Friday, April 04, 2008

CLL Treatment: Purine analogues

With the introduction of purine analogues, a class of drug better able to achieve complete remission in chronic lymphocytic leukaemia, the possibility has arisen of treating the disease in a similar way to other leukaemias—eg, with induction chemotherapy to achieve complete remission followed by consolidation treatment to eliminate minimal residual disease. Progress towards this end has been limited for several reasons. Complete remission in chronic lymphocytic leukaemia allows for up to 30% of chronic lymphocytic leukaemia cells to remain in the bone marrow;[121] many patients live long and symptom-free lives without achieving complete remission; and most are elderly and are not candidates for more intensive treatments. Purine analogues cause profound suppression of T-cell immunity [122] and can trigger autoimmunity.[123] If the induction-consolidation strategy is not to be followed, these hazards could outweigh the benefits.

The purine analogue fludarabine, alone or in combination, has become the standard of care in most countries other than the UK. Researchers in a meta-analysis [124] looked at five trials of 1838 patients randomly allocated either an alkylator-based regimen or a purine analogue. Individuals treated with purine analogues had significantly higher overall and complete response rates and longer progression-free survival than did those treated with alkylator-based regimens, but overall survival did not differ between treatment groups. Three further large trials had not been assessed at the time the meta-analysis was undertaken, and a difference in overall survival could yet arise as further data accumulate. However, because patients who fail one regimen can respond very well to another, this question might never be resolved. Because of this factor and because the natural history of chronic lymphocytic leukaemia is so long, researchers doing clinical trials have adopted progression-free survival as a surrogate for overall survival as the primary endpoint. However, such a strategy can be misleading.[125]

Findings of a trial in which a higher monthly dose of chlorambucil (70 mg/m2) was compared with fludarabine showed that response rates and median progression-free and overall survival did not differ between groups. Furthermore, fewer toxic effects arose in the chlorambucil group—ie, neutrophil counts lower than 1×109/L, admission for more than 1 day, and grade 1 and 2 diarrhoea. The frequency of autoimmune haemolytic anaemia was similar in both groups but seems to have been more severe in the fludarabine group than in the chlorambucil group, since two patients treated with fludarabine died from the complication.[126]

Combinations of purine analogues and alkylating agents have been tested in three randomised trials. In an Intergroup trial,[127] a fludarabine plus chlorambucil regimen had to be abandoned as too toxic. Workers on a German CLL4 trial compared fludarabine plus cyclophosphamide with fludarabine alone as first-line therapy in 375 patients younger than age 66 years,[128] and a similar comparison was undertaken in a British CLL4 trial [126] in 390 patients without age restriction. Findings of both CLL4 studies showed the combination was significantly better than fludarabine alone in terms of overall and complete response rates and progression-free survival, but overall survival did not differ between groups. Moreover, the combination was significantly more toxic than fludarabine alone in terms of neutrophil counts lower than 1×109/L, admission to hospital for more than 1 day, grade 3 and 4 nausea and vomiting, grade 1 or 2 alopecia, and grade 1 or 2 diarrhoea. However, autoimmune haemolytic anaemia was significantly less frequent with the combination. In Intergroup trial E2997,113 complete response rates were reported as 24·6% for fludarabine plus cyclophosphamide and 5·3% for fludarabine alone. Median progression-free survival was 33·5 months and 19·9 months, respectively. Both these differences were statistically significant.

Another purine analogue, cladribine, has been assessed in a three-way, randomised phase III study.[129] Researchers compared the agent alone and in combination with cyclophosphamide or cyclophosphamide plus mitoxantrone. The three-drug combination produced significantly more responses and complete remissions at the expense of more bone-marrow toxic effects. Progression-free and overall survival did not differ between groups. Mitoxantrone has also been used in combination with fludarabine plus cyclophosphamide in a phase II trial in relapsed or resistant chronic lymphocytic leukaemia.[130] The findings of this trial were remarkable because the complete remission rate was 50%, with a third of these patients having no detectable disease with a very sensitive method.


121 BD Cheson, JM Bennett and M Grever et al., National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment, Blood 87 (1996), pp. 4990–4997.

122 MJ Keating, S O'Brien and S Lerner et al., Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy, Blood 92 (1998), pp. 1165–1171.

123 H Myint, JA Copplestone and J Orchard et al., Fludarabine-related autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia, Br J Haematol 91 (1995), pp. 341–344.

124 M Steurer, G Pall and S Richards et al., Single-agent purine analogues for the treatment of chronic lymphocytic leukaemia: a systematic review and meta-analysis, Cancer Treat Rev 32 (2006), pp. 377–389.

125 M Cavo and M Baccarani, The changing landscape of myeloma therapy, N Engl J Med 354 (2006), pp. 1076–1078.

126 D Catovsky, S Richards and E Matutes et al., Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial, Lancet 370 (2007), pp. 230–239.

127 KR Rai, BL Peterson and FR Appelbaum et al., Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia, N Engl J Med 343 (2000), pp. 1750–1757.

128 BF Eichhorst, R Busch and G Hopfinger et al., Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia, Blood 107 (2006), pp. 885–891.

129 T Robak, JZ Blonski and J Gora-Tybor et al., Cladribine alone and in combination with cyclophosphamide or cyclophosphamide plus mitoxantrone in the treatment of progressive chronic lymphocytic leukemia: report of a prospective, multicenter, randomized trial of the Polish Adult Leukemia Group (PALG CLL2), Blood 108 (2006), pp. 473–479.

130 F Bosch, A Ferrer and A Lopez-Guillermo et al., Fludarabine, cyclophosphamide and mitoxantrone in the treatment of resistant or relapsed chronic lymphocytic leukaemia, Br J Haematol 119 (2002), pp. 976–984.


Anonymous said...

Didn't subsequent trials show little or no value to the addition of mitoxantrone? That is my recollection, at least. The drug has some history in clinical trials for CLL, that I do know.

One thing that is left unsaid here is that longer complete remissions and progression-free survival can be accompanied by a better quality of life.

With CLL, often that is all that one can hope for. That, and a quick and painless end.

Terry Hamblin said...

One small, flawed, phase II trial from MD Anderson CC. It is amazing how people are taken in. Mitoxantrone trials continue and are quite encouraging.

It is quite difficult to demonstrate that quality of life is better in patients who have a single remission compared to that of patients who have two yet live the same time.

Anonymous said...

It certainly would be difficult to quantify 'quality of life', but I can tell you that patients can experience it very vividly, even if they can't put the positive changes in number form.

It's interesting that I've never encountered a discussion of mitoxantrone with any hematologist I've consulted. Is this a UK or continental drug (in lieu of drugs available elsewhere)?

Anyway, I'm passed the point where such a drug would help, so it's a moot point for me.

Terry Hamblin said...

Mitoxantrone is very similar to adriamycin - it is blue rather than red - but it is reputed to be less likley to cause hair loss and perhaps be less toxic to patients, though this might just be a matter of dose. Adriamycin has long been used in CLL - in France they insist that a regien that includes half dose adriamycin is extremely effective. Mitoxantrone was first introduced in Spain as FCM. It gave responses as good as FCR. Currently there are trials looking at FCMR.

Terry Hamblin said...

In these articles I am trying to report what has been established by phase III trials, or when these are unavailable the best available evidence. This is not a comprehensive review of all possible treatments.

Anonymous said...

And I for one am very appreciative of the effort. I enjoy getting your perspective. Reading abstracts without the depth of knowledge you have is a hit-or-miss affair; sometimes you miss the forest for the minutiae of the trees (or the duff on the forest floor for that matter).