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.
36 comments on "Campath for Consolidation"
Always hard at work for us. Thanks for the research update.
Not at the FCR stage yet, relying on R only at this point, although
the response to the second round of treatment is slower and less robust.
I will now know what to say when offered the Campath consolidation later as
my disease progresses.
Thanks for doing my thinking for me.
Dave Mikol
An eye opening article, Chaya. As always, Thank you.
Hope you warm-up soon.
Leslie Eisenberg
Welcome home Chaya,
I hope you enjoyed your visit to your other home.
It is disappointing to see that a “cleaner” remission response with added Campath does not necessarily translate into an extension of life, and may in fact cause death from infection due to drug toxicity.
Was is heartening is that scientists and volunteers are still looking for new information.
Fred
A valuable analysis indeed and a welcome home to you.
WWW
Thank you for your sending the study and for your analysis.
Carter
Where would we be without our ‘translator’? Good to have you back Chaya.
Molly
Thank you Chaya for bring this trial to our attention and your astute commentary. From all the studies I have read, I have never put much faith in Campath- too harsh and too many normal B & T cells wiped out; not enough specificity. This is also a small trial group. Of course for those R refractory or otherwise with their backs against the wall it has its use. It is VERY expensive & the side effects are very serious. As a first treatment protocol, this study is not encouraging. I realize that all these combinations need to be explored but maybe it is time for a new generation of treatments to be aggressively pursued. We seem stuck in the fludarabine, rituxan, cyclophosphamide, campath, Trenda rut and are not getting the OS increases we need.
We need to explore cal 101, revlimid, Humax, dentric vaccines (GRNVAC), TRU016, MT103 Bite therapies, and autologous SCT with idio-vaccine conditioning (Bandandi), etc. much more aggressively and get what works from the lab to the trials to the bedside. I think idio vaccines should be given another try but with 2 major failures it might be hard to raise venture capital.
Thank you for the update,Chaya.
Monique
Appreciate the information and translation, thanks again. Mike
Thank you for taking the time and effort to provide us with the information. It’s always appreciated. Rich
Kay
Thanks so much for bringing this study to our attention and your commentary. Kay
Thank you so much Chaya. This is just the kind of study I have been wondering about. I know my oncologist plans to use FR when my time comes to start and I was wondering what the results of using this regimen versus other protocols would be. Do you know of any studies comparing effectiveness and toxicity as well as overall survival of FCR vs. FR?
Thanks,
Tim
Thanks for the update, my husband is going through Campath treatment now,he is feeling better and his counts have improved. I was wondering what the outcome would be after he is finished with Campath.
Not sure I like what I read. He is feeling so much better right now I was afraid about getting my hopes up too high.
Glad you made it back from India, enjoy your daughter and have a safe trip back to AZ.
Joan
Thanks again Chaya — I wish the news had been good — certainly glad I didn’t go in that direction when it was presented to me……..thanks to my ‘gut’ feeling and excellent advise from a good friend!
Would like to see some positives on when it ‘would’ be the flavor of choice for me tho……such a confusing diease this CLL
Darlene Dorsey
My husband started with f – 6months later was on fcr and followed up 1 yr. later with campath in Sept. 07. Our local oncologists office did not evaluate him for cmv, which he got and was hospitalised for 2 weeks. He ended up with several different serious medical problems due to his immune system being dangerously suppressed, and has been in the hospital several times since. One stretch lasted a very long 46 days. He is currently doing much better even though his counts are still extremely low and may now have a new low normal. The last flow cytometry showed no cll cells found. We have really been through a fight since this started in 2002 but it seems as though Campath(while damaging his already weak body and immune system)saved his life. We go to the oncologist next week for his 3 month check up. Please keep him in your prayers for a good Dr. visit. Thanks to Chaya for all of the information. You have been a great educator for me and always enable me to go to the Dr. and have confidence that I am asking the right questions.
Thank you for the abstract info and your analysis. Enjoy your family and then your home.
Linda
It is always hard to make an oncologist do what “you want”I mean here you have read about new tricks but your Doc does not think high about it.
What to do? This is as hard as research itself: to get a treatment you want.
JACK
Excellent as always Chaya, and particularly in this case because forewarned is forearmed. It’s also wet and cold in Cornwall but we don’t get much snow here. We can however get cut off because of snow on the moors between us and the rest of the UK!
Safe travels
Lawrence
(In remission after FCR)
Chaya thank you so much for your continuous and valuable review of treatment options and study results. This is a very timely review for me, I am MRD’s+ after HDMP + R and the possible use of Campath for Consolidation Therapy F/U was mentioned. But the MD did say he was concerned w/toxicity. After reading the study results and your clarification, this is not an option for me. I moved from AZ to the Midwest and today with the cold wish I too was back in Phoenix. Stay well.
Nancy (Chicago)
I want to again thank you for all the information you provide for us. I’m glad you are back in the states. I had to laugh as my Dr. sent me the slides she got from a seminar she went to which you have addressed in your German studies. So when I opened up the slides and went through them, I said to my husband, oh I already know this stuff and he of course looked at it and said he did not understand it. I said well Chaya provides me with all this information so I am already up on it. He said you understand it, and I said basically. But I think what is important here is because of the information you provide to us, we as patients can ask more informed questions and our providers can talk to us because they know we understand what they are talking about. I thank you very much for this. One question though, is what medication is given to protect from shingles? I can not think of the name of the medication.
Mocha:
Shingles is caused by reactivation of a type of Herpes virus. Majority of adults carry traces of this virus in our bodies and under normal circumstances a healthy immune system keeps it from reactivating. But in CLL patients and anyone who is immune suppressed, the virus can wake up and cause a bad case of shingles.
Fortunately, we have antiviral drugs that work against this particular virus (Varicella zoster virus). The technical names are ‘famcyclovir’, ‘acyclovir’ ‘valacyclovir’. They may have different brand names in different countries. These antivirals have been in long term use as daily prophylaxis by millions of people (for prevention of genital herpes) and considered very safe. Frankly, my husband PC was on daily Famvir for the duration of his CLL and there was never any worry about it.
I liked the comment by “mschwalm48” about current treatment combinations and the need to explore and understand them better. I dream of a master grid that displays EVERY known treatment protocol. Then each one has a corresponding window summarizing study/trial data, anecdotal data, etc. This data would be contributed by many, then master-list condensed. If it even went so for as delineating results by CLL bucket flavor … now that would be something!
Thanks for the great and valuable input on Campath Chaya. I’m one of those back against the wall campath users. I just finished my second course with good response, following good response from the first round a couple years ago. Antibiotics and paranoid sanitary habits have kept me infection free, “knock on wood”.
Great to have you back. Bob Larkin
Jerry:
I had Campath consolidation in April 2005, following HDMP+R and achieved MRD negative, but only temporaily. The BMB showed no CLL but my T cells were almost wiped out. After nearly 5 years, my blood counts are still in the normal range, no enlarged sleen or lymph nodes and my last BMB revealed only 2 or 3 percent CLL type cells in the marrow. My T cells levels have improved but are still significantly below normal and the new ones may be naive having no disease fighting ability yet. In the meantime, I have suffered from no infections or serious illnesses.
However, my good result (so far) may be more attributable to my favorable FISH and other lab findings rather than the treatment. Moreover, perhaps the more beneign HDMP+R treatment combined with the Campath consolidation is less damaging than the FR treatment combined with Campath. Fludarabine + Campath seem like a very harsh combination.
Chaya,
Welcome home and thank you, again. Some side line good news for anyone on anti shingle meds at least in the US. Acyclovir has just gone generic !!! Maybe now the docs won’t be so unwilling to deal with writing it,as writing for generics is so much less trouble, and since it seems to have few if any long term effects as you say, and it keeps shingles at bay it’s wonderful.
off to pick up my first script of this, new generic version for $10 rather than over $300 depending on dosing.
beth
Hi Chaya,
The bitter reality is that there is not much research going-on exclusively for cll most of the big pharma’s do not have products in their pipeline for cll on the other hand big strides are being taken in CML the drugs being tested for cll are mostly those drugs which were developed for other conditions but failed and now being tested in cll to get something out of it, so there is not much hope for the future, after some time the docs starts making hypes of some new drug now a days its revlimid actually doctors are paid large amounts by Big Pharma for creating these false hypes / hopes, nowdays celgene is doing it quite successfully. We are standing almost at the same place where we were 10 years ago and I dont think the picture will change after 10 years the condition will remain incurable, unfortunately there is clearly not much aggressive effort going on for CURE except the expensive / risky sct. Thanks for your true input chaya.
Chaya,
Your review is on Campath consolidation ,but I want to comment on the FR. The CR rate of 29%, half of which were MRD negative, seems much lower than numbers I have seen out of MDACC where they say they gat CR responses in the 70% range on patients like this with FCR. Expect for those with 11 q del, I doubt the Cyclophosphamide makes that big of a difference
Can we trust the numbers out of Houston?
Be well
Brian
Hi,
With refrence to my earlier commentary how unfortunate we cll’rs are the latest trial for cll is using 50 years old drug bendamustine, just imagine the technology/science by comparing 1960’s car with 2010 one….
all the discarded/failed drugs are being tested on cll’rs.
Sorry, I forgot something to add I was thinking we might see a clinical trial of ASPIRIN for cll….
Chaya,
Thank you for CLL Topics, Inc. and for this latest very informative posting.
My oncologist at Mayo is thinking of using frontline Campath when I need treatment, so of course I was very motivated to read your opinion. You can believe I will ask for his rationalization for using something with so high a risk of infection and (as yet) no evidence of longer OS. I am grateful to have your help in educating myself about CLL..
Margaret
I would like to remind all of you about the value of Campath in treating patients with 17p deletion in their FISH. These patients had few options prior to the advent of Campath and possibly Revlimid and flavopiridol. None of the conventional drugs work in 17p deleted cases because in these patients the p53 pathway does not work the way it should – a pathway that is essential for cell kill using conventional chemotherapy drugs such as fludarabine and cyclophosphamide. Revlimid and flavopiridol are still works in progress to some degree. Campath is available, here and now. It is a huge boon for these patients.
Mkali:
I understand your frustration and bitterness. But I cannot agree totally with your perspective. Just a few years ago we had no monoclonal antibodies. Yes, I am talking about Rituxan and Campath and now Arzerra. There is concrete proof that patients are doing better because of the addition of Rituxan to conventional chemotherapy. Compared to FC, FCR has been shown to actually increase overall survival!!! How wonderful is that? It would not have been possible just a few short years ago.
Yes, we can use more and better drug options, too many patients are still not getting optimum therapy even with the drugs we do have, and the clinical trial process does not always play out right. But there is no question there has been progress, we should not lose sight of the gains that have been made; crucial knowledge gained at the expense of brave volunteers putting their lives on the line to get us the information.
Let us not throw the baby out with the bathwater.
I totally agree with Chaya. Mkali, you have to understand that medical research is like any other business. If you want high quality researchers, they need to be payed and have equipment and space to do their work. Since CLL is not a common disease, there is only a trickle of cash flow due to donations. While the government funds some medical research, it will never be the top priority. Medical centers continue to face rising costs and research continues to get more expensive due to the complexity and advanced techniques that are being explored. Medical centers have had to diverted money from research to keep the doors open to provide their primary mission – clinical services. It is not a question of right or wrong or fair, it is a fact in the world we live in.
Research dollars from large Pharmaceutical Companies are absolutely necessary to make ends meet in the research world. These funds not only to pay for the specific Pharmaceutical Company’s protocol but also to buy the equipment necessary for advanced research and to pay the salaries of the researchers working on unrelated protocols like T cell modulation in hopes that one day stem cell transplant is an obsolete form of treatment.
Will that happen in my lifetime? No one knows the answer to that question but remember, stem cell transplant has gone from just a dream to a realistic hope for a cure for CLL patients in less than 40 years. When I was first diagnosed with CLL 5 years ago, stem cell transplant was thought to be too risky for CLL patients. As Chaya has informed us over the last several months, transplant is rapidly becoming the consensus treatment for younger CLL patients with aggressive forms of CLL. A lot of this change has to do with the progress that has been make in reduced intensity conditioning transplants and improved protocols for controlling transplant related mortality. Most of this data was based on the lessons learned while developing transplant protocols for other forms of leukemia and lymphoma.
I am eternally grateful for the CLL patients before me that were willing to risk their lives to advance the science and help make treatment protocols safer and more effective. But I am also grateful for the CML, AML, ALL, and other leukemia and lymphoma patients that also contributed to these advancements. Without the knowledge gained from the sacrifices of these patients, transplants for CLL patients and possible cures for our disease would still be just a dream.
I understand your frustration. My best friend’s Mother died of Hodgkin’s disease when he was a teenager, a year before effective treatment for Hodgkin’s disease was available. None of us can predict the future. However, there is now more reason for hope than ever before. However, we must be as willing to take the risks necessary to advance the treatment of CLL as we are to accept the advances in treatment that have been gained by the courage of those who have gone before us.
Steven Karan
I was under the impression that their were more patients with CLL than CML. If so, why is more money and effort being spent on CML?
Wayne
Happy Holidays, and Peace to all………….
Given that FCR is now apparently accepted as the “gold standard”, I wonder why both arms of patients were given FR, rather than FCR. I wonder whether this (FCR) might have improved the efficacy of Campath.
Given that all the patients were previously untreated, would one have expected the overall results (average PFS and OS for the whole group of patients) to have been rather better than what was achieved?
Antony
Apologies but due to some confusion on my part I posted the above comment before reading your 20 September article on Campath. Having read it it seems that there are overwhelming reasons not to administer Campath. So please ignore the issue I raise in the second sentence of the first paragraph above.
Antony
Antony,
It was a very good question regardless of newer information. I have an un-official answer.
When I was first diagnosed, I was offered this trial from UofC. After talking to the doctor for quite a while, she had told me that based on my age she would recommend FCR. When I asked why is FCR better than the trial she said that the C in the combination makes it more toxic and is much harder on older patients. She said that younger people handle it much better and FR is the recommended approach for older adults. She said part of her goals was to see if the addition of campath made FR as effective as FCR for older adults.
Again, this is just what I remember AND only one of the doctors opinions. But a good question none the less.
Tom
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