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Alert Number 223

AIHA and FCR Therapy

Date: March 25, 2007

One of the most important functions of the immune system is being able to tell the difference between friend and foe. Autoimmune disease happens when this ability is lost, and “friendly fire” causes murder and mayhem, real invaders like bacteria and viruses are ignored while innocent red blood cells and platelets are destroyed in droves.

Two of the most important forms of autoimmune disease in CLL are AIHA (autoimmune hemolytic anemia) and ITP (idiopathic thrombocytopenic purpura). Red blood cells are the target in AIHA and platelets are killed in ITP. AIHA is far more common than ITP in CLL patients. Onset of either of these autoimmune diseases makes treating and controlling CLL far more complicated and it is important to diagnose these conditions sooner rather than later. For example, fludarabine has been implicated in AIHA. If you are one of the unlucky folks at high risk of AIHA, it hardly makes sense to initiate therapy with fludarabine.

But how about the various combinations of fludarabine plus other drugs, are they also high risk for patients with risk factors for AIHA? How about RF, or FCR or my personal favorite combo, FCR Lite? Will the addition of the magic mouse juice of Rituxan make things betterand reduce the risk of AIHA? This is not a facetious question. After all, Rituxan has been used as a drug to treat AIHA. Surely it will counter some of the negative effects of fludarabine?

I expect the largest repository of information on how patients fare after FCR is maintained at M. D. Anderson, the institution that has taken the lead in FCR therapy. The abstract below comments on the risk of AIHA after FCR therapy. I expect similar trends can be extrapolated for FR and FCR Lite protocols as well. Out of 300 patients who underwent FCR therapy, M. D. Anderson found 6.5% (19 patients) developed AIHA or PRCA (pure red blood cell aplasia, another autoimmune disease where red blood cells are destroyed). This is not wonderful news, but it is not terrible news either. The researchers conclude risk of AIHA is not unduly increased by treatment with FCR combo.

Another important snippet of information is buried in this abstract. Patients and their local hem/oncs depend on the direct antiglobulin test (DAT) for detecting AIHA. It appears this test is not fool-proof, and sometimes patients test negative for it even when they have AIHA. It is important to do all the other tests as well, such as increased bilirubin levels (bilirubin is one of the waste products created when red blood cells are killed), increased levels of reticulocytes (baby red blood cells, an indication the body is desperately trying to make up for the adult red blood cells getting killed), low levels of haptoglobin and elevated levels of lactate dehydrogenase. Moral of the story: make sure you get the full battery of tests and don’t depend on just DAT to tell you whether or not you have AIHA.

Another obvious fact that sometimes is easy to miss: AIHA is more likely in patients who have high tumor load. This makes sense — an increased number of crazy CLL cells milling around increases the chances of the rest of the immune system go bonkers as well, go into a shoot-first-and-ask-questions-later mode. It is not always easy to understand what “high tumor load” means. For some of us, the disease is mostly centered in the blood and that is easy to monitor in monthly CBC tests. However, for many CLL patients (especially those with 11q and 12 Trisomy FISH defects), the disease likes to hang out in the lymph nodes. Enlarged lymph nodes and spleen can squirrel away vast numbers of CLL cells, far more than you can ever see in the blood. Sure enough, M. D. Anderson found a link between increased level of B2M (beta 2 microglobulin, a marker for tumor load) and a higher risk of AIHA. I have had reason to be reminded recently that autoimmune disease plays a major role in the progression of CLL. It is important to keep an eye out for it. Below is the link to our prior articles on the subject. I would particularly want you to read the bit about the connection between AIHA and viral infections in the first article, and the need to make sure you are adequately protected against infections while you battle autoimmune disease. It is a simple thing to do, and yet few oncologists seem to be pro-active in doing this. It is up to you to make sure it gets done.

Anemia Can be a Silent Killer
Regulatory T-cells (TREGS) and Autoimmune Disease
Possible Benefits of IVIG Therapy

Be well,



Br J Haematol. 2007 Mar;136(6):800-5

Immune anaemias in patients with chronic lymphocytic leukaemia treated with fludarabine, cyclophosphamide and rituximab - incidence and predictors

Borthakur G, O'Brien S, Wierda WG, Thomas DA, Cortes JE, Giles FJ, Kantarjian HM, Lerner S, Keating MJ.

Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX

Immune anaemias (IA) [auto-immune haemolytic anaemia (AIHA) and pure red cell aplasia (PRCA)] are complications of chronic lymphocytic leukaemia (CLL). Fludarabine has been associated with AIHA, whereas both rituximab and cyclophosphamide have been used to treat this condition. Combining these agents with fludarabine may reduce the likelihood of AIHA. We report on the incidence, outcome and pretreatment predictors of IA in 300 patients treated with fludarabine, cyclophosphamide and rituximab (FCR). Nineteen patients (6.5%) developed IA [AIHA (5.8%), PRCA (0.7%)] on or after treatment with FCR. Most patients (82.4%) with AIHA had a negative direct antiglobulin test (DAT). Additional markers of haemolysis (indirect hyperbilirubinaemia, reticulocytosis, low haptoglobin and elevated lactate dehydrogenase levels) confirmed the presence of AIHA in these patients. The majority of patients responded to therapies including steroids, ciclosporin, i.v. immunoglobulin, etc. High pretreatment levels of beta-2 microglobulin predicted for development of IA. No haemolytic crisis was observed during FCR therapy in eight patients with AIHA prior to FCR. Thus, the incidence of IA among CLL patients treated with FCR was comparable with historical rates. The diagnosis of AIHA can be considered even if the DAT is negative. Pre-existing AIHA need not preclude front-line FCR therapy.

PMID: 17341265

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