October 14, 2004
by Chaya Venkat
The Good and the Not-so-good News About Rituxan
Rituxan therapy, either as single agent or in combination with other drugs, has become the corner-stone of CLL therapy. We have probably more articles devoted to Rituxan (Rituxan Therapy) than any other drug, and with good reason. At the heart of it all is the unique capability of Rituxan to target CD20, a marker that is expressed by mature B-cells, and only by mature B-cells. That single fact gives Rituxan its enviable low-toxicity profile. True, there are some limitations and we should be aware of them, please do read the other articles on Rituxan on our website. But making good therapy choices is all about being prudent but not over-reacting, a pragmatic weighing of the risks versus rewards.
This article is for the purpose of discussing the recent warning issued by Genentech regarding safety (Topics Alert 49, October 11 2004) as well as a new Rituxan combination that sounds quite promising, both in terms of improved response and low toxicity. The "bad news" is not so bad, and as for the "good news", get this: this new potential Rituxan side-kick is already commercially available, and has a demonstrated record of low toxicity in human trials. Not much stands in the way of a clinical trial with this new Rituxan combination, if we can only get moving on it! First, the "bad news".
"Dear Doctor" Letter from Genentech:
One of the conditions often imposed by the FDA when a new drug is approved for marketing is that the manufacturer must do post-market surveillance for potential problems. This makes sense since clinical trials look at small number of people, and it is only when the drug is used by very large number of people that all the nits and nats become apparent. Here is a case where post-marketing monitoring of Rituxan use has brought forward a new risk factor, and Genentech has properly brought it to the attention of doctors, as mandated by the FDA. You can read Genentech's letter, as well as the latest Rituxan Product Information by clicking on the links below.
What is the common theme here? Basically, many of these viruses (Herpes, Hepatitis, Epstein-Barr, TB, CMV etc) establish small, dormant populations in your body which never quite disappear and once infected you are stuck with them for life. Very high percentages of our populations are now infected with viruses such as Herpes, EBV and the like. In healthy people with intact immune systems, these viruses are held in check and not allowed to proliferate into full blown infections, a stalemate is declared between your body and the virus. This stalemate truce is broken when our immune systems are compromised, unable to do their job. One such scenario is right after therapy to control the CLL. Old fashioned chemotherapy with drugs such as fludarabine, cyclophosphamide, chlorambucil, prednisone, etc., has always been infamous for less-than-perfect selectivity, killing many perfectly healthy cells along with CLL cells, the level of the toxicity depending on the specific drug, its dosage and combination with other drugs. It is easy to see how CLL patients with less than perfect immune function can become sitting ducks after going through heavy-duty chemotherapy.
While monoclonal antibodies, by comparison, are considered "smart drugs" because of their specific targeting capability, here too it is not a zero risk scenario by any stretch of the imagination. Campath, for example, targets CD52, a marker that is present on all mature B-cells (good and bad), as well as T-cells, NK cells and several more cell lines as well. So it stands to reason that Campath therapy is invariably accompanied by deep and across the board deficits in the immune function, a problem that may last for several months after completion of therapy. Indeed, many of the cell lines do not fully recover even one year later (Campath Therapy). The risk of serious infections and reactivation of some old enemies is quite real, and that is why it is strongly recommended that patients be protected with pre-emptive anti-viral and anti-bacterial medications.
There have been several reports linking delayed onset neutropenia to Rituxan therapy. The percentage of cases where this has been observed is small, and no one seems to be quite clear as to the mechanism of how this comes about.
Br J Haematol. 2003 Jun;121(6):913-8.
Delayed-onset neutropenia associated with rituximab therapy.
Chaiwatanatorn K, Lee N, Grigg A, Filshie R, Firkin F.
Department of Haematology, St Vincent's Hospital, Fitzroy, Victoria 3065, Australia.
The characteristics of severe neutropenia with a delayed onset following administration of rituximab have been evaluated in 53 consecutively treated patients. All but one patient received rituximab for the treatment of non-Hodgkin's lymphoma. Eight episodes of grade 4 neutropenia were detected between 1 and 5 months after rituximab, when administered alone on five occasions, and on three occasions in combination with chemotherapy, where neutrophil counts had recovered prior to the development of neutropenia. In three episodes, the patients presented with sepsis. Development of neutropenia did not correlate with either the presence of detectable disease or the administration of further treatment. Neutropenia was associated with selective depletion of neutrophil precursors in all but one episode, where it was associated with generalized bone marrow hypoplasia. All episodes developed after a period of either normal or mildly depressed neutrophil counts following treatment with rituximab, and persisted for between several days and several months, before undergoing spontaneous recovery in four instances, and after administration of filgrastim in the remainder. Episodes of neutropenia were associated with disordered immune status manifested by lymphopenia and hypogammaglobulinaemia, raising the possibility that either disturbance of the balance of lymphocyte subsets or an immune dyscrasia induced by rituximab resulted in the development of this type of neutropenia.
Other than the usual infusion related side effects some patients experience, Rituxan therapy was thought to be remarkably free of serious adverse effects, until now. The naive assumption is that since Rituxan targets only B-cells, and viruses are generally handled by T-cells, we should be free of the pesky viral reactivations that plague Campath users. It is not quite that simple. There is very strong cross-talk between B-cells and T-cells, each influences the other's growth and maturation, and each cell line controls proper functioning of the other. This latest warning from Genentech confirms that perspective. Rituxan therapy does not give us a free pass as far as viral reactivation is concerned. True, most of the cases reported in this post-market surveillance dealt with use of Rituxan in combination with other chemotherapy drugs, which may have contributed greatly to the window of vulnerability when the immune system was sufficiently compromised to allow viral reactivation.
Does this mean we avoid therapy regimens containing Rituxan? Not at all. Rituxan is still the single most important drug available to us today. All this new warning says is that we need to be aware of this potential risk down the road. The action item is quite simple. If you think you may have been exposed to hepatitis, make sure your doctor knows about it before you initiate Rituxan therapy. Make sure you get tested for the tell-tale markers of this virus ahead of time, and if you are positive for it, make sure you get adequate medications to protect you against its reactivation. Since this letter went from Genentech to healthcare providers, your doctor should be aware of it. Just in case he/she is not, you can print out the Genentech letter from the link above, that should be enough to convince your doctor to follow the game plan. Here is a quote from the Genentech letter, as well as their Product Label, it is quite explicit:
Persons at high risk of HBV infection should be screened before initiation of RITUXAN. Carriers of hepatitis B should be closely monitored for clinical and laboratory signs of active HBV infection and for signs of hepatitis during and for up to several months following RITUXAN therapy. In patients who develop viral hepatitis, RITUXAN and any concomitant chemotherapy should be discontinued and appropriate treatment including antiviral therapy initiated.
New Rituxan combination
Now for the "good news".
Unfortunately for us, CLL patients do not have as deep a response to Rituxan as do patients with other B-cell cancers such as follicular lymphoma, for example. We have discussed in prior articles several approaches to enhancing the response to Rituxan therapy by means of adding other drugs. These cover a wide field, including immune system enhancers such as Neupogen (G-CSF), Leukine (GM-CSF), EGCG, CPG-ODN, PT-100, Beta Glucan, IL-2, etc., as well as older chemotherapy drugs such as fludarabine, prednisone, cyclophosphamide, chlorambucil etc. In particular, we have discussed in detail combination of Rituxan with Neupogen and EGCG (Neupogen as Booster to Rituxan Monotherapy, The Difficult Case of the Round-Headed Kid), as well as the present "gold standard" combination of Rituxan with fludarabine (Fludarabine Monotherapy No Longer the Gold Standard, RF Therapy Clinical Trial).
I am please to report on a new combination that sounds promising. Fenretinide is an analogue of vitamin A. It belongs to the retinoid family (chemical name is N-(4-hydroxyphenyl)retinamide, or 4-HPR for short). It has been around for quite a while and has been through a host of clinical trials for cancers ranging from breast cancer, prostate cancer, ovarian cancer and other solid cancers, as well as a long term maintenance drug to prevent recurrence of cancer after therapy, or simply as a way of preventing the cancer from taking root in the first place. It has been used as a single agent (with only modest results) as well as in combination with other drugs. You can get a sense of the amount of work done with this vitamin A analogue by typing the word "Fenretinide" into your Google search engine, I got more than 6,000 hits. As you can see from the "Expert Opinion" abstract below, prior disappointment with this drug is now giving way to renewed interest, new ways of administering it and new combinations using this drug are generating quite a bit of interest.
Expert Opin Investig Drugs. 2003 Nov;12(11):1829-42.
Fenretinide: a prototype cancer prevention drug.
Malone W, Perloff M, Crowell J, Sigman C, Higley H.
National Cancer Institute, Division of Cancer Prevention, Chemopreventive Agent Development Research Group, Bethesda, MD.
Fenretinide (N-4-hydroxyphenylretinamide [4-HPR]) is a synthetic retinoid that has been examined in in vitro assays, preclinical animal models and clinical trials as a cancer chemopreventive agent. Its pharmacology, toxicity and mechanisms of action initially suggested an increased therapeutic index relative to native retinoids for the control of tumours of the breast, prostate, bladder, colon, cervix and head and neck. Although fenretinide at the doses and schedules used in several pivotal Phase II and III clinical trials has not been proven to be efficacious in reducing the incidence of cancer or in retarding the development of preneoplastic lesions, encouraging observations regarding unanticipated preventative activity, such as for ovarian cancer control, have arisen from these studies. Research in cancer therapy and the elucidation of molecular pathways activated by fenretinide have also yielded clues about how this agent might be better used in a prevention setting. Current trials are underway to re-examine both dose and schedule of fenretinide administration as well as the target tissues of interest. Investigations of potential synergism between fenretinide and other candidate chemopreventative molecules with complementary mechanisms of action may support future assessments of this prototype cancer prevention drug or its newer analogues.
The most important point I get from reviewing all this prior work is that Fenretinide has shown very little toxicity at the dose levels needed to see physiological effects in human beings. OK, it is good to know it is not toxic, but does it do us any good in fighting CLL? The abstracts below answer that question. The first paper is hot off the presses, if you want to read the full text of the article write to us and we will help you locate it. The second paper by the same authors is available free of charge, you can read it by clicking on the link I have provided.
Blood. 2004 May 1;103(9):3516-20. Epub 2003 Dec 24.
Fenretinide enhances rituximab-induced cytotoxicity against B-cell lymphoma xenografts through a caspase-dependent mechanism.
Gopal AK, Pagel JM, Hedin N, Press OW.
Seattle Cancer Care Alliance, Mailstop G6-800, Rm 6802, University of Washington, 825 Eastlake Ave E, Seattle, WA 98109.
The anti-CD20 monoclonal antibody rituximab induces remission in 40% to 60% of patients with indolent B-cell lymphoma, but virtually all patients have relapses. We evaluated the efficacy of concurrent administration of another biologic agent, N-(4-hydroxyphenyl) retinamide (4HPR, fenretinide) with rituximab against a variety of human B-cell lymphoma cell lines (Ramos, DHL-4, and FL-18) in vivo. Concurrent 4HPR and rituximab administration prevented tumor progression of lymphoma-bearing mice in a minimal disease model (rituximab + 4HPR, 100% progression free; rituximab alone, 37.5% progression free, P =.01; 4HPR alone, 12.5% progression free, P <.01; controls, 0% progression free, P <.01). Combinations of 4HPR + rituximab exceeded the predicted 50% additive rate of disease control from each agent alone (P =.038). Administering 4HPR and rituximab to mice with established tumors induced complete responses (CRs) in 80% of animals compared with 20% to 40% CRs using either agent alone (P =.07), resulting in significantly improved survival. Tumors harvested from 4HPR + rituximab-treated mice displayed elevated caspase activation compared with untreated controls (P =.02). Adding a broad-spectrum caspase inhibitor in vivo fully abrogated the antitumor effects of 4HPR + rituximab (P =.05). These results establish the efficacy of 4HPR/rituximab combinations, confirm their caspase-mediated mechanism of action, and offer the potential for disease control with minimal toxicity for patients with B-cell malignancies.
Clin Cancer Res. 2001 Aug;7(8):2490-5.
Synergistic effects of the fenretinide (4-HPR) and anti-CD20 monoclonal antibodies on apoptosis induction of malignant human B cells.
Shan D, Gopal AK, Press OW.
Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA 98195, USA.
Retinoids have been shown to be clinically useful in the biological therapy of certain myeloid and T-cell malignancies, whereas CD20 has proven to be an effective target in B-cell lymphoma immunotherapy. Both retinoic acid derivatives and anti-CD20 monoclonal antibodies have also been shown to induce apoptosis of malignant cells in vitro. Retinoid-induced apoptosis is thought to be mediated by nuclear retinoid receptor binding and transcriptional activation, whereas CD20 ligation appears to initiate transmembrane Ca(2+) influx with resultant programmed cell death. In this report, we evaluate the in vitro effects of N-(4-hydroxyphenyl) retinamide (4-HPR) with and without anti-CD20 antibodies in B-cell lymphoma lines. We demonstrate that 4-HPR inhibits the growth of malignant B-cells beyond that of all-trans-retinoic acid and 13-cis-retinoic acid. We also show that this 4-HPR-mediated growth inhibition is attributable to apoptosis, is consistent across a variety of malignant B-cell lines (Ramos, Ramos AW, SU-DHL4, and Raji), peaks at 96 to 144 h, and is attainable with concentrations as low as 2 microM. As with CD20-mediated apoptosis, we show that the final common pathway includes caspase activation that can be blocked by 2-val-Ala-Asp-fluoromethyl ketone (z-VAD), a specific inhibitor of caspase function. Coincubation of a 2 microM concentration of 4-HPR and the anti-CD20 antibodies rituximab and tositumomab exhibited a supra-additive increase in levels of apoptosis induction of 24% (P = 0.009) and 42% (P = 0.0019) relative to expected additive levels of these same agents. These in vitro findings suggest that the potential in vivo synergy of these well-tolerated drugs may augment the previously demonstrated clinical activity of anti-CD20 monoclonal antibodies in the treatment of B-cell malignancies.
Below is one of the figures from the authors' 2004 paper. Mice infected with two different types of B-cell cancers were treated with Rituxan alone, Fenretinide (4HPR) alone, or by a combination of Rituxan + Fenretinide. As you can see, the mice that got both of the drugs in combination were the lucky ones, they lived a lot longer than the mice who received only one of the two drugs.
Blood. 2004 May 1;103(9):3516-20. Epub 2003 Dec
Please remember these are mouse studies, yet to be proven in human subjects. However, I have no quarrel with the authors' logic. They recognize the less than wonderful response rates for Rituxan as single agent therapy in many B-cell cancers including CLL, and that the present strategy of improving these response statistics by the addition of other chemotherapy drugs (such as fludarabine, cyclophosphamide, prednisone) is at the cost of increasing the toxicity of the combination. They suggest that Fenretinide may be the best "Goldilocks" scenario, increasing Rituxan response rates without incurring additional toxicity. The following are quotes from the conclusions section of their 2004 paper.
"Our observations in this in vivo lymphoma xenograft model suggest that the combination of Fenretinide + rituximab might have a major clinical impact on the 50 000 patients who are diagnosed each year in the United States with B-cell non-Hodgkin lymphomas. Most current clinical strategies to improve the efficacy of anti-CD20 antibodies have focused on the addition of traditional chemotherapeutic agents. Although responses may be improved, significant hematopoietic and nonhematopoietic toxicities are inevitably incurred with chemotherapy. Fenretinide affords a potentially less toxic approach to enhance rituximabís efficacy because it has been found to be well tolerated in a large number of chemopreventive and therapeutic trials".
"Combining 4HPR and anti-CD20 antibody therapy in the clinic is particularly appealing. Unexpected toxicity would be unlikely from this combination based on the known tolerability of 4HPR alone and the moderate toxicity of rituximab that is typically limited to infusional reactions. Unlike traditional chemotherapy, one could envision use of this drug combination to induce responses and to maintain long-term remissions. Sustained exposure to this combination could be particularly effective in patients with indolent B-cell lymphoma in which the major oncogenic abnormality is thought to be an inability of cells to undergo normal apoptosis".
My thoughts exactly.
For those of you who follow the science we try to present in our articles, here is an interesting little nugget of information. We discussed the potential value of ROS (reactive oxygen species) generation in our article on mitochondria (Exciting New Drugs on the CLL Horizon), as a way of destabilizing the mitochondrial survival, which in turn leads to inevitable cell death. I found it interesting that Fenretinide works by several mechanisms involving ROS generation and caspase activation, both of which are linked to mitochondrial death. In other words, combining Rituxan + Fenretinide may work with Rituxan tagging the B-cells, and in addition to all the other mechanisms of cell kill associated with the monoclonal antibody, we have the additional effect of the cells getting destabilized by Fenretinide and therefore that much easier to kill.
I wonder if similar synergistic effects will be
seen by combination of Rituxan with several other new small molecule drugs we
have discussed in recent days, such as
Adaphostin and the Celebrex-derived
under investigation at Mayo Clinic and Ohio State respectively. Adaphostin and
OSU03012 are also thought to work through mitochondrial pathways, similar to
Fenretinide. All of these small molecule drugs have the advantage of potentially
better drug transport, the ability of getting into all the nooks and crannies of
the lymph nodes and bone marrow that are not normally accessible to the bulky
Rituxan molecule. In addition to increasing the response to Rituxan therapy,
some of these drugs may play an important role as maintenance medications, a way
of prolonging the hard won remissions, keep the party going longer. If more of
us can have a deeper response to Rituxan therapy without additional toxicity,
and that response can be made to last longer by maintenance medications, such
that repeat therapy need be done only once every couple of years or so, what is
not to like? I will be quite happy to welcome that development, it is a lot
better than anything we have right now.
You can contribute to support our efforts.