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CME/CE

Changing Paradigms in the Treatment and Monitoring of CML

  • Authors: Chairperson: Brian J. Druker, MD; Faculty: John Goldman, DM; Stephen D. Nimer, MD; Stephen G. O'Brien, MD, PhD; Jerald P. Radich, MD; Charles L. Sawyers, MD
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Target Audience and Goal Statement

This continuing education program is intended for physicians, pharmacists, and registered nurses in the specialties of medical oncology, oncology/hematology, and hematology.

The goal of this educational activity is to provide an update to oncologists, hematologists, oncology nurses, and pharmacists on current developments in the treatment and monitoring of patients with chronic myeloid leukemia (CML).

Upon completion of this activity, participants should be able to:

  1. Review new developments in the treatment of CML.
  2. Explain the therapeutic utility of disease-monitoring techniques for CML.
  3. Discuss current data on types of responses achieved with different therapeutic approaches.
  4. Identify optimal treatment strategies for the management of Ph+ leukemias.
  5. Describe how therapies might be integrated to maximize therapeutic outcome.


Author(s)

  • Brian J. Druker, MD

    JELD-WEN Chair of Leukemia Research, Professor of Medicine, Division of Hematology and Medical Oncology, Oregon Health & Science University (OHSU), Director of the OHSU Cancer Institute Leukemia Center; Joint academic appointments: Department of Cell and Developmental Biology and the Department of Biochemistry and Molecular Biology

    Disclosures

    Disclosure: Brian J. Druker, MD is a consultant for Novartis Pharmaceuticals Corporation.

  • John M. Goldman, DM

    Professor of Leukaemia Biology; Chairman, Department of Haematology, Imperial College Faculty of Medicine at Hammersmith Hospital, London, United Kingdom.

    Disclosures

    Disclosure: John Goldman, DM has nothing to disclose.

  • Stephen D. Nimer, MD

    Head of the Division, Hematologic Oncology, Chief of the Hematology Service, Memorial Sloan-Kettering Cancer Center, New York, NY; Professor of Medicine, Cornell University Medical College

    Disclosures

    Disclosure: Stephen D. Nimer, MD receives Clinical Trial Support from Novartis Pharmaceuticals Corporation and also serves on the Novartis Speakers' Bureau.

  • Stephen G. O'Brien, MD, PhD

    Head of the Division, Hematologic Oncology, Chief of the Hematology Service, Memorial Sloan-Kettering Cancer Center, New York, NY; Professor of Medicine, Cornell University Medical College

    Disclosures

    Disclosure: Stephen D. Nimer, MD receives Clinical Trial Support from Novartis Pharmaceuticals Corporation and also serves on the Novartis Speakers' Bureau.

  • Jerald P. Radich, MD

    Clinical Research Division, Program in Genetics and Genomics, Fred Hutchinson Cancer Research Center, Seattle, Washington.

    Disclosures

    Disclosure: Jerald P. Radich, MD has nothing to disclose.

  • Charles L. Sawyers, MD

    Professor of Medicine, Department of Medicine, Urology, and Pharmacology; Peter Bing Chair; Director of Prostate Cancer, Program Area, UCLA Jonsson Comprehensive Cancer Center; Associate Chief of Basic Research, Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.

    Disclosures

    Disclosure: Charles L. Sawyers, MD receives grants/research support from Novartis Pharmaceuticals Corporation.


Accreditation Statements

    For Physicians

  • This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME). The Postgraduate Institute for Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

    The Postgraduate Institute for Medicine designates this educational activity for a maximum of 3.0 category 1 credits toward the AMA Physician's Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity.

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    For Nurses

  • This educational activity for 3.5 contact hours is provided by Postgraduate Institute for Medicine. Postgraduate Institute for Medicine is an approved provider of continuing education by the Colorado Nurses Association, an accredited approver by the American Nurses Credentialing Center's Commission on Accreditation.

    The Postgraduate Institute for Medicine is approved by the California Board of Registered Nursing, Provider Number 13485, for 3.5 contact hours. This certificate must be retained by the licensee for a period of four years after the course ends.

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    For Pharmacists

  • The Postgraduate Institute for Medicine is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

    The Postgraduate Institute for Medicine designates this continuing education activity for 3.0 contact hours (0.30 CEUs) of the American Council on Pharmaceutical Education (Universal Program Number 809-999-03-004-H01).

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For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]


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This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page.

Follow these steps to earn CME/CE credit:

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CME/CE

Changing Paradigms in the Treatment and Monitoring of CML

Authors: Chairperson: Brian J. Druker, MD; Faculty: John Goldman, DM; Stephen D. Nimer, MD; Stephen G. O'Brien, MD, PhD; Jerald P. Radich, MD; Charles L. Sawyers, MDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED

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Monitoring and Management of CML , Presented by John M. Goldman, DM

A History of Leukemia

  • I am happy to be talking about chronic myeloid leukemia (CML).

  • Monitoring and Management of CML

    Slide 1.

    Monitoring and Management of CML

    (Enlarge Slide)
  • I've gone back a few years, actually to 1845, to remind people of some of the early descriptions, probably the first descriptions, of leukemia anywhere in the world.

    In Edinburgh, there was John Hughes Bennett, and this is taken from one of his very early papers in 1845, and in Berlin, Virchow, who was a very young man when he first described what was later called leukemia. Virchow writes Weifes Blut.

  • Slide 2.

    (Enlarge Slide)
  • There probably was no important innovation in the understanding of CML until the work of Nowell and Hungerford, working in Philadelphia in 1960. They were able to recognize an abnormality in the chromosomes of the leukemia cells of a small number of patients with what they called chronic granulocytic leukemia. I guess chronic myeloid and chronic granulocytic are almost synonymous.

  • Slide 3.

    (Enlarge Slide)
  • It looked almost like a Y chromosome, but they looked at women to be sure that it probably wasn't a Y chromosome, and the discovery depended a lot on the improvement of techniques to look at chromosomes. Until about 1960 there had been debate as to the actual number of chromosomes in human cells. It was thought at one stage to be 48, and people sort of centered eventually on 46.

  • Slide 4.

    (Enlarge Slide)
  • This is the original Nowell and Hungerford paper published in 1960. All 7 individuals showed a similar minute chromosome, and none had any other frequent or regular chromosome change. They also were normal cells. "The findings suggest a causal relationship between the chromosome abnormality observed and chronic granulocytic leukemia."

    This is a moral for people on the verge of a very important discovery in leukemia. First of all, you can keep your paper remarkably short; this is the whole paper. And secondly, your last sentence is well worth planning carefully.

  • A Minute Chromosome in Human Chronic Granulocytic Leukemia

    Slide 5.

    A Minute Chromosome in Human Chronic Granulocytic Leukemia

    (Enlarge Slide)
  • Let's jump to more modern times now. This is a scheme of the normal chromosome 9 and 22, and 9q+ and 22q-, and the juxtaposition of ABL and BCR sequences on the Philadelphia chromosome, and also the interesting reciprocal fusion gene BCR-ABL, which is of considerable interest at the present time.

    Nowell and Hungerford didn't name this the Philadelphia chromosome; that probably is the work of the Edinburgh group in 1960. Jacobs and others, in honor of Nowell and Hungerford of Philadelphia, called it Philadelphia 1 in the expectation that there would be many more specific chromosomal defects recognized from Philadelphia. But I think we can drop the "1" now and just call it the Philadelphia chromosome.

  • The t(9;22) Translocation Produces the Philadelphia (Ph) Chromosome

    Slide 6.

    The t(9;22) Translocation Produces the Philadelphia (Ph) Chromosome

    (Enlarge Slide)

Methods for Detecting Disease and Monitoring Response to Treatment

  • My task is to address the issue of how to monitor a patient responding to treatment, and by treatment I mean anything that you care to consider in terms of treating CML.

  • What Is the Best Method for Monitoring a Patient's Response to Treatment?

    Slide 7.

    What Is the Best Method for Monitoring a Patient's Response to Treatment?

    (Enlarge Slide)
  • There's a hierarchy of measurable phenomena in the disease, hematologic being the most obvious, cytogenetic less obvious, and molecular the most sensitive or specific for CML.

  • Rank Order of Recognizable Disease

    Slide 8.

    Rank Order of Recognizable Disease

    (Enlarge Slide)
  • Over the years, we put together a hypothetical relationship as to how one might relate the total number of leukemia cells in a person's body at different times responding to treatment with the molecular finding of transcripts expressed as BCR-ABL/ABL, a ratio, and then as a percent, both on a log scale. When you have 1012 cells in your body, you have a leucocytosis. But as you treat a person with anything that's effective, you reduce the leucocytosis and leave them Philadelphia positive. As the treatment is more effective, you reduce the Philadelphia positivity and leave them positive by reverse transcriptase-polymerase chain reaction (RT-PCR), and then as you increase the effectiveness of the treatment, the RT-PCR becomes negative, but you may still have a million leukemia cells in the body.

    In no sense is RT-PCR negativity comparable or identical to eradication of leukemia from the body. Eradication of leukemia from the body I put as A1, but this is A2 where you still have a substantial number of leukemia cells, but below the level of RT-PCR detection.

  • Relative Sensitivities of the Principal Methods for Detecting Disease

    Slide 9.

    Relative Sensitivities of the Principal Methods for Detecting Disease in Responding and Relapsing Patients

    (Enlarge Slide)
  • To look at white cells, you need the microscope or the Coulter counter. To look at chromosomes, conventional metaphase chromosomes have a sensitivity of the order of 5% perhaps, and fluorescence in situ hybridization (FISH), which can be done as well on peripheral blood as bone marrow, has perhaps a slightly higher order of sensitivity for the simple reason that you can look at more cells with comparative ease.

    Southern blotting has been very useful in the past, and Western blotting has also been very useful in the past, but neither technique is now used routinely for monitoring low levels of disease simply because RT-PCR, which can be used on bone marrow or peripheral blood, has a high degree of sensitivity, up to 1 in 100,000, 1 in a million.

  • Sensitivities of the Methods to Detect Leukemia in Responding and Relapsing Patients

    Slide 10.

    Sensitivities of the Methods to Detect Leukemia in Responding and Relapsing Patients

    (Enlarge Slide)
  • This is an example of FISH with a double fusion probe, which stains BCR one color and ABL another color. On the left is a normal interphase, and on the right a CML cell. The normal genes are 9 and 22 separate, and the fusion on 9q+ and 22q- give what should be a yellow signal, or a fused blue and red signal. In reliable hands, it is a most reproducible technique.

  • Vysis Dual Fusion BCR-ABL Probe

    Slide 11.

    Vysis Dual Fusion BCR-ABL Probe

    (Enlarge Slide)

Chronic Myeloid Leukemia Transcripts and Use of Polymerase Chain Reaction

  • Switching to BCR-ABL at the molecular level, this is a schematic representation of the transcripts that characterize CML, and 98% or 99% of patients have one or the other, or both these transcripts, which are very specific for CML. If you try to do a PCR at the DNA level as we have done in the past, the breakpoint on BCR is variable, and the breakpoint on ABL is even more variable, so you need primers specific for each patient.

    The elegance of doing it off the cDNA is that your primers are disease specific and not patient specific, and that greatly facilitates the situation.

  • BCR-ABL Transcripts in CML

    Slide 12.

    BCR-ABL Transcripts in CML

    (Enlarge Slide)
  • Here is an example of the way in which nested primer PCR is established, amplifying across the breakpoint in 2 steps and giving a signal corresponding to the b3a2 or the b2a2 junctions. Just a few patients have both junctions present at the time of diagnosis, which is of considerable interest.

  • Residual Disease: Nested PCR

    Slide 13.

    Residual Disease: Nested PCR

    (Enlarge Slide)
  • The nested primer can be adapted by introducing a competing molecule that you amplify in the same amplification sequence with the unknown. The competitor has an insert that makes the size different and therefore you can differentiate it from the unknown BCR-ABL. Using this technique, you work out an equivalence point where the strength of the amplification for the competitor and for the unknown material is approximately equal, as shown by the arrow. And then reading off a standard curve, you can work out roughly how many transcripts were present in the original material.

  • Competitive RT-PCR

    Slide 14.

    Competitive RT-PCR

    (Enlarge Slide)
  • Nested primer PCR has largely, but not entirely, been replaced by cycle real-time quantitative PCR where there are 2 technologies. One involves the hydrolysis of the probe, which is attached to the unknown material in the presence of a fluorescent dye and a quencher, and the advent of the exonuclease removes the quencher and allows the material to become fluorescent.

    The other is a technique involving resonance energy transfer by hybridization called the LightCycler technology. The essence of it is that after a given number of amplification cycles, you suddenly get a fluorescent signal that can be measured and again applied to a standard curve, and off the standard curve you can read the approximate number of BCR-ABL transcripts. This is the principle of the TaqMan real-time PCR, which is much simpler to use than the nested primer technology, although there's some debate as to the possibility that the nested primer technology could still be more sensitive, and could perhaps be more sensitive by a factor of 10.

  • Real-Time Quantitative RT-PCR

    Slide 15.

    Real-Time Quantitative RT-PCR

    (Enlarge Slide)

Molecular Monitoring in Chronic Myeloid Leukemia

  • What's the purpose of molecular monitoring in CML? What are the uses? It's useful for early detection of relapse after allografting. It's useful for monitoring the results of giving donor lymphocytes in the transplant situation. It's useful for looking at leukemia cell contamination, and for monitoring response in complete cytogenetic responders to interferon or to imatinib.

  • Clinical Value of Molecular Monitoring in Chronic Myeloid Leukemia

    Slide 16.

    Clinical Value of Molecular Monitoring in Chronic Myeloid Leukemia

    (Enlarge Slide)
  • Here you have an example of the use of this technique after allografting. These are 2 separate patients monitored over time after allografting. One was weakly positive at the RT-PCR level, and then became negative. The other, as you can see from the increasing numbers, relapsed at the RT-PCR level, at the molecular level, got donor lymphocyte infusions, and then became negative thereafter. The chromosomal relapse came after the molecular relapse, but also responded to the donor lymphocyte infusions.

  • Early Detection of Relapse Post SCT

    Slide 17.

    Early Detection of Relapse Post SCT

    (Enlarge Slide)
  • This is looking at molecular data in 2 groups of patients, one treated by allogeneic stem cell transplant and the other by interferon alfa. Both groups of patients have achieved cytogenetic remissions. If you have a cytogenetic remission after allografting, in most cases the BCR-ABL transcript is undetectable, but not all.

    Conversely, after interferon most complete chromosomal remission patients will still have detectable disease in the peripheral blood or bone marrow, but there'll be just a few negatives.

  • Molecular Evidence of Leukemia in Complete Cytogenetic Responders - 1

    Slide 18.

    Molecular Evidence of Leukemia in Complete Cytogenetic Responders - 1

    (Enlarge Slide)
  • Looking at interferon-treated patients, the median level of transcript numbers in complete chromosome responders has predicted value. On the left are patients who in the duration of observation did not relapse, did not have progressive disease, and on the right are patients who did have progressive disease, in some cases to blastic transformation.

    The median level for the non-progressors vs the progressors is perhaps one log or more than one log lower. So in the interferon responders, the level of molecular disease is predictive.

  • Complete Cytogenetic Responders After IFN Therapy: MRD Levels Predict Risk of Relapse

    Slide 19.

    Complete Cytogenetic Responders After IFN Therapy: MRD Levels Predict Risk of Relapse

    (Enlarge Slide)

Imatinib and an Update on the IRIS (0106) Study

  • We'll switch now to a few points about imatinib (STI571).

    The update on the IRIS 0106 study, which compares the results of imatinib with interferon/ara-C in previously untreated patients shown in May of 2002, showed that the complete chromosome remission rate in previously untreated patients treated with imatinib was 68%. I gather the update will show that the 18 months of follow-up gives a figure of chromosomal response rate in the range of 70%, which is a remarkable achievement, and I draw your attention to the comparison figure of 7% in the control arm.

  • Best Cytogenetic Response in the IRIS (0106) Study - 5/2002

    Slide 20.

    Best Cytogenetic Response in the IRIS (0106) Study - 5/2002

    (Enlarge Slide)
  • This summarizes some molecular monitoring of patients in this study, interferon/ara-C in red and imatinib in blue. It summarizes data from Australia, and the data are expressed as log depletion starting with a baseline of untreated patients. The important point is that the reduction in molecular monitoring, the reduction in transcript numbers within the first 3 months is very rapid, and more rapid with imatinib than with interferon/ara-C.

    There is the suggestion of a plateau, but these are very early data, up to a maximum of 1 year, and one can't draw too many conclusions from these data. The molecular analysis of the 0106 study in totality is similar, but perhaps not identical to what I've just shown from Australia.

  • Log Depletion of BCR-ABL in CCR Patients - Imatinib (n=171) vs IFN/Ara-C (n=14)

    Slide 21.

    Log Depletion of BCR-ABL in CCR Patients - Imatinib (n=171) vs IFN/Ara-C (n=14)

    (Enlarge Slide)
  • Turning to the United Kingdom, we've looked at 92 patients who achieved complete chromosomal remission treated in various phases of CML. Many of them had already had interferon previously, and of the 92, 8 appeared to satisfy our criteria for absent or undetectable transcripts in their peripheral blood. I'm slightly unhappy about the term PCR negativity because it depends so much on the nature of your PCR reaction, but 84 patients still had measurable disease in a range not very different from the chromosome responders to interferon alfa. And the duration of follow-up from starting treatment is very much shorter in the imatinib-treated patients than in the interferon-treated patients.

  • Molecular Evidence of Leukemia in Complete Cytogenetic Responders - 2

    Slide 22.

    Molecular Evidence of Leukemia in Complete Cytogenetic Responders - 2

    (Enlarge Slide)

How Should Patients With Chronic Myeloid Leukemia Be Monitored?

  • How then should a patient responding to treatment be monitored?

  • How Then Should a Responding Patient Be Monitored?

    Slide 23.

    How Then Should a Responding Patient Be Monitored?

    (Enlarge Slide)
  • It's important to stress that I don't know the answer. All I can do is make some suggestions, which are certainly subject to discussion and criticism. In a responding patient, a patient whose leukocyte count and platelet count are now in the normal range, it would be reasonable to look at the cytogenetics at 3-month intervals, although I'm quite sure some of our patients will object to that.

    Once the patient is Philadelphia negative for a minimum period of perhaps 6 months, I think it would be reasonable to omit marrow examinations, and the combination of RT-PCR on blood and FISH on blood may be acceptable. The problem with this is that you may miss evidence of clonal evolution in the Philadelphia-positive population, if there is one, but there may also be evidence of clonal evolution in the Philadelphia-negative population, which is a very interesting observation.

    I think you can use the argument that a rising RT-PCR value, a rising number of transcripts, could indicate the need for a bone marrow, but you may miss clonal evolution in the Philadelphia-negative population.

    The final point is that we don't have good criteria at the present time for defining relapse at the molecular level. That relates partly to the fact that different laboratories are still using slightly different techniques, and partly to the fact that we just don't know the clinical significance of a 2-log increase in transcript numbers.

  • Monitoring of Responding Patients

    Slide 24.

    Monitoring of Responding Patients

    (Enlarge Slide)