Sunday, August 15, 2010

Splenic irradiation for CLL

Splenic irradiation is the forgotten treatment for CLL. Perhaps it is because there is no profit to be made from it by the drug companies, but for certain individuals there are advantages compared to drug treatment. I should say up front that it is not a cure, but then nothing is short of an allograft. Nor is it likely to produce the very long remissions that are possible with FCR, but there are very many patients for whom FCR is too toxic. But there are some patients for whom splenic irradiation is the ideal treatment and CLL physicians are very resistant to using it.

I first came upon it was a young doctor when it was an option in the MRC CLL 1 and 2 Trials which began in 1978. I was actually a co-author of the report of those trials which were published in 1991 (Catovsky D, Richards S, Fooks J, Hamblin TJ. Leukemia and Lymphoma 1991; Supplement pp 105-112). In CLL 1 the overall survival of patients treated with splenic irradiation was 5 years compared to 3.8 years for those treated with chlorambucil. The numbers were small and did not reach statistical significance, and the dose of chlorambucil was only 40mg/sq m. However in CLL 2 the overall survival for those treated with splenic irradiation was 3.4 years compared to 4.1 years for chlorambucil. Again the difference was not statistically significant. The conclusion that we drew was that splenic irradiation was not an inferior treatment to the dose of chlorambucil used in the original fludarabine trial or the recent alemtuzumab trial.

I am grateful to my friend Stacie who has sent me a 2001 paper that reviews several trials of splenic irradiation (SI) in CLL. It is from a journal that I don't normally read. (Weinmann M, Becker G, Einsele H, Bamberg M. Radiotherapy and Oncology 2001; 58:235-246.)

Of late, SI has only been used in patients with hypersplenism who were considered unfit for splenectomy, even if performed by keyhole surgery. But in the past it was used as a therapeutic modality which attempted to control the disease as a whole rather than that which is localized to the spleen. How it was supposed to work is a bit of a mystery, but it certainly did work, with some patients (22-38%) achieving what was then thought of as a complete remission. There are various theories why it works. One suggested that there is a circulation of all malignant cells through the spleen so that they all get a dose of radiation as they are passing through, but experiments with radiolabelled lymphocytes do not seem to confirm that. Other suggestions are that there is an induced change to the array of lymphocyte subpopulations or to the cytokine environment that has an effect on the survival of CLL cells. However, this is still speculation and we don't really know how it works.

Hypersplenism is the effect that a large spleen has on the neutrophil, platelet and red cell count because of pooling in the spleen or active destruction. If you take the spleen out, these levels return to normal or even overshoot. The same effect can be achieved with splenic irradiation. It is seldom so complete as splenectomy, and it may not be long lasting (remissions of 7-18 months have been reported) but the effect can be repeated, up to four times. One advantage is that with the blood count restored some patients are able to go ahead and have the chemotherapy that they were previously denied because of their low counts.

Apart from restoration of the blood count, SI can shrink a painful or uncomfortable spleen and make substantial inroads into the tumor mass, by reducing white counts and shrinking nodes. The rare 'complete remissions' would not be so defined by modern criteria.

The dose of SI has varied in different trials. In our MRC trials, we used 100 cGy weekly up to a total of 1 Gy, but later studies used larger doses. Typical doses would be 0.5 to 1Gy given daily or 1-3 times a week to a total of 5-10 Gy. Larger doses than this seem to confer no extra benefit.

The most severe side effects seem to have been transient thrombocytopenia and neutropenia and these counts need to be monitored to guard against infection or bleeding. Neither neutropenia nor thrombocytopenia is a contraindication to SI and some patients who are refractory to chemotherapy also respond.

Long term toxicity does not seem to be a major problem, and although radiation does damage T cells, a regimen of carefully titrated doses allows the treatment to be monitored. For many countries in which fludarabine is regarded as expensive and rituximab a wistful dream, SI is a very cheap option for treatment.


Chaya Venkat said...


Has anyone looked at using radiation as a way of controlling very large abdominal nodes - not just the spleen? Can this be an option in the case of CLL patients who have been around the block many times and used up all their drug options? I am not talking about curative or even long term remissions - just something that will help reduce disease related B-symptoms and make the patient more comfortable.


Deb Light said...

That is very interesting Dr. Hamblin.I hope Stacie and her CLL Twin (LadyDi's husband) will give it a try.

Thanks for your insight on this.

God Bless,
Deb Light

Terry Hamblin said...

Undoubtedly irradiation of abdominal nodes will shrink them and this will be of value for relief of pain and discomfort, but it won't raise the platelet count or neutrophil count and won't have a systemic effect the way that splenic irradiation may have.

Anonymous said...

My NIH oncologist, Dr Marti, agrees with Dr Hamblin that splenic irradiation does have a role for patients such as myself.

After reading many papers on splenic irradiation, IF I decide to treat one more time, this will be the path I pursue.

This German study that Dr Hamblin mentions is the most informative of any I have reviewed. It was impressive to read the different mechanisms by which irradiation works.

Also, the paper states that " [in CLL] 100% OBSERVED RESPONSE IN TERMS OF SPLENIC SIZE WITH DOSES [CUMULATIVE DOSES] OF 5 Gy and higher."

It also states, "Amazingly, in some studies a substantial part [22~38%] achieved complete hematological remission including remission in bone marrow, liver or lymph nodes."

As a late stage CLL patient ~diagnosed 14 years ago this week~ I realize that irradiation is not without risks but appears to have a slight edge over even low dose chemotherapy for myself.

Dr Hamblin, I appreciate the time and information you have so willingly shared to help me make this decision.


Anonymous said...

Dr Hamblin, perhaps this is not the spot to ask what I will to...
Do monoclonal B cells show circadian rhythms as T cells? I have MBL. Yesterday morning (around 6:20am) my total lymph count was 4600 (CD4 1800 and CD8 900 - so the rest of it probably contained B monoclonal cells, B polyclonal cells and NK cells, right?) and neutrophils were around 2900. Today I went for a blood count again to make sure: 2400 total lymph and 4500 neutrophils. I have slight cold symptoms only. Since I was diagnosed with MBL my total lymph counts ranges from 3000 to 4800. Is it like that really? Thank you so much. I am confused.

Terry Hamblin said...

Such fluctuations undoubtedly occur and things like exercise can make a difference. The level of cortisone in the blood (which has a diurnal rhythm) undoubtedly effects levels

Anonymous said...

Even B monoclonal cells might be affected by, per example, cortisol levels? Stress raises cortisol so how does this substance affect lymph cells? Rise them up or make them lower? Thank you again.

Terry Hamblin said...

Corticosteroids raise the lymphocyte count by changing the compartment that they reside in. Cortisone levels are highest in the early morning and can cause a rise in lymphocytes then.

Craig M. Newmark said...

Dr. Hamblin,

Here's one data point on the connection between the spleen and CLL that may be of interest.

11 years ago I had slowly progressing CLL, but my red count starting dropping. My oncologist determined that my spleen was "sequestering" red cells.

He offered me a choice of four treatments: chemo, splenic radiation, splenectomy, or watch-and-wait. I elected a splenectomy. Since then, my CLL has not progressed and my white count has fallen to almost normal.

When I was diagnosed in 1993 (age 36), I read that the prognosis was somewhat more favorable for a splenic version of the disease. I apparently am consistent with that finding.


Terry Hamblin said...

Binet and Dighiero did publish a paper suggesting that the splenic version of CLL was more benign. We later discovered that these cases were in fact splenic lymphoma with villous lymphocytes or splenic marginal zone lymphoma (same thing- different name)

Anonymous said...

Dr Hamblin,
Would you know of any studies using partial splenic embolization (PSE) in CLL ? PSE is an invasive but rather simple procedure successfully used for the past 20 years to manage thrombocytopenia secondary to hypersplenism. thank you.

Terry Hamblin said...

I know of no systematic studies