Many prognostic markers have been identified in chronic lymphocytic leukemia, but there have been few opportunities to assess their relative importance in a large randomized trial. The aim of this ...study was to determine which of the available markers independently predicted outcome in patients requiring treatment and to use these to define new risk groups.
A broad panel of clinical and laboratory markers, measured at randomization in patients entering the LRF CLL4 trial, was assessed with respect to treatment response, progression-free and overall survival, at a median follow-up of 68 months.
Using the factors identified as independent predictors for progression-free survival, patients were subdivided into three risk groups: 6% had poor risk with known TP53 loss of greater than 10%; 72% had an intermediate risk without TP53 loss (≤ 10%) and with at least one of: unmutated IGHV genes and/or IGHV3-21 usage, 11q deletion, β-2 microglobulin greater than 4 mg/L; 22% had a good risk (with none of the above and mutated IGHV genes). The 5-year progression-free survival rates for these three groups were 0%, 12% and 34%, respectively, and the corresponding 5-year overall survival rates were 9%, 53% and 79% (both P<0.00005 independent of treatment allocation). In the intermediate risk group 250 patients, with data for all three risk factors, were further subdivided into intermediate-low (one risk factor) or intermediate-high (2 or 3 risk factors). The 5-year progression-free survival rates were 18% and 7% (P=0.0001) and the 5-year overall survival rates were 68% and 40% (P<0.00005), respectively.
This study demonstrates the role of biomarkers in prognosis and shows that, in patients requiring treatment, disease stage may no longer be an independent predictor of outcome. If validated independently, the risk groups defined here may inform the design of future trials in chronic lymphocytic leukemia.
We analyzed by flow cytometry the expression of CD20 and FMC7 in cell suspensions from 932 patients, including 630 cases of chronic lymphocytic leukemia (CLL), 23 cases of other B-cell leukemias, and ...279 cases of B-cell non-Hodgkin lymphoma (B-cell NHL). CD20 was positive in 94.5% of cases; FMC7 was positive in 35.7%. There was a correlation between CD20 and FMC7 expression in patients with B-cell NHL (P < .001) but not CLL (P = .1). We also tested a scoring system in which FMC7 was replaced by CD20 and compared it with our current scoring system for CLL. With this modification, the accuracy of the scoring system for differentiating CLL from other non-CLL disorders fell from 94.4% to 81.5%. In CD20+ CLL, the intensity of CD20 expression correlated with FMC7 and low scores (P < .001 for both comparisons). We suggest that the particular conformation of CD20 recognized by FMC7 is manifested only in cells with strong CD20 expression, which is not the case for CLL. FMC7 is of greater diagnostic value than CD20 for distinguishing CLL from other B-cell disorders; we recommend its continued use for this purpose.
Summary
Hairy cell leukaemia variant (HCL‐variant) and splenic marginal zone lymphoma (SMZL) are disorders with overlapping features. We investigated the prognostic impact in these disorders of ...clinical and molecular features including
IGH
VDJ
rearrangements,
IGHV
gene usage and
TP
53 mutations. Clinical and laboratory data were collected before therapy from 35 HCL‐variant and 68 SMZL cases. End‐points were the need for treatment and overall survival. 97% of HCL‐variant and 77% of SMZL cases required treatment (P = 0·009). Survival at 5 years was significantly worse in HCL‐variant 57% (95% confidence interval 38–73%) compared with SMZL 84% (71–91%); Hazard Ratio 2·25 (1·20–4·25), P = 0·01. In HCL‐variant, adverse prognostic factors for survival were older age (P = 0·04), anaemia (P = 0·01) and
TP
53 mutations (P = 0·02). In SMZL, splenomegaly, anaemia and
IGHV
genes with >98% homology to the germline predicted the need for treatment; older age, anaemia and
IGHV
unmutated genes (100% homology) predicted shorter survival.
IGHV
gene usage had no impact on clinical outcome in either disease. The combination of unfavourable factors allowed patients to be stratified into risk groups with significant differences in survival. Although HCL‐variant and SMZL share some features, they have different outcomes, influenced by clinical and biological factors.
An adequate bone marrow sample is essential for a rapid diagnosis of acute leukaemia by multicolour flow cytometry enabling the assignment of lineage and choice of therapy.
Diagnosis is sometimes ...delayed due to difficulties in of obtaining a bone marrow aspirate due to a ‘dry tap’.
In this study we evaluated immunophenotyping of mechanically disaggregated unfixed bone marrow trephine biopsies from 62 paediatric and adult patients at diagnosis (mostly acute leukemia). We compared the results to immunophenotyping of blood and aspirate samples and the trephine biopsy histology.
In 26 of 62 cases no disease was present in the blood and the aspirate was a ‘dry tap’. In 24 of 26 cases a diagnosis was reached by immunophenotyping from the disaggregated bone marrow biopsy. Results were concordant with histopathology in all 24 cases (22 acute lymphoblastic leukemia(ALL) cases, 2 acute myeloid leukemia (AML) cases). In 2 cases insufficient cells were obtained from the disaggregated biopsy to reach a diagnosis.
In 36 of 62 cases immunophenotyping was performed on disaggregated unfixed bone marrow trephine biopsies and compared to immunophenotyping on blood and/or aspirate as well as histology. The immunophenotyping findings were concordant in 33 cases between the (21 ALL, 6 AML, 3 myelodysplastic syndromes|(MDS), 3 other haematological malignancies). In 3 cases insufficient cells could be obtained from the disaggregated biopsy. In one of these the histology from the bone marrow biopsy showed cortical bone only, while the other two showed AML and MDS.
In conclusion these data confirm earlier reports that immunophenotyping of mechanically disaggregated unfixed trephines is a useful diagnostic adjunct particularly where a dry tap has occurred.
No relevant conflicts of interest to declare.
CD123 is an antibody that identifies the a chain of the human interleukin-3 receptor and is expressed in a variety of normal hematopoietic cells, acute leukemia and hairy cell leukemia (HCL). The aim ...of the study was to investigate the diagnostic value of CD123 expression in B-cell disorders with circulating hairy and villous lymphocytes.
We investigated the diagnostic value of CD123 expression in neoplastic cells from 59 patients with B-cell disorders with circulating hairy or villous lymphocytes: HCL (n=24), the variant form of HCL (n=11) and splenic lymphoma with villous lymphocytes (SLVL) (n=24). Cells from 12 patients with chronic lymphocytic leukemia were used as controls. Immunophenotypic analysis was performed by flow cytometry on 77 samples from peripheral blood (n=48), bone marrow (n=25) and spleen cell suspensions (n=4).
Our findings show that cells from 95% of typical HCL express CD123 with strong to moderate intensity while this molecule is absent in circulating cells from most cases of HCL-variant (91%) and SLVL (97%).
We conclude that CD123 is a useful new marker for distinguishing B-cell disorders with circulating villous lymphocytes as its expression is characteristic of typical HCL with high sensitivity and specificity. However CD123 does not allow the distinction between HCL-variant and SLVL, as both are CD123 negative.
A scoring system, based on the immunophenotypic analysis of a panel of five membrane markers (CD5, CD22, CD23, FMC7, SmIg) was shown to be useful in the distinction between chronic lymphocytic ...leukemia (CLL) and other B-cell lymphoproliferative diseases (non-CLL). We investigated whether the monoclonal antibody SN8 (CD79b) could improve our previous scoring system. Peripheral blood samples of 298 patients with CLL and 166 patients with non-CLL were analyzed by flow cytometry. Using the five standard markers, the accuracy of the scoring system was 91.8%, using a cutoff of 4 points or higher, to distinguish CLL from non-CLL. This was increased to 96.6% if SN8 was added and a cutoff of 4 points or higher was also used. A similar accuracy, 96.8%, was observed if CD22 was excluded and a cutoff of 3 points or higher was used. Thus, the replacement of CD22 by SN8 in the original scoring system significantly increases its potential to discriminate between CLL and other B-cell lymphoproliferative diseases.
ZAP-70, CD38 and IGHV mutations have all been reported to have prognostic impact in chronic lymphocytic leukemia (CLL), both individually and in paired combinations. We aimed to determine whether the ...combination of all three factors provided more refined prognostic information concerning the treatment-free interval (TFI) from diagnosis. ZAP-70, CD38 and IGHV mutations were evaluated in 142 patients. Combining all three factors, the ZAP-70− CD38− Mutated group showed the longest median TFI (62 months, n = 37), ZAP-70+ CD38+ Unmutated cases the shortest (11 months, n = 37) and cases discordant for ≥1 factor, an intermediate TFI (27 months, n = 68) (p = 0.006). Analysis of discordant cases revealed values that were otherwise masked when measuring single prognostic factors. The presence or absence of cytogenetic abnormalities did not explain the variability among discordant cases. Simultaneous analysis of ZAP-70, CD38 and IGHV mutations in CLL provides more discriminatory prediction of TFI than any factor alone.
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