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CML Experts Commentaries on the Hammersmith Protocol for CML Clinical Decisions in the IM Era on Monitoring IM Therapy

Compiled by Anjana


If you remember, Prof. Goldman in his article recommended 3-monthly BMB's in the initial stages of IM therapy and reducing the frequency in the later stages as well as emphasized regular monthly monitoring of blood counts and PCR. He pointed out that FISH was useful although its values can sometimes be misleading because of the
inclusion of the lymphoid cells resulting in lower than normal values (as some patients on our list found out).

Here's what the other experts had to say on how they would monitor patients on IM therapy:

Francois-Xavier Mahon, MD (France):

"Chronic myelogenous leukemia (CML) is characterized by a biological event which both drives the leukemia and forms a marker for its continuing presence. The best way to monitor the response of individual patient's treatment is thus to follow either the proportion of Philadelphia chromosome (Ph)+ cells in the marrow or the level of "residual" disease, ie, BCR-ABL transcripts, at the molecular level."

Dr. Mahon is recommending cytogenetics as well as PCR tests.

Tim Hughes, MD (Australia):

"Frequent (every 1 to 2 months) and accurate quantitation of BCR/ABL levels in the blood will hopefully provide early warning of poor response, providing an opportunity to take the allograft option while the patient still has good prospects of cure. There is now good evidence that the molecular response after 2 to 3 months of therapy is a strong predictor of subsequent clinical and cytogenetic response."

Dr. Hughes is talking about Q-PCR monitoring.

Dr. Hughes gave an insight on how to screen for mutations in the absence of sensitive screening techniques and unavailability of these techniques except in selected centers.

"Serial mutation screening, once imatinib commences, may be valuable in high-risk cases but in nearly all cases, a rise in BCR/ABL levels (usually >1 log) is seen around the time of mutation detection and may be used as an indication of the need for mutation screening."

Andreas Hochhaus, MD (Germany):

"Since their introduction in the early 1990s, reverse-transcriptase polymerase chain reaction (RT-PCR) techniques have been rapidly incorporated into the management of CML patients. Because qualitative PCR was of limited value, quantitative PCR assays were developed to estimate the amount of residual disease in positive specimens. A variety of real-time PCR instruments are available and different approaches can be applied.

However, regardless of the apparatus actually used, a worldwide standard should be based on some simple considerations:

1. The sensitivity that can be obtained in PCR analysis depends on the number of cells and the total amount of RNA analyzed and on the use of a single or nested PCR approach.
   

Ideally, 5 Ã-- 107 white blood cells (WBCs), corresponding to 10 to 20 mL of peripheral blood, should be used.
(2) In multicenter studies with centralized molecular analysis, RNA should be stabilized at the bedside.
(3) The level of BCR-ABL transcripts per volume cDNA should be related to the expression of a commonly agreed standard gene, for example, total ABL. The definition of "undetectable BCR-ABL" in a given patient should be closely related to these universal recommendations. An "international Study on Standardization of Residual Disease Detection in BCR-ABL-positive Leukemia" was launched recently. If standardization can be achieved, quantitative PCR will become a robust basis for clinical decision making in patients on imatinib therapy."

Dr. Hochhaus is talking not only about the importance of Q-PCR but the need for standardization across the board.

Brian J Druker, MD (USA):

"After starting imatinib, we monitor blood counts at least once per month and obtain marrow samples every 6 months until a complete cytogenetic remission is obtained, then yearly thereafter. We have dispensed with a marrow sample at 3 months, as we would not change therapy based on the results. For example, if a patient had a CHR, but no cytogenetic response at 3 months, we would continue imatinib therapy for at least 3 more
months. Marrow samples are obtained yearly after a complete cytogenetic response is obtained to monitor for the emergence of clonal abnormalities in the Ph- clone, which thus far has been uncommon. Quantitative RT-PCR for Bcr-Abl is performed every 3 months on peripheral blood or marrow as results correlate quite well."

Dr. Druker is recommending Q-PCR monitoring with yearly BMB after CCR.

George Q. Daley. MD, PhD (USA):

"First, Goldman et al recommend monitoring imatinib-treated patients by cytogenetics on a bone marrow sample taken every 3 months to assess whether a patient is making progress toward complete cytogenetic remission, and to identify nonresponders or those who lose response. But given that popular patient websites provide intense coverage of the latest breaking news in the CML field, there are bound to be numerous inquiries to physicians about the need for molecular monitoring. It is important to point out the highly experimental nature of monitoring of BCR/ABL transcript number by quantitative polymerase chain reaction (PCR) and screening for mutations that might contribute to drug-resistance by DNA sequencing. These techniques are not routinely available to the vast majority of clinicians treating CML patients, and while cutting edge, have not yet proven to translate directly into improved patient outcomes."

Dr. Daley is cautions about the still experimental nature of Q-PCR.

Jorge Cortes, MD (USA):

"Patients have to be assessed with cytogenetic analysis, fluorescence in situ hybridization (FISH), and competitive, quantitative polymerase chain reaction (PCR) at the time of diagnosis. It is inappropriate to start therapy based only on a peripheral blood PCR for the Bcr/Abl rearrangement.

Patients with clonal evolution have a survival disadvantage when treated with imatinib as a single agent, and this can only be discovered at diagnosis by cytogenetics.

Continued Next Page

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