Monday, September 08, 2008

Non Hemic Autoimmunity in CLL

Although everyone is familiar with the autoimmune complications of chronic lymphocytic leukemia (CLL), a clear understanding of their pathogenesis is still wanting. More than twenty years ago Hamblin et al established that the overwhelming majority of such complications involved the formed elements of the blood, and especially red cells[1]. Autoimmune haemolytic anemia (AIHA) occurs in around 15% of patients with CLL, and, conversely, CLL causes 14% of all cases of AIHA[2]. More recently workers in Aberdeen have produced a plausible hypothesis to explain this, suggesting that CLL cells act as atypical antigen presenting cells for the Rh protein[3, 4]. Two other hypotheses have been put forward to explain the high prevalence of autoimmunity in CLL.

One possibility is that the immunoglobulin produced by the CLL has autoantibody activity. However, most cases of CLL produce very little immunoglobulin. It is possible that this mechanism applies in the very rare cases of cold agglutination syndrome and acquired angioedema[5], but most autoimmune complications result from the immune response to the tumor rather than from the tumor itself.

The strikingly high incidence of AIHA after treatment with fludarabine, a drug known for its suppression of T lymphocytes, led Myint et al to suggest that suppression of regulatory T cells might be responsible for AIHA in CLL[6] and it was subsequently confirmed that regulatory T cells are increased in the peripheral blood in CLL especially in advanced disease, but they are exquisitely sensitive to treatment with fludarabine[7]. Regulatory T cells were recognized from the study of mice thymectomized at three days of age, which developed various autoimmune diseases when reconstituted with cells from syngeneic spleen or bone marrow[8]. In humans they can be recognized by their CD4+, CD25+, FoxP3+ immunophenotype. In CLL they are thought to play a part in both the global immunodeficiency[9] and in the suppression of any immune attack on the leukemia[10].

Non-hemic autoimmunity in CLL is very rare, but at least two syndromes, glomerulonephritis and paraneoplastic pemphigus, have been clearly identified[2]. Interestingly, both have been triggered by treatment with fludarabine[11-17]. In this issue of Leukemia Research Qian et al[18] describe a patient with CLL who developed both ANCA-positive glomerulonephritis and paraneoplastic pemphigus after treatment with the combination of fludarabine, cyclophosphamide and mitoxantrone. These conditions have not been seen together previously in a single patient. Subsequently, after treatment with prednisolone, cyclophosphamide and rituximab the patient developed neurological symptoms with dizziness and weakness in his left arm and leg without changes in tendon reflexes, and later status epilepticus and coma which was eventually fatal. Magnetic resonance imaging revealed a lesion in the right parietal lobe which could not be identified further.

The authors have attributed the cerebral lesion to a third paraneoplastic syndrome, namely paraneoplastic neurological syndrome (PNS), and have suggested a vasculitic mechanism on rather indirect evidence. PNS has recently been defined to distinguish it from neurological syndromes that are merely coincidental with a cancer[19]. Since the abnormality in this patient is not a classical neurological syndrome (such as Lambert-Eaton syndrome, Guillain-Barré syndrome or stiff person syndrome etc), did not occur within two years of the diagnosis of cancer and onconeural antibodies were not detected, this case does not meet the diagnostic criteria of PNS. Although described in association with a wide variety of neoplastic conditions, PNS has not previously been described in association with CLL. Apart from those attributable to Herpes Zoster infections, neurological syndromes are indeed rare in CLL and most have been attributed to leukemic infiltration of the CNS[20] or progressive multifocal leukoencephalopathy[21-23].


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Anonymous said...

Would this imply that Rh=ve patients with CLL are more likely to develop AIHA?

Terry Hamblin said...

No, the Rh molecule is always there. There are 5 antigens on Rh: C or c, D, and E or e. Rh negative people have cde/cde antigens by they still have the Rh molecule.

Anonymous said...

To me, fludarabine seems like a very dangerous drug. The problem is that almost every oncologist offers some combination of drugs that involve fludarabine.

This article is quite concerning, since these infection and autoimmune diseases can indeed kill.

I see fludarabine linked to secondary malignancies, Richter's transformation, autoimmune disease, fatal infections, and so on.

Aren't there safer options?

I definitely need treatment, but gosh I hate to pick the wrong therapy, one that will kill me before the disease runs its course, and kills me.