Changing Natural History Of

Molica and Levato (173) analyzed 518 CLL patients diagnosed between 1970 and 1998 by forming three groups. Group I consisted of 75 patients, group II consisted of 149 patients, and group III consisted of 293 patients diagnosed with CLL in the time periods 1970-1979, 1980-1989, and 1990-1998, respectively. As expected, there was no difference between age and sex in these three time periods. The median survival values were 38, 54, and 93 mo for the time periods 1970-1979, 1980-1989, and 1990-1998, respectively. This was associated with an increase in stage A patients:

Fig. 43. Probability of disease progression, as indicated by the treatment-free interval in the patients in five genetic categories. The median treatment-free intervals for the groups with 17p deletion, 11q deletion, 12q trisomy, normal karyotype, and 13q deletion as the sole abnormality were 9, 13, 33, 49, and 92 mo, respectively. The differences between the curves were significant (p < 0.001). Twenty-five patients with various other chromosomal abnormalities were not included in the analysis. (From ref. 144, Dohner et al., 2000, Fig. 2. Copyright © 2000 Massachusetts Medical Society. All rights reserved.)

Fig. 43. Probability of disease progression, as indicated by the treatment-free interval in the patients in five genetic categories. The median treatment-free intervals for the groups with 17p deletion, 11q deletion, 12q trisomy, normal karyotype, and 13q deletion as the sole abnormality were 9, 13, 33, 49, and 92 mo, respectively. The differences between the curves were significant (p < 0.001). Twenty-five patients with various other chromosomal abnormalities were not included in the analysis. (From ref. 144, Dohner et al., 2000, Fig. 2. Copyright © 2000 Massachusetts Medical Society. All rights reserved.)

Fig. 44. (opposite page) Chromosome 13. (Modification or combination of Figs. 5 and 6 in ref. 165, Bullrick and Croce, 2001 and ref. 166, Tyazhelova et al., 2001. The figure legend is taken from refs. 165, Bullrick and Croce and 164, Stilgenbauer et al., 2001.) Chromosome banding and recently FISH and CGH have confirmed 13q14 deletions in CLL. Although RB1, a prominent tumor suppressor gene, is located in this region, biallelic deletions in CLL are rare. Homozygous deletions at the D13S25 locus suggested a CLL gene located telomeric to RB1/D13S273 and centromeric to D13S31 and D13S294. LOH and YAC cloning led to the definition of a minimum region of loss, and BAC, PAC and cosmid contigs have further defined two core regions of loss. The smaller of the two core regions is bounded by D13S273 and D13S272 and contains three genes: Leu1, Leu2, and Leu5. This is contrary to the findings of Tyazhelova et al. (166), who find at least 10 genes (DLeu through DLeu10, where D signifies "deletion"). R. Dalla-Favera says that based on work from his laboratory and in agreement with several others reports, there are no critical genes in this area and that the assignment of genes in this region on the basis of sequences is arbitrary (IWCLL Meeting, San Diego, CA, March, 2002, personal communication). Absence of mutational inac-tivation of these 3genes or 10 genes suggests that they are not critical genes in B-CLL leukemogenesis.

Fig. 44. (continued from previous page) The larger core region of loss is bounded by D13S272 and D13S25. Tyazhelova et al. (166) have investigated large nucleotide sequences in the q14 region of chromosome 13. They suggest an arbitrary division of two intervals: D13S1168 to D13S319 and GCT16C05 to D13S25. The D13S1168 to D13S319 interval is rich in Alu repeats, whereas the GCT16C05 to D13S25 interval is rich in LINE repeats. In addition, they define a new human gene, C13orf1 (chromosome 13 open reading frame 1), that is conserved in the nematode C. elegans, the fruit fly D. melanogaster, and the mouse. Another potential tumor suppressor gene has been designated PLCC (putative large CLL candidate, EST AA431979). Stilgenbauer et al. (164) pointed out that these 13q14 deletion clusters in CLL are also seen in 50% of patients with mantle cell lymphoma (MCL), and Bullrick and Croce (165) state that 13q14 deletions are associated with the transition of MGUS to multiple myeloma. One can imagine one gene (number of Alu repeats) controlling the level of the absolute lymphocytosis and the other genes controlling the transition from a benign B-cell monoclonal lymphocytosis to CLL or MCL or MGUS to MM. (With permission from MAIK "Nauka/Interperiodica," Moscow, Russia and by courtesy of Marcel Dekker, Inc.)

Fig. 44. (continued from previous page) The larger core region of loss is bounded by D13S272 and D13S25. Tyazhelova et al. (166) have investigated large nucleotide sequences in the q14 region of chromosome 13. They suggest an arbitrary division of two intervals: D13S1168 to D13S319 and GCT16C05 to D13S25. The D13S1168 to D13S319 interval is rich in Alu repeats, whereas the GCT16C05 to D13S25 interval is rich in LINE repeats. In addition, they define a new human gene, C13orf1 (chromosome 13 open reading frame 1), that is conserved in the nematode C. elegans, the fruit fly D. melanogaster, and the mouse. Another potential tumor suppressor gene has been designated PLCC (putative large CLL candidate, EST AA431979). Stilgenbauer et al. (164) pointed out that these 13q14 deletion clusters in CLL are also seen in 50% of patients with mantle cell lymphoma (MCL), and Bullrick and Croce (165) state that 13q14 deletions are associated with the transition of MGUS to multiple myeloma. One can imagine one gene (number of Alu repeats) controlling the level of the absolute lymphocytosis and the other genes controlling the transition from a benign B-cell monoclonal lymphocytosis to CLL or MCL or MGUS to MM. (With permission from MAIK "Nauka/Interperiodica," Moscow, Russia and by courtesy of Marcel Dekker, Inc.)

Fig. 45. Distribution of Ig gene sequences as either unmutated (A, bottom) or mutated (A, top). (B) Difference in the time to treatment in these two groups: median time to treatment in Ig-mutated CLL patients 95 mo; median time to treatment in Ig-unmutated CLL patients 28 mo. (From ref. 172, Rosenwald et al., 2001, by copyright permission of the Rockefeller University Press.)

Fig. 45. Distribution of Ig gene sequences as either unmutated (A, bottom) or mutated (A, top). (B) Difference in the time to treatment in these two groups: median time to treatment in Ig-mutated CLL patients 95 mo; median time to treatment in Ig-unmutated CLL patients 28 mo. (From ref. 172, Rosenwald et al., 2001, by copyright permission of the Rockefeller University Press.)

26.3% in group I, 50.3% in group II, and 72% in group III. Despite this increasing early stage distribution, survival values did not change when they were analyzed according to individual stages. Even when controlled for early smoldering CLL (so-called stage A) and compared with age- and sex-matched controls, CLL remains an incurable disease with a decreased overall survival. Earlier diagnosis and better health care for the elderly contribute to some of the observed changes. Molica and Levato (173) further note that an increase in survival has occurred mainly in the high-risk category patient. However, given that the introduction of purine analogs has not increased overall survival, they consider the improvement in overall survival to be a function of time to the prevention and treatment of both disease- and treatment-related complications. This has probably led to or accounted for the observed gain in overall survival of stage C patients in the last decade. It should be noted that Rozman et al. (174) have noted a shift in the age of onset of CLL in Spain, and this is thought to be partially related to the increase in longevity in Spain over the last 50 yr.

Fig. 46. Higher (A) and lower (B) B-cell gene expression in Ig-unmutated CLL. (From ref. 172, Rosenwald et al., 2001, by copyright permission of the Rockefeller University Press.)

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