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 enough 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 comments 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 Clive 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 visit 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. This 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 HCT. 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 risks 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 require 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 depends 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 frontline 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 have 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 pretty much hemolysis-free -- for another three weeks.

On Tuesday, July 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. How 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 for 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 Rituxan 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.