Not all monoclonals are the same!
Campath was the very first monoclonal antibody that was approved for use in CLL, across the board. Heck, they even got the FDA to approve frontline use of this drug! (I think they did it the sneaky way, in my humble opinion, by comparing Campath against lower than normal dose of chlorambucil – an unfair strawman comparison. But that is another story).
Campath has one huge thing going for it that Rituxan does not. Campath is thought to work even in high risk cases with poor cytogenetics, those with the dreaded 17p deletion. As we have seen in a prior article “Crystal clear results on FCR“, patients with 17p deletion get little joy from FCR. Since Campath can do what Rituxan cannot in this group of high risk patients, I suppose it is a reasonable question to ask if replacing Rituxan with Campath is a good ides. Hence this clinical trial of FC+Campath in high risk and previously treated patients.
FC + Campath
The results of this clinical trial were presented at the latest ASH2010 conference. 43 patients were planned for this study, and they managed to get all 43 patients to enroll. There is no question this was a high risk group. More than half of the group had either 11q or 17p deletion, indications of high risk. All had been previously treated, this combinations of FC+Campath was being considered as salvage therapy.
Fludarabine, Cyclophosphamide, and Alemtuzumab (FCC) In Relapsed/Refractory Patients with B-Cell Chronic Lymphocytic Leukemia (CLL): Final Report of the Italian Study
Marco Montillo, MD1, Alessandra Tedeschi*,1, Francesca Ricci*,1, Alfonso Zaccaria*,2, Monica Crugnola*,3, Mauro Spriano*,4, PierAngelo Spedini*,5, Fiorella Ilariucci*,6, Lilj Uziel*,7, Immacolata Attolico*,8, Angelo De Blasio*,9, Eleonora Vismara*,1, Enrica Morra1 and Valeria Belsito Petrizzi*,10
Abstract 1384
Introduction: Purine Analogues in combination with cyclophosphamide (C) have a relevant advantage over monotherapy approach in patients(pts) with CLL. However, pts in complete remission (CR) eventually relapse and require treatment, demonstrating the need for improved treatments able to induce “better quality” and thus more durable responses. Monoclonal antibody alemtuzumab (CAM), directed towards CD52 antigen expressed on the surface of CLL cells has been proven to be the most effective antibody in CLL treatment. As previously reported by Elter et al. (JCO 23:7024-7031.2005) CAM appears to have synergistic activity with fludarabine (F) in vivo in relapsed and refractory CLL. Therefore, we designed a phase II study to determine the efficacy and safety of a 4-weekly combination regimen consisting of F, C, and CAM in CLL with relapsed or refractory disease after at least 1 line of treatment.
Methods: The FCC regimen consisted of oral F 40 mg/m2/day and oral C 250 mg/m2/day immediately followed by sc CAM 10 mg/day (Days 1–3). A-2 day escalation of CAM was administered prior to the first cycle. This combination was repeated on Day 29 for up to 6 cycles. According to the safety profile of the schedule described above the dose of CAM was increased after the first cohort of 10 treated patients from 10 mg to 20 mg. Minimal residual disease (MRD) was measured by 4-color flow cytometry.
Anti-infective prophylaxis included acyclovir 400 mg twice daily and trimethoprim sulfamethoxazole (TMP + SMX) 1000 mg given every other day from treatment initiation until 6 months after treatment end. CMV antigen in blood was tested in 7–days interval.
Results: Recruitment was stopped when the planned number of 43 patients have been enrolled in the trial. The median age of the patients was 60 years (range, 39–77), 26/43 (60%) were male, 42/43 (98%) had Binet stage B and C disease, and the median number of prior treatment regimens was 2 (range, 1–4); 32/43 (74%) of patients were relapsed while 11/43(26%) were refractory to prior therapy.
Pretreatment included F in 93% of patients (F+C 35%) and monoclonal antibodies (MoAb) in 39.5% of patients (Rituximab 28%, CAM 19%; both MoAb 7%). More than a half of pts presented with deleted 11q or 17p with 28% of pts showing 17p as the sole aberration. Unmutated IgVH was detected in 23/34 (68%) pts while 17/43 (52%) were tested positive for ZAP70. Median number of given cycles was 4. Myelosuppression of all grades was the most commonly occurring adverse events. Grade III-IV neutropenia episodes were observed in 66% of the administered courses while grade III-IV thrombocytopenia episodes were detected only in 8.0 % of cycles. Symptomatic CMV reactivation occurred in 8 cases, no CMV disease was recorded. Twelve major infections occurred, including hepatitis B virus (HBV) reactivation (1 patient), pneumonia (8 episodes), and sepsis (3 episodes). Two major late infections were also observed: 1 tuberculosis and 1 aspergillosis. There were 8 deaths among 29 responding patients due to disease progression (5 patients), Richter’s syndrome (2 patients), and one major late infection (tuberculosis). Progressive disease was the cause of death in 11 cases among 14 non-responding patients. An overall response rate (ORR) of 67% (29/43) was recorded with 13 pts (30%) achieving CR (MRD- in 6 pts) and 16 PR (37%). Higher ORR (p=0.003) was observed in pts not previously treated with MoAb. After a median follow up of 16.7 months (range, 1–49.5 mo) patients receiving FCC had a median PFS of 24.4 months. Finalized data of all patients will be presented.
Conclusion: Results from the final analysis of this new, 4-weekly dosing FCC regimen suggest that combination therapy with F, C and CAM is effective. Poor prognostic factors were strongly represented in these patients, including 68% unmutated IgVH and 54% deleted 17p or 11q. Although there were a number of major infections, most were manageable.
Disclosures: Montillo: Bayer: Research Funding, Speakers Bureau; Genzyme: Research Funding, Speakers Bureau.
Editorial
I suppose substituting Campath for Rituxan in FCR is a reasonable research concept. Reasonable, but not really out-of-the-box creative, and certainly not prudent – in my opinion. Sometimes I get the feeling that researchers are ticking off drug combinations in a grid of all possible combinations and permutations, not really putting brain in gear – or for that matter, putting patients’ safety front and center.
The last couple of sentences in the abstract “combination therapy with F, C and CAM is effective” and “Although there were a number of major infections, most were manageable” had me hitting the roof. “Manageable” did you say? “Effective combination”?
I beg to differ. Please let me to count the ways.
- There were 8 cases of CMV reactivation.
- 12 major infections occurred (that is a whopping 28%) including hepatitis B, pneumonia, sepsis, tuberculosis, aspergillosis.
- 2 patients had Richter’s transformation.
- All in, 19 patients out of 43 died!!! How is that for “manageable“? And “effective“?
- In spite of this very high intensity combination, 16 patients had progressive disease while on therapy.
I don’t know about you, but with this kind of track record, I would not want to be on this combination.
Mind you, I am very aware this is a high risk group of patients. In the last two years, it has become increasingly clear that for patients with 17p deletion there are only a limited number of choices. Campath is one of them. But this combination of Campath with F+C has got to be one of more over-the-top high toxicity combinations. And the very high percentage of patient deaths in this study proves it. I wonder if the patients would have done better if they just went home to hospice, rather than follow this therapy protocol. At the very least, they would have had more peace and quiet.
These clinical trial results are one more reason why I am so interested in all the work being done with lenalidomide (Revlimid) – another drug that works in 17p deleted cases – but with low toxicity with respect to T and NK cells. Unlike this combination of FCC, where both fludarabine and Campath are justly infamous for destroying T-cell and NK cell populations, Revlimid actually increases T-cell and NK-cell counts and their efficacy. That in turn means we may hope for fewer life threatening infections with Revlimid based therapy. Other drugs are in the pipeline as well, though in early stages. CAL-101 is another drug that may work with high risk patients. Other kinase inhibitors may do so as well. We can only hope and keep our fingers, toes and eyes crossed.
There is only one scenario where we can consider total destruction of T-cell and NK-cell populations with a certain amount of equanimity: just ahead of a mini-allo stem cell transplant, when new T-cells and NK-cells from the graft are going to take the place of your own home grown variety. These cell lines are so very important in protecting us against infections of all sorts, as well as secondary cancers (skin cancer) and transformation to more dangerous and aggressive lymphoma (Richter’s transformation).
Adding to the toxicity bill by piling on more and more T-cell destroying drugs is not the answer. Even if patients get remissions from such combinations, it is a case of winning the battle but losing the war.
You notice I did not even bother to parse the response statistics. Do you particularly care whether or not you got a CR response, if you are also at much higher risk of kicking the bucket due to uncontrolled infection a short while later? Both Campath and fludarabine kill T-cells. And it takes a long time for these cell lines to come back, especially following Campath therapy. Combining these two drugs (Campath + fludarabine) should have a huge red danger mark associated with it.
More is not necessarily better. I am coming to the conclusion that piling on the toxicity is not the answer. I keep telling patients to weigh the risks and rewards of any therapy choice. I wonder if I should be preaching that sermon to researchers as well – if they would bother to listen. We know enough by now to have been able to predict the deadly toxicity of this combination, even without having done this trial. Were these patients counselled that they may have a better chance if they chose to go for a mini-allo transplant? I do realize not everyone can have a transplant, there are lots of barriers including lack of a well matched donor. But surely we can do better than FC+C for our relapsed and high risk patients?
20 comments on "FCC: There have to be better options than this!"
Strong and clear. Also hard to argue with.
…I keep waiting to hear about a report on the Lumilixamab trial the ended in June. It is supposed to be more selective about which WBCs it attacks than Campath or even R, avoiding the CD-20 that the good guys also have. Has this report shown up somewhere that anyone here has noticed?
Thanks Chaya for spelling this so clear.
Campath is a serious drug that has to be treated with great respect, I had it few months after Fluradabine in preparation for a Reduce Intensity SCT, knowing all the risks and being taken care by the medical team with a very strict protocol of test to monitor almost everything and all the prophylactics needed to protect me.
Even with all the precautions I managed to get two infections and the reactivation of CMV all at once after week 8th. which kept me in hospital for 4 weeks and lost 7 kg.
I am here to tell the tale, but many are not, I personally never would use FCC, in my personal circumstances we decided to let pass a few months after fluradabine to allow for the body to recover before starting Campath/HDMP.
How can anyone would think to use both such toxic drugs in combination is something I just do not understand.
Thanks for reporting this paper, I was aware of it but you made it so clear and readable.
Brillant analysis and conclusion, Chaya! To my oppinion, it shows the dangerous involvement of resarch, pharma industry and FDA in USA (and a couple of Health Administrations in Europe). One thing is the withhold of these “manageable” side effects (or diminish it). As you name it “winning the battle but loosing the war”. Also a big discussion right now in the newspapers here in Switzerland and Germany. Thanks god there are some people who call a spade a spade. As you do.
When my doctor prescribed my treatment over 3 years ago, I remember her telling me that we weren’t going to use fludarabine because of my specific condition. I had PCR instead of FCR.
I’m wondering now if she knew (or suspected) she was going to follow it up with Campath. I know that a Campath chaser is different than using it at the same time as the P & C, but at that time maybe they didn’t know any different. Things move pretty fast in this field these days.
It’s hard to keep up…so, again, many thanks to you Chaya for your efforts in keeping us aware of the latest and the greatest (and the worst).
Great article and warning. Thanks Chaya.
This reminds me of a comment my oncologist made years back. He told me that Campath is a great drug if you can keep people from dying on it. –Seems to be what the study found.
Patients need to be aware of the danger with Campath. While it is a very good treatment for CERTAIN people, Dr. Keating said a couple of years ago that Tom was not a candidate for campath because he felt it was too dangerous for his immune system to take the hit. He still stands by his decision on this and we totally agree. If Tom had tried Campath last year, I doubt he’d be washing the dishes right now.
Jenny Lou
My first “strip mall” oncologist wanted to put me on Campath immediately. Fortunately, I found a CLL Specialist through CLL Topics.org. That is key- in my opinion, to treating this beast.
Jenny’s illustration saays it all.
Randy
Good message for the unwary. Patients need oncologists to hear you Chaya!
Thanks,
WWW
What this trial shows are two things: 1] Campath is a very difficult drugs to handle and 2] the outlook for relapsed and refractory disease with del 17p is dire.
I am not as optomistic as you about Revlimid. Its record with this group of patients is really not very good, with only the occasional responder – though it does do better if 17p is not involved. The other options for del 17p (apart from transplant) are also pretty dismal. That being said Campath itself is no great shakes if there is bulky disease.
As for the side effects, although there were 8 cases of CMV reactivation they were all caught early enough with gancyclovir so as to avoid CMV disease.
I, myself would not give this regime to someone who had a previous history of hepatitis B or C, or TB unless they were covered by appropriate prophylaxis. Pneumonia and septicemia are always hazards in patients who receive FC without Campath.
The risk of Richters transformation is greater with fludarabine, but I’m not sure how much Campath adds to it. The deaths were mainly in patients who did not respond to this treatment, which demonstates what a bad risk group of patients they were.
For this group of patients, my preference would be to enter them into a phase 3 trial comparing HDMP + Campath versus HDMP + Campath + Revlimid, or a phase 2 trial of one of the new enzyme inhibitors like CAL 101 or PCI-32765.
Of course, RIC allograft would be the fall back position for suitable patients
Dear Chaya, Thanks for a great article yet again. I am about to start treatment for my CLL, my Dr. is suggesting Rituxan and Trenda combo. Any thoughts or info on Trenda? Thanks Anna
Chaya,
I re-read the part on combining fludara and campath. The two that would make me run for the hills.
This past summer I had my third series of chemo. My oncologist and I had a heated discussion. I cannot take fludara again at my age. 77.
In 2002 with a different oncologist and had R/F. I had many problems.
I could not swing back for a very long time.
Campath would be a “no” with my SLL.
Thanks for a very powerful article and reminder.
Many Blessings to you, Chaya and I look forward to all you articles.
Rita
Cheya,
We are new to this site and even though my husband has been treated for the last 4 years to get control over this ugly disease we still have limited knowledge. He was treated with Campath injections but developed a bad reaction to the site of injection and the Campath had to be stopped. After it was stopped I was glad he did because I read an article on your website about Campath and how it is ineffective on CLL with Bulky disease. My husband suffers greatly from the Bulky Disease since his lymph glands are so enlarged they resemble jumbo size eggs lined around his throat and neck. His CT scan showeed his abdomen is loaded with enlarged lmyphnodes so much that his stomach looks like a full term pregnant woman. Hard and distended. We read about the clinical trial CAL-101 and wondered if that is a direction we should go. He is 57 years old with refractory and infiltrated bone marrow and Bulky disease. He has had 4 rounds of chemo beside the Campath try since 2007 and cannot obtain a clean remission. He has had FCR and TREANDA and RITUXIN combo and twice. Still nodes get larger and larger. Platelets get lower and lower. JUst finished an 8 week regimen of ARZERRA and no change at all. Oncologist has stopped treatment but offered nothing else. How do we get into this CAL-101 trial? Please HELP!!
Paula K
Paula:
Please refer to our earlier article on CAL-101. There I gave links to the four on-going CAL-101 trials. Each link will take you to the http://www.clinicaltrials.gov site that has all the inclusion criteria and contact information.
Go through the inclusion criteria carefully to see which of the trial criteria he fits. The next step is to call the phone number given as contact information, to get him enrolled in the trial. You can do this yourself, or you can get your oncologist to do it for you, whichever is easier or works faster for you.
CAL-101 is still an experimental drug in very early stage clinical testing. It is available only inside of a clinical trial, not to the general public. Also, it really sounds like you husband has pretty aggressive disease. I cannot be sure the CAL-101 clinical trials are his best option. In any case, I am not a medical doctor and it would be very unethical of me to give medical guidance. I strongly advice you to visit a CLL expert center and get solid advice on what he should do next. He needs far more help than we can offer on this patient education and advocacy site.
Cheya,
Thank you for responding so quickly. I appreciate it so much. I did call the contact link and also the email address for the #4 of the 4 trials and I have gotten no response. I will continue to call. Could you recommend a CLL expert center? Also appreciated greatly and thanks again!
Paula K
Paula:
The CLL Research Consortium is a group of high pedigree CLL research centers that collaborate on many projects and clinical trials. Here is a link to their site, showing the participating centers.
http://cll.ucsd.edu/sites.html
Wow am I thankful for all of the information you provide us. Another great enlighting article. It is so informative. I so appreciate what you do for all of us and how you keep us so informed. Thank you again for all the time and effort you put into this for all of us. I also think it is so nice that Dr. Terry Hamblin takes the time to add his comments. I also think it is great that so many respond and tell about what they have been going through and I thank them also for their comments. I don’t feel alone knowing so many are going through the same thing I do. I don’t have the words for how gratiful I am for this information.
Great article, Chaya.
Thank you,
Monique
Cheya,
All I can say right now is you are an amazing woman who truly cares about people and science and education in all equal measures. I wanted you to know that we reached the CAL-101 trial facilitator you mentioned and today we are on our way to Maryland to meet Dr. Boccia MD at the Center for Cancer and Blood Disorders. My hopes are high and I pray that this is the answer to our prayers. Your information site for those with CLL is a blessing and I pray that you can continue to help all of us who live with or care for those with this ugly horrific disease. Our love goes out to you for what you gave us just by responding to one persons email!!! Peace be with you and yours.
Thank you!
Paula**
Paula,
If you would like to contact me via Face Book under TSvi Howard Epstein, I can send you a couple references about a drug I am taking. It interrupts a Kinase path in a fashion somewhat similar to CAL-101 and seems to shrink lymph nodes, but increases WBC. My nodes are down about 75%. The studies on CLL are small, but unlike CAL-101 it is approved for something else and available if your husband’s oncologist thinks it is worth a try. My use is off-label. My case is anecdotal. I am a lab rat experiment, not in a trial. Pioneers can end up with arrows in the back, even if some reach Oregon (where I live). More discussion here would violate Chaya’s rules for this site.
Paula,
I had bulky abdominal mass (15 cm x 15 cm) and was fludarabine and campath refractory. Three cycles of oxaliplatin, fludarabine, cytarabine, and rituximab (OFAR) decreased my mass to the point that individual nodes could be identified. I was able to realistically consider transplant since my largest node was down to 6 cm following the treatment. OFAR is definitely a heavy duty treatment and was very hard on my platelet counts. My platelets would bottom out between 8 and 10 days post treatment and with each successive cycle the nadir would last a couple of days longer before the counts returned to baseline. I had one platelet transfusion after the first cycle, two after the second, and four after the third. Some patients were able to tolerate six cycles but most only tolerate between two to four. If your husband does not qualify for CAL-101, OFAR might be another option. Chaya has my contact info if you would like to talk. I wish you the best during your meeting in Maryland.
Steven
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