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Acute myelocytic leukemia

Acute myelogenous leukemia (AML), also known as acute myeloid leukemia, is a cancer of the myeloid line of blood cells. The median age of patients with AML is 70; it is rare among children. more...

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Myeloid leukemias are characterized as "acute" or "chronic" based on how quickly they progress if not treated. Chronic myelogenous leukemia (CML) is often without symptoms and can remain dormant for years before transforming into a blast crisis, which is markedly similar to AML.


Specific chromosomal abnormalities are seen in patients with some forms of AML. These chromosomal abnormalities tend to disrupt genes that encode for transcription factors needed for myeloid stem cells to differentiate into specific blood components. Without differentiation occurring, these myeloid precursor cells fill the bone marrow and spill out into the blood. The overpopulation of the bone marrow with myeloid precursors also results in supression of normal marrow stem cells, giving rise to the symptoms of anemia (lack of red blood cells), thrombocytopenia (lack of platelets), and neutropenia (lack of neutrophils).


World Health Organization (WHO) classification

The World Health Organization (WHO) classification of acute myeloid leukemia (AML) attempts to be more applicable and produce more meaningful prognostic information then the older French-American-British (FAB) criteria, described below.

The WHO criteria are:

  • AML with characteristic genetic abnormalities, which includes AML with translocations between chromosome 8 and 21 , inversions in chromosome 16 and acute promyelocytic leukemia (APL). Patients with AML in this category generally have a high rate of remission and a better prognosis compared to other types of AML.
  • AML with multilineage dysplasia. This category includes patients who have had prior myelodysplastic syndrome (MDS) or a myeloproliferative diseases (MPD) that transforms into AML. This category of AML occurs primarily in elderly patients
  • AML and MDS, therapy related. This category includes patients who have had prior chemotherapy and/or radiation and subsequently develop AML or MDS.
  • AML not otherwise categorized. Includes subtypes of AML that do not fall into the above categories.
  • Acute leukemias of ambiguous lineage. Acute leukemias of ambiguous lineage (also known as mixed phenotype acute leukemia) occur when the leukemic cells can not be classified as either myeloid or lymphoid cells or where both types of cells are present.

French-American-British (FAB) classification

The older French-American-British (FAB) classification system divided AML into 8 subtypes, M0 through to M7 based on the type of cell from which the leukemia developed and degree of maturity. This is done by examining the appearance of the malignant cells under light microscopy or cytogenetically by characterization of the underlying chromosomal abnormality. Each subtype is characterised by a particular pattern of chromosomal translocations and have varying prognoses and responses to therapy. Although the WHO classification is more useful, the FAB system is still in use.


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Chronic Myelocytic Leukemia - Part II: Approaches to and Molecular Monitoring of Therapy
From Clinical Laboratory Science, 1/1/05 by Randolph, Tim R

DATA SOURCES: Current literature.

DATA SYNTHESIS: Chronic myelocytic leukemia (CML) was initially described in 1845 and is considered one of the first leukemias discovered. Effective approaches to therapy were not instituted until arsenic was first administered in 1865. Since then, four major therapeutic milestones have been achieved; the development of alkylating agents like busulphan and 6-thioguanine in 1953, alpha Interferon in 1983, bone marrow transplantation in 1986, and tyrosine kinase inhibitors in 1998. The discovery that the protein product of this fusion gene expresses constitutive tyrosine kinase activity prompted the synthesis of a designer drug, imatinib mesylate, which binds the fusion protein and neutralizes the tyrosine kinase activity. Molecular methods of detecting BCR-ABL transcripts are showing promise in confirming drug resistance and predicting patient outcomes in response to imatinib mesylate therapy. Evidence of drug resistance can guide physicians in selecting alternative therapeutic approaches early in the course of the disease to potentially rescue non responders. Although the success of clinical trials has been dramatic, drug resistance and disease relapse are issues to be considered.

CONCLUSION: The discovery that the BCR/ABL fusion protein exhibits increased and constitutive tyrosine kinase activity led investigators to develop an inhibitor to this activity. The synthesis of imatinib mesylate, currently marketed as Gleevec(TM) or Glivec^sup R^, is in stage III clinical trials and has proven to be the most successful antileukemic drug to date. As in CML, an understanding of the leukemogenic mechanisms involved in other leukemias will provide the groundwork for the development of therapeutic interventions tailored to the specific molecular defects identified, eventually rendering obsolete the shotgun approaches to massive cell killing produced by chemotherapy.

ABBREVIATIONS: ABL = Ableson oncogene found in a strain of mouse leukemia virus; ASH = American Society of Hematology Annual Meeting; BCR = breakpoint cluster region; CCR = complete cytogenetic response; CHR = complete hematologic response; CML = chronic myelocytic leukemia; INF = interferon; MCR = major cytogenetic response; MMR = major molecular response; RT-PCR = reverse transcriptase-polymerase chain reaction; SCT = stem cell transplant.

INDEX TERMS: BCR/ABL; chronic myelocytic leukemia; Philadelphia chromosome; t(9;22); tyrosine kinase inhibitor.

Clin Lab Sci 2005;18(1):49

LEARNING OBJECTIVES: Following careful study of this review, the reader will be able to:

1. Describe the first documented therapy for CML.

2. Discuss the chemotherapeutic approach to CML treatment.

3. Discuss one advantage and one disadvantage of alpha interferon and bone marrow/stem cell transplants in the treatment of CML.

4. Discuss the therapeutic approach to CML involving tyrosine kinase inhibitors to include:

a. molecular target of tyrosine kinase inhibitors,

b. function of the tyrosine kinase inhibitors,

c. effectiveness of therapy,

d. drug resistance and adverse events,

e. alternative therapeutic approaches in patients with drug resistance.


The approach to CML therapy has evolved over the years and is on the threshold of a potential cure for many patients. The first documented therapy that was effective for CML was arsenic, first administered in 1865 by a German physician named Lissauer. ' In this patient, arsenic therapy was shown to reduce the WBC count, diminish the splenomegaly, and improve anemia, all contributing to the amelioration of symptoms. This therapeutic approach was continued until 1903 when radiotherapy was instituted.2 In 1912, benzene was introduced in conjunction with radiotherapy as a treatment for CML.3 An alternative form of radiotherapy using radioactive phosphorous was initiated in 1938.'

Nitrogen mustards, an agent of chemical warfare, were administered to CML patients in 1947.5'6 These experiments with nitrogen mustards led to the development of other alkylating agents, such as busulfan which was introduced in 1953, and ushered in the modern era of chemotherapy.7 Long-term survival was improved for the first time and busulfan combined with 6-thioguanine became the mainstay of treatment for the next 35 years. Alpha interferon was introduced in 1983 as a therapeutic approach that not only increased survival, but it also induced Philadelphia chromosome negativity and reduced progression to blast crisis.8 This therapy was supplemented with bone marrow transplantation in 1986 for patients under 55 years of age and became the mainstay until recently.9 The future direction of therapy lies in tyrosine kinase inhibitors and other molecules that block key steps in the leukemogenic signal transduction pathways leading to full transformation.


Until recently, the standard approach to CML therapy was to reduce the tumor burden with tumor reducing chemotherapy. Although CML precursors were engaged in cell division to a greater extent than normal myeloid stem cells, they were not active enough to be significantly affected by aggressive chemotherapy, as is used in acute leukemias. The more commonly used drugs to treat CML were busulfan, hydroxyurea, 6-mercaptopurine, and 6-thioguanine. Hematologie remissions were achieved in 75% of patients treated with busulfan or hydroxyurea but these remissions only lasted two to three years. Although hydroxyurea is preferred over busulfan due to lesser toxicities and prolonged survivals, (56 months vs. 44 months respectively), neither drug produced a clinically acceptable rate of cytogenetic response or slowed disease progression toward blast crisis.10,11

The advent of alpha Interferon (INF-α) improved outcomes in CML patients when used as initial therapy by inducing cytogenetic remissions and increasing survival rates from 35% to 55%.12 These findings earned INF-α the position of firstline therapy in CML patients who were not eligible for allogeneic bone marrow transplantation. INF-α reduces myeloid cell numbers by stimulating a cell-mediated, anti-tumor host immune response. INF-α also induces apoptosis in the leukemic clone and restores integrin-mediated adhesion to collagen. Binding of CML progenitors to bone marrow stroma induces natural proliferation inhibition mechanisms.13 INF-α has improved the rate and duration of hematologie remissions to between 60% to 80%, produced major cytogenetic responses (MCR) (

Dramatically improved response rates can be achieved when cytarabine (Ara-C) is administered with INF-α.M At 18 months post therapy, the INF-α with Ara-C arm of the IRIS (International Randomized INF vs. STI571) study revealed a hematological remission rate of 93%, an MCR of 34%, and a CCR of 15%. However, some patients experienced severe side effects, developed drug resistance, and succumbed to relapses at rates similar to chemotherapy. Most important, the majority of patients achieving CCR following interferon therapy retained the BCR-ABL gene and its products as detected by molecular methods like RT-PCR and fluorescent in situ hybridization (FISH).15

As techniques improved, bone marrow and stem cell transplants have become a viable form of therapy, especially in younger patients in the chronic phase of CML, due to the curative potential of the treatment. Relapses occur in 15% to 30% of transplanted patients but relapses become infrequent beyond the fiveyear survival threshold. Long-term survivals were reported between 50% and 80% with disease free survival rates between 30% and 70%. Normal hematopoietic progenitors exist in the CD34(+), HLA-DR(-) cell pool and can be mobilized from autologous and allogeneic donors for stem cell transplants. To be considered a good candidate for transplantation, patients need to be less than 50 years old, in the chronic phase of the disease, and within one year of diagnosis. The patient would receive ablative chemoradiotherapy, followed by transplant. Unfortunately, the combination of limited numbers of HLA compatible related donors and age limitations of CML patients, results in only 15% to 20% of CML patients qualifying for transplantation. IfHLA matched unrelated donors are considered, the candidacy rate for transplantation increases to 30%.16

In contrast, autologous transplants usually result in relapse within one year, due to residual disease in the patient, or in the bone marrow preparation. If bone marrow transplant is performed in the chronic phase of the disease, the five-year survival rate is 50%. This statistic drops to 30% if performed in the accelerated phase, and to 15%, if performed in blast crisis phase. Stem cell transplant remains the treatment of choice for young patients (70% of patients who have relapsed following allogeneic transplantation with a sibling donor. The mechanism of activity in DLI appears to be T cells directed at CD34(+) CML progenitor cells.16

The future of CML therapy appears to be focusing on specific molecular targets that block signal transduction pathways altered by the BCR-ABL fusion protein. The first and most promising therapeutic intervention involves synthetic tyrosine kinase inhibitors. Since most, if not all, of the transforming capability of the fusion protein stems from its tyrosine kinase activity, selective inhibition of this activity has proven successful. STI-571, formerly called CGP57148, is a synthetic tyrosine kinase inhibitor designed to selectively inhibit the tyrosine kinase activity of the BCR/ABL fusion protein by binding the ATP binding cleft. Binding of STI571 to the ATP binding cleft blocks the binding of ATP thus preventing the abnormal phosphorylation events caused by the BCR-ABL fusion protein.

Phase I/II clinical trials involving CML patients resistant to interferon have been underway since June 1998 and the results look very promising. When given as a 300+ mg oral daily dose, all CML patients achieved complete hematological remissions (defined as a normal white blood cell count) with some cytogenetic remissions in three weeks of therapy. In many cases, even patients who failed standard INF-α therapy have achieved complete hematologie remission. The drug must be taken daily because it has a short half-life of 12-14 hours. Some patients achieved cytogenetic responses suggesting that the therapy may be inducing apoptosis in the malignant clone. STI-571 would be considered effective if its only function was to inhibit the tyrosine kinase activity that causes the malignant phenotype, but if it also kills the malignant cells by inducing apoptosis, the effectiveness is dramatically amplified. The drug appears to have minimal side effects and no dose-limiting toxicities have been encountered.17 STI-571 is also called imatinib mesylate (imatinib) and is manufactured commercially by Novartis Pharmaceutical under the name Glivec^sup R^ or Gleevec(TM). Studies are underway to maximize imatinib dosing, to combine imatinib with other therapies, and to monitor the effectiveness of therapy using molecular monitoring techniques.


The most effective molecular monitoring approach to date involves the quantitation of BCR-ABL transcripts that remain in blood after therapy. Competitive or real-time quantitative reverse transcriptase PCR (Q-PCR) was first used to monitor patients receiving INF-α+ or allogeneic stem cell transplants (allo-SCT).18"21 Results demonstrated a correlation between the copy number of BCR-ABL transcripts in the blood and the Ph 1 + metaphases in the bone marrow for patients on INF-α and was a predictor of cytogenetic and he;matologie relapse in patients who received allo-SCT.21"23 As with INF-α, Q-PCR has also demonstrated close correlation between PhI+ metaphases in bone marrow and BCRABL transcripts in peripheral blood from patients receiving imatinib therapy.24'25 One study reported that 28 patients who achieved CCR following imatinib therapy had

Laboratories are beginning to report BCR-ABL copy number from peripheral blood in terms of the number of log reductions in copy number compared to the patient's original, pre-treatment copy number (baseline). This is a more universal reporting method that partially corrects for differences in testing sensitivities between labs and in initial tumor burden between CML patients. Using this nomenclature, the IRIS study defined a major cytogenetic response as a 3-log reduction or greater in BCR-ABL transcripts detectable in peripheral blood. Maximum sensitivity for most assays is at least 4.5-logs below baseline so maximum measurable response was defined by the IRIS study as 4.5-logs below baseline. Although molecular monitoring of BCR-ABL appears to correlate with karyotyping analysis and is predictive of therapeutic response, karyotype analysis is still valuable. Chromosomal abnormalities, other than PhI, occur in some CML patients treated with imatinib as first-line therapy and are predictors of disease progression, thus warranting periodic karyotype analysis.28


Although hematological remissions are extremely high when imatinib is given as first-line therapy, major molecular responses (MMR), as defined as a >3-log reduction in BCRABL transcripts from baseline, are more difficult to achieve. The IRIS study group reported that 39% of newly diagnosed CML patients achieved MMR after 12 months of imatinib therapy. This is a more impressive result when compared to a MMR of 2% in the patients treated with a combination of INF-α and Ara-C. In addition, 20% of patients demonstrated a 2- to 3-log reduction in BCR-ABL transcripts from baseline and 19% achieved a 4-log or greater reduction following 12 months of imatinib therapy. Maximum molecular response of >4.5-log reduction was also observed in other smaller studies.27 It is expected that the MMR is likely to increase as patients on first-line imatinib therapy are followed beyond one year. Data suggest that CCR and MMR are good predictors of disease progression. Among all the patients in the IRIS study that achieved CCR on imatinib, 58% also achieved MMR and none of these patients showed disease progression in the subsequent 12-month follow-up period. In addition, there is only a 15% probability ol disease progression among the imatinib-treated patients who did not achieve CCR, and a 3% among those who achieved CCR but not MMR.

The primary goal of imatinib therapy is to achieve underectable levels of BCR-ABL transcripts in the blood that would produce ongoing remission and avoid disease progression. However, it is unclear if imatinib therapy alone can permanently disable the BCR-ABL leukemogenic pathway and/or eliminate BCR-ABL bearing CML cells through apoptosis or other mechanisms. Eventually, imatinib may need to be withdrawn from patients who have achieved longterm MMR (at undetectable BCR-ABL levels) and followed to determine if reemergence of BCR-ABL transcripts will occur. As for the present, it is of much greater concern that strategies be developed to address patients who have lost remission through the generation of additional cytogenetic abnormalities or resistance to imatinib therapy.


Primary resistance to imatinib has been defined as newly diagnosed CML patients who do not achieve complete hematologie remission (CHR) by three months, MCR by six months, or CCR by twelve months. In the IRIS study using newly diagnosed CML patients on 400 mg/day imatimib, 4% did not achieve CHR at three months, 23% did not reach MCR at six months and 31 % failed to attain CCR at twelve months. These imatinib resistant patients represented between 20% to 30% of the study group.29 However, in patients treated with 800 mg/day imatinib who had previously failed on INF-α, all 36 achieved CHR and only 11% did not reach CCR.30 Some experts predict that approximately 90% of newly diagnosed CML patients might achieve CCR given higher doses of imatinib. Nevertheless, the 10% of patients predicted of having primary resistance can't be explained by the currently identified mutations and polymorphisms in BCR-ABL.31

Acquired resistance to imatinib is defined as a loss of a previously established response (CHR, MCR, CCR) or progression of disease and is a much greater problem. In the IRIS study, 8% of patients treated with imatinib developed resistance in 18 months while other studies report patients who began imatinib therapy both early and late in the chronic phase of CML who developed resistance at a rate of 15% and 25%, respectively, after 14 months.29'31 There are two dominant theories that explain acquired resistance to imatinib; expansion of CML cells with transforming mechanisms independent of the BCR-ABL protein or genetic lesions that have altered the BCR-ABL protein either quantitatively or qualitatively. An example of the former theory would involve CML cells that previously had or have since developed additional genetic mutations, whether detectable or not, that possess transforming capabilities independent of BCR-ABL. However, the latter explanation is the more common scenario. Over 23 distinct point mutations have been identified in the BCR-ABL kinase domain and associated with imatinib resistance. The incidence of point mutations increases with the duration of the disease.

This suggests that the CML clone is incurring sequence errors during DNA replication, which is consistent with most cancer models. These point mutations are presumably occurring in multiple loci within the genome but many have been identified in the BCR-ABL kinase domain. The mutations are not necessarily stimulated by imatinib because similar mutations have been identified in many patients who have had CML for months to years but have never been exposed to imatinib.

However, these mutations are affecting the binding affinity of imatinib, resulting in resistance. The mutant clones will either not bind imatinib or bind it at a lower affinity resulting in continued proliferation of CML cells in the presence of imatinib. This process will select for imatinib resistance clones and promote disease progression.31'33 It is unclear if the control of cell proliferation initially induced by imatinib when administered early in the course of the disease will reduce mutations that produce imatinib resistance.

A potential strategy to rescue CML patients who have developed imatinib resistance involves the identification of the particular BCR-ABL mutation present and the administration of specific tyrosine kinase inhibitors unaffected or less affected by that mutation. For those mutations that abrogate imatinib binding, imatinib should be discontinued or used in combination with another tyrosine kinase inhibitor less affected by the mutation. In cases where the binding affinity of imatinib is diminished, dose escalation may prove successful.3KB Prognosis for imatinib resistant patients appears particularly poor if the mutation is in the P-loop of the ATP phosphate binding domain.31 However, a class of small molecule kinase inhibitors, called pyrido-pyrimidines, are currently being tested to determine kinase inhibition in both wild-type BCR-ABL proteins and in BCR-ABL mutants that have developed acquired imatinib resistance. These molecules are potent tyrosine kinase inhibitors and appear to bind the ATP binding site of BCR-ABL using different contact points as compared to imatinib. Von Bubnoff tested 13 different pyrido-pyrimidines in a murine system and found all to exhibit tyrosine kinase inhibition and reverse the CML phenotype.34 However, three of these molecules exhibited potent tyrosine kinase inhibition: SKI DV-2-43, PD166326, and SKI DV-MO16.34 In preliminary studies using a mouse model of CML, PD166326 inhibited BCR-ABL tyrosine kinase activity between 4 and 100 times greater than imatinib. Further studies are underway to determine the effectiveness of PD166326 at treating CML without crippling normal tyrosine kinase pathways and without inducing drug related sequalae.35

Three additional therapeutic approaches for patients who have developed imatinib resistance are to combine imatinib with drugs that inhibit other enzyme systems downstream of the tyrosine kinase activity of BCR-ABL, with chemotherapeutic drugs, or with CML vaccines. O'Hare found that a Src/Abl kinase inhibitor, AP23464, exhibited an 8-fold greater inhibition of BCR-ABL than imatinib using wild-type expressing Ba/F3 cells.36 In addition, it also inhibited several other cell lines expressing common imatinib resistant BCR-ABL mutations.36 Two farnesyl transferase inhibitors, Lonafarnib (SCH66336)37 and Tibifarnib (Zarnestra(TM), R115777)38 have been shown to reverse the CML phenotype in imatinib resistant patients when administered with imatinib. Favorable results have also been achieved in imatinib resistant patients when combining chemotherapeutic agents like semi-synthetic homoharringtonine (Myelostat^sup R^) and 5-aza-2'-deoxycytidine (decitabine) with imatinib.39'40 A CML vaccine, CMLVAXlOO, has been shown to reduce the number of PhI positive cells in patients treated with imatinib who were exhibiting consistent residual disease. Over half of the patients achieved CCR and half of these CCR patients were negative for BCR-ABL transcripts by real-time quantitative PCR.41


Even in light of the promising results achieved with imatinib, the most appropriate therapeutic approach to patients newly diagnosed with CML is still under discussion. It is clear that imatinib therapy has proven superior to the previously established treatment regimen using INF-α and Ara-C. However, several questions concerning imatinib therapy still remain. First, what are the long-term outcomes for patients who respond to imatinib therapy? Are they cured or will some, many, or all eventually succumb to some form of drug intolerance or resistance resulting in relapse? How should imatinib non-re sponders be treated? What criteria should be applied to imatinib treated patients to distinguish responders from nonresponders to determine the efficacy of continuing imatinib therapy? In addition, allo-SCT has proven successful and potentially curative in a subset of CML patients. However, in contrast to the safety of imatinib, allo-SCT incurs the risk of transplant-related mortality, morbidity, and chronic graft-versus-host disease, limiting the procedure to only low risk candidates. What criteria should be used to determine which patients are better served by allo-SCT versus imatinib therapy?

It seems clear that there is a subset of patients who hold the hope of cure if they receive an uncomplicated allo-SCT. The ideal candidate for allo-SCT is a CML patient who is less than 40 years old, in the chronic phase of the disease, and within one year of diagnosis, and has an HLA-identical donor. The decision is more complicated if the patient is slightly older, just outside the one-year diagnosis window, or the donor is not a perfect HLA match. Other variables that complicate the decision to proceed with allo-SCT include recipient/ donor gender combinations and CMV seiOstatus.421"13 Once the patient's clinical features exceed these parameters, imatinib therapy is likely to be the better choice. AlIo-SCT may also be a viable option for CML patients who are expected to show imatinib resistance or in patients who have failed imatinib therapy. Currently, there are no reliable markers to predict imatinib resistance but mutations in the ATP binding site of the BCR/ABL fusion protein will produce such a resistance. Another version of transplantation that has shown success is the reduced intensity conditioning transplantation (RIST). The procedure is designed to gradually ablate host hematopoietic tissues by donor T cells and can be administered as an original graft, given again in the post-transplan t period or by additional lymphocyte infusions. One study reported an overall disease free survival of 85% at five-year post RJST with all survivors being negative for BCR-ABL by RT-PCR.44 Some argue that a strategy that combines the effects of imatinib and allo-SCT may be a viable approach. Since imatinib produces a more durable and complete remission than INF-α, it is possible that allo-SCT outcomes may be improved if imatinib is used as the pre-transplant conditioning regimen instead of INF-α. Another combination approach may be to use imatinib following allo-SCT to reduce residual disease. This approach has not been studied as a primary strategy but has been successful when performed as a rescue procedure following the failure of allo-SCT therapy.45

Therapeutic approaches to patients who failed to respond to front-line imatinib therapy or who have lost remission is also under debate. Data suggest that there are at least five possible approaches to this problem: 1) increasing the dose of imatinib to 600 or 800mg/day46'47; 2) adding another agent to the imatinib regimen like INF-α, Ara-C, hydroxyurea, decitabine, or homoharringtonine48,49; 3) changing the treatment to one or more of these agents without imatinib50; 4) autologous transplant51; and 5) new tyrosine kinase inhibitors. Adoptive immunotherapy (vaccines) approaches are currently being investigated to include using the el4a2 fusion protein, proteinase 3, Wilm's tumor protein, and heat shock protein 70 (Hsp-70) as the vaccine material but results are not as promising as hoped.52"55

In summary, it seems reasonable to start all newly diagnosed patients on imatinib and measure their hematologie, cytogenetic, and molecular response at 12 months. Those patients who are responding and meet the criteria for allo-SCT would be given that option. Those who are responding to imatinib but do not meet the allo-SCT criteria would continue on imatinib therapy. Those who demonstrate primary resistance to imatinib by not achieving hematologie remission at three months, MCR by six months, and CCR by twelve months would be dose escalated on imatinib, treated with a combination of drugs with or without imatinib, or potentially started on a next generation tyrosine kinase inhibitor. For any given patient with imatinib resistance, selection of the appropriate next generation tyrosine kinase inhibitor would be based on the identification of the mutation that produced the imatinib resistance. If remission is achieved through second-line therapy, patients would be evaluated as a transplant candidate. If patients are not eligible for transplant, second-line therapy would continue. This same strategy could be applied to patients who achieve remission but eventually develop an acquired resistance to imatinib. Autologous transplant could also be considered for those patients experiencing imatinib resistance. .


Portions of this article were previously presented at several state professional meetings and an audio conference, and published by Educational Reviews, Inc.


1. Gunz FW. The dread leukemias and lymphomas. In: Blood: pure and eloquent. New York: McGraw Hill;1980. p 511-46.

2. Senn N. case of splenomedullary leukemia successfully treated by the use of roentgen rays. Med Rec of New York 1903;64:281-2.

3. Geary CG. The story of chronic myeloid leukaemia. BrJ Haematol 2000;110(1):2-11.

4. Forkner CE. Leukemia and allied disorders. New York: Macmillan; 1938. p 126-35.

5. Wilkinson JF, Fletcher F. Effect of α-chloroethylamine hydrochloride in leukemia, Hodgkin's disease, and polycythcmia vera: report of ] 8 cases. Lancet 1 947;2:540-5.

6. Wintrobe MM, Huguley CM, McLennan MT, and others. Nitrogen mustard as a therapeutic agent for Hodgkin's disease, lymphosarcoma, and leukemia. Ann Intern Med 1947;27:529-39.

7. Galton DAG. The use of myleran in chronic myeloid leukemia. Lancet 1953:1:208-13.

8. Talpaz M, McCredie KB, Mavligit GM, and others. Leukocyte interferon-induced myeloid cyto-reduction in chronic myeloid leukemia. Blood 1983;62:1052-6.

9. Goldman JM, Apperley JF, Jones LM, and others. Bone marrow transplantation for patients with chronic myeloid leukemia. N Engl J Med 1986;3l4:202-7.

10. Hehlmann R, Heimpel H, Hasford J, and others. Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. Blood 1994;84:4064-77.

11. Osarogiagbon UR, McGlave PB. Chronic myelogenous leukemia. Curr Opinion in Hematol 1999;6(4):241-55.

12. Sawyers CL. Medical progress: chronic myeloid leukemia. N Engl J Med 1999;340(17):1330-40.

13. Bhatia R, Verfaillie CM. The effect of interferon-alpha on beta-1 integrin mediated adhesion and growth regulation in chronic myelogenous leukemia. Leuk Lymphoma 1998;28:24l-54.

14. Guilhot F, Chastang C, Michallet M, and others. Interferon-alpha2b combined with cytarabine versus Interferon alone in chronic myelogenous leukemia. N Engl J Med 1997:337:223-9.

15. Brizard F, Chomel JC, Veinstein A, and others. Does BCR-ABL genomic rearrangement persist in CML patients in complete remission after interferon-alpha therapy? Leukemia 1998; 12:1076-80.

16. O'Brien SG. Autografting for chronic myeloid leukaemia. Baillieres Clin Haematol 1997:10:369-88.

17. Druker BJ, Talpaz M, Resta DJ, and others. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344(l4):1031-7.

18. Lion T, Gaiger A, Henn T, and others. Use of quantitative polymerase chain reaction to monitor residual disease in chronic myelogenous leukemia during treatment with Interferon. Leukemia 1995:9:1353-60.

19. Kurzrock R, Estrov Z, Kantarjian H, and others. Conversion of interferon-induced, long-term cytogenetic remissions in chronic myelogenous leukemia to polymerase chain reaction negativity. J Clin Oncol 1998:16:1526-31.

20. Radich JP, GooleyT, Bryant E, and others. The significance of BCRABL molecular detection in chronic myeloid leukemia patients "late," 18 months or more after transplant. Blood 2001:98:1701-7.

21. Olavarria E, Kanfer E, Szydlo R, and others. Early detection of BCRABL transcripts by quantitative reverse transcriptase-polymerase chain reaction predicts outcome after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood 2001:97:1560-5.

22. Branford S, Hughes TP, Rudzki Z. Monitoring chronic myeloid leukaemia therapy by real-time quantitative PCR in blood is a reliable alternative to bone marrow cytogenetics. Br J Haematol 1999:107:587-99.

23. Lin F, van Rhee F, Goldman JM, and others. Kinetics of BCR-ABL transcript numbers in chronic myeloid leukemia patients who relapse after bone marrow transplantation. Blood 1996;87:4473-8.

24. Wang L, Pearson K, Pillitteri L, and others. Serial monitoring of BCR-ABL by peripheral blood real-time polymerase chain reaction predicts the marrow cytogenetic response to imatinib mesylate in chronic myeloid leukaemia. BrJ Haematol 2002;! 18:771-7.

25. Kantarjian HM, Talpaz M, Cortez J, and others. Quantitative polymerase chain reaction monitoring of BCR-ABL during therapy with imatinib mesylate (STI571; Gleevec) in chronic-phase chronic myelogenous leukemia. Clin Cancer Res 2003:9:160-6.

26. Hughes T, Branford S. Molecular monitoring of chronic myeloid leukemia. Semin Hematol 2003:40:62-8.

27. Lin F, Drummond MW, O'Brien SG, and others. Molecular monitoring in CML who achieve complete cytogenetic remission on imatinib. Blood 2003:102:1143.

28. Marktel S, Marin D, Foot N, and others. Chronic myeloid leukemia in chronic phase responding to imatinib: The occurrence oi additional cytogenetic abnormalities predicts disease progression. 2003:88:260-7.

29. O'Brien SG, Guilhot F, Larson RA, and others. Imatinib compared with interferon and low dose cytarabine for newly diagnosed chronicphase chronic myeloid leukemia. N Engl J Med 2003:348:994-1004.

30. Cortez J, Giles F, O'Brien S, and others. Result of high-dose imatinib mesylate in patients with Philadelphia chromosome-positive chronic myeloid leukemia after failure of interferon-Ot. Blood 2003:102:83-6.

31. Branford S, Rudzki Z, Walsh S, and others. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutation in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 2003:102:276-83.

32. Shah NP, Nicoll JM, Nagar B, and others. Multiple BCR-ABI. kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2()02;2:1 17-25.

33. Branford S, Ruclzki Z, Walsh S, and others. High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Phpositive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood 2002:99:3472-5.

34. von Bubnoff N, Veach DR, Miller WT, and others. Pyrido-pyrimidine kinase inhibitors suppress wild-type and mutant BCR-ABL. ASH Meeting. 2003; Abstract #808.

35. Wolff NC, Veach DR, Tong WP, and others. PD166326, a novel tyrosine kinase inhibitor, has greater anti-leukemic activity than imatinib in a murine model of chronic myelogenous leukemia. ASH Meeting. 2003; Abstract #96.

36. O'HareT, Stoffregen EP, Abdullah OM, and others. Potent inhibition of imatinib-resistant variants of BCR-ABL by a novel dual selective Src/Abl kinase inhibitor AP23464: implications for CML therapy. ASH 2003; Abstract #59.

37. Cortez J, O'Brien S, Ferrajoli A, and others. Phase 1 study ot imatinib and lonafarnib (SCH66336) in patients (pts) with chronic myeloid leukemia (CML) refractory to imatinib mesylate. ASH 2003; Abstract #3382.

38. Cortez J, Garcia-Manero G, O'Brien S, and others. Phase I study of imatinib and tipifarnib (Zarnestra'M, Rl 15777) in patients with chronic myeloid leukemia in chronic phase refractory to imatinib. ASH 2003; Abstract #3383.

39. Burton CH, Ranger A, Nadal E, and others. Semi-synthetic homoharringtonine (Myelostat") for chronic myeloid leukemia in accelerated phase after imatinib failure. ASH 2003; Abstract #3380.

40. lssa JP, Garcia-Manero G, Talpa/, M, and others. Phase II study of 5-aza-2' deoxycytidine (decitabine) in patients (pts) with Philadelphia (Ph) chromosome positive chronic myelogenous leukemia (CML) resistant or intolerant to imatinib mesylate. ASH 2003; Abstract #3385.

41. Bocchia M, Gentili S, Abruzzese E, and others. Imatinib plus CMLVAXlOO (0210-derived multipeptide vaccine): Induction of complete molecular responses in patients with chronic myeloid leukemia (CML) showing persistent residual disease during treatment with imatinib mesylate. ASH Meeting. 2003; Abstract #93.

42. Gratwohl A, Hermans J, Goldman JM, and others. Risk assessment for patients with chronic myeloid leukaemia before allogencic blood or bone marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Lancet 1998:352:1087-92.

43. Craddock C, Szydlo RM, Dazzi F, and others. Cytomegalovirus seropositivity adversely influences outcome afterT-depleted unrelated donor transplant in patients with chronic myeloid leukaemia: the case for tailored graft-versus-host disease prophylaxis. Br ) Haematol 2001;112:228-36.

44. Ori R, Shapira MY, Resnick I, and others. Nonmyeloablativc allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase. Blood 2003;101:441 -5.

45. Olavarria E, Craddock C, Dazzi F, and others. Imatinib mesylate (ST1571) in the treatment of relapse of chronic myeloid leukemia after allogenelc stem cell transplantation. Blood 2002;99:3861-2.

46. Kantarjian HM, Talpaz M, O'Brien S, and others. Dose escalation of imatinib mesylatc can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 2003;101:473-5.

47. Zonder JA, Pembcrton P, Brandt H, and others. The effect of dose increase of imatinib mesylate in patients with chronic or accelerated phase chronic myelogenous leukemia with inadequate hematologie or cytogenetic response to initial treatment. Clin Cancer Res 2003:9:2092-7.

48. Scappini B, Onida F, Kantarjian HM, and others. In vitro effects of STl 57 !-containing drug combinations on the growth of Philadelphia-positive chronic myelogenous leukemia cells. Cancer 2002;94:2653-62.

49. Tipping AJ, Mahon FX, Zafirides G, and others. Drug responses of imatinib mesylate-resistant cells: Synergism of imatinib with other chemotherapeutic drugs. Leukemia 2002; 16:2349-57.

50. Visani G, Russo D, Ottaviani E, and others. Effects of homoharringtonine alone and in combination with alpha Interferon and cytosine arabinoside on "in vitro" growth and induction of apoptosis in chronic myeloid leukemia and normal hematopoietic progenitors. Leukemia 1997;! 1:624-8.

51. McGlave PB, Dc Fabridis P, Deisseroth A, and others. Autologous transplants for chronic myelogenous leukaemia: Results from eight transplant groups. Lancet 1994;343:1486-8.

52. Pinilla-lbarz J, Cathcart K, Korontsvit T, and others. Vaccination of patients with chronic myelogenous leukemia with bcr-abl oncogene breakpoint fusion peptides generates specific immune responses. Blood 2000.-95:1781-7.

53. Molldrem JJ, Clave E, Jiang YZ, and others. Cytotoxic T lymphocytes specific for a nonpolymorphic proteinase 3 peptide preferentially inhibit chronic myeloid leukemia colony forming units. Blood 1997;90:2529-34.

54. Gaiger A, Carter L, Greinix H, and others. WTl-spccific serum antibodies in patients with leukemia. Clin Cancer Res 2001 ;7:76 Is-Ss.

55. Udono H, Srivastava PK. Heat shock protein 70-associated peptides elicit specific cancer immunity. J Exp Med 1993;178:1391-6.

Tim R Randolph MS CLS(NCA) is an assistant professor in the Department of Clinical Laboratory Science, Daisy School of Allied Health Professions, Saint Louis University Health Sciences Center, St Louis MO.

Address for correspondence: Tim R Randolph, Department of Clinical Laboratory Science, Daisy School of Allied Health Professions, Saint Louis University Health Sciences Center, 3437 Caroline St, St Louis MO 63104-1111. (314) 977-8518, (314) 977-8503 (fax).

Shirlyn B McKenzie PhD CLS(NCA) is the Focus: Myelocytic Leukemias guest editor.

Copyright American Society for Clinical Laboratory Science Winter 2005
Provided by ProQuest Information and Learning Company. All rights Reserved

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