By Kanti Rai, M.D.
Dr. Rai is currently the Chief of Hematology-Oncology at the Long Island Jewish Medical Center.

Case Presentation:
A colleague recently sought my opinion on a 57-year-old male patient free of any symptoms, who was found to have an elevated leukocyte count done as part of a routine annual check-up.

A year earlier, the patient's blood count was entirely normal. Upon examination, there was enlargement of cervical and axillary lymph nodes, all about one centimeter in diameter, and the spleen was palpable at the left costal margin. Hemogram revealed WBC 22,000/mm ³ , 75% mature-appearing, lymphocytes, hemoglobin/ hematocrit 13.8 g/dl and 40%, respectively, and platelet count 200,000/mm ³. Blood chemistries included normal LDH, uric acid, and immunoglobulins. Blood lymphocyte flow-cytometry revealed that lymphocytosis consisted of monoclonal IgM+/IgD+ kappa light chain + cells which were CD 19+, CD20+, CD5+, and CD23+; three color flow study showed CD38 positivity of CD 19+/CD 5+ cells. The question I was asked was whether this 57-year-old asymptomatic patient, newly discovered to have clinical Stage II B-CLL, should be started on chemotherapy.

The Answer:
My response to this colleague was that this patient should not be exposed to any therapeutic intervention at this time and should remain under follow-up at intervals of one to two months. The exception to this recommendation would be if he wished to enter a prospective randomized clinical trial in which one arm was a fludarabine/rituximab-based chemotherapy while the other arm was observation.

The Basis for the Question:
My colleague's concern about this patient was based on the facts that, even though he was completely free of “B” symptoms, the patient was relatively young for the diagnosis of CLL; his blood lymphocyte count, generalized adenopathy and splenomegaly, all albeit modest in extent, had developed within a 12-month period; and the leukemic lymphocytes were CD38+, a marker associated with patients who come to require chemotherapy sooner and who also have a worse overall survival than those who are CD38 negative.

The Premise is Correct:
Although all the above-noted concerns are true, we still do not have any evidence that initiating early treatment in the patient under discussion will be to his advantage, either in increasing his life-expectancy or in maintaining a better quality of life. Prognostic criteria based on genomics, cytogenetics, and molecular biology have recently shed new light on the pathophysiology of CLL. Using fluorescent in-situ hybridization techniques and DNA probes for each chromosome at risk in B-CLL, it has been found that patients with the single cytogenetic abnormality of deletion 13q have the longest survival, while those with deletion 17p and 11q have the shortest, and those with normal karyotype or trisomy 12 have survival statistics between these two extremes. Patients whose lymphocyte IgVH genes have hypermutations or those whose leukemic lymphocytes do not co-express CD38 or are ZAP-70 negative have significantly longer survival than those with the respective converse findings.

But the Rush to Action is Premature:
Exciting as all these findings are, they are relatively new, and most, if not all, of the reported observations are based on retrospective studies. A few years and maturing of results of prospectively conducted studies (which have not even been initiated yet on large patient populations) will be required before these observations can be applied to the care of all patients with CLL. The methodologies of testing ZAP-70 have to be standardized before they can be introduced in the new prospective clinical studies. Testing for status of IgVH gene hypermutation is likely to remain in the research domain for now and cannot be expected to become a clinically usable tool in the near future. CD38 expression is the only test which is already a clinical reality, but, in my opinion, we still need to develop a wider-based experience in prospective trials before we can feel comfortable in using it to make therapeutic decisions on newly diagnosed CLL patients.

When to Initiate Therapy?
In the Clinical Practice Setting:
Even though I accept that the patient under discussion might soon reach a point when initiating therapy will not be arguable, using the acceptable norms of clinical practice today, I would keep him under the “wait and watch” (some people call it “wait and worry”) category, for now. If this patient develops “B” symptoms, or his nodes or spleen become progressively larger during the period of observation, or his lymphocyte count continues to escalate rapidly or his hemoglobin or platelets start to decline, I would not hesitate in initiating chemotherapy.

In the Setting of Clinical Investigation:
What I would recommend to this patient is to consider entering a prospective clinical study. Several of these are currently in the process of being launched, in which asymptomatic, early stage patients who have bad prognostic features, such as CD38+, or ZAP-70+, or 17p- or 11q-, are randomized between early treatment and wait-and-watch arms. Only when the results of such studies mature will we be able to tell for sure whether early intervention is beneficial to the patient. One should, however, ensure that the “treatment” arm of such a study offers a proven and effective treatment.

Dr. Rai receives nominal research grant support from Berlex Laboratories.