CLL symptoms

The Professors' Posts

CLL Symptoms including the itch

TERRY HAMBlIN

How can you tell if a particular symptom is caused by CLL?

It is very difficult. Just because there is a temporal relationship does not mean that there is a causal relationship. In other words if two things happen at the same time it doesn't mean that one cause the other. For example, supposing St Swithin's day has no rain, and the next 40 days are also dry, you might conclude that If it doesn't rain on St Swithin's day than it won't rain for another 40 days. But we all know that at that time of the year in some countries there is often a dry spell in June and July. If year on year the same thing happens it enters folk lore so that people look out for St Swithin's day and begin to think that a dry St Swithin's day is the cause of the dry spell.

It's the same with symptoms. By chance the start of fairly common symptoms such as fatigue or itch will occur at the same time that CLL is diagnosed. If it happens frequently enough then people will begin to think that the CLL cause the itch. It may have, but how can we be sure. Of course, if we treat the CLL and the itch goes way, that is quite good evidence, but it might be that the treatment for CLL was also a good treatment for the itch. Or it might be that the CLL caused impaired immunity, which allowed a function infection of the skin and the fungus caused the itch, but the treatment of the CLL made the fungus and thus the itch worse. See how difficult it is?

We are pretty sure that some problems are definitely complications of CLL - hemolytic anemia, shingles, etc - with others we ae highly suspicious - leg cramps, severe reactions to insect bites. With others we are not sure one way or the other - itching, fatigue. The only way to be sure is to make a formal study comparing matched groups of CLL patients and healthy adults.

In Hodgkin's disease, which is somewhat similar to CLL, intractable itch is a severe and recognised complication, so it may be for CLL, but it is rare enough not to be in the text books. LIST members can help us to understand CLL by reporting unusual symptoms.

TERRY HAMBlIN

I haven't been following the itching debate. I can't remember a CLL patient who complained of it, though it is quite common in Hodgkin's disease.

Naltrexone is an opiate antagonist that is sometimes given during the withdrawal stage of heroin addiction.

This is what I have been able to find out about it.

Itch is known to be transmitted by specific C neurons that have slow conduction velocities, lasting response to histamine, and extensive terminal branching. Nevertheless, no specific "itch center" appears to exist in the brain. Studies show that itch activates several areas of the forebrain, with significant overlap with the activation areas for pain. Pain is known to inhibit itch by central and peripheral mechanisms. Scratching and rubbing skin stimulates myelinated A neurons by mechanoreceptors that activate spinal suppression of itching.

Four clinical forms of itch have been described; clinically significant itch may have elements of one or more types.

Pruritoceptive itch results from skin inflammation, dryness, or damage; this is the familiar itch resulting from an insect bite or urticaria.

Neuropathic itch occurs with any disease along the afferent neuronal pathway. Several neurologic diseases, such as postherpetic neuralgia, multiple sclerosis, and central nervous system neoplasms, can cause this form of itching.

Neurogenic itch is a result of the central action of opioid neuropeptides and occurs in patients with cholestasis and renal failure. In these patients, itch can be debilitating, and treatment with opioid antagonists such as naloxone or naltrexone is recommended.

Psychogenic itch has no physiologic basis; it may be an independent behavior or associated with parasitophobia.

Different manufacturers should produce exactly the same product.

TERRY HAMBlIN

I did a medline search on itching and came up with 9609 references about it. The journal Dermatological Therapeutics devoted a whole issue to it in 2005. So this is a current and ongoing unsolved problem.

Itch is not a common complication of CLL, but it is quite common in two other hematological conditions, Hodgkin's disease and polycythemia vera. I have had much trouble over the years trying to relieve the itch in these patients. One thing we know works, but is not long lasting - scratching. It also has the side effects of residual sores.

Antihistamines have been the residual stand by. Both H-1 inhibitors like Piriton and H-2 inhibitors like cimetidine. I often used them together, but they weren't all that successful - though they work for the itching of insect bites. Topical steroids are good for allergic itching but they are not much use in the itching of lymphoma.

Suggestions that I have seen include tacrolimus ointment or pimecrolimus cream 1% (Elidel). This has some merit and ther have been reports of it working in Hodgkin's disease. Other hace suggested the application of cafeine - in the form of coffee or coca-cola. It is said to work for the itching of psoriasis.

The oral opiate antagonist Naltrexone has been reported to be effective.

Here is the summary of a recent review by the palliative care people at Oxford, which may be helpful:

In origin, itch can be cutaneous ("pruritoceptive", e.g. dermatitis), neuropathic (e.g. multiple sclerosis), neurogenic (e.g. cholestasis), mixed (e.g. uraemia) or psychogenic. Although itch of cutaneous origin shares a common neural pathway with pain, the afferent C-fibres subserving this type of itch are a functionally distinct subset: they respond to histamine, acetylcholine and other pruritogens, but are insensitive to mechanical stimuli. Histamine is the main mediator for itch in insect bite reactions and in most forms of urticaria, and in these circumstances the itch responds well to H(1)-antihistamines. However, in most dermatoses and in systemic disease, low-sedative H(1)-antihistamines are ineffective. Opioid antagonists relieve itch caused by spinal opioids, cholestasis and, possibly, uraemia. Ondansetron relieves itch caused by spinal opioids (but not cholestasis and uraemia). Other drug treatments for itch include rifampicin, colestyramine and 17-alpha alkyl androgens (cholestasis), thalidomide (uraemia), cimetidine and corticosteroids (Hodgkin's lymphoma), paroxetine (paraneoplastic itch), aspirin and paroxetine (polycythaemia vera) and indometacin (some HIV+ patients). If the remedies specified fail, paroxetine and mirtazapine should be considered. Ultraviolet B therapy, particularly narrow-band UVB, may be superior to drug treatment for itch in uraemia.

Here is are references to itching and CLL

Intractable pruritus in non-Hodgkin lymphoma/CLL: rapid response to IFN alpha.

_Radossi P_ (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term="Radossi+P"[Author]) , _Tison T_ (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term="Tison+T"[Author]) , _Vianello F_ (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term="Vianello+F "[Author]) , _Dazzi F_ (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term="Dazzi+F"[Author]) ._Br J Haematol._ (javascript:AL_get(this, 'jour', 'Br J Haematol.');) 1996 Sep;94(3):579.

This is a letter without an abstract.

_Dermatology._ (javascript:AL_get(this, 'jour', 'Dermatology.');) 1996;192(2):110-5.

B-cell chronic lymphocytic leukemia associated with high serum IGE levels and pruriginous skin lesions: successful therapy with IFN-alpha 2b after failure on IFN-gamma.

_Neuber K_ (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term="Neuber+K"[Author]) , _Berg-Drewniock B_ (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term="Berg-Drewniock+B"[Author]) , _Volkenandt M_ (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term="Volkenandt+M"[Author]) , _Neumaier M_ (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term="Neumaier+M"[Author]) , _Zeller W_ (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term="Zell er+W"[Author]) , _Gross G_ (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term="Gross+G"[Author]) , _Ring J_ (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term="Ring+J"[Author]) .

Department of Dermatology, University Hospital Eppendorf, University of Hamburg, Germany.

BACKGROUND. Chronic lymphocytic leukemia of the B-cell type (B-CLL) associated with highly elevated serum IgE levels and skin involvement has rarely been observed. Furthermore, not much is known about therapeutic strategies in such diseases. OBJECTIVE. We describe a 56-year-old male patient with a 5-year history of chronic and relapsing pruritic skin lesions as well as recurrent Staphylococcus aureus infections of the skin. RESULTS. Histologically, a lymphocytic and eosinophilic skin infiltrate was seen. Laboratory analysis revealed lymphocytosis (46.5%), eosinophilia (11.9%) as well as markedly elevated serum IgE levels (140,000 IU/ml). Immunohistology showed dermal B cells with intracytoplasmic IgE. Bone marrow biopsy showed a diffuse infiltrate of small lymphoplasmacytic lymphocytes. Over 80% of blood and bone marrow lymphocytes were CD5 +, CD19 +, CD20 +, CD23 + and CD38 +. Based on these findings, the diagnosis of B-CLL was made. The strong pruritus was resistant to antihistamines and steroids. Therefore, a trial with interferon (IFN) gamma 50 micrograms s.c. daily was started in order to suppress elevated serum IgE but failed. After 1.5 million units s.c. of IFN-alpha 2b every second day for 2 weeks, pruritus and serum IgE levels diminished markedly (48,000 IU/ml). Skin lesions, pruritus as well as skin infection and serum IgE level improved under continuing IFN-alpha 2b therapy for 2 years. CONCLUSION. In cases with suspected hyper-IgE syndrome, hematological neoplasias have to be excluded. The results argue for a benefical effect of IFN-alpha 2b in suppressing IgE production and symptoms of pruritus in an early-stage B-CLL.

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