We present the clinicopathologic findings and survival data on. 10 patients with acute lymphoblastic leukemia (ALL) and a rare t(8;14)(q11.2;q32). There were ...
Leukemia (2000) 14, 238–240 2000 Macmillan Publishers Ltd All rights reserved 0887-6924/00 $15.00 www.nature.com/leu
Acute lymphoblastic leukemia with an unusual t(8;14)(q11.2;q32): a Pediatric Oncology Group study Z Kaleem1, JJ Shuster2, AJ Carroll3, MJ Borowitz4, DJ Pullen5, BM Camitta6, MM Zutter1 and MS Watson7 Divisions of 1Surgical Pathology and 7Medical Genetics, Washington University School of Medicine, St Louis, MO; 2POG Statistical Office and Department of Statistics, University of Florida, Gainesville, FL; 3Department of Human Genetics, University of Alabama at Birmingham, AL; 4Department of Pathology, Johns Hopkins University, Baltimore, MD; 5Department of Pediatrics, University of Mississipi, Jackson, MS; 6 Midwest Children Cancer Center, Milwaukee, WI; and the Pediatric Oncology Group, Chicago, IL, USA
We present the clinicopathologic findings and survival data on 10 patients with acute lymphoblastic leukemia (ALL) and a rare t(8;14)(q11.2;q32). There were five male and five female patients, nine Caucasians and one Black, aged 4–17 (median 10.9) years. Three had Down syndrome. Eight (80%) patients had a white blood cell (WBC) count ⬍50 × 109/l at presentation. No patient had central nervous system involvement or a mediastinal mass. Two patients had concurrent splenomegaly and hepatomegaly. Adenopathy was absent in four, minimal in three, moderate in one and prominent in two patients. All eight cases where immunophenotyping was performed by flow cytometry showed a B-precursor phenotype with expression of CD10 (CALLA). Only one case exhibited t(8;14)(q11.2;q32) as the sole karyotypic abnormality. Three patients were classified as standard-risk and seven high-risk by NCI (National Cancer Institute) consensus risk group categories. All patients achieved complete remission and seven patients were in complete continuous remission (CCR) after chemotherapy designed for B-precursor ALL. Three patients relapsed after 23.5, 31.3 and 32.1 months of EFS; the first patient also had t(9;22)(q34;q11), the second had a WBC count of 126 × 109/l at presentation while the third patient had no high risk features except for age 10 years. Thus, from our data, the t(8;14)(q11.2;q32) does not appear to confer an increased risk of relapse. Further observations are needed to confirm this conclusion. Leukemia (2000) 14, 238–240. Keywords: lymphoblastic leukemia; t(8;14)(q11.2;q32); prognosis
Introduction Clonal cytogenetic abnormalities, seen in more than 80% of cases of acute lymphoblastic leukemia (ALL), confer important prognostic information that retains significance in multivariate analysis.1–5 Complete remission (CR) rate, remission duration, as well as event-free survival (EFS) are all significantly correlated with specific karyotypic abnormalities.6–8 A rare, nonrandom t(8;14)(q11.2;q32) has been described in patients with ALL. Only 11 other cases of t(8;14)(q11.2;q32) were identified in the English medical literature.9–15 This translocation is distinct from the more common translocation involving c-myc on chromosome 8q24 [t(8;14)(q24;q32)] that is associated with a mature B cell phenotype and requires intensive chemotherapy (Figures 1a and 1b).16 Because of its rarity, little information is available on patient characteristics and disease outcome. We describe the clinicopathologic findings and outcomes of 10 patients with ALL and a t(8;14)(q11.2;q32) and summarize the findings of 11 previously reported cases.
Figure 1 (a) G-banded partial karyotype of a case of ALL showing t(8;14)(q11.2;q32). (b) Diagrammatic representation of translocation (8;14)(q11.2;q32).
Materials and methods Correspondence: MS Watson, Division of Medical Genetics, Department of Pediatrics, Washington University School of Medicine, St Louis, MO 63110, USA; Fax: 314 454 2075 Received 9 July 1999; accepted 21 October 1999
The 10 patients were identified from 8717 patients registered on the Pediatric Oncology Group (POG) classification studies 8600, 9000 and 9400. One of the 10 patients from study 8600 (patient 1) has previously been reported.10 The bone marrow
Acute lymphoblastic leukemia with t(8;14)(q11.2;q32) Z Kaleem et al
Table 1
Case
1 2 3 4 5 6 7 8 9 10
239
Summary of the clinicopathologic findings of 10 cases with t(8;14)(q11.2;q32)
Age (years)/Sex
WBC count ×109/l
EFS (months)
Outcome
Modal
13/F 17.2/F 17.1/F 16.5/M 8.9/F 10/F 4/M 8.5/F 10.3/M 11.6/M
126 4.0 2.0 8.0 7.0 172 20 8.6 23.8 11.0
31.3 32.1 112.2 108.2 97.7 98.7 23.5 30 23.6 NA
Fail Fail CCR CCR CCR CCR Fail CCR CCR CCR
46 46 47 50 56 47 46 47 46 47
Additional abnormalities
i(9)(q10) none add(16)t(16;?)(q24;?),+21c +X,+4,+5,+der(14)t(8;14)(q11.2;q32) +X,der(3)t(3;8)(q27;q13),+5,+7,+8,+10,+14,+18,+21,+21,+22 del(13)(q14),+der(14)t(8;14)(q11.2;q32) der(X)t(X;8)(q28;q11.2),t(9;22)(q34;q11.2),add(17)(p13) del(9)(p13p22),+21c t(1;5)(p32;q31) +21c
EFS, event-free-survival; ND, not done; NA, not available; CCR, complete continuous remission. Table 2
Ref.
9 10 10 10 11 12 13 13 14 14 15
Summary of the 11 previously reported cases of ALL with t(8;14)(q11.2;q32)
Age (years)/Sex
WBC count ×109/l
Down Synd
15/M 4/M 13/M 17/M 4/NG 9/M 48/NG 29/M 3.9/M 32/M 4/M
51 4 93 240 93 7.3 6 3.5 34 1.9 30
Noa NG NG NG NG NG No No Yes Yes Yes
Organomegaly
Liver, Spleen NG NG NG Liver, Spleen NG NG NG Liver Submandibular Liver, Spleen
Phenotype
Null cell Early pre-B Early pre-B Pre-B Biphenotypic Null cell Early pre-B Early pre-B Early pre-B Early pre-B Early pre-B
Add Ch Ab
Present NG NG Ph+ Ph+, others None None None None (+21c) None (+21c) None (+21c)
Outcome
NG NG NG NG Alive, Alive, NG NG Alive, Died, Alive,
9+ m 51+ m 6+ y 8.5 m 5+ m
Add Ch Ab, additional chromosomal abnormalities; NG, not given. a Mental retardation but no Down syndrome.
samples were collected and processed for cytogenetic study as previously described.5 Briefly, bone marrow samples were transported overnight in RPMI 1640 with 15% fetal calf serum and were cultured for 24 h at 37°C. Cells were exposed to colcemid (0.05 g/ml) for 2.5 h at 4°C and harvested routinely. Routine slide preparation and Giemsa banding were performed. Specimens for immunophenotyping were sent to the POG immunophenotyping reference laboratory. Ficoll–Hypaqueenriched blasts at a final concentration of 5 × 106/ml were stained in a final volume of 100 l by two-color immunofluorescence with a panel of monoclonal antibodies directly conjugated with fluorescein isothiocyanate (FITC) or phycoerythrin (PE). Antibodies against CD10, CD34 and CD45 were tested with FITC conjugates, and CD19, CD20, CD22 and HLA-DR were tested with PE conjugates. Additional markers tested in some of the cases included CD13, CD33, CD15, CD24 and CD9. Stained cells were analyzed by FACScan flow cytometer (Becton Dickinson, San Jose, CA, USA). Because of the small number of patients, the study should be viewed as purely descriptive. No statistical comparisons were deemed to be appropriate. Results The patient data are summarized in Table 1. Of patients entered on B-precursor studies, 4873 patients had satisfactory cytogenetic studies (normal, 1221; abnormal, 3652) and only
10 (0.2%) showed t(8;14)(q11.2;q32). There were equal numbers of male and female patients. The median age at presentation (10.9 years) was higher than in non-infant B-precursor patients without this translocation in the POG database (4.7 years). None of the patients were infants. Three of the 10 patients had Down syndrome as compared to 3% of the noninfant B-precursor protocol patients in the POG. Organomegaly was not prominent. Adenopathy was absent in four, minimal in three, moderate in one and prominent in two patients. No patient had a mediastinal mass or central nervous system involvement. Among the characteristic laboratory features were a low WBC at presentation (⬍50 × 109/l in 80% of patients) and a high frequency of additional chromosomal abnormalities including hyperdiploidy (50 and 56 chromosomes) in two cases. All eight cases in which immunophenotyping was performed had a B-precursor phenotype with expression of CD10. Seven of the 10 patients were classified as higher risk (WBC ⬎50 × 109/l or age ⭓10 years) and three as standard risk (WBC ⬍50 × 109/l and age ⬍10 years) according to CTEP/NCI consensus risk group designations.17 All patients were treated on protocols designed for B-precursor ALL. All patients had a complete response to induction chemotherapy. For the nine patients where EFS was available, six were in complete continuous remission. Three patients relapsed after 23.5, 31.3 and 32.1 months of EFS. Of these, the first patient had t(9;22), the second patient had a WBC of 126 × 109/l while the third patient had no high risk features except for age ⬎10 years. Leukemia
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Discussion The clinicopathologic findings on 10 patients described in this report are very similar to the 11 previously reported cases of ALL with t(8;14)(q11.2;q32) (Table 2). These patients tend to be older children and adolescents with a WBC of ⬍50 × 109/l in most cases. Hepatosplenomegaly and lymphadenopathy were uncommon. CNS involvement or a mediastinal mass at presentation was not a feature. The increased association of Down syndrome with this subset of ALL is of particular interest and merits further investigation. Except for one biphenotypic ALL with B-lymphoid and myeloid antigen expression and two cases with a null-cell phenotype, all reported cases had a Bprecursor immunophenotype with expression of CD10 whenever provided. An interesting finding was the presence of additional karyotypic abnormalities in most cases. A candidate gene located at 8q11, c-mos, may be the potential sequence upregulated by translocating to IgH locus at 14q32.18 C-mos is a serine/threonine kinase that is expressed at low levels in normal T- and B-lymphocytes.19,20 Although the precise role of c-mos in humans is still incompletely understood, it appears to act as an upstream activator of mitogen-activated protein kinase (MAPK).21 MAPK is required for Cdc2 activation, thus promoting cell growth.22 Cmos and the flanking regions of its gene are mutated in some benign pleomorphic adenomas of the salivary glands.23 Further investigation of its potential involvement in leukemia genesis is warranted.
7 8 9 10
11
12 13
14
15
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