Going For a Home Run With Campath Consolidation

There is some evidence  that patients who get a squeaky clean MRD negative remission after completion of therapy (negative for Minimum Residual Disease; which means no trace of CLL detected even when using our most sensitive flow cytometry methods) tend to have longer remissions. Patients with deep remissions hope that they don’t have to go back for a re-tread job as quickly. Campath has been used by many researchers in this role, as a way of consolidating the gains already obtained by other therapy regimens, a way of putting patients who have obtained ‘only’ a CR into the coveted MRD negative category.

The million dollar question, as always, is the cost side of the equation. What does it cost in terms of safety, adverse effects, bridges burned etc. to go for the extra value of deeper remission? And while we are about it, is it wishful thinking on our part that using Campath to force patients into deeper remissions actually translate into longer remissions and longer overall life?  Or would the toxicity of the drug itself neutralize any potential benefits of Campath consolidation?

Here is the latest information on the subject, fresh from ASH 2009 abstracts. Credible information from a highly regarded group, as well as large size patient cohort makes this an important study. I know many of you are considering Campath consolidation as followup after FR, FCR, R+HDMP, whatever. For you this information is an important piece of the puzzle as you make your decisions.  Some of you have been through the Campath consolidation protocol already.  Remember, water under the bridge does not come back.  Second guessing yourself does not help.  And who knows, you may have been one of the lucky ones. The abstract itself is given below, followed by my two own two cent commentary.

Consolidation Therapy with Subcutaneous (SC) Alemtuzumab After Fludarabine and Rituximab (FR) Induction Therapy Improves the Complete Response (CR) Rate in Chronic Lymphocytic Leukemia (CLL) and Eradicates Minimal Residual Disease (MRD) but Is Associated with Severe Infectious Toxicity: Final Analysis of CALGB Study 10101

Thomas S Lin, MD, PhD1, Kathleen A Donohue1*, John C. Byrd, MD1, Margaret S Lucas1*, Eva Hoke1*, Elizabeth M Bengtson, MD1, James N Atkins, MD2*, Brian K Link, MD3, Kanti R Rai, MD1 and Richard A Larson, MD1

Background: Alemtuzumab (Campath-1H) is approved for the treatment of CLL. CALGB sought to determine whether alemtuzumab can improve the CR rate and eradicate MRD after induction chemoimmunotherapy by performing a phase II study administering FR followed by alemtuzumab consolidation to previously untreated, symptomatic CLL patients (pts). We previously reported preliminary toxicity data (Lin et al. ASH 2007) and now report final toxicity and response data. Methods: Pts received fludarabine 25 mg/m2 IV on days 1-5, and rituximab 50 mg/m2 IV on day 1, 325 mg/m2 on day 3, and 375 mg/m2 on day 5 of cycle 1 and then only on day 1 of cycles 2-6, repeated every 28 days for up to 6 cycles. Four months after the last fludarabine dose, pts with stable (SD) or responsive disease by NCI 96 criteria received 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). Pts received standard Pneumocystis (PCP) and Varicella zoster virus prophylaxis and were monitored weekly by PCR for Cytomegalovirus (CMV) viremia. When unacceptable serious infectious toxicity was noted in pts who received alemtuzumab after achieving CR from FR induction, the study was amended so that only PR or SD pts received alemtuzumab after FR. Results: Median age of pts (n=102) was 61 years (range, 23-82), 74% were male, and 30% were Rai stage III/IV. FR was well tolerated; 93% of pts received at least 3 cycles, and 77% completed all 6 cycles. Overall, complete and partial response (OR, CR, PR) rates after FR induction were 90%, 29% and 61%, and 15% were MRD negative by flow cytometry. Fifty-eight pts received alemtuzumab, and 42 (72%) completed the planned 6 weeks of therapy. OR, CR, and PR rates after alemtuzumab (n=58) 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. By intent-to-treat for all patients enrolled, OR, CR, and MRD negativity were attained by 90%, 57% and 42% of pts. With a median follow up of 34 months, median progression free survival (PFS) was 37 months (95% CI, 33-43 months); PFS was 73% and overall survival (OS) 86% at 2 years. 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. Similarly, 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. As we previously reported, 5 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 grade 5 toxicities occurred both during and for up to 7 months after alemtuzumab therapy. Conclusions: Alemtuzumab consolidation improved the CR and MRD negative rates after FR induction. However, alemtuzumab consolidation resulted in significant toxicity, particularly severe infections in pts who achieved a CR after FR induction. Longer follow up is needed to determine if the improved CR and MRD negative rates following alemtuzumab consolidation will eventually result in improved PFS or OS, especially among pts who achieved a PR after FR induction.

My two cents

This study reports final analysis and results of a rigorous study done by “CLLGB” (which includes the prestigious expert group at Ohio State, headed by Dr. John Byrd) on the advisability of using Campath to improve remissions obtained after FR (fludarabine + Rituxan) combination therapy. The patients registered in this Phase II clinical trial were previously untreated CLL patients whose disease had progressed to the point where it needed therapy. The patient profile is summarized in the chart below.

The way I see it, these guys were not the toughest nuts to crack, they were not chosen on that basis.  But they clearly needed therapy. The FR part of their therapy was pretty standard issue and as expected it was pretty well tolerated. 93% of the patients completed at least 3 cycles of FR, and as many as 77% completed all six cycles of FR.  Bear in mind six monthly cycles is standard for most chemoimmunotherapy regimens such as FR and FCR.

The response to FR was pretty much what one would expect.  While the overall response was a satisfactory 90%, the percentage of patients who got a CR was less than a third (29%) and the percentage who got MRD negative remission was only 15%. This is where Campath consolidation comes in, an attempt to kick some of the partial responses into full CRs, and more of the CR remissions into full blown MRD negative status.  Think of Campath consolidation as an effort to do the final pesky detailing of your car to get rid of the last few specks of dirt left behind after a more cursory car wash.

Of the 102 patients who participated in this study, just over half (58 patients) went on to get the Campath consolidation. This involved getting subcutaneous Campath thrice weekly for six weeks, a total of 18 shots. The dosage was 30mg each shot, except the first week where the dosage was gradually increased from 3mg to 10mg to 30mg on the third shot for the week. Patients were protected with prophylactic drugs to guard against pneumonia and shingles and were also monitored on a weekly basis for signs of CMV reactivation. These precautions are now standard operating procedure for patients getting Campath therapy. If your local guy is not doing this due diligence to protect you while getting Campath, you need to sit down and have a serious conversation with him about it.

Campath Consolidation Results

The chart below compares the response statistics after FR and after follow-up Campath consolidation. Please remember 102 patients were in the original FR group, but only 58 of these guys went on to get Campath consolidation upon completion of the FR. I have given the results as percentages for both groups so that you can better compare the results.

While not everyone benefited after getting Campath (the overall response was still 91% “only”, not 100%), there were significantly more CRs and even more important, significantly more MRD negative cases. It seems clear that Campath consolidation does indeed clean out some of the remaining CLL cells, making the remissions deeper.  But do the remissions last longer?  Can patients expect to live longer because they got deeper clean-out of CLL as a result of Campath consolidation?

Here is the kicker: at the two year mark, comparing patients who got the Campath consolidation and those that did not get Campath consolidation, there was no statistically significant difference in the percentage of patients still alive (84% versus 88%), or who were still in remission  (76% versus 70%).  The deeper remissions after Campath consolidation did not translate into longer remissions or better chances of staying alive, at this two year check point. The cars were cleaner after detailing, but they did not stay cleaner for a longer period of time.  Bummer!!! When rubber meets the road, patients go through the Campath consolidation in the hope that they will stay in remission longer, or have better odds of staying alive because hopefully the Campath did a better job of clearing out the last traces of CLL. These important goals were not achieved in this study, not over the two year follow-up period.

Toxicity

OK, no improvement in overall survival or longer remissions. What was the cost side of the equation for this disappointing result? Sounds like the price tag was pretty high. The percentage of patients who had Grade 3-4 toxicity are significantly higher than I would expect from standard FR therapy without any Campath consolidation. 6 patients died due to a variety of infections after getting Campath consolidation. Some of these fatal infections occurred as much as 7 months after completion of Campath therapy. I am not surprised by this. Earlier work has shown that infection fighting T-cell counts are a small fraction of what they were, for as much as a year after completion of therapy. Moral of the story, don’t think you are home free as soon as you have completed the Campath therapy. You need to be vigilant about infections for a good while after that, perhaps continue with the prophylaxis drugs and careful monitoring for six months or more.

Bottom line? The authors are rightly concerned about the level of toxicity and the deaths associated with infections after Campath consolidation. These patients need to be followed for longer period of time to see if the increased number of CRs and MRD negative remissions actually translate into better overall survival and longer remissions. The two year statistics reported above are disappointing, but perhaps over longer term the differences will become more significant. Sub-set analysis may also shed light on specific groups of patients who might have benefited from Campath consolidation.  It will be interesting to see if high risk patients with 17p deletion (FISH high risk deletion) benefit by getting Campath consolidation because Campath is thought to work independent of the p53 pathway that is damaged in 17p deleted cases.

All in all, another rather deflating report about Campath. I would have liked to see Campath consolidation hitting the ball out of the park, with clearly identified benefits to patients (longer life, longer remissions) right up front. That is unfortunately not the case it seems.

On a personal front, I am back from India and nursing my jet lag while visiting my daughter and her husband.  The snow in Maryland was a rude shock but it sure is nice having grownup kids! After enjoying a few days more of the pampering I will head back home to the warmer climate of sunny Sedona, AZ.