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Report on the Relative Efficacy of Oral Cancer Therapy for Medicare Beneficiaries Versus Currently Covered Therapy

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Part 3. Imatinib for Chronic Myeloid Leukemia (CML)


Policy Context of the Current Technology Assessment

Section 641 of the Medicare Prescription Drug, Improvement, and Modernization Act (MMA) calls for a demonstration that would pay for drugs and biologicals that are prescribed as replacements for drugs currently covered under Medicare Part B. The demonstration project will be national in scope and will be limited to 50,000 beneficiaries or $500,000,000 in funding, whichever comes first. Forty percent of the funding for this demonstration will be reserved for oral anti-neoplastic drugs.

The Center for Medicare and Medicaid Services (CMS) has requested an assessment of the efficacy of selected oral cancer therapies included in the demonstration relative to drugs currently covered under Medicare Part B. This assessment will provide information that will be used to evaluate the likely effects of the demonstration on patient outcomes and may also provide underlying information to be used for cost-effectiveness analyses that will be completed by CMS.

The scope of the assessment will be limited to the following demonstration drugs and conditions:

  • Imatinib for treatment of chronic myeloid leukemia.
  • Imatinib for treatment of gastrointestinal stromal cancer.
  • Gefitinib for treatment of non-small cell lung cancer.
  • Thalidomide for treatment of multiple myeloma.

This report is responsive to the first item: an assessment of imatinib for the treatment of chronic myeloid leukemia (CML).

Clinical Context of the Current Technology Assessment

Chronic myeloid leukemia (CML, a.k.a. chronic myelogenous leukemia) is a malignant clonal disorder resulting from the cancerous transformation of a very primitive hematopoietic stem cell.13,14 CML's hallmark is the 9;22 translocation that produces the BCR-ABL gene, ultimately leading to an abnormal tyrosine kinase protein that renders the malignant activity. Imatinib is a competitive inhibitor of this tyrosine kinase that works by blocking the signal from the BCR-ABL protein, so that the cancerous cells stop growing. Imatinib was the first targeted cancer drug to be approved by the Food and Drug Administration (FDA) in 2001.

As a sign of imatinib's potential, more than 110 relevant phase II-III and predictor studies have been published in a short interval. This "clinical context" section is provided as both a scientific primer to review the emerging science behind imatinib, and as a structural framework that will ultimately be used to organize the studies reviewed.

This section is organized in according to the following:

  • Burden of illness.
  • Diagnosis.
  • Staging
    • Chronic phase.
    • Accelerated phase.
    • Blastic phase/blast crisis.
  • Treatment
    • Approach to treatment
      • Newly diagnosed.
      • Relapsed.
    • Goals of treatment.
    • Efficacy and tolerability of treatment options other than imatinib.
  • Prognosis and prognostic factors
    • Clinical prognostic factors.
    • Medical prognostic factors.

Incidence and Prevalence

Incidence and Prevalence. There are approximately 4,600 new cases of CML diagnosed in the United States (U.S.) annually, accounting for 13-15 percent of all cases of adult leukemia, with about 850 deaths annually.15,16 The incidence is 1-2 cases per 100,000 population, and incidence increases with age.16 CML occurs predominantly in middle-aged adults, with a median age variably reported between 45 and 67 years.14,16,17 Up to 76 percent of patients are older than 50 years at the time of diagnosis and 64 percent are over 60 years.17 CML rarely occurs in children, with an incidence rate less than 1/20th that seen in adults over age 45.18


Presentation and diagnosis. In developed countries, most patients are diagnosed when asymptomatic based on laboratory abnormalities. Typical laboratory findings include a markedly elevated white blood cell count (leukocytosis), anemia, and elevated platelets (thrombocytosis). Diagnosis and staging require a peripheral complete blood count with a white blood cell differential analysis, bone marrow examination with quantification of the percentage of blasts and basophils, and cytogenetic studies for the Philadelphia chromosome or its variants (see below). Histopathologic examination the bone marrow aspirate demonstrates excessive numbers of cells (hypercelluar marrow) with a shift in the myeloid series to immature forms; the number of immature cells increases as patients progress from chronic to blastic phases of the disease.19 White blood cell differential counts of both peripheral blood and bone marrow demonstrate a spectrum of mature and immature granulocytes similar to that found in normal marrow. Increased numbers of eosinophils, basophils or monocytes may be present, and a megakaryocytosis may be noted in the marrow. Lymphocyte counts are usually suppressed, and the myeloid/erythroid ratio in the marrow is usually markedly elevated.

When symptomatic at diagnosis, most patients present with fatigue, weight loss, abdominal fullness, bleeding and/or night sweats.20 Bruising and an enlarged spleen are common.

Role of the Philadelphia chromosome. The "Philadelphia chromosome" (Ph) is seen in >90 percent of cases of CML.21 Ph is a balanced reciprocal translocation between chromosomes 9 and 22 (Figure 1a); the cytogenetic designation is t(9;22)(q34;q11).13 ABL is transferred from chromosome 9 to 22. DNA from chromosome 22 is shifted to 9 to take ABL's place. This translocation leads to the fusion of two parts of normal genes, the ABL gene on a portion chromosome 9 with a section on chromosome 22 called BCR. ABL is hooked with a breakpoint promoter region (BCR); this promoter area provides a continuous signal to the cell to transcribe the gene for the tyrosine kinase protein coded in ABL. The BCR-ABL gene is transcribed into messenger RNA (mRNA) and the mRNA is subsequently translated into the tyrosine kinase protein (Figure 1b). The tyrosine kinase fusion protein that is produced is continuously active irrespective of regulatory influences within the cell (i.e., constitutively active). This uncontrolled enzymatic activity then usurps the normal physiologic processes of the cell.

The formation of the BCR-ABL fusion gene within a pluripotential hematopoetic stem cell is the first step in developing CML.13 The exact mechanism prompting formation of BCR-ABL is unknown. Daughter cells of the mutated stem cell all have BCR-ABL; all of the mutated cells more readily survive and produce progeny as compared to normal hematopoetic cells. The mutated CML cells with their constitutively active ABL tyrosine kinase protein gradually displace the normal cells within the bone marrow and other hematopoetic areas. The exact reason that cells with BCR-ABL more easily divide and take over is not known; however, growth-stimulating hormones and defective mechanisms of cell death are likely involved.13

Importantly, the mutated CML cells only displace normal hematopoetic cells and do not destroy residual normal stem cells. Therefore return to a normal or nearly normal hematopoetic state after eliminating the CML cells is presumed possible.

Detection of BCR-ABL and the tyrosine kinase fusion protein. Bone marrow cytogenetic analysis (Figure 1b) has long been considered the gold standard for evaluating CML and the presence of Ph.16 Only cells going through the cell cycle are measured, so quiescent cells with Ph may be missed. Cytogenetic analysis is described in terms of the percent of metaphase cells with the cytogenetic abnormality.

Currently, reverse transcriptase polymerase chain reaction (RT-PCR) analysis is the most sensitive way of detecting BCR-ABL mRNA transcripts; it can be performed on peripheral blood (Figure 1b).11,22 RT-PCR can be used to pick up evidence of the mRNA, even when low copy numbers are present. Despite being an excellent tool, RT-PCR does have problems. The threshold of detection is such that the test may be negative and a patient could still harbor a million or more residual CML cells.13 Alternatively, patients who appear to be disease-free by other parameters may continue to have evidence of BCR-ABL mRNA by RT-PCR for years after disease regression.11 Low levels of BCR-ABL mRNA can also be detected by RT-PCR in the blood of healthy individuals, and this risk must always be considered when evaluating results.23 Another limitation is that RT-PCR is dependent upon active transcription in order to detect an abnormality; quiet non-dividing interphase CML cells may be missed.22 Recently, RT-PCR has also indicated "real-time" or quantitative PCR, indicating the ability to measure the number of mRNA copies present, extrapolating back to the amount of DNA and the number of cells with BCR-ABL genes in them. To avoid confusion between traditional RT-PCR and newer methods, the original PCR technique will be termed RT-PCR and the newer technique quantitative RT-PCR (Q-RT-PCR). Q-RT-PCR is most commonly expressed in terms of the ratio of BCR-ABL to ABL transcripts.

Other methods of detecting Ph include fluorescence in situ hybridization (FISH) which will detect dividing (metaphase) and interphase CML cells (Figure 1b). FISH uses two-color labeling to identify pieces of different chromosomes that shouldn't be near each other. Some authors report a high false positive rate that may decrease the utility of this test when the proportion of CML cells to normal cells drops less than 10 percent.16 DNA sequencing and Southern blot analysis (Figure 1b) provide information on the exact genetic mutation, but are not practical for widespread clinical application. Western blots and immunoprecipitation (Figure 1b) can be used to evaluate the tyrosine kinase fusion protein product.

Ph-negative CML. There are a small group of patients with Ph-negative CML.24 True Ph-negative CML has a poorer prognosis than Ph positive CML, however the majority of "CML Ph-negative" patients actually have Ph detectable by RT-PCR or Southern blot. Prognosis for those patients whose Ph is only detectable by very sensitive methods is the same as it is for those patients with readily detectable Ph.25 Patients with true Ph-negative CML by RT-PCR have a course more consistent with chronic myelomonocytic leukemia, which is a different illness; some authors argue that no patients with CML are truly Ph-negative.26


Stage and course. The information provided in the physical exam, peripheral white blood count, bone marrow examination, and cytogenetic studies, FISH or RT-PCR are used to determine the patient's stage of illness and predict their course. The staging in CML is usually described in terms of "phases".

CML historically has had a triphasic course, presenting in an initial chronic phase (CP) with a median duration of 3-5 years, invariably progressing over time to an accelerated phase (AP) with a median duration of 6-18 months and finally to blastic phase (BP) lasting 3-6 months.14,27 Blast crisis (BC) is a period within BP that resembles acute leukemia, with two-thirds of patients having an acute myeloblastic or undifferentiated type of leukemia and the other one-third having an acute lymphoblastic leukemia.16 In BC, patients have fever, malaise and an enlarging spleen in addition to the increasing number of blasts in their blood or bone marrow. In up to one-fourth of patients, blast crisis develops without an intervening accelerated phase.28 The terms BP and BC are often used interchangeably (reviewers comments) and may not be as distinct as the literature suggests; for this reason, we have grouped BP and BC in the review of studies cited in this document and described this stage of disease in the same way as the authors of each individual study had in the original manuscript. The basic characteristics of the stages are provided in Figure 2.

Varying phase assignments. The definitions of the three phases or "stages" of CML have fluctuated through the years. The definitions presented in Figure 2 reflect that reported on the NIH Web site, Staging criteria have been proposed from MD Anderson29, Sokal and colleagues30, the International Bone Marrow Transplant Registry31, and others. The discrepancies among the stages are most important for "accelerated phase" where some patients with chronic phase CML by MD Anderson or other criteria would be reclassified as "accelerated phase" by the International Bone Marrow Transplant Registry (IBMTR). Since stage is such an important prognostic factor, "stage migration" due to varying use of definitions may make comparison of efficacy outcomes difficult outside of the randomized controlled trial setting. This is especially true for bone marrow transplant analyses that use the IBMTR criteria and compare results to historical controls using other criteria.31


Approach to treatment. Treatment planning requires matching the likely most effective therapy with the patient in terms of diagnosis, phase of illness, previous therapies, and patient preference. Assuming that the diagnosis of Ph+ CML has been verified and the patient wishes to proceed with therapy, treatment planning can be considered within the matrix shown in Figure 3.

Treatment goals and assessment. Treatment in CML is aimed at reduction in the leukemic cell burden, and hopefully "cure." Reduction in the total white blood cell count is termed the "hematologic response." Reduction in the number of Ph cells is the "cytogenetic response." Since Ph+ cells produce mRNA that leads to the BCR-ABL tyrosine kinase protein, reduction in the amount of mRNA produced is an indicator of reduction in the number of active Ph+ cells. This is called "molecular response."

The goals of treatment for CML are to achieve a hematologic remission (normal complete blood count and physical examination), to achieve cytogenetic remission (normal chromosome returns with 0 percent Ph-positive cells), and, most recently, to achieve molecular remission (negative RT-PCR result for the mutational BCR-ABL mRNA; Figure 4). Major cytogenetic and molecular responses predict survival;11 although minor or minimal cytogenetic responses are of little prognostic significance.

Cytogenetic and molecular responses are divided into major, minor and minimal responses. Molecular responses are measured by Q-RT-PCR and are most commonly expressed as log reductions from median pre-therapeutic value.32,33 Importantly, the vocabulary for the description of molecular responses has been evolving, and have included descriptions in "change in median ratios," longitudinal graphs, and transcript velocity. The measure of log reduction is becoming more standard.

The need for a complete molecular remission is hard to determine, as is the exact definition of "cure" in CML. CML patients who are alive and disease-free 5 years after an allogeneic stem cell transplant are generally considered to be cured.13,34 Even when patients are in CCR, evidence of CML can be found. Bhatia and colleagues showed that all of the 15 patients in Complete CR studied had evidence of BCR-ABL in their CD34+ cells as identified by FISH or RT-PCR up to 61 months after starting imatinib.27 O'Dwyer reported similar findings for seven patients in Major CR.35 Using sensitive RT-PCR techniques Paschka, et al. found evidence of BCR-ABL in all samples of CCR patients on imatinib.10 Taken together, these data support the notion that complete remission in CML may be conversion to a low grade chronic disease with continuous potential for relapse over the long term. Using the previous definition from the transplantation literature that "cure" is continued Complete CR at 5 years,13,34 "cure" may be a relative state of disease control rather than complete eradication. Whether "cure" indicates complete eradication of all CML clones or a minimal residual disease burden that can be kept in check by the patient's immune surveillance system is unknown. The "graft-versus-leukemia" effect described for allogeneic stem cell transplants is an example of this presumed immune surveillance.36

Disease progression can be defined in several ways. Older studies predominantly present disease progression in terms of loss of hematological or cytogenetic response.28,37 Newer studies describe recurrence of Ph positive cells. More recently, disease progression has been defined as > 10-fold increase in BCR-ABL/ABL percent as determined by Q-RT-PCR.33

Treatment options. Treatment of CML is usually initiated when the diagnosis is established;14 however, the optimal front-line treatment for chronic-phase CML is controversial. Some argue that the only consistently successful curative treatment of CML for more than half of eligible patients has been allogeneic bone marrow or stem cell transplantation.[Goldman, 2003 #666;] Ideally the patient is transplanted in chronic phase.16 However, many patients are not eligible for this approach because of age, comorbid conditions, or lack of a suitable donor. Currently, for patients able to undergo transplant the 5-year survival rates are quoted as 50-80 percent for overall survival and 30-70 percent for disease-free survival.16 In a 2003 phase II study of 131 CML patients in newly diagnosed chronic phase (median age 43 years, range 14-66), 1-year survival was estimated at 91 percent and 3-year survival at 86 percent.39 The 15-30 percent who are going to relapse do so within the first 5 years. In addition, there is substantial morbidity and mortality from allogeneic bone marrow or stem cell transplantation; a 15-30 percent treatment-related mortality can be expected.17 In the 2003 study of 131 transplanted CML patients, 65 percent developed acute graft vs. host disease (GVHD), 7 percent had Grade 3 or 4 GVHD, and 60 percent developed clinically extensive chronic GVHD at 1 year after transplant.39 The estimated rate of non-relapse-related death was 10 percent (95 percent CI, 5-15 percent) at 1 year and 14 percent (95 percent CI, 7-21 percent) at 3 years. Pulmonary toxicity, infection, and GVHD were the main causes of death.

Prior to the approval of imatinib, the therapy of choice for those patients not eligible for transplant was interferon alfa. Long-term data demonstrate that approximately 10-30 percent of patients treated with interferon alpha have a complete cytogenetic response (CCR) with no evidence of the BCR-ABL translocation by any available test and the majority of these patients are disease-free beyond 10 years.13 In a single-institution review of 512 early CP patients treated with interferon-based therapies between 1981 and 1995, 27 percent achieved a CCR and those patients who achieved a CCR had a 10-year survival was estimated at 78 percent.40 In a systematic review and meta-analysis of seven randomized trials comparing interferon with traditional myelosuppressive chemotherapy such as hydroxyurea or busulfan, interferon was more efficacious with statistically better survival (p<0.00001 overall).41 The annual death rate was reduced by 30 percent (standard deviation (SD) 6 percent) with the use of interferon; 5-year survival rates were 57 percent with interferon alpha and 42 percent with chemotherapy (absolute difference 15 percent (SD 3 percent), p<0.00001). Doses ranged from 2-9 million units/day. Maintenance of therapy with interferon is required. Some patients experience side effects that preclude continued treatment.

Interferon combined with cytarabine is more efficacious than interferon alone. In a randomized control trial (RCT) of interferon-alpha 2b (5 million units/m2/day) with hydroxyurea (50 mg/kg/day) induction, interferon plus cytarabine (monthly 10-day courses of 20 mg/m2/day) with hydroxyurea induction, or hydroxyurea induction alone involving 810 participants with newly diagnosed CP CML, interferon plus cytarabine was superior with 41 percent achieving Major cytogenetic response (CR) vs. 24 percent for interferon alone (p=0.001).42 The estimated 3-year survival was 86 percent for interferon plus cytarabine and 79 percent for interferon alone (p=0.02). Cytarabine was discontinued for evidence of CCR on two occasions; interferon was continued indefinitely unless intolerable. Major side effects leading to discontinuation of interferon plus cytarabine therapy and affecting >15 percent of participants included weight loss/asthenia (48 percent), nausea/vomiting/diarrhea (45 percent), hematologic toxicity other than low platelets (31 percent), mucositis (21 percent), low platelets (20 percent), rash (19 percent) and depression (15 percent). Major side effects leading to discontinuation of interferon therapy and affecting >15 percent of participants included weight loss/asthenia (20 percent), nausea/vomiting/ diarrhea (14 percent), and depression (21 percent). Overall, 26 percent of interferon plus cytarabine and 27 percent of interferon only participants discontinued therapy due to adverse effects.

Myelosuppressive therapy has also been a mainstay of treatment with the goal to convert a patient with CML from an uncontrolled phase to one with hematologic remission and normalization of the physical examination and laboratory findings.16 Hydroxyurea, an inhibitor of deoxynucleotide synthesis, is the most common agent used. Most patients achieve hematologic remission within 1-2 months however the duration is limited and rarely is a cytogenetic or molecular remission obtained. Other agents include busulfan, an alkylating agent. In a RCT comparing hydroxyurea to busulfan for chronic phase CML, the median survival was 45.4 months for busulfan and 58.2 months for hydroxyurea (p=0.008).43 Less than 3 percent of patients across the study had a cytogenetic response. Side effects were predominantly described for busulfan, consisting of pulmonary fibrosis and prolonged marrow suppression lasting for months. Adverse events were virtually unseen with hydroxyurea.

Since tyrosine kinase activity is required for the transforming function of the BCR-ABL fusion protein, a specific inhibitor of the kinase could be an effective treatment for patients with CML.13 Imatinib mesylate is a compound that inhibits the BCR-ABL protein. Imatinib has been shown to have activity in all phases of CML, including interferon-refractory CML and CML which has recurred after a stem cell transplant. The efficacy and tolerability profile of imatinib for CML is the major focus of this review. However, no long-term data exist as yet in regard to the durability of response, and there only emerging data about the efficacy of salvage strategies using interferon alfa or allogeneic stem cell transplantation after disease progression on imatinib. New agents for imatinib-refractory CML are in development or being tested.

Considerations when evaluating treatment efficacy. Differences in characteristics at presentation and response to therapy may depend on the particular population under investigation and referral patterns, as CML patients referred for clinical trials and to tertiary care centers tend to be younger and more commonly in good-risk categories.16 Other challenges to interpreting this literature include the following:

  • Participant population characteristics.
  • Well established prognostic factors exist that may be variably represented in the participant population.
  • Stage migration.
  • Moving baseline for survival.
  • Contribution from supportive care.
  • Ph only detected in 90-95% of CMLs and Ph-negative CML may not be CML at all.
  • Not all Ph positive diseases are CML.
  • RT-PCR is best test for detection but is not entirely sensitive and may be abnormal in healthy individuals.

Prognosis and Prognostic Factors

Prognosis. Exact figures for median survival are difficult to determine. Historically, median survival for CML was 3 years from the time of diagnosis with less than 20 percent of patients alive at 5 years.16,29 Most current documents quote median survival of untreated CML as 4-6 years, with initial improvements due to earlier diagnosis, better supportive care, and improved anti-CML therapy.29 In the pre-imatinib era of 1993, median survival was 5-6 years; 75-85 percent were alive at 3 years, 50-60 percent at 5 years, and more than 30 percent alive at 10 years.29 Historically, chronic phase patients with HLA-identical sibling donors can expect approximately 50 percent chance of cure with an allogeneic stem cell transplant.

The MD Anderson single-institution experience prior to imatinib was reported by Kantarjian, et al. in 2004.44 Among a historical cohort of 204 patients with early chronic-phase CML (i.e., diagnosed within 12 months) treated at their institution from 1982 to 1992 with interferon-based therapies, 37 (18 percent) had undergone allogeneic transplant as first line therapy, 27 (13 percent) homoharringtonine-based therapy, 86 (42 percent) hydroxyurea and/or busulfan, 24 (12 percent) cytarabine-based regimens, and 30 (15 percent) on other regimens. Among the 37 patients who underwent allogeneic transplant as initial treatment, the estimated 5-year survival was approximately 55 percent and 10-year survival was 42 percent. Sixty additional patients underwent allogeneic transplant after failure of a previous treatment, and 17 percent were still alive after a median followup of 109+ months after the transplant. Among the patients who received homoharringtonine-based therapy as initial treatment, the estimated 5-year survival was approximately 40 percent and 10-year survival was approximately 32 percent. Among the patients who received some other therapy as initial treatment, the estimated 5-year survival was approximately 22 percent and 10-year survival was approximately 20 percent.

Clinical prognostic factors. Certain patient and disease factors denote poorer survival; these include:

  • Increased spleen size (splenomegaly).
  • Older age.
  • Male gender.
  • Elevated serum lactate dehydrogenase (LDH).
  • Cytogenetic abnormalities in addition to the Ph.
  • A higher proportion of marrow or peripheral blood blasts (higher phase/stage).
  • Elevated basophil count.
  • Elevated eosinophil count.
  • Elevated platelet count.
  • Anemia (low hemoglobin).

These prognostic factors have been variably combined in several different scoring systems. The most commonly reported of these is the Sokal score, as originally described by Sokal and colleagues in the 1980s.30,45 The Sokal score was developed in the pre-interferon chemotherapy era, and may be less useful in the current era.45 The Hasford score46 was developed later and is better validated, especially for patients receiving interferon or bone marrow transplant.47

Cytogenetic response is an independent prognostic factor for improved survival, and has been the therapeutic goal of many trials.16 An understanding of the relationship between molecular response and survival is developing, but in general molecular response—and specifically early molecular response—correlates with survival.48

Molecular prognostic factors. There are a number of variations of Ph and the tyrosine kinase fusion protein that still lead to CML, most notably variant genetic rearrangements and variant protein products (Figure 1). First, in up to 10 percent of cases, the BCR-ABL is produced by variant genetic rearrangements whereby DNA from other regions in the genome is contributing to the BCR-ABL product.49 Despite their genetically complex nature, historically these variant rearrangements have not conferred any specific phenotypic or prognostic impact as compared to CML with a standard Ph chromosome, except perhaps abnormalities involving chromosome 17. These variant rearrangements accumulate with time, a process called "cytogenetic evolution" (sometimes called "karyotypic evolution" or "complex cytogenetics"). In most instances, standard Ph is the sole chromosomal anomaly during chronic phase, whereas additional genetic changes are demonstrable in 60-80 percent of cases in blastic phase/blast crisis. Example secondary chromosomal changes include +8, +Ph, i(17q), +19, -Y, +21, +17, and monosomy 7. Molecular genetic abnormalities preceding or occurring during blastic phase/blast crisis include overexpression of the BCR-ABL transcript, upregulation of the EVI1 gene, increased telomerase activity, and mutations of the tumor suppressor genes RB1, TP53, and CDKN2A. The cytogenetic evolution patterns vary significantly in relation to treatment given during chronic phase. Overall, the data on genetic rearrangements suggest that a variety of molecular mechanisms rather than a single genetic defect drives the progression from chronic to blastic phases.13

Second, 10-15 percent of CML patients have deletions of the resultant DNA on chromosome 9.50 Essentially the residual chromosome 9 that is left over after formation of Ph on chromosome 22 is also susceptible to variations, predominantly through how much DNA is deleted. These residual chromosome 9 deletions are also influential in CML's aggressiveness. Such deletions negatively affect prognosis, decreasing survival by up to 20 percent at 5 years.50-54

Third, there are different versions of the resultant fusion protein. Depending on the site of the breakpoint in the BCR gene, the fusion protein can vary in size from 185-230 kiloDalton; each fusion gene encodes the same portion of the ABL gene but differs in the length of BCR sequence. The most common in adult CML is a 210-kiloDalton protein called p210BCR-ABL.16 The mRNAs for this protein are designated e13a2 (formerly b2a2) and e14a2 (formerly b3a2), and the specific mRNA does not appear to have prognostic significance.13

Fourth, there can be genetic mutations and problems with production of the BCR-ABL protein that lead to specific protein abnormalities. These are of particular interest for this discussion as they can produce resistance to targeted drugs like imatinib. In particular, aberrations that lead to changes in the ATP binding loop ("P loop") of the protein and the imatinib binding pocket are being studied.55

The Technology

The BCR-ABL tyrosine kinase protein is a cytoplasmic protein.13 In the normal state, ABL, sends a signal inside the cell telling it to grow only as needed. ABL is protective against toxic stress such as DNA damage. When Ph forms, the mutant BCR-ABL gene is continuously being transcribed into mRNA and subsequently the abnormal BCR-ABL protein. The mutant BCR-ABL promotes continuous cell division, even in the face of toxic stress. This constant signal tells the cancerous cells to keep growing and leads to the malignant state.

Imatinib (STI-571, trade name Gleevec™ (U.S.) or Glivec™ (non-U.S.)) is a derivative of 2-phenylaminopyrimidine. Imatinib is a competitive tyrosine kinase inhibitor that targets several different tumor proteins, including the one that causes >95 percent of cases of CML which is encoded in the BCR-ABL gene. Imatinib works by blocking, or turning off, the signal from the BCR-ABL protein, so the cancerous cells stop growing.

Imatinib is available as an oral medication and is usually taken once a day at a recommended dose of either 400 mg/day or 600 mg/day. Imatinib should be administered with a meal and a large glass of water. Doses over 600 mg/day should be administered in divided doses, e.g., 400 mg twice daily. Tablets are available in 100 mg and 400 mg forms. Treatment can be continued as long as there is no evidence of disease progression or unacceptable toxicity.

Imatinib was originally approved for patients with newly diagnosed advanced CML and interferon-refractory CP CML by the Food and Drug Administration (FDA) in May 2001 under the accelerated approval program.56 It was the first FDA-approved drug to target an intracellular signaling molecule for cancer therapy. Subsequently it was approved for first-line and relapsed settings of all phases of CML on December 20, 2002.

Scope and Key Questions

The key questions for this review were developed with experts in the field of oncology, health economics, and health policy. The key questions are as follows:

  1. In patients with chronic myeloid leukemia, what is the effect of imatinib compared to interferon alpha or best supportive care on overall survival, disease free survival, remission rates (PR, CHR, cytogenetic remission), and quality of life (QOL)?
  2. In patients with chronic myeloid leukemia, what is the effect of imatinib compared to interferon alpha or best supportive care on adverse effects, tolerability, and compliance with treatment?
  3. What patient or tumor characteristics distinguish treatment responders from non-responders and have potential to be used to target therapy? In addressing this question, we will focus on the following:
    1. Predictive patient or tumor characteristics that are related to the mechanism of action of the drug (i.e., molecular target; performance status, while a powerful predictor of outcome, is not related to mechanism of action).
    2. Candidates for diagnostic testing (even if not commercially or clinically available currently (e.g., PCR)).
    3. Patient or tumor characteristics that are associated with clinically important differences in treatment response.

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