Low- dose Rituxan – first round results

I have now completed my 12-week protocol of low-dose Rituxan, accompanied by methylprednisolone -- 72 mg a day over nine days. The purpose was to treat both my chronic lymphocytic leukemia and a nasty bout of autoimmune hemolytic anemia (AIHA) that reached its nadir on March 14.

The early returns are in, and the protocol did a pretty good job: It reduced my bulky lymph nodes by about 50% and lowered my absolute lymphocyte count (ALC) to within a few thousand points of normal. It did this while putting the kabosh (my medical term) on the anemia and restoring my red counts to at or near normal.

The jury is still out on how long these effects will last -- and that is a crucial question -- but so far, so good. Tomorrow I will finally be getting an infusion of IVIg, which should further help with the AIHA and which should also give me some much-needed immunity against infection, which was driving my white count up when treatment started March 12, and which also may have triggered the AIHA.

It is at this point that I should remind everyone that my results are what the researchers call anecdotal; that this was not a randomized, controlled study; and that your mileage may vary and probably will.

Background

The idea behind this protocol was inspired by the R + HDMP (Rituxan + high dose methylprednisolone) trials at UC San Diego. As readers know, I have used single-agent Rituxan several times over three years with diminishing results. So I looked into what could be done to boost my response without dipping my toes into traditional chemotherapy; as tempting as some of those chemo protocols are, the problem is that one can and will develop disease resistance to them. They cannot be reused indefinitely and they come with their own set of potentially dangerous toxicities. Ergo, it is best not to use them until you really, truly have to.

R + HDMP was one of the few ideas out there that did not involve either alkalyting agents (chlorambucil, cyclophosphamide) or purine anologues (fludarabine, pentostatin). UCSD has conducted two trials of R + HDMP in chemo-naive patients, one in 2004 and one just completed. I have corresponded with patients who have been in the trials and last year I made a trip to San Diego to see Dr. Januario Castro, one of the principal investigators in the trials.

Overall -- and this is my impression based on everything I have been able to learn -- it appears that participants are getting decent results, including normalized white counts, elimination of most or all lymph nodes, and dramatic reduction of CLL in the bone marrow. It also appears, from the perspective of time and distance, that these remissions are perhaps not as deep as those that can be obtained by such protocols as FR and FCR; rarely do they seem to be minimum residual disease negative, and patients are almost always offered Campath as a follow-up. Campath, a highly immunosuppressive monoclonal antibody, deepens and extends the remission.

When I saw Dr. Castro last May, he predicted I would get about 18 months out of R+HDMP. But there were certain factors that mitigated against my doing it. First, because I had had Rituxan in the past, I did not qualify for the trial at UCSD, nor would my insurance have covered regular treatment there; I believe the protocol is sufficiently tricky (read: potentially dangerous) that it should be done in a controlled setting where the doctors are experienced with it. Dr. Castro essentially agreed with me on that point and is not a fan of doing it off-study, aka “off-label.”

My then-new doctor, Dr. Belle, was also not interested in doing it off-label. She thought the amount of steroid used (1 gram/m2 of methylprednisolone x 3 cycles) was way over the top.

Indeed, I had to ask myself: Even if I could do R+HDMP in San Diego, would it be worth it for a relatively short 18-month remission? Would I want to follow up with Campath, which is an important drug – the only thing besides steroids that works on 17p-deleted CLL – that cannot be reused indefinitely?

In the end, all these factors conspired to cause me to abandon the thought of doing R+HDMP. So I began to think in the opposite way: could less be more, or could it at least be adequate? If I am probably not going to get a sterling, extremely durable CR regardless, what can I do to just control the CLL a little better?

Last year, around the time that I saw Dr. Castro, Dr. Ron Taylor of the University of Virginia was speaking at conferences about his studies of low-dose Rituxan in CLL. I went into this subject in some detail here.

If Rituxan has synergy with methylprednisolone, which it apparently does, based on both the San Diego studies and studies in the UK, then what can they do together at lower doses?

Dr. Belle was sympathetic to my quest to control CLL by low-toxicity means, and thus a little, informal protocol was born: LDR + LDMP (Low-dose Rituxan + low dose -- at least comparatively -- methylprednisolone).

I would be getting 20 mg/m2 of LDR three days a week for 12 weeks, and we would add the steroid in midway, after the blood counts had been reduced. This plan was turned on its head by the arrival of the AIHA, which coincided almost perfectly with the start of the LDR. As Dr. Belle said on March 14, while I sat in the infusion chair for my second dose of LDR, looking rather peaked with a hemoglobin of 8.9, “It looks like you have AIHA. How would you like to start the steroid early?”

And so we did. Starting March 14, and for nine days following, I took 72 mg of methylprednisolone each day (this being based on the standard amount of prednisone used to treat AIHA, recalculated to reflect my body mass and the differences in the pharmacokinetics of the steroids). After the ninth day, we stepped the steroid down over the following month.

My LDR + LDMP experience

The LDR, all 42 mg of it, was infused each time without premeds. Only once, when the bag was run through a bit too quickly, did I get an infusion reaction. Keep in mind that I am an experienced Rituxan user and that I know my limits, as it were. My advice to anyone using Rituxan for the first time, in whatever dose, is to make sure you are adequately premedicated with IV Benadryl, Tagamet, and a steroid such as Solu-Cortef -- all these things are designed to tamp down any infusion reaction before it begins. I did take allopurinol to guard against tumor lysis.

Some patients have had LDR at home via a self-administered subcutaneous shot. My insurance plan and the doctor’s office both had policies precluding this, which would have been convenient as we live two hours from the infusion center. This three-day-a-week schlep became so burdensome that we experimented, halfway through, with cutting back the infusions to two days a week (Monday and Friday). As it turned out, this made no difference in the rate at which the counts reduced, so we stuck with two days a week. Each infusion took about 20 minutes, and then we were off searching out yet another Vietnamese restaurant or buying unnecessarily large packages of things at Costco.

I took the methylprednisolone in 4mg tablets, meaning I was popping 18 of them a day at the height of it all. Overall, the steroid experience was a long, strange trip.

On the plus side, the steroid initially reduced my disease bulk by about 90%. I lost six pounds in the first two days, a lot of it probably lymph node and spleen weight. My neck was at its pre-CLL appearance within 72 hours.

But I continued losing weight; at first I thought it was muscle loss but the steroid appeared to be burning up fat cells instead. I lost 20 pounds over nine days and wrote here about my desperate efforts to eat enough to avoid losing too much weight (talk about living in a bizarro world . . .). As much as I hoped that I would be able to keep most of the weight off when I was done with the steroid, I hadn’t counted on the AIHA making aerobic exercise impossible. Not only did I not feel up to it much of the time, my heart was working overtime (I had less oxygen in my blood and it was under enough strain already. AIHA is not for the faint of heart, so to speak.) Gradually, then, I have regained just about all of the weight.

Steroids are also known for some other physical and psychological effects. My sleep was disturbed to some extent, and I found myself getting up earlier than usual and then having to take naps. Sometimes I had a little more energy than I should have had, but the AIHA tended to counter that. At certain times I had a sense of well-being that I am not generally used to; indeed, I found myself being a little more extroverted than normal. Sometimes, however, I would get worried, and I would obsess over a perceived problem or symptom. I wouldn’t call it paranoia, just a greater state of concern than usual.

One legitimate concern for me when it came to steroids was my history of squamous cell skin cancers. The immunosuppressive nature of steroids can lead to such cancers, as well as to infections running amok. Midway through the steroids I had my dermatologist gave me a complete exam, which I passed. As to infections, I was on several prophylactic meds to guard against them: Bactrim, acyclovir, diflucan, and later augmentin. Dr. Belle also ordered herpes, CMV and EBV titers to see if any of these posed a hidden danger. The last two were negative but the former was “high,” which led to the acyclovir: the last thing I needed in the midst of all this was to come down with shingles.

Steroids can cause a dramatic reduction of nodes in CLL, but the effects are rather transitory. I have been fortunate in that my nodes did not return completely within a month or two. Overall, I am guessing that they are at about 50% of what they were when I started. The painful pelvic nodes have quieted down considerably. My neck is still reasonably svelte. My disease bulk has probably been set back by about a year.

None of my previous Rituxan treatments were very effective on nodes 2.5 - 3 cm or larger. I tried adding Neupogen, EGCG, and Beta Glucan as boosters at various times but the steroid was the first thing that made a difference. I always intuitively felt that it would.

I do not know the extent to which the LDR may have prevented a complete return of the nodes once the steroid was tapered down. I did notice that, after an infusion, the nodes in my neck would recede a bit, feel a bit smaller. But this effect was transient and after a couple of days they would return to their baseline. Now that I am done with the LDR, it will be interesting (in a watching-a-traffic-accident kind of way) to see how fast they grow.

One of the mysteries in my results has to do with the reduction of the ALC. When I started on March 12, it was 162k and rapidly rising, probably due to an infection that may also have triggered the AIHA. After the steroids pushed things out of the nodes and marrow, the count went to a high of 361k on March 20. Then it dropped to 263k on March 26 and 92k on April 2.

Why such a dramatic drop? The LDR could not have been responsible for the entire reduction, especially as I wasn’t even using it one of those weeks (long story, another post). The steroid would not have been responsible for that much of the cell kill. My theory is that the antibiotics and antiviral drugs I was on finally put an end to that infection I mentioned, and that the CLL therefore naturally ramped down. It is also entirely possible that some of the CLL could have sneaked back into the spleen, liver and less noticeable nodes as the steroid was stepped down during that time.

I do know that once my counts were below 100k, the LDR reduced them, consistently, by 10-15k per week until a plateau was reached. The only bump upward came when, after I was off the prophylactic Bactrim, it appeared I had caught a new bug, or the old one had returned (monocytes and granulocytes also increased). I began the augmentin then and the counts resumed their downward course. They hit 8.6 on May 21 and then began to dither around, rising a bit, then falling again to a low of 7.3 on June 5. On June 11 they were at 8.4 and they were at 12.1 by June 15. Essentially, then, I hit my plateau about eight or nine weeks in. A whole 12 weeks of LDR is probably not necessary in my case.

That bottom number, 7.3, was lower than the low reached during my previous Rituxan therapy, last October, when the ALC dropped to 22.6. I was then using Dr. John Byrd’s thrice-a-week protocol of standard-dose Rituxan.

By comparison, here are my other lowest ALCs following Rituxan therapy, dating back to January 2004: First treatment 2.3, second 4.9, third 5.1. Considering how much Rituxan I’ve had since I started – almost 20,000 mg total – I think the 7.3 is a pretty good result. Keep in mind that it was reached by using the amount of Rituxan that would normally be given in less than two standard doses.

Worth a mention here is the effect that all this had on my platelets. They were at 197 when treatment began on March 12. They reached a high of 325 on March 19, likely because the steroids had emptied out the spleen. There was a slow decline to 151 on May 11. Then they dropped like a rock to below normal (baseline of 130) for the first time ever -- to 99 on May 18 and then to 85 on May 21. Dr. Lord made the assumption that I had developed ITP and now had Evans Syndrome, which is the double booby prize of having both AIHA and ITP. But it turns out he was wrong. The platelets began to climb back into the normal range, and were 135 by June 15. An anti-platelet antibody test turned out negative.

So, what knocked the platelets down? Going on nothing other than a hunch, I suspect the Rituxan. Last October, when I did standard-dose Rituxan three days a week, my platelets took a big hit during the first 48 hours, then they slowly recovered. I am guessing that some tipping point in their relation to Rituxan was reached this time.

It should also be noted that my immunoglobulins declined during the treatment, my IGG dropping from 746 on March 20 to 382 on June 15. It is suspected that Rituxan can erode IGG, but none of my previous Rituxans appeared to cause a decline, even though a lot more of the antibody was in my system then. Was it the Rituxan? Was it fate? What I do know is that at the higher number my IGG was pretty much ineffective at keeping away infections, so IVIg was in the cards for me regardless.

Last but by no means least, there’s the AIHA. (I say “by no means least” because once you’ve had it, you never want to have it again.) The rather dramatic hemolysis stopped immediately after I started taking the steroid. But I have been surprised at how long it has taken for my red counts to return to a semblance of normalcy. Apparently this is not uncommon and I am rather lucky: there are people who are on steroids for months and months to get a handle on AIHA. (Given my weight loss problem, I am not sure how I could have managed that.) Here are my red counts at their worst,
on March 14: RBC 2.65, HGB 8.9, HCT 26.9.
On June 11, RBC was 4.07, HGB 12.8, HCT 38.5
(Normal: RBC 4.7 - 6.10; HGB 13.0 - 17.0; HCT 36.0 - 52.0)

The bigger picture

In a discussion of AIHA on the ACOR list, Dr. Terry Hamblin once wrote, “Some cases of CLL present with AIHA, and indeed once the AIHA has been treated with steroids, the CLL is barely detectable.”

Given my bulky disease, it would have been too much for me to hope that the CLL would resolve along with the AIHA. But in some patients, those with fewer nodes and more indolent CLL, LDR+LDMP may enhance the chance of just such a remission.

Chlorambucil (CB) plus prednisone was once a fairly standard treatment for CLL. CB killed the CLL while the steroid reduced the nodes. Studies showed no improved survival by adding the prednisone, but it did help relieve discomfort.

Nowadays, with Rituxan available, some of that same cell kill can be accomplished without adding an alkylating agent. The methylprednisolone, which has established cell kill properties at higher doses, may retain some of them at lower ones, though this is not definitely established by any means, and it may also still exhibit some synergy with Rituxan.

In some patients, this combination may provide CLL control at minimal cost in terms of toxicity (while having the added bonus of combatting AIHA, which is a property of Rituxan as well as the steroid). Besides reducing nodes, it also clears out the marrow better than Rituxan alone.

Ideally, such a soft-glove approach should have been administered to me a year or two ago when my lymphadenopathy was less extensive. I did in fact suggest to my second hem/onc, Dr. Chopin, that prednisone be added to my standard-dose Rituxan in October 2005. She refused to do it, saying simply, “It’s not done.”

Well, folks, there’s a first time for everything. As far as I’m concerned, low-dose Rituxan is a no-brainer for most patients using the drug as a single agent. (I say this not only based upon my personal experience, but also upon Ron Taylor’s pilot studies and anecdotal reports from other patients.) Adding pulsed doses of methylprednisone that are consonant with the steroid dosages normally used in CLL is also logical.

Now, in my case, it remains to be seen how well this will ultimately work. Dr. Belle and I realized that the first 12 weeks would be just the beginning. On the very day she was dismissed from practice, we talked about doing another cycle or two -- pulsed steroid and four weeks of LDR starting one month after completion of the first cycle, and so on. The idea is to reduce the overall bulk with each cycle until it is down to a more acceptable and manageable level.

Would it have worked? Will I ever know? Since Dr. Belle is gone, I am now seeing Dr. O’Leary, who is open to the approach, but who is thinking of using it as maintenance at three month intervals. I’ll be seeing him in one month to see where my counts and nodes are and to discuss whether it can wait that long.

Dr. O’Leary, by the way, told me that he has had good luck with Rituxan and cyclophosphamide, which is the kissing cousin of good old chlorambucil. Most of us know by now that Dr. Hamblin has advocated R + CB as a useful treatment. It is interesting to note that I have stumbled across another doctor who is impressed by the results he gets with something very similar.

Certainly the question of “What next?” has been on my mind if and when LDR + LDMP ceases to hold the fort. Should I dip my toes in the chemo waters and add something that starts with a “C,” perhaps? In a future post I’ll discuss my thinking on where to go from here.

A LDR clinical trial note

There is a study of LDR underway at the NIH in Bethesda, MD. I understand they still have openings. If you’re interested in LDR, consider giving them a call. This link explains the trial and has contact information.