Tuesday, November 17, 2009

Alemtuzumab at ASH

Alemtuzumab is thought to be a superior monoclonal to rituximab for the treatment of CLL. The question ought then to be asked as to whether FCA would be superior to FCR. In fact the ASH abstracts report just such a trial from France and Belgium.

178 previously untreated patients under the age of 65 who did not have del 17p, were randomized between standard FCR and FCA, with the alemtuzumab being given sc in a dose of 30mg for 3 days every 28 days. Although the overall response rate and CR rate were not statistically different, they were both greater for the FCR arm (96% v 85% and 78% v 58%). The trial is too immature to calculate PFS or OS. The trial was terminated because of excess toxicity in the FCA arm. Febrile neutropenia was twice as common in the FCA arm and there were 7 deaths with FCA and none with FCR.

The German CLL2 trial looked at the safety profile of FCA in 61 patients aged 36-78, some of whom had been previously treated. Twelve out of 56 patients died within 6 months of completing treatment of which 5 were treatment-related. The fact that 7 died of CLL or concomitant disease suggests that this was a particularly sick group of patients. Serious adverse events included CMV-reactivation (5 patients), herpes-zoster-reactivation (1 patient), pneumonia (5 patients, 2 of which had Aspergillosis-pneumonias), AIHA (1 patient) and fever of unknown origin (12 patients). It was felt that there was more toxicity with this regimen than for FA, which had been tested previously.

If it is not to be used as a substitute for rituximab, how then might it best be used? The CALG conducted a trial of alemtuzumab as consolidation treatment after FR induction. The results were hardly promising. Patients who had stable disease or responsive disease 4 months after the last dose of fludarabine were treated with SC alemtuzumab 3 mg on day 1, 10 mg on day 3, and 30 mg on day 5, and then thrice weekly thereafter for 6 weeks (18 total doses). Fifty-eight pts out of the original 102 received alemtuzumab, and 42 (72%) completed the planned 6 weeks of therapy. OR, CR, and PR rates after alemtuzumab were 91%, 66% and 26%, and 50% were MRD negative. Twenty-eight of 45 pts (62%) in PR after FR who received alemtuzumab attained CR. Of 11 pts in CR after FR who received alemtuzumab, 5 were MRD negative prior to consolidation and 3 of the other 6 converted to MRD negative afterwards. Two-year PFS (76% vs 70%, p=0.54) and OS (84% vs 88%, p=0.89) were similar for pts who did and did not receive alemtuzumab. There were no differences in PFS or OS among the 30 pts in CR after FR whether or not they received alemtuzumab, although the numbers were small.

Grade 3-4 neutropenia and thrombocytopenia were observed in 43% and 19% of pts during alemtuzumab therapy. Grade 3-4 non-hematologic toxicity was observed in 41% of pts, including 19% infections and 19% febrile neutropenia, during alemtuzumab therapy. Five pts in CR after FR who received alemtuzumab died from infections (viral meningitis, Listeria meningitis, Legionella pneumonia, CMV and PCP pneumonia), and one pt in PR after FR who received alemtuzumab died of Epstein-Barr (EBV) viremia without evidence of EBV lymphoma. These deaths occurred both during and for up to 7 months after alemtuzumab therapy. Patients had received standard Pneumocystis (PCP) and Varicella zoster virus prophylaxis and were monitored weekly by PCR for Cytomegalovirus (CMV) viremia.

The MDS Anderson has added alemtuzumab to FCR as CFAR; it is given as -30mg iv on days 1, 3 and 5 of each course. Eighty patients with previously treated CLL received CFAR for an intended total of 6 courses. There were 21 CR (27%), 3 NPR (4%) and 29 PR (37%) for an ORR 67%. Median OS and time to treatment failure (TTF) were 16.6 and 10.6 months respectively for all pts. For pts achieving CR, median OS (50+ months) and TTF (28+ months) have not been reached. Grade 3/4 infectious complications included pneumonia (n=7) or sepsis (n=3). Other infections included minor infections (n=32), CMV reactivation (n=13), and other herpes virus infections (n=5). CFAR is an effective therapy in this group of heavily treated pts with CLL. They demonstrated favorable responses in patients younger than 70 years with F-sensitive disease who had 5 or fewer prior therapies. They concluded that CFAR is a good salvage regimen for patients who have received prior FC based regimen.

CFAR has also been used as first line treatment in patients with high risk disease, defined as those with a beta-2-microglobulin greater than 4. Sixty patients under the age of 70 were enrolled. Thirty-five patients couldn't complete the intended 6 courses. The reasons included delayed recovery of counts (18), infection (8), AIHA (4), treatment failure (3) and patient choice (2). The overall response rate was 92% with CRs in 70%, but the median time to progression was only 38 months. Patients with 17p deletion, 11q deletion and unmutated IgVH had significantly shorter times to progression (18 months, 27 months and 33 months respectively.

Eleven (19%) patients have died: 4 with disease progression after achieving CR; 2 who did not respond; 2 with Richter's transformation; 1 who developed AML; 1 due to metastatic lung cancer; and 1 due to severe pneumonia 8 months after achieving CR. Grade 3/4 neutropenia and thrombocytopenia occurred in 31% and 13% courses respectively. Major infections, including pneumonia and sepsis, were reported for 10(17%) pts. Minor infectious such as bronchitis, urinary tract infections and herpes zoster were reported for 15(25%) pts. These figures are similar to figures obtained for FCR at MDACC. CMV reactivation occurred in 7 (12%) patients, but many of the patients who were spared this were on valgancyclovir prophylaxis. There was one death due to CMV pneumonia. CFAR does not seem to be much of an improvement over FCR.

Alemtuzumab is licensed for first line use in CLL. The ASH papers do not support the idea that it should be used in this way whether as FCA or CFAR. FCR remains the best first line treatment. The use of alemtuzumab as consolidation treatment can be seen to be hazardous on the basis of the CALGB trial and indeed on the basis of an earlier German trial. Early evidence from a British trial not reported at ASH, suggests that these hazards can be overcome. The place of alemtuzumab in fludarabine refractory disease awaits determination. It may also have a place in stem cell transplantation, but I will report on this on another day.

1 comment:

Anonymous said...

As this data amply demonstrates, alemtuzumab is drug to be used with great respect.

Certainly we should be grateful for the volunteers who underwent these trials.

I have had alemtuzumab more than once, but have been extremely careful vis-a-vis the timing of the drug and it's monitoring. I have avoided any difficulties. I must admit, however, that the results achieved were less than I had hoped for.

As therapy evolves and newer agents are employed, there may yet be a very logical place to utilize this very powerful agent in a reasonably safe and effective manner to achieve (in concert with other agents working in completely different ways) excellent long term results.

Cal 101, for example, does not seem to be very effective in clearing CLL from the bone marrow. Perhaps some brave and clever research will find an effective way to employ alemtuzumab with this agent (or others) to achieve the desired goal of long term remission with minimal risk.