Molecular Genetics

In 1987 and 1989, Shen et al. (99) and Kipps et al. (100) made a major contribution to the molecular analysis of Ig genes in CLL. Their initial observation was that the B-cell antibody repertoire in CLL was limited. This was based on the finding that certain variable (V) region heavy chain (H) Ig genes were expressed more frequently and in fact that certain genes within a given family were expressed at an even higher frequency. Further analysis by Fais et al. (101) in 1998 of the B-cell receptor (BCR) showed that it can be either mutated or unmutated. Continued

Fig. 35. Overall survival of all CLL cases with typical and atypical morphology. (From ref. 97, Criel et al.. 1999, Fig. 2.)

analysis of the Ig genes in CLL led to a further finding that some patients had their Ig gene nucleic acid sequence in a germline configuration (102). This meant that the Ig gene in a given CLL clone varied less than 1.5% from known germline Ig gene sequences. On the other hand, some patients had an Ig gene sequence that demonstrated multiple somatic mutations (102). Clones bearing germline, unmutated Ig genes were thought to arise from pregerminal center lymphocytes. Clones bearing somatically mutated Ig genes were thought to arise from postgerminal center lymphocytes. These two types of lymphocytes are also referred to as naïve (virgin) and memory cells. Recently the naïve cells were termed "naïve, experienced" (103). Independent memory cells were also postulated to have developed via an alternative or germinal center pathway. Patients with germline naïve cell CLL had a shorter life span, required more regimens of chemotherapy, and were treated sooner. Just the opposite was seen for patients with mutated, memory cell CLL; they had a longer survival, required treatment later, and had fewer courses of chemotherapy. What is remarkable is that the initial findings of the clinical correlation of Ig gene sequences reported by Damle et al. (104,105) have been confirmed in two subsequent independent reports (106,107). Of interest is an identical finding by Sakai and colleagues (108) in familial CLL. Naylor and Capra (109) in their editorial point out that the reports of Damle et al. (104) and Hamblin et al. (106) put to rest two previous questions concerning Ig gene analysis: the existence of unmutated and mutated IgVH genes and restricted use.

Fig. 36. Survival of typical CLL (A) and atypical CLL (B) with a normal karyotype vs abnormal karyotype and trisomy 12. (From ref. 97, Criel et al., 1999, Fig. 3.)

Fig. 37. Survival curves for 145 patients with B-CLL from date of diagnosis, comparing patients whose cells are CD38+ and who have unmutated IgVH genes (n = 34), with those whose cells are CD38- and who have mutated IgVH genes (n = 70) and those whose cells gave discordant results for the two assays (n = 41). (From ref. 110, Hamblin et al., 2002, Fig. 5. Copyright American Society of Hematology, used with permission.)

Fig. 37. Survival curves for 145 patients with B-CLL from date of diagnosis, comparing patients whose cells are CD38+ and who have unmutated IgVH genes (n = 34), with those whose cells are CD38- and who have mutated IgVH genes (n = 70) and those whose cells gave discordant results for the two assays (n = 41). (From ref. 110, Hamblin et al., 2002, Fig. 5. Copyright American Society of Hematology, used with permission.)

In the initial report by Damle et al. (104,105), a correlation was shown with Ig gene sequence and CD38 expression. Those CLL patients with 30% or more lymphocytes positive for CD38 expression were also found to have the germline configuration. Unfortunately, this observation of the correlation between CD38 expression and Ig gene status has not been confirmed (111). However, a recent paper has appeared showing a striking correlation between CD38 expression and survival in CLL (112). In this report, 20% or more of the cells positive for CD38 cells were associated with a worse prognosis. This was an excellent three-color flow cytometric study. It also showed further subgroups within early Rai or Binet stage disease. D'Arena et al. (113) showed that patients expressing more than 30% CD19/CD38-positive cells had atypical morphology, trisomy 12, and a diffuse bone marrow pattern. An interstitial bone marrow pattern, 13q14 deletion, and early Binet stage were associated with CD38-negative BCLL. Median survival was 90 mo in the CD38-positive group, and median survival had not reached 180 mo in the CD38-negative group. Heintel et al. (114) found a strong positive correlation with P2-microglobulin levels of 3 mg/L or more (p < 0.0001) and interpreted this to mean that CD38 is a marker of tumor mass as well as disease progression. They also showed that a borderline association was found with LDT of less than 12 mo (p = 0.05). They too noted discordance between the two groups.

In conclusion, Ig gene mutational status and CD38 expression stand as newly defined independent prognostic indicators. Other recent publications tend to support the relationship between CD38 expression with Ig gene configuration, with rare exceptions (115-119). This is where things stood until 2002, when Hamblin et al. (110) re-examined the relationship between Ig gene mutation status and CD38 expression as independent prognostic variables for survival. Their major contribution was to confirm the relationship between unmutated IgVH genes and CD38 positivity and mutated IgVH genes and CD38 negativity and to unravel the effects of discordant values. Survival of the discordant group is intermediate to the CD38-positive unmutated and CD38-negative mutated patients. These results are shown in Fig. 37.

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