Early treatment for poor-risk patients

I am grateful to Beth Fillman for drawing my attention to this paper which I missed when it first came out in 2008.

In about 2002 I was gave a number of lectures in America, promoting the use of prognostic markers in CLL. One of the ideas I had was for the early treatment of patients with poor risk markers with some of the new, less toxic agents that were then becoming available. There was a great deal of resistance to the idea since a number of published papers had seemed to say that there was no point in treating patients early since their overall survival was not affected. My counter was that I certainly agreed that there was no point in treating all comers since a large proportion would never need treatment, but now we could predict those who would eventually need treatment why not start when the tumor burden was low. In addition, the old studies had been done with chlorambucil, which was less effective than some of the treatments now available.

However, there were some legitimate arguments that deterred any trial taking place. One was that early treatment might select out a drug resistant population and change the natural history of the disease. Another problem was that the only real reason to do such a trial was that it might improve overall survival, but if it did, the end-point would be in the distant future and which drug company would be prepared to fund such a trial.

However, it seems as though Clive Zent and Neil Kay and their colleagues at the Mayo Clinic did do such a trial and the results have been published in Cancer.

Patients to be included in the study fulfilled the 2008 Guidelines (more than 5000 monoclonal B cells per cu mm) and they had to be high risk with either 1] del 17p, 2] del 11q or 3] unmutated IGHV genes plus at least one of ZAP-70+ or CD38+.

My only quibble over these selection criteria is that we now know that some patients with del 17p have a smoldering disease that does not require treatment in the short term and probably should not be treated up from. Almost all of these patients have mutated IGVH genes, so it would probably be wise to insist that this trial was confined to patients with unmutated IGVH genes.

The inclusion of del 17p patients was justified by the choice of therapy, which included sc alemtuzumab combined with rituximab. The treatment lasted only 31 days with the alemtuzumab being given three times a week and the rituximab once a week.

30 patients were recruited: 20 men and 10 women. 25 had unmutated IGVH genes, 9 del 17p, 8 del 11q, and 13 the other poor-risk factors.

Toxicity was minimal. mild skin redness and itchiness at the site of alemtuzumab injection was common, but only one patient had mild 'shake and bake' from the rituximab. One patient had symptomatic CMV infection that was successfully treated with foscarnet and two others had asymptyomatic CMV activation requiring valganciclovir. Two patients had fever and rash due to Bactrim prophylaxis and there were three other minor non-hematologic toxicities. Neutropenia was mild except in five patients and there were no neutropenic infections. There was no grade 3 or 4 anemia or thrombocytopenia. Low monocytes were common. T cell levels also fell and recovery of CD8 levels took longer than 6 months and of CD4 levels longer than 12 months.

There were 27/30 responses (11CRs, 10 nodular PRs and 6 PRs. 6 had no detectable disease by immunohistochemistry of the bone marrow and 6 were MRD negative. 19 patients showed disease progression and one has died following a stem cell transplant. The median duration of response was 14.4 months. There was no selection for more malignant clones and no clonal evolution. Nine patients have required subsequent therapy with varying regimens. Overall, there have been 4 CRs, 3 PRs and 2 progressive diseases following chemotherapy.

I'm not sure what to make of these results. They tell us that if you treat patients with bad risk markers with an unusual regimen containing no chemotherapy, there will be a high response rate without much toxicity, but the responses will be shortlived at about 14 months. There will still be the odd patient that does very badly. Does such an approach confer any long term benefit? It is hard to tell and in order to find an answer, the authors dredged up a comparison cohort from their records, consisting of 117 patients. They were similar in age, stage and prognostic markers. The median time to first chemotherapy was 4.4 years in the trial group and 1.9 years for the comparison cohort. Looked at another way, at 4 years 60% of the treated patients were chemotherapy free, but only 30% of the untreated cohort.

I think this has to be regarded as a failed trial. treating early (at least with this very non-toxic regimen) does not produce a majority of patients with MRD negative disease who might be cured. Although double the number of patients remained chemotherapy free at 4 years, we do not know whether this would translate into longer life. It does confirm what others have found, namely that patients who achieve MRD negativity have the longest remissions. The options for further study in this field are to use this regimen for longer in the hope that more treatment would produce a greater effect for no more toxicity; or to make a more serious attempt to achieve MRD negativity with something like FCR followed by Campath; or perhaps the use of an agent like lenalidomide which interferes with the engine room of the disease - the tissue phase.

The reason for early treatment would only be the possibility of cure for some patients and this could be recognized only by a prolonged phase III study. However, a treatment that produced MRD negativity in a substantial proportion of patients for a substantial length of time might be an effective surrogate.