Chronic Leukemias
Chaitra Ujjani
Bruce D. Cheson
I. INTRODUCTION
Although the chronic leukemias have traditionally been grouped together to underscore their differences from the aggressive, acute leukemias, they are a heterogenous collection of disorders as well. Chronic leukemias can be broadly divided into those arising either from hematopoietic stem cells or mature lymphocytes. The unifying feature among the chronic leukemias is that, initially, there is relatively normal maturation of the progeny of the neoplastic clone. Malignant hematopoiesis is effective and results initially in increased numbers of mature-appearing cells in the peripheral blood and bone marrow that have few morphologic abnormalities. Functionally, however, both chronic myelogenous leukemia (CML) and chronic lymphocytic leukemia (CLL) cells are less competent than their nonleukemic counterparts. The relatively normal morphologic appearance is in marked contrast to the acute leukemias where maturation arrest with consequent bone marrow failure is the hallmark of the disease. Nonetheless, chronic leukemias have a heterogeneous biology. They differ considerably in pathogenesis, natural history, and treatment approaches, which are discussed further in detail in this chapter.
II. CHRONIC MYELOGENOUS LEUKEMIA
CML is a relatively uncommon malignancy, accounting for 15% to 20% of adult leukemias in the United States. The estimated incidence in 2015 is 6,660 new cases.1 The median age at diagnosis is 53 years, occurring slightly more frequently in men. Less than 10% of cases are under 20 years of age. Ionizing radiation, including therapeutic radiation, is the only known risk factor for CML. There is no known genetic predisposition to the disease; however, there have been reports of families in which multiple members develop myeloproliferative neoplasms, including CML.
CML is a clonal hematopoietic stem-cell disorder caused by a balanced translocation between the long arms of chromosomes 9 and 22 [t(9;22)(q34;q11.2)], also known as the Philadelphia (Ph1) chromosome. The hybrid BCR-ABL gene resulting from the t(9;22) has been noted in almost all cases of CML and is considered pathognomonic. The BCR-ABL fusion protein results in constitutive tyrosine kinase signaling activity that mediates the biologic hallmarks of CML through activation of a mitogenic signaling pathway, altered cellular adhesion to the extracellular matrix, inhibition of apoptosis, and downstream activation of a complicated network of signaling pathways including
RAS, mitogen-activated protein kinase, Myc, phosphatidylinositol 3 kinase, NF-k-B, and Janus kinase signal transducer and activator of transcription pathways.2
RAS, mitogen-activated protein kinase, Myc, phosphatidylinositol 3 kinase, NF-k-B, and Janus kinase signal transducer and activator of transcription pathways.2
A. Diagnosis
Approximately 90% of patients with CML present in the chronic phase (CP) of the disease and may be asymptomatic. Symptoms, when present, may include fatigue, bone aches, weight loss, and abdominal discomfort related to splenomegaly. The identification of a marked leukocytosis (usually greater than 25 × 109/L) due to a neutrophilia of all stages of maturation with a myelocyte “bulge” (i.e., myelocytes outnumbering the more mature metamyelocytes), shift to the left of differentiation, absolute basophilia and eosinophilia, thrombocytosis, and mild anemia are key factors in the initial diagnosis. Leukocytes in CML, while morphologically normal, exhibit a cytochemical abnormality with low leukocyte alkaline phosphatase (LAP). The low LAP score is thought to be a consequence of relatively low levels of granulocyte colony-stimulating factor and is useful in differentiating CML from a reactive leukocytosis or “leukemoid reaction,” typically due to infection and associated with a normal or elevated LAP score.
While the diagnosis of CML can be suggested by findings in the peripheral blood, a bone marrow aspiration and biopsy are used for confirmation of the diagnosis. The bone marrow is invariably hypercellular with a myeloid-to-erythroid ratio in the range of 10 to 30:1. All stages of myeloid maturation are usually seen with myelocyte predominance. Megakaryocytes are typically increased in number and are characteristically smaller than normal. Up to 40% of patients will display increased reticulin fibrosis, which typically correlates with the degree of megakaryocytosis. The blast percentage varies with the phase of the disease as described below.
Up to 95% of patients with CML demonstrate the t(9;22) (q32;q11.2) reciprocal translocation that results in the Ph1 chromosome.3 Complex translocations of other chromosomes (variant Ph1) and cryptic translocations of 9q34 and 22q11.2 account for the remaining patients. The latter are unable to be identified by standard cytogenetic testing and are therefore referred to as “Ph-negative.” Fluorescence in situ hybridization (FISH) analysis to identify the BCR-ABL1 fusion gene or reverse transcription (RT)-polymerase chain reaction (PCR) to identify the BCR-ABL1 fusion mRNA is necessary in these patients for confirmation of the diagnosis. As such, bone marrow samples must be submitted for standard karyotyping (e.g., chromosomal banding analysis [CBA]), metaphase/interphase FISH, and RT-PCR. If a bone marrow biopsy is not feasible for diagnosis, FISH can be performed on the peripheral blood. The molecular pathogenesis in CML involves three different breakpoint regions in the BCR gene on chromosome 22. More than 90% of patients with CML express the 210-kDa
oncoprotein, which is referred to as the p210 BCR-ABL1 protein. The remaining patients express either p230 BCR-ABL1 or the p190 BCR-ABL1 fusion proteins. There are no distinct differences in the clinical courses of these patients.
oncoprotein, which is referred to as the p210 BCR-ABL1 protein. The remaining patients express either p230 BCR-ABL1 or the p190 BCR-ABL1 fusion proteins. There are no distinct differences in the clinical courses of these patients.
While the Ph1 is the initiating event in CML, additional nonrandom chromosomal or molecular changes appear to be necessary for progression to accelerated phase (AP) or blast phase (BP).3 Clonal evolution occurs in up to 80% of patients in the accelerated and blast crisis phases, and, if noted during the CP, confers a worse prognosis. The most commonly observed karyotypic abnormalities include trisomy 8, trisomy 19, duplication of the Ph1 chromosome, and isochromosome 17q (causing deletion of the p53 gene on 17p). Telomere shortening has also been associated with disease evolution. It is not known how these chromosomal changes contribute to the loss of cell differentiation that characterizes advanced-stage disease.
B. Classification
CML is characterized by three evolutionary phases, each carrying a different clinical and hematologic picture, natural history, and treatment outcome.
1. Chronic phase
Approximately 90% of patients present with CP-CML, about half of which are asymptomatic. This phase is marked by a leukocytosis in the peripheral blood and marked granulocytic hyperplasia in the marrow; however, less than 10% of myeloblasts are present in both peripheral blood and bone marrow. Absolute eosinophilia and basophilia are commonly present (in contrast to reactive leukocytosis). Without treatment, the CP will typically run an indolent course of 3 to 5 years before progressing to the AP, although the duration can be highly variable.
2. Accelerated phase
The AP is typically characterized by a loss of previously controlled white blood cell (WBC) counts and clonal evolution, including the development of new chromosomal abnormalities in addition to the persisting or reemerged Ph1 chromosome or the gain of a second Ph1 chromosome. Peripheral blood counts show one or more of the following: 10% to 19% blasts, basophils greater than 20%, platelets <100,000/µL, unrelated to ongoing treatment or >1,000,000/µL, unresponsive to therapy (Table 20.1).4 These laboratory findings are often accompanied by the re-emergence or progression of symptoms such as fever, bone pain, and fatigue, or worsening splenomegaly. Without treatment, the AP lasts 4 to 6 months.
3. Blast phase
The BP, also called “blast crisis,” is the progressed transformation of CML to a phase resembling acute leukemia. CP patients typically transform to BP at a rate of 1% per year; thus, most
patients will have a known prior diagnosis of CML. The BP lasts a few months without treatment and is defined by the acute leukemia criteria of at least 20% blasts in the bone marrow or peripheral blood (Table 20.1).4 However, patients with 20% to 29% blasts seem to carry a better prognosis than those meeting the older criterion of greater than 30% blasts. Extramedullary tumor masses (chloromas) can occur in both the APs and BPs. The majority of cases (50% to 60%) will express a poorly differentiated myeloid phenotype (acute myelogenous leukemia [AML]), while the remainder shows lymphoid (pre-B acute lymphocytic leukemia [ALL], 30%) or an undifferentiated or mixed-lineage phenotype. Persistence of the Ph1 chromosome including additional Ph1 chromosomes, other cytogenetic abnormalities, and BCRABL kinase domain mutations may be present. The acquisition of del 17p is more commonly associated with a myeloid blast crisis. Patients with de novo Ph1 chromosome-positive B-cell ALL typically express p190 BCR-ABL1 and lack the Ph1 chromosome in myeloid cells, whereas patients with lymphoid BP-CML are often characterized by p210 BCR-ABL1 and have persistence of the Ph1 chromosome even after chemotherapy-induced hematologic remissions.
patients will have a known prior diagnosis of CML. The BP lasts a few months without treatment and is defined by the acute leukemia criteria of at least 20% blasts in the bone marrow or peripheral blood (Table 20.1).4 However, patients with 20% to 29% blasts seem to carry a better prognosis than those meeting the older criterion of greater than 30% blasts. Extramedullary tumor masses (chloromas) can occur in both the APs and BPs. The majority of cases (50% to 60%) will express a poorly differentiated myeloid phenotype (acute myelogenous leukemia [AML]), while the remainder shows lymphoid (pre-B acute lymphocytic leukemia [ALL], 30%) or an undifferentiated or mixed-lineage phenotype. Persistence of the Ph1 chromosome including additional Ph1 chromosomes, other cytogenetic abnormalities, and BCRABL kinase domain mutations may be present. The acquisition of del 17p is more commonly associated with a myeloid blast crisis. Patients with de novo Ph1 chromosome-positive B-cell ALL typically express p190 BCR-ABL1 and lack the Ph1 chromosome in myeloid cells, whereas patients with lymphoid BP-CML are often characterized by p210 BCR-ABL1 and have persistence of the Ph1 chromosome even after chemotherapy-induced hematologic remissions.
TABLE 20.1 WHO Criteria for Diagnosis of Accelerated and Blast Phase CML4 | ||||||||||||||
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C. Prognosis
A number of factors indicate an increased risk for progression, including older age, splenomegaly, elevated platelet counts, and higher numbers of peripheral blood myeloblasts, eosinophils, or basophils. The Sokal prognostic system and the Hasford classification utilize a formula factoring in age, spleen size, and the hematologic picture to assign low, intermediate, and high groups
differing in prognosis.5,6 The median overall survival (OS) with the latter score was 96, 65, and 42 months, respectively. Both classifications were developed in patient cohorts receiving interferon, as opposed to tyrosine kinase inhibitors (TKIs), limiting their usefulness. The European Treatment and Outcome Study (EUTOS) score is a newer prognostic model developed and validated on data from 2,060 patients receiving imatinib.7 On the basis of spleen size and percentage of basophils, patients could be risk stratified to low- and high-risk groups, associated with a 5-year progression-free survival (PFS) of 90% versus 82%, p = 0.006. The model was able to predict that 34% of high-risk patients would not achieve a complete cytogenetic remission by 18 months. The EUTOS score has not yet been widely implemented into clinical trial design, nor had it been validated with second- and third-generation TKIs. Regardless of pretreatment characteristics, however, the most important and best prognostic predictor of long-term survival is the quality of the response to treatment by minimal residual disease, which is measured by the degree of cytogenetic and molecular response.
differing in prognosis.5,6 The median overall survival (OS) with the latter score was 96, 65, and 42 months, respectively. Both classifications were developed in patient cohorts receiving interferon, as opposed to tyrosine kinase inhibitors (TKIs), limiting their usefulness. The European Treatment and Outcome Study (EUTOS) score is a newer prognostic model developed and validated on data from 2,060 patients receiving imatinib.7 On the basis of spleen size and percentage of basophils, patients could be risk stratified to low- and high-risk groups, associated with a 5-year progression-free survival (PFS) of 90% versus 82%, p = 0.006. The model was able to predict that 34% of high-risk patients would not achieve a complete cytogenetic remission by 18 months. The EUTOS score has not yet been widely implemented into clinical trial design, nor had it been validated with second- and third-generation TKIs. Regardless of pretreatment characteristics, however, the most important and best prognostic predictor of long-term survival is the quality of the response to treatment by minimal residual disease, which is measured by the degree of cytogenetic and molecular response.
D. Therapy
1. Imatinib (gleevec)
Imatinib is a small-molecule TKI of the BCR-ABL tyrosine kinase. Targeting and inhibiting the BCR-ABL mitogenic pathway with imatinib has achieved dramatic cytogenetic and molecular levels of responses with prolonged disease control in CML. The most comprehensive source of information about the imatinib therapy for patients with CP disease is the International Randomized Study of Interferon and STI571 (IRIS) trial, a phase randomization of imatinib versus the combination of interferon-α and cytarabine in previously untreated patients with CP-CML. At 18 months, 76% of patients achieved a complete cytogenetic response (CCyR) with imatinib compared with 15% with interferon-α and cytarabine (p < 0.001).8 At 8 years of follow-up, the event-free survival (EFS) was 81%, freedom from progression AP/BP was 92%, and estimated OS was 85%.9 Patients who achieved a ≥3 log reduction in the level of BCR-ABL transcript (major molecular response [MMR]) by 18 months had minimal risk of disease progression over the next year. Of the 98 patients who underwent long-term monitoring of BCR-ABL transcript levels, 86% remained in an MMR (<0.1% BCR-ABL) at 8 years. The results of the IRIS trial have been supported in several prospective trials and registry surveys including the PETHEMA, SPIRIT, CAMELIA, GIMEMA, and German CML study groups.10,11,12,13,14 On the basis of the initial results from the IRIS study, imatinib was approved for the treatment of CML. The standard initial dosing for CP disease is 400 mg orally daily. Close monitoring of the BCR-ABL transcript is crucial in the management of CML.
2. Imatinib resistance
Unfortunately, patients can develop resistance to imatinib. Primary resistance without a complete hematologic response (CHR) occurs within 3 to 6 months of initiating TKI therapy in 2% to 4% of patients.15 Primary cytogenetic resistance (i.e., failing to achieve a partial cytogenetic response at 6 months) occurs in 15% to 25% of patients. Secondary resistance is the loss of a previously achieved response. After 7 years of follow-up, 17% of patients treated with imatinib in the IRIS study developed secondary resistance after achieving a CCyR.16 Resistance to imatinib is more frequently seen in AP and BP than in CP. When resistance is observed, a repeat bone marrow with cytogenetics and screening for the new kinase mutations should be performed in order to identify the most appropriate next TKI. Mechanisms of resistance can be BCR-ABL dependent, such as gene amplification or point mutations, or BCR-ABL independent because of mechanisms that alter the drug uptake and efflux.17 Point mutations of the BCR-ABL tyrosine kinase domain can occur at various sites and confer different levels of resistance.18 The T315I mutation that occurs at the ATP-binding site is associated with the highest level of resistance.19 Switching to second- or third-generation TKIs is presently the standard of care for imatinib failure or resistance. An allogeneic stem-cell transplant in eligible patients with resistance to multiple TKIs may be an additional option.
3. Second-generation TKIs
a. Dasatinib (sprycel)
Dasatinib, a piperazinyl derivative that targets many tyrosine kinases, was selected for its potent inhibitory activity against SRC and ABL kinases, including the active conformation of BCR-ABL1 and most mutated forms (except T315I). The drug was shown to be effective for the treatment of Ph+ leukemia and was initially approved for the treatment of patients with imatinib-intolerant and imatinib-resistant disease who have Ph+ CML in CP, AP, and BP in 2006. The approval was based on data from four single-arm multicenter studies (n = 445).20 Among the patients with CP, the CCyR was 33%. Major hematologic responses were seen in 59% of AP, 32% of myeloid BP, and 31% lymphoid BP. For patients receiving 100 mg daily, at 6 years of follow-up, the PFS was 49% and OS was 71%.21 Forty-two percent of patients had evidence of a MMR with BCR-ABL <0.1%. Dasatinib was approved in previously untreated CML in 2010 on the basis of the DASISION study in which 519 patients were randomized to dasatinib 100 mg daily or imatinib 400 mg daily.22 Dasatinib demonstrated a higher CCyR at 12 months of 77% compared with 66% (p = 0.007) as well as higher rate of MMR at any time (52% vs. 34%). At 3 years of follow-up, however, there was no significant difference in PFS or OS.23
b. Nilotinib (tasigna)
Nilotinib is an aminopyrimidine derivative that inhibits the tyrosine kinase activity of the unmutated and several mutated forms of BCR-ABL (except T315I, and to a lesser extent Y253H, E255K, and E255V) with higher in vitro potency and selectivity than imatinib. Similar to dasatinib, nilotinib is effective for the treatment of Ph+ leukemias and was registered for treating imatinib-intolerant and imatinib-resistant patients with Ph+ CML in CP and in AP at a dose of 400 mg twice daily in 2007. In an international phase II study of 321 patients, 45% achieved a CCyR.24 The estimated 4-year PFS and OS were 57% and 78%. The drug was approved for previously untreated patients on the basis of the ENESTnd study, which demonstrated higher CCyR (87% at 2 years), MMR (73% at 3 years), and molecular response (MR)4.5 (32% at 3 years; see Table 20.2) compared with imatinib.25,26,27 Thus far, survival rates are comparable between the arms.
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4. Third-generation TKIs
a. Bosutinib
Bosutinib is a dual inhibitor of SRC and ABL tyrosine kinase, which has notable activity in most imatinib-resistant BCRABL kinase domain mutations, except for T315I and V299L. It was approved in 2012 for Ph+ CP-CML in patients who were intolerant or resistant to at least one prior TKI. A single-arm study demonstrated that bosutinib was able to induce CCyR in 46% who were resistant to imatinib and 54% of patients who were intolerant.28 Neither the median PFS nor OS had been reached at analysis, but the estimated 2-year PFS and OS were 81% and 91%. For patients who had received at least two TKIs, the CCyR was 24% (CHR 73%) with a year 2-year PFS and OS of 73% and 83%.29 Bosutinib has been compared to imatinib in the frontline setting as well, but did not reach its primary endpoint of a superior CCyR to ensure Food and Drug Administration (FDA) approval.30
b. Ponatinib
Ponatinib is a pan-BCR-ABL kinase inhibitor with activity despite all kinase domain mutations including the T315I. It received accelerated approval for CP-, AP-, or BP-CML that was resistant or intolerant to prior TKIs. In the PACE study (n = 449), ponatinib induced an MCyR in 54% of CP-CML patients including 70% of those with the T315I mutation.31 The median duration of response (DOR) had not yet been reached at the time of analysis. The major hematologic response rate in AP- and BPCML was 52% and 31%, whereas the DOR was 9.5 months and 4.7 months, respectively. Because of an increased risk of arterial thrombosis, the drug was temporarily suspended. Ponatinib is currently recommended only for patients with the T315I mutation or those in whom no other TKI is appropriate.
5. Disease monitoring during TKI therapy
Patients receiving TKIs should be monitored closely to assess for treatment toxicity and to evaluate for response. The definitions of response and milestones for treatment are listed in Tables 20.2
and 20.3, respectively.32,33 A reasonable approach, modifiable to an individual patient, is as follows:
and 20.3, respectively.32,33 A reasonable approach, modifiable to an individual patient, is as follows:
a. Complete blood count every 2 weeks until CHR has been achieved, then every 3 months.
b. Bone marrow cytogenetics via CBA of marrow cell metaphases (at least 20 metaphases) should be performed at diagnosis, 3, 6, and 12 months after initiating therapy until a CCyR is achieved, and then every 12 months. FISH on blood cells can be used instead once a CCyR has been achieved. CBA should be performed at 18 months if patient is not in MMR or did not achieve a CCyR at 12 months. It should also be performed if the patient develops rising BCR-ABL1 transcript levels without an MMR.
c. Peripheral blood quantitative RT-PCR for BCR-ABL mRNA at diagnosis and every 3 months with ongoing treatment for 3 years and every 3 to 6 months thereafter. It should be performed if there is a rising BCR-ABL1 transcript level with an MMR and repeated within 1 to 3 months for confirmation.
d. BCR-ABL1 kinase domain mutation analysis should be performed in the setting of suboptimal response or failure with therapy and prior to any change in TKI.34
The timing and level of response are important management milestones. The earlier a cytogenetic and molecular response is achieved, the longer the ultimate response will last. Achievement of a CCyR by 12 months was associated with a longer PFS
and OS than for patients who failed to reach a CCyR.35 More recently, quantitative PCR on peripheral blood has become the monitoring method of choice, and demonstration of an MMR by 18 months is associated with a durable remission.36 Several studies have also shown the prognostic benefit of early molecular response, not only with imatinib, but second-generation TKIs as well. Achievement of a BCR-ABL1 transcript level ≤10% by 3 months has been associated with a better estimated OS with imatinib,37 dasatinib,23 and nilotinib.38
and OS than for patients who failed to reach a CCyR.35 More recently, quantitative PCR on peripheral blood has become the monitoring method of choice, and demonstration of an MMR by 18 months is associated with a durable remission.36 Several studies have also shown the prognostic benefit of early molecular response, not only with imatinib, but second-generation TKIs as well. Achievement of a BCR-ABL1 transcript level ≤10% by 3 months has been associated with a better estimated OS with imatinib,37 dasatinib,23 and nilotinib.38
TABLE 20.3 Milestones and Definitions of Response to First-Line TKI16 | ||||||||||||||||||||||||
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6. Choice of TKI
With three TKIs available for the initial treatment of CML, the most appropriate choice remains unclear. As higher rates of patients reach BCR-ABL1 transcript levels ≤10% by 3 months with second-generation TKIs than imatinib, many advocate the use of these newer agents. It should be noted that this decision is extrapolated from an estimated OS as opposed to a demonstrated benefit in OS. Other factors that should be considered include financial cost to the patient and comorbidities that may be affected by a particular TKI. Imatinib, although tolerated well overall, is associated with mild nausea, diarrhea, peripheral and periorbital edema, hepatotoxicity, and cardiotoxicity. Dasatinib is associated with pleural and pericardial effusions, an increased risk of bleeding, and pulmonary arterial hypertension. Nilotinib can cause pancreatitis, hyperglycemia, hepatotoxicity, cardio and peripheral vascular events, as well as QT prolongation. Bosutinib, like imatinib, is associated with fluid retention and gastrointestinal effects. As previously mentioned, ponatinib can cause arterial thrombosis; additionally, it can cause heart failure, hypertension, hepatotoxicity, fluid retention, pancreatitis, and an increased risk of bleeding.
7. TKI cessation
It should be noted that TKIs can only control, but not completely eradicate the CML clone. Therefore, patients continue on therapy until progression or intolerable toxicity. Discontinuation of imatinib was explored in the Stop Imatinib (STIM) study in which 100 patients with CP or AP and sustained complete molecular remission for at least 2 years.39 At a median follow-up of 17 months, 54 patients had relapsed. Of the 42 relapsed patients with long-term follow-up, all were sensitive to imatinib reinduction and none had developed mutant BCR-ABL phenotypes. Other studies have also demonstrated that patients are able to maintain the same degree of response for a period of time and can be successfully reinitiated on therapy on recurrence.40,41,42 As these are preliminary data, however, current recommendations are to continue TKI therapy indefinitely unless dictated otherwise as part of a clinical trial. Cessation of therapy can be considered in a very select population, such as pregnant woman, but
frequent monitoring is necessary. Trials evaluating the cession of second-generation TKIs are ongoing.
frequent monitoring is necessary. Trials evaluating the cession of second-generation TKIs are ongoing.
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