Date: April 18, 2004
by Chaya Venkat
Campath: Jumping the Gun;
Steroid-Campath Combinations: A Sledgehammer;
Campath plus GCSF Can be Dangerous;
Campath Looking Better and Better
Campath Therapy — MRD and Survival
PCR Negative Remission — Is this a Cure?
Conventional wisdom used to be that CLL is an incurable disease, no point in trying to mop up the last remaining cancer cell in the patient's body. How things have changed in the last few years. With the advent of the monoclonal antibodies such as Rituxan and Campath, as well as synergistic effect of combining conventional chemotherapy drugs such as fludarabine and cyclophosphamide with these new immunotherapy drugs (FRC, RPC, FR, (Rituxan + Campath), (Campath + Fludarabine), and so on), there is now a glimmer of hope. The hope is that some day we will be able to hit the cancer hard enough and from so many different directions all at the same time, that it has no more escape hatches left. An outright victory, the magic word "CURE", is almost within our grasp. Almost, but not quite yet. All the more reason for you to be smart in making your therapy decisions, play for time and stay as healthy as possible in the mean while. Live to fight another day when the odds are even more in your favor.
Those of us who have been around the block a couple of times already are quite familiar with the term Complete Response (CR), and we know all too well that it does not mean what it seems to be saying in English. Complete Response does not mean the CLL has been defeated, utterly destroyed and you can go home cured of the disease. It is just a relative term, a "CR" is better than a "PR" (partial response), which in turn is better than a "NR" (no response). Welcome to the world of clinical jargon and acronyms. Almost all CLL patients with a CR after therapy will relapse, it is just a matter of time.
Another very important acronym is minimal residual disease (MRD). We have become a lot better at measuring and estimating the last traces of cancer cells in the body. A response that is defined a CR by traditional measurements is quickly seen to be not so complete after all. Very often there are a few lurking cancer cells present that can be detected by more sophisticated tests, such as polymerase chain reaction (PCR). A patient who is "PCR positive" is one that still has some cancer cells left, which may (or may not) grow back to full fledged disease down the road. The coveted "PCR negative" status means that there are no CLL detectable even with this sensitive technique. "PCR negative" does not mean there are absolutely no CLL cells left, just that we cannot detect them even with out best methods. You can read more about PCR and what it means in terms of long lasting remissions in What Does It Mean to be PCR Negative? and PCR Negative Remission – Is This a Cure?
The logical question follows: if a patient is in CR remission after therapy, but is still PCR positive and therefore still has some cancer left behind, can we treat the patient again almost right away, while he is still in remission, to try and get rid of the last bit of the cancer? Can we hope to hit a home run, convert a CR to a deep and sustainable PCR negative status? Hopefully get this patient a remission that is so sustained that there is no reason not to call it a full 100% cure? This is the hot new frontier of CLL clinical trials. Many researchers are tagging a "consolidation" phase at the tail end of a full fledged therapy regime, to see if the one-two punch can take the tumor kill all the way to completion.
We have heard of several patients who have participated in various combo therapies, and then gone on to receive Campath therapy as a way to improve their response status. I understand the RPC combo trial (replacing the more common fludarabine in "FRC" with its sister drug pentostatin, this trial is administered at Ohio State as well as other locations) is also considering addition of Campath at the tail end of the RPC, to treat residual traces of the disease. The potential benefits of such an approach are obvious, who would not like to go the extra step if it means a much deeper, hopefully PCR negative response, dare we say a cure?
But what about the downsides? Trust me, there are always downsides to consider, there is no free lunch in the cancer business. This article discusses the potential downsides of "consolidation therapy" (another phrase that means the same thing as mop-up of MRD) following quickly upon the heels of primary therapy. The potential benefit of a deeper response and longer remission has to be weighed in the context of the more aggressive therapy translating into greater risk of adverse effects.
There are a bewildering number of ways in which the available drugs can be combined and administered, but in this article we will focus on Campath as the drug of choice, the one chosen to clean up the last bits of CLL left behind after other "induction" therapy. The two abstracts below are both from top rated researchers, one from the prestigious German CLL study group and the other is from M. D. Anderson. The two reports issued within a few months of each other, the German paper is less than a couple of weeks old. CLL Topics is nothing if not cutting edge! If a patient were to take no more than a cursory glance at the two abstracts below, he would be justified in throwing up his hands in despair, the conclusions seem so different. The German study was stopped mid-stream due to severe infections that were a lot worse than expected in the Campath consolidation group as compared to the control group who had no such consolidation. The Anderson study did not seem to run into as many severe infections, the study sailed through to the end. What gives? To repeat a phrase I use all too often, the devil is in the details.
If you want to read the full text articles of this and the Anderson articles, write to us at and we will help you locate the articles. The articles are worth reading, especially if Campath consolidation is something you are considering. This is an exceptionally well designed and well controlled trial, I am impressed by the quality of detail presented on each individual patient who participated in the trial. I summarize the major points below:
|Toxicity||Grade 1||Grade 2||Grade 3||Grade 4|
|Number of Patients|
The researchers had a pre-agreed trigger point at which to pull the plug on the trial. After a median of 4 weeks, this trigger point was reached when severe infections in seven of 11 patients caused stopping of the trial. Infections included one life threatening grade 4 pulmonary aspergillosis and seven grade 3 infections including four CMV reactivations, one herpes infection, 1 herpes zoster infection and one reactivation of pulmonary tuberculosis. In addition, four patients had severe myelosuppression which did not resolve after an interval of 14 days. In sharp contrast, only two episodes of mild infections were recorded in the control group: a herpes zoster infection (grade 2) and a sinusitis (grade 1) several months after the randomization. Neither of these is hardly worth writing about.
For all their pain and suffering, how did the patients respond in terms of the CLL? At a median follow-up of under 2 years from start of chemotherapy with F or FC, all patients in the Campath consolidation as well as control group were alive, so we will have to wait some time to see if there is a difference in overall survival. Calculating progression free survival (PFS) from the start of consolidation with Campath, none of the Campath group had progressed while half of the control group had progressed by about 18 months. The paper has a lot more details of the change in status, number of patients who had resolution of MRD in the bone marrow, effect on lymph nodes etc. Bottom line, the Campath consolidation did clear out more of the CLL, but the cost may have been too high in terms of toxicity and infection, at least in this particular protocol.
In the abstracts and papers we discuss below, the researchers use the generic name "alemtuzumab" for the same agent that we know as Campath (that is the trade name). Don't be confused by this.
Leukemia. 2004 Apr 8 [Epub ahead of print]
Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission - experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG).
Wendtner CM, Ritgen M, Schweighofer CD, Fingerle-Rowson G, Campe H, Jager G, Eichhorst B, Busch R, Diem H, Engert A, Stilgenbauer S, Dohner H, Kneba M, Emmerich B, Hallek M.
 1Klinikum Grosshadern, Medical Clinic III, Ludwig-Maximilians-University, Munich, Germany  6Medical Clinic I, University Hospital, Cologne, Germany.
Patients with CLL responding to initial chemotherapy with fludarabine alone (F) or in combination with cyclophosphamide (FC) were randomized for treatment with alemtuzumab (30 mg i.v. TIW, 12 weeks) or observation. Of 21 evaluable patients, 11 were randomized to alemtuzumab before the study was stopped due to severe infections in seven of 11 patients. These infections (one life-threatening pulmonary aspergillosis IV; four CMV reactivations III requiring i.v. ganciclovir; one pulmonary tuberculosis III; one herpes zoster III) were successfully treated and not associated with cumulative dose of alemtuzumab. In the observation arm, one herpes zoster infection II and one sinusitis I were documented. At 6 months after randomization, two patients in the alemtuzumab arm converted to CR, while three patients in the observation arm progressed. After alemtuzumab treatment, five of six patients achieved a molecular remission in peripheral blood while all patients in the observation arm remained MRD-positive (P=0.048). At 21.4 months median follow-up, patients receiving alemtuzumab showed a significant longer progression-free survival (no progression vs mean 24.7 months; P=0.036). In conclusion, a consolidation therapy with alemtuzumab is able to achieve molecular remissions and longer survival in CLL, but a safe treatment regimen needs to be determined.
The article does not say it in so many words, but I expect this was a Phase -II trial. 41 patients were recruited for the trial, all of whom received the Campath consolidation therapy. There was no control group. The scenarios are quite similar but not identical in the two trials, making it harder to do a straight apples and apples comparison.
|Disease Site||Number of Evaluable Patients||Responders|
|Lymph Nodes||13||2 (13%)|
|Bone Marrow Nodules||31||15 (48%)|
|Bone Marrow Lymphocytes > 30%||7||6 (86%)|
As expected, the response in the lymph nodes was disappointing, Campath seems to have a hard time clearing these out.
Once again, If you wish to read the full text article, write to us and we will help you locate it.
Cancer. 2003 Dec 15;98(12):2657-63.
Alemtuzumab as treatment for residual disease after chemotherapy in patients with chronic lymphocytic leukemia.
O'Brien SM, Kantarjian HM, Thomas DA, Cortes J, Giles FJ, Wierda WG, Koller CA, Ferrajoli A, Browning M, Lerner S, Albitar M, Keating MJ.
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX
BACKGROUND: The objective of this study was to investigate the efficacy and safety of alemtuzumab, the humanized anti-CD52 monoclonal antibody, in patients with B-cell chronic lymphocytic leukemia and residual disease after chemotherapy.
METHODS: Forty-one patients received alemtuzumab 3 times weekly for 4 weeks. The first 24 patients received 10 mg per dose, and the next 17 patients received 30 mg. All patients received infection prophylaxis during therapy and for 2 months after treatment.
RESULTS: The overall response rate was 46%, including 39% of patients who received the 10 mg dose and responded versus 56% of the patients who received the 30 mg dose. The major reason for failure to respond was the presence of adenopathy. Residual bone marrow disease cleared in most patients, and 11 of 29 patients (38%) achieved a molecular disease remission. The median time to disease progression had not been reached in responders with a median follow-up of 18 months. Six patients remained in disease remission between 24-38 months after therapy. Infusion-related events were common with the initial doses, but all such events were NCI Common Toxicity Criteria Grade 1-2. Infections were reported to occur in 15 patients (37%), and 9 of these infections were reactivation of cytomegalovirus. Three patients developed Epstein-Barr virus positive, large cell lymphoma. Two patients had spontaneous resolution of the lymphoma and, in one patient, the lymphoma resolved after treatment with cidofovir and immunoglobulin.
CONCLUSIONS: Alemtuzumab produced significant responses in patients with residual disease after chemotherapy. Bone marrow disease was eradicated more frequently than lymph node disease, and molecular disease remissions were achieved. A randomized trial comparing alemtuzumab with observation after chemotherapy is indicated.
Copyright 2003 American Cancer Society.
Since their study came after the Anderson study, the German research team made a thoughtful attempt at explaining why the two studies (as well as other studies they reviewed) had such different results. Again, I refer you to the full text paper for the fine details, here are the major points:
The discussion in the German paper as to why the two trials had different results is interesting and points out some very important differences. It underlines an important concept in science, that researchers can often learn more from a failure than a successful experiment. The participants in the German study need to be thanked by the rest of us in the patient community - they have made the way easier for the patients who follow in their footsteps.
But precisely because of the protocol differences identified by the German team, as well as different methodology used in reporting the data, it is hard to compare the two trials head-to-head. It strikes me one of the reasons for the "different" results obtained in the two trials could be the subjective yardsticks used to define success and the definition of tolerable toxicity. Sort of "beauty is in the eyes of the beholder" kind of thing. Perhaps cultural differences have a role as well, the cautious German approach versus the more can-do Texan ethos of Anderson. The Anderson trial did not have an internal yardstick for comparison, since there was no well matched control group. We will have to make do with this apples and oranges comparison between the German trial and the Anderson trial.
Frankly, I found the hematological toxicity in the Anderson trial to be quite as unacceptable as in the German trial. Just about every patient had neutropenia or thrombocytopenia, quite a few of them serious grade 3-4 variety. True, there were no grade 3-4 infections, but to balance that there were three cases of EBV positive large cell lymphoma. This 'transformation' of the original CLL to a more aggressive variety, or the initiation of a brand new secondary cancer, is quite troubling to me. The lymphoma cleared up on its own in 2 of the three patients, but both of them died soon after, scant comfort there for patients. Did either study hit the proverbial home run, in terms of getting a substantial percent of the patients into long term PCR negative status and therefore lasting remissions? After all, that is the whole rationale for the double punch of consolidation therapy. On that point, the glass is half full or half empty, depending on your perspective. One thing is clear: a lot remains to be done in fine-tuning the use of Campath for consolidation therapy, to make it more effective with less risk of dangerous infections and hematological toxicity.
Here is the problem in a nutshell: your immune system performs an indispensable function in your body. It is the police, FBI, CIA, army, navy, marines, and air force, all combined. Without a functioning immune system, you are at the mercy of every stray bug out there, as well as home grown secondary cancers. As CLL patients, we are starting from behind, with a poorly functioning B-cell component, a very important part of the immune system. Then you hit it with fludarabine, a potent chemotherapy agent that is very effective in killing cancer cells. It is, unfortunately, not entirely selective or non-toxic: it kills and maims several other parts of your immune system. Some patients in these trials had both fludarabine and cyclophosphamide, both of which are known to be mutagenic. There have been some concerns raised recently on combining purine analogs with alkylating agents (as in F and C), and potential risk of secondary myeloid cancers down the road. I guess neither the German or Anderson study followed the patients long enough yet to check that one out.
Chances are that at the end of the F or FC therapy, the majority of the patients had immune systems function reduced significantly, across the board and including each component of the immune system. Given enough time, most patients would gradually recover from this nadir. But that is the hitch. As the immune system recovers, so too does the CLL, since it has not been wiped out completely at this point. The trick is to wait long enough for the patient to recover some level of immune function, but not so long that the CLL makes a strong comeback, before initiating the Campath consolidation. Waiting too long may close the window of opportunity to kick the CLL while it is down and out and perhaps deliver the death blow to the cancer.
The German study group felt they probably did not wait long enough. What is the danger in not waiting "long enough"? Well, Campath therapy is hardly easy on the immune system. The CD52 marker, the target for Campath, is not only exhibited by all B-cells, it is also exhibited by T-cells, monocytes and macrophages, all of which are therefore fair game. While no one seems to measure complement levels I would bet that this last piece of the immune system is also terribly depleted after Campath therapy.
How long does it take for the immune system to make a comeback after Campath therapy? I am glad you asked, because an excellent paper was published just last month by a top rated CLL research team from Sweden. Dr Eva Kimby and her colleagues are among my favorite researchers for both for the quality of their research as well as their detailed and thorough publications. This study showed that even 9 months after completion of Campath therapy, T-cells, B-cells and NK cells were still at less than 25% of the normal values. This is quite a serious window of vulnerability. Throw in neutropenia, and we are talking about real risk. The serious infections and hematological toxicity measured in both the German and Anderson studies document exactly how vulnerable patients are in this respect.
Both studies took pains to protect patients with pre-emptive medications. But is this enough? Apparently not, since one study had to be stopped midway, and the other one had at least a couple of patients dying due to complications. Don't get me wrong, there will be some CLL patients with a version of the disease that is so intractable, or the CLL has become so refractory after many layers of therapy that drastic measures are needed to get any kind of response at all. Beggars cannot be choosers, they say. When your back is against the wall, you make the best decisions you can, among the choices still open to you.
But what if you are relatively new to the CLL scene, had pretty good prognostics and many options to choose from, would it be your best bet to get full-bore fludarabine plus cyclophosphamide therapy, followed by Campath consolidation? You tell me. The Anderson study is rather skimpy on patient characteristics and provides almost no modern prognostic information leaving one to wonder exactly who was inducted into this trial. Fortunately, the German paper had a wealth of information on each patient. Some were merely Rai stage 2, some had the good mutated IgVH status, some had the best of the best FISH aberrations, the 13q deletion. It is quite a gamble for such patients to opt for FC followed by Campath consolidation. Perhaps they will get lucky, be among the patients that got the PCR negative response. But too many did not, and the price tag was too steep. Failure after one of these heavy duty combinations also carries a stiff penalty in burned bridges, in addition to the toxicity and risk of infections. What next for these folks, bone marrow transplants? What if they did not have well matched sibling donors lined up? A less than perfect unrelated donor match (MUD) is hardly something one would want for Christmas, not if there are better options to be had.
None of these are easy choices to make, and there is no crystal ball that will guide you to the best possible option for you. But the more you learn, the more you understand the nature of the risks involved in these choices, the better prepared you will be to make the right call when it is your turn to make a decision. Here are some suggestions that come to my mind:
Leukemia. 2004 Mar;18(3):484-90.
Cellular immune reconstitution after subcutaneous alemtuzumab (anti-CD52 monoclonal antibody, CAMPATH-1H) treatment as first-line therapy for B-cell chronic lymphocytic leukaemia.
Lundin J, Porwit-MacDonald A, Rossmann ED, Karlsson C, Edman P, Rezvany MR, Kimby E, Osterborg A, Mellstedt H.
Department of Haematology, Karolinska Hospital, Stockholm, Sweden.
Little information is available on long-term immune reconstitution after therapy with alemtuzumab in B-CLL patients. We present long-term follow-up data for blood lymphocyte subsets analysed by flow cytometry in previously untreated B-CLL patients who received alemtuzumab subcutaneously as first-line therapy. All lymphoid subsets were significantly (P<0.001) and profoundly reduced; the median end-of-treatment counts for CD4(+), CD8(+), CD3(-)56(+) (natural killer (NK)), CD3(+)56(+) (NK-T) and CD19(+)5(-) (normal B) cells were 43, 20, 4, 1 and 8 cells/microl, respectively. The median cell count of all subsets remained at <25% of the baseline values for >9 months post-treatment. CD4(+) and CD8(+) levels in blood had reached >100 cells/microl in >50% of the patients at 4 months after the end of treatment. One patient had a cytomegalovirus reactivation and one patient developed Pneumocystis carinii pneumonia during therapy. No opportunistic or other major infections were recorded during unmaintained, long-term follow-up. There was no correlation between the cumulative dose of alemtuzumab and the severity or length of immunosuppression. CD52(-) T-cell subsets occurred during the treatment and comprised >80% of all CD4(+) and CD8(+) cells in the blood at the end of therapy. These subpopulations declined gradually during unmaintained follow-up. The relationship between these observations and the safety/antitumour effects of alemtuzumab is discussed.
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Topic: Campath Therapy