Samer A. Srour and Muzaffar H. Qazilbash
EPIDEMIOLOGY
Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm characterized by dysregulated proliferation of mature granulocytes secondary to deregulated tyrosine kinase. It was first described in Europe during the 1840s as reviewed by Geary and Deininger, and currently accounts for 15% to 20% of newly diagnosed leukemia in adults with a median age of 54 years. The age-adjusted incidence of CML is 3.3 per one million person-years, with male predominance. The average person’s lifetime risk of being diagnosed with CML is about 1 in 625, and there has been a notable increase in the incidence and prevalence of CML over last decade, likely related to increased use of Philadelphia (Ph) chromosome testing and improved survival with the use of tyrosine kinase inhibitors (TKIs), respectively.
PATHOPHYSIOLOGY
CML is a clonal disorder of hematopoietic stem cells. The reciprocal translocation between the long arms of chromosomes 9 and 22 [t(9;22)], the Ph chromosome, is the initiating event and the diagnostic hallmark of CML. This translocation results in the transfer of the Ableson (ABL) gene on chromosome 9 to an area of chromosome 22 termed the breakpoint cluster region (BCR), resulting in the BCR-ABL fusion gene. This fusion gene results in the expression of the constitutively active protein tyrosine kinase, BCR-ABL1 oncogene, which plays the central role in the pathogenesis of CML leading to an uncontrolled proliferation of granulocytes, predominantly neutrophils but also eosinophils and basophils at various maturation stages. The BCR-ABL1 gene fusion is present in all CML patients, and the majority express the 210 kDa oncoprotein, while less than 10% express either the 190 kDa or 230 kDa oncoprotein. The different-molecular-weight isoforms are generated due to different breakpoints and mRNA splicing. Patients who lack BCR-ABL1 are considered atypical CMLs, and an alternative diagnosis to BCR-ABL- positive CML should be sought. If left untreated, majority of patients with chronic phase (CP) CML will progress to accelerated phase (AP) and/or blast phase (BP), which is likely a multistep process that remains poorly understood. However, it is notable that the bulk of genetic changes occur in transition from CP-CML to AP, and that clonal evolution plays a major role in progression to BP.
DIAGNOSIS AND CLINICAL FEATURES
Symptoms and Signs
Patients with CML present in the CP in over 85% of cases, and the diagnosis is mostly incidental. Up to 50% of patients are asymptomatic at presentation. Symptoms are usually related to underlying cytopenias or splenomegaly. The following are the common symptoms at presentation:
Fatigue and malaise
Anorexia and weight loss
Left upper quadrant discomfort/early satiety associated with splenomegaly
Dyspnea on exertion
Bleeding
Laboratory Features
The diagnosis of CML may be accomplished with peripheral blood testing. An elevated white blood cell count with a left shift, including higher than normal percentages of basophils, eosinophils, myelocytes, and metamyelocytes, in addition to thrombocytosis are suggestive of CML. Although identification of Ph chromosome on cytogenetic analysis or the detection of BCR-ABL fusion transcript by fluorescence in situ hybridization (FISH) analysis or polymerase chain reaction (PCR) in peripheral blood may be sufficient for initial presumptive diagnosis, a bone marrow aspiration/biopsy and cytogenetic analysis are mandatory before initiation of treatment for staging purposes and to detect chromosomal abnormalities other than Ph chromosome. This would guide the choice of initial therapy and subsequent disease monitoring, including clonal evolution. The absolute value of the transcript level by PCR testing is not important for initial diagnosis or staging, but it is essential for subsequent evaluation of response.
Differential Diagnosis
Leukoerythroblastic reaction in response to infection, inflammation, or malignancy
Chronic myelomonocytic leukemia
Juvenile myelomonocytic leukemia
Chronic eosinophilic leukemia
Chronic neutrophilic leukemia
Atypical CML
Idiopathic myelofibrosis
Essential thrombocytosis
Polycythemia vera
STAGING AND PROGNOSTIC FACTORS
CML is characterized by three distinct clinical phases. Minor differences in defining disease stages exist among study groups, but the World Health Organization (WHO) classification is widely adopted (Table 25.1). In the recently published 2016 revised WHO classification, no major changes were noted in defining the 3 CML phases but “provisional” criteria were added to AP definition to include failure of tyrosine kinase treatment and/or acquisition of BCR-ABL1 mutations while on treatment. While over 85% of patients are diagnosed in the more indolent stage termed CP, if left untreated most patients will eventually progess within 3 to 5 years to an AP, followed by an aggressive blastic phase. Twenty to 25% of patients can progress directly from CP to BP, which is characterized by ≥20% blasts in the bone marrow or peripheral blood, or the development of extramedullary disease outside of the spleen.
Prognosis of patients with CML has improved markedly over past 2 decades with the introduction of TKIs, leading to 10-year survival rates exceeding 80% for CML patients in CP, but remains relatively poor for those in AP or BP. Risk stratification scores are commonly used for patients in CP. The Sokal and Hasford risk scores are derived from patients treated with conventional chemotherapy or recombinant interferon alpha (rIFNα), and use clinical and laboratory features at diagnosis such as age, spleen size, platelet count, and peripheral blood blasts, eosinophils and basophils (Table 25.2). The Sokal score has been shown to correlate with both, the response rates to imatinib mesylate (IM) and survival outcomes. The 6-year follow-up data from the IRIS trial (International Randomized Study of Interferon vs. STI571) confirmed the prognostic value of the Sokal scoring system; the 6-year overall survival (OS) and event-free survival (EFS) estimates were 94% and 91%, respectively, for low-risk patients; 87% and 81% for intermediate-risk patients, respectively; and 76% and 67% for high-risk patients, respectively. More recently, the European Treatment and Outcome Study (EUTOS) and the EUTOS long term survival (ELTS) scores were introduced, but are not commonly used in the United States.Additional cytogenetic abnormalities may develop in over 80% of patients in the accelerated and blast crisis phases. Clonal cytogenetic evolution, while on treatment, confers a worse prognosis especially when it includes one of the “major route” abnormalities such as trisomy 8, trisomy 19, duplication of the Ph chromosome, and isochromosome 17q. The depth and timing of hematologic, cytogenetic, and molecular responses to treatment is correlated with prognosis as well.
TREATMENT
Historically, treatment options for CML included conventional cytotoxic chemotherapy (such as hydroxyurea and busulfan), interferon α, and allogeneic hematopoietic stem cell transplantation which remains the only potentially curative option. The introduction of TKIs have revolutionized the treatment of CML in the past two decades leading to practice changes in treatment algorithms, treatment goals, monitoring tools, and the expectations of patients and physicians. The mainstay of frontline CML therapy is currently IM or one of the second-generation TKIs such as nilotinib and dasatinib. The more recently approved agents, bosutinib and ponatinib, are mostly used for subsequent lines of treatment, or in some individual cases as frontline. The newer agents can overcome some of the genetic mutations that underly TKI resistance, and can lead to quicker and deeper cytogenetic and molecular remissions when compared to IM. Omacetaxine, a subcutaneously bioavailable semisynthetic form of homoharringtonine, was recently approved for CML treatment in patients who had progressed after treatment with at least two TKIs.
Hydroxyurea
Hydroxyurea is a cytotoxic antiproliferative agent that is administered orally and is used when a patient has an elevated white blood cell count (>80 × 109/L) to allow rapid control of blood counts. It induces hematologic responses in 50% to 80% of patients and is continued until confirmation of diagnosis; however, it does not alter disease course. Allopurinol may be added to prevent tumor lysis syndrome when starting hydroxyurea.
Interferon
Recombinant IFNα-based regimens were the standard therapy for chronic-phase CML before the discovery of IM. Majority of patients achieved complete hematologic remission (CHR), but complete cytogenetic responses (CCyR) were noted in minority of patients. While effective and even curative in some patients, with earlier studies showing that 10-year OS exceeding 70% for those who achieve CCyR, these agents had significant adverse effects that greatly impair the quality of life and adherence to treatment. IFN is no longer recommended for fronline treatment in CML. However, it can be considered in specific circumstances such as during pregnancy given its relative safety compared to TKIs.
Tyrosine Kinase Inhibitors
With the advent of IM, CML had set the bar for how a malignancy could be effectively treated with targeted therapy, and ushered a new era of research in this field. IM is a phenylaminopyrimidine derivative that inhibits the BCR-ABL tyrosine kinase by competitive binding at the ATP-binding site. Although active in all phases of CML, the most durable responses are seen in newly diagnosed patients in CP. Results of the pivotal IRIS trial established the superiority of IM, and at 8-year follow-up, the estimated EFS was 81%, freedom from progression to CML-AP or CML-BP 92%, and OS 85%. When only CML-related deaths were considered, OS reached 93%. An estimated 7% of patients progressed to accelerated-phase CML or blast crisis. As a result, IM 400 mg daily was established as the standard of care for patients with newly diagnosed chronic-phase CML. The most common adverse events seen with IM are skin rash, muscle cramps, edema, myelosuppression, diarrhea, and liver function test abnormalities.
The high rate of complete cytogenetic response with IM has shifted the goal of therapy to achieving molecular responses measured by PCR. Response criteria are summarized in Table 25.3. Duration of remission and survival are related to the depth of molecular response achieved. As more information has become available, the responses to TKI therapy have become the most important marker of overall prognosis. This makes molecular monitoring an essential component of CML management. More recently monitoring schema have become available that help to determine when a second-generation TKI would be appropriate as well as timing to refer for allogeneic stem cell transplant. If there is suboptimal response to IM, BCR-ABL1 kinase domain mutational analysis is indicated and treatment options include an increase in IM dose, switching to a second-generation TKI, and an early referral for allogeneic transplant. At this time there are no definite data favoring one option over another although the failure of IM predicts for poorer prognosis. Most experts refer patients for stem cell transplant evaluation after suboptimal response to 2 TKIs. The revised and updated LeukemiaNet treatment recommendations based on initial and subsequent response are summarized in Table 25.4 and 25.5.
Second and Third Generation Tyrosine Kinase Inhibitors
Second-generation TKIs include dasatinib, nilotinib, and bosutinib that are more potent than IM. Dasatinib and nilotinib are approved for frontline therapy by the U.S. Food and Drug Administration. There remains no consensus on the preferred first line TKI, although there are experts who would advocate starting therapy with a second-generation TKI in light of better complete cytogenetic response and major molecular response (>75%) and lower rates of transformation to advanced phases with the newer agents. However, IM has the advantage of having the longest safety data, with expectations to be available in a generic form in the near future, and to-date there is no overall survival benefit shown with the use of the second generation TKIs. Awaiting longer term safety and efficacy data, baseline patient- and disease-factors as well as the availability, cost, and distinct safety profile for first and second generation TKIs may influence initial choice of treatment. Dasatinib can be associated with significant pleural effusions, increased bleeding risk secondary to platelet aggregation inhibition, and pulmonary artery hypertension, and hence it should be avoided in patients with underlying lung disease and/or at increased risk for bleeding. Nilotinib has been associated with prolonged QT interval, increased risk of vascular events (including peripheral artery occlusive disease), hyperglycemia, and pancreatitis; therfore, in presence of an alternative its use should be avoided in patients with cardiac arrhythmias, peripheral vascular disease, uncontrolled diabetes, and/or pancreatitis.
Bosutinib, a dual kinase inhibitor, has proven activity in imatinib-resistant CML patients with CCyR of approximately 40%. Bosutinib is not active against the T315I mutation, however it has shown activity in patients with BCR-ABL1 mutations resistant to dsastinib (F317L) and nilotinib (Y253H and F359C/I/V). There are several third-generation TKIs in the pipeline. These agents have activity against the BCR-ABL/T315I mutation that is mainly responsible for resistance to IM and second-generation TKIs. Ponatinib was approved recently by the FDA for use in patients failing second-generation TKIs or with the BCR-ABL/T315I mutation. Ponatinib has shown potent activity against several other BCR-ABL1 mutations. Because of its serious cardiovascular events, ponatinib use is limited to patients who have failed other TKIs and/or have T315I mutation. Recent data suggested a decreased risk of cardiovascular events at lower doses, and hence ongoing studies are assessing efficacy and safety of reduced-dose ponatinib. As more information is gathered regarding mutational status, better decisions can be made on the optimal TKI selection for CP patients. Currently, mutational status is checked at the time of failure of initial TKI therapy; however, the argument can be made that ascertaining mutational status at diagnosis leads to a decreased rate of failure and hence a better durable response by choosing the right TKI while the disease is at its earliest stage. This is a topic of ongoing clinical trials. For patients who are diagnosed in AP or BP, a second-generation TKI alone or combined with cytotoxic chemotherapy is recommended, followed by allogeneic stem cell transplant for eligible patients.
Omacetaxine
Homoharringtonine is a natural alkaloid that is obtained from various Cephalotaxus species and its mechanism of action is through inhibition of protein synthesis and promotion of apoptosis. The semisynthetic derivative, omacetaxine, has been shown to have benefit in IM-resistant CML and for those patients with T315I mutation. Evidence is based on two phase 2 studies. The first study examined the use of omacetaxine in patients with IM-resistant CML harboring T315I mutation and showed favorable complete hematologic response, major CyR and CCyR in 77, 23, and 16 percent, respectively. The second phase 2 study included patients who had failed or were intolerant to at least 2 TKIs. The CHR, MCyR, and CCyR were 70, 18, and 9 percent, respectively, with a median duration of response of 11 months. In a pooled analysis from the two aforementioned studies, omacetaxine was found to be effective in patients with advanced phase CML, particularly the AP with median PFS and OS of 4.8 and 17.6 months, respectively. The most frequent grade 3/4 toxicities are thrombocytopenia, neutropenia, anemia, and diarrhea. Omacetaxine is FDA approved for CML patients in CP or AP who had failed or were intolerant to at least two TKIs.
Allogeneic Stem Cell Transplantation
Allogeneic stem cell transplantation has been long shown to be the only potentially curative treatment for CML, and remains the most viable treatment option for patients diagnosed in AP, BP, or with known resistant mutations against TKIs. Despite the advances made with TKIs and long-term remissions exceeding 10 years in some patients, there is a consensus that current treatment is not curative, and should be continued indefinitely given the high risk of relapse after stopping TKIs. CML is a disease in which graft versus leukemia plays an important role and there are extensive reports of the use of donor lymphocyte infusions leading to durable complete remissions. An analysis from the Center for International Blood and Marrow Transplant Research (CIBMTR) reported outcomes on 2,444 patients who received myeloablative allogeneic stem cell transplant in first CP and survived in continuous complete remission for ≥5 years. OS for the entire patient population was 94% at 10 years and 87% at 15 years. Compared to matched general population, these patients had a 2.5 times higher risk of death at 10 years due to complications such as multiorgan failure, infection, graft versus host disease, relapsed disease, and secondary malignancies. However, mortality rates approached that of the general population at 15 years post–allogeneic transplant for those who survived. Improvements in HLA typing, management of infections, supportive care, conditioning regimens, and immunosuppressive agents have contributed to a significant improvement in transplant outcomes. Reduced-intensity regimens have been safely used in older patients and patients with comorbidities. In recent years, advances in alternative donor transplantation including the use of mismatched related donors and unrelated umbilical cord blood as stem cell sources have made allogeneic transplants available to patients that previously were unable to find a matched related or unrelated donor. Interestingly, patients who were resistant to TKIs prior to transplant become responsive posttransplant, which has prompted a number of studies that are evaluating the role of TKIs in the posttransplant setting.
Summary
Imatinib, dasatanib, and nilotinib are all approved and acceptable options for newly diagnosed chronic-phase CML. Treatment choice should be individualized based on cost, patient characteristics, and drug safety profile. After the failure of imatinib as frontline therapy, a second generation TKI such as dasatinib or nilotinib is recommended. When a second generation TKI is used as frontline therapy and fails, an alternate second generation TKI may be used. These patients may also be considered for allogeneic stem cell transplantation and/or enrollment in clinical trials. Ponatinib is considered after failure of other TKIs and is the treatment of choice for patients with T315I mutation. Omacetaxine is indicated for patients who have failed or are intolerant to at least two previous TKIs and is effective for patients with T3151 mutation. Allogeneic stem cell transplantation remains the preferred choice for eligible high-risk patients such as those who have failed two TKIs, harbor T3151 mutations, and those with advanced-stage CML.
TABLE 25.1World Health Organization (WHO) Criteria for Chronic Myeloid Leukemia Stages
Stage | Features |
Chronic phase | Blast cells in blood or marrow <10% Basophils in blood <20% Platelets >100 × 109/L |
Accelerated phase* | Blast cells in blood or marrow 10%–19% Basophils in blood 20% or more Persistent thrombocytopenia (<100 x 109/L) unrelated to therapy Thrombocytosis (>1000 x 109/L) unresponsive to therapy Persistent or increasing splenomegaly and/or WBC (>10 x 109/L) count unresponsive to therapy Additional clonal chromosomal abnormalities at diagnosis or any evidence of new clonal chromosomal abnormality while on treatment |
Blastic phase | Blast cells in blood or bone marrow ≥20% Extramedullary blast proliferation Large foci or clusters of blasts in the bone marrow biopsy |
*“Provisional” response-to-tyrosine kinase inhibitor (TKI) criteria were added in the 2016 revised WHO classification to define accelerated phase CML. These included: Hematologic resistance to the first TKI (or failure to achieve a complete hematologic response to the first TKI); or any hematological, cytogenetic, or molecular indications of resistance to 2 sequential TKIs; or occurrence of 2 or more mutations in BCR-ABL1 during TKI therapy.
TABLE 25.2Sokal and Hasford Risk Indexes
Risk Category | Risk Index | Median Survival |
Sokal | ||
Low | <0.8 | 5 y |
Intermediate | 0.8–1.2 | 3.5 y |
High | >1.2 | 2.5 y |
Hasford | ||
Low | ≤780 | 98 mo |
Intermediate | 781–1,480 | 65 mo |
High | >1,480 | 42 mo |
Sokal risk index was defined based on patients treated with conventional chemotherapy. Hasford risk index was defined based on patients treated with rIFNα-based regimens.
Sokal score: EXP [0.0116 × (age − 43.4) + 0.0345 × (spleen size [cm below costal marigin] − 7.51) + 0.188 × [(platelet count/700)2 − 0.563] + 0.0887 × (myeloblasts − 2.1)].
Hasford score: [0.666 when age ≥50 y + 0.042 × (spleen size [cm below costal marigin]) + 1.0956 (when platelet count ≥ 1,500 × 109/L) + 0.0584 × myeloblasts + 0.2039 (when basophils ≥3%) + 0.0413 × eosinophils (%)]× 1,000.
TABLE 25.3Response Criteria
Complete hematologic response (CHR) | WBC < 10 × 109/L No immature granulocytes Less than 5% basophils, Platelets <450×109/L Spleen nonpalpable |
Complete cytogenetic response (CCyR) | No Ph+ metaphases |
Partial cytogenetic response (PCyR) | 1%–35% Ph+ metaphases |
Minor cytogenetic response (mCyR) | 36%–65% Ph+ metaphases |
Minimal cytogenetic response (minCyR) | 66%–94% Ph+ metaphases |
No cytogenetic response (NoCyR) | ≥95% Ph+ metaphases |
Major molecular response (MMR) | BCR-ABL: ABL ≤0.1% on the International scale |
Complete molecular response (CMR) | BCR-ABL transcript undetectable by RT-Q-PCR |
TABLE 25.4Definition of the Response to Frontline Treatment with Any Tyrosine Kinase Inhibitor
Warnings | Failure | Optimal Response | |
Baseline | High-risk chronic myeloid leukemia or—clonal abnormalities in Ph+ cells | Not applicable | Not applicable |
3 Mo | BCR-ABL1 >10%and/or Ph+ 36%–95% | No hematologic response and/or Ph+ >95% | BCR-ABL1 ≤10% and/or Ph+ ≤35% |
6 Mo | BCR-ABL1 1%–10% and/or Ph+ 1%–35% | BCR-ABL1 >10% and/or Ph+ >35% | BCR-ABL1 <1% and/or Ph+ 0% |
12 Mo | BCR-ABL1 >0.1%–1% | BCR-ABL1 >1% and/or Ph+ >0% | BCR-ABL1 ≤0.1% |
Then, and at any time | Clonal abnormalities in Ph- cells (–7, or 7q–) | Loss of any aforementioned responses and/or acquisition of either BCR-ABL1 mutations and/or clonal chromosomal abnormalities in Ph+ cells | BCR-ABL1 ≤0.1% |
The definitions are the same for patients in chronic phase, accelerated phase, and blastic phase and apply also to second-line treatment, when first-line treatment was changed for intolerance. The response can be assessed with either a molecular or a cytogenetic test, but both are recommended whenever possible.
Adapted from Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122: 872–884.
TABLE 25.5Treatment Recommendations for Second Line and Subsequent Treatment for Chronic Phase Chronic Myeloid Leukemia*
Second line, secondary to intolerance to the first TKI Any alternative TKI approved in the first line setting (imatinib, dasatinib, nilotinib) |
Second line, secondary to failure of imatinib first line One of the second generation TKIs (dasatinib, niltotinib, bosutinib) HLA typing for patient and siblings |
Second line, secondary to failure of dasatinib first line One of the alternative second generation TKIs (niltotinib, bosutinib) HLA typing for patient and siblings; search for an unrelated stem cell donor and consider allogeneic stem cell transplantation |
Second line, secondary to failure of nilotinib first line One of the alternative second generation TKIs (dasatinib, bosutinib) HLA typing for patient and siblings; search for an unrelated stem cell donor and consider allogeneic stem cell transplantation |
Third line, secondary to failure of and/or intolerance to 2 previous TKIs Any alternative second or third generation TKI or omacetaxine Allogeneic stem cell transplantation is recommended to all eligible patients |
Any line, detection of T315I mutation Ponatinib or omacetaxine HLA typing for patient and siblings; search for an unrelated stem cell donor and consider allogeneic stem cell transplantation |
Abbreviations: TKI, tyrosine kinase inhibitor.
*Taken into consideration the National Comprehensive Cancer Network (NCCN V1.2016) Guidelines and the European LeukemiaNet recommendations.
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