Agnes S.M. Yong and A. John Barrett
Although chronic myelogenous leukemia (CML) is rare, it has achieved great prominence in medical literature because its biologic basis has been elucidated in unprecedented detail. As a result, CML became the model for the development of effective molecularly targeted and immune-based treatments for leukemia. Nowell and Hungerford reported the unique, unusually small G group chromosome in patients with CML in 1960 and named it the Philadelphia (Ph) chromosome1 This was the first association of a human malignant disease with a consistent chromosomal marker. In 1973, the Ph chromosome was identified as the truncated chromosome 22 consequent to a reciprocal translocation involving chromosome 9.2 It was not until the 1980s that the fusion partners of the translocation were identified as the ABL1 oncogene on chromosome 9 and the breakpoint cluster region (BCR) on chromosome 22.3,4 The BCR-ABL1 oncoprotein was found to have tyrosine kinase activity, and when the gene was inserted into mouse stem cells it induced leukemia in recipient animals.5 Until the 1990s, allogeneic stem cell transplantation (SCT) was the preferred first-line treatment in eligible CML patients as the disease is highly susceptible to a graft-versus-leukemia effect from transplanted donor lymphocytes.6 The advent of imatinib mesylate (Gleevec), the first of a new class of small molecule drugs designed specifically to block the BCR-ABL1 tyrosine kinase, has supplanted SCT for the majority of patients as these drugs confer durable disease control, particularly in the earlier stages of CML.7 Second-generation tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib, which are more potent pharmacologically, have recently been shown to be more efficient in rapidly reducing the leukemic load compared to imatinib, and are now advocated as first-line treatment for CML.8,9 Despite progress in CML biology and treatment, fundamental questions about its origin remain unanswered. Evidence suggests that a predisposition to develop CML precedes the clonal expansion of BCR-ABL1 translocated stem cells,10 and the discovery of very low levels of BCR-ABL1 in the blood of normal individuals who do not develop CML raises the possibility that the BCR-ABL1translocation alone is not sufficient to cause leukemia.11 The emergence of drug resistance to TKIs in the era of molecular targeting for CML has driven the development of third-generation TKIs such as ponatinib. However, only a proportion of TKI-resistant CMLs are attributable to mutations of the BCR-ABL1 kinase domain. Drugs targeting alternate non-kinase dependent and stem cell pathways are also being pursued. Unfortunately, advanced phases of CML still are largely refractory to available treatments.
EPIDEMIOLOGY
Rare: incidence of 1.5 in 100,000
Represents 10% to 15% of all leukemias
Incidence increases with age (median age of diagnosis = 65); exceedingly rare in children Male predominance (1.5:1)
Worldwide distribution: no sociogeographic preponderance
Ionizing radiation is the only known causative factor, leukemia occurs usually within 6 to 8 years of exposure
No known genetic factors determine susceptibility to CML
PATHOPHYSIOLOGY
Leukemic Hematopoiesis Originates in a Multipotent Stem Cell
BCR-ABL1 translocation is found in all cells of the myeloid lineage (erythroid and granulocyte precursors and megakaryocytes) as well as in B cells but not in T cells.12 There are two major hypotheses for this observation: first, the acquisition of BCR-ABL1 may occur in a multipotent stem cell with little or no T differentiation capacity; second, T cells bearing BCR-ABL1 may be systematically eliminated. Unregulated proliferation of BCR-ABL1-positive stem cells is responsible for massive expansion, primarily in granulocyte production, that leads to leukocytosis.
Clonal Dominance
The BCR-ABL1-positive clone outcompetes normal hematopoiesis. At diagnosis it is common to find a mixed population of Ph-positive and Ph-negative cells in the bone marrow. With time, normal stem cells are progressively replaced by CML stem cells. CML CD34+ progenitor cells require less hematopoietic growth factors than do normal progenitors for survival and proliferation, a characteristic that may be partially due to the presence of an autocrine production of hematopoietic growth factors by CML cells.13
Molecular Basis of Chronic Myelogenous Leukemia in the BCR-ABL1 Translocation14
The BCR-ABL1 oncoprotein is a constitutively activated tyrosine kinase that phosphorylates intermediate molecules in several important pathways, affecting proliferation, maturation, resistance to apoptosis, and cell adhesion, ultimately resulting in the typical leukemic phenotype.
Genomic Instability
CML is characterized by progression to refractory acute leukemia. CML usually starts as a relatively benign disorder that evolves to an accelerated phase (AP), when the leukemia is much more difficult to control and additional chromosomal abnormalities appear, followed by a progressive increase in blast cells in blood and marrow, termed the blastic phase (BP) or blast crisis, when the disease transforms to an acute myeloid or B lymphocytic leukemia.15Clonal evolution, which is matched by increasing malignant behavior of the leukemia, has a variable pace but is inevitable.
PRESENTATION
Classic Presentation
CML presents with an insidious history of increasing fatigue, lassitude, weight loss, night sweats, massive splenomegaly, and gout. Some patients have leukocyte counts greater than 300 × 109/L and experience symptoms of leukostasis with headache, focal neurologic deficits, and priapism.
Typical Presentation in the Developed World
Overt symptoms and signs are rarely encountered because the diagnosis is made earlier. Commonly, patients present with fatigue, with or without moderate weight loss, abdominal discomfort, and early satiety from an enlarged spleen, or simply due to the chance observation of an elevated leukocyte count. CML should be considered in the differential diagnosis of a patient at any age presenting with splenomegaly and with white blood cell count.
Rare Presentations
Rare presentations include chloroma, petechiae, and bruising. These features suggest progression of CML to an accelerated or blastic phase. Unlike other leukemias, CML seldom if ever presents with bacterial or fungal infection because neutrophil function is preserved.
DIAGNOSIS
While blood and bone marrow examinations share features with other myeloproliferative disorders, the typical presentation with high leukocyte count and a hypercellular marrow with basophilia is pathognomonic of CML. Chromosome and molecular analysis confirm the presence of a BCR-ABL1 translocation.
Blood Count
Leukocyte number varies between being slightly elevated to over 200 × 109/L; counts as high as 700 × 109/L are occasionally encountered. The platelet count is normal or elevated and there is often a mild normochromic normocytic anemia.
Blood Film
Blood film is of great diagnostic value, because many of the typical features of CML are unique—a left shift with circulating myeloblasts, myelocytes, metamyelocytes, and band forms. The hallmark of CML is basophilia with basophil counts often exceeding 1 × 109/L. Sustained basophilia is almost never encountered outside CML and some cases of mastocytosis. Eosinophilia and occasional nucleated red blood cells are also common findings. Platelet morphology is usually normal but giant forms can be seen.
Bone Marrow
The aspirate shows cellular spicules and the biopsy is hypercellular with almost complete effacement of the fat spaces. There is granulocytic hyperplasia of the neutrophil, eosinophil, and basophil series. Megakaryocytes are normal or increased and may show reduced numbers of nuclei. Sea-blue histiocytes are commonly seen in CML marrows. Fibrosis of the marrow is a feature of accelerated phase CML, as is an increase in blasts over 10%. Blastic phase shows more than 20% blasts.
Chromosome Analysis
The typical karyotype of CML shows the reciprocal translocation t(9;22)(q34;q11) (Fig. 13.1). Variants include three-way translocations between chromosomes 9, 22 and 11, or 19. An additional chromosome abnormality or Ph chromosome duplication usually indicates a more advanced disease stage. Fluorescence in situ hybridization (FISH) is a rapid and sensitive technique to detect the Ph chromosome directly in blood or marrow since it does not rely on dividing cells.
Molecular Diagnosis
More than 95% of patients presenting with the clinical and morphologic features of CML will have Ph chromosomes in the marrow. Of the 5% who are Ph-negative, half have a cryptic BCR-ABL1 transcript detected by polymerase chain reaction (PCR). The remaining patients are described as atypical Ph-negative CML. A few such cases are morphologically indistinguishable from Ph-positive CML but most have atypical features on careful examination and are classified under myelodysplastic/myeloproliferative neoplasms.16 Molecular analysis provides further information of the precise transcript. Depending on the BCR breakpoint, four common BCR-ABL1 transcript variants are possible: e13a2 and e14a2 (formerly b2a2 and b3a2), both encoding the 210 kD BCR-ABL1 oncoprotein (p210); e1a2, which is more common in Ph-positive acute lymphoblastic leukemia, encoding the 190 kD BCR-ABL1 oncoprotein (p190); and e19a2, which encodes the 230 kD BCR-ABL1 oncoprotein of chronic neutrophilic leukemia. No prognostic or diagnostic significance is attached to either the e13a2 or the e14a2 variant in CML. Rarely, unusual transcript variants, such as e1a3 or e6a2, have also been described.17
FIGURE 13.1 The Philadelphia chromosome. G-banded metaphase preparation showing the diminutive Ph-positive chromosome and extra chromosomal material on the long arm of chromosome 9.
DIFFERENTIAL DIAGNOSIS
The diagnosis of CML is made in three stages (Fig. 13.2):
Persisting leukocytosis without any obvious infective cause suggests a myeloproliferative neoplasm, prompting further examination of the blood and bone marrow.
Morphology and blood count will show either typical features of CML (basophilia being especially significant) or suggest other myeloproliferative neoplasms (high platelet counts, essential thrombocythemia; high red cell count, polycythemia vera; teardrop red cells, myelofibrosis). Dysplasia suggests a hyperproliferative myelodysplastic syndrome.
Definitive diagnosis requires chromosome analysis of the bone marrow. Cytogenetics will identify the Ph-positive chromosome and the BCR-ABL1 translocation in all but a small percentage of patients with a morphologic diagnosis of CML. Confirmation of the presence of BCR-ABL1 transcripts by PCR is advised as it aids in disease monitoring following treatment18 (Fig. 13.3).
COURSE OF CHRONIC MYELOGENOUS LEUKEMIA
CML is a multistage disease that progresses from chronic phase (CP) to AP and then to BP (Fig. 13.4).
Chronic Phase
Untreated patients in CP show a gradual rise in the leukocyte count with emergence of splenomegaly and ultimately the full picture of a myeloproliferative neoplasm with B symptoms, weight loss, and hyperleukocytosis.
FIGURE 13.2 Differential diagnosis of CML and related disorders.
Duration of CP is highly variable: some patients progress within months of diagnosis directly to AP and BP, while others can remain for more than a decade in stable CP. Sometimes patients present in AP or BP without a clear preceding CP; in this circumstance, it is important to distinguish CML presenting as acute leukemia from de novo (Ph-negative) acute leukemia since the treatment approaches are distinct.
Median time to progression from CP to AP has increased in the era of TKIs, and because the diagnosis of CML tends to be made earlier.
FIGURE 13.3 PCR for BCR-ABL1 transcripts to monitor treatment in CML. (Courtesy S Branford, IMVS/SA Pathology, Adelaide, Australia.)
FIGURE 13.4 Course and clonal evolution of CML.
Accelerated Phase
AP is characterized by one or more of the following19 (Table 13.1):
Clonal evolution by a further mutation. Patients may acquire new chromosomal abnormalities such as a second Ph chromosome.
Escape of the blood counts from treatment control.
Organomegaly.
Leukocytosis, basophilia, thrombocytosis, or thrombocytopenia in a patient previously well controlled with therapy.
Myelofibrosis with teardrop cells in the blood smear and increased marrow reticulin.
Chloromas in external soft tissues, the retroperitoneal spaces, paraspinal areas (leading to nerve root compression) and in intramedullary spaces.
Blastic Phase
Signs and symptoms of acute leukemia: bone pains, weight loss, and B symptoms, increasing numbers of blasts in the blood and marrow.
Marrow failure: decreasing red cell count and platelets. (Neutrophil counts are better conserved.)
Clonal evolution: further chromosomal abnormalities.
Characterization of Acute Leukemia in Blastic Phase
Approximately 60% of patients develop myeloid BP resembling acute myeloid leukemia (AML); the remainder has lymphoid BP reminiscent of acute lymphoblastic leukemia (ALL). In both phenotypes, blasts are poorly differentiated. Auer rods are not seen and the lymphoid or myeloid origin of the leukemia is only reliably determined by cytochemical stains and surface phenotype, revealing either a pre-B ALL (PAS block-positive, TdT-positive, CD10+, CD19+, CD33±, CD34±) or an undifferentiated AML (peroxidase weak-positive, CD33+, CD34+, CD13±). A peculiar feature of CML is the variability of its subsequent evolution. Patients achieving remission from AML can re-enter CP only to relapse again with ALL or vice versa.
PROGNOSTIC FACTORS
Poor prognosis (tendency to rapid progression to BP):
High leukocyte counts (>100 × 109/L).
Massive splenomegaly and constitutional symptoms.
Patients of African origin.
High basophil counts.
Of predictive scores using patient characteristics at diagnosis which were validated in the preimatinib era to determine outcome and survival,20,21 the Sokal score still appears to be prognostic in patients who are treated with imatinib.7,22,23
TREATMENT
Treatment of CML involves diverse, evolving approaches18 outlined in the algorithm in Figure 13.5. The drugs commonly used to treat CML are detailed in Table 13.2.
CML treatment is guided by disease monitoring using regular blood counts and bone marrow examination to document hematologic changes, chromosome analysis of marrow or FISH analysis of blood or marrow to detect response or progression at the karyotypic level, and PCR for BCR-ABL1 mRNA transcripts in the blood to quantify response at the molecular level (see Fig. 13.3). The degree of disease bulk reduction determines the appropriate monitoring approach, and the degree of response is defined as hematologic response, cytogenetic response, and molecular response or complete molecular remission18(Fig. 13.6).
Treating Newly Diagnosed Chronic Myelogenous Leukemia in Chronic Phase
The great majority (>80%) of CML patients is diagnosed in CP. Initial treatment is aimed at reducing disease bulk and obtaining hematologic remission (normalization of blood counts). Subsequent therapy is tailored toward achieving either a “cure” or “minimal residual disease” (MRD).
Imatinib, 400 mg daily.
Add hydroxyurea 0.5 to 2.5 g daily for patients with leukocyte counts over 100 × 109/L or with massive splenomegaly.
Allopurinol, 300 mg daily until blood counts normalize.
Monitoring Response to Imatinib18,24
Full blood counts should be monitored every 2 weeks until complete hematologic response (HR), equivalent to normalization of blood counts, is achieved. Complete HR should be confirmed on two subsequent occasions.
Bone marrow aspiration every 6 months to assess cytogenetic response, analyzing at least 20 metaphases for the Ph chromosome. Patients who achieve complete cytogenetic response (0% Ph) have a prolonged period without disease progression (see definitions in Fig. 13.6). The cytogenetic response improves over time in responding patients, and once complete cytogenetic response is achieved and confirmed on two subsequent occasions, bone marrow examinations for cytogenetics can be performed every 12 months to detect possible onset of dysplasia or clonal changes in the Ph-negative cells.25
Quantitative PCR for BCR-ABL1 transcripts in the blood should be performed at least every 3 months. Serial BCR-ABL1 measurements are clinically useful to document if patients are responding to treatment with declining transcripts, have stable (plateau) levels of transcripts, or are losing their response as signaled by rising transcripts. Reduction of BCR-ABL1 transcripts by 3 or more logs below a standardized baseline value for untreated patients (major molecular response) is associated with particularly good outcome.
FIGURE 13.5 Treatment algorithm for CML.
FIGURE 13.6 Disease monitoring in CML.
Achieving Minimal Residual Disease
Administer imatinib at the maximum tolerated dose (up to 800 mg daily). Continue treatment indefinitely, unless loss of response occurs (see below).
Over 85% of CML-CP patients treated with imatinib from diagnosis achieve a complete cytogenetic response (0% Ph) and of these, 80% have a 3 log reduction in BCR-ABL1 transcripts by the 4-year follow-up.7 This MRD status is associated with longer survival. Upfront treatment with imatinib may reduce the number of leukemic progenitors at risk of clonal evolution and disease progression. CP-CML patients who are treated with imatinib from diagnosis and achieve complete cytogenetic response appear to have decreasing annual rates of disease progression to AP or BP with longer follow-up.24 Although the ultimate duration of imatinib treatment is still unclear, current recommendations are to continue treatment until relapse or progression of disease.18 A complete molecular remission (undetectable BCR-ABL1transcripts in the blood by PCR) is achieved by less than 10% of patients in complete cytogenetic remission. Imatinib has been discontinued in patients with complete molecular remission for a minimum of 2 years in two clinical trials in France and Australia26,27 and found that up to 60% of patients relapse within a few months of cessation, suggesting that imatinib does not totally eradicate CML in most patients. Monitoring of patients who have not yet relapsed is ongoing, but some patients have ceased imatinib for up to 5 years without relapse, reflecting the heterogeneity of either disease biology or immune control.
Suboptimal Response or Loss of Response to Imatinib Treatment
Failure to achieve a hematologic remission with a combination of imatinib and hydroxyurea is uncommon unless the disease has already progressed to AP.
Failure of imatinib treatment18
No HR in 3 months
No cytogenetic response (Ph >95%) in 6 months
Less than partial cytogenetic response (Ph >35%) in 12 months
No complete cytogenetic response (any Ph detected) in 18 months
Loss of previously achieved responses—for example, loss of complete HR, or complete cytogenetic response.
Suboptimal response to imatinib treatment18
No cytogenetic response (Ph >95%) in 3 months
Less than partial cytogenetic response (Ph >35%) in 6 months
No complete cytogenetic response (any Ph detected) in 12 months
No major molecular response in 18 months
Loss of previously achieved responses: loss of major molecular response; additional chromosomal abnormalities in Ph+ cells in serial bone marrow examinations.
Patients who lose an initial response to imatinib may have developed drug resistance due to point mutations of the BCR-ABL1 gene, which result in amino acid changes in the catalytic domain of the BCR-ABL1 protein (“kinase domain mutation”), resulting in impaired imatinib binding.28 Alternatively, CML may have progressed to AP or BP. A bone marrow aspirate is indicated to determine the status of the disease, and analysis for kinase domain mutations should be undertaken.
When stable MRD is not achieved or disease progression not responding to higher doses of imatinib is encountered, treatment with second-generation inhibitors of BCR-ABL1 tyrosine kinase such as dasatinib or nilotinib is indicated.18
Patients who have not achieved a satisfactory cytogenetic response or who have progressed after an initial response to TKIs should be offered an allogeneic SCT from a human leukocyte antigen (HLA)-identical sibling or a well-matched unrelated donor.
For patients unsuitable for SCT or without a matched donor, cytosine arabinoside (ARA-C) and interferon-α (IFN-α) improve the degree of response in a proportion of cases. Some patients may benefit from enrolling in clinical trials investigating the efficacy of combining TKIs with ARA-C or IFN-α, or exploring the use of SCT from the alternative donor sources of cord blood or haploidentical SCT. More experimental approaches with novel TKIs, aurora kinase inhibitors, autologous SCT, and peptide vaccines are also being evaluated.
Allogeneic Stem Cell Transplantation:Treatment with Curative Intent
SCT from an HLA-matched sibling in CP within a year of diagnosis achieves long-term disease control and survival of 70% (approximately 60% for patients with CP who undergo transplantation more than a year from diagnosis). Age has a major impact on outcome, results being especially favorable for the minority pediatric CML population, while patients older than 40 years of age have lower disease-free survival (DFS). Disease stage is the other major variable affecting transplantation success. Both transplant-related mortality (TRM) and relapse are higher in transplants performed for AP and BP (Fig. 13.7); however, patients who achieve a second CP have a better chance of DFS and results have improved in the imatinib era. Most reported results analyze survival in the first 5 years. Longer-term follow-up indicates that late relapses and deaths from chronic graft-versus-host disease (GVHD) continue to cause late mortality many years after transplant. In evaluating outcome after transplant for CML, measuring DFS underestimates the final cure rate because donor lymphocyte infusions can cure relapsed disease. In summary, the long-term, allogeneic SCT from a matched sibling results in cure in approximately 65% of individuals in CML CP. In the imatinib era where SCT is usually a second-line option for imatinib resistance, DFS of greater than 50% can be expected using reduced intensity SCT and applicable to patients up to the age of 75.
Unrelated Donor Transplants
There is now a large experience in transplants for CML using unrelated volunteer donors. Age, timing of transplant (early or late CP, more advanced disease), and degree of matching each strongly affects the success of the transplant. For low-risk patients (defined as younger than 40 years, in first CP, less than 1 year from diagnosis and with an HLA-matched unrelated donor) DFS of approximately 60% can be achieved; poorer results can be anticipated from patients with less favorable presentations. However, reduced intensity transplants have improved the outlook for older patients. Thus it is appropriate to offer lower intensity SCT to patients with CML up to the age of 70 who have no significant comorbidities.
FIGURE 13.7 Probability of survival after HLA-identical sibling donor transplants for CML from 1998 to 2009 by disease status and year.
Selecting Patients for Allogeneic Transplantation
Gratwohl et al.29 described a simple scoring system to predict the chance of a successful transplant outcome (Table 13.3). SCT is no longer recommended as primary therapy for CP-CML for the majority of patients.30 However, as SCT has a definite curative potential with long-term survival documented over many decades, it is still appropriate to recommend it for young patients under the age of 30 who are expected to have a particularly low morbidity and mortality, and also in circumstances in which there is difficulty obtaining TKIs due to economic reasons. For other patients, imatinib is the first-line treatment, followed by other TKIs, and SCT is reserved for patients who fail to respond, progress, or present with CML beyond CP.
Treatment of Accelerated Phase
Allogeneic SCT is the most substantiated curative therapy for CML AP and should be offered to patients with a fully or partially matched HLA-identical donor. However, up to 40% of patients with CML AP respond to imatinib 600 mg daily.16 Furthermore, second-generation TKIs are effective in imatinib-resistant disease. Alternatively interferon in combination with ARA-C can achieve disease control. Experimental treatment approaches include SCT from a mismatched-related donor and high-dose chemotherapy or radiation followed by autologous SCT.
Treatment of Blastic Phase
The first step in managing CML BP is to determine whether the leukemia has developed into lymphoid or myeloid BP. The average survival upon progression to BP is between 6 and 10 months, slightly longer for lymphoid BP.31Patients who have not already developed resistance to imatinib should be treated immediately with 800 mg daily. Many patients treated de novo with imatinib will have a complete or at least a partial response. Imatinib-refractory patients may benefit from second-generation BCR-ABL inhibitors such as dasatinib or nilotinib, but those with rapidly progressing leukemia require induction chemotherapy with standard regimens—ALL-like for lymphoid BP: daunorubicin 45 mg/m2 days 1 and 2, vincristine 2 mg/m2 weekly, prednisolone 60 mg/m2 daily for 3 weeks, and AML-like for patients with myeloid BP: daunorubicin 50 mg/m2 daily for 2 to 3 days with ARA-C 200 mg/m2 daily for 5 to 7 days. Lymphoid BP patients also require prophylactic central nervous system treatment to prevent meningeal leukemia. Up to 40% of patients achieve a second CP but most relapse rapidly. Allogeneic SCT, although considered salvage therapy and associated with significant TRM in patients who have progressed to BP, offers the only chance of cure and should be offered to eligible patients. A significant number of patients have prolonged cytopenia after successful eradication of blasts; for this reason moderate intensity remission induction chemotherapy is often used (such as “2 + 5” for myeloid BP, and avoidance of high-dose ARA-C regimens such as hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) for patients with lymphoid BP). Sometimes further remissions can be induced, especially when the relapse occurs in the alternate lineage. Patients who have few clinical options may benefit from entering clinical trials of investigational agents.
SPECIAL ISSUES IN CHRONIC MYELOGENOUS LEUKEMIA MANAGEMENT
Treatment of Relapse after Transplantation
Durable molecular remissions after donor lymphocyte infusion (DLI) are achieved between 3 and 12 months after DLI in as many as 80% of patients relapsing in CP and in more than 90% of molecular relapses. Predictably, the occurrence of GVHD results in a much higher probability of leukemic response, and the antileukemic effect of DLI is greatest in the absence of immunosuppression. While DLI is often effective, it may cause bone marrow failure and lethal GVHD. Bone marrow failure is a greater risk in patients with no detectable residual donor marrow cells at relapse. Marrow aplasia in these patients can be prevented or treated by infusing more donor stem cells. Despite concerns that DLI in the setting of unrelated donor transplants would result in excessive toxicity, response and durable remission rates are similar to those seen after matched-sibling DLI. GVHD remains a hazard but does not appear to be more frequent or more severe than that encountered after matched-sibling DLI. Imatinib has been combined successfully with DLI in treatment of relapse.32
Leukostasis is an uncommon problem in CML and only occurs in a minority of patients with high leukocyte counts (over 300 × 109/L). In patients with priapism or neurologic deficit, emergency leukapheresis can be effective but may require several large-volume apheresis sessions to lower the leukocyte count significantly. At presentation such patients should receive high-dose hydroxyurea (up to 4 g daily) or ARA-C 1 g/m2 daily for 2 to 3 days with allopurinol 300 mg daily, adequate hydration, and monitoring of blood chemistry. Imatinib may be started once control of the leukocyte count has been achieved.
Splenic infarcts usually occur when the disease is uncontrolled. Treatment is symptomatic, while attempts to lower the blood count are made. Splenectomy is not generally indicated.
Myelofibrosis causing significant cytopenias can be treated by splenectomy but this maneuver is frequently followed by increasing symptomatic hepatomegaly. Myelofibrosis is not a contraindication for allogeneic SCT and diminishes after successful SCT.
Chloromas often respond poorly to chemotherapy and are best treated with local radiotherapy.
Psychological Responses of Patients with CML
Psychological responses of patients with CML to their disease. Patients presenting with CML are often asymptomatic and may have difficulty accepting that they have a potentially lethal disease. Perhaps for this reason some will explore alternative treatments and attempt psychosomatic techniques to control their leukemia. The complexity of disease evolution and the dilemmas of treatment in CML make it essential to educate patients about their leukemia, in order to provide them an informed basis for making treatment decisions.
EVOLVING STANDARD OF CARE
Second-generation Tyrosine Kinase Inhibitors or Imatinib in Combination with Interferon-α as First-line Treatment
There is currently debate regarding whether CML patients diagnosed in CP should have dasatinib or nilotinib as first-line therapy rather than imatinib. Two recent trials8,9 have shown a more rapid achievement of therapeutic endpoints with upfront dasatinib or nilotinib compared with imatinib. However, survival benefit has not been demonstrated, and these second-generation TKIs are generally more costly than imatinib. In view of the shorter clinical experience with second-generation TKIs, their long-term side effects with prolonged therapy are also unknown. There are ongoing clinical trials accruing to address these questions. In favor of earlier switching to second-line treatment is a recent study which found that assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients treated with any TKI.33
Combination therapy of imatinib with IFN-α has been shown to achieve better molecular responses compared to imatinib alone in some recent clinical trials34-36 but not in others.37 Survival benefit has not been demonstrated in patients receiving combination therapy, who generally had more side effects than those on imatinib alone.
Third-Generation Tyrosine Kinase Inhibitors
BCR-ABL1 kinase domain mutations such as T315I which are highly resistant to imatinib, dasatinib, and nilotinib in many patients herald the onset of advanced phase CML. Ponatinib, a third-generation TKI with activity against T315I mutations, has shown very promising results in clinical trials, with a good balance of efficacy and acceptable side-effect profile compared to other emerging therapies for resistant CML.
References