A long time ago I promised to review the German experience with reduced intensity conditioning allograft in CLL which was published in the October 7th 2010 issue of Blood.
They treated 113 patients from 16 centers. The patients were poor-risk, defined as refractory to or relapsed within 12 months of treatment with a fludarabine containing regimen, or relapse after autologous SCT or progressive disease in the presence of either del 11q or del 17p and/or unmutated IGHV genes or use of V3-21. Patients were aged between 18 and 65 with an ECOG score of 1 or better, normal organ function. Patients with Richter's syndrome were excluded. Related and unrelated donors were matched at 6 loci (more recently 10 loci are preferred).
Conditioning was Fludarabine 30mg/sq m for 5 days and cyclophosphamide 500mg/sq m for 5 days. With unrelated donors ATG 10 mg/kg/d was given for 4 days. The donor source was peripheral blood harvests generated by G-CSF stimulation. For a limited period (June 2002 to November 2005 an alternative conditioning regimen was used, FC + 2Gy TBI on day -9 and alemtuzumab 20mg/d for 5 days. After November 2005 an intensified conditioning regimen was introduced for refractory patients consisting of fludarabine 30 mg/sq m.d for 5 days, busulfan 4mg/kg/d for 3 days, cyclophosphamide 30 mg/kg/d for 2 days. GVHD prophylaxis was with cyclosporin A. Some patients received short courses of methotrexate or mycophenolat mofetil. DLI was admoinistered no earlier than 4 weeks after complete withdrawal of cyclosporin A in case of incomplete donor chimerism or MRD.
13 patients had to be excluded from analysis because of ineligibility. 10 patients did not receive a transplant (1 progressive disease, 3 Richter's transformation, 2 refusal, 4 no donor found).
Of the remaining 90, 24 had uncontrolled refractory disease at time of SCT. Of the 90, del 17p was found in 13, and del 11q in 26. 40% had sibling donors the rest volunteer donors. 65 patients had FC conditioning, 12 FCB and 12 the alemtuzumab-containing regimen.
Neutrophil and platelet recovery occurred in 85/86 with data available and complete donor chimerism was achieved in 66/80 and incomplete chimerism in a further 6. 7 failed to engraft and one had graft failure after partial chimerism - these failures only occurred with the FC and Alemtuzumab regimens. 6/7 had some degree of mismatch and 2 had marrow rather than peripheral blood grafts. 7/8 had autologous recovery and one was salvaged with a 2nd transplant. No patient died of the conditioning which caused a median time in hospital of 22 days (range 0-150 days). There were 2 unrelated deaths in the first 3 months.
Clinically significant GVHD occurred in 45% either after primary transplant or after DLI but grade 3 or 4 GVHD was seen in only 14%. Chronic and extensive GVHD was 73% at 2 years. 65% of those who were alive at 1 year were still on systemic immunosuppression.
33 of the 90 patients died; 16 of progressive disease, 4 of acute GVHD, 5 of chronic GVHD, 5 of infection, 1 of transplantation-associated microangiopathy and 2 of unknown causes. Non-relapse mortality at 4 years was 23% and overall survival at 4 years was 65%. Of the 10 patients who did not get a transplant 7 had died (5 from progressive CLL and 2 from off-protocol allograft)
A CR after allograft was achieved in 73% though 11% of these were already in CR at the time of allograft. A further 21% achieved a PR. At 4 years the relapse rate was 40%. Taking account of the 17 relapse-free mortality cases, the single secondary malignancy and the 8 non-engraftments, the event free survival at 4 years was 42%.
There were some MRD measurements in some of the patients. In those who had data available 39/52 were event-free at 1 year and 27/52 were MRD negative. There were 2 relapses and one non-relapse death among the 27 who were MRD negative at 12 months. 2 others became MRD +ve on follow up. Patients who had a clear GVL effect had the worst GVHD effect. 15 patients required DLI and 5 became MRD negative following this.
So what factors can predict a good or poor outcome? First of all, this study confirms that allografting is an effective treatment for del 17p patients. But having uncontrolled disease at the time of transplant definitely affected outcome adversely. This suggests that once teh criteria for allograft are met it is foolhardy to delay until the disease bulk increases so that no other hope is left. Some patients elect to do just that. Better to grasp your courage and take the chance.
Because matching was only available at 6 rather than 10 loci, many of the grafts would today be considered partially mismatched. This gave the opportunity to assess whether this made a difference. It didn't. This ought to encourage patients to go ahead with an allograft even though a fully matched donor is not available.
There was a high rate of chronic GVHD. One way of avoiding this is to T-deplete the graft. The attempt to do this with alemtuzumab in this study was unsuccessful with shorter event-free and overall survivals. However the authors feel the small numbers involved and the non-randomized allocation of patients to receive T-cell depletion, by no means rule alemtuzumab out of court. I shall have more to say about this later.
In summary, this is the most complete study of RIC transplants in CLL yet published. 60% of patients will be still alive at 4 years and it is the most effective way of treating TP53 deficient disease. However this 60% are not all cured and chronic GVHD is still a major hazard. Finally, if you are taking this option, don't leave it too late.