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ASH 2024 Highlights

Date: December 12, 2024

by Chaya Venkat

Latest in Hematology

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Editor's Note: As an on-line publication, CLL Topics was able to send three reporters to the 46th ASH Annual Meeting and Exposition. Here is a summary and some highlights of the event, reported from the CLL patient's point of view. Further articles and analyses are in the works.

I bet most of you have seen this Far Side cartoon: the dog (named Ginger) appears to be listening intently as his owner gives him a serious lecture about staying out of the garbage. But from Ginger’s point of view, all he’s saying is “blah blah GINGER blah blah blah blah blah blah blah GINGER blah blah blah blah blah...” Parts of the ASH meetings were like that. We the non-medical folks heard "blah blah blah IgVH blah blah CLL blah blah prognosis blah blah survival blah...” Kidding aside, I was impressed by the number of papers and posters that dealt with CLL at this year's ASH - I am told this was an unusually high percentage. We also attended several symposia that were more general, dealing with the broader issue of all hematological cancers. I fully expected to be blown away by the science and was pleasantly surprised that the blah blah factor was not quite as much as I thought it would be. This article gives the major highlights; some of these highlights will be fleshed out in full length articles in the weeks to come.

PC, Bill and I worked our fingers to the bone, our days often started with breakfast meetings at 6:00 AM and ended late, after dinner with new contacts. The social highpoint of the trip was meeting two CLL friends face-to-face for the first time. Malcolm Airst looks every inch the athletic stud I thought he would be, Lise is as pretty as she is sweet. Special hello to Victoria, who goes to show Malcolm has good taste and good luck as well. It rained in sunny San Diego on most of the days we were there, but we hardly noticed that since we were in buildings all of the time, nose to the old grindstone. I think all three of us got our money's worth of education.

Prognostics is the best game in town.

No question about it, just about every paper dealt with the pivotal question of modern molecular markers and how they define prognosis and response to therapy. The risk stratification we used in our article (What Type of CLL Do You Have?) in defining the three risk buckets is fully vindicated. IgVH gene mutation status is king, followed by cytogenetics. 13q deletions are the lucky Bucket A folks; normal karyotype, 12 Trisomy and the less common 6q deletions are in Bucket B, intermediate risk; 11q (ATM) or 17p (p53) deletions / mutations are in the high risk Bucket C.

While every one seems to agree that ZAP-70 is a good surrogate in that it parallels IgVH mutation status (low ZAP-70, below 20%, goes with mutated IgVH and therefore carries good prognosis), it appears we are far from having well defined and universally accepted measurement technique for ZAP-70. The commercial labs out there will sell you anything you want, but the results may not be worth the money. Even some of the major cancer centers are having problems validating each other's results. Part of the problem is defining standards and methodology, part of it is due to purely technical issues. Do you know that a ZAP-70 positive sample can gradually become ZAP-70 negative, during the time it is shipped from the point of blood collection to the lab where the actual analysis is performed? The preferred way of doing this test is to get your blood drawn on site at the research center where the analysis will be done - and right away with no long delays as FedEx does its 'overnight' shipping.

The good news is that I hear Dr. Maher Albitar, the pathologist who gave such huge credibility to the CLL testing at M. D. Anderson, is now at Quest Diagnostics, and he signs off on their IgVH gene mutation work. In case you are interested in getting this test done, here is the contact information for Quest. Do write and let us know how they work, cost, responsiveness, insurance coverage and the like.

Quest Diagnostics
Nichols Institute
33608 Ortega Highway
San Juan Capistrano, CA 92690
Phone: 800-631-1390

If you are able to get credible information on the IgVH gene mutational status, the problems with getting ZAP-70 becomes less important. Quest seems to provide not just a yes / no answer to the question of IgVH gene mutation status, but also gives the level of the mutations status. One of the papers presented by Dr. Terry Hamblin made it clear that people with, say, a 7% deviation from the unmutated state are better off than those with merely 2% deviation, who are nevertheless better off than those with less than 2% mutation. Remember, the sensitivity of this test depends on the number of CLL cells in your blood. If you are in deep remission and your CBC looks just fine, that is not the time to get a blood test done to see your IgVH status. Wait until you have enough CLL cells in the blood, as shown by elevated lymphocyte counts.

Paper after paper made it clear: FISH results are very important. People with poor cytogenetics (which basically mean those with ATM (11q) or p53 (17p) deletions or mutations) have shorter time to therapy after initial diagnosis, poorer response to conventional therapy, shorter remissions and shorter overall survival. We have already discussed the sad fact that these poor risk folks get shorter remissions with single agent fludarabine (Fludarabine Monotherapy No Longer the Gold Standard), or RF combo therapy (Shopping for Therapies). At this ASH meeting Dr. John Byrd of Ohio made no bones about his findings that Rituxan as single agent does not work in p53 (17p) deleted or mutated folks. He cited his published results with a small number of patients as well as yet-to-be-published results with several more 17p-deleted patients he has treated. None of them responded to Rituxan monotherapy. (Those of you with 17p deletions, before you jump off the cliff, I have more to say on this subject, on a positive note, so read on.)

Since R and F as single agents do not work with 17p mutated folks, and the RF combo does not work well either, how reasonable is it to assume FRC or RPC are likely to work? My bet is that none of these regimens will work very well, or give sustained remissions, in this bunch of poor cytogenetics patients. Campath is the solitary exception that has been shown to be active in 17p deleted/mutated patients, thus far. This is the single biggest reason for knowing your FISH status before you start therapy. No therapy is entirely a pleasant walk in the park, not even Rituxan monotherapy. Why on earth would you subject your body (and perhaps your wallet) to this insult, if there is not much chance of getting a decent remission out of it? Moral of the story, get your FISH test done at a minimum - and preferably both FISH and IgVH tests - before you make therapy decisions. And yes, it may be important to repeat the FISH test once every while since there is this nasty thing called clonal evolution. You may think you are 'living large and laughing easy' in the plush Bucket A, only to find you have been kicked downstairs to a less comfortable Bucket B or C. The only way you can make smart choices is by having the right information at the point where you are making therapy decisions.

Epigenetic Therapies: a Bright Ray of Hope

All the CLL papers really hammered home the fact that patients with poor prognostic indicators do indeed have poor prognosis. Sounds rather redundant when phrased that way but it was amazing to me how far we have come from the (recent) days of the one-size-fits-all approach. Just a few years ago all patients waited until they needed therapy, as indicated by the appearance of B symptoms, then they all got the same therapy. Now we can be a bit smarter about it: we risk stratify patients according to their FISH and IgVH status, then decide what are the best options available. The problem is, there are not that many good options available for the Bucket C folks.

There was a full symposium dedicated solely to the development of epigenetic approaches to hematological cancers. If you have not read it thus far, I really think you should read our article on the subject. It gives you a nice cartoon explanation of how this new approach works, pretty pictures and all. (Epigenetics). Otherwise, the rest of this section may not make much sense to you.

I will describe what the various papers had to say in more detail later on. Here is one slide, from one presentation, that caught my eye. Lady had CML. She initially responded well to Gleevec (imatinib mesylate), the miracle drug that has been talked up on so many news shows. Two years later, she relapsed, as most CML patients on Gleevec seem to do. Even when her daily Gleevec dose was increased substantially there was no improvement: her counts continued to increase alarmingly. This has been seen over and over in CML patients, the words "Gleevec refractory" have the same doom and gloom impact in that disease as the words "fludarabine refractory" have in CLL.

Why do people become refractory to drugs? Is this resistance always permanent? Fortunately in this lady's case, the resistance was not permanent. A low dose of decitabine, the demethylating agent we discussed in our epigenetics review (Epigenetics), was co-administered along with the Gleevec. Not only did she respond again to the Gleevec, this time around her response was a lot better than the first time. She had a deeper, "pcr negative" or molecular remission, and she is still disease free several years later. It appears her Gleevec sensitive marker was still there, just buried under methyl gunk and therefore not able to respond. Clear away the debris, remove the methyl groups by using low-dose decitabine, and the gene was once more able to interact with Gleevec, do what had to be done. What a happy ending.

This raises the inevitable question in my mind, can some of our CLL patients become re-sensitized to important drugs such as fludarabine, by the simple process of making epigenetically silenced genes wake up and do their job? We know now that fludarabine does not work for p53 deleted cases, in fact fludarabine monotherapy may select for a new p53 deleted clone to become the dominant player (Fludarabine Monotherapy No Longer the Gold Standard). You may recall, each of our chromosomes is a pair, there are two alleles. In other words, chromosome 17 has two p53 genes, not just one. If FISH analysis says one of the p53 genes has been mutated, or deleted, what about the other p53 gene? Most patients I have come across have only these single allele losses, the second gene in the pair should be there doing double duty for its missing twin. Could it be that when one gene goes AWOL, sometimes its twin also stops working because it is covered over with methyl gunk and therefore silenced? The epigenetics symposium gave me some hope that the new approaches to waking up silenced genes may be effective, by waking up the remaining good ATM or p53 genes. This may not work in all cases, such as for instance in patients where both of the genes are compromised, i. e., both alleles have defective or deleted genes. But if it works for some of us at least, that is still good news! HDAC inhibitors and demethylating agents may have an important role to play in reversing or improving response to other chemotherapy drugs.

Stem Cell Transplants

This is such an important subject, I will be writing a couple of full length articles on it in the next week or so. We gathered a great deal of information from some of the commercial stem cell and cord blood banks. I will be publishing these links as well. Some of the banks have on-line sites where you can do a preliminary free check to see the likelihood of finding a match, if you know your HLA details. For now, I will summarize the highlights of the various stem cell transplant sessions I attended, as well a little quick background of the technology so you can follow the logic.

• Most of the experts agree that if you are a relatively young CLL patient, and you are unlucky enough to have one of the poor cytogenetic types (ATM (11q) or p53 (17p) deletions / mutations) and perhaps unmutated IgVH to boot, your best chance of living out your natural life span is a stem cell transplant, the sooner the better. People with smoldering CLL may live for decades without needing therapy, and when they do progress to the point where therapy becomes necessary, chances are good they will respond well, get long remissions out of it. Not so the folks with poor prognostics. The stark truth of the matter is that, with rare exceptions, each round of therapy will yield progressively shorter remissions for the poor prognosis group, none will last long or provide a high quality of life. One CLL expert said this to me: " When we get a young guy with bad prognostics, we try to get him into as deep a remission as we can then send him to the transplanters right away. No point in wasting the first deep remission - we may not get another chance".
• Not all stem cell transplants are created equal. In autologous stem cell transplants, the patient's own stem cells are harvested, cleaned and stored. The patient is then treated with really heavy duty chemo (often with the addition of whole body radiation), and when they have completely nuked every CLL cell in the patient's body (unfortunately along with a lot of other cells as well), the previously saved stem cells are given back. Since these are the patient's own cells, there is no question of graft versus host disease. Engraftment is usually pretty good. There are, however, major problems with overall toxicity due to the heavy pretreatment, and autologous transplants are not curative. The lucky ones get a long remission, the unlucky ones get a shorter one. But eventually everyone relapses and has to get into the therapy game once more.
• One of the eye-opening papers at this year's ASH spelled out the chances of poor prognostic patients after autologous stem cell transplants. Yes, you guessed it right, these folks have predictably shorter remission periods, higher overall mortality after an autologous stem cell transplant. More on this important paper later.
• Allogeneic stem cell transplants need a healthy donor for the stem cells. Almost no one at this year's ASH was talking about full myeloablative allogeneic stem cell transplants. Myeloablative means they try to get rid of the entire CLL cell population before giving you the donor stem cells. This is done by using heavy duty chemo and/or whole body radiation. All of the focus is now on the so called mini-allo transplants. The trick is to use a "reasonable" (?!!) amount of drugs to reduce the tumor load to a solid "CR". ('CR' stands for 'complete response'. I have rarely seen a more ironic term since CRs in CLL invariably relapse). The patient still has CLL cells in his body when the healthy donor stem cells go in. There is a period of fine tuned balance between controlling the graft versus host disease (GvHD), where the newly introduced immune system cells start attacking various parts of the host body, and the next phase when the very important and much needed graft versus leukemia (GvL) sets in. GvHD is controlled by immune suppressive drugs such as cyclosporine to keep the grafted immune system under a tight leash. As the GvHD wears off, the level of cyclosporine is reduced, and the hope is that the powers of the healthy immune system can go to work, GvL will be robust, and it will hunt down and kill every single CLL cell in the body.
• If all of this sounds terrifically complicated and tough, it is. The good news is that a certain percent of CLL patients who undergo mini-allo transplants are actually cured. CURED, as in the English sense of the word. Right now, mini-allo transplants are the only therapy that have proven to have this potential for a real cure in CLL.
• There is a definite treatment related mortality in any kind of a transplant. Some patients do very well, sail right through with minimal problems. Not so others. I will spell out the statistics in the full length articles. What are some of the distinguishing features of the good responders?

• Age. Younger patients tend to do better, because they are in better shape to start with. Older patients can compensate for this by getting into fighting trim before they get into this game!
• Another important advantage of relative youth is that the thymus is likely to be more robust. The thymus is an important organ of the immune system. It is the school where immature T-cells learn the facts of life. The thymus shrinks and its function decreases as we age, irreversibly so. Older patients have less thymus function and there appears to be little that can be done about it.
• Patients with perfectly matched grafts from siblings do a lot better than those with unrelated donors, or those with less than a perfect match between them and the donor.
• Patients who have had a lot of therapy before getting into the transplant have poorer chances. There is an inevitable and cumulative toll of therapy, and your body can only take so much before the insults start adding up to an intolerable burden. If you have poor prognostics (one more reason to know what bucket you are in!), it may not be smart to wait it out too long, or try too many variations of the chemo-immunotherapy combination alphabet soups out there before taking the plunge. The real price of that pcr negative response which relapsed all too soon after your FRC therapy may be that you become a poorer risk for a mini-allo transplant later on.
• There is a real art to the delicate balance between controlling nasty GvHD, and encouraging the curative powers of GvL. Doctors who have done more than a couple of CLL mini-allo transplants are likely to do it better than the guy who has just begun doing it. You do not take in your hundred thousand dollar sports car to be serviced by any car mechanic in greasy overalls, do you? The same thing works in transplants as well. Shop for a team that has the best track record, never mind the warm and fuzzy stuff. Don't be intimidated, ask the questions and interview the doctors until you are satisfied with your choice. Transplants are generally done by a team of specialists, not just one doctor with terrific bedside manners. My advice is to look for a team that works well together, not a single prima donna.

• Mini-allo transplants have one big problem. Not everyone is blessed with a perfectly matched sibling and for ethnic minorities it is very difficult to get a matched unrelated donor. "MUD" transplants are tough, the toughest part being locating a perfectly  matching donor. Less than 30% of people who need a MUD transplant succeed in finding a good match. Some try their luck with less than a perfect match and end up with less than perfect results - higher chances of relapse, death.
• I attended a whole series of presentations on the subject of cord blood transplants. This is a rapidly expanding field with a very steep learning curve. In past decades, the blood in the umbilical cord and placenta of newborn babies was used to treat other children with cancer (or other diseases that needed a stem cell transplant). Just in the past few years, the field has expanded to include adults treated with cord blood. The disadvantage is that while cord blood is chock full of very healthy baby stem cells, it comes in small quantities and that means a small dose for a large adult. Japanese adults with cord blood transplants do better, since most of them weigh around 60 kilograms! All those super sized hamburgers and Krispy Kremes means the average U.S. patient is likely to be a lot bigger and therefore will receive a smaller dose of stem cells per kilogram of body weight. I will discuss this topic in greater detail in later articles For now here are some new developments in the arena of adult cord blood transplants:

• Several teams are looking at using double cords (cords from two babies) per patient, in order to boost the number of stem cells per kilogram of body weight of the recipient.
• There are indications that it might be possible to grow in the lab armies of stem cells from a single cord blood, so that the expanded numbers are then sufficient for the body weight of the adult recipient. This technology is still in its infancy, might take more than a couple of years before all the kinks are worked out.
• One paper suggested that hyaluranon (this molecule is everywhere in our bodies, part of the infrastructure and cartilage) may help the newly infused cord blood stem cells find their way home to the bone marrow and stay there (homing and adhesion). A nice cookie crumb trail to get the kiddy stem cells get home quickly to the bone marrow, where they belong!
• The advantage of cord blood is that it is relatively easy to match all comers. Baby stem cells are not set in their ways and a little mismatch between the donor and the patient is not a big deal. Therefore people who had no luck in finding an adult MUD may have much better chances of finding a sufficiently good match in cord blood. Some of the cord blood banks have realized this is a lucrative market - one of them even had a sales pitch for me in the exposition hall. Buy one cord blood, and they will give a 20% discount on the second. Another bank couple of booths down had a better deal, buy one cord and get a second one  free. Dracula would have loved these sales pitches.
• Since cord blood from babies has few fully mature T-cells, there is much less acute GvHD in these transplants. That is the good news. The bad news is that until the new graduating class of T-cells report in for duty, the patient is vulnerable to infections. Full engraftment takes longer with cord blood and the patient is vulnerable during this period. Good thymus function is particularly important, since the immature T-cells need schooling. But once this is accomplished, the new graduates from the school of thymic education provide a wide and full repertoire of protection. Since these kiddie T-cells have been educated in your own educational facilities, so to speak, they are fully indoctrinated in your body's way of doing things. That is why there is so much less GvHD, these stem cells do not see your body as foreign - to these baby cells you are the only home they have ever known. Neat stuff!

• Here is the bottom-line: cord blood transplants for adults are generating a tremendous amount of enthusiasm and energy. Some very bright researchers are working in this area and it has great promise. But, as one leading researcher put it, the learning curve is very steep right now, and it really matters who does the transplant. The survival statistics, too, are a little scary right now, especially for heavily pre-treated folks. But these odds should keep getting better over the next few years. I think it is reasonable to hope so. If you can keep yourself healthy in the meanwhile, stay away from indulging in too much chemo that damages your thymus, get into fighting trim by doing your bit to exercise, eat right and lead a virtuous life, cord blood mini-allo transplants may become a very real choice with much better stats than right now. This is especially valuable if you do not have a friendly well matched sibling and you are not of cookie-cutter Caucasian ethnicity.

Genasense

Dr. Kanti Rai presented the results of a phase -3 randomized clinical trial for fludarabine refractory CLL patients. One arm got the combination of fludarabine + cyclophosphamide, the other arm got the two chemo agents plus Genasense. For those of you who may not have heard about Genta Corporation's Genasense drug, this is called an "anti-sense" molecule that blocks production of bcl-2. Bcl-2 controls the ability of cells to commit suicide. CLL patients typically have high levels of bcl-2 expressed by their CLL cells, indicating the resistance of these cancer cells to a nice dignified suicide. This was a large international patient cohort, with many institutions participating in the trial. 120 patients got the Genasense + chemo, while 121 patients got just the chemo. Remember, these were late stage patients who have already been through the wars.

There are any number of ways in which to slice and dice the information. You can read the more rosy version on the Genta site, in their press release after the ASH conference. For my money, there was no difference in the number of patients who responded in the two arms, looking at the people who got CR, nPR or PR. (Genasense arm: 11 CR, 8 nPR, 30 PR, total 49. Chemo only arm: 3 CR, 5 nPR, 46 PR, total 54). There was also no difference in the time to disease progression between the two arms. The statistics on serious grade 3 / 4 hematological toxicity was also the same between the two arms, the Genasense arm had a tad more thrombocytopenia, and the control arm had slightly higher neutropenia, nothing much to write home about. Neither group has reached median survival limits as of yet, but the best I could figure from looking at the survival curves thus far is that there is not likely to be a huge difference on this front either. Bottom line, unless you get a sense of happiness in getting a good label put on your response, there just was not a whole lot to be excited about in these trial results. No difference in relapse rates for the two groups, no difference in serious adverse effects.

Genasense was a really neat idea, and I had high hopes for this technology. It seemed right for CLL, since it targeted bcl-2, the villain that made CLL cells so hard to kill. I am sure there will be a lot of spin in the months to come as the data is presented just so, but to my admittedly layperson perspective there is less here than I hoped. But this much has to be said: a lot of credit goes to the many researchers and institutions that were involved in carrying out this double arm randomized trial with robust number of patients recruited for each arm. Clinical trials such as this are absolutely necessary to fully explore the potential value of new drug candidates, and they are a real hassle to conduct. Negative (or lukewarm) results do not take away from the good faith hard work that goes into the conduct of such trials, nor does it minimize the honor due to the 241 patients who volunteered for this trial. Take a bow, ladies and gentlemen. We owe you.

"Gene Therapy" Revisited

The phase 1 and phase 2 "Gene Therapy" trials at UCSD generated a flurry of interest, with the novel approach of making CLL cells better targets for killing by the body's own defense mechanisms. The science was based on the fact that CLL cells are well camouflaged, attracting little attention from the body's own killer T-cells. One of the ways in which CLL cells can be made to be more visible and therefore become better targets is to activate the CD40 marker that they carry. The attractiveness of the approach to patients is its potential for non-toxicity. We have reviewed these clinical trials at UCSD extensively on our website, and here is the link in case you have not read these articles: Gene Therapy.

In the UCSD trials, blood from the patients was collected, certain cell lines separated, and these cells were grown into large armies, transfected with a de-fanged adenovirus vector carrying the ligand ("soul mate") of the CD40. These doctored cells were then infused back into the patient, and it was shown that the interaction between the infusion introduced CD40-ligand and the CD40 on the CLL cells did indeed "light up" the CLL cells, and as expected there was an immune response against the CLL cells. Unfortunately, the response was incomplete and short-lived in most of the patients who participated in these trials.

At the ASH we heard the interim results of another take on a similar approach, this time called a "vaccine" trial, conducted at Baylor College of Medicine, Houston. Here the level of CD40-ligand expressing cells were not given in the massive intravenous infusions as was done in the UCSD trials, instead it was given more like a vaccine, a quick jab in the arm. The other major difference was that interleukin-2 was co-administered, since this was thought to make the "vaccine" more potent. 8 patients have been treated thus far, getting between 5 to 8 of the subcutaneous injections. As in the UCSD trials, there was clear indication of an immune response, validating the concept that CD40 ligation makes the CLL cells better targets. But, once again, the actual bang for the buck in terms of disease response was both limited and short-lived. The presenter of the paper called this the good news and bad news of the clinical trial. The researchers plan to recruit additional patients, test out different dosages of the "vaccine", to see if the response and duration can be improved.

In our reviews of the prior CD40-ligand based work at UCSD, we drew attention to the fact that this approach was being tried in patients some of whom had very high tumor load. This later "vaccine" version at Baylor also used volunteers from all Rai stages, no doubt some of these late stage folks had significant tumor load. This raises the inevitable question of out-numbered armies. In most of the vaccine approaches that have proven to be successful in NHL and other cancers, the protocols call for very significant pre-therapy to reduce the tumor load to minimum levels, thereby asking the vaccine to do no more than cleaning up the last few remaining cells. We think this (mopping up low tumor burden) is a realistic approach, one that should be emulated in CLL as well. The administration of CD40-ligand based "gene therapy" or "vaccine therapy" to patients with huge numbers of CLL cells is possibly setting up for failure, with the numerous CLL cells overwhelming the meager resources of the body to mount an immune attack. CD40-ligation based approaches do not seem to be able to do the heavy lifting of massive tumor load clearance.

A second question is the well documented effect of CD40 ligation in up regulating NF-kB in the CLL cells. This up regulation of NF-kB (nuclear factor kappa B) has the demonstrated effect of increasing proliferation rate of the CLL cells, as well as increasing their resistance to cell kill. The analogy that comes to mind is a hornets' nest. You mess with a fully loaded nest only at your own peril, only when you are fully loaded for bear. You either make sure you have enough ammo to get them, or you leave them well enough alone. Rattling their nest just enough to make them really angry, but not enough to kill them off completely is not such a good idea. You are not likely to achieve victory and chances are they are going to get you! It seems to me that too little is a bad deal here, the vaccine does not have a chance of complete CLL eradication and the majority of the CLL cells surviving the process will be that much harder to kill, that much more likely to go into a proliferative frenzy, because we have succeeded in up-regulating the important NF-kB factor on these cells. We can debate whether the patients are in a worse off situation after getting their CLL cells all riled up in this fashion.

This issue of NF-kB activation as a consequence of CD40 ligation has been kicked around quite a lot, in a number of solid research papers. I found it hard to understand why this important marker was not measured in the UCSD work (they measured a whole host of immune response indicators, but for some reason not the NF-kB, which I understand can be measured rather readily). Sure enough, the folks from Baylor did not measure NF-kB either. I actually stood up after their paper and asked the presenter why this was not measured. His answer was that they realize NF-kB can be up regulated by CD40 ligation, but they did not get around to measuring it. Oops. Research should not be about asking only the convenient questions, in the opinion of this layperson reporter.

If you were considering volunteering for the continuation of this "vaccine" clinical trial at Baylor, at the very least you should ask the researchers to clearly spell out to your satisfaction the results they have obtained thus far. I am all for donating our bodies to science, but we have the right to ask a few tough questions first. The other scuttlebutt is that the original gene therapy approach is going to be re-visited at M. D. Anderson, possibly with some modifications, under the able guidance of Dr. Bill Wierda. We hope that if this is the case, it will be for patients with low tumor burden (people who have only MRD) and have relatively intact immune systems, so that the vaccine or gene therapy has a fighting chance for success. And we hope NF-kB levels will be measured before and after! It would be nice to get this controversy resolved.

Bits and Pieces

Dr. Neil Kay of Mayo presented results of their ongoing phase 2 clinical trial with the  RPC (Rituxan, pentostatin, cyclophosphamide) chemo immunotherapy combination. The idea is that replacing fludarabine in the FRC combo with pentostatin may reduce the level of hematological toxicity. Both fludarabine and pentostatin are purine analogs, fludarabine has been more heavily used but pentostatin has a reputation for being less myelosuppressive. The interim results presented showed impressive response rates. It is too early to say how this plays out in terms of remission duration, or overall survival. There are some indications that indeed the immune suppression is a little lower. You may want to read the first person account of Katie (not her real name) who has recently completed RPC therapy (Katie's Story). This clinical trial is still recruiting patients (chemo naive folks are welcome too), and available at multiple centers. My concern with this trial would be the same as the concern I have with all of the chemo-immunotherapy combinations out there, such as RF, FRC. What is the true price tag of the CRs obtained by these combinations? How long do the remissions last, what are the options when it becomes necessary to initiate therapy again? If RF has significantly shorter remission times for the poor prognostic patients, those with 11q or 17p defects, how reasonable is it to expect the same trend will not show up in other chemo-immunotherapy combinations using Rituxan? Campath is a different ball game. This very valuable monoclonal antibody is the only one, thus far, that has shown ability to deal with 17p deleted CLL patients. I for one would like to see Berlex's "FluCam"  clinical trial start up again, hopefully with a more patient-friendly protocol.

Did you know Terry Hamblin looks a lot like a kindly version of "Inspector Morse" of the PBS series? And a puckish sense of humor to match. He presented a paper showing women do a lot better than men with CLL, on just about all counts. Someone asked the question if this was because the women took hormone replacement therapy, since estrogen is supposed to protect against CLL. Terry responded, "well... these ladies did not look like they were taking hormone replacement therapy..." That got a response from a bunch of women sitting just behind me, old enough to know all about reduced hormone levels after menopause and skin that no longer looks dewy fresh as a consequence. PC and I spent a very pleasant evening over dinner with Terry. Nice to see CLL expertise does not necessarily rule out idealism or optimism.

Dr Bill Wierda looks younger than my daughter. He cleans up well and looked very sharp when he dressed up for making his presentation, and blushed very nicely when I told him so. Lucky that with my very grey hair and less than svelte figure, my compliments can be seen as nothing more than a motherly pat on the back. Dr. Wierda spoke of "C-FAR" (combination of cyclophosphamide, fludarabine, Alemtuzumab aka Campath, and Rituxan) as salvage therapy in CLL. I suppose beggars cannot be choosers, and if there is nothing much else out there, salvage therapy is good. But boy is this one tough combination.

I managed to corner Dr. John Byrd, questioned him about the inclusion criteria for their latest clinical trial using low-dose decitabine and valproic acid (Epigenetics). This is a young man who needs to slow down, just a little, he is juggling more balls than any other single person at ASH. It is very clear he is one of our best and brightest minds and we do not want to risk burn-out! Getting back to the clinical trial, the inclusion criteria require patients be fludarabine refractory, or have some reason (such as autoimmune disease, AIHA for example) why fludarabine cannot be used. I asked about patients who just will not accept fludarabine therapy, because they do not want to. I was pleasantly surprised when he said that would qualify the patient for entry into the clinical trial! In other words, you do not have to have had fludarabine and flunked out, all you need to enter this clinical trial is that you have a 'religious' or other objections against partaking fludarabine. Useful bit of information, right?

Dr. Tait Shanafelt of Mayo confirmed they are hoping to start the Adaphostin clinical trial (Target Mitochondrion) early in 2024. If Bill Wierda looks younger than my daughter, Tait Shanafelt looks like her kid cousin, and sharp as a tack. I am impressed by this new crop of CLL experts that are being groomed for leadership at some of our best cancer centers. These guys are comfortable in the new age of genomics, computer data bases and high tech instrumentation. I also got the distinct impression they are not insecure or put off by patients who are well informed and come prepared with savvy questions. I had understood this clinical trial will also have the same requirement for fludarabine relapsed patients, similar to the inclusion criteria of Dr. Byrd's trial discussed above. When asked, Dr. Shanafelt also confirmed that patients who refuse fludarabine therapy for whatever reason, will be considered eligible for his Adaphostin trial.

Rumor has it that UCSD has opened a clinical trial where Rituxan is combined with Neupogen in one arm of the study, and Leukine in the other arm of the study. I am very happy to hear this, we have been pushing this combination of Rituxan with Neupogen or Leukine (G-CSF or GM-CSF) for more than a year! Harvey rocks! Rejoice, all ye Round-headed Kids! (The Difficult Case of the Round-headed Kid).

I am feeling a little punchy after all the hard work of ASH, so I will end this overview with a really bad joke. A group of lions is called a pride of lions, a bunch of fish are called a school of fish and so on. What do you call a giant gathering of hematologists? Give up? Why, a hemorrhage of hematologists. I knew that would get a few groans!