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Constantine S. Tam, MB, BS
Susan Lerner, MS
Michael J. Keating, MB, BS

New Prognostic Markers in CLL

The recent proliferation of new "prognostic markers" in chronic lymphocytic leukemia (CLL) has provided valuable insights into the biology of the disease1. In particular, significant survival differences when patients are classified by immunoglobulin heavy chain variable region (IGVH) mutation status2,3, fluorescent in-situ hybridization (FISH) abnormalities4 or zeta-associated protein-70 (ZAP-70) 5 expression confirm the longstanding clinical suspicion that CLL is not a single disease but rather a collection of heterogeneous entities sharing a common morphologic and immunophenotypic profile 6. In many ways, the current status of CLL is reminiscent of the period before the cytogenetic classification of acute myeloid leukemia (AML) that ultimately led to the risk-stratification of AML therapy 7.

FISH and ZAP-70 are now becoming available to the treating clinician both in academic centers and through commercial laboratories. With the ever-decreasing cost of automated sequencing and computerized genetic database programs, IGVH mutation determination will likely soon be available to most academic clinicians. How should these new markers be incorporated into routine clinical practice, and should they influence decision making? Although it is intellectually rewarding and scientifically interesting to fully understand a particular patient's full prognostic profile, the performance of these markers represent a useful return-on-investment only if they somehow change the way a patient is monitored or managed. A critical examination of the scientific studies supporting these new markers will uncover the fact that they provide surprisingly little relevant information to the practicing clinician.

Problems with Current Studies

The studies in IGVH mutation, FISH status and ZAP-70 expression all ultimately led to statistically significant and clinically relevant differences in CLL survival2-5. They were, however, performed in patients receiving predominantly alkylator-based therapy, whereas the typical new CLL patient diagnosed today would likely receive a purine-analogue based combination, with or without the addition of the monoclonal anti-CD20 antibody rituximab, as initial therapy. Three randomized trials have shown that fludarabine is superior to alklyators as initial therapy 8-10, and three subsequent trials have confirmed that the combination of fludarabine & cyclophosphamide (FC) is in turn superior to fludarabine alone 11-13. The phase II evaluation of FC & rituximab (FCR) at the MD Anderson Cancer Center has shown that FCR approximately doubles the effectiveness of FC in terms of complete remission rate and time to progression 14, and that the median first remission duration of FCR is comparable to the total survival of patients receiving fludarabine alone (figure 1). It is well established in other diseases that the development of effective therapy neutralizes the adverse risk of traditional markers, with prominent examples being the development of all-trans retinoic acid and imatinib containing chemotherapy in the treatment of acute promyelocytic leukemia and Philadelphia positive acute lymphoblastic leukemia respectively 15-16. In CLL, it is not currently known whether information derived from treatment developed three generations ago remain relevant in the age of chemo-immunotherapy, although there are indications that IGVH and FISH status may still be somewhat useful (see later).

The retrospective nature of some of these studies also confound interpretation. For example, only the Dohner study assessed consecutive patients 4, whereas the other three studies selected patients samples depending on availability 2,3,5. This is particularly problematic with regards to the treatment status of the patients, as patients with advanced, treatment refractory diseases are expected to present for more frequent follow-ups and be more available for correlative studies. Indeed, of the four studies, only the Dohner study clearly stated the proportion of pretreated patient in the cohort. Lastly, survival was dated from the time of diagnosis (not the time of testing) in two studies, and not specified in the other two. The problem with this approach is that it assumes the relevant prognostic marker will not change over time, which in the case of FISH is already known to not be true17.

Information from Recent Studies

The three recent phase III comparisons of fludarabine vs FC have included some of the new CLL markers in their baseline assessment, and early data regarding their usefulness in the age of purine analogue therapy (before the addition of rituximab) are emerging. IGVH mutation status was evaluated in the ECOG E2997 and did not affect response rate, nor did it reach statistical significance with regards to progression free survival (21 months for unmutated, 30 months for mutated)18. In contrast, a pooled analysis of patients enrolled in a randomized phase II comparison of fludarabine vs fludarabine & rituximab suggested that unmutated patients may experience shorter remissions 19. A potential explanation for this discrepancy was that complete remissions were uncommon among patients receiving fludarabine without rituximab (approx 5% and 25% for fludarabine and FC respectively), and the majority of patients in E2997 therefore progressed from a state of clinically overt residual disease, where the effect of IGVH mutation may have been diluted. This is analogous to the situation with failed induction in AML, where the risk related to adverse cytogenetics is diluted by the common risk of refractory leukemia.

All three trials confirmed that CLL patients with FISH 17p deletion, although rare, responded poorly to fludarabine or FC and experienced short survival after the initiation of therapy (median less than three years) 11,12,18. Data from the United Kingdoms trial suggested that 17p deletion may require a "critical" threshold of 20% deletion on FISH interphases to confer its negative prognostic significance11. In this study, however, specimens were directly processed for FISH without preceding culture, and the results may therefore not be comparable to those generated in North America, where a preceding "overnight" culture of specimens prior to FISH processing is the norm (Daniel Catovsky, personal communication). The data surrounding 11q deletion is less straightforward, with early studies of fludarabine vs fludarabine & rituximab suggesting that it may be associated with inferior remission duration19. However, 11q deletion CLL is commonly associated with bulky lymphadenopathy20, and cyclophosphamide may be a particularly active agent in debulking nodal disease. Indeed, in the E2997 trial 11q deletion patients receiving FC have similar remission durations as patients with trisomy 12 or negative FISH study18.

Recommendations for Clinical Preactice

There is no compelling evidence to change current clinical practice based on the new CLL markers. Outside the setting of a clinical trial evaluating the effect of early therapy, the decision to initiate therapy should still be based on assessment of disease stage, complications, clinical symptoms and the rate of progression21. With the exception of patients with FISH 17p deletion, FC (or related regimens) remain appropriate frontline treatment regardless of IGVH mutation status, FISH abnormality or ZAP-70 positivity. Patients with 17p deletion represent a special subgroup: published results of fludarabine or FC suggest that such patients should not receive these regimens as frontline therapy, although our institutional experience indicates that 17p deletion patients may be responsive to rituximab and that rituximab-containing regimens such as FCR or CFAR (FCR & alemtuzumab) may be highly effective (Tam et al, unpublished work). In order to provide further information about the impact of novel prognostic markers, new therapeutic trials in CLL should continue to incorporate prospective assessment of these factors in the study design.

Figure 1: Overall survival (solid lines) and time to progression (broken lines) for patients enrolled in phase II evaluation of fludarabine monotherapy or FCR as initial therapy at the MD Anderson Cancer Center.

References

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