS, while hepatomegaly and splenomegaly were associated with worse EFS. Recursive partitioning analysis showed that the most important single favorable prognostic factor was a WBC level less than 50 x 10(3)/microL and, for patients with WBC counts below this level, the most important predictor of EFS was blast cell expression of the pan-T antigen defined by the monoclonal antibody (MoAb), L17F12 (CD5). For patients with higher WBC levels, the most important predictor of EFS was blast cell expression of THY antigen. The recursive partitioning analysis defined three groups of patients with widely varied prognoses identified as follows: (1) those with a WBC count less than 50 x 10(3)/microL who lacked massive splenomegaly and had blasts expressing CD5 had the best prognosis (66%, SE = 7%, EFS 4 years, n = 84); (2) those with (b1) WBC counts less than 50 x 10(3)/microL with either massive splenomegaly or who had blasts lacking CD5 expression, or (b2) WBC counts greater than 50 x 10(3)/microL with expression of the THY antigen had an intermediate prognosis (39%, SE = 7% EFS at 4 years, n = 94); (3) those with WBC counts greater than 50 x 10(3)/microL and whose blasts lacked expression of THY antigen had the poorest outcome (EFS = 19% at 4 years, SE = 8%, n = 63). A three-way comparison of EFS according to these groupings showed significant differences among the three patient groups (P less than .001). The recursive partitioning was able to classify 241 (95%) of the patients.(ABSTRACT TRUNCATED AT 400 WORDS)     

Prognostic impact of persistent cytogenetic abnormalities at complete remission in adult patients with acute lymphoblastic leukemia

In acute myelogenous leukemia, the persistent detection of abnormal cytogenetics at complete remission (ACCR) is associated with inferior outcomes. However, the prognostic significance of ACCR in adult patients with acute lymphoblastic leukemia (ALL) is unknown. We evaluated 272 adult patients with ALL and abnormal cytogenetics at baseline who were treated with frontline induction chemotherapy, achieved complete remission (CR) and had cytogenetic analysis performed at the time of CR. ACCR was observed in 26 patients (9.6%). Median relapse‐free survival was 22 months (95% CI, 12 months to not reached) for patients with ACCR vs. 48 months (range, 30–125 months) in patients with normal cytogenetics at CR (NCCR; P = 0.31). Median overall survival also did not differ significantly between the ACCR (99 months [range, 17 months to not reached]) and NCCR groups (67 months [range, 47 months to not reached], P = 0.86). The specificity of ACCR for minimal residual disease (MRD) positivity by multi‐parameter flow cytometry (MFC) was 43%, and there was overall poor correlation between these two methods for the detection of residual disease. When patients were stratified by MRD status, the presence or absence of persistent cytogenetic abnormalities at CR did not add additional prognostic information. This study suggests that there is poor association between MRD assessment by MFC and the presence or absence of cytogenetic abnormalities at CR in adult patients with ALL. ACCR was not associated with adverse outcomes in ALL and did not add additional prognostic information when MRD status by MFC was known. Am. J. Hematol. 91:385–389, 2016. © 2016 Wiley Periodicals, Inc.     

Prognostic implications of cytogenetic studies in an intensively treated group of children with acute lymphoblastic leukemia

We assessed the prognostic significance of leukemia cell cytogenetics by analyzing bone marrow aspirates obtained at time of diagnosis in 165 children on a single protocol for acute lymphoblastic leukemia (ALL). These children were assigned to six mutually exclusive cytogenetic categories as follows: (1) hyperdiploid, with 50 or more chromosomes (n = 35); (2) hyperdiploid, with 47 to 49 chromosomes (n = 11); (3) diploid (n = 42); (4) pseudodiploid (n = 34); (5) hypodiploid (n = 9); and (6) insufficient data (n = 34). At a median follow-up of 5 years, there were no statistically significant differences between any of these cytogenetic categories in either event-free or overall survival. Those children with chromosomal translocations (n = 26) appeared to fare the same as those lacking translocations (n = 105). The absence of karyotypic prognostic significance was observed not only within the overall group, but also when the results were stratified by standard- risk and high-risk status. Of the specific structural chromosome changes that we studied, only the Philadelphia chromosome (Ph) appeared to confer a poor prognosis, although there were too few such cases to achieve statistical significance. Although we did not detect the event- free survival differences that have been described previously in hyperdiploid, hypodiploid, and pseudodiploid childhood ALL, our findings must be viewed as preliminary given the small number of children in some of the cytogenetic categories. We think that the prognostic implications of these cytogenetic features might have been nullified by improvements in therapy.     

Isochromosomes in childhood acute lymphoblastic leukemia: a collaborative study of 83 cases.

Cytogenetic analysis of leukemic cells from 2,805 children with newly diagnosed acute lymphoblastic leukemia (ALL) identified 83 cases (3%) that had a stemline with at least one isochromosome. The i(9q) was present in 28 (1%), the i(17q) in 23 (0.8%), and the i(7q) in 23 (0.8%). Other isochromosomes--i(21q), i(6p), i(1q), i(8q), or i(Xq)--were found in only 12 cases (0.4%). The isochromosome cases were more likely than were other ALL cases to have a pre-B immunophenotype (38% v 25%, P = .02) and leukemic cell hyperdiploidy greater than 50 (37% v 24%, P = .02); five cases had both features. The i(9q) was associated with age greater than 10 years (P less than .05) and the pre-B immunophenotype (P = .05); both the i(17q) and i(7q) had high frequencies of hyperdiploidy greater than 50 (P less than .0001 and P = .05, respectively). The t(1;19)(q23;p13) was a common feature (23%) in cases with the i(9q), i(7q), i(6p), or i(1q). These findings establish the i(9q), i(17q), and i(7q) as nonrandom chromosomal abnormalities in ALL. The prognostic significance of the presence of isochromosome(s) remains to be determined.