GENERAL PRINCIPLES
Leukemia is the result of somatically acquired genetic mutations leading to the dys-regulation and clonal expansion of myeloid and/or lymphoid progenitor cells. The accumulation of neoplastic cells, both in the bone marrow and in the peripheral tissues, manifests as cytopenias with associated complications, elevation of the total WBC count, and dysfunction of the various involved organs. The diagnosis is typically suspected based on an abnormal CBC and peripheral smear and then confirmed on bone marrow biopsy. The prognosis and treatment depend on the age of the patient, accurate determination of the type of the leukemia, and cytogenetics and molecular markers.
ACUTE MYELOGENOUS LEUKEMIA
GENERAL PRINCIPLES
Definition
The acute leukemias are the result of abnormal clonal proliferation of mutated progenitor cells. The mutations cause a block in the maturation process, leading to an accumulation of immature cells. The expansion of the abnormal clone leads to suppression of the other elements in the marrow, often producing clinical bone marrow failure and making the patient gravely ill. The clinical course of untreated acute leukemia is very brief, with patients succumbing in days to weeks from the complications of marrow failure. Therapy involves intensive chemotherapy regimens, prolonged hospitalizations, and, potentially, stem cell transplantation.
Classification
The French–American–British (FAB) group identifies nine subtypes of AML that are based on morphology and staining (Table 29-1). They indicate the myeloid lineage and the degree of differentiation. Cytogenetic evaluation is crucial, as it helps to determine treatment and prognosis (Table 29-2). For example, the M3 subtype (acute promyelocytic leukemia; APL) is associated with the translocation 15;17, a distinct clinical phenotype (DIC), a good prognosis, and tailored therapy. M7 is associated with a poor clinical outcome in the absence of transplantation. The World Health Organization (WHO) has developed a classification system of AML based not only on morphologic findings but also on genetic and clinical findings (Table 29-3).1 In the WHO system, AML is defined by >20% myeloblasts in the bone marrow aspirate. Patients with clonal cytogenetic abnormalities such as t(8;21), inv(16), and t(15;17) have AML regardless of the blast percentage. Gene mutations are increasingly being recognized as important diagnostic and prognostic markers in myeloid neoplasms. These include, among others, NPM1, CEBPA,FLT3,RUNX1, KIT, WT1, DNMT3A, and MLL in AML; and GATA1 in myeloid proliferations associated with Down syndrome. Although over- and underexpression of genes has proved to affect the prognosis in some myeloid neoplasms, at the present time analysis of gene dosage by quantitative RT-PCR is not practical on a daily basis, nor have gene expression arrays been introduced into routine use.2 There are four main groups of AML recognized in this classification system:
1. AML with recurrent genetic abnormalities
2. AML with myelodysplasia-related features
3. Therapy-related AML and MDS
4. AML, not otherwise specified
· AML with recurrent genetic abnormalities. This WHO category contains AML variants that contain genetic abnormalities of prognostic significance:
o AML with t(8;21)(q22;q22); RUNX1-RUNX1T1. This leukemia is associated with a more favorable prognosis. The presence of c-KIT mutations is an adverse prognostic features in patients with t(8;21).
o AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CEFB-MYH11 (previously acute myelomonocytic leukemia, AMML, FAB M4Eo). This leukemia occurs in younger patients and can present as an extramedullary myeloid sarcoma. It is associated with a more favorable prognosis although cases with an additional c-KIT mutation may do more poorly.
o APL with t(15;17)(q22;q12); PML-RARA. It is notable that the malignant cells in APL are promyelocytes, making this another AML where the presence of 20% blasts is not required. Outcomes in this variant of AML are generally favorable. It can present with disseminated intravascular coagulation (DIC).
o AML with t(9;11)(p22;q23); MLLT3-MLL. This type of leukemia is usually monocytic and more common in children. It can present with DIC, and high white cell counts with gingival or skin infiltration. It has an intermediate prognosis.
o AML with t(6;9)(p23;q34); DEK-NUP214. This is a rare type of leukemia that is associated with basophilia, pancytopenia, and dysplasia. It has a generally poor prognosis.
o AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1. This leukemia is also rare, accounting for only 1% or 2% of cases. Patients are anemic but may have normal or elevated platelet counts. It is frequently associated with dysplasia and is associated with aggressive disease and a short survival time.
o AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1. This type of leukemia is also rare, but is typically a megakaryoblastic process occurring in infants, although it is not seen in patients with Down Syndrome. Sometimes it can present as a mass and mimic sarcoma.
· Two provisional entities identified at the molecular level are
o AML with mutated NPM1. The mutation is seen in about one-third of all cases of AML making it overlap other types. In almost all cases, the mutation is seen in AML with normal cytogenetics. The presence of the NPM1 mutation confers a better prognosis, but only if it is seen alone. When seen in conjunction with mutations in FLT3, it is associated with a poor prognosis.
o AML with mutated CEBPA. Mutation in CEBPA is seen in ~6% to 15% of AML, commonly in cases with a normal karyotype. Cases with this mutation are associated with a good prognosis.
· Mutation in FLT3 occurs in 30% to 40% of patients with AML and normal cytogenetics. Patients with this mutation often present with high WBC counts. Two variants exist: FLT3 mutation with internal tandem duplication and a less prevalent mutation affecting the tyrosine kinase domain of the enzyme. The presence of a FLT3 mutation can overcome the favorable effects of NPM1 and CEBPA mutations when they occur concurrently.
Epidemiology
AML is the most common acute leukemia in adults and accounts for ~80% of cases in this group. In the United States, the incidence has been stable at 3 to 5 cases per 100,000 population. In contrast, AML accounts for less than 10% of acute leukemias in children less than 10 years of age. In adults, the median age at diagnosis is ~65 years. The incidence increases with age with ~1.3 and 12.2 cases per 100,000 population for those under or over 65 years, respectively. The male-to-female ratio in ~5:3.
Risk Factors
Radiation, previous chemotherapy with alkylating agents or topoisomerase inhibitors, myelodysplasia, myeloproliferative disorders, aplastic anemia, and exposure to benzene are known risk factors for the development of AML. Higher risk for AML is seen in people with Down syndrome (particularly AML-M7), Turner, and Klinefelter syndromes. In most cases, no risk factors are clearly defined.
DIAGNOSIS
Clinical Presentation
Marked cytopenias from leukemic infiltration of the marrow result in diverse presentations, including fatigue, pallor, and dyspnea on exertion from anemia; hemorrhage from thrombocytopenia; and fevers and infection from neutropenia. Extramedullary tissue invasion by leukemic cells (most commonly with AML-M5) may result in hepatomegaly, splenomegaly, lymphadenopathy, rashes (leukemia cutis), gingival hypertrophy, CNS dysfunction and cranial neuropathies, intestinal involvement, lytic bony lesions, or even establishment of infiltrative masses (granulocytic sarcomas or chloromas). With myeloblast counts >50,000, leukostasis may occur, resulting in dyspnea from pulmonary infiltrates or CNS dysfunction (ranging from somnolence to cerebral ischemia). Spontaneous tumor lysis syndrome may cause hyperuricemia, hyperphosphatemia, hypocalcemia, or hyperkalemia and renal failure. Patients may also present with disseminated intravascular coagulation (DIC; with excessive bleeding), which is more commonly seen in the M3 and M5 subtypes.
Diagnostic Testing
Workup should include the following.
· CBC. Pancytopenia or leukocytosis may be present
· Coagulation profile. INR, prothrombin time, partial thromboplastin time, D-dimer, and fibrinogen to look for DIC.
· Electrolytes. Tumor lysis may cause hyperkalemia, hypocalcemia, hyperphosphatemia, or hyperuricemia.
· Lactate dehydrogenase (LDH)
· Peripheral smear. Leukemic myeloblasts on Wright–Giemsa stain of the peripheral blood and bone marrow aspirate demonstrate large nuclei with scant cytoplasm and may contain Auer rods (eosinophilic needlelike inclusions).
· Lumbar puncture. This should be done if neurologic symptoms are present.
· Bone marrow aspirate and biopsy, evaluated for the following:
o Morphology and histochemical staining
o Flow cytometry, to distinguish AMLs from lymphoid and to determine the subtype of AML
o Cytogenetics, which is critical in the initial workup for AML since it provides a wealth of prognostic information and helps to guide therapy
o Molecular studies, abnormalities in certain genes, such as mutations in FLT3, nucleophosmin (NPM1), KIT, or CEBPA, to confer prognostic significance in adult patients with AML
TREATMENT
Treatment is divided into two phases: induction and consolidation. The goal is to achieve remission, defined as <5% blasts in the bone marrow and recovery of peripheral blood counts.
· Induction chemotherapy consists of 7 days of cytarabine (Ara-C) and 3 days of an anthracycline (daunorubicin or idarubicin; “7 + 3” regimen). Complete remission can be obtained in ~70% to 80% of patients <60 years and in ~50% of older patients. In patients with AML who are older than 60 years of age, escalation of the dose of daunorubicin to twice the conventional dose effects a more rapid response and a higher response rate than does the conventional dose, without additional toxic effects.3 Patients are generally admitted to the hospital during induction for nearly a month, require frequent blood and platelet transfusions, and often have febrile neutropenia.
· Consolidation therapy is essential to prevent relapse and is guided by cytogenetics, age, and patient comorbidities. Therapeutic options include allogeneic bone marrow transplantation or further chemotherapy with high-dose cytarabine (HiDAC) or other regimens. HiDAC is efficacious in younger patients and those with core binding factor leukemia. It is considered too toxic for general use in patients over 60 years with AML due to a higher incidence of cerebellar ataxia (>30% in patients ≥60 years), which is irreversible in some patients. Autologous transplants offer little to no benefit over chemotherapy.
· For promyelocytic (M3) leukemia, all-trans retinoic acid (ATRA) is given with induction chemotherapy. ATRA ameliorates the coagulopathy associated with M3 but is also associated with the potentially dangerous APL differentiation syndrome. Maintenance therapy with lower-dose ATRA is commonly used. Recent data show that consolidation with arsenic trioxide (ATO) decreases risk of relapse and improves overall survival. Relapse occurs in 5% to 10% of patients with APL and in ~20% to 30% of those with high-risk APL as defined as those who present with a white blood cell count above 10,000 and a platelet count less than 40,000. ATO is the treatment of choice for most patients with relapsed APL. Second complete remission can be obtained in 85% to 88% of patients. It is unclear whether adding ATRA to ATO is better than ATO alone. ATO is able to penetrate the blood-brain barrier and so can be used in patients with CNS involvement. If a second remission is obtained and reverse transcription polymerase chain reaction (RT-PCR) testing is negative for the PML/RAR-alpha transcript, consolidation with either autologous hematopoietic cell transplantation (HCT), allogeneic HCT, or further ATO is recommended. If PCR negativity is not obtained, allogeneic HCT becomes the favored treatment.
· In the case of relapse, patients should be salvaged with intensive chemotherapy and then considered for allogeneic bone marrow transplantation. Patients who are not transplant candidates, due to age or comorbidities, should be considered for treatment on clinical trials.
COMPLICATIONS
Leukostasis may cause symptoms that require emergent cytoreduction with hydroxyurea and/or leukapheresis. Tumor lysis syndrome, fever, and neutropenia are all concerns as well (see Chap. 35). Cytopenias should be supported with transfusions, and coagulopathy should be corrected. Prospective trials have identified 10,000/μL as a relatively safe transfusion threshold for platelets during inpatient induction chemotherapy. If the patient has received a bone marrow transplant, he or she should be followed closely for symptoms of opportunistic infections and graft-versus-host disease (see Chap. 31).
PROGNOSIS
Leukemia can typically be divided into good, poor, and intermediate prognostic groups.
· Good-prognosis leukemias are those with favorable cytogenetics: translocation (15;17) (associated with M3 AML), translocation (8;21) (associated with M2 AML), and inversion 16 (associated with M4 AML with eosinophilia). These patients are typically offered induction therapy followed by chemotherapy-based consolidation, as they have a relatively high rate of cure by this strategy (~60% to 70%).
· Poor prognostic indicators include age >60 years; AML secondary to myelodysplastic syndrome or antecedent hematologic disorder; deletion of 5q, 7q, or trisomy 8; and lack of the favorable cytogenetics noted earlier. Patients with poor-prognosis leukemia have a high rate of relapse and should be considered for allogeneic bone marrow transplant in first remission.
· Patients with normal cytogenetics fall into an intermediate risk group, and management should be individualized after remission. New molecular prognostic markers such as mutations in the FLT-3, NPM, DNMT3A, and MLL genes may help guide therapy in this group. Clinical trials are always ongoing, and whenever appropriate, patients in all groups should be considered for participation. Since 1970, the 5-year survival rate has increased from 15% to 40% with advances in antileukemic and supportive therapies (i.e., antibiotics, antifungals, improvement in transfusion medicine).
ACUTE LYMPHOBLASTIC LEUKEMIA
GENERAL PRINCIPLES
Definition
Acute lymphoblastic leukemia (ALL) results from the abnormal proliferation of a lymphoid hematopoietic progenitor cell. It accounts for 80% of childhood leukemias and 20% of adult acute leukemias. The median age at diagnosis is 13 years old, with 39% of cases diagnosed in patients older than 20 years. People with Down syndrome are at a higher risk for developing ALL. This section deals only with adult ALL, which has a worse prognosis than childhood ALL.
Classification
Classification is based on morphologic (FAB system) and immunophenotypic information (Table 29-3). Many different translocations have been reported in B ALL, three of which predict response to intensive chemotherapy.
· The Philadelphia chromosome: t(9;22)(a34;q11); BCR/ABL is the most frequent rearrangement in adult ALL and is associated with a poor prognosis. It is present in 25% of adult and 3% of childhood cases. The incidence of t(9;22) increases with age and is present in 40% to 50% of patients older than 60 years.
· t(v;11q23); MLL rearranged: associated with a poor prognosis, seen in infants <1 year and adults.
· t(12;21)(p12;q22) TEL/AML1: associated with a good prognosis and hyper-diploidy, this is the most common rearrangement seen in children.
The t(9;22) and t(v;11q23) are often associated with a pro-B immunophenotype and a poor prognosis, while the t(12;21) is associated with common pre-B ALL.
DIAGNOSIS
Clinical Presentation
The clinical phenotype of ALL is very similar to that of AML. Patients present with malaise, fatigue, dyspnea, and bone pain. Patients also typically have signs of marrow failure such as bleeding, bruising, fever, and infection. More commonly than in AML, in up to 10% of patients, the CNS may be involved at presentation, manifesting as headache and/or cranial nerve palsies. Leukostasis may also be present. Hepatosplenomegaly and lymphadenopathy can be seen. ALL can be associated with an anterior mediastinal mass (in T-cell subtypes) or large abdominal lymph nodes (in B-cell subtypes).
Diagnostic Testing
Basic workup is similar to that for AML. A peripheral smear will usually demonstrate the presence of circulating blasts. Bone marrow will be hypercellular, with >30% blasts. Cytoplasmic granules and Auer rods should be absent. However, it can be extremely difficult to diagnose ALL on clinical and morphologic grounds alone. Immunophenotyping is often necessary to distinguish ALL from AML. Thirty percent of adult ALL patients exhibit the Philadelphia chromosome t(9;22), as seen in chronic myelogenous leukemia (CML).
TREATMENT
Therapy for ALL consists of multiple phases.
· Induction chemotherapy typically consists of vincristine, a steroid, and an anthracycline. Most protocols include l-asparaginase as well. One regimen is hyper-CVAD (cyclophosphamide, vincristine, dexamethasone, and doxorubicin alternating with high-dose methotrexate and cytarabine with incorporated intrathecal therapy).4 These multiagent protocols carry the burden of profound myelosuppression, and patients must be followed for infectious and cytopenic complications. Induction mortality rates range from 3% to 20% but these regimens boast complete remission rates of 65% to 90%. The BCR-ABL tyro-sine kinase inhibitor imatinib has been incorporated into induction regimens in patients who harbor the Philadelphia chromosome (t(9;22)).
· CNS prophylaxis is an important component of therapy for ALL, as it has a high incidence of recurrence in the CNS. Regimens typically consist of intrathecal methotrexate and cytarabine.
· Maintenance therapy is typically continued for 2 years, often with mercaptopurine, prednisone, vincristine, and methotrexate (the so-called POMP regimen).
· Relapse, unfortunately, is common in adult ALL. Salvage chemotherapy regimens are able to induce a second complete remission in ~30% to 70% of persons, and when consolidated with allogeneic stem cell transplantation ~40% of patients will be alive at 4 years.
PROGNOSIS
Although 60% to 90% of patients can expect to undergo a complete remission with induction chemotherapy, the majority of patients will relapse. Patients who are younger and have good prognostic indicators have a cure rate of 50% to 70%. Those who are older and have poor prognostic indicators have a cure rate of only 10% to 30%. Adverse risk factors are summarized in Table 29-4.
CHRONIC MYELOGENOUS LEUKEMIA
GENERAL PRINCIPLES
Epidemiology
CML accounts for 14% of all leukemias and 20% of adult leukemias, with an annual incidence of 1.6 cases per 100,000 adults. Since the advent of imatinib, the annual mortality has decreased to 1% to 2%. The median age at presentation is 65, and incidence increases with age.
Etiology
The etiology is unclear; no correlation with monozygotic twins, geography, ethnicity, or economic status has been observed. However, a significantly higher incidence of CML has been noted in survivors of the atomic disasters at Nagasaki and Hiroshima, in radiologists, and in patients treated with radiation to the spine for ankylosing spondylitis.
Pathophysiology
· CML is associated with the fusion of two genes: BCR (on chromosome 22) and ABL1 (on chromosome 9) resulting in the BCR-ABL1 fusion gene. This abnormal fusion typically results from a reciprocal translocation between chromosomes 9 and 22, t(9;22)(q34;q11), that gives rise to an abnormal chromosome 22 called the Philadelphia (Ph) chromosome. It is this derivative chromosome 22 which harbors the BCR-ABL1 fusion gene. The BCR-ABL1 fusion gene results in the formation of a unique gene product, the BCR-ABL1 fusion protein. This protein product includes an enzymatic domain from the normal ABL1 with tyrosine kinase catalytic activity, but relative to ABL1, whose kinase activity is tightly regulated, the kinase activity of BCR-ABL1 is elevated and constitutive due to fusion with a portion of BCR. It is this deregulated tyrosine kinase that is implicated in the pathogenesis of CML.5
· Blast-phase CML is characterized by cytogenetic evolution in ~70% of patients. The most common chromosomal abnormalities are trisomy 8, in 30% to 40% of patients, additional Ph chromosome, in 20% to 30%, and isochromosome 17, in 15% to 20%. Corresponding mutations in p53 are also seen in 20% to 30% of patients, amplification of c-myc in 20%, and, less commonly, mutations and deletions of ras, Rb, or p16. As with de novo AML, complex cytogenetics are associated with decreased response rates and survival.
· The natural history of CML is a triphasic process.
o Most patients present in chronic phase, characterized by an asymptomatic accumulation of differentiated myeloid cells in the bone marrow, spleen, and peripheral blood. CML usually progresses through a transient accelerated phase, lasting 4 to 6 months, and then inevitably to blast phase, an incurable acute leukemia that is fatal within 3 to 6 months. In the 2 years after initial diagnosis of CML, 5% to 15% of untreated patients will enter blast crisis. In subsequent years, the annual rate of progression increases to 20% to 25%, with progression commonly occurring between 3 and 6 years after diagnosis.
o The definition of accelerated-phase CML relies on several clinical and laboratory features and is characterized by increasing arrest of maturation. Current WHO criteria include at least one of the following: 10% to 19% blasts in peripheral blood or bone marrow, ≥20% peripheral basophils, thrombocytopenia <100,000/μL and lack of response to therapy, increasing spleen size and increasing WBC unresponsive to therapy, and cytogenetic evidence of clonal evolution. Once either accelerated phase or blast crisis occurs, the success of any therapy declines dramatically.
DIAGNOSIS
Clinical Presentation
In most patients, CML is diagnosed incidentally. Symptoms can result from concurrent anemia and splenomegaly (fatigue, early satiety, and sensation of abdominal fullness) but may also include weight loss, bleeding, and bruising in advanced disease.
Diagnostic Testing
· Blood smear shows leukocytosis with a myeloid shift. In contrast to cases of acute leukemia, in which an arrest in maturation is the rule, granulocytes at all stages of maturation are observed. Anemia and thrombocytosis are common, while basophilia (>7%) occurs in only 10% to 15% of patients. Leukocyte alkaline phosphatase (LAP) activity is usually reduced but can be increased with infections, stress, on achievement of remission, or on progression to blast phase.
· The diagnosis is confirmed by the detection of the Ph chromosome t(9;22) (q34.1;q11.21). In 5% of patients a BCR-ABL fusion can be detected without classic Ph chromosomal cytogenetics, and rarely translocations can involve three or more chromosomes. The bone marrow is typically hypercellular and devoid of fat. All stages of myeloid differentiation are present and megakaryocytes may be increased, suggesting that chronic-phase CML is a disease of discordant maturation, where a delay in myeloid maturation results in increased myeloid cell mass.
TREATMENT
Chronic-Phase Chronic Myelogenous Leukemia
The two main treatment options for patients with newly diagnosed CML in chronic phase are
· BCR-ABL tyrosine kinase inhibitors (TKIs), such as imatinib, dasatinib, and nilotinib
· Allogeneic hematopoietic cell transplantation (HCT)
As the only treatment option with proven ability to cure CML, allogeneic HCT was the primary therapy for younger patients in chronic phase before the development of TKIs. However, now that TKIs have demonstrated long-term disease control and good tolerability, most patients are not referred for allogeneic transplantation as initial therapy. Instead, they are treated with TKIs and careful follow-up, with allogeneic HCT reserved for patients with refractory or progressive disease.
· Imatinib mesylate (Gleevec) is a targeted TKI, which antagonizes the activity of the ABL tyrosine kinase, as well as c-Kit and platelet-derived growth factors alpha and beta. At nanomolar concentrations, imatinib binds to the inactive conformation of the BCR-ABL ATP-binding pocket, resulting in competitive inhibition of BCR-ABL and growth inhibition of BCR-ABL-positive bone marrow progenitor cells. In a large Phase III trial, patients randomized to imatinib 400 mg daily had complete hematologic and cytogenetic remission rates of 95% and 74%, respectively, which was clearly superior to the standard arm of interferon-alfa + low dose cytarabine.6Although a few case reports are emerging of patients with continued complete cytogenetic response after imatinib withdrawal, relapse is common, and lifelong maintenance therapy is recommended at this time. Side effects of imatinib mesylate are generally mild but include hematologic suppression (neutropenia, thrombocytopenia, and anemia), constitutional symptoms (diarrhea, edema, and rash), and rare organ damage (elevated transaminases, hypophosphatemia, and potentially cardiotoxicity). These can usually be managed with growth factors or dose reduction but occasionally require discontinuation, either briefly or permanently.
· Since the development of imatinib, more potent, second-generation TKIs have been developed. The three second-generation TKIs that have been studied most extensively are dasatinib, nilotinib, and bosutinib. Nilotinib and dasatinib are approved for the treatment of newly diagnosed CML. Phase III trials comparing dasatinib or nilotinib to imatinib as initial therapy for CML in chronic phase have demonstrated faster and deeper responses with these second-generation TKIs. At 12 months, the rates of major molecular response for nilotinib and dasatinib (~45%) were nearly twice that for imatinib. The rates of complete cytogenetic response by 12 months were significantly higher for nilotinib and dasatinib (~80%) than for imatinib (~65%).7,8 Further follow-up is needed to confirm whether the substantial short term improvements will result in longer term benefits, such as improved survival.
o The side effect profiles of dasatinib and nilotinib are different from each other and compare favorably to that of imatinib. A choice among agents should take into consideration these drug side effect profiles and the patient’s comorbidities. For example, dasatinib might be preferred in a patient with a history of pancreatitis, elevated bilirubin, or hyperglycemia, while nilotinib might be chosen for a patient with a history of pleural or pericardial disease or effusions. Patients who are currently being treated successfully with imatinib who have achieved complete cytogenetic response with good tolerance of the side effects, should be continued on imatinib and should not be switched to dasatinib or nilotinib.
· Increased risk of progression to accelerated and blast phase has been demonstrated if patients do not achieve specific clinical goals. These currently include the following, from the time a patient starts TKI therapy:
o 3 months: complete hematologic response with normal peripheral counts and a >1 log reduction in BCR-ABL transcripts by quantitative PCR (qPCR)
o 6 months: cytogenetic response with <35% Ph chromosome-positive bone marrow cells
o 12 months: complete cytogenetic response with undetectable Ph chromosome
o 18 months: major molecular remission with a 3 log reduction by qPCR of peripheral BCR-ABL
Failure to reach any of these goals warrants close follow-up, ABL tyro-sine kinase domain mutation analysis, dose escalation, and/or change to second-line TKI and consideration of hematopoietic stem cell transplant.
· Resistance to imatinib has been noted in 2% to 4% of patients annually for the first 3 years of imatinib therapy and may decrease thereafter. Point mutations in the SH1 kinase domain are commonly associated with resistance. These mutations either decrease the affinity for imatinib binding in the ATP-binding pocket or shift the kinetics of BCR-ABL to prefer the active conformation, to which imatinib will not bind. Imatinib resistance can be overcome with either increasing doses or a second-line TKI, although the point mutation T315I confers a high degree of resistance to all available TKIs.
· While effective, chemotherapy is second-line to the well-tolerated TKIs. Hydro-xyurea, busulfan, and interferon-alpha have been used with some success.
· Allogeneic hematopoietic stem cell transplant from either related or unrelated donors remains the only known curative therapy for CML. Transplantation from a matched sibling donor during chronic phase is associated with a 10-year survival of 50% to 70%, but this decreases to 20% to 40% and <20% in accelerated and blast phase, respectively.
Accelerated and Blast-Phase Chronic Myelogenous Leukemia
· As advances are made in the treatment of CML, fewer patients (~7% at 5 years) are progressing to accelerated phase or blast crisis. In addition, 10% to 15 % of patients will initially present in accelerated phase or blast crisis. In general, an attempt is made to return the patient to a chronic phase with plans to proceed to allogeneic hematopoietic cell transplantation after an initial response. Imatinib has been shown to improve survival in accelerated phase at higher doses (600 to 800 mg), but responses are often short lived.
· Treatment of BP-CML remains a challenge, with survival of only 2 to 4 months in nonresponders. Treatment is dictated by hematologic features. Myeloid features are seen in 50% of patients, lymphoid in 25%, and undifferentiated in 25%. Typical AML induction chemotherapy is used for BP-CML with myeloid features and ALL induction chemotherapy for lymphoid features. Each has a response rate of only 30%. Transplant during BP-CML remains the only curative options, but it is associated with a ~80% risk of relapse and a 5-year survival of only ~5%.
MONITORING/FOLLOW-UP
Follow-up during initial treatment requires CBC monthly, peripheral BCR-ABL qPCR every 3 months, and bone marrow biopsy every 6 months until major molecular remission is achieved. Once molecular remission is documented, BCR-ABL transcripts should still be followed every 3 months, with an annual bone marrow exam for cytogenetics. Rising BCR-ABL transcripts should be quickly reevaluated and treatment altered accordingly.
CHRONIC LYMPHOCYTIC LEUKEMIA
GENERAL PRINCIPLES
Chronic lymphocytic leukemia (CLL) is characterized by the progressive accumulation of monoclonal, functionally incompetent lymphocytes. Patients with CLL commonly develop complications associated with the intrinsic immune dysfunction that results in immunodeficiency and the development of autoimmune disorders. CLL is considered to be identical to the mature (peripheral) B-cell neoplasm small lymphocytic lymphoma (SLL).
Classification
Classification of CLL is based on the extent of systemic infiltration of lymphocytes. This helps to determine the prognosis and initiation of treatment (Table 29-5). Molecular and cytogenetic markers have become increasingly useful for prognostication.
Epidemiology
CLL is the most common form of leukemia in adults, accounting for ~30% of adult leukemia in Western countries. According to the SEER cancer database, from 2000 to 2003 the median age at presentation was 72 years, and only 13% of patients were <55 years old at the time of diagnosis. Nearly 4% of elderly individuals have a monoclonal lymphocytosis, although most of these do not progress to CLL. The age-adjusted incidence rate for CLL was 3.8 per 100,000 per year, with a ~2:1 male:female ratio.
Pathophysiology
CLL is an accumulation of malignant, immunologically incompetent, but mature B-cell lymphocytes. The malignant cells of CLL express high levels of the antiapoptotic protein, bcl-2, and express common B-cell antigens CD19, CD20, and CD23. Of note, CD5 antigen, a T-cell antigen, is found in all cases of CLL. A Coombs-positive, warm antibody, hemolytic anemia occurs in 10% of patients, and an immune thrombocytopenia occurs in ~5% of patients. In 5% of patients, Richter syndrome develops, which is a malignant transformation to diffuse large B-cell lymphoma.
Risk Factors
Patients with a history of immunodeficiency syndromes have an increased risk of CLL. There are no clear environmental or occupational risk factors that predispose to CLL, and patients who are exposed to radiation do not appear to have an increased frequency of CLL.
DIAGNOSIS
Clinical Presentation
Many patients are discovered by routine CBC and are asymptomatic. However, chronic fatigue is a common initial complaints. With bone marrow involvement, patients may develop severe fatigue, anemia, bruising, weight loss, and fever. On physical exam, splenomegaly, hepatomegaly, and lymphadenopathy can be present. With advancing immunodeficiency, herpes zoster infections, Pneumocystis jiroveci pneumonia, and bacterial infections become more frequent.
Diagnostic Criteria
The essential diagnostic criteria for CLL identified by the CLL international working group include an absolute lymphocytosis of >5000/μL with a typical morphology, a bone marrow infiltrated with small lymphocytes accounting for >30% of nucleated cells, and a typical immunophenotype (CD5+, CD23+, CD10−, CD19+, CD20+dim, CyclinD1−, CD43±) (Table 29-6).
Differential Diagnosis
It is important to consider benign causes of lymphocytosis, including Epstein–Barr virus mononucleosis, chronic infections, autoimmune diseases, drug and allergic reactions, thyrotoxicosis, adrenal insufficiency, and postsplenectomy. The other possible malignancies to consider are hairy cell leukemia (HCL), cutaneous T-cell lymphoma, other indolent non-Hodgkin lymphomas (mantle cell, follicular, lymphoplasmacytic), and large granular lymphocytic leukemia.
Diagnostic Testing
A CBC with differential reveals an absolute lymphocytosis, with >95% small lymphocytes. A blood smear should show mature lymphocytes. The classic smudge cell is nonspecific, but more than 30% smudging has been suggested as a poor prognostic marker. Anemia and/or thrombocytopenia may be present from bone marrow infiltration or from an autoimmune phenomenon. It is important to assess renal and hepatic function, LDH, uric acid, beta-2-microglobulin, Coombs anti-globulin, serum protein electrophoresis, quantitative immunoglobulins, chest radiograph, and CT scan of the chest, abdomen, and pelvis. Patients with CLL typically have at least 30% lymphocytes in the bone marrow. A bone marrow biopsy should be obtained for cytogenetics. Cytogenetic markers have been noted to predict overall progression of disease and response to therapy. Important molecular markers include ZAP70 and IgVH (immunoglobulin heavy chain variable region) gene rearrangements.
TREATMENT
· It is not necessary to initiate therapy early in the course of CLL. However, CLL patients may be immunocompromised, and fever or any other signs of infection need to be evaluated promptly. Indications for therapy include eligibility for a clinical trial, symptoms (fevers, sweats, weight loss), obstructive or advancing lymphadenopathy, hepatosplenomegaly, stage III or IV disease, rapid elevation in lymphocyte count with a doubling time <6 months, and complications including immune hemolysis, thrombocytopenia, recurrent infections, threatened organ function, and transformation.
· There is no agreed upon standard treatment regimen for symptomatic CLL.9 Treatment options include purine analogs (e.g., fludarabine, pentostatin), alkylating agents (e.g., chlorambucil, bendamustine), monoclonal antibodies (e.g., rituximab, alemtuzumab), or combinations of these agents. These treatment options have not been directly compared with each other. When prospective randomized trials have been performed, most of these regimens have been compared with chlorambucil, an alkylating agent that had been a standard of care for decades. While overall survival rates with these different regimens are similar, they differ in their rates of complete remission (CR), time to progression, and associated toxicities. For example, randomized clinical trials have established higher CR rates and progression-free survival intervals for fludarabine over alkylating agents, and for combination therapies such as FC (fludarabine, cyclophosphamide) over fludarabine alone; however, no difference in overall survival has been demonstrated. With elevated leukocyte counts, consideration of tumor lysis risk and prevention is important prior to therapeutic intervention. In addition, patients treated with purine analogs should be considered for prophylaxis against Pneumocystis and varicella zoster.
· Patients with del(17p) or del(11q) are at high risk of either not responding to initial treatment, or relapsing soon after achieving remission.10 The appropriate treatment for these patients remains undefined at this time. Options include
o Initial treatment with fludarabine combinations, followed by alemtuzumab, either after a number of cycles of initial debulking chemotherapy, or at the time of relapse.
o Consideration of non-myeloablative allogeneic hematopoietic cell transplantation for younger patients with a matched related or matched unrelated donor.
· Alemtuzumab is the only FDA-approved agent that has demonstrated activity in cells lacking p53 function, as seen in patients with CLL and chromosome 17p deletion.
· Refractory and relapsed disease may be treated with retreatment of prior agents, if relapse is >12 months, or with further combination therapy.11 FCR (fludarabine, cyclophosphamide, rituximab) and PCR (pentostatin, cyclophosphamide, rituximab) have both shown response rates of 30% to 60% in fludarabine-pretreated populations. Alemtuzumab is showing increasing promise as a single or combined agent in refractory disease.
· Autologous and allogeneic bone marrow transplantations are being explored as treatment options. Improved results have been noted with nonmyeloablative therapies. Young patients with high-risk disease should be considered for this therapy.
COMPLICATIONS
· Autoimmune hemolytic anemia (AIHA) and autoimmune thrombocytopenia occur more frequently in advanced-stage patients and those with unmutated IgVH. These complications should be evaluated with reticulocyte count, haptoglobin, LDH, and Coombs assay. The results should be interpreted in context of other features, as the reticulocyte count may be low due to bone marrow suppression or infiltration, the LDH may be elevated due to the disease, not hemolysis, and treatments such as fludarabine may induce AIHA by themselves. Treatment is typical of other AIHA and autoimmune thrombocytopenia processes with prednisone or equivalent glucocorticoid at a dose of 1 mg/kg/d, tapered after control of blood counts. Splenectomy may be needed if the blood counts do not improve on steroids. Local irradiation or splenectomy can control the effects of hypersplenism.
· Infection can result from hypogammaglobulinemia, T-cell dysfunction, and decreased phagocytic function. Hypogammaglobulinemic patients with recurrent infections should be treated with intravenous immunoglobulin, 400 mg/kg IV, every 3 to 4 weeks (goal IgG trough, ~500 mg/dL), which reduces serious bacterial infection rates without altering overall survival. Patients treated with fludarabine or alemtuzumab develop therapy-related T-cell immune defects and are at a significantly increased risk of cytomegalovirus (CMV) reactivation, Pneumocystis, varicella zoster, herpes viruses, Listeria, and other opportunistic infections. Prophylaxis against Pneumocystis,herpes simplex virus, and varicella zoster virus, as well as monitoring for CMV reactivation should be considered when treating CLL patients with these agents.
PROGNOSIS
Diffuse marrow involvement, rapidly increasing lymphocyte counts, and initial lymphocytosis of >50,000/μL indicate a poor prognosis for an individual patient with early-stage disease. Anemia and thrombocytopenia correspond with decreased median survival time. Overall, CLL is an indolent disease, and median survivals of >10 years are reported in stages 0, I, and II. Thus, patients may die of other conditions rather than from CLL. However, if a patient presents with advanced disease, the course may be rapid, with a median survival of months to years. It is unclear whether cytotoxic therapy improves survival, although it can effectively palliate disease-related symptoms. Advances in supportive care and infection therapy have improved survival and quality of life.
HAIRY CELL LEUKEMIA
GENERAL PRINCIPLES
Hairy cell leukemia (HCL) is an uncommon chronic B-cell lymphoproliferative disorder originally termed “leukemic reticuloendotheliosis” in the 1920s. It was described as a distinct clinical entity by Bouroncle and colleagues in 1958, and named HCL in the 1960s because of the prominent irregular cytoplasmic projections of the malignant cells. It accounts for 2% to 3% of all leukemias, usually affecting men >55 years old.
DIAGNOSIS
Clinical Presentation
Most patients present with malaise and fatigue. On physical exam, splenomegaly and hepatomegaly are evident in 95% and 40%, respectively. With more advanced disease, pancytopenia develops, and patients may present with bleeding or recurrent infections (bacterial, viral, fungal, or atypical mycobacterial).
Diagnostic Testing
A peripheral smear and bone marrow reveal the pathognomonic mononuclear cells. These cells have characteristic irregular hairlike projections around the border of the cytoplasm. CBC frequently shows anemia and thrombocytopenia and, less frequently, granulocytopenia. Although bone marrow aspiration is frequently unsuccessful, the biopsy may show the characteristic hairy cells. Hairy cells exhibit a mature B cell phenotype and typically express one or more heavy chains and monotypic light chains. Hairy cells strongly express pan-B cell antigens including CD19, CD20, CD22, and CD25, and usually lack expression of CD5, CD10, CD21, and CD23, and characteristically express CD11c, CD103, CD123, cyclin D1, and annexin A1. Also, hairy cells are TRAP (tartrate-resistant acid phosphatase) positive. Hairy cell leukemia is differentiated from CLL, lymphomas, and monocytic leukemia based on the characteristic cell morphology, TRAP test, and immune phenotype. There is no formal staging system.
TREATMENT
As with other chronic leukemias and lymphomas, early treatment does not improve overall outcome. The decision to treat is based on the development of cytopenias (hemoglobin, <10 g/dL, absolute neutrophil count, <1000/μL; platelets, <100,000/μL) and recurrent infections. Several treatment options are available (Table 29-7). Typically, cladribine or pentostatin is used. However, both of these agents induce significant and prolonged immunosuppression. Prophylaxis for herpes simplex virus and Pneumocystis, especially if concurrent steroids are used, is advised.
OUTCOME/PROGNOSIS
Before treatment, median survival was between 5 and 10 years. Survival has markedly improved with current therapies, as most untreated and pretreated patients have excellent response rates to cladribine or pentostatin (85% to 97%), with 4-year survival rates of up to 96%.
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