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    Radioimmunotherapy: Underappreciated Option?

    Date: September 6, 2024

    by Chaya Venkat

    A Protocol Waiting for a Trial

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    Antibodies with a Punch

    There are two radioimmunotherapy on the market right now, Bexxar and Zevalin, both are FDA approved and commercially available. How long they will stay on the market is a question and a real worry. As PC pointed out in his recent Topics Alert and the accompanying article on our website (Radioimmunotherapy Reimbursement Cuts), both are at risk of becoming causalities of the reimbursement wars. I would like to give you a little heads up on what these two drugs do, their track record thus far, and their potential value to CLL patients, especially those with early stage but poor prognosis disease.

    Both Bexxar and Zevalin are monoclonal antibodies that target the CD20 marker on B-cell cancers like CLL. Both carry a radioactive payload. In other words, once the offending (CD20 carrying) cell has been tagged by either of these drugs, the radioactivity that they carry will kill the cell – with no help needed from the rest of the immune system, thank you very much. You can see why this is a big deal. “Cold” monoclonal antibody drugs such as Rituxan and HuMax-CD20 carry no such lethal weapon with them and the majority of the cell kill happens only when the rest of your own immune system gets into the act, whether it be complement, effector cells such as macrophages, neutrophils, T-cells, etc. This greatly diminishes the activity of the “cold” monoclonals compared to “hot” radioimmunotherapy drugs such as Bexxar and Zevalin.

    CLL Differs From NHL In Significant Ways

    Bexxar and Zevalin have become important drugs in the treatment of non-Hodgkin’s lymphoma, particularly follicular lymphoma. Why have we heard so little about these two drugs in the CLL community? One simple reason: bone marrow involvement. CLL patients tend to have more of the cancer cells in their bone marrow, compared to NHL patients. Imagine the scenario – all those CLL cells in the bone marrow with their CD20 markers flashing like neon lights attracting the “hot” monoclonals. Once they are tagged, the CLL cells are killed by the radioactive payload carried by the drug molecules. So far, so good. But the story does not end there. The radiation also kills other neighboring cells within a narrow band, what we would call ‘collateral damage’ in the language of war. This can be a good thing, if the surrounding cells are not exactly innocent themselves, say if they are also CLL cells or they are so-called “nurse like cells” that help and protect CLL cells. If this is the case, we are getting more bang for the buck, one smart bomb killing a whole cluster of bad guys. Indeed, this is what we hope happens in the swollen lymph nodes, huge bunches of bad cells and their collaborators getting killed by each Bexxar or Zevalin molecule.

    But in the bone marrow, things are not so simple or clear cut. In addition to the cluster of CLL cells or cells that actively support the tumor architecture, there are also precious stem cells, progenitor cells that make red blood cells, platelets, neutrophils, etc. If too much of the “hot” monoclonal is attracted into the bone marrow, and stays there because it is attached to the CD20 markers on the CLL cells, the radioactivity can damage innocent and very precious stem cells that just happen to be in the neighborhood. NHL patients can tolerate Bexxar and Zevalin therapies because they have lower levels of cancer cells in their bone marrow. For them, less of the radioactive drug is attracted to the bone marrow and retained there and therefore there is less damage to the stem cells. Don’t get me wrong – NHL folks also have some amount of bone marrow involvement, just not as much as CLL patients.

    How Low Is Sufficiently Low?

    Well, researchers have typically used 20% bone marrow involvement as the cut-off point. So, whether or not you have CLL or NHL, if your bone marrow involvement is sufficiently low (below this cut-off point) it is safe to use Bexxar and Zevalin. It does not have to be zero bone marrow involvement.

    A recent clinical trial we reviewed uses this concept (Bexxar: An Introduction to Radioimmunotherapy). This clinical trial at the Fred Hutchinson Cancer Research Center in Seattle is recruiting chemo-naïve CLL patients. The trial puts them through “standard” therapy of 6 monthly cycles of Rituxan + fludarabine as a way of getting their bone marrows sufficiently cleaned out, then treats them with Bexxar as a way of deep MRD (minimal residual disease) clearance. It sounded like a great idea to me, and we gave this clinical trial a good write up on our website. As we pointed out in that review, the median duration of the Bexxar-induced remissions in follicular lymphoma are something to envy.

    RF + Bexxar Clinical Trial for CLL

    Guess what, patients are not flocking to this clinical trial in any great numbers, at least not from our community. In fact, as several of you have pointed out to me in your emails, the major drawback is the upfront six months of RF therapy in the trial protocol. Rituxan + fludarabine is a well researched combination, quite successful in getting high percentage of responses, especially in chemo-naïve patients, and therefore quite adequate to clear out the bone marrow sufficiently in almost all of the patients looking to follow up with a Bexxar shot. But RF therapy is no picnic, the published results reviewed on this website point to definite toxicity and adverse effects.

    If you are a chemo-naïve patient looking for a therapy, you are likely to fall into one of two camps. If you are in the first camp, you want to get the CLL taken down a peg or two (or as many pegs as possible!), but without a lot of damage or adverse effects and without a lot of heavy duty therapy. Six months of RF therapy followed by Bexxar appears to be a bit too much to swallow for this crowd. True, the Bexxar part of it is relatively painless, just a single therapeutic infusion of the hot monoclonal, with remarkably low adverse effects. But as we pointed out in our RF + Bexxar clinical trial review, this low toxicity and patient-friendly aspect of Bexxar is thoroughly overwhelmed by the need for six months of slogging through Rituxan + fludarabine, upfront. The “kindler and gentler” camp followers are more likely to consider single agent monoclonals like Rituxan and Humax-CD20, with or without ‘kindly’ adjuvants like EGCG, Leukine, or even Fenretinide.

    The second camp will consider RF, FRC, CFAR, R+HDMP, Campath + HDMP, a host of other alphabet string combinations in an effort to take a significant “manly” whack at the CLL. These are the more conventional approaches to frontline CLL therapy these days, especially for patients with aggressive disease or poor prognosis. Chances are good that first time around, as chemo-naïve patient, you will get a good response, may be even a full blown “Complete Response” (CR) with little or no detectable disease. Why would you mess with success? Why go through the cost, hassle and hardship associated with participating in a clinical trial for RF + Bexxar, when you can just do the RF therapy conveniently at your local oncologist? Why not simply ride the remission you are likely to get after working hard at it for 6 months of RF, without trying to gild the lily by adding Bexxar on top of the RF?

    I can see the logic of both camps, and I can see how this explains the lack of enthusiasm for the RF + Bexxar trial.

    A Subtle Finesse, Our Behind the Scenes Efforts

    Bexxar and Zevalin have yielded outstanding results in follicular lymphoma patients – enough to make me jealous and want the same thing for our guys. Obviously, these hot monoclonals are not for everyone. The crucial requirement to have less than 20% bone marrow involvement is no trivial hurdle. The last thing you want to do is fry your bone marrow with too much radiation by using Bexxar or Zevalin at a time when your bone marrow involvement is higher than the safety point. How to achieve this, in a way that does not negate the low adverse effect and patient-friendly profile of Bexxar and Zevalin? How to use Bexxar and Zevalin safely in CLL, with a patient-friendly protocol? Below is the scenario I hoped to make real.

    1. Start with early stage CLL patients, but those with high risk profiles and therefore likely to need assertive therapy early on. I would also add to this group older patients, those that are not good candidates for heavy duty chemotherapy combinations, or those unwilling to try fludarabine containing regimens because they are at high risk of autoimmune disease such as AIHA.
    2. Treat them with multiple cycles of single agent HuMax-CD20, in order to reduce bone marrow involvement. There is reason to hope that HuMax-CD20 will do a better job of clearing out the bone marrow than its earlier rival Rituxan.
    3. However, HuMax-CD20 is still an experimental drug and not commercially available. In a pinch, I would not sneeze at the chance of using Rituxan (plus or minus the adjuvants of your or your oncologist’s choice, such as EGCG, Leukine, Neupogen). While Rituxan monotherapy does not yield many CRs (hardly any, as a matter of fact), because it does not work very well on enlarged lymph nodes, it is pretty good at clearing CLL cells in the blood and not too shabby in clearing bone marrow either – especially in chemo-naïve patients. HuMax-CD20 would be my first choice in this role, but I will take Rituxan if I do not have access to HuMax-CD20.
    4. After 4 weekly infusions of HuMax-CD20 or Rituxan, it is time to stage the patient. First, it is important to wait for a couple of weeks, make sure the remaining CLL cells in your body are back to expressing their usual level of the CD20 marker (you may want to review our report: CD20 Shaving with Rituxan). Fortunately, Prof. Ron Taylor of the CD20-shaving-reaction fame assured me that any shaving of CD20 marker is fully reversed in a couple of weeks.
    5. Now for the crucial test: a bone marrow biopsy to check the level of CLL present in your bone marrow. If you are lucky and the cold monoclonal has done its job and you are below the 20% cut-off, you can proceed on to the Bexxar or Zevalin part. Either of these hot drugs need only one single infusion. (Bexxar also needs a tiny dose-finding infusion ahead of time, to see how your body handles the drug and therefore allowing them to calculate the exact amount you should get). For just a little more than the fuss and muss of standard issue four weeks of Rituxan monotherapy, you would have had access to much more potent therapy. Your chances of getting a very deep remission and a substantial remission period are much better in this combination approach.
    6. What if your bone marrow is not sufficiently clean, and you are not eligible to get the radioimmunotherapy with Bexxar or Zevalin? Well, this is where you get off the train, but you are no worse off than you were if had gone through conventional, single agent HuMax-CD20 or Rituxan therapy.

    I liked this concept so much that I contacted both GlaxoSmithKline (GSK) and Genmab about this concept. It made sense, GSK now owns rights to both Bexxar and HuMax-CD20 (Genmab has cut a deal with GSK on HuMax-CD20). As always, Genmab has been responsive in getting back to us, but much less so GSK. Not all pharmaceutical companies have yet understood the need to take patient advocacy groups seriously, in this new era of proactive and well informed patients. But that is neither here nor there, I am used to having a certain percentage of my emails falling on deaf ears. I would have been delighted if they got around to it at their own sweet pace, but when we did get it, the final answer was disappointing. GSK is not willing to give this interesting clinical trial of HuMax-CD20 + Bexxar high priority, certainly it will not be considered before 2024, if then. Bummer!!

    OK, back to the drawing board. Since we cannot get GSK interested in HuMax-CD20 + Bexxar, what is wrong with switching gears and going ahead with Rituxan + Zevalin? Frankly, I am not sure that there is a great deal to chose between Bexxar and Zevalin, based on what we know at this point in time. Both Rituxan and Zevalin are commercially available, and frankly there is nothing stopping you from “negotiating” with your local oncologist into trying this combination right now, on your own. But I would rather see this done properly, in a clinical trial with all the safety and monitoring bells and whistles in place. I think this combination has the allure of possibly very high response rates and long remissions, with significantly lower adverse effect profile.

    There is More Than One Way to Skin a Cat

    I can use a little help here. If several people are trying to get door(s) open, it works better than just little ol’ me pushing and shoving. If you have sufficiently high level / influential contacts that can make things happen, this is a good time to speak up. I will be more than happy to take it from there, once you get the door open just a bit. Obvious locations where this clinical trial has a natural fit:

    1. M. D. Anderson. They have pioneered in Rituxan + Leukine as a kindler and gentler option for older CLL patients, with good results. They have a good feel for how effective this combination is at clearing out the bone marrow. If it is pretty good at that job, how about adding Zevalin as an MRD clean up after the R + Leukine, to get these people a long-lasting remission? The R + Leukine combination by itself is not able to give long lasting remissions in CLL. Remember, this combination of R (+ Leukine) + Zevalin sidesteps the need for fludarabine, something many patients with a tendency to AIHA wish to avoid like the plague.
    2. Sarah Cannon Cancer Center (Tennessee). Our old friend Dr. Hainsworth has long been a champion of single agent Rituxan therapy, and even maintenance Rituxan therapy in order to prolong remissions. I understand Dr. Ian Flynn of CRC (CLL Research Consortium) fame is also there now. Would it not be a better idea to get the longer remissions by using a Zevalin chaser after the standard 4 weekly infusions of Rituxan? Would this not be more effective in clearing out MRD (minimum residual disease) and therefore get long remissions, rather than all too frequent Rituxan maintenance infusions?
    3. Ohio State. These folks are at the cutting edge of all CLL clinical trials. I have great respect for Dr. John Byrd and his team. The only issue is whether they have so much on their plates right now that there is no room for this additional clinical trial.
    4. Fred Hutchinson Cancer Research Center. After all, these are the guys that got the whole ball rolling, by starting their RF + Bexxar clinical trial for CLL patients – I am grateful to them for that. However, it might be hard to get them to consider a lower impact R + Zevalin clinical trial, since it would interfere with the present RF + Bexxar trial already on their books.
    5. Mayo Clinic. I hear rumors that there may be a Rituxan + EGCG clinical trial down the road, building on the encouraging results of our favorite EGCG (Green tea) trial. I wonder if we can tempt them to with a combination of Rituxan + EGCG + Zevalin, the first two to get good bone marrow clearance, and the last to finish off minimum residual disease.
    6. Last but not least, there is this little problem of MONEY. I was hoping we could get the big pharmaceutical company interested in it (GSK), since they are the ones with deep pockets and they are also the ones likely to reap commercial reward if the trial is successful. But that was not to be. Anybody has high level contacts within Genentech? These guys make tremendous amount of money marketing Rituxan, perhaps they can be tempted to support this trial? The simple truth of the matter is that clinical trials like this take lots of money (think a million or so), and there is no way we can raise that sort of cash by our lonesome selves. As we have done before with other clinical trials, we can provide a small percentage of the total funds, our good faith support as it were, but nowhere near the full amount.
    7. I just heard Cell Therapeutics, a Seattle based company has purchased the US rights to Zevalin from Biogen Idec., the same folks that invented Rituxan. Small world.

    Help Me to Help Us

    If you have any bright ideas, I am willing to listen. I am afraid the window of opportunity is not going to stay open for long for either Bexxar or Zevalin. With the reimbursement issue we pointed out a couple of days ago, it is not out of the question that this important and possibly very beneficial technology will fade away into the sunset, before anyone takes a serious look at using these drugs for CLL patients. I am sorry we were not able to tempt GSK sufficiently to play ball with us. We have one more shot, see if we can spring lose some combination of Rituxan + Zevalin instead. As I said above, I can use your help on this one.

    In the meanwhile, below are a bunch of abstracts that should fill in the blanks, back up my comments above with good science.


    Cancer. 2024 May 1;109(9):1804-10.

    Long-term responses in patients with recurring or refractory B-cell non-Hodgkin lymphoma treated with yttrium 90 ibritumomab tiuxetan.

    Witzig TE, Molina A, Gordon LI, Emmanouilides C, Schilder RJ, Flinn IW, Darif M, Macklis R, Vo K, Wiseman GA.

    Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, Minnesota.

    BACKGROUND: Radioimmunotherapy with radiolabeled monoclonal antibodies to CD20 produces a high response rate in patients with recurring non-Hodgkin lymphoma (NHL), but the durability of those remissions is not well defined.
    METHODS: Data on patients with recurring NHL treated with yttrium Y 90 ibritumomab tiuxetan in 4 clinical trials were reviewed to identify patients with a long-term response, defined as a time to progression of 12 months or longer.
    RESULTS: Long-term responses were seen in 37% (78/211) of patients. At a median follow-up of 53.5 months (range, 12.7-88.9) the median duration of response was 28.1 months and the median time to progression was 29.3 months. A third of these patients had been treated with at least 3 previous therapies, and 37% of them had not responded to their last therapy. The findings in patients with follicular lymphoma (n=59) were similar to those in the overall population of long-term responders. The estimated overall survival at 5 years was 53% for all patients treated with 90Y ibritumomab tiuxetan and 81% for long-term responders.
    CONCLUSIONS: A single dose of 90Y ibritumomab tiuxetan can produce durable responses and prolonged overall survival in a substantial number of patients in whom previous therapies have failed. Copyright (c) 2024 American Cancer Society

    PMID: 17380530

    Cancer. 2024 Aug 15;107(4):686-95.

    Recommendations for the use of yttrium-90 ibritumomab tiuxetan in malignant lymphoma.

    Weigert O, Illidge T, Hiddemann W, Dreyling M.

    Department of Internal Medicine III, University of Munich, Munich, Germany.

    Radioimmunotherapy (RIT) with Yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin) combines the tumor targeting attributes of a monoclonal antibody against the CD20 antigen and the pure beta-radiation of 90Y. High efficacy and a favorable safety profile have been demonstrated in Phase II and III clinical trials enrolling patients with CD20+ B-cell non-Hodgkin lymphoma (B-NHL). On the basis of these results, 90Y-ibritumomab tiuxetan was approved in the United States for the treatment of patients with follicular lymphoma (FL) or transformed B-NHL. In the European Union its use was restricted to FL, refractory to or relapsed after rituximab. There are a number of important clinical trials currently evaluating 90Y-ibritumomab tiuxetan in other subtypes of lymphoma such as diffuse large-cell and mantle-cell lymphoma, as consolidation therapy or as part of myeloablative regimens. In light of the constantly increasing clinical experience with RIT, clinicians face the challenge of how to best integrate this promising new treatment option into existing established treatment algorithms. By incorporating the most recent data in this rapidly developing field, this review article focuses on current recommendations for the use of 90Y-ibritumomab tiuxetan in patients with malignant lymphoma, outlines future perspectives, and provides practical recommendations for patient management.

    PMID: 16826593

    3: Semin Radiat Oncol. 2024 Jul;17(3):176-83.

    Radioimmunotherapy as a therapeutic option for Non-Hodgkin's lymphoma.

    Macklis RM.

    Cleveland Clinic Lerner College of Medicine and Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, OH

    Radioimmunotherapy (RIT) represents a relatively new antibody-based radiopharmaceutical treatment for patients with various kinds of tumors. Although the field has a long history of preclinical and clinical investigations using many different agents, to date, only 2 of these immunologically targeted radiopharmaceuticals have been cleared for commercial sale. Both of these agents ((90)Y-ibritumomab tiuxetan or "Zevalin" [Biogen-Idec, Boston, MA] and (131)I-tositumomab or "Bexxar" [GlaxoSmithKline Research, Triangle Park, NC]) are directed against the CD20 surface antigen found on normal mature B cells and greater than 95% of B-cell non-Hodgkin lymphoma (NHL). Both compounds produce similar impressive clinical outcomes (approximately 20%-40% complete response rates and 60%-80% overall response rates for patients with indolent B-cell NHL). Current protocol-based investigations of anti-CD20 RIT relate to new clinical uses and new CD20(+) targets.

    PMID: 17591564

    Oncogene. 2024 May 28;26(25):3614-28.

    Radioimmunotherapy for B-cell lymphoma: Y90 ibritumomab tiuxetan and I(131) tositumomab.

    Davies AJ.

    Department of Medical Oncology, St Bartholomew's Hospital, London, UK.

    Radioimmunotherapy, targeting the CD20 antigen, in B-cell lymphoma has clearly demonstrated efficacy and tolerability over the preceding 15 years. As a result, two products are available with Food and Drug Administration approval for marketing - Y(90) ibritumomab tiuxetan and I(131) tositumomab, given as the Zevalin and Bexxar therapeutic regimens, respectively. Both demonstrate high-response rates and durability of remission in the relapsed/refractory disease setting. Data are emerging regarding their utility as initial therapy, and furthermore, they are been investigated for use sequentially with chemotherapy, and in the myeloablative setting. As yet however, how to best use these agents in the clinical disease course remains uncertain.

    PMID: 17530015

    Best Pract Res Clin Haematol. 2024;19(4):655-68.

    Radioimmunotherapy for B-cell non-Hodgkin lymphoma.

    Witzig TE.

    Division of Hematology, Department of Internal Medicine, Mayo Clinic and Mayo Foundation, Stabile 6, 200 SW First Street, Rochester, MN

    Radioimmunotherapy (RIT) combines the targeting advantage of a monoclonal antibody with the radiosensitivity of non-Hodgkin lymphoma (NHL) cells. There are now two radioimmunoconjugates (RICs) - ibritumomab tiuxetan (Zevalin) and tositumomab (Bexxar) - that are approved by the FDA in the US for relapsed low-grade or follicular B-cell NHL. Both agents target the CD20 antigen on B-cell lymphoma cells. In relapsed disease, single doses of RIT produce an 80% overall response rate, with approximately 20% of patients achieving durable responses. RIT is very well tolerated and is delivered on an outpatient basis over 1 week. The only significant toxicity is reversible myelosuppression. Both RIT agents have demonstrated high anti-tumor activity in patients who are refractory to rituximab. Current trials are testing RIT as initial therapy with rituximab maintenance, as adjuvant therapy after chemotherapy, or in high-dose protocols with stem-cell support.

    PMID: 16997175

    Int J Radiat Oncol Biol Phys. 2024;66(2 Suppl):S46-56.

    Cure of incurable lymphoma.

    DeNardo GL, Sysko VV, DeNardo SJ.

    Radiodiagnosis and Therapy, Division of Hematology/Oncology, University of California Davis Medical Center, Sacramento, CA.

    The most potent method for augmenting the cytocidal power of monoclonal antibody (MAb) treatment is to conjugate radionuclides to the MAb to deliver systemic radiotherapy (radioimmunotherapy; RIT). The antigen, MAb, and its epitope can make a difference in the performance of the drug. Additionally, the radionuclide, radiochemistry, chelator for radiometals and the linker between the MAb and chelator can have a major influence on the performance of drugs (radiopharmaceuticals) for RIT. Smaller radionuclide carriers, such as antibody fragments and mimics, and those used for pretargeting strategies, have been described and evaluated. All of these changes in the drugs and strategies for RIT have documented potential for improved performance and patient outcomes. RIT is a promising new therapy that should be incorporated into the management of patients with B-cell non-Hodgkin's lymphoma (NHL) soon after these patients have proven incurable. Predictable improvements using better drugs, strategies, and combinations with other drugs seem certain to make RIT integral to the management of patients with NHL, and likely lead to cure of currently incurable NHL.

    PMID: 16979440




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