Chronic Leukemias
Khaled el-Shami
Bruce D. Cheson
The chronic leukemias have traditionally been grouped together to underscore their differences from the aggressive, acute leukemias. Chronic leukemias can be broadly divided into those arising either from mature lymphocytes or from hematopoietic stem cells or any of their nonlymphoid progenitors. 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) cells and chronic lymphocytic leukemia (CLL) cells are less functionally 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 heterogeneous biology and natural history and may evolve into aggressive and difficult-to-treat phase(s) with ineffective hematopoiesis resulting in progressive marrow failure and organ infiltration.
I. CHRONIC MYELOGENOUS LEUKEMIA (CML)
CML is a relatively uncommon malignancy, accounting for 15% of adult leukemias in the United States. The annual incidence of CML is 1.5 cases per 100,000 with a slight male predominance. The median age at diagnosis is 53 years. Less than 10% of cases are under 20 years of age. Ionizing radiation is the only known risk factor. There is no known genetic predisposition or sociogeographic preponderance.
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), also known as the Philadelphia (Ph1) chromosome]. The hybrid BCR-ABL gene from the (9;22) translocation has been noted in almost all cases of CML and is considered pathognomonic. This BCL-ABL fusion protein results in constitutive tyrosine kinase signaling activity that mediates the biologic hallmarks of CML through activation of a mitogenic signaling pathways; 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.
The molecular pathogenesis in CML involves three different breakpoint regions in the BCR gene, resulting in distinct disease phenotypes. More than 90% of patients with CML express the 210-kDa oncoprotein, with a minority of patients expressing either a 185-kDa or 230-kDa oncoprotein without significant differences in the natural history of the disease.
CML is a triphasic process consisting of an indolent, chronic phase (CP) that lasts for several years prior to progression to a treatment-resistant accelerated phase, eventually transforming into a blastic phase (BP) similar to an acute leukemia, which is fatal in most cases. The finding in CML that the Ph1 chromosome is present in lymphoid, erythroid, as well as myeloid elements supports the idea that a neoplastic event involves a pluripotent stem cell.
A. Diagnosis
Approximately 90% of patients with CML present in the CP of disease and may be entirely 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), lack of significant circulating blasts, absolute basophilia, frequent thrombocytosis, and mild anemia are key factors in the initial diagnosis. Leukocytes in patients with CML, while morphologically normal, exhibit a cytochemical abnormality with low leukocyte alkaline phosphatase (LAP) or neutrophil alkaline phosphatase when scored. 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, in which the score is typically elevated or normal. Other less specific laboratory features include elevated elastase, lactate dehydrogenase, vitamin B12 (secondary to production of B12-binding protein haptocorrin by leukocytes), and uric acid levels. A bone marrow aspiration and biopsy is needed in all patients in whom CML is being considered, which will not only confirm the diagnosis, but also provide information necessary to stage and risk-stratify the disease. 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 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. Blasts usually account for less than 5% of the marrow cells, and more than 10% indicates transformation to an accelerated phase. Up to 95% of patients with CML demonstrate the t(9;22) (q32;q11.2) reciprocal translocation that results in the Ph1 chromosome. The rest have either variant translocations, such as complex translocations involving other chromosomes or cryptic translocations of 9q34 and 22q11.2 that cannot be identified by routine cytogenetics. These are referred to as “Ph-negative” and require 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. Therefore, bone marrow samples of patients with suspected CML should be examined both by standard karyotyping (e.g., G-banded metaphase preparation) as well as interphase FISH. Of note, 10% to 15% of patients with CML harbor large deletions flanking the breakpoint on chromosome 9 and/or chromosome 22. Patients with such deletions have a shorter survival and time to progression to accelerated-phase (AP) or BP disease.
While the Ph1 is the initiating event in CML, progression to AP or blast crisis appears to require the acquisition of other nonrandom chromosomal or molecular changes (i.e., clonal evolution, which occurs in 50% to 80% of patients in the accelerated and blast crisis phases and, if noted during the chronic phase, 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 (CP) is the initial presentation of CML in approximately 90% of patients. This phase is marked by immature myeloid cells 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). The CP will typically run an indolent course of 3 to 5 years before progressing to the accelerated phase, even without treatment, although the duration can be highly variable.
2. Accelerated phase (AP) (Table 19.1) is poorly defined, but is usually marked by a loss of previously controlled white blood cell (WBC) counts and clonal evolution, with the development of new chromosomal abnormalities in addition to the persisting or re-emerged Ph1 chromosome. Peripheral blood counts show one or more of the following: blasts of at least 10%, basophils greater than 20%, or a fall in the platelet count to no more than 100,000/µL, unrelated to ongoing treatment. These laboratory findings are often accompanied by the re-emergence or progression of symptoms such as fever, bone pain, and fatigue, or worsening splenomegaly. The median survival prior to imatinib therapy was only 18 months; however, with imatinib, the estimated 4-year survival rate exceeds 50%.
3. Blast phase (BP) (see Table 19.1), also called “blastcrisis,” is the progressed transformation of CML to acute leukemia. It is defined by the acute leukemia criteria of at least 20% bone marrow blasts. However, patients with 20% to 29% blasts seem to carry a better prognosis than those meeting the older criterion of greater than 30% blasts. A majority of cases (50% to 70%) will express a poorly differentiated myeloid phenotype (acute myelogenous leukemia [AML]), while the remainder shows lymphoid (pre-B acute lymphocytic leukemia [ALL]) or an undifferentiated or mixed-lineage phenotype. Recent studies have identified BCR-ABL kinase domain mutations in 30% to 40% of these patients. Persistence of the Ph1 chromosome including additional Ph1 chromosomes and other cytogenetic abnormalities may be present. Extramedullary tumor masses (chloromas) can occur in both the APs and BPs. Durable responses to chemotherapy, using various acute leukemia regimens, are typically uncommon, and median survival in this phase is 3 to 6 months. ALL evolutions in general have a better response and prognosis than AML evolutions. A CP remission can occur with treatment as the blastic progeny clone is eradicated, but the CP Ph1 stem cell typically persists. Transcription factor-induced aberrant lineage priming of leukemic stem cells can bring about variability in subsequent evolution whereby patients achieving remission from a myeloid BP can re-enter a CP then relapse with a lymphoid BP (or vice versa).
TABLE 19.1 WHO Criteria for Diagnosis of Accelerated and Blast Phase CML
Accelerated Phase
Blast Phase
Blasts 10%–19% of WBCs in peripheral blood or bone marrow
Blasts ≥20% in peripheral blood or bone marrow
Peripheral blood basophils >20%
Extramedullary blast proliferation
Persistent thrombocytopenia <100 × 109/L unrelated to therapy or persistent thrombocytosis >1000 × 109/L unresponsive to therapy
Large foci or clusters of blasts in the bone marrow biopsy
Increased spleen size or worsening leukocytosis unresponsive to therapy
Cytogenetic evidence of clonal evolution
WBC, white blood cell.
C. Prognosis
Separation of these three stages is imprecise, and approximately 25% of patients progress directly from CP to BP. Although the duration of the CP is difficult to predict, a number of factors indicate an increased risk for progression, including greater 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 with 5-year survivals of 76%, 55%, and 25%, respectively. Both classifications were developed in patient cohorts receiving interferon, and none have thus far been validated during the imatinib era, limiting their usefulness. Regardless of pretreatment characteristics, the most important and best prognostic predictor of long-term survival is the quality of the response to treatment by minimal residual disease (MRD), which is measured by the degree of cytogenetic and molecular response.
D. Therapy
Hydroxycarbamide (also known as hydroxyurea) is a ribonucleotide reductase inhibitor frequently used to control the high WBC count while confirming the diagnosis of CML. The usual dose of hydroxycarbamide is 40 mg/kg/d. The dose is then adjusted individually to keep the WBC count in a range between 4 and 10 × 109/L.
Hydroxycarbamide does not reduce the percentage of cells bearing the Ph chromosome, and therefore, the risk of transformation to the BP is unchanged. Its use should be limited to temporary control of hematologic manifestations prior to starting definitive therapy. The “imatinib (Gleevec) era” has revolutionized the treatment of CML but also ushered in some questions of treatment uncertainty.
1. Imatinib (Gleevec) is a small molecule tyrosine kinase inhibitor (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 IRIS trial. With a follow-up of 7 years, imatinib was discontinued for adverse events in 5% of patients and for lack of efficacy in 15% of patients. Seventy-five percent of patients with complete cytogenetic response (CCyR) have maintained the response so far. The 6-year event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) rates were 83%, 93%, and 88%, respectively. Based on these results, 400 mg oral daily is deemed the standard initial dosing in CP disease. Maintaining imatinib dosing at greater than 300 mg daily is pharmacologically important to achieve effective inhibitory plasma concentrations. The results of the IRIS trial have been replicated in a prospective, multicenter German CML phase IV study, which reported a 5-year overall survival of 94% and a 2-year EFS of 80%. Studies addressing dose escalation of imatinib in early CP showed that 800 mg of imatinib was well tolerated and is associated with a high rate of cytogenetic and molecular responses, which are also attained more rapidly with the higher dose. However, whether such an approach results in long-term benefit or improvement in survival remains to be seen.
2. Imatinib can only control, and not completely eradicate, the CML clone, therefore being unable to cure the disease. Allogeneic stem cell transplantation is the only known curative therapy for CML. The question regarding the timing of transplant during CP CML remains controversial. However, it is clear that imatinib is the initiating therapy in treating CP CML and that close molecular monitoring of the BCR-ABL transcript is important to best manage an individual with CML.
3. Side effects of imatinib. Overall, imatinib is well tolerated. Side effects are generally mild and include nausea, peripheral and periorbital edema, muscle cramps, diarrhea, weight gain, and fatigue. Imatinib is metabolized through the CYP450 pathway, causing potential drug interactions. Rare organ damage can occur including liver toxicity, hypophosphatemia, and
potential cardiotoxicity. Myelosuppression is the most common grade 3 to 4 toxicity, with neutropenia and thrombocytopenia during the first few months of treatment. These can be managed with growth factors or dose reductions; however, they may require discontinuation of the drug, which may be temporary or permanent.
4. Disease monitoring during imatinib therapy is used to assess for early hematologic treatment toxicity and to evaluate the ongoing and ultimate disease response, with the treatment goal of achieving MRD measured by a CCyR and a 3-log reduction molecular response (Table 19.2). A reasonable approach, modifiable to an individual patient and case, is as follows:
Complete blood count (CBC) weekly until stable, then every 4 to 6 weeks.
Marrow cytogenetics at diagnosis, at 6 and 12 months of initial treatment, and yearly with ongoing treatment.
Peripheral blood quantitative RT-PCR for BCR-ABL mRNA at diagnosis and every 3 months with ongoing treatment.
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. A partial cytogenetic response (1% to 35% Ph-positive metaphases) by 3 to 6 months predicts an 80% to 95% likelihood of achieving an eventual CCyR. Quantitative PCR on peripheral blood is the monitoring method of choice. There is a significant correlation between the molecular response at 3 months and cytogenetic response at 12 months. At 42 months of follow-up, those patients with a CCyR by 12 months and a major molecular response (greater than 3-log reduction in BCR-ABL mRNA) had a PFS of 98% compared to 90% if less than 3-log reduction and 75% for patients without a CCyR. There is no absolute latest point in time at which a patient should have a CCyR before considering an altered treatment approach. That must be individualized based on age and other viable treatment options available. In a young patient who is a transplant candidate, if there is not an early optimal response within 6 to 12 months, consideration of this alternative therapy is appropriate.
TABLE 19.2 Response Criteria in CML
Type of Response
Definition
Complete hematologic response
Normalization of complete blood count and differential WBC, resolution of splenomegaly
Minor cytogenetic response
35%-90% Ph+ metaphases
Partial cytogenetic response
1%–34% Ph+ metaphases
Complete cytogenetic response
No Ph+ metaphases
Major cytogenetic response
0%-34% Ph+ metaphases (complete + partial)
Major molecular response
≥3-log reduction of BCR-ABL transcript by qRT-PCR
Complete molecular response
No BCR-ABL transcript by qRT-PCR
PCR, polymerase chain reaction; RT, reverse transcription; WBC, white blood cell.
5. Imatinib resistance can either be primary or secondary. Primary resistance without a complete hematologic response (CHR) occurs in approximately 5% of patients. Primary cytogenetic resistance (i.e., failing to achieve a partial cytogenetic response at 6 months or complete at 12 months) occurs in 15% of patients. After 42 months of follow-up, 16% of patients treated in the IRIS study developed secondary resistance or overtly progressed. In patients previously treated with interferon-α, 26% in CP developed resistance or progression. Imatinib resistance is much higher in APs (73%) and BPs (95%). When resistance is observed, a repeat bone marrow with cytogenetics and screening for the new kinase mutations should be performed to identify the T315I mutation, which is a marker of failure for all the currently available TKIs.
Strategies to overcome imatinib resistance remain challenging. Overt phase progression forces a treatment change, as the current therapy is ineffective. Mutation changes are clearly a harbinger of phase progression, but in a variable time frame. Imatinib dose escalation up to 800 mg can be attempted; however, tolerance and durability remain limiting factors. Switching to second-generation TKIs, either dasatinib or nilotinib (see subsequent discussion) is presently the standard of care for imatinib failure or resistance. The addition of conventional chemotherapy agents, either interferon or cytarabine, may also be considered if unacceptable toxicity to second-generation TKIs develop. An allogeneic stem cell transplant in eligible patients with imatinib resistance may be an additional option.
6. Alternative treatments
a. Dasatinib (Sprycel), 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 approved for the treatment of patients with imatinib-intolerant and imatinib-resistant disease who have Ph+ CML in CP, AP, and BP. A prospective, randomized study of four different doses and schedules identified a dose
of 100 mg once daily as an efficacious and well-tolerated dose. In patients with imatinib-intolerant disease in CP, the major cytogenetic response (MCyR) and the CCyR rates were 76% and 75%, respectively, with median time to MCyR being 2.8 months. In patients with imatinib-resistant disease in CP, the MCyR and the CCyR rates were 51% and 40%, respectively. The median time to CCyR and major molecular response was 5.5 months. In 80% to 90% of patients in CP, the responses were maintained for 2 years, the PFS was greater than 80%, and the OS was greater than 90%. In 150 patients with imatinib-resistant disease in CP, the results were superior in patients whose therapy was changed to dasatinib 70 mg twice daily compared with those in whom the imatinib dose was increased to 800 mg.
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 194 patients in imatinib-resistant CP, the MCyR and the CCyR rates were 48% and 30%, respectively, whereas in imatinib-intolerant patients the respective rates were 47% and 35%. For all patients in CP, 1-year OS was 95%, and the proportion of patients remaining in MCyR after 1 year was 96%. Nilotinib was recently tested in a phase II study in upfront therapy of early CP at a dose of 800 mg daily showing a CCyR of 98% and a major molecular response of 70%. In a randomized trial, nilotinib was superior to imatinib as initial therapy and may become the new standard.
c. Allogeneic stem cell transplant. As mentioned previously, allogeneic transplantation remains the only known curative treatment for CML. The appropriate patient and the optimal timing of transplantation in CP CML remain controversial. To assist in patient selection, a transplantation risk score has been proposed by the European Blood and Bone Marrow Transplantation Group to assess both transplant-related mortality as well as long-term survival (Table 19.3). In most transplant series, a relationship appears to exist between the interval from diagnosis to transplantation and outcome (i.e., the earlier the disease at the time of transplant, the better the outcome). Five-year survival rates after myeloablative transplantation range from 60% to 80% in CP disease to 25% to 40% in AP and 5% to 10% in BP. It is appropriate to considerRelated posts:
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