Treatment of CLL

I am in the midle of writing a review of CLL for the Lancet Oncology.
Here is a first draft of the section on treatment. The finished article will probably be nothing like this, but I wrote this to summarize the evidence from clinical trials.


The majority of patients with CLL present without symptoms or signs, simply because a blood test has been requested for an unrelated reason. Many of these patients never progress. Clearly, there is no need to treat such patients, but those who do need treatment often present in the same way. Several trials have asked whether it is safe to delay treatment until progression occurs. A meta-analysis of 2048 such patients in 7 trials randomised between immediate or deferred treatment with chlorambucil (with or without prednisolone) suggested no benefit for either arm. [CLL Trialists’ Collaborative Group. Chemotherapeutic options in chronic lymphocytic leukaemia: a meta-analysis of the randomised trials. J Natl Cancer Inst, 1999, 91, 861-8] In a French study, [Dighiero G, Maloum K, Desablens B et al. Chlorambucil in indolent chronic lymphocytic leukaemia. N Engl J Med, 1998, 338, 1506-14] 51% of patients allocated to the deferred treatment arm eventually required treatment, and 27% eventually died of a cause related to CLL.

Standard management for CLL therefore includes a period of watchful waiting until features of progression occur. These features have been codified by a working group sponsored by the American National Cancer Institute [Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, Rai KR. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87:4990-7] (Table 1).

With the appearance of more effective treatments than chlorambucil and better ways of determining which patients are unlikely to progress this question should be revisited, and randomized trials of early versus delayed therapy for patients with poor-risk prognostic markers are planned or under way in Germany, the US and the UK.

Several trials have evaluated the effect of adding an anthracycline to alkylating agents in more advanced cases. A meta-analysis of 10 trials involving 2035 stage B and C patients [CLL Trialists’ Collaborative Group. Chemotherapeutic options in chronic lymphocytic leukaemia: a meta-analysis of the randomised trials. J Natl Cancer Inst, 1999, 91, 861-8] showed that the presence of an anthracycline in the combination does not affect the outcome.

Purine analogues
Although the purine analogue, fludarabine, has not been approved by the National Institute for Clinical Excellence for first line use in CLL in England and Wales, its use, either alone or in combination, has become the standard of care in most other countries. A meta-analysis [Steurer M, Pall G, Richards S, Schwarzer G, Bohlius J, Greil R; on behalf of the Cochrane Haematologic Malignancies Group.Single-agent purine analogues for the treatment of chronic lymphocytic leukaemia: a systematic review and meta-analysis. Cancer Treat Rev. 2006 ;32:377-89] looked at five trials with 1838 patients randomized between an alkylator-based regimen and a purine analogue. Patients treated with a purine analogue had significantly higher overall and complete response rates, and longer progression-free survivals, that those treated with alkylator-based regimens, but overall survival was not significantly different. Three further large trials had not been evaluated at the time of analysis and we may yet see a difference in overall survival as more data accumulate. However, because patients failing one regimen may respond very well to the other arm of the study, this question may never be resolved. Because of this, because and because the natural history of CLL is so long, those conducting clinical trials have adopted ‘progression-free-survival’ as a surrogate for overall survival as the primary trial end-point. However, with such a strategy there is a danger of being misled [Cavo M, Baccarani M. The changing landscape of myeloma therapy.
N Engl J Med. 2006;354:1076-8].

The situation is further complicated by trials in which a higher dose of chlorambucil is used (70 mg/m2/month rather than 40). Response rates and progression-free survivals not significantly different from those of fludarabine may be achieved with less toxicity [Catovsky D, Else M, Richards S, Hillmen P. The lack of survival differences in randomized clinical trials in CLL nay be related to the effect of second line therapies. A report from the LRF CLL4 trial. Blood 2006; 108: suppl1: 94a (abstract 304)].

Combinations of purine analogues and alkylating agents have been tested in three randomized trials. In the American Intergroup trial [Rai KR, Peterson BL NEJM 2000; 343:1750-7] the fludarabine plus chlorambucil arm had to be abandoned as too toxic. The German CLL4 trial [Eichhorst BF, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C, Siehl S, Jager U, Bergmann M, Stilgenbauer S, Schweighofer C, Wendtner CM, Dohner H, Brittinger G, Emmerich B, Hallek M; German CLL Study Group. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood. 2006;107:885-91] compared fludarabine with fludarabine plus cyclophosphamide (FC) in 375 patients under the age of 66. The British CLL4 trial [Catovsky D, Else M, Richards S, Hillmen P. The lack of survival differences in randomized clinical trials in CLL may be related to the effect of second line therapies. A report from the LRF CLL4 trial. Blood 2006; 108: suppl1: 94a (abstract 304)]
conducted a similar comparison in 390 patients without age restriction. Both found the combination significantly better in terms of overall and complete response rates and progression free survival, but there was no significant difference in overall survival. In both trials the combination was significantly more toxic.

In the British CLL4 trial the effect of prognostic markers on outcome was evaluated prospectively [Oscier DG, Wade R … Prognostic factors in the UK LRF CLL4 trial Blood 2006; 108: (suppl 1): 92a (abstract 299)]. Importantly, the prognostic factors had a greater effect on overall survival than the choice of therapy. Patients with del 17p in >20% of cells had a very short median survival, and those with mutated VH genes had a significantly longer survival than those with unmutated VH genes, no matter which treatment they were given. This clear distinction emphasises how difficult it is to compare the results of phase II trials that have taken place at different times and different places, yet it is on just such information that off-license treatment of CLL with monoclonal antibodies has become so widespread.

Another purine analogue, cladribine, has been evaluated in a three-way randomized phase III study, comparing it with its combination with cyclophosphamide or cyclophosphamide plus mitoxantrone [Robak T, Blonski JZ … Blood 2006; 108:473-9]. The three-drug combination produced significantly more responses and CR at the expense of more marrow toxicity. There were no significant differences in either progression-free or overall survival.

Immunochemotherapy
Rituximab, the chimeric, monoclonal anti-CD20, is only moderately active as a first line agent in CLL [Hainsworth JD, Litchy S,. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003;21:1746-51] with an overall response rate of 51% and a CR rate of only 4%. However, when added to fludarabine or FC impressive responses have been reported.

In a randomised phase II study [Byrd JC, Peterson BL… Blood 2003; 101:6-14] rituximab added to fludarabine produced higher responses when given concurrently than given sequentially. An analysis of VH mutational status and FISH for del 11q23 and del 17p13 stressed the importance of these prognostic markers in evaluating trial results [Byrd JC, Gribben JG …. J Clin Oncol 2006; 24:437-43]. The patients enrolled on this trial were compared with matched historical controls selected from the fludarabine arm a previous Cancer and Leukemia Group B trial. In a multivariate analysis controlling for pre-treatment characteristics (but not for modern prognostic markers) the addition of rituximab appeared to improve significantly progression-free and overall survival [Byrd JC, Rai K …. Blood 2005;105:49-53].

The combination of fludarabine, cyclophosphamide and rituximab (FCR) has been tested in the front-line and the relapsed and refractory setting. As first line therapy [Keating MJ, O’Brien S… J Clin Oncol 2005;23:4079-88], overall response rates of 95% with complete remissions (CR) in 70%. The same group produced overall response rates of 88% with 35% CR in historical controls treated with FC. However, only 33% of the FCR-treated patients were Rai stage III and IV, compared with 50% of the FC-treated patients, and no modern prognostic markers have been reported for either of these phase II trials.

In the relapsed and refractory setting [Wierda W, O’Brien S…. J Clin Oncol 2005; 23:4070-8; Wierda W, O’Brien S .... Cancer 2006; 106:337-45] FCR can also produce high response rates (73%) and CR (25%). Again, comparison with historical controls suggests that FCR is superior to FC or to fludarabine alone, but although the multivariate analysis included serum 2-microglobulin levels interphase cytogenetics and VH mutational status were not studied.

Another purine analogue, pentostatin, has been evaluated in combination with cyclophosphamide and rituximab in a phase II trial of previously untreated patients [Kay NE, Geyer SM …. Blood 2007; 109:405-11]. This trial is valuable in that the prognostic markers, VH gene mutations, CD38 expression, ZAP-70 expression and interphase cytogenetics were reported. The overall response rate was 91% with 41% CR. Patients with p53 anomalies had poor responses. The authors claimed that this regimen is less toxic than FCR.

In a phase II study the addition of mitoxantrone to FCR appeared to add only toxicity rather than increased efficacy [Faderl S, Wierda W… Blood 2006; 108 (suppl 1):803a (abstract 2836)].

Alemtuzumab appears to be one of the few agents capable of killing CLL cells with mutated or deleted p53 genes. It has been used as first-line therapy in a phase III trial in which it was compared with chlorambucil at a dose of 40 mg/m2/month. Overall response rate and progression-free survival were significantly better for Alemtuzumab [Hillmen P Skotnicki A …. Blood 2006; 108 (suppl 1):93a (abstract 301)].

Drug-resistant CLL
Most effective therapies for CLL require an intact p53 pathway. High dose methyl prednisolone produced an overall response rate of 77% in a cohort of patients with advanced refractory CLL [ThorntonPD, Matutes E …. Ann Hematol 2003;82:759-65] and Alemtuzumab is also able to produce high levels of response in p53 deleted CLL [Stilgenbauer S, Blood 2004; 104: (Suppl 1) 140a (abstract 478)]. The combination of these agents produced 100% response with 60% CR in a small cohort of patients with p53 defects [Petit AR, Matutes E, Oscier D. Alemtuzumab in combination with high-dosemethylprednisolone is a logical, feasible and highly active therapeutic regimen in chronic lymphocytic leukaemia patients with p53 defects. Leukemia 2006; 20:1441-5].

Flavoperidol, a cyclin-dependent kinase inhibitor, has proved a very effective killer of p53 deleted CLL cells in vitro, but was almost completely ineffective in vivo because it was so highly bound to human serum albumin. By altering the infusion schedule it has been possible to obtain partial remissions of long duration in 42% of CLLs with p53 deletions [Byrd JC, Lin TS… Blood 2007; 109:399-404]

Table 1

NCI guidelines for beginning treatment
At least one of these must be present


1. At least one of the following disease-related symptoms must be present
a. Weight loss of > 10% of body weight in the previous 6 months;
b. Extreme fatigue so that the patient cannot work of perform usual activities;
c. Fevers of greater than 38°C for at least 2 weeks without evidence of infection;
d. Night sweats without evidence of infection.
2. Evidence of bone marrow failure shown by the development of, or worsening of, anemia or thrombocytopenia.
3. Autoimmune hemolytic anemia and/or thrombocytopenia poorly responsive to corticosteroids.
4. Massive (>6cm below the costal margin) or progrtessive splenomegaly.
5. Massive lymph nodes or clusters of nodes (>10 cm in longest diameter) or progressive lymphadenopathy.
6. Increase in lymphocyte count by >50% over two months or an anticipated doubling time of <6 months.

Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease is not sufficient for
beginning therapy, nor is any particular level of lymphocyte count.