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Therapy Choices

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Rituxan plus Campath

Date: July 29, 2004

by Chaya Venkat

Double Dose of Monoclonals

double drip

We have discussed Rituxan and Campath, the two monoclonal antibodies that have become household words for us, both as single agents and in various combinations with other drugs. (Related articles: Rituxan, Campath, Fludarabine Monotherapy No Longer the Gold Standard, Hitting a Home Run with Campath Consolidation, The Difficult Case of the Round-Headed Kid, etc.). Now here is this interesting paper from M. D. Anderson that discusses the results of a clinical trial where both Rituxan and Campath are used together, concurrently. I would like to discuss the results of this important clinical trial, the logic for trying this approach, as well as speculate why the results may turned out the way they did. The abstract of the article is given below, as well as a link to the free full text article. If you are considering a double dose of both monoclonals in the near future, perhaps by way of participating in a clinical trial, I urge you to read the full text M. D. Anderson article below as well as this review.

Abstract

Article in Blood Journal (Free Full-text)

Blood. 2003 May 1;101(9):3413-5. Epub 2003 Jan 09.

Experience with alemtuzumab plus rituximab in patients with relapsed and refractory lymphoid malignancies.

Faderl S, Thomas DA, O'Brien S, Garcia-Manero G, Kantarjian HM, Giles FJ, Koller C, Ferrajoli A, Verstovsek S, Pro B, Andreeff M, Beran M, Cortes J, Wierda W, Tran N, Keating MJ.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.

We explored the safety and efficacy of rituximab plus alemtuzumab in patients with relapsed or refractory lymphoid malignancies. Forty-eight patients were treated and were assessable for response (32 with chronic lymphocytic leukemia [CLL], 9 with CLL/prolymphocytic leukemia [PLL], 1 with PLL, 4 with mantle cell leukemia/lymphoma, 2 with Richter transformation). The overall response rate was 52% (complete remission, 8%; nodular partial response, 4%; partial response, 40%). With a median follow-up of 6.5 months (range, 1-20 months), the median time to progression was 6 months (range, 1-20 months); median survival, 11 months (11+ months for responders vs 6 months for nonresponders). Most toxicities were grade 2 or lower and infusion-related. Infections occurred in 52% of the patients. Cytomegalovirus (CMV) antigenemia assays were positive in 27% of the patients, but only 15% were symptomatic and required therapy. The combination of rituximab and alemtuzumab is feasible, has an acceptable safety profile, and has clinical activity with a short course in a group of patients with poor prognoses.

PMID: 12522009
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The Logic for Combining the Two Antibodies

At first blush, there is an irresistible urge to combine Rituxan and Campath, sort of like a double scoop of ice cream. If one scoop is good, two must be better, right? Kidding aside, there is interest in finding out if there is synergy by combining these two important drugs. Here are some possible reasons for doing the experiment:

Synergy where 1 + 1 equals more than 2 is not an unreasonable hypothesis in this case, and I am glad to see this report where the concept was well examined.

The Clinical Trial Design:

Forty two patients with various B-cell cancers participated in this study. The bulk of them, 32 patients to be precise, had CLL. Since the paper breaks out the information very nicely by disease type, for all practical purposes we can pick out the details as they pertain to CLL. All of the patients had been treated before, an average of 4 therapies. These were patients who had been round the block more than a few times, and almost half of them were refractory to both purine analogs (fludarabine) and alkylating agents (cyclophosphamide). 79% of the patients were Rai Stage III or higher. The average Beta 2-Microglobulin (B2M) was a whopping 5.2. Most of the patients had shabby hemoglobin and platelet levels as well. Tough crowd, these were not your 'virgin' and chemo naive patient cohort. If you are not familiar with some of these prognostic indicators and what they mean, you might want to read What Type of CLL Do You Have?, which describes them in great detail.

The trial lasted 4 weeks. Each week, on day 1, patients got the now-standard 375 milligrams/ meter square of Rituxan infusion. On days 3 and 5 of the same week, 30 milligrams of Campath was administered intravenously. The exception to this was week one, when they gradually lead up to the full strength of Campath dose, by administering 3, 10 and 30 milligrams of Campath on days 3,4 and 5 respectively. The picture below may make it easier to get your arms around the details of dosage.

Schedule of Treatment with Rituxan and Campath
Keating, et al., Blood, 1 May 2003, Vol. 101, No. 9, pp. 3413-3415

All patients received prophylactic antibiotics and antivirals, and the antibiotics were continued for at least 2 months following completion of therapy. If things went well and there were no toxicity issues, patients could opt for a second set of 4 weeks, if they wanted to try to improve their response. While this kind of flexibility in clinical trial design makes it hard on the researchers in terms of sorting out the therapy statistics, I am sure the patients who participated in this trial appreciated the chance to see if they can get a deeper response by prolonging the therapy.

The Results:

This is how our guys did. Not all of the 32 CLL patients had disease in all of the possible locations, the table below shows how the 'evaluable' patients did in clearing out CLL in each of the locations. The only caveat I must point out is that the 21 out of 30 patients who are shown as having a response in lymph nodes, actually shrinkage of the lymph nodes to half their previous size was considered a response. In other words, the 70% response rate shown here is a bit on the generous side, the bar for defining response was set a little low. Roughly speaking, more than three quarters of the patients had clearance of peripheral blood and liver/spleen, while only little over one third of them probably had good clearance in bone marrow and lymph nodes. Drat. Looks like the usual weaknesses of the two monoclonal drugs, ineffective clearance of bone marrow and bulky lymph nodes, did not go away by simply combining the two monoclonals.

Response by Disease Site
Keating, et al., Blood.

Location

Responders

Peripheral Blood

26 of 29 (90%)

Liver/spleen

8 of 10 (80%)

Bone Marrow

9 of 25 (36%)

Lymph Nodes*

21 of 30 (70%)

CR

2 of 32 (6%)

(CR+PR)

20 of 32 (63%)

* Indicates decrease in size of lymph nodes by 50% or more.

The median time to progression and overall survival are rather bleak - half of the patients relapsed within 6 months, and half were dead before the end of one year. But these results have to be seen in the light of the very advanced stage of each of these patients, this was clearly a salvage effort.

Infections and other toxicity issues were not that bad, most of the adverse events were grade 2 or lower (the NCI grading system goes something like this: 1 = piece of cake; 2 = you are a big boy, you can take it; 3 = you are entitled to complain; 4 = Ouch!! This is the pits.) Roughly half the patients experienced at least one infectious episode. Pneumonia (fungal or bacterial) was the most frequent, but no one died due to fatal infections during the period of the clinical trial. Basically, the infections were at the level one would expect with four week course of Campath. The addition of Rituxan did not seem to make things worse on this front.

The authors of this study agree that the responses are comparable to those achieved with the pivotal single-agent Campath study. An abstract and link to the full text of this article too are given below, for your reading pleasure. True, this study used only 4 weeks of Campath + Rituxan, while the single agent Campath was administered for 8 weeks. But, remember patients in the double-dip study could opt to go for an additional 4 weeks after finishing the first four weeks on the Rituxan + Campath clinical trial. Unfortunately, the authors saw no difference in response between patients who received 8 weeks Rituxan + Campath therapy and those who received 4 weeks only. Using Campath-only in fludarabine refractory patients, the median time to progression was 8.7 months (versus 6 months in this double dip study), and half the patients died by 16 months (versus 11 months in the Rituxan + Campath study).

Survival and Progression
Keating, et al., Blood

 

Campath + Rituxan

Campath Only

Median Time to Progression

6 months

8.7 months

Median Overall Survival

11 months

16 months

The two studies are not strictly comparable, not your well matched patient cohorts and well balanced two arm study. Within the uncertainties of the comparison, the results are roughly the same, it is clear that there was no big difference in time to relapse or overall survival between the two studies. Not only was there no extra synergy by using Rituxan and Campath together, there was not even simple additive advantage. The response seen by combining Rituxan with Campath was no more than was obtained with just Campath alone. Moral of the story, in this particular example, doubling up on the monoclonals was no better than using just one, and 8 weeks of R + C were not better than 4.

Abstract

Article from Blood Journal (free full-text)

Blood. 2002 May 15;99(10):3554-61.

Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study.

Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, Albitar M, Brettman L, Santabarbara P, Wacker B, Rai KR.

M. D. Anderson Cancer Center, Houston, TX.

This study investigated the efficacy, safety, and clinical benefit of alemtuzumab (Campath-1H) for patients with relapsed or refractory B-cell chronic lymphocytic leukemia exposed to alkylating agents and having failed fludarabine therapy. Ninety-three patients received alemtuzumab in 21 centers worldwide, with the aim to obtain an overall response rate of at least 20%. Dosage was increased gradually (target 30 mg, 3 times weekly, for a maximum of 12 weeks). Infection prophylaxis was mandatory, beginning on day 8, and continuing for a minimum of 2 months after treatment. Responses were assessed at weeks 4, 8, and 12, and patients were followed for 34 months. Overall objective response in the intent-to-treat population (n = 93) was 33% (CR 2%, PR 31%). Median time to response was 1.5 months (range, 0.4-3.7 months). Median time to progression was 4.7 months overall, 9.5 months for responders. At data cut-off, 27 patients (29%) were alive; overall median survival was 16 months (95% CI: 11.8-21.9) and 32 months for responders. Nineteen responders survived more than 21 months. Clinical benefit was observed both in responders and in patients with stable disease. The most common adverse events were related to infusion, generally grade 1 or 2 in severity, occurring mainly in the first week. Grade 3 or 4 infections were reported in 25 patients (26.9%). However, only 3 (9.7%) of 31 patients who responded to alemtuzumab treatment developed grade 3 or 4 infections on the study. Alemtuzumab induced significant responses in these patients with clinical benefit in the majority and with acceptable toxicity in a high-risk group.

PMID: 11986207
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Twenty-twenty Hindsight Explanation

Now that the researchers and patient volunteers have done the real work, we can sit back and see if we can explain why the results came out the way they did. The whole point of clinical trials is to learn from them, increase our understanding of the disease and how best to tackle it. Negative or disappointing results are just as valuable, if we can learn from them and improve therapy options for patients in the future. My review here is based on prior articles that discussed the mechanisms of how monoclonals such as Rituxan carry out their cell kill. You may wish to refresh your memory of some the details by reading How Does Rituxan Work in CLL?, Complement Dependent Response in Rituxan Therapy, and related articles in our Rituxan Therapy section. There is still a great deal to learn, and Campath's mechanisms of action are still more of a mystery than Rituxan's.

Abstract

J Immunol. 2004 Mar 1;172(5):3280-8.

Rituximab infusion promotes rapid complement depletion and acute CD20 loss in chronic lymphocytic leukemia.

Kennedy AD, Beum PV, Solga MD, DiLillo DJ, Lindorfer MA, Hess CE, Densmore JJ, Williams ME, Taylor RP.

Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA.

Complement plays an important role in the immunotherapeutic action of the anti-CD20 mAb rituximab, and therefore we investigated whether complement might be the limiting factor in rituximab therapy. Our in vitro studies indicate that at high cell densities, binding of rituximab to human CD20(+) cells leads to loss of complement activity and consumption of component C2. Infusion of rituximab in chronic lymphocytic leukemia patients also depletes complement; sera of treated patients have reduced capacity to C3b opsonize and kill CD20(+) cells unless supplemented with normal serum or component C2. Initiation of rituximab infusion in chronic lymphocytic leukemia patients leads to rapid clearance of CD20(+) cells. However, substantial numbers of B cells, with significantly reduced levels of CD20, return to the bloodstream immediately after rituximab infusion. In addition, a mAb specific for the Fc region of rituximab does not bind to these recirculating cells, suggesting that the rituximab-opsonized cells were temporarily sequestered by the mononuclear phagocytic system, and then released back into the circulation after the rituximab-CD20 complexes were removed by phagocytic cells. Western blots provide additional evidence for this escape mechanism that appears to occur as a consequence of CD20 loss. Treatment paradigms to prevent this escape, such as use of engineered or alternative anti-CD20 mAbs, may allow for more effective immunotherapy of chronic lymphocytic leukemia.

PMID: 14978136
____________

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(+) (T-cell), 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.

PMID: 14749699
____________

Leuk Res. 2004 May;28(5):495-507.

Alemtuzumab (CAMPATH 1H) does not kill chronic lymphocytic leukemia cells in serum free medium.

Zent CS, Chen JB, Kurten RC, Kaushal GP, Marie Lacy H, Schichman SA.

Department of Internal Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham Street, slot 501 and 508, Littleock, AR.

The mechanism of action of alemtuzumab (CAMPATH 1H) in chronic lymphocytic leukemia (CLL) is uncertain. We tested the hypothesis that alemtuzumab alone can induce apoptosis in cultured CLL cells. Purified peripheral blood B-lymphocytes from CLL patients were treated in serum free medium (AIM-V). There was minimal spontaneous apoptosis in untreated cells. Alemtuzumab ligation did not alter the membrane distribution of CD52 in single cells but many cells formed transient, small, tightly adherent clusters. Alemtuzumab alone did not induce apoptosis. In contrast, alemtuzumab plus complement was rapidly cytotoxic. We conclude that alemtuzumab does not cause apoptosis in purified CLL B cells cultured in serum free medium.

PMID: 15068903
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J Clin Oncol. 1997 Apr;15(4):1567-74.

Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leukemia. European Study Group of CAMPATH-1H Treatment in Chronic Lymphocytic Leukemia.

Osterborg A, Dyer MJ, Bunjes D, Pangalis GA, Bastion Y, Catovsky D, Mellstedt H.

Department of Oncology (Radiumhemmet), Karolinska Hospital, Stockholm, Sweden.

PURPOSE: CAMPATH-1H is a human immunoglobulin G1 (IgG1) anti-CD52 monoclonal antibody (MAb) that binds to nearly all B- and T-cell lymphomas and leukemias. We report the results of a multicenter phase II trial that used CAMPATH-1H in previously chemotherapy-treated patients with chronic lymphocytic leukemia (CLL).
MATERIALS AND METHODS: Twenty-nine patients who had relapsed after an initial response (n = 8) or were refractory (n = 21) to chemotherapy were treated with CAMPATH-1H administered as a 30-mg 2-hour intravenous (IV) infusion thrice weekly for a maximum period of 12 weeks.
RESULTS: Eleven patients (38%) achieved a partial remission (PR) and one (4%) a complete remission (CR) (response rate, 42%; 95% confidence interval [CI], 23% to 61%). Three of eight patients (38%) with a relapse and nine of 21 refractory patients (43%) responded to CAMPATH-1H therapy. CLL cells were rapidly eliminated from blood in 28 of 29 patients (97%). CR in the bone marrow was obtained in 36% and splenomegaly resolved completely in 32%. Lymphadenopathy was normalized in only two patients (7%). The median response duration was 12 months (range, 6 to 25+). World Health Organization (WHO) grade IV neutropenia and thrombocytopenia developed in three (10%) and two patients (7%), respectively. Neutropenia and thrombocytopenia recovered in most responding patients during continued CAMPATH-1H treatment. Lymphopenia (< 0.5 x 10(9)/L) occurred in all patients. Two patients had opportunistic infections and four had bacterial septicemia.
CONCLUSION: CAMPATH-1H had significant activity in patients with advanced and chemotherapy-resistant CLL. The most pronounced effects were noted in blood, bone marrow, and spleen. Preferential clearance of blood may allow harvesting of uncontaminated blood stem cells for use in high-dose chemotherapy protocols.

PMID: 9193354
___________

Blood. 2004 Jun 29

From the bench to the bedside: ways to improve rituximab efficacy.

Cartron G, Watier H, Golay J, Solal-Celigny P.

Universite Francois Rabelais, UPRES-EA Immuno-Pharmaco-Genetique des Anticorps therapeutiques (IPGA), Tours, France; CHRU Bretonneau, Oncologie Medicale et Maladies du Sang, Tours, France; Canceropole Grand Ouest, France.

Rituximab is a chimeric IgG1 monoclonal antibody that specifically targets the CD20 surface antigen expressed on normal and neoplastic B lymphoid cells. Rituximab is currently used in the treatment of both follicular and aggressive B-cell non-Hodgkin's lymphomas. Despite its demonstrated clinical effectiveness, its in vivo mechanisms of action remain unknown and could differ by subtype of lymphoma. Rituximab has been shown to induce apoptosis, complement-mediated lysis (CDC) and antibody-dependent cellular cytotoxicity (ADCC) in vitro and there is some evidence pointing towards an involvement of these mechanisms in vivo. Rituximab also has a delayed therapeutic effect as well as a potential "vaccinal" effect. Here, we review the current understanding of the mechanism of action of rituximab and discuss approaches that could increase its clinical activity. A better understanding of how rituximab acts in vivo should make it possible to develop new and more effective therapeutic strategies.

PMID: 15226177
____________

Editorial

Science grows as we understand things better, and this is true even if the results of a particular clinical trial are not as positive as we might have hoped. This clinical trial was worth doing, and the researchers as well as the patients who volunteered for it deserve our sincere thanks. It is one of those concepts that could have turned out a lot better, too bad it did not. We would never have known, if the trial had not been done. If the results had been less ambiguous, if there had been the slightest hint of synergy or even simple additive advantage in going for the double-scoop of monoclonals, I can see the logic for repeating the clinical trial with "tweaked" protocol designs. Change from concurrent administration used in this clinical trial to sequential administration for example, with Campath doing mop-up "MRD" duty after Rituxan has done its bit, or the addition of growth factors such as Neupogen (G-CSF) to boost neutrophil counts and thereby improve ADCC, change the actual dosages of each drug used or changing the length of the clinical trial from 4 weeks to eight weeks, these are some of the protocol changes that can be considered. However, in the opinion of this reporter, the results of the Anderson study leave little room for much optimism along these lines, any improvements seen by such tweakings of the protocol are likely to be marginal at best. Why not use our resources elsewhere?

Campath is an important drug in our arsenal. Frankly, it is rapidly becoming the bullet of last resort, especially in combination with chemotherapy drugs such as fludarabine. For some of us, FluCam type combinations are necessary as preparatory regimens before going into "mini-allo" bone marrow transplants. It would make sense to save this bullet for that purpose or some other such rainy day, not use it for a short lived remission. True, no one has demonstrated that Campath cannot be used again and again, that using it once in this context will burn any bridges. However, I do not think any of us would want to go through multiple layers of Campath-based therapy, not unless there is substantial advantage in doing so. It is not exactly a patient friendly drug, certainly not when it is administered intravenously.  Hopefully subcutaneous administration of Campath will soon become the accepted standard of care.

There is also the real-world issue of public policy and dollar costs of things. Monoclonal antibody therapy is not cheap by any stretch of the imagination. Even those of us with good medical insurance coverage, where our insurers pick up the bulk of the tag, we need to realize that in the ultimate analysis we the tax-payers of this country pay for everything. Does it make sense to go for overkill on use of monoclonal antibody therapy, when the improvement in remission period or overall survival are just not there, and may be marginal at best even by further fine-tuning?

Bottom line, we thank the patient volunteers who participated in this clinical trial, and the Anderson researchers for doing this pivotal trial. their prompt publication of these unequivocal results makes it possible for patients to judge the value of participating in future clinical trials using the same concept with minor differences. Patient participation in clinical trials is crucial for improving our understanding of this disease, both for ourselves and our children. But we also need to be informed consumers, checking out the details and supporting clinical trials that are likely to expand our understanding and lead to better therapy options, not just more me-too versions that add little to the sum of our knowledge.

Frankly, we should be looking for other creative concepts to try, other combinations that hold greater promise of synergism. I for one would like to see clinical trials incorporating monoclonal therapy (Rituxan or Campath) followed by low dose-flavopiridol therapy to clean up minimum residual disease (MRD). Recent reports (Flavopiridol: A Drug that May Save Lives) suggest flavopiridol is a very potent drug in CLL, and it works independent of the p53 pathway; therefore it should work even with our "Bucket C" patients with 17p deletion demonstrated by FISH. In fact, flavopiridol is so potent that one of the risk factors is excessive tumor lysis, that can be triggered by too many cancer cells getting killed  over a very short period, and this risk factor may be reduced by using flavopiridol drug in mop-up or MRD duty, where the tumor burden is already significantly reduced. Since it is a small molecule drug, compared to the huge size of monoclonal antibodies such as Campath and Rituxan, it may be able to get into all the nooks and crannies of the lymph nodes and bone marrow, therefore better able to clear out these hard-to-reach locations. Indeed, this concept may have higher potential for the kind of synergy that the Anderson researchers were hoping for, a better chance of getting long lasting remission that may result in longer overall survival.

 

 

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