Tuesday, July 24, 2007

The A-I-freaking-H-A

Not long ago, I was a reasonably content little watcher-and-waiter, using single-agent Rituxan to plug the holes in my CLL dike. Water still gathered around my ankles, but I muddled through the puddle with a quality of life that looked a lot like it did before CLL.

Now, after the
arrival of autoimmune hemolytic anemia (AIHA), the unwelcome house guest that does not want to leave, I hear voices. Specifically, I hear the AIHA mimicking the imperious tones of King Louis XV of France. Louis, who toward the end of his reign sensed a collapse of the old order in the not-too-distant future, is reported to have said: “Apres moi, le deluge!”

AIHA is a sign of many things. It is a sign that chronic lymphocytic leukemia has gummed up my immune system en
ough to create a situation where my macrophages are attacking and destroying my red blood cells. It is a sign that my quality of life is diminishing because of my disease. It is a sign that my carefully nurtured avoidance of real chemotherapy is going to end sooner rather than later. And it is a sign that I had better have my long-term treatment strategy thought through and in place.

What is AIHA?

AIHA is a not-completely-understood fact of life for about 5% to 11% of CLLers, depending upon whose statistics you read. It can occur at any stage of the disease, though according to a recent Italian study it appears to be a bigger issue in the middle and later stages, in older patients, and in those who have had more therapy. It takes off when the immune system loses its ability to distinguish “self” from “non-self.” The end result is that the body creates antibodies to its own red blood cells and macrophages go on the attack, which leads to hemolysis -- literally the “breaking open” or destruction of red blood cells.

As Dr. Kanti Rai and his group at Long Island Jewish Medical Center put it in a 2002 study (bracketed co
mments mine):

“CLL is known to be associated with various autoimmune phenomena. AIHA is the commonest manifestation of such disorders in CLL. . . .
The exact role of B lymphocytes in the pathogenesis of AIHA associated with CLL remains unclear. It has been suggested that complex interactions between the 'B' and the 'T' lymphocytes result in breakdown of self-tolerance, which eventually leads to the formation of antibodies against self-antigens such as erythrocytes [red blood cells] and platelets [which is the cause of that other joy of CLL, Immune Thrombocytopenia, or ITP].” The double whammy of having AIHA and ITP together is called Evans Syndrome.

AIHA can arise naturally but it can also be triggered by treatment with single-agent fludarabine or single-agent chlorambucil. When those
drugs are used in combination with others, such as Rituxan and cyclophosphamide, the risk of triggering an attack is pretty much eliminated.

How do you know if you’ve got it?

A big problem patients face is doctors who mistake tanking red counts for marrow impaction when it is really an autoimmune problem. Drs. Wei Ding and Cliv
e Zent of the Mayo Clinic go into this issue in a new article called Diagnosis and Management of Autoimmune Complications of CLL/SLL. This overview is worth reading and sharing with your doctor.

My own experience illustrates the need for patients to be on top of things. If I have learned one thing about CLL, it is to never, ever take what your doctor says for granted. Sometimes they are flat-out wrong.

Back in March, I noticed a suspicious drop in my hemoglobin (HGB) from one CBC to another -- it had been 13.0 on Feb. 28 and by Friday, March 9 was 10.8. (Hemoglobin is the protein molecule in red blood cells that carries oxygen from the lungs to the body's tissues and returns carbon dioxide from the tissues to the lungs. The iron contained in hemoglobin is responsible for the red color of blood.)

When I mentioned this to my hem/onc, Dr. Belle, that Friday, she said it was probably just marrow impaction. This didn’t ring right to me, but it was at the end of our visi
t and she was already out the door. When I arrived back at her office the following Monday, absolutely convinced by symptoms (and research) over the weekend that I had AIHA, the head nurse looked at me like I was an idiot and repeated the same line. Only my insistence that I be tested for AIHA led to its diagnosis and treatment in a timely manner. Had I not made myself a pain in the ass, which is not easy to do when you are feeling anemic, I would have ended up in the emergency room requiring transfusions. On that Monday my HGB was 10.2. Two days later, when the diagnosis was confirmed and I began steroid and low-dose-Rituxan therapy, it was down to 8.9.

What made me suspect AIHA, besides the unusual drop in my hemoglobin, which had never been below normal, was three things: First, I woke up in the middle of the night to what only can be described as a marching in my ears. Th
is was the sound of my heartbeat, working harder to provide oxygen to the blood. Second, I began to notice that my urine was turning an orange-red. This, it turns out, was due to red blood cells being destroyed and passed through the kidneys. Third, I began to have trouble doing things, such as walking up the stairs or squatting down to get carrots out of the vegetable crisper in the refrigerator, without becoming winded. This was subtle -- indeed, in retrospect I had been noticing small changes for a month or more -- but it definitely accelerated as the hemolysis increased.

My guess is that low-level hemolysis had been occurring since sometime in February, as even a HGB of 13, while at the bottom end of normal, is low for me. The hemolysis continued in early March and hit its stride over that weekend of March 10 and 11. By March 12, I was looking noticeably paler, which is no mean feat given my natural Pillsbury doughboy complexion.

Besides watching for symptoms, be aware of those blood tests. Monitor your total red blood count (RBC), your hemoglobin, and your hematocrit (HCT). The hematocrit is the proportion, by volume, of the blood that consists of red blood cells. When you get to what the infusion nurses call “10/30" -- HGB of 10, HCT of 30 -- you are in a potentially dangerous enough situation to require a transfusion.

Marrow impaction generally leads to a slow, tapered decline in RBC, HGB, and H
CT. Anything suspiciously dramatic should raise an autoimmune red flag.

To diagnose AIHA, some of the more common tests done are haptoglobin level, reticulocyte count, and direct Coombs (aka DAT, or drect antiglobulin test). Coombs positivity means that antibodies are found on the surface of red blood cells. Haptoglobin is a protein that forms a complex with hemoglobin, and its decline is indicative of autoimmune anemia when associated with falling hemoglobin and increased reticulocyte count. Reticulocytes are baby red cells -- if the levels are high, this means the bone marrow is pumping them out to compensate for the destruction of red blood cells. If your marrow is impacted by CLL, you won’t be able to churn them out; if the count is higher than normal, your problem is likely to be autoimmune.

What to do about it?

Treatment can be geared to the AIHA specifically or to both the AIHA and the CLL. Again, like so much in CLL treatment decision-making, the question is of risks v. rewards. One can try to manage AIHA through a lighter touch, but this ri
sks a sooner relapse.

Like CLL, AIHA is hard to get rid of completely. It can become a sleeping dragon, but the issue of relapse must be taken seriously, as I have learned the hard way.

The Mayo article points out that 65% of patients who respond to steroids, which are frontline management for AIHA, “will have evidence of recurrence of hemolysis as the prednisone dose is decreased and will requ
ire either maintenance corticosteroids or alternative therapy.”

Perhaps you don’t mind being on steroids for just about forever, but there are serious consequences to their long-term use, among these being a reduction or loss of vision. It also doesn’t make a lot of sense to take an immune-compromised patient, which you are just by having CLL, and put them on a long-term therapy that works by further immunosuppression. (Ding and Zent of Mayo point out that pneumonia is a risk here.) Like a big band aid, steroids only stop the macrophages from doing their job; steroids don’t get to the root of the problem. And what’s worse is that you can become refractory to steroids -- which means they won’t work on the AIHA anymore.

Ding and Zent (sounds like a discount warehouse store) point out that AIHA is not something that is likely to go away easily: “Autoimmune cytopenia can complicate all stages of CLL and can cause severe morbidity and mortality. Accurate and early diagnosis of the autoimmune cytopenia is important for optimal management. Therapy de
pends on the clinical severity of the cytopenia and CLL. Appropriate therapy can be highly effective but is rarely curative. All patients require careful long-term follow-up and early intervention for relapse.

The message here is that AIHA takes your CLL to a whole ‘nother level. Especially for those with severe AIHA, like me, it may be worth pulling out some of those chemo guns that you’ve been saving.

Rituxan and steroids

Rituxan can be effective in treating AIHA and is often added to the steroids to create a combination fron
tline treatment. It can also be used by itself. After my CLL diagnosis in 2003, I tested Coombs positive but had no evidence of hemolysis, which is not uncommon. (According to Ding and Zent, “Autoantibodies specific for RBCs are detectable by the direct antiglobulin test in up to 20% of patients with advanced CLL but cause AIHA in only a minority of these patients.”) After a course of Rituxan for my CLL, I converted to Coombs negative. And then I went happily on my way, assuming that a nice byproduct of my continued Rituxan therapies would be that Coombs positivity, and therefore the possibility of AIHA, would be held at bay.

This may ha
ve worked for awhile, but it didn’t work forever, as I found out in March.

As readers of this blog know, in June I completed 12 weeks of low-dose Rituxan, which included nine days of methylprednisolone for the AIHA. It appeared to work, as the numbers show, even though I remained Coombs positive (more about those italics later):

On March 14, my RBC was 2.65, HGB 8.9, and HCT 26.9. On June 11, the RBC was 4.07, HGB 12.8, and HCT 38.5. And on June 19, I was treated by my health insurer to $18,000 worth of IVIG, which I figured would pretty much put the nail in the AIHA coffin. (IVIG, according to the Mayo authors, “
can induce a rapid but usually short-duration response.”) It did clear up my sinus infection, thank you.

And the result of all that therapy was that I was pre
tty much hemolysis-free -- for another three weeks.

On Tuesday, Jul
y 10, I began to notice the tell-tale signs again. Darker urine was the first one, and then a little marching in the ears. I considered going to the ER but I had a longstanding appointment with my GP on Thursday, and one with my new hem/onc, Dr. O’Leary, on Friday. Blood work was taken Thursday and I began the steroids again pending the outcome; on Friday I learned that my RBC was 2.82, my HGB 9.4, and my HCT 27.7. The hemolysis had been worse than I expected.

As I write this I am on steroids again, 14 days worth of methylprednisolone at 72 mg/m2. The first week showed a marginal improvement in my situation, but Dr.O’Leary felt it was time to add some standard-dose Rituxan to the mix, so I am now scheduled for four weeks of that.

It is interesting to compare my first-week response from March, when I had steroids combined with low-dose Rituxan, and my first-week response in July, when I had steroids alone:

Methylprednisolone + low-dose Rituxan

. . March 14 . . March 21 . . Change (+)

RBC . . 2.65 . . 2.86 -- .21

HGB . . 8.9 . . 10.4 --- 1.5

HCT . . 26.9 . . 31.6 --- 4.7

Methylprednisolone alone

. . July 13 . . July 20 . . Change (+)

RBC . . 2.82 . . 2.91 -- .09

HGB . . 9.4 . . 9.8 --- .4

HCT . . 27.7 . . 30.6 -- 2.9

The Rituxan clearly boosted my response. Ho
w it works against AIHA is not exactly understood. Ding and Zent again: “Although rituximab is highly effective against the normal B cells responsible for synthesis of anti-RBC antibodies, this does not explain the rapid responses to therapy that have been observed.”

Dr. O’Leary is thinking, and he may be right, that four standard doses of the stuff will do more against the AIHA than all the low-dose -- which amounted to just two standard doses over 12 weeks -- did.

Avoiding yet another relapse, or biting the
chemo bullet

And then what? So we get my HGB and HCT back to normal, or
close. How do we prevent a relapse?

The key may be found in a recent abstract by Kanti Rai et al, following up on their earlier study (links to follow). What the researchers found was that patients who converted to Coombs negativity had a much longer remission on average (23 months) than those who did not convert (8.8 months).

“This finding that Coombs conversion portends a longer duration of response suggests treatment goals f
or AIHA should be a conversion to Coombs negative, and not stopped with recovery of HGB,” the authors wrote.

So for me, as for many of you with AIHA, the big question is: Will the treatment I am doing lead to that conversion? Standard-dose Rit
uxan has done it for me in the past, but that was before I developed full-blown AIHA. Putting steroids together with standard-dose Rituxan seems like it is worth a try. If you can accomplish a task through less invasive means, do so. But given the seriousness of AIHA, by all means you have to accomplish the task.

If this treatment fails to give me that Coombs conversion, then it is time to consider what else can be done. And one good answer I have found is right in Kanti Rai’s study: Rituxan plus cyclophosphamide and dexamethasone.

Rai has used R+CD with success in steroid-refractory patients. The initial study showed that all eight patients treated achieved median hemoglobin of 14.2 for a median duration of 13 months. Later data with a larger patient sample, which included some with ITP by the way, indicated a mean duration of 22 months. (Many of these responders had already had fludarabine, it is interesting to note.)

An added plus for me is that cyclophosphamide is supposed to be especially helpful in 11q-deleted cases such as mine, according to Drs. John Byrd and Michael Keating. Besides controlling AIHA, the therapy might also help delay any incipient marrow inpaction, and it should provide excellent clearance of nodes. It is the direction I had been expecting to move toward anyway -- Rituxan plus an alkalyting agent -- and so it fits with my long-term plans.

And I am making those plans, which I will discuss in a future post. After Louis XV, the deluge indeed came and Louis XVI lost his head. I am hoping to
keep mine.


Anonymous said...

Interestingly enough, I had an episode of the 'pounding in the ears'. I went to a same-day clinic appointment, where I was tested for high blood pressure. I did not think of low hemoglobin, and neither did the doctor on call.

However, it went away after a few days, and blood tests never showed a drop in hemoglobin or other indications of AIHA. We never did find out what it was.

Anonymous said...

As always, David, your posts are informative and interesting. Thanks lots for the heads-up on the Mayo Clinic article. I did a quick read this evening---and also followed a reference the authors make to a 1967 article in Blood by Daneshek in which he writes about the autoimmune connections or manifestations that appear with CLL. Of particular note to me is his very specific reference to vasculitis (of which Behcet's in one disorder). Perhaps, even more interesting is the note in the article that so little work has been done in the area of autoimmune disorders in CLL -- but that statement was made 40 years ago and it is true today: there appears to be little published research. Daneshek mentions, among others rheumatoid arthritis, Sjorgren's, Lupus,and vasculitis but that was 40 years ago.

My best wishes to you during this important time of information-gathering and decision-making.

voltaire said...


I had my one and only AIHA episode in Rome three years ago. Hemoglobin dropped to 3 after I dropped on the sidewalk outside the Vatican Museums. Because I was an American (no coverage by socialized medicine)I was brought to a private clinic (Clinico Pio Undice)and cared for by Dr. Massimo Gentile of the Sapienza. He used a Rituxan and Fluradabine combination with massive steroid (decatron) therapy. I also had four transfusions. One month later I was on a plane home and my Hemoglobin has held fairly steady at 14-15 since.

David Arenson said...

I am learning a great deal from the experiences of other patients in comments here and elsewhere. AIHA is becoming another "new normal" to cope with; it seems many patients do get past it with time and steroids, or by stronger treatment. Only time will tell what will be needed in my case. A hemoglobin of 3 is the lowest I've heard of, almost unimaginable to me given what 8.9 did to slow me down.

One thing I am sensitive to, and think it is wise for patients to be, is the warning signs of hemolysis, which I mentioned in the post. Nipping it in the bud is very helpful, especially as it seems to take a lot longer for counts to recover than for them to decline. The bigger the hole you get in, the longer it takes to get out of it.

Mark said...


I revisited your site with a simple question but since my CLL characteristics are similar to yours and I have AIHA, your article reminded me of how much more reading I have to do.

I was recently treated for AIHA with 8 rounds of standard Rituxan at Sloan K and my HGB quickly jumped to 14.2 from a low of 9.7 four months ago. I've gone from a serious energy depletion to being able to exercise again. However, I'm still waiting for a sense of immuno brain to lift. I still haven't been able to return to serious work, which for me is writing (poetry & stories).

Well here's the original question: is there anything over the counter or prescription that will help reduce the swelling in my neck, currently 18" around. I was a pencil neck for a month following the 5 days of pre-treatment Prednisone but now several months later I'm back to being a walrus.

Chaya has discussed Beta Glucans as a possible vehicle for ushering CLL from the nodes into the bloodstream but a closer reading revealed a strong caution about complications using Beta Glucans with AIHA.

Any thoughts?


David Arenson said...


There are two ways to get the lymph nodes to go down. One is to use steroids, which as you have found don't have long-lasting effects. The other is to use chemotherapy, which comes with its own sets of risks and rewards. As I post later in the blog ("The Joy of Coombs Negativity"), my R-C(V)P therapy gave me long-lasting node (and disease) reduction as well as an end to the AIHA.

I can think of no over-the-counter or natural supplements that do much to reduce the nodes. (Avoid ibuprofen for this -- see my later post on "Ibuprofen and AIHA.") If your disease characteristics are indeed similar to mine (11q deletion), then you have a CLL clone that is predisposed to staying in the nodes.

My suggestion is to learn to live with the thick neck if you are doing OK otherwise. If the AIHA rears its head again, you may need to consider stronger steps that will also have the effect of reducing the nodes for a long time.

Good luck in your journey,


mschaeffer33 said...


Have you come across any research into low-dose therapy for CLL? Since CLL is a chronic disease, why not a little FCR over time rather than a whole lot at once?

Also, since I'm walrus-necked from CLL, why not a little prednisone every day rather than a whole lot during treatment with Rituxan? Five days of Prednisone pills prior to treatment with Rituxan took my neck from 18 1/2 inches to a svelte 17.


David Arenson said...


Many AIHA patients are kept on low doses of prednisone for long periods to keep the beast in its cage. But this may or may not control the nodes, depending on how aggressive the CLL is, and steroids have bad side effects over the long term, include osteopenia, osteoporosis, vision problems, weight gain, and so on.

This is why they are not prescribed as a control for CLL -- that, and they don't work all that well, certainly not well enough to justify their long term use.

One of the problems with a little FCR over time is that disease resistance is a very real concern. Dr. John Byrd told me that some people can become refractory (resistant) to fludarabine after just one use. You also have the problem of T cell suppression from FCR; a small dose every few weeks will keep you in a constant state of depleted T cells, neutropenia, and inability to fight infection. Not to mention the accompanying nausea, etc, of having the chemo.

I have used Rituxan as a single agent extensively because, as a monoclonal antibody, it has fewer downsides than purine analogues and alkalyting agents. This is one control that can be used periodically. It is not super effective, and it can also have bad side effects, and disease resistance can also build, but it will not leave you immunosuppressed like FCR.

I have tried low-dose Rituxan and written extensively about it in the blog. I found that it was only helping control the CLL while I was taking it and that it had no long-term effect.

The bottom line is that treatments for CLL have evolved as they have for a reason, because they work better that way at less risk and physical cost to the patient.


David Arenson said...


One thing I forgot: If you are looking for a CLL control that you can take a little at a time, there is chlorambucil, trade name Leukeran. It's given in pill form and is pretty well tolerated. It's the oldest chemo drug for CLL. Check Dr. Terry Hamblin's blog (link at right) to do a search on it; there are some patients who do pretty well with it, especially when it is combined with Rituxan.


mschaeffer33 said...


I copied Terry on my original note and he did cite chlorambucil for control. But what could I add to that to tackle the bulkiness?


David Arenson said...


Prednisone had been combined with chlorambucil to help reduce bulky nodes. This is palliative -- studies have shown it makes the patient more comfortable but does not increase overall survival. Still, it would be one possible option. I would encourage you to think of adding Rituxan to the mix to increase the depth and duration of the remission.


Anonymous said...

Interestingly my haemoglobin dropped to below 5 (40mg of prednisalone and 4 units of blood brought it under control) after my first cycle of FCR – consultant has ‘blamed’ the fluradabine for the haemolysis, stopped the treatment and is now talking of a mix of bendamustine and retuximab. Jim.