Rituxan Therapy el pt

Single Agent Rituxan

Date: July 24, 2024

by Chaya Venkat

Rituxan As Frontline and Maintenance Therapy

With its reputedly low toxicity profile and narrow targeting of B-cells, Rituxan is an attractive candidate for use as a frontline monotherapy in CLL. However, you might have heard that Rituxan was first approved by the FDA for use in Non Hodgkins Lymphoma, a B-cell malignancy closely related to CLL, and some of the early work with Rituxan as a monotherapy was done with that disease.

Rituxan as Frontline and Maintenance Therapy in NHL

The following abstract provides a good lead-in to the work that has been done in this area. Do remember however, that this is in NHL. Compared to NHL, CLL cells exhibit lower intensity CD20, the marker that Rituxan homes in on. Also, it has been reported that the the CLL cells shed the CD20 marker to some degree, and that the higher dosage of Rituxan needed in CLL is partly due to all this soluble CD20 that sops up the drug without it having done any good.

Abstract

Semin Oncol 2024 Feb;29(1 Suppl 2):25-9. 

Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin's lymphoma: interim follow-up of a multicenter phase II trial. 

Hainsworth JD. Sarah Cannon Cancer Center, Centennial Medical Center, Nashville, TN.

The purpose of this study is to evaluate the activity of rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA) in the first-line treatment of patients with indolent non-Hodgkin's lymphoma, and to evaluate the role of scheduled maintenance courses of rituximab in prolonging duration of remission. Sixty-two patients with stages II to IV indolent non-Hodgkin's lymphoma (follicular or small lymphocytic) who had received no previous systemic therapy entered this multicenter, community-based trial. All patients received rituximab 375 mg/m(2) weekly for 4 consecutive weeks, and were evaluated for response at week 6. Patients who had an objective response or stable disease continued treatment every 6 months with repeat 4-week courses of rituximab for a total of four treatment courses. Interim results of this ongoing trial are available. When evaluated at week 6, 28 of 60 evaluable patients (47%) had objective response and 27 patients (45%) had minor response or stable disease. With further follow-up and repeat courses of rituximab, the major response rate increased from 47% to 65% and the complete response rate increased from 7% to 27%. Response rates were similar in patients with follicular lymphoma and small lymphocytic lymphoma (63% and 66%, respectively). Median progression-free survival has not been reached, but will be greater than 24 months. There has been no cumulative toxicity observed with repeat courses of rituximab. Rituximab is highly effective as a first-line single agent for the treatment of indolent non-Hodgkin's lymphoma. The initial response rate can be improved by using scheduled maintenance courses of rituximab administered every 6 months. Final information regarding duration of response and time to progression awaits further follow-up.

Copyright 2024 by W. B.  Saunders Company.
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This is an important, must-read paper on Rituxan, for all you folks out there that want to explore its use as frontline, single agent therapy. Note the date of publication: there will be updates and follow-ons to this trial that will become available as time goes on. As far as I can tell from the abstract, he results are very encouraging.

Notice that the abstract talks about NHL most of the time, not CLL (what else is new?), but it does discuss SLL and says the response is not different for this version compared to NHL. Since we are all now convinced (?) that SLL and CLL are the same thing with different names, it seems to me this paper is very relevant to us.

There is an earlier report of the same trial  with fewer patients accrued at that time and without some of the data from the maintenance phase of the trial. The URL to the full-text of that earlier article: Blood Journal Article.

Background:

Rituxan (generic name rituximab) is marketed by Genentech and IDEC Pharmaceuticals. It is a monoclonal antibody that targets CD20 antigen that is present on all B-cells. It has now been approved by the FDA for treatment of NHL, and is under investigation at a number of hospitals and research facilities for CLL as well. Much of the work reported to date has been use of Rituxan in combination with other more conventional chemotherapy drugs, such as the famous Rituxan-Fludarabine-Cyclophosphamide (RFC) combination. Where Rituxan has been used as a single agent, it has been mostly in relapsed and refractory patients who had been through several prior chemotherapy regimes. This study addresses the issue of use of Rituxan as single agent therapy, in previously untreated NHL and SLL/CLL patients, including both early and late stage patients.

The Patients:

The paper charts the progress of 62 patients recruited since March 1998 through May 1999. Don't be discouraged by the reference to NHL in the title: 24 of the patients were SLL ("of the CLL variety"), and therefore the results are very applicable to us. None of the patients had any prior chemo, but 2 had had radiation and relapsed after it. Both early and late stage patients were included, but not patients in immediate and urgent need of therapy for disease related  problems. In general, the study did not include patients who had other major complicating factors, or in very poor health.

The Trial:

This phase-2 trial was administered in a multi-center community based approach, by the Minnie Pearl Cancer Research Network, (Centennial Medical Center, Nashville, TN), and supported in part by a grant from Genentech, the maker of Rituxan. The drug administration was on an outpatient basis.

Rituxan at a standard dose of 375 mg/m² was administered intravenously once a week for four consecutive weeks by local administering physicians. Patients were monitored closely for infusion related events, which were mild in general, and treated as needed with Tylenol, and antihistamines, but not steroid based drugs. Overall, the injections were well tolerated, with infusion related issues pretty much limited to the first of the four infusions. 2 of the 62 patients dropped out before the completion of this phase due to some complications.

Patients were evaluated after 6 weeks (i.e., two weeks after the completion of this four week part of the trial). Patients who had decrease or stabilization of their disease continued on to the "maintenance" phase of the trial. 5 patients whose disease had progressed during this time were dropped from the study. I guess these were the "failures", for whom Rituxan had not worked very well. In these cases it was up to the treating physician and the patient as to whether Rituxan therapy was continued, but it was outside of the trial.

Results:

Here is how it stacked up, at the end of the 4 week initial phase of the trial: out of the original 62 patients, 28 patients (45%) responded (24 partial responses, 4 complete responses), 27 patients (44%) had stable disease and the remaining 7 patients (11%) were dropped from the study because of disease progression or other problems. I did not get the sense that sophisticated flow cytometry, bone marrow biopsies or FISH analysis etc were conducted to judge the molecular nature of the response. Or, if such tests were conducted, the results are not reported here.

The remaining 55 patients continued on to the maintenance phase of the trial, which consisted of Rituxan administered over a four week period, once every six months. Interestingly enough, the response rate increased from the 45% above to 65% during the maintenance period. The number of complete responses went from 4 patients as discussed above to 16 patients. "Repeat maintenance administration of Rituxan has not been associated with either cumulative toxicity or opportunistic infections". The median time to progression of disease is yet to be reached, but in any case it will be greater than 24 months. (To put that in English, if you were a participant in this trial, and you continued on to the maintenance phase of it, you would have a better than even chance of not having your disease progress at all, for more than 2 years. And the drug itself appears to be very well tolerated over multiple injections, with few side effects, by a  large majority of the patients).

And here is the interesting part for us CLL folks: "response rates are similar in patients with follicular lymphoma and those with SLL (63% versus 66%, respectively). Time to progression curves regarding these two patient subsets are also identical". Up to now, it has been my impression that NHL cells had higher, more intense CD20 expression, and therefore responded more to Rituxan, while CLL patients with lower levels of CD20 expression did not respond as well, and that a higher dosage of Rituxan was needed to get the same response rate in CLL patients as in NHL. Well, this study used the same dosage for both NHL and SLL (CLL) patients, and the response rates and progression free time were the same in both cases. Also, the higher response rates for the patients as a whole in this study could be due to the fact that Rituxan is being used here as frontline therapy, with patients who had not been treated with prior chemotherapy regimes. Much of the prior clinical data dealt with patients after several rounds of prior chemotherapy.

This clinical trial is still continuing, and the paper cites "Interim results of this ongoing trial are available", but does not say how they can be obtained. I will do what I can to try and obtain updates, meanwhile those of you with connections to helpful oncologists may wish to try and get this information for the rest of us, by contacting Dr. J. D. Hainsworth at 1-615-342-1725. The web site for Sarah Cannon Cancer Center with which Dr. Hainsworth is associated is http://www.sarahcannon.com/

Unanswered Questions

1. Rituxan seems to have an increased effect with repeated doses. Is there some mechanism for this enhanced sensitivity with multiple use?
2. The study does not break out the response rates of early stage and late stage patients. My guess is that patients who went into the study with lower tumor burdens had better response rate, and longer progression free time. Is this in fact so?
3. Complete response and partial response are defined from size of nodes and blood work, but I do not know if more sophisticated work was done to evaluate last remaining traces of disease. For example, does complete response mean "PCR negative"? Were bone marrow biopsies done to see if marrow infiltration was resolved? How about other markers such as kappa: lambda light chain ratio? How did the hemoglobin, red blood cell count and platelet counts fare? How did the rest of the immune system fare, how long did it take for the T4 and T8 cell populations to recover? We need a lot more data on exactly what was achieved in terms of a "complete" or "partial response". No doubt the work was done, in my opinion, not just reported here.
4. Was quantitative flow cytometry done before and after? Did the percentage of CD20 positive cells decrease with each additional course of Rituxan, especially for CLL patients? If the Rituxan selectively wiped out all the CD20 positive cells, eventually the malignant cells remaining may become resistant to further administration of Rituxan. I would expect this would be more of an issue for CLL patients than for NHL patients, since CLL cells are supposed to have a lower expression of CD20 to begin with.
5. Is this study still recruiting? What is the contact information? Are there other studies that are working along the same lines, use of Rituxan as single agent front line therapy, especially for CLL patients?
6. Is it possible for local oncologists to work with Dr. Hainsworth's group, or the folks at Genentech, to define similar protocols for their patients, outside the clinical trials? How does one proceed to get this dialogue going? Is it possible to get a copy of the detailed research protocol used in this study, as well as the instructions given to the participating physicians on administration of the drug, data collection and monitoring of the patients? 
7. What is the time frame over which Rituxan is expected to be approved by the FDA for use in CLL? Do insurance companies cover the cost of Rituxan now? Does Medicare cover it? How much does it cost per dose? Can one expect any assistance from Genentech in this context?

Study Update

Journal of Clinical Oncology, Vol 20, No 20, (October 15)

Rituximab as First-Line and Maintenance Therapy for Patients With Indolent Non-Hodgkin's Lymphoma

By John D. Hainsworth, Sharlene Litchy, Howard A. Burris, III, Daniel C. Scullin, Jr, Steven W. Corso, Denise A. Yardley, Lisa Morrissey, F. Anthony Greco

From the Sarah Cannon Cancer Center and Tennessee Oncology, Professional Limited Liability Corporation, Nashville, TN; Consultants in Blood Disorders and Cancer, Louisville, KY; and Upstate Carolina Community Clinical Oncology Program, Spartanburg, SC.

PURPOSE: To evaluate response to single-agent rituximab in patients with indolent non-Hodgkin's lymphoma (NHL) and no previous systemic therapy, and the feasibility, toxicity, and efficacy of maintenance rituximab, administered at 6-month intervals, in patients with objective response or stable disease after first-line rituximab therapy.

PATIENTS AND METHODS: Patients with indolent NHL (follicular or small lymphocytic subtypes) previously untreated with systemic therapy received rituximab 375 mg/m2 intravenously weekly for 4 weeks. Patients were restaged at week 6 for response; those with objective response or stable disease received maintenance rituximab courses (identical dose and schedule) at 6-month intervals. Maintenance was continued for a maximum of four rituximab courses or until progression. Between March 1998 and May 1999, 62 patients were entered onto this trial; minimum follow-up was 24 months.

RESULTS:  Sixty patients (97%) completed the first 4-week course of rituximab and were assessable for response. All have now completed rituximab therapy; 36 (58%) received four courses at 6-month intervals. The objective response rate at 6 weeks was 47%; 45% of patients had stable disease. With continued maintenance, final response rate increased to 73%, with 37% complete responses. Response was similar in patients with follicular versus small lymphocytic subtypes (76% v 70%, respectively). Median actuarial progression-free survival was 34 months. Two patients experienced grade 3/4 toxicity with the first dose; one patient was removed from treatment. No cumulative or additional toxicities were seen with maintenance courses.

CONCLUSION: Rituximab is highly active and extremely well tolerated as first-line single-agent therapy for indolent NHL. First-line treatment with scheduled maintenance at 6-month intervals produces high overall and complete response rates and a longer progression-free survival (34 months) than has been reported with a standard 4-week treatment.
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The Swiss Study

The following is a report on a study done by the Swiss Group for Clinical Cancer Research. The dosages and method of administration are surprisingly similar to the Hainsworth study. The results are also quite similar. Once again, what seems to matter is whether or not the patients had prior chemo. Those who had Rituxan as frontline therapy (i.e., no prior chemo), the response rates, event-free survival, etc., were much better. Also helpful was a continuation of the Rituxan as maintenance therapy.

Press Report

June 17, 2024, Monday 09:02 AM Eastern Time

Investigational Data From Randomized Study of Extended Therapy With Rituxan Demonstrates Potential to Delay Disease Progression in Patients With Indolent NHL

DATELINE: LUGANO, Switzerland, June 17, 2024 Study Presented at the International Conference on Malignant Lymphoma Genentech, Inc. (NYSE:DNA), IDEC Pharmaceuticals Corporation (Nasdaq:IDPH) and Roche today announced initial positive results of a randomized multi-center study evaluating extended therapy with single agent Rituxan(R) (Rituximab) in patients with both chemotherapy-naive (front-line) and relapsed indolent non-Hodgkin's lymphoma (NHL). Professor Michele Ghielmini from the Swiss Group for Clinical Cancer Research (SAKK) discussed the study results during an oral presentation at the Eighth International Conference on Malignant Lymphoma (ICML). The study enrolled 202 patients of which 188 patients were eligible. At the time of study entry, 59 patients had received no prior therapy and 129 patients had received some form of prior chemotherapy for their NHL. All patients received an induction course of Rituxan (375mg/m2 weekly for 4 weeks). The overall response rate was 66 percent (39/59 patients) for chemotherapy-naive patients and 46 percent (59/129) for those with relapsed disease. At week 12, 151 of the 188 patients (80 percent) who achieved either a complete response (CR) or a partial response (PR), or experienced stable disease from the initial course of Rituxan were randomized to receive either extended therapy with Rituxan (one dose 375mg/m2 at month 3,5,7,9 for a total of four doses) or no treatment and were observed. A CR is defined by disappearance of all signs of cancer and a PR is defined as a decrease in tumor size of more than 50 percent. After a median of 25 months follow-up, the primary endpoint of event-free survival was 22.4 months in patients receiving extended therapy (n=73) compared to 13.6 months for patients who did not receive extended Rituxan therapy and were observed (n=78). For chemotherapy-naive patients, event-free survival was 35.6 months for extended Rituxan therapy compared to 18.3 months for those patients who did not receive extended Rituxan therapy. Event-free survival is defined as ongoing survival without events including disease progression or relapse, death or initiation of new alternative treatment. According to the authors, there was no clinically significant increase in adverse events or infections for patients receiving extended Rituxan therapy compared to the observation control arm. Adverse events in this study were similar to those seen in the pivotal trial of Rituxan (see Rituxan safety information below).

"For this patient group, the risk of relapse is extremely high and with each successive relapse the duration of remission decreases," said Professor Ghielmini. "Clearly the results of this study are encouraging for people with this form of non-Hodgkin's lymphoma."

"We are encouraged with the initial data from this study that both chemotherapy-naive and relapsed indolent NHL patients had an improvement in the primary endpoint of event-free survival when receiving extended Rituxan therapy compared to observation only," said Kip Benyunes, M.D. associate director, Medical Affairs at Genentech. "Of note, chemotherapy-naive patients who received extended therapy had a 100 percent improvement, from 18 to 36 months, in the time to disease progression compared to patients who did not receive additional therapy. Furthermore, large randomized Phase III studies in both indolent and aggressive NHL are being conducted by the U.S. cancer cooperative groups. These ongoing studies will enroll more than 1,000 patients and will provide further data on the potential use of Rituxan as a maintenance therapy in these disease settings."
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Single Agent Rituxan in CLL

The following paper published in May 2024, from the team led by Dr. Hainsworth, addresses the use of Rituxan as frontline and single agent therapy for CLL/SLL. This is a must-read paper if Rituxan monotherapy may be in your near future. 

Abstract

Journal of Clinical Oncology, Vol 21, Issue 9 (May), 2024: 1746-1751 © 2024 American Society for Clinical Oncology

Single-Agent Rituximab as First-Line and Maintenance Treatment for Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma: A Phase II Trial of the Minnie Pearl Cancer Research Network

John D. Hainsworth, Sharlene Litchy, John H. Barton, Gerry Ann Houston, Robert C. Hermann, James E. Bradof, F. Anthony Greco

From the Sarah Cannon Cancer Center and Tennessee Oncology, Professional Limited Liability Corporation, Nashville, TN; Jackson Oncology Associates, Jackson, MS; Northwest Georgia Oncology Centers, PC, and Well Star Health System, Marietta, GA; and Upstate Carolina Community Clinical Oncology Program, Spartanburg, SC.

Purpose: To assess the efficacy and toxicity of first-line single-agent rituximab, followed by re-treatment with rituximab at 6-month intervals, in previously untreated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Patients and Methods: Forty-four previously untreated patients with CLL/SLL received rituximab 375 mg/m2 weekly for 4 consecutive weeks. All patients were required to have one or more indications for treatment. Patients with objective response or stable disease continued to receive identical 4-week rituximab courses at 6-month intervals, for a total of four courses.

Results: The objective response rate after the first course of rituximab was 51% (4% complete responses). Twenty-eight patients received one or more additional courses of rituximab. At present, the overall response rate is 58%, with 9% complete responses. After a median follow-up of 20 months, the median progression-free survival (PFS) time was 18.6 months, and the 1- and 2-year PFS rates were 62% and 49%, respectively. Treatment was well tolerated, with only two episodes of grade 3 to 4 infusion-related toxicity. No cumulative toxicity or opportunistic infections occurred.

Conclusion: Single-agent rituximab, used at a standard dose and schedule, is active in the first-line treatment of patients with CLL/SLL, producing substantially higher response rates than previously reported in relapsed or refractory patients (51% v 13%, respectively). Re-treatment with rituximab at 6-month intervals is well tolerated. The PFS time of 18.6 months in patients with CLL/SLL seems shorter than the 36- to 40-month median PFSs previously reported with first-line plus maintenance rituximab in patients with follicular lymphoma. Additional follow-up is required to fully assess the impact of this treatment strategy.

Supported in part by grants from Genentech Inc, South San Francisco, CA; Idec Pharmaceuticals Corp, San Diego, CA; and The Minnie Pearl Cancer Foundation, Nashville, TN.
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While we all like the low toxicity profile of this monoclonal antibody, do notice the low percentage of CRs. Compared to the kind of overall responses and deep remissions patients get with RF or RFC type of chemotherapy plus monoclonal antibody combinations, there is no question that Rituxan by itself has a hard time getting the same kind of response in CLL patients.

I do not think anyone knows for sure why only a fraction (about 50%, depending on the trial you look at) of the people who respond to a Rituxan therapy the first time respond the second time. You have to read Hainsworth's article carefully to catch that statistic. There seems to be general consensus that CD20 marker depletion is not likely to be the cause for the resistance, since this marker is thought to be restored when the B-cells grow back after Rituxan therapy. Perhaps there is a selection process in that the CLL cells left behind after the first Rituxan therapy have up-regulation of complement inhibitory proteins such as CD55 and CD59. The role of complement in Rituxan therapy is a subject we have discussed extensively, try looking it up on our website if you are a new member. See below for a discussion of resistance to Rituxan.

I do not know of any studies that looked at efficacy of combo treatments like RFC being compromised by prior use of Rituxan. I think that the cell kill mechanisms are so varied, different and so much stronger in RFC or RF type of combinations, compared to Rituxan only therapy, that doing the R alone first is not likely to burn your bridges for doing RFC or RF later on. That is just my opinion. As I said, I have not seen any clinical studies on this subject.

Side Effects and Toxicity

These are the side effects and toxicity data from an earlier report of the Hainsworth study. It was a phase II study, with 41 patients, roughly equal number of NHL and SLL/CLL. As you can see, the infusion related side effects were pretty minor, and the therapy was carried out on an out-patient basis. Earlier results of this study were reported in a Blood article (Blood 95: 3052-3056, 2024) by Hainsworth, et al. You can look this up on the Blood-online site I mentioned a while back. The whole article is free for anyone to read. Suggest you do just that!

Side Effects and Toxicity
Hainsworth, J., et al., Blood

Toxicity	Number (%) - Grade 1/2	Number(%) - Grade 3/4
Infusion-related
Fever	9 (22%)	0 (0%)
Chills / rigors	12 (29%)	0 (0%)
Flushing	4 (10%)	1 (2%)
Nausea / vomiting	5 (12%)	0 (0%)
Hypotension	1 (2%)	0 (0%)
Angioedema	1 (2%)	0 (0%)
Bronchospasm	1 (2%)	0 (0%)
Chest pain /cardiac ischemia	0 (0%)	1 (2%)
Other Toxicity
Fatigue	11 (27%)	0 (0%)
Leukopenia	2 (5%)	0 (0%)
Anemia	3 (7%)	0 (0%)

A Potential Problem with Protracted Rituxan Use

Here is a troubling report on the protracted use of Rituxan as maintenance therapy. The abstract below from Blood suggests that in the process of wiping out all the b-cells (both normal and malignant b-cells are wiped out, since both carry the CD20 units) Rituxan may be wiping out the memory banks of the body's b-cell based immune system.

Recall there are two types of immune responses, the cellular response mediated by T-cells, and the antibody response mounted by b-cells. This type of response by the b-cells is also called "humoral response". Under normal circumstances, once an antigen is recognized by the b-cell component of the immune system, a distinct memory of that particular antigen is maintained by the body, in the form of "memory b-cells", so that if that particular nasty antigen is ever seen again, the body can quickly marshal its forces and create a great number antibody secreting b-cells targeted to fight just that particular antigen. You can read much more about both cellular and humoral responses in the second URL given below.

The article from Blood raises questions on the possible fate of the important memory b-cells, after Rituxan treatment(s). If the memory b-cells are also  wiped out, along with all the other b-cells, then the body has no way of remembering a particular antigen presenting bacteria or the like it had encountered before.

Once more, turning a deficit to a positive attribute, if Rituxan drastically reduces b-cell mediated antibody response, it may be a way of treating some types of auto-immune diseases, where the body's own antibodies start attacking various tissues. Interesting stuff. If any one buys this article, do let us know if there are more details in the full text that were not obvious in reading the abstract.

Abstract

Rituximab treatment results in impaired secondary humoral immune responsiveness

Lizet E. van der Kolk, Joke W. Baars, Martin H. Prins, and Marinus H. J. van Oers

From the Department of Hematology and the Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam, and the Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, Amsterdam, The Netherlands.

In lymphoma patients, treatment with chimeric CD20 monoclonal antibodies (rituximab) results in a depletion of normal and malignant B cells, persisting for 6 to 9 months. This B-cell depletion leads neither to a decrease in immunoglobulin levels nor an increase in the number of infectious complications. However, the effect of rituximab treatment on the immune responsiveness is unknown. In 11 patients with relapsed, low-grade lymphoma, we investigated the effect of rituximab treatment on the humoral immune response to 2 primary antigens and 2 recall antigens. After rituximab treatment, the humoral immune response to the recall antigens was significantly decreased when compared with the response before treatment. Already before rituximab treatment, none of these patients was able to mount a response to the primary antigens. These findings are relevant regarding the feasibility of rituximab in maintenance treatment and may also offer a rationale for the treatment of antibody-mediated autoimmune diseases with rituximab.

Efficacy of Rituxan in Re-treatment

The following comments relate to a paper in the Journal of Clinical Oncology that describes the results of re-treatment with Rituxan in Lymphoma patients. The abstract is quoted below.

The news is encouraging. Repeat treatments did not cause HACA (human anti- chimeric antibodies), there was no cumulative myelosuppression, infusion related problems got no worse than the first time around, and the development of CD20 negativity was extremely rare. The best part is that the time to disease progression or remission period looks to be getting better with repeat treatments. The trials have not been going on long enough to get real good quantitative numbers on this part, but the indications are there.

The discouraging part is that the overall response rate is still not as high as one would wish, and this is particularly true in the case of CLL, if Rituxan is used as a stand alone therapy without other drugs. New approaches to up-regulating the level of CD20 expression in CLL cells may be worth watching, in this context. Rituxan seems to work best when it is combined with other therapies that do the actual killing of the tumor cells, with good old Rituxan making the cancer cells much more susceptible to getting killed. My fond hope would be a combination of monoclonals like Rituxan, in combination with vaccines like the idiotype vaccine approach in Dr. Bendandi's group (see previous articles), or CTL therapy or gene therapy approaches, all of which have been extensively discussed in this forum.

Abstract

Rituximab Anti-CD20 Monoclonal Antibody Therapy in Non-Hodgkin's Lymphoma: Safety and Efficacy of Re-Treatment

By Thomas A. Davis, Antonio J. Grillo-López, Christine A. White, Peter McLaughlin, Myron S. Czuczman, Brian K. Link, David G. Maloney, Robin L. Weaver, Jay Rosenberg, Ronald Levy

From the Stanford University, Stanford; IDEC Pharmaceuticals Corp, San Diego, CA; University of Texas M.D. Anderson Cancer Center, Houston, TX; Roswell Park Cancer Center, Buffalo, NY; University of Iowa, Iowa City, IA; and Fred Hutchinson Cancer Research Center, Seattle, WA.

PURPOSE: This phase II trial investigated the safety and efficacy of re-treatment with rituximab, a chimeric anti-CD20 monoclonal antibody, in patients with low-grade or follicular non-Hodgkin's lymphoma who relapsed after a response to rituximab therapy.

PATIENTS AND METHODS: Fifty-eight patients were enrolled onto this study, and two were re-treated within the study. Patients received an intravenous infusion of 375 mg/m2 of rituximab weekly for 4 weeks. All patients had at least two prior therapies and had received at least one prior course of rituximab, with a median interval of 14.5 months between rituximab courses.

RESULTS: Most adverse experiences (AEs) were transient grade 1 or 2 events occurring during the treatment period. Clinically significant myelosuppression was not observed; hematologic toxicity was generally mild and reversible. No patient developed human antichimeric antibodies after treatment. The type, frequency, and severity of AEs in this study were not apparently different from those reported in the phase III trial of rituximab. The overall response rate in 57 assessable patients was 40% (11% complete response and 30% partial responses). Median time to progression (TTP) in responders and median duration of response (DR) have not been reached, but Kaplan-Meier estimated medians are 17.8 months (range, 5.4+ to 26.6 months) and 16.3 months (range, 3.7+ to 25.1 months), respectively. These estimated medians are longer than the medians achieved in the patients' prior course of rituximab (TTP and DR of 12.4 and 9.8 months, respectively, P > .1) and in a previously reported phase III trial (TTP in responders and DR of 13.2 and 11.6 months, respectively). Responses are ongoing in seven of 23 responders.

CONCLUSION: In this re-treatment population, safety and efficacy were not apparently different from those after initial rituximab exposure.
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Resistance to Rituxan

One of the encouraging things about Rituxan therapy has been the concept that while the remissions are not very long in CLL patients, generally in the range of 10-12 months or so, it is thought possible to re-treat with Rituxan, and get an equivalent or even better remission a second or third time. 

Since Rituxan targets CD20 positive B-cells, the question arises if treatment with Rituxan depletes these CD20 positive cells, and what is left behind is a sub-clone population that no longer exhibits the CD20 marker. In that case, at least in those patients where this happens, Rituxan would not be effective a second time. 

The abstract below suggests that while during therapy CD20 positive cells are temporarily depleted, once the treatment is finished, the CD20 positive population gradually builds up again. These researchers conclude that prolonged and multiple therapies with Rituxan are feasible and useful. Good news, all the indications are that the normal mechanisms by which patients become "refractory" to certain chemotherapy drugs are not applicable in the case of monoclonal antibody drugs such as Rituxan. At least as far as we know now.

Abstract:

Exp Hematol 2024 Dec;29(12):1410-6

Selection of B-cell chronic lymphocytic leukemia cell variants by therapy with anti-CD20 monoclonal antibody rituximab. 

Pickartz T, Ringel F, Wedde M, Renz H, Klein A, von Neuhoff N, Dreger P, Kreuzer KA, Schmidt CA, Srock S, Schoeler D, Schriever F. 

Charite der Humboldt-Universitat zu Berlin, Campus Virchow-Klinikum, Medizinische Klinik mit Schwerpunkt Hamatologie und Onkologie, Berlin, Germany. 

OBJECTIVE: Anti-CD20 chimeric monoclonal antibody rituximab  (Mabthera; IDEC-C2B8) is currently tested in several clinical trials for the treatment of B-cell chronic lymphocytic leukemia (B-CLL). In the present study, we investigated whether rituximab therapy may select for CD20(-) subclones. 

MATERIALS AND METHODS: Leukemic B-CLL cells were isolated from patients with B-CLL and sensitivity to rituximab-induced cell death was examined. Levels of CD20 protein and mRNA were determined using flow cytometry and real-time PCR, respectively. Clonality analyses of leukemic cells throughout rituximab therapy were performed by GeneScan analysis of patient clone specific rearrangements of the complementarity determining region III of the heavy chain immunoglobulin. 

RESULTS: Cytotoxicity  of rituximab in vitro did not depend on the protein levels of CD20. During therapy with rituximab CD20(+) B-CLL cells were depleted and CD20(-) leukemic cells emerged. After treatment, the initial CD20(+) B-CLL cell clone reexpanded. CD20(-) B-CLL cells retained their capacity to synthesize the CD20 molecule. 

CONCLUSIONS: These data support the concept that in B-CLL rituximab treatment may not lead to  the emergence of CD20(-) leukemic variants. Our findings support clinical studies investigating the benefit of prolonged period of rituximab therapy in B-CLL disease. 

PMID: 11750099
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Member questions on resistance to Rituxan touched on the topic of CD-20 expressing cells repopulating after depletion on treatment with Rituxan and whether Rituxan will work every 6 months.

Here are my thoughts on the subject:

1. While it is true that Rituxan therapy does not seem to give rise to a clonal population that is CD20 negative, there is very good evidence that some patients do develop resistance to this monoclonal. This point is clearly illustrated in the following observation: only about 50 - 60% of CLL patients who had previously responded to Rituxan therapy respond the second time around. This has been shown to be the case pretty unambiguously. Clearly, the 50% that did not respond the second time, but had responded the first time, have developed resistance.
2. Broad statistics applicable across the board to most patients cannot be derived from the experience of one patient. Rituxan maintenance therapy makes sense for a subset of patients, for whom it works well, Malcolm is an example of that. We cannot logically infer from his experience that there is no need to be concerned about possible resistance to Rituxan for all patients. 
3. Selection for CD20 negative population is not the only mechanism for development of resistance to Rituxan. We have discussed at length the role of complement inhibitory proteins. There is now quite a bit of information suggesting that Rituxan therapy may select for more resistant CLL in some people, where the expression of these complement inhibitory proteins is up-regulated. There is also recent information that cancer cells may be able to circumvent ADCC attack by T-cells and NK cells, protect themselves against the lethal attack of perforin and granzyme B (more on  that in a later article).
4. I agree with you, the reason why more local oncologists are reluctant to get going with frontline Rituxan therapy for CLL patients is the high cost, as well as the fact that it would be "off-label" till the FDA approves it for that purpose. Insurance companies are not happy for paying for it till that happens. 

There are several papers out there regarding re-treatment efficiency of Rituxan. This one from IDEC's own website was the easiest to locate for me (see their online documentation). A brief excerpt is given below, followed by my painfully detailed recap of the statistics. You might locate additional interesting material on the www.rituxan.com website. However, keep in mind that the Biogen-Idec and Genentech websites seem rather fluid and the documents do not stay put for long. You are almost better off doing a site search or a Google search from scratch.

Abstract

Initial Treatment with Eight Weekly Infusions:

In an investigational Phase II multi-center, single-arm, multiple-dose study, 37 patients with relapsed or refractory, low grade NHL received 375 mg/m2) of Rituxan once a week for a total of eight weekly infusions. Overall response rates were 57 percent (21/37 patients) with 14 percent of patients experiencing complete responses and 43 percent partial responses. The projected median duration of response is 13.4 months. 

Re-treatment: 

In another investigational Phase II multi-center, single-arm study, 60 patients with relapsed or refractory, low grade or follicular NHL were retreated when they relapsed after obtaining an objective clinical response with their initial four-week course of Rituxan. These patients received 375 mg/m2 once weekly dose of Rituxan for an additional four weeks. Of the 60 patients, 58 received a second course and two received a third course of Rituxan. The overall response rate was 38 percent (23/60 patients) with 10 percent achieving complete responses and 28 percent partial responses. The projected median duration of response is 15 months. 

The key words in the description of the re-treatment are that the sample of patients used in the re-treatment were ones that had obtained a clinical response to their first treatment of Rituxan. Of these 60 patients, all of whom had obtained a response the first time around, only 23 of this group of 60 got an objective response upon receiving as second treatment. 37 patients who got a response the first time around did not respond to re-treatment. 

These statistics vary a bit depending upon the nature of the disease (NHL versus CLL), naive or pretreated patients, 4 week initial therapy or 8 week initial therapy. But in each and every one of these clinical trial, the only patients who went on to a re-treatment series of Rituxan therapy in the trial were those who "passed" the first time around. Non-responders were weeded out of the trials and did not go on to receive re-treatment. There is absolutely no escaping the fact that roughly half of the people who responded the first time around, did not respond to re-treatment. I don't know what to call this except resistance. 

Statistics is a dismal field, boring as they come. But any one who wants to learn about clinical trials, or pay poker, or bet on the horses, has to have some idea of the odds. Just because the odds of getting a royal flush in poker is are very low, it does not mean that no one will ever get a royal flush. There is always the lucky so-and-so that gets this rare combination of cards. Similarly, just because your neighbor won the jackpot in the lottery getting his ticket at the local deli does not mean your chances of becoming rich are now a slam-dunk. 

Stated in terms of therapy, just because only roughly half the patients respond to re-treatment, you can't be sure you will not respond either. You have a roughly fifty-fifty chance of being in the group that does respond the second time around. Other side of the coin, just because one of our members responded three times in a row just goes to show that he is a lucky patient with the right phenotype and karma, this does not guarantee in any way that you will respond regular as clockwork every time you try Rituxan. 

There is no question in my mind that advent of Rituxan has changed the landscape for many of us. This is one of the most important drugs out there for us right now. Heck, P.C. went for Rituxan frontline monotherapy based on my recommendations, and he is doing very well. But we do not serve our community well if we gloss over the details, suggest "blanket" assurances  that do not have the pesky little caveats and conditions attached to them. It would be easier if the answers were absolute, but they are not. We have to develop a healthy respect for the details, the little side clauses and caveats, if we are not going to be sand-bagged down the road. 

Is there risk of gradual depletion of immunoglobulins with a chronic Rituxan maintenance therapy? Is there risk of losing too many memory B-cell functions with repeated and deep B-cell depletion? Is there risk of delayed onset of neutropenia after repeat use of Rituxan therapy? These are not dumb questions, and the answers are no slam-dunk either. Careful research is needed before we can assess the level of these risks. It takes hard nosed pragmatism to walk a careful line between unwarranted panic based on skimpy research findings of risks, and equally unwarranted assumptions of risk-free use of this monoclonal based on single patient response.  

For right now, the track history of this monoclonal is that it does not appear to have negative effects except for a very small percentage of patients. But Rituxan has not been around all that long, and has not been used in CLL patients all that long. The jury is out on long-term and delayed effects. On the issue of developing resistance to Rituxan, we have pretty solid evidence that a subset of patients do develop resistance to Rituxan. This is no free lunch, folks. 

Our discussion of individual cases serves an important and useful function. But what it is not supposed to do, was not meant to do, is give the false impression that individual responses are automatically translatable to the general patient base. Statistics just does not work that way. 

Limitations of Rituxan Monotherapy in CLL

Rituximab Therapy for CLL patients with High Risk Mutations

While our experience with Rituxan as frontline and maintenance therapy for CLL is still limited, a consensus seems to be developing that while the remissions are not as long as they can be with more heavy duty therapy like the RFC combo, the monoclonal therapy is less damaging to the bone marrow. Several things to keep in mind if you are thinking of taking this route: it might not be the best thing to do for some people.

First, you should have a quantitative flow cytometry done, to check both the percentage of cells that are CD20 positive, as well as the intensity. Typically, the percentage is 80% or higher for CLL patients. The intensity gives a sense of how many CD20 markers there are on each cell. Intensity is reported as 1+ (dim); 2+ (medium); and 3+ (bright). Conventional wisdom is that it is good to have high numbers both on the percentage and intensity, for the Rituxan to be as effective as possible. 

Second, while Rituxan usually does a great job on clearing out the peripheral blood, it does not work so well on bone marrow or heavily swollen lymph nodes (To recap: a normal WBC does not tell the whole story. Only 5-10% of the total burden of CLL cells are in the blood. The rest reside in the bone marrow, spleen, lymph nodes. Cleaning out the blood and getting the WBC "normal" is only a temporary thing, the numbers will soon get replenished from the vast stores in the bone marrow, lymph nodes etc.) So, if you are considering Rituxan only approach, it might be advisable not to wait too long, certainly before the lymph nodes get too large. Part of the problem, I think, is that monoclonal antibodies are very large molecules, they travel with ease through the blood stream but have difficulty navigating the narrow and convoluted capillaries of the bone marrow and spleen, etc. 

Third, you may want to consider getting a bone marrow biopsy done, to get a sense for the nature of the infiltration. If the marrow is heavily infiltrated, and the pattern of infiltration is "diffuse" rather than "nodular", that is not good news, and you may be better off hitting the CLL with bigger guns. Also, there was an abstract I came across from Anderson (wish I saved it) that seemed to suggest the percentage and intensity of CD20 marker may be different in the bone marrow specimen than in the peripheral blood. May be worth checking out. In any case, getting a bone marrow biopsy prior to initiating therapy may be worth considering, since it would establish a data point to check against, after the therapy is over. A little bit like having a mammogram done when you turn 50, so that there is a reference point. BMB's need not be horror stories. My husband has had 3 of them done at M.D. Anderson. He felt there was some pressure, some stiffness later on, but not much more. Please see my previous article on precautions to take prior to getting a bone marrow biopsy done. 

Fourth, if you can get it done, it might be worth finding out what type of a cytogenetic abnormality you have. The test is called "FISH" (Fluorescent In-Situ Hybridization) analysis. You may read about the different types of abnormalities, what they mean by way of prognosis and survival expectancy in an article titled Genetic Abnormalities in Blood Cancers. 

Below is an ASH abstract that discusses the cytogenetic abnormalities and how they may predict response to Rituxan therapy. Two of the "bad" mutations to have are the deletion of (17p13) gene and deletion of (11q22 or 23) genes. Both are associated with rapid progression of the CLL, and the first one is also associated with poorer response to Fludarabine therapy as well as alkylators such as Cyclophosphamide. The abstract below confirms that deletion of (17p13) also means poor response to Rituxan only therapy. The good news is that the other "bad" mutation, deletion of (11q22 or 23) seems to respond quite well to Rituxan. 

In addition to all these considerations, there are also the mundane and pragmatic considerations such as will your insurance go along with Rituxan-only approach, and if not, can you afford the hefty costs of such therapy. 

I guess the bottom line on all this is that if you have a "bad" cytogenetic abnormality, high level of bone marrow infiltration and diffuse type of bone marrow infiltration, swollen lymph nodes or spleen, and low intensity or percentage of CD20 positive cells, you are wasting precious time in trying to get by on Rituxan alone. We  are all different in how we respond to all these drugs, abstracts like this one give us a little glimpse into our chances with a particular approach. But in order to use this information, we need to have a better fix on our particular brand of CLL. Most local oncologists (especially those in HMOs!) seem to be reluctant to order anything more than routine CBC's. They are either afraid of running up the costs, or afraid of getting results which they are unfamiliar with and have trouble interpreting. If you are in w&w, and thinking about therapy choices down the road in a little while, my advice is to get to a good CLL center if you can, and get some of these more sophisticated diagnostic tests done. May be you are the text-book candidate for Rituxan only, and in that case why do you want to poison your system for no reason with more toxic drugs. But perhaps Rituxan alone is not going to do the job, your diagnostics suggest that you might be better off doing something more drastic than that. Knowledge is power, it helps you make better choices. 

Abstract

Interphase Cytogenetics Are Predictive of Chronic Lymphocytic Leukemia (CLL) Response to Thrice Weekly Rituximab Therapy. 

Lisa L. Smith, Nyla  Heerema, Marcy L. Hackbarth, Ian W. Flinn, Donn Young, John H. Proffitt, John C. Byrd. 

The Division of Hematology- Oncology, The Ohio State University, Columbus, OH.; Vysis Incorporated, Downer's Grove, IL.; Johns Hopkins University, Baltimore, MD. 

Select cytogenetic abnormalities such as del(17p13.1) and del(11q22- q23) have become recognized as predictive of rapid disease progression and inferior survival in patients with chronic lymphocytic leukemia (CLL). Similarly, abnormalities of del(17p13.1) have been associated with lack of response to alkylator and fludarabine therapy. We sought to determine the impact of the four most common interphase cytogenetic abnormalities including del (17p13), del(11q22.3), trisomy 12 and del(13q14.3) in 31 CLL patients relative to response to thrice-weekly rituximab therapy. All patients receiving this  therapy had symptomatic CLL. Response assessment was performed utilizing the NCI 96 criteria. Of these 31 patient samples, successful hybridization of all the probes was possible in 28 (90%). The clinical characteristics of these 28 patients included a median age of 64 with 7 (25%) being female. The patients received a median of 3 (range 0-6) therapies, and 15 (54%) were fludarabine refractory. Advanced stage (modified Rai 3 or 4) was present in 20 (71%) patients. Interphase abnormalities were noted in 25 of the 28 patients and included del(13q14.3) [n=16, 57%], del(11q22.3) [n=10, 36%], +12 [n=6, 21%] , del(17p13.1) [n=5, 18%], and normal [n=3, 11%]. Only a minority of each of these occurred as sole abnormalities. We therefore prioritized the abnormalities utilizing the criteria published by Dohner and colleagues (N Eng J Med 343: 1910-1916) [del(17p13.1) > del(11q22.3) >trisomy 12 > del(13q14.3)]. Response to rituximab was noted to vary by cytogenetic group: del (17p13.1), 0% [n=5]; del(11q22.3), 66% [n=9]; del(13q14.3), 86% [n=7]; +12, 25% [n=4], and normal, 0% [n=3]. Response was significantly lower (p=0.05) in patients with del(17p13.1) as compared to those with other abnormalities. These data suggest that interphase cytogenetics in CLL may be predictive of response to rituximab therapy with divergent response rates noted in the two high- risk [del(11q22.3) and del(17p13.1)] patient groups. Further studies examining the importance of interphase cytogenetics in predicting response to rituximab combination therapy in CLL are indicated. 

Keywords: FISH\ CLL\ Rituximab
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When to Start Single Agent Rituxan Therapy

I am certainly in no position to second guess members' oncologists or make therapy decisions for them. The best I can do is give you my logic in advising my husband to start therapy sooner rather than later. You will have to judge for yourself whether the logic is applicable in your situation. I am sorry I cannot go into the specifics of his personal medical situation, I respect his choice of privacy as much as I would respect privacy of any of our members.

The logic goes like this: I am interested in Rituxan only therapy because it is considered to be relatively non-toxic, and not damaging to the immune system. At best, it would give a patient good remission, especially if it is followed up with regular maintenance administration of the same protocol every six months. Please see my previous articles on the subject of why I think the standard dose of 375 mg/m2 and once a week for four weeks is preferable to the higher dosages and longer induction periods tried in several clinical trials. More is not necessarily better, it is important to keep in mind the pharmacokinetics of the drug and other depletion of other important components such as complement. Gradually, consensus seems to be building around the protocol outlined in Dr. Hainsworth's papers (see previous articles describing the details of Dr. Hainsworth's work). I do think, however, that Rituxan is not for every one. While it is not entirely clear why some CLL patients respond and others don't, to my mind it is prudent to have CD20 levels and intensity checked out prior to making the decision to use Rituxan.

At worst, Rituxan may be ineffective by itself in a given patient, in which case one has the option of choosing to escalate the stakes to a higher level at a later date, by adding other agents to the therapy, such as Fludarabine, or Fludarabine and Cyclophosphamide.

But based on what I have been able to figure out, it seems clear to me that since a major part of the actual tumor lysis in Rituxan therapy for CLL happens with the active participation of the rest of the immune system, including T-cells, NK cells, Neutrophils, macrophages etc, initiating this therapy sooner is better than later. We all know that as the CLL progresses, other cell lines are diminished. A lot of us who monitor our CBC data closely know that neutrophil and granulocyte numbers drop gradually over time, as the disease progresses. T-cell and NK cell and dendritic cell counts are not routinely monitored in most cases, but there is ample evidence in literature that all of these effector cells are made "anergic" or less effective in how they function, because the system is flooded with inhibitory cytokines and chemokines of various sorts, as a direct result of the growing CLL population. There is no question in my mind that later stage patients and/or those with larger tumor loads have poorer immune systems than early stage patients. This is easily reflected in the greater incidence of infections of various sorts and reduced levels of immunoglobulins in the serum. The logic follows that later stage patients are not able to utilize the benefits of Rituxan-only therapy as well as early stage patients, because their immune system is no longer up to the job of doing its share of heavy lifting. A combo therapy such as RFC might be more appropriate in these cases, where the other chemotherapy drugs take over the job of killing the tumor cells tagged by Rituxan.

There is also a lot of evidence that goes to show that CLL cells evolve as time goes on, adding more genetic aberrations to the nature of the clone. A patient with relatively benign aberration at the start of his disease may end up with more complex and refractory aberrations as the disease progresses. Once again, it may not be that easy to nip the disease back to square one at later stages. This type of clonal evolution has been documented in a significant percentage of patients.

Later stage patients may also become victim to other complications, such as AIHA, ATP, swollen spleen, liver, etc. Therapy choices are a lot harder when there are multiple problems to be resolved.

Later stage patients are generally in poorer health, subject to B-symptoms, less able to exercise and keep fit. Any therapy is more easily tolerated and effective, when the body is otherwise in good condition. The jocks on our site are not kidding, things work better when you are in good shape to begin with.

Unlike NHL, most CLL patients have bone marrow involvement, and the degree of this involvement increases with time. Percent of the bone marrow that is involved, and the pattern of involvement (diffuse or nodular) becomes worse over time, if the disease is allowed to progress unchecked. As we have discussed several times on CLL Topics, while it is easy to bring down the B-cell counts in peripheral blood, that is only the tip of the iceberg. Cleaning out the bone marrow, spleen, liver and swollen lymph nodes is harder to do, and yet those are the locations where the bulk of the disease resides.

As I mentioned in my article of last night, there seems to be a shift in the CLL paradigm. Till recently, the only drugs that were available were palliative, treated the symptoms with no hope of a cure, and at the risk of ever increasing damage to the bone marrow and immune system as a very result of the drugs. There was no survival advantage in early initiation of therapy, and there was a price to pay down the road, when the patient relapsed and often became refractory. Now too, single agent Rituxan is not a curative drug for CLL, at least not yet. It may become one down the road as we learn more about how it works, perhaps in combination with other monoclonals or immunomodulatory drugs like Interleukin-2, GM-CSF etc. But the big difference is that there seems to be very little toxicity associated with it, and I have seen nothing that suggests patients are likely to become refractory to it later on. In fact, the limited data available seems to suggest that second and third administrations of Rituxan give rise to somewhat longer average remissions rates, compared to the first administration.

Finally, given the rate at which new information and new drugs are becoming available, buying a couple of years of time now is more important than it was before. Couple of good years, with low level disease and therefore no symptoms or ancillary complications is worth a lot, especially if it is not at the price of toxicity and damage to the immune system. The ball game may be quite different in a couple of years. 

This article reflects the logic I used in guiding our therapy choices, by no means is all this proven or cast in concrete. While the watch & wait paradigm might be changing for newly diagnosed CLL patients, we are not yet at a point where early treatment is an obvious and standard choice for all patients. It is still a guessing game, but we can improve the odds a little bit by being better informed.

New Rituxan Clinical Trials at Sarah Cannon

Two new clinical trials have been announced for NHL/SLL/CLL patients. I checked, CLL patients are definitely included in the two studies. They should be interesting to a lot of our members.

I was able to get the full study protocols (very detailed and very long) by contacting a nice young lady called Lisa Grissim at Sarah Cannon Cancer Center at Nashville, TN. Her contact information is below, tell her Chaya sent you. Unfortunately, I am not allowed to publish the protocols, best I can do is give you an overview, and if you are interested, you can get you oncologist to contact Sarah Cannon. The trials are under the guidance of Dr. John Hainsworth. He is rapidly becoming one of my all time favorite CLL experts. Many of the participants in the trials are cared for by local oncologists, who do the actual administration of the protocol. This makes for a much more convenient situation for patients.

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The first clinical trial is called LYM-5. The objective of the study is to compare the maintenance regime developed by Dr. Hainsworth (once a week Rituxan at standard dose, for four weeks, followed by a repeat of the same thing six months later, for a total of 4 sets of infusions spread out over 2 years). In this approach the maintenance doses of Rituxan are administered every six months whether or not the patient has relapsed. This approach will be compared against patients who receive only the first four weeks of therapy, and will be re- treated only if they relapse, and only at the time of relapse and not sooner. Rituxan is the only agent used, no other chemotherapy drugs are involved in this study.

This trial is open to CLL patients who have been through at least one previous chemotherapy regimen. "Naive" patients are excluded, as are patients who have received Rituxan previously. It is OK whether or not you are symptomatic, but you must have sufficient kidney and liver functions.

Note that there is a control group and an experimental group in this trial, patients will be randomized into one or the other of the two groups. But both groups will receive Rituxan, but only one group will get the maintenance doses every six months. The other group will get more juice only as their disease progresses.

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The second clinical trial is called LYM-21. In this multi-center phase II trial, they will investigate the use of Fludarabine plus Rituximab, followed by Campath-1H, in previously untreated patients with CLL/SLL. Patients who are elderly, or who are considered unlikely to tolerate this combination therapy well, will receive single agent Rituximab followed by Campath-1H. Note this trial is for patients who have not received any therapy up to that point. For those who get the Fludarabine, it will be given at 25mg/m2 IV, days 1- 4 of week 1, week 5, week 9 and week 13. Rituxan will be given at 375mg/m2 slow IV infusion, weeks 1, 2, 3, 4, 5, 9, and 13. Campath (30mg) will be administered by slow IV infusion three times weekly for four weeks. During the first week, there will be a dose escalation, with the first dose administered at 3mg, second dose 10mg, and the third dose at the full dose of 30mg.  Personally, I wish they had decided to administer the Campath part of the protocol at lower doses, and subcutaneously. There is now quite a bit of work done that says this approach will be kinder and gentler to the patients.
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If you are interested, you (or your oncologist) can get copies of both protocols by contacting:

Lisa Grissim, The Sarah Cannon Cancer Center, 250 25th Avenue North Suite 110 Nashville, TN 37203.
voice: 615/986-4341 fax: 615/750-1740

Let me know if you run into problems on this front, I will see what I can do to help you out.

One final thought: many insurance companies that are reluctant to shell out the big dough for Rituxan for CLL are more willing to do this in the context of a clinical trial. Sarah Cannon is now considered a leading edge facility for Rituxan trials, and very much into supporting community based oncology programs.

Also, if you have an oncologist that does not believe in all this new fangled monoclonal stuff, getting these detailed protocols from a prestigious cancer center may help change his/her mind. The clinical trials are administered by Sarah Cannon, but I get the feeling that majority of the patients are cared for (actual drug administration, follow-up monitoring) etc by local oncologists who register with the cancer center. These are all details that you have to sort out before you jump into things. I found the office staff at Sarah Cannon to be exceptionally helpful and efficient, something that is often missing in the big name cancer centers.

What About Insurance?

A member raised a question on whether single agent Rituxan is approved for CLL and whether insurance reimbursement is available for this therapy. His insurer had indicated his doctor would have to submit his evaluation of need at the time of treatment for determination of coverage.

Good point. Our insurance company said the same thing. This is one reason why it is important to have a good working relationship with your local oncologist. 

Our local doc was not entirely eager to initiate Rituxan either. We got our specialist at the CLL Research Consortium Center to weigh in, and he felt that Rituxan could be beneficial. We also got together the pivotal clinical trial reports from Hainsworth's group, as well as the abstract of the work done by Dr. Thomas at M. D. Anderson, both of which showed that Rituxan was effective as frontline therapy in previously untreated CLL patients. Both of these references are cited in several previous articles. Let me know if you have trouble locating them.

Armed with these documents, we discussed with our local oncologist the pros and cons. Her major concern was that Rituxan is not likely to give deep remissions that last as long as, say, RFC type combo therapies. We assured her we were not expecting a deep remission or PCR negative state, but that a couple of years of holding the disease at bay is worth it to us, especially in view of the rapidity with which new modalities are being developed. Who knows what becomes available in just a couple of years. I think this was her biggest concern, patients who were not realistic in their expectations of what Rituxan can and cannot achieve. It also helped that my husband had relatively small lymph nodes, and no spleen or liver enlargement. 

I think if you are well prepared, well informed, realistic in your expectations and have a good working relationship with your doctor, you can make the case for Rituxan, and have the doc make the same case for you with the insurance company. That particular hurdle is becoming a lot less of a problem in the U.S., but I believe it is still a major problem outside the country. The message from our Canadian member a few days ago was shocking, it is one thing to say that Rituxan is not approved by law, but quite another to scare patients with inaccurate information about its toxicity. This drug has been pretty thoroughly investigated, both here and in Europe. It is the least toxic of the drugs currently available to CLL patients. However, I would like to see its response rates improve further, especially with later stage patients or previously treated patients.

That is how it worked for us anyway. Hope this is of some use to you.

Rituxan as First Choice - One Size Does Not Fit All

A member asked why initial therapy with Rituxan would not be appropriate for all patients - the way he saw it, "Why try Fludara or Chlorambucil, which could destroy my immune system and marrow, Why not try Rituxan? If it doesn't work, I can always go for RFC or RF or Campath later. If it doesn't work the first, second, third or forth time, I can always go for another treatment. I don't think I've burned any major bridges and meanwhile I have a normal life …"

In fact I agree with this member's logic for himself. I have put my money where my mouth is to some degree, and recommended Rituxan frontline monotherapy for my husband P.C. as well. And like you, he has done well on it, and no, I do not think either of you have burned any major therapy bridges, most likely. 

Unfortunately, the issue here is not one (or two) individuals, but trying to figure out the logic of how to make these therapy decisions, for the many different patients out there. Let me give you an example of a hypothetical patient who would not have benefited by following your example and P.C's, without carefully checking out how the statistics apply specifically to him.

Let us assume this patient has been smart, got an iron clad diagnosis, and full blown prognostic testing. There is no doubt about it, he has CLL. He is IgVH gene un-mutated, has high CD38 expression on CLL cells, dim and low CD20 expression. His absolute lymphocyte count has doubled in the last 8 months. He has lymph nodes were small to begin with, but have begun to pop up all over, and grown in size over the last few months. Local oncologist thinks his spleen is probably involved as well. (I could keep gilding the lily for this unfortunate man, give him a high bone marrow involvement, and rather low levels of neutrophils. But I think I have enough to make my point).

Should he insist on 8 weeks of Rituxan therapy, followed by waiting 2-3 months to see how well it worked? We are talking another 5-6 months since he began the Rituxan therapy. True, he has not burned any therapy bridges in the sense that he can still try the RF or RFC type therapy, if the Rituxan therapy did not work well. Also true, if the Rituxan did not work for him, and statistics say it does not work for a significant percentage of CLL patients even the first time, his lymphocyte count could be sky high by now, with lymph nodes, spleen and bone marrow to match. So, was this a no-risk try, nothing to lose, and therefore the correct choice?  

I do not think so. First, if he had done his homework, he would have realized that the statistics (there is that ugly word again!) do not favor patients with bulky disease. There is also some not-yet-definitive suggestion that low CD20 and high CD38 expression does not make for good chances for good response to Rituxan. Very few CLL patients get CR with Rituxan monotherapy in any case, and patients with his profile are most unlikely to get the few CRs. At best, he can hope to get a partial response. 

So what is wrong with a PR, he has not burnt any bridges, you ask. Well, based on the prognostic indicators I saddled this guy with, the odds are he has one of the more aggressive and hard to treat diseases. Perhaps his bone marrow became more impacted and his spleen grew bigger while he went through the Rituxan therapy plus 2-3 month wait to see if it worked. By now, his compromised bone marrow may not be able to make the necessary cell lines. By the time he gets around to saying "OK, the Rituxan did not work so great, now what"? he is 5-6 months past where he was, and he has a tough situation to deal with. 

Bone marrow insufficiency, poor Hg production, poor platelet production, may make spleen removal a problem. Surgeons do not like to operate on patients who are low on HG, RBC and platelets, too much risk. Without getting a splenectomy first, he may be looking at a situation where future therapy choices such as RF or RFC may not be as effective either, since the spleen may sop up the precious drugs before they can do any good. 

Has his choice of Rituxan as frontline monotherapy cost him anything? You bet, big time!! It is called "opportunity cost". In going after a low probability choice (Rituxan has poor statistics for CLL patients with bulky disease and aggressive disease), he has lost a window of opportunity where he could have handled more heavy-duty therapy with more ease, and perhaps better results. 

The issue is not whether it worked for any one particular patient.  In  this member's case and in  P.C.'s the CLL was well behaved, and in P.C's case it was also early stage. P.C. also had 98% CD20 positive cells, in both peripheral blood and bone marrow, and low CD38. There were no guarantees, but the odds were that he would do better than the average CLL Joe on Rituxan therapy. And if he did not, not much is lost since he is in early stage and has a relatively indolent disease. For him, the time frame for window of opportunity was pretty long and therefore the choice was low risk, low cost. The logic of Rituxan monotherapy as frontline worked for him. It may not work for every other patient out there. My efforts to keep drumming in the details regarding statistics and caveats is to try and get people to make therapy choices that are pragmatic and right in their particular case.  

Yes, I have gilded the lily for this hypothetical case, to illustrate my point. But the scenario is not all that extreme, and in fact I have to make the CYA statement now, any resemblance between my fictitious patient and real patients/Topics members is purely coincidental and not by intent. And you can't prove otherwise.  

If we keep insisting Rituxan is a no-cost option, without taking the trouble to point out the small print that this may not be the case for all patients, we run the risk of at least a few patients not bothering to do their home work enough to figure out whether or not it is the right choice for them. Topics is all about empowerment, and we do not serve our members well, in my opinion, if we do not make every effort to present both sides of the argument. It makes finding answers more complex and frustrating, no easy slam-dunk and no-cost choices. One shoe does not fit all, in this situation, your shoes may be wrong size and shape for some one else. An individual can afford the logic that works for him, even though it is a narrow focus. A group of very diverse patients cannot afford the narrow focus.