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Alert Number 228

Refractory AIHA: What Comes After Steroids and Rituxan?

Date: April 22, 2007

Autoimmune hemolytic anemia (AIHA) is a frequent complication in CLL. This is a case where the body turns on itself, becomes incapable of telling friend from foe, and starts killing off perfectly innocent red blood cells. Since red blood cells contain hemoglobin, the carrier of life giving oxygen, AIHA is nothing to kid about. “Hemolysis” (killing of red blood cells) can bring even the strongest jock to his or her knees – think of it as being gradually strangled from the inside out. If you notice sudden and rapid onset of debilitating fatigue and your red blood cell counts (RBC), hemoglobin and hematocrit numbers start nose-diving over a short period of time, it is important to consider AIHA as a possible culprit.

AIHA responds well to steroid therapy. More recently, Rituxan has been added as a second line defense, since most patients eventually become resistant to steroid therapy to control the hemolysis. IVIG has been suggested as a way of controlling the AIHA as well. But what is a patient to do when (if) he becomes refractory to steroid and Rituxan therapy to control AIHA? Transfusions become mandatory, red blood cells donated by generous strangers. However, this is a slippery slope since the transfused red blood cells are also attacked by the body’s immune system gone berserk. Patients who become severely transfusion dependent may have to be hospitalized — and they develop other complications as well.

Over the past year or so, I have been seeing anecdotal information about using Campath to treat AIHA, one patient at a time. This is the first time that I have seen a report of cluster of CLL patients (5 of them!) treated with Campath. And the report comes from Karolinska Institute in Sweden, one of the research centers that I respect greatly. The results look promising and I am relieved to find yet another drug that works in refractory AIHA.

Campath is well known to us in the CLL community: it is the first monoclonal antibody that has received FDA approval for treatment of CLL. What is the mechanism of its use in AIHA? I suspect it has to do with the wide-angle targeting of CD52, the marker that Campath goes after. CD52 is expressed by many of the cell lines of the immune system, not just CLL cells. The bad news is that Campath is therefore not very focused in its cell kill and is justly infamous for its immune suppression. That is also the good news, from the perspective of AIHA. Remember, in AIHA the hapless red blood cells are killed by the body’s own immune system. The immune suppression after Campath therapy means the immune system is flat on its back, unable to kill much of anything, including innocent red blood cells.

The hope is that when the immune system gradually recovers, it would have forgotten some of its earlier bad habits. Think of this a re-boot of the system. When your computer crashes, and the keyboard freezes up and does not let you do anything, the last recourse is switch off the power to shut everything down and then re-boot the system from scratch. Killing off most of the B-cells and T-cells (and other cell lines) with Campath therapy may well “re-boot” the system and hopefully allow it to come back up, less garbled.

Below are links to a few articles that you should read, if AIHA is a concern to you. The article on regulatory T-cells (“Tregs”) may give rise to other thoughts on the subject, especially on the use of Campath in AIHA. Splenectomy is scary to contemplate, but it is often necessary and not as bad as it sounds. The good news is that the Rai staging is not quite accurate in spelling out doom and gloom for CLL patients with anemia, when the anemia is caused by AIHA. It is far worse to have anemia caused by bone marrow failure. We do have several ways of treating AIHA; bone marrow failure, on the other hand, is much harder to treat.

Possible Benefits of IVIG
Rai Staging Superceded
Topics Alert #80: Anemia Can Be a Silent Killer

Be well,



Leukemia. 2007 Mar;21(3):511-4.

Treatment of severe refractory autoimmune hemolytic anemia in B-cell chronic lymphocytic leukemia with alemtuzumab (Campath)

Karlsson C, Hansson L, Celsing F, Lundin J.

Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.

Progressive B-cell chronic lymphocytic leukemia (B-CLL) is often complicated by autoimmune hemolytic anemia (AIHA), which in some cases may be refractory to conventional therapy such as corticosteroids, rituximab and splenectomy. We report here on 5 patients (median age 66 years, range 59-69) with advanced B-CLL, all of whom developed severe transfusion-dependent AIHA resistant to conventional therapy and received subcutaneous (SC) or intravenous (IV) alemtuzumab, a humanized monoclonal antibody that targets the CD52 antigen as salvage treatment for AIHA. Alemtuzumab was well tolerated with only minor 'first dose' reactions. All 5 patients responded with a >or=2.0 g/dl rise in hemoglobin (Hb) concentration, in the absence of further transfusions, after a median time of 5 weeks (range 4-7), and the mean Hb increased from 7.2 g/dl at baseline to 11.9 g/dl at end of treatment. All patients remained stable, without further AIHA episodes, after a median follow-up time of 12 months with a mean Hb of 12.5 g/dl (range 12.2-12.9). For patients with severe, refractory CLL-related AIHA, who have not previously responded to conventional therapy, alemtuzumab is an effective agent.

PMID: 17215854


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