Prognostic Subgroups in B-Cell Chronic Lymphocytic Leukemia Defined by Specific Chromosomal Abnormalities

Juliusson, Gunnar; Oscier, David; Fitchett, M.; Ross, Fiona; Stockdill, G.; Mackie, M. J.; Parker, A. C.; Castoldi, Gian Luigi; Cuneo, Antonio; Knuutila, Sakari; Elonen, Erkki; Gahrton, Gösta

doi:10.1056/nejm199009133231105

Cited by 556 publications

(350 citation statements)

References 32 publications

Supporting

Mentioning

319

Contrasting

Unclassified

Order By: Relevance

“…Although uncommon at the time of diagnosis (generally <5%) (Juliusson et al , 1990), the percentage of patients with CLL whose disease harbours del(17p) increases to as much as 10% when therapy is first indicated and can be identified in >40% of multiply relapsed and/or heavily pre‐treated patients (Zenz et al , 2012). Patients with CLL and del(17p) have shorter times to treatment and inferior responses to treatment than other subgroups of CLL patients (Tam & Stilgenbauer, 2015).…”

mentioning

confidence: 99%

Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials

et al. 2018

View full text Add to dashboard Cite

SummaryPatients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) with deletion 17p [del(17p)] have poor outcomes with chemoimmunotherapy. Ibrutinib is indicated for the treatment of CLL/SLL, including del(17p) CLL/SLL, and allows for treatment without chemotherapy. This integrated analysis was performed to evaluate outcomes in 230 patients with relapsed/refractory del(17p) CLL/SLL from three ibrutinib studies. With a median of 2 prior therapies (range, 1–12), 18% and 79% of evaluable patients had del(11q) or unmutated IGHV, respectively. With a median follow‐up of 28 months, overall response rate was 85% and estimated 30‐month progression‐free and overall survival rates were 57% [95% confidence interval (CI) 50–64] and 69% (95% CI 61–75), respectively. Patients with normal lactate dehydrogenase or no bulky disease had the most favourable survival outcomes. Sustained haematological improvements in haemoglobin, platelet count and absolute neutrophil count occurred in 61%, 67% and 70% of patients with baseline cytopenias, respectively. New onset severe cytopenias and infections decreased in frequency over time. Progression‐free and overall survival with ibrutinib surpass those of other therapies for patients with del(17p) CLL/SLL. These results provide further evidence of the robust clinical activity of ibrutinib in difficult‐to‐treat CLL/SLL populations.

show abstract

mentioning

confidence: 99%

Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Although a number of recurrent chromosome aberrations have been identi®ed, no gene to date has been found to be consistently involved (Juliusson et al, 1990;DoÈ hner et al, 1997a).…”

mentioning

confidence: 99%

“…The most common structural chromosome aberrations in B-CLL involve band 13q14 (Juliusson et al, 1990), to which the RB1 tumor suppressor gene has been localized (Friend et al, 1986). Monoallelic RB1 deletion was frequently observed in B-CLL but disruption of both RB1 alleles occurred rarely (Liu et al, 1992(Liu et al, , 1993Stilgenbauer et al, 1993).…”

mentioning

confidence: 99%

Expressed sequences as candidates for a novel tumor suppressor gene at band 13q14 in B-cell chronic lymphocytic leukemia and mantle cell lymphoma

et al. 1998

View full text Add to dashboard Cite

Deletions a ecting the interval between the RB1 gene and marker D13S25 at band 13q14 are the most frequent genetic abnormalities of B-cell chronic lymphocytic leukemia (B-CLL) and indicate the presence of a novel tumor suppressor gene in this region. In the current study, a high resolution physical map of fragments spanning one megabasepair (Mb) of genomic DNA at the critical 13q14 segment was constructed. To de®ne the minimal region of loss within the RB1 and D13S25 interval, we screened 322 B-CLLs for deletions at either of the two loci. Thirty mantle cell lymphomas (MCLs) were included in the analysis because we observed a 13q14 deletion pattern similar to B-CLL in this disease. The incidence of 13q14 deletions was 51% in B-CLL and 70% in MCL, respectively. No frequent loss of the BRCA2 gene at band 13q12 was found. Detailed deletion mapping at band 13q14 with probes from the RB1 ± D13S25 interval lead to the identi®cation of a critical deletion region 400 kb in size. Within this region two segments were most frequently a ected, one at D13S272 120 kb in size and another 240 kb distal of D13S272 80 kb in size. From these two segments expressed sequences were identi®ed as candidates for the putative 13q14 tumor suppressor gene involved in the pathogenesis of B-CLL and MCL.Keywords: deletion mapping; FISH; exon ampli®cation; DIRVISH The molecular pathogenesis of B-CLL, the most frequent leukemia in Western countries, is not well understood (Rozman and Montserrat, 1995). Although a number of recurrent chromosome aberrations have been identi®ed, no gene to date has been found to be consistently involved (Juliusson et al., 1990;DoÈ hner et al., 1997a).The most common structural chromosome aberrations in B-CLL involve band 13q14 (Juliusson et al., 1990), to which the RB1 tumor suppressor gene has been localized (Friend et al., 1986). Monoallelic RB1 deletion was frequently observed in B-CLL but disruption of both RB1 alleles occurred rarely (Liu et al., 1992(Liu et al., , 1993Stilgenbauer et al., 1993). Based on the observation that the distal marker D13S25 was deleted more frequently than RB1, a novel B-CLL tumor suppressor gene located in vicinity to this marker was postulated (Brown et al., 1993;Liu et al., 1993;Chapman et al., 1994).Subsequent studies aimed at the localization of this gene have been thus far inconclusive. Devilder et al.(1995) localized a minimal deletion segment distal of D13S25. However, comparing deletions of RB1 and D13S25 lead us to the hypothesis that the critical segment is localized proximal of D13S25 (Stilgenbauer et al., 1995). This was supported by Liu et al. (1995) who found loss of D13S319 located less than 680 kb proximal of D13S25 more frequently deleted than other 13q14 markers. Bullrich et al. (1996) recently assembled a YAC contig to order new markers in the region and identi®ed a minimal deletion between D13S25 and the marker 206XF12 located less than 550 kb proximal of D13S25. However, in this study deletions did not appear to cluster in a single critical region and the poten...

show abstract

“…35 In a large cooperative study on 433 patients, 36 the most common abnormalities were trisomy 12 (n = 67), structural abnormalities of chromosome 13 (n = 51), and structural abnormalities of chromosome 14 (n = 41, mainly 14q+ aberrations). The chromosome aberrations in our patients did not involve chromosomes 12, 13 and 14.…”

Section: Discussionmentioning

confidence: 99%

Four aged siblings with B cell chronic lymphocytic leukemia

F¹,

Dinkelaar

Hagemeijer

et al. 1997

Leukemia

View full text Add to dashboard Cite

All four aged siblings (Ͼ80 years) of one family presented with B cell chronic lymphocytic leukemia (B-CLL). In an attempt to find common characteristics in the four patients, we performed detailed immunological marker analysis, Southern blot analysis of immunoglobulin (Ig) genes, and cytogenetic studies. In three patients clonality of the B-cells could be proven by single Ig light chain expression, but in the fourth patient no Ig light chain expression was detected and clonality of the B cells could only be demonstrated by Southern blot analysis of the Ig genes. Interestingly, in two patients, the Ig gene rearrangement patterns were compatible with the presence of two independent B cell clones, whereas in the two other siblings a monoclonal rearrangement pattern was found. All four patients showed clonal chromosome aberrations, which were different in each patient. In the two patients with biclonal Ig gene rearrangement patterns, two unrelated clones could also be demonstrated by the cytogenetic studies. These combined Ig gene and cytogenetic data indicate the presence of two different B-CLL in two of the four patients. Remarkably, the B-CLL cells of the two oldest patients expressed the CD8 antigen, which is rarely observed. Our finding of six different B-CLL in the four living siblings indicates that the members of this family are highly susceptible to the development of B-CLL. However we could not identify a common factor to explain this susceptibility further. In contrast to the literature, the occurrence of two B-CLL in one patient and the expression of CD8 were not associated with clinically aggressive disease in this family.

show abstract

Prognostic Subgroups in B-Cell Chronic Lymphocytic Leukemia Defined by Specific Chromosomal Abnormalities

Abstract: Chromosomal analysis provides prognostic information about overall survival in addition to that supplied by clinical data in patients with B-cell CLL.

Cited by 556 publications

References 32 publications

Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials

Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials

Expressed sequences as candidates for a novel tumor suppressor gene at band 13q14 in B-cell chronic lymphocytic leukemia and mantle cell lymphoma

Four aged siblings with B cell chronic lymphocytic leukemia

Contact Info

Product

Resources

About