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CLL: Molecular Markers + Clinical Judgment Should Guide Therapy

Fuerst, Mark

doi: 10.1097/01.COT.0000305569.72800.43
Chemotherapy Foundation Symposium

NEW YORK CITY—A risk-adaptive approach to the treatment of chronic lymphocytic leukemia (CLL) should include the use of new molecular genetic markers, but the patient's clinical picture should ultimately guide patient care. That was the conclusion of long-time CLL researcher Kanti Rai, MD, Professor of Medicine at Albert Einstein College of Medicine in Bronx, NY, speaking here at the Chemotherapy Foundation Symposium.

“In the past, most treatment of CLL was empirically based, but we are now moving into hypothesis-based treatment,” he said. “The old method of classifying patients on whether to start treatment was based on clinical stage, lymphocyte doubling time, and the pattern of lymphocytic infiltration. New molecular genetic criteria help us more accurately prognosticate CLL.”

“Use all modern technology, but don't leave your clinical judgment at home,” warned Dr. Rai, who more than 30 years ago devised the clinical staging of CLL that is still in use today.

What is the best way to integrate the newly described molecular and cytogenetic prognostic markers in decision-making regarding therapeutic intervention? In most cases, he said, these new markers—mutational status of IgVH (immunoglobulin heavy chain variable regions) genes, expression of ZAP-70 and CD38, and fluorescence in situ hybridization (FISH) cytogenetics—and the patient's clinical picture are in concordance with each other, and physicians do not have mutually conflicting evidence. However, there are frequent situations in which there is no concordance among these new markers—for example, mutated IgVH genes with ZAP-70 positivity, or unmutated IgVH genes and CD38 negativity.

“In these cases, I use clinical judgment and do not yield to the power of any one of these items,” Dr. Rai said. “I put great emphasis on how a patient feels and how a patient looks in deciding whether treatment should be initiated.”

“For example, if a patient presents with significant symptoms of severe fatigue, major degrees of night sweats or weight loss, or bulky nodes or hyperlymphocytosis over a relatively short period of time, and has all or many of the markers of good prognosis—del 13q as sole abnormality by FISH, or mutated IgVH genes, ZAP-70 negativity, or CD38 negativity—I disregard those test results and start therapy.”

“Conversely, if a patient remains free of symptoms, has no clinical evidence of disease progression, but has any or many markers of bad prognosis—del 17p or del 11q, unmutated IgVH genes, ZAP-70 positive, or CD38 positive—I again disregard the test results and am guided by the patient's clinical behavior.”

In poor-risk cytogenetics patients, three new novel agents may prove to be effective, he said. Alemtuzumab has been found to be particularly effective in del 17p patients; lenalidomide has shown a 44% response rate in patients with del 17 or del 11q; and flavopiridol, which works via a p53-independent pathway, has shown a 47% response rate in patients with del 17p and an 81% response rate in patients with del 11q.

During the past few years, the treatment options for CLL patients have become so numerous that both physicians and patients may be confused, Dr. Rai noted. When should treatment be initiated in a previously untreated patient with CLL? He said that for most cases he continues to use the 1996 guidelines from the NCI-Working Group on CLL.

“If a patient, who has been followed on an observation-only or wait-and-watch basis, starts to show evidence of progressive disease, I consider that therapeutic intervention is appropriate,” he said.

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Evidence of Progressive Disease

Such evidence would include a combination of symptoms:

* Development of disease-related symptoms, such as extreme fatigue, unintentional weight loss (10% of base-line weight in about a six-month period), extreme sweating, especially at night, or frequent infections requiring antibiotics.

* Signs of rapidly increasing enlargement of lymph nodes or spleen or development of hugely enlarged, bulky nodes or spleen.

* Signs of rapidly increasing hyperlymphocytosis in blood.

* “I do not consider a modest lymphocytosis, such as an absolute lymphocyte count [ALC] increasing within six months from 10,000/mm3 to 20,000/mm3, by itself a reason to start therapy,” he said. “However, an increase from a baseline of 100,000/mm3 to 200,000/mm3 in six months would be an adequate reason to begin therapy.”

There are no published data that show that any threshold of ALC by itself mandates initiation of therapy. “But in my experience, ALC or higher than 200,000/mm3 puts a patient at risk for hyperviscosity-related complications, and I will start therapy even in the absence of symptoms,” he said.

Another symptom that would lead to therapy is a rapid decrease in hemoglobin or platelet levels, especially when accompanied by corresponding symptoms. Merely because these levels have decreased to certain thresholds, such as hemoglobin below 11gm/dl in a patient who suffers from no symptoms of anemia, or platelets below 100,000/ mm3 without evidence of bleeding from skin or gingiva, does not rate immediate initiation of therapy, Dr. Rai said.

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What Is the Therapeutic Goal?

What is the therapeutic goal? “I ask myself this question every time I am faced with a patient who obviously needs to start on some chemotherapy for CLL,” he said. An older patient with comorbid conditions including heart disease, diabetes, emphysema, and a stroke who has a relatively short actuarial life expectancy should receive palliative therapy with the goal of reducing the tumor mass and trying to reduce disease-related symptoms.

“Fludarabine and rituximab either with or without additional cyclophosphamide, or replacing fludarabine by pentostatin. will be inappropriate choices for such a patient because they each carry certain known toxicities and a risk of requiring additional treatment for neutropenic sepsis,” he said.

“Palliative therapy with chlorambucil or cyclophosphamide with judicious use of prednisone, given on intermittent regimens, would be best for such a patient.”

On the other hand, for a patient who is otherwise in good general health, with an ECOG performance status of 0 or 1, and who has evidence of advancing and progressive disease, “my therapeutic goal will be to achieve either a complete remission by clinical criteria or the best possible and achievable partial remission,” he continued.

“My own preferred choice for front-line therapy in CLL happens to be the fludarabine and rituximab regimen with the two agents given concurrently or simultaneously.”

Dr. Rai noted that others, including Michael Keating, MD, Professor of Medicine at the University of Texas M. D. Anderson Cancer Center, have found good results with adding cyclophosphamide to this regimen.

“Because the fludarabine/rituximab/cyclophosphamide regimen has considerably more myelotoxicity, I choose this regimen as my second-line therapy following fludarabine and rituximab,” Dr. Rai said. “Because pentostatin and fludarabine have not been tested in a head-to-head comparison in a prospectively conducted manner, I do not know if pentostatin/rituximab is equal or superior to fludarabine/rituximab.”

“And I don't know if pentostatin is equal to or superior to fludarabine when added to cyclophosphamide and rituximab. At this time, I feel that these two drugs are equally effective.”

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Achieving Molecular CR by 4C Flow Cytometry Necessary Endpoint?

Dr. Rai also questioned, in the front-line setting, whether achieving molecular complete remission or a complete remission by four-color flow cytometry criteria is a necessary endpoint.

“As attempting to achieve such an objective, beyond clinical complete remission, entails more therapy and therefore more immediate toxicities and unknown late toxicities, such as myelodysplasia and acute myeloid leukemia, without any proven evidence that it leads to a cure, I consider achieving a complete remission by clinical criteria as the most desirable and safe goal in front-line therapy of CLL,” Dr. Rai said.

“What is the therapeutic end-point in CLL? Naturally, we would like to aim for a cure, but in our attempts to get rid of the last leukemic cell, what are we doing to the patient's quality of life? Perhaps the best achievable beneficial response ought to be our therapeutic endpoint for now.”

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Not All Low-Risk Patients Do Well

Asked for her opinion for this article, Janice Gabrilove, MD, Associate Chairman of the Symposium, said, “We need to completely assess CLL patients. Gone are the days when we looked at a white blood cell count and told a patient he would live forever. Now we know that not all low-risk patients do well. Molecular phenotyping of patients is a prerequisite. We are better armed to discuss the treatment choices that patients may have.”

Dr. Gabrilove, Professor of Medicine, Hematology, and Medical Oncology at Mount Sinai School of Medicine in New York City, explained that in her clinical assessment of CLL patients outside of a clinical trial, she looks specifically at ZAP-70, CD38, and cytogenetics by FISH.

“I clinically type patients into low, intermediate, or high risk of disease,” she said. “Then I define prognostic markers by the presence of cytogenetics. If all of the risk factors are good and the patient is asymptomatic, I may suggest a watch-and-wait strategy. If the markers are mixed, I discuss therapy with the patient. If CD38 is increased, this means the disease may be aggressive sooner. If the cytogenetics are good, the disease may be more indolent. I let the patient know what we are looking at in terms of therapy.”

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Monitoring Test for Metastatic Colorectal Cancer Approved by FDA

The FDA has approved the CellSearch System, the first diagnostic test to automate the detection of circulating tumor cells, as a tool for monitoring metastatic colorectal cancer.

The system, currently approved for monitoring metastatic breast cancer, identifies and counts circulating tumor cells in blood samples to predict progression-free and overall survival in patients with metastatic colorectal or breast cancer.

This method identifies such cells earlier than the current standard of care and serial testing for circulating tumor cells, in combination with other clinical monitoring methods, will aid physicians in assessing disease progression, allowing them to make more informed decisions earlier.

Researchers conducted a prospective, multicenter clinical trial to assess approval for the CellSearch System. The study involved 430 metastatic colorectal patients at 55 clinical centers in the United States and Europe who were about to enter first- or second-line therapy.

The data showed that circulating tumor cells are a good predictor of progression-free survival and overall survival, and that the combination of the cell analysis with radiological assessment may provide the most accurate assessment of prognosis.

A request has also been filed with the FDA for approval of use of CellSearch in monitoring metastatic androgen-independent prostate cancer.

This was based on data reported at the most recent ASCO Annual Meeting showing that measurement of circulating tumor cells before and after administering chemotherapy in men with androgen-independent prostate cancer provided more reliable prognostic information about survival and disease progression and could be obtained earlier—i.e., in two weeks compared with the six to eight weeks needed for measurement of prostate-specific antigen levels.

© 2007 Lippincott Williams & Wilkins, Inc.
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