Updated: January 6, 2010
Campath as Single-Agent Frontline Therapy
FDA Expands Approval
Jumping the Gun
The FDA approved Campath for use in treating relapsed or refractory CLL in May 2001. The drug has since proved useful, especially in those cases with p53 deletions which are otherwise resistant to treatment. However, the antibody produces severe immune suppression and other side effects and its use has been limited. Most recently, based on the results of a clinical trial that compared Campath with chlorambucil, the FDA has expanded the use of the drug to include frontline single-agent treatment of CLL. In this article, Jumping the Gun, we examine the value of the broader use of Campath as frontline single-agent therapy for CLL. (9/24/07)
An Expert Looks at Therapies for p53 Defective CLL
A Sledgehammer To Be Used Wisely
A defect in the p53 gene is a poor prognostic marker and predicts aggressive disease. Patients who have this defect tend to respond poorly to standard chemotherapy. Finding new and better ways of treating CLL patients with p53 defects is therefore a major priority in CLL clinical research. In his article, Steroid-Campath Combinations, Dr. Andrew Pettitt of the Royal Liverpool University Hospital evaluates agents that have promise in this area and addresses the important questions of when to treat such patients and how far to go with the treatment. (8/31/06)
Campath plus G-CSF Can Be Dangerous
A Scary Story: Telling It Like It Is
The combination of Campath and G-CSF appears logical enough as an approach to reaping the benefits of Campath therapy while keeping the immune suppression and infections typically associated with it under control. However, the co-administration of G-CSF with intravenous Campath to patients enrolled in a phase II trial at Ohio State produced unexpected and discouraging results. The prompt publication of the results is a credit to the Ohio State team. It is important that we understand the results of this trial as we consider our therapy alternatives. Read about it in Campath plus G-CSF. (6/20/05)
MRD and Survival
The Half-full Glass
Good News for the Tough Cases
Another piece of solid clinical research with important implications has just been published online in the Journal of Clinical Oncology on Feb. 28, 2005. In it, Paul Moreton, et al., report on the results of a 7-year phase II study involving late stage and refractory patients. The British team concludes that eradication of minimum residual disease with Campath has a surprisingly good effect on survival in this cohort of tough cases. We review the Moreton article and offer our analysis in Campath Therapy — MRD and Survival. (3/6/05)
German Clinical Trial Was Terminated Early Due to an Unacceptable Incidence of Severe Infections
Hitting a Home Run Is Not Easy
Campath is a promising agent in CLL but it does have significant immunosuppressive effects. There is a great deal of interest in using Campath as a cleanup agent after more traditional chemotherapy or chemo-immunotherapy to eliminate minimum residual disease (MRD). Recently published results from a German CLL research group are revealing. The study was halted early as the consequence of an unacceptably high level of severe infections. We compare these results with those reported by M. D. Anderson and comment on the variance between the two sets of clinical results in the article titled Campath Consolidation — A Home Run? (4/18/04)
Campath — Looking Better?
Proves Effective in Early Stage and Difficult Cases
Experts Get Better at Using the Anti-CD 52 Antibody
We review the current status of research and clinical trials involving Campath-1H. This fully humanized monoclonal antibody has been approved by the FDA for use in relapsed CLL but current research reveals that it could have critical application as a frontline therapy in a subset of high risk cases. It is a powerful therapeutic agent that is slowly finding wider applicability in early stage patients. The techniques of administration have improved and so have the techniques of managing the serious immune suppression attendant to its use. Our review article, Campath Looking Better?, explores these and other aspects of Campath therapy. (2/3/04)
Side Effects and Treatment of MRD
by Chaya Venkat
Molecular Model of Campath-1H
(Copyright © M. R. Clark, Cambridge University.
The development of a form of Campath that may be administered subcutaneously would be better than the intravenous version used now. I have cited some abstracts outlining the use of subcutaneous Campath in clinical trials, especially to treat minimal residual disease.
The subcutaneous form has fewer infusion-related side effects, possibly because the cytokine storm unleashed by IV administration is avoided by using the subcutaneous form because the drug seeps into the blood stream so much more slowly. Most of the infusion related chills, rigors and other unpleasant side effects are due to the rapid rate and high level of cytokines released by IV administration of this drug.
Having said that, there is still the more long term and serious issue of general immune toxicity. Campath targets the CD52 marker. The good news is that most CLL patients have a high percentage of their B-cells exhibiting this marker, and generally at a pretty high intensity. This is not always the case, for example, where Rituxan is concerned. Only a portion of CLL patients have a high enough percentage of the B-cells exhibiting the Rituxan target antigen, CD20, at sufficient intensity, to make them good candidates for Rituxan therapy.
The bad news is that B-cells are not the only ones that exhibit the Campath target marker CD52. This marker is also expressed by most if not all T-cells and monocytes. T-cells are a critical part of the immune system, and monocytes are the precursors of macrophages, the cells responsible for both killing and cleaning up the debris of all sorts of pathogens, including cancer cells. This aspect of the non-specificity of Campath is not something that can be avoided by going to the subcutaneous administration. One can still expect a serious level of immune suppression, because Campath kills not just the B-cells, but all the T-cells and monocytes and macrophages as well. This is why it is important to be on preventive broad spectrum antibiotics, antivirals and anti-fungals during and for quite a while after Campath therapy, to avoid precipitating opportunistic but life threatening infections. In early clinical trials with Campath, an unacceptable number of patients were hospitalized and a few even died because these precautions were not taken.
There is a very detailed monograph on the use of Campath for CLL, by Dr. Kanti Rai. It provides a lot of details on how it works, what to expect, future lines of investigation etc. One fact sticks in my mind: some of the special function T-cell lines killed by Campath do not fully recover even after a couple of years.
Since both of the monoclonals (Rituxan and Campath) when used as single agent therapies seem to have trouble giving deep remissions for patients with bulky disease, whether it be large lymph nodes, heavily infiltrated bone marrow and/or enlarged spleen and liver, it seems to me that their preferred role would be in combinations with other chemotherapy drugs in these cases, and as monotherapies only when the tumor burden is low. In my opinion, Rituxan monotherapy is a good choice for patients in early stage disease, who have the required CD20 positivity. Campath may have a role to play in eliminating the last traces of minimal residual disease after other chemotherapy regimes.
For my money, Campath is a good drug to have available as a backup option. But it would not be my first choice, by a long shot.
There seems to be a learning curve associated with each of these new drugs. It was Rituxan's turn first. It was not supposed to be effective in CLL, only approved for NHL. Now there are ongoing and encouraging clinical studies, such as the Hainsworth study that we have discussed in detail at this website, that say Rituxan has significant activity in CLL too. A maintenance regime of this monoclonal has a great deal to offer patients who are reluctant to take on the toxicity of conventional chemotherapy drugs. And the story does not end there either, in addition to combos such as RFC, we are just beginning to see interest in combination of Rituxan with immune system modulators such as Interferon alpha and granulocyte colony stimulating factors (G-CSF) to boost immune functions.
Rituxan targets the CD20 marker on B-cells. This marker is present to some degree on all B-cells, not just malignant B-cells. Hence Rituxan therapy involves targeting of all B-cells. However, stem cells and progenitor cells are not attacked, since they do not have this marker. Once therapy is over, the bone marrow gradually replenishes the B-cell repertoire.
Campath, on the other hand, attaches to the CD52 marker, which is present on B-cells and T-cells. It, too, does not damage the stem cells, but unlike Rituxan, it attacks T-cells as well. Risk of opportunistic infection is higher with Campath therapy, since there is a period during which not only the B-cells but the T-cells are also depleted, and the patient is at risk until the bone marrow gradually repopulates both these important cell lines. We have come a long way from the early days of Campath use and the protocols for Campath use now routinely include drugs to protect the patient from infections of various sorts during this window of vulnerability.
Both with Rituxan and Campath, there is the issue of infusion related side-effects, mandating very slow infusion rates, with constant monitoring. It makes the process both cumbersome and expensive. Now comes this report (see the attached abstract below) that suggests we can get away from some of the infusion related problems by going to subcutaneous injections of Campath, versus the usual IV infusion. But more important, it is a credible study of frontline use of Campath as single agent for CLL patients. I urge you to read this abstract carefully: the numbers are quite impressive! Overall response rate of 87% and 19% complete remission is pretty exciting. I have no doubt this will be tweaked up further in the months and years to come, with innovative combinations of the type we are beginning to see with Rituxan.
This game is all about choices. Until just a few years ago, Chlorambucil and Cyclophosphamide were it. Then came Fludarabine, and it became the gold standard for treating CLL. Now we have anti-CD20 Rituxan, and anti-CD52 Campath. Soon to be followed by anti- CD23 IDEC152 (more on that in a later article). A few years ago, if you became refractory to Fludarabine, it was curtains for you, soon. Now you are just getting started! Stay healthy, people. There is a new day dawning, I can smell it in the air. There are more effective and less toxic therapies coming down the pike, and you can make the best use of these developments by keeping yourself informed, and taking care of yourselves in the meantime, both physically and emotionally.
I have attached the abstract of the Campath study below.
Blood, 1 August 2002, Vol. 100, No. 3, pp. 768-773
Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL)
Jeanette Lundin, Eva Kimby, Magnus Björkholm, Per-Anders Broliden, Fredrik Celsing, Viktoria Hjalmar, Lars Möllgård, Peppy Rebello, Geoff Hale, Herman Waldmann, Håkan Mellstedt, and Anders Österborg
From the Departments of Hematology and Oncology, Karolinska Hospital, and Huddinge University Hospital, Stockholm, Sweden; and Therapeutic Antibody Center, Oxford, United Kingdom.
This phase II study determined the efficacy and safety of alemtuzumab, a humanized anti-CD52 monoclonal antibody, delivered subcutaneously as first-line therapy, over a prolonged treatment period of 18 weeks in 41 patients with symptomatic B-cell chronic lymphocytic leukemia (B-CLL). Injections were administered subcutaneously 3 times per week, from week 2 to 3 onward. An overall response rate (OR) of 87% (95% CI, 76%-98%; complete remission [CR], 19%; partial remission [PR], 68%) was achieved in 38 evaluable patients (81% of intent-to-treat population). CLL cells were cleared from blood in 95% patients in a median time of 21 days. CR or nodular PR in the bone marrow was achieved in 66% of the patients and most patients achieved this after 18 weeks of treatment. An 87% OR (29% CR) was achieved in the lymph nodes. The median time to treatment failure has not yet been reached (18+ months; range, 8-44+ months). Transient injection site skin reactions were seen in 90% of patients. Rigor, rash, nausea, dyspnea, and hypotension were rare or absent. Transient grade IV neutropenia developed in 21% of the patients. Infections were rare, but 10% patients developed cytomegalovirus (CMV) reactivation. These patients rapidly responded to intravenous ganciclovir. One patient, allergic to cotrimoxazole prophylaxis, developed Pneumocystis carinii pneumonia. Alemtuzumab is highly effective as first-line treatment in patients with B-CLL. Prolonged treatment is important for maximal bone marrow response. Subcutaneous administration induced very few "first-dose" flulike symptoms and may reduce health care costs in comparison with the intravenous infusions.
Bear with me as I repeat some of the material I have discussed in earlier articles. Consolidation therapy after de-bulking is rapidly becoming the single most promising approach to produce very satisfactory results for large percentage of patients. We need to be aware of these developments, many of us will face these decisions sooner or later.
"MRD" stands for Minimum Residual Disease. We are all familiar with the terms "Complete Remission" and "Partial Remission". We are also aware that in general, even patients who get a "complete remission" after a particular chemotherapy regime will eventually relapse, and the CLL will be on the war path again. Till recently, we did not know how to measure the level of completeness of the remission, we just knew there were enough cancer cells left behind to re-seed the cancer down the road.
Now we have better analytical techniques, generally "PCR" (Polymerase Chain Reaction) techniques, that look for a particular marker or feature of the cancer, and make it possible to detect at the level of one cancer cell in a population of 100,000 cells. Someone who is in "PCR negative" status is indeed in a deep remission, and stands a good chance that the remission will be a long, long one, perhaps one that lasts for the natural life span of the individual. If this were the case, the distinction between a complete "cure" virus PCR negative remission becomes just a semantic one, and most of us would not care about it one way or the other!
So, the game plan now seems to be to get as many patients as possible into PCR negative status. What we are finding out is that a multi- pronged approach seems to work best. The abstract below (ASH 2002) describes a group of patients who had been through Fludarabine therapy, which took care of the bulk of the cancer cells. This was followed by a mop-up ("Consolidation" ) using Campath, to kill as many as possible of the remaining cancer cells, in other words take care of the "MRD".
Couple of points to remember: Campath has demonstrated significant toxicity at high dosages. It has become obvious that while it does an excellent job of clearing the peripheral blood of CLL cells, and does a good job of clearing the bone marrow as well, it does not do such a good job clearing bulky lymph nodes. Campath as frontline and single agent therapy in CLL does not seem to get as deep a remission as other approaches, especially in patients with lymphadenopathy (swollen lymph nodes).
There is also the concern that since Campath targets CD52, a marker present on most B-cells, T-cells, monocytes, macrophages and other important cell lines, there is significant and profound immune suppression with use of high dose intravenous administration of Campath. We have gotten better at administering antibiotics and antivirals along side of Campath, and this has improved patients' resistance to opportunistic infections, but there is still some risk of secondary malignancies and lymphoproliferative diseases.
The logic that makes sense therefore is to use a therapy that does a good job getting rid of the bulk of the disease, especially in the lymph nodes, by using some other drug or combination of drugs, and then use the Campath at lower dosages to do the mop-up job. Save the big guns for the last bit, so to speak.
In this study, the researchers used subcutaneous injections, rather than intravenous administration of the Campath, which seems to control the toxic side-effects very well. I expect that giving the drug as an injection under the skin means that the drug will be absorbed slowly by the body, and this slower rate of drug delivery seems to work better than pumping it directly into the circulating blood. It is also a lot less hassle for the patient and the hospital to get the Campath as one injection, as opposed to getting hooked up to an IV.
In addition to the significantly reduced toxicity, I am impressed that a very large majority of the patients improved the status of their remissions in this study. Only time will tell whether a deep, PCR negative remission will add significantly to overall survival and overall time to reappearance of the disease. I would be willing to wager this would be the case, but we have to wait for passage of time to confirm this very important end point.
 Sequential Subcutaneous Administration of CAMPATH-1H as Treatment of Minimal Residual Disease in CLL Patients Responding to Fludarabine (FAMP).
Marco Montillo, Alessandra Tedeschi, Anna Maria Cafro, Valentina Rossi, Giovanna D'Avanzo, Ester Pungolino, Roberto Cairoli, Pierluigi Oreste, Silvio Veronese, Bruno Brando, Enrica Morra.
Dept of Haematology; Dept of Pathology; Lab of Immunology of Transplants, Niguarda Ca' Granda Hospital, Milano, Italy
Background and Objectives : Recent observations suggested that targeted monoclonal antibodies might be best employed in lymphoid malignancies under conditions of minimal residual disease. This prompted us to investigate the role of Campath-1H as treatment of patients with chronic lymphocytic leukemia (CLL) in whom fludarabine (FAMP) had produced a marked disease debulking with persistance of bone marrow (BM) infiltration or a complete remission (CR) without the disappearance of the molecular aberration (IgH monoclonal expression). As intravenous Campath -1H is almost invariably associated with reactions sometimes of grade 3-4 WHO, we adopted the subcutaneous route of administration, which proved to induce rare and mild adverse reactions with comparable efficacy.
Design and methods: Twelve patients (9 males, 3 females) with a median age of 55 years (range 41-62) who responded to FAMP (2 CR, 6 PRN, 4 PR), according to NCI Working Group Criteria, received subcutaneous Campath-1H, thrice a week for 6 weeks in escalating dose up to 10 mg. Monoclonal rearrangement of IgH was present in all patients before immunotherapy. Patients received acyclovir and cotrimoxazole as infection prophylaxis. G-CSF, at the dosage of 5- 10mg/Kg/die, or intermediate-dose Ara-C (800 mg/m2/q 12h x 6 doses), were administered to obtain a peripheral blood stem cell (PBSC) mobilization.
Results: All patients were evaluable for response. The four patients in PR before CAMPATH-1H reached a CR, two of them obtaining a molecular remission. Five out of six patients in PRN showed a CR after immunotherapy, with policlonal rearrangement of IgH gene in one case.The last patient in PRN showed no change after treatment. Finally one of the two patients in CR before CAMPATH-1H converted to a molecular CR. In nine out of nine patients PBSC harvesting was successfull; all collected more than 2.5 x106/kg. Collection was policlonal for IgH gene rearrangement in five cases. One patient has been transplanted after CTX and TBI as conditioning regimen, without complications and with rapid hemopoietic engraftment. All patients were evaluable for toxicity. A grade 1-2 WHO skin reaction was observed in 6 patients in the site of injection. No infectious episodes were recorded. Four out of five patients presenting CMV reactivation, without pneumonia, were successfully treated with oral gancyclovir.
Conclusion: Subcutaneous Campath-1H administered to CLL patients with residual BM disease after FAMP proved to be safe and effective. Of twelve patients, four obtained a molecular CR and six converted into a morphologic and immunophenotypic CR. In all of nine patients submitted to PBSC mobilization, this treatment also allowed a harvest uncontaminated with CD5/CD19 double-positive CLL cells, which was policlonal for IgH gene rearrangement in five cases.
Keywords: Campath -1H\ CLL\ Minimal residual disease
Fludarabine plus Campath
Results of Phase II Trial
by Chaya Venkat
Below is an ASH2002 abstract, describing the results of a Phase-II clinical trial, for previously untreated ("naïve") CLL patients, using a combination of fludarabine plus Campath. While the patients had not been previously treated, they were presumably in Rai Stage 2 or higher, with good reasons for initiating treatment.
The fludarabine was administered first, at what seems to me to be the standard dose for this drug, a total of 20 infusions over a period of 4 months. Then there was a waiting period of 2 months, and those patients that got at least a "stable disease" or better after the two month waiting were treated with Campath. The Campath too was apparently at standard dose, via intravenous administration, over a period of 6 weeks.
So. We are talking of a total of 32 weeks for the administration of the protocol. A total of 57 patients took part in this study. Several dropped out along the way, due to a variety of causes (including death!), so that only 36 out of the 57 patients actually finished the whole process. It seems to me that the vast majority of the patients had relatively serious therapy related problems, including infections with CMV (Cytomegalovirus). All in all, 15 patients had CRs, and 18 patients had PRs. Two patient died during the course of the clinical trial, as a result of opportunistic infections.
The percentage overall response depends on what you are looking at as the base. In my view, since these were all chemo-naive patients, and had good and valid other options (such as R, RF and RFC etc), using the base of the whole study group of 57 patients, a total of 33 patients had a partial response or better, for an overall response rate of 58%. This was at the expense of a very prolonged 32 week protocol, and significantly more side effects in terms of infections etc than we have become used to seeing for this type of patients. Both Fludarabine and Campath are tough on the immune system, and it is not surprising that opportunistic infections were much more common in this clinical study than in patients who went through RFC, for example.
When scientists talk about "non-overlapping toxicities", they mean that if for example the first drug might make you barf, but the second one makes you run for the john, it is OK to administer them together. In the case of Fludarabine and Campath, I am concerned that there is worry about overlapping toxicities, both make you have less defenses against opportunistic infections, especially if they are administered at the standard full dose. The present standard for RFC protocol at Anderson has deliberately scaled back the amount of "F" used, and many of the consortium specialists are talking about dropping the "C" part altogether, going with just "RF". I can see a day when Rituxan is gradually scaled up, with multiple and maintenance regimes, accompanied by scaled down administration of Fludarabine as needed to assist the patient's own immune system in the cell kill, but only to the extent needed.
I would have been happier if this study had used the European approach of reduced and subcutaneous administration of Campath after the patients finished the Fludarabine part of the trial. All in all, 32 weeks is too long, the overall response rate of 58% is not good enough, and the toxicity was too high. For my money, I would not volunteer for Phase-III of this approach, not unless they modify it significantly. I think there are better alternatives available, today.
 A Phase II Trial of Fludarabine Followed by Alemtuzumab (Campath-1H) in Previously Untreated Chronic Lymphocytic Leukemia (CLL) Patients with Active Disease: Cancer and Leukemia Group B (CALGB) Study 19901.
Kanti R. Rai, John C. Byrd, Bercedis L. Peterson, Richard A. Larson.
Long Island Jewish Medical Center, Albert Einstein College of Medicine, New Hyde Park, NY; Ohio State University, Columbus, OH; Duke University, Durham, NC; University of Chicago, Chicago, IL; Cancer and Leukemia Group B, Chicago, IL
Since the demonstration of efficacy of fludarabine (F) as a single agent in front-line therapy of CLL (NEJM 2000;343:1750), CALGB has been systematically conducting studies to improve the complete response (CR) rate in this disease by combining F with monoclonal antibodies. Here we report results of a phase II study using sequential administration of F followed by alemtuzumab. Our primary goal was to determine the toxicity and response rates in previously untreated CLL patients (pts) with active disease who met the NCI-WG 1996 criteria for initiation of treatment. Treatment included F 25 mg/m2/day x 5 intravenously (IV), monthly x 4, followed by observation for 2 months when an evaluation of initial response was performed. Patients achieving a response of stable disease (SD) or better were treated with a 6-week course of alemtuzumab. Alemtuzumab was given at 30mg IV three times a week after a stepped up dosing during the first week (3 mg as the first dose and increasing, as tolerated, to 10mg, and to 30mg). Prophylaxis with trimethoprim- sulfamethoxazole DS and acyclovir was required during and for 6- months after alemtuzumab therapy. Evaluation of final response status was performed two months after completion of therapy. Between Feb 2000 and Feb 2001, 57 pts were enrolled. One patient died prior to starting F. Toxicity and efficacy data are based on 56 pts who started F therapy. Eleven pts experienced major infections requiring parenteral antibiotics and/or hospitalization during the F period, and one pt died of septicemia from a Gram positive organism. Two pts (4%) achieved a CR and 29 (52%) a partial response (PR) after F phase of therapy. Twenty pts either had progression of disease (n=10) or died during F therapy phase (n=1), or discontinued treatment due to F toxicity (n=3), or withdrew consent (n=3), or whose data on post-F phase have not been received (n=3). Thus, data on 36 pts who received alemtuzumab are available. Alemtuzumab-infusion-related reactions occured in virtually all pts but were manageable with appropreate measures and were grade 1 or 2 in most cases. Grade 3 or worse major infections (requiring parenteral antibiotics and/or hospitalization) were recorded in 12 pts during or following alemtuzumab therapy. Infections with CMV occurred in 8 pts during or within 4 months following alemtuzumab. The outcome of CMV was fatal in one case, complete or partial resolution occured in 6, and persistent CMV in one. After the fatal CMV event, vigorous surveillance for CMV by weekly qualitative PCR-based testing was initiated to enable early recognition and prompt discontinuation of alemtuzumab and institution of antiviral therapy. Among 36 pts who entered the alemtuzumab phase of therapy, there were 15 CRs (42%) and 18 PRs (50%) with an overall response rate of 92% (NCI-WG 1996 criteria). Out of 11 pts with SD after F, 3 achieved CR and 5 had PR following alemtuzumab. Among all 56 pts (intention to treat population) the CR and PR incidence was 27% and 43% respectively. After a median of 10 months, 87% of 56 pts were alive. These early results are encouraging but a longer follow up will be necessary to determine if alemtuzumab given after initial cytroreduction with F leads to an improvement in the natural history of CLL.
Keywords: Alemtuzumab and fludarabine\ Chronic lymphocytic leukemia\ Initial therapy
Editor's Note: Patients who have a clinical trial with this combination of agents may want to read our coverage of the FluCam 106 trial and its prospective successor.
Campath plus Rituxan
by Chaya Venkat
One of our members expressed interest in the combination of Campath and Rituxan as front-line therapy for CLL. Here is a reference that might help. The abstract does not give a lot of details, and it refers to refractory CLL patients.
Some thoughts on this combination, that may or may not be relevant. It is clear now that Rituxan works by targeting the CD20 positive cells. T-cells are spared in this process. And these "effector cells" are important because they are the ones to do much of the actual killing of the B-cells after they have been tagged by Rituxan. Both complement dependent cytotoxicity (CDC) and anti-body dependent cellular cytotoxicity (ADCC) are important mechanisms for Rituxan to do its job.
Campath, on the other hand, targets CD52. This marker is present on B-cells, T-cells and a lot of other cell lines besides. I wonder whether the researchers in the clinical trial cited below administer the Campath and Rituxan simultaneously, and if so, whether the depletion of T-cells by Campath would negatively impact the efficacy of Rituxan. Also of concern to me would be the more pervasive immunosuppression due to Campath, as compared to the relatively more benign Rituxan. I have not heard of real problems with opportunistic infections after Rituxan therapy, something to worry about after Campath therapy.
It might be a better idea to administer the Rituxan, go through the full set of cycles and let it do its job, then do a mop-up of residual disease with low dose and possibly subcutaneously administered Campath. The subcutaneous administration of Campath seems to be much better tolerated than IV administration, possibly because the drug enters the blood stream much more gradually when it is injected under the skin. Just some things to think about, we will know more about these sorts of combinations as we get to hear the results of these clinical trials.
Semin Oncol 2002 Feb;29(1 Suppl 2):75-80
Conceptual aspects of combining rituximab and Campath-1H in the treatment of chronic lymphocytic leukemia.
Nabhan C, Rosen ST.
Division of Hematology/Oncology, Department of Medicine, Northwestern University Medical School, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL
Monoclonal antibody-based therapy has emerged as a novel approach in the treatment of hematologic malignancies. The safety and tolerability of monoclonal antibodies make these compounds attractive and easy to administer, even in elderly, heavily pretreated patients. Chronic lymphocytic leukemia is an incurable disease with few therapeutic options once patients fail purine analogue-based therapy. Two monoclonal antibodies have shown activity in this disease. The first is rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA), a chimeric human-mouse anti- CD20 antibody. The second is Campath-1H, a humanized form of a rat antibody active against CD52. We hypothesize that combining both antibodies in patients who have failed conventional therapies and express both CD20 and CD52 might have enhanced efficacy and therapeutic benefit. This concept is being explored at our institution in the context of a phase I/II clinical trial. The outcome and feasibility of this combination opens the way for future combination therapies using novel biologic agents.
Copyright 2002 by W.B. Saunders Company.
Campath Consolidation Therapy
German Clinical Trials
by Chaya Venkat
The URL below takes you to a very extensive report on the structure of the clinical trials underway to study the effectiveness of using Campath as consolidation therapy. This German study is working with about 90 CLL patients who have undergone Fludarabine or Fludarabine plus Cyclophosphamide chemotherapy and are in remission.
Unlike the abstract I posted earlier today, the Campath administration cited in this study is full strength and intravenous. I have not yet seen a full blown report of the results, but the tit bits I hear are that while the approach does indeed seem to do an terrific job of clearing out remaining traces of CLL, it also has significant toxicity and patients may have trouble tolerating it. I reiterate my comments in the earlier article, Campath is a great drug to use, at lower dosages and the subcutaneous administration seems to slow down the delivery rate enough to make the infusion related toxicity a lot easier to take.
The URL below will take you to a PDF format file. Don't get discouraged by the German in early pages, the later discussion is all in English. I will be looking to find the report detailing the results of this very important study.
Consolidation therapy with CAMPATH-1H (alemtuzumab) in patients younger than 65 years with chronic lymphocytic leukemia who are in complete or partial remission after initial cytoreduction with fludarabine or fludarabine plus cyclophosphamide.
Fludarabine alone (F) or in combination with cyclophosphamide (FC) is not a curative treatment; nearly all patients will eventually relapse. Therefore there is an urgent medical need to look for consolidation therapies which are able to prolong progression free survival or which can shift fludarabine-induced partial remissions to complete remissions or eradicate minimal residual disease in complete - but still PCR-positive - responders. There is no standard post-remission therapy available at the moment. Possible treatment options are high-dose chemotherapy followed by autologous stem cell transplantation or humanized monoclonal antibodies against antigens expressed on CLL cells.
CAMPATH-1H (alemtuzumab) is directed against the CD52-antigen which is present in high density on CLL-cells (B- and T-CLL cells) and has shown high response rates and long response duration in patients with fludarabinerefractory CLL. CAMPATH-1H was highly effective in clearing peripheral blood and bone marrow from leukemic cells whereas its activity on bulky lymph nodes and splenomegaly was limited. Thus, CAMPATH-1H seems to be most suitable for the treatment of (minimal) residual disease. The goal of this trial is to test if consolidation therapy with CAMPATH-1H is able to significantly prolong progression free survival in patients responding to prior chemotherapy with F or FC. The study addresses the following questions:
**Does consolidation therapy with CAMPATH-1H result in a prolonged progression-free survival in comparison to patients who do not receive further treatment?
**Is it possible to eliminate (minimal) residual disease by treatment with CAMPATH-1H (to turn a PR into a CR? to turn a PCR-positive CR into a PCR-negative CR?)?
**Does consolidation therapy with CAMPATH-1H translate into a survival benefit or even cure compared to patients with no further treatment?
**How is the safety profile and the quality of life in patients treated with CAMPATH-1H as consolidation therapy?
Campath in Autoimmune Disease
Clearing Out the Immune System
by Chaya Venkat
Among some of the life threatening complications experienced by CLL patients are a variety of autoimmune diseases. Autoimmune diseases can happen as a "normal" progression of the disease, where the screwed up immune system cells fail to make the fine distinctions between "self" and "non-self", and start attacking other cells of the body. There is also a lot of evidence that several varieties of autoimmune diseases can be triggered by chemotherapy drugs, Fludarabine features prominently on this list.
Autoimmune diseases span a wide spectrum, including for example, type-1 diabetes, rheumatoid arthritis, severe depletion of platelets (thrombocytopenia), depletion of red blood cells (hemolytic anemia, red cell aplasia), depletion of infection fighting neutrophils. All of these can be life threatening in advanced stages, and therapeutic strategies are complex, depending upon what else is going on with the patient.
Below is an abstract in PubMed that talks about use of Campath in several autoimmune situations. Basically, Campath is good at destroying all immunocytes that have the CD52 marker, which includes all B-cells and T-cells, monocytes and macrophages. I guess the logic is that by destroying all of the immune system cells, but leaving the stem cells intact, you get to clean house, then hopefully repopulate with a better behaved bunch of immune system cells. Sounds pretty drastic, but I suppose the remedy must be tailored to the seriousness of the problem. Sort of "Noah's Ark" approach, a drastic method but hopefully effective in getting rid of the bad guys.
The effect of treatment with Campath-1H in patients with autoimmune cytopenias.
Willis F, Marsh JC, Bevan DH, Killick SB, Lucas G, Griffiths R, Ouwehand W, Hale G, Waldmann H, Gordon-Smith EC.
Department of Haematology, St. George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK.
We describe 21 patients with severe and life-threatening autoimmune cytopenias resistant to standard immunosuppression who were treated with the monoclonal antibody Campath-1H. Four patients had autoimmune neutropenia, four had autoimmune haemolytic anaemia, four had pure red cell aplasia, one had immune thrombocytopenia purpura (ITP), three had autoimmune haemolytic anaemia and ITP (Evan's syndrome), three had autoimmune pancytopenia (ITP, autoimmune neutropenia and autoimmune haemolytic anaemia), one had ITP (associated with acquired Glanzmann's disease) and autoimmune neutropenia, and one had ITP and red cell aplasia. Campath-1H was administered at a dose of 10 mg/d as an intravenous infusion for 10 d. Responses were seen in 15 patients, which were sustained in six. Relapse occurred in eight patients after Campath-1H treatment. Patients entering the study later, received cyclosporine after Campath-1H in an attempt to reduce the incidence of relapse. Three patients received a second course of Campath-1H; all responded but later relapsed. Fourteen patients are alive at a median of 12 months (range 4-61) after Campath-1H. Campath-1H represents an alternative therapeutic option for severe, refractory autoimmune cytopenias.
Br J Haematol 2001 Sep;114(4):891-8
Minimum Residual Disease
Campath for MRD Treatment
by Chaya Venkat
We have all heard the words "Complete remission" (CR) and "Partial Remission" (PR) with reference to outcomes of clinical trials. The "PR" bit is easy to understand, it is the proverbial half full glass approach. Close, but no cigar.
CR is a more confusing term. Strictly as an English phrase, "Complete Remission" should mean that all of the cancer cells in your body have been killed, and you are in "complete" remission. Not quite. In past years, the standard approach to looking for cancer cells is to look at, say, a couple of hundred or so cells. If there are no cancer cells to be seen in this sample, you are declared to be in CR. But this does not mean there is not the odd malignant cell, that just did not make it into the sample that was examined, just because there are so few of the blighters. However, even these last few cells, so called "Minimal Residual Disease" or MRD, may be sufficient to restart the process of gradual accumulation of the cancer cells. This is why even patients in CR eventually relapse.
We now have more sophisticated ways of checking the status. There is something called PCR (Polymerase Chain Reaction) that allows us to check for presence of cancer cells to the tune of one in 100,000. Much more sensitive than the methodology that was used previously to define CR. So, if you are declared to be "PCR negative", it still does not absolutely guarantee that there are no cancer cells any where in your body, but you can see the odds are much better (about a thousand fold better) than if you were merely CR, but PCR positive.
None of our leading lights want to go on record yet, I think it is only a matter of time before they do so, but the general feeling seems to be we are getting close to where we can declare CLL to be a curable disease, if only we can get a much higher percentage of deeply "PCR negative" patients. Hence the tremendous interest in follow-up treatments to mop up the remaining few CLL cells, convert the patients in CR into PCR negative status. There is real hope that combinations of therapies, dealing a one-two punch, the first punch to clear out the bulk of the cancer, and the second punch to eradicate the remaining traces, may actually be the cure we are looking for. A few PCR negative patients have relapsed (remember there is no absolute guarantee that even at the PCR level you are entirely free of all cancer cells), but the large majority PCR negative patients continue to be in remission. Only time will tell if this remission is indefinite, and can be ultimately classified a "cure".
We have seen reports that patients who have been through RFC and similar protocols, and have not made it to PCR negative status, are sometimes recommended to go in for a second line mop-up therapy to finish the job. Very often, that second line is use of Campath, or radio labeled versions of Rituxan. It is a hard call to make, when you are feeling good, in "complete remission", how does one justify going back for another round of chemotherapy? Only time will tell if the brave souls who decide to do this were fools for subjecting their bodies to more toxicity, or visionaries that actually made the right choice, that cured their "incurable" cancer by making this decision. Below is the PubMed abstract of a paper on use of Campath to treat MRD. As expected, some of the patients did make it from CR to PCR negative, so-called "molecular remission".
Safety and efficacy of subcutaneous Campath-1H for treating residual disease in patients with chronic lymphocytic leukemia responding to fludarabine.
Montillo M, Cafro AM, Tedeschi A, Brando B, Oreste P, Veronese S, Rossi V, Cairoli R, Pungolino E, Morra E.
Dipartimento di Ematologia Oncologia, Divisione di Ematologia, Ospedale Niguarda Ca' Granda, piazza Ospedale Maggiore 3, 20162 Milan, Italy.
Background and Objectives. Recent observations suggested that targeted monoclonal antibodies might be best employed in lymphoid malignancies under conditions of minimal residual disease. This prompted us to investigate the role of Campath-1H as treatment for patients with chronic lymphocytic leukemia (CLL) in whom fludarabine (FAMP) had produced a marked disease debulking with persistence of bone marrow (BM) infiltration or a complete remission (CR) without the disappearance of the molecular aberration (IgH monoclonal expression). As intravenous Campath-1H is almost invariably associated with reactions, sometimes of WHO grade 3-4, we adopted the subcutaneous route of administration, which proved to induce rare and mild adverse reactions but had comparable efficacy. Design and Methods. Nine patients (7 males, 2 females) with a median age of 55 years (range 41-61) who responded to FAMP (1 had a CR, 5 a nodular partial remission [PRN], and 3 a partial remission [PR]), according to NCI Working Group Criteria, received subcutaneous Campath-1H, three times a week for 6 weeks in escalating doses up to 10 mg. Monoclonal rearrangement of IgH was present in all patients before immunotherapy. Patients received acyclovir and cotrimoxazole as infection prophylaxis. Granulocyte colony-stimulating factor (G-CSF), at the dosage of 5-10 mg/kg/die, or intermediate-dose Ara-C (800 mg/m2/q 12h 6 doses), was administered to obtain peripheral blood stem cell (PBSC) mobilization. Results. All patients were evaluable for response. Five patients, 2 in PR and 3 in PRN after FAMP treatment, reached a CR. Three patients, one in PR, one in PRN and one in CR, converted to a molecular remission. In four out of seven patients PBSC harvesting was successful; more than 2.5 106 cells/kg were collected from all these patients. Collection was polyclonal for IgH gene rearrangement in three cases. One patient has been transplanted after cyclophosphamide and total body irradiation as conditioning regimen, without complications and with rapid hemopoietic engraftment. All patients were evaluable for toxicity. A WHO grade 1-2 skin reaction was observed in 5 patients at the site of injection. No infectious episodes were recorded. Two out of three patients presenting cytomegalovirus reactivation, without pneumonia, were successfully treated with oral gancyclovir. Interpretation and Conclusions. Subcutaneous Campath-1H administered to CLL patients with residual BM disease after FAMP proved to be safe and effective. Of nine patients, three obtained a molecular CR and five converted into a morphologic and immunophenotypic CR. In four of seven patients submitted to PBSC mobilization, this treatment also allowed a harvest uncontaminated by CD5/CD19 double-positive CLL cells, which was polyclonal for IgH gene rearrangement in three cases.
Frontline Treatment of CLL
by Chaya Venkat
We have talked about Rituxan, now is a good time to discuss Campath, the other monoclonal antibody that is out there.
Rituxan targets CD20 antigen on B-cells. Campath on the other hand targets CD52, which is present on both B-cells and T-cells. Both monoclonals spare the stem cells, so that after a period of immune suppression, the stem cells get to work and gradually repopulate all the cells (good and bad) that had been killed as a result of therapy. In weighing risks and rewards, it pays to remember though that it takes a while for the immune system to come back up to speed, and during that period of immune suppression, one has to be very careful not to catch something.
Reading the paper below, it sounds to me that the specialists are gradually learning how to administer the drug, whether it should be IV or subcutaneous ( in the first case the drug is fed into your blood system via a saline drip, and the second case it is injected into you, just under the skin), and what drugs to give to protect the patient from opportunistic infections while the immune system is down and not recovered yet.
I have written before with the title "Campath scares me". It still does, but perhaps it is gradually becoming less scary, and more valuable as another weapon in the fight against CLL. I will try to keep an open mind about this MOAB, especially since apparently it is being tried as frontline monotherapy, without other standard chemotherapy drugs. Please pay attention to the details of the results below: clearing the blood was the easiest, bone marrow next, lymph nodes seem to be the hardest to clear. The authors state explicitly that better results are obtained if the tumor load is not very high, and the nodes are not bulky. Makes sense, the same seems to apply to Rituxan as well.
CAMPATH-1H therapy of patients with previously untreated chronic lymphocytic leukemia (CLL).
Jeanette Lundin1, Magnus Björkholm1, Fredrik Celsing1, Geoff Hale2, Victoria Hjalmar1, Eva Kimby1, Ove Tullgren1, Hermann Waldman2, Håkan Mellstedt1, Anders Österborg1.
1Karolinska Hospital, Stockholm, Sweden; 2Therapeutic Antibody Centre, Oxford, United Kingdom
CAMPATH-1H, a CDR-grafted, human IgG1 monoclonal antibody, recognizes CD52 expressed on normal B and T lymphocytes as well as on leukemic B CLL cells. This antibody induces a major response (CR+PR) in 30-40% of previously treated CLL patients as well as in 8/9 previously untreated patients. An extended phase II clinical trial was initiated to evaluate the clinical effects of subcutaneous long-term (18 wks) administration of CAMPATH-1H to previously untreated CLL patients requiring therapy. CAMPATH-1H, 30 mg/injection, was given s.c. tiw. Response evaluation was performed at 6, 12 and 18 weeks (NCI criteria). Prophylactic treatment with acyclovir and cotrimoxazole was given to all patients. 28 patients have been included. Twenty-seven were evaluated for toxicity and 23 for response. The overall response rate was 87% (4 CR + 16 PR). Twenty-two out of 23 patients
(96%) had achieved CR in blood, one patient had PR. The bone marrow was evaluated in 23 patients, 15 (65%) had CR, 4 (18%) had PR. In 19 patients with lymphadenopathy, 4 patients (21%) had CR of the enlarged lymph nodes and 13 (68%) PR. Most patients had mild or moderate "first dose" flu-like symptoms and local skin reactions which resolved upon continued therapy. Three patients had CMV reactivation causing fever without pneumonitis. Seven patients (25%) had transient grade IV neutropenia. One patient experienced autoimmune thyroiditis 6 patients developed transient exanthema/eczema. The median time to treatment failure has not been reached (16+months). Conclusions: The anti-tumor effect of CAMPATH-1H in previously untreated CLL patients is encouraging. Prolonged administration of CAMPATH-1H resulted in a high frequency of CR in the bone marrow which in most patients was confirmed by a negative flow cytometry analysis. The best effect in CLL is probably noticed during the early phase of the disease when the immune system is not heavily immune-compromised.
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