Gary Schiller, Dennis A. Casciato, and Ronald L. Paquette
CHRONIC LYMPHOCYTIC LEUKEMIA
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Western countries, accounting for one-third of cases. The incidence in the United States is 3.5 per 100,000. The disease is rare in Asians. Ninety percent of patients are >50 years of age, and the median age at diagnosis is approximately 65 years. Men are affected more often than women by a ratio of 2:1.
B. Etiology
1. Genetic factors. The vast majority of cases are sporadic, but familial clusters of CLL have been described. The incidence in relatives of patients with leukemia is two- to threefold greater than that of the general population. The etiology in the majority of cases is unknown.
2. Immunologic factors. Inherited and acquired immune deficiency is often associated with CLL and other lymphoproliferative neoplasms. This observation supports a concept that defective immune surveillance may result in proliferation of malignant cell clones and increased susceptibility to potential leukemogenic transduction, such as by viruses.
3. Molecular and cytogenetic aberrations. Somatic mutations of the immunoglobulin gene take place in the germinal center of secondary lymphoid follicles after antigen exposure. IgVH hypermutations are detected in approximately half of the cases of CLL, indicating that the cells are derived from postgerminal center or memory B cells and do not express ZAP-70, a molecule usually required for selective activation of T cells but aberrandy expressed in some cases of (B-cell) CLL. Some cases of CLL show characteristics of naive B cells with unmutated antigen receptors and are ZAP-70 positive.
Chromosomal abnormalities are detected in >80% of cases of CLL by use of interphase fluorescence in situ hybridization (FISH). CLL is characterized by loss or gain of chromosomal genetic material rather than by translocations. Conventional cytogenetics typically miss these abnormalities. Incidence, genes involved, and clinical features of the most common chromosome abnormalities are shown in Table 23.1.
4. Radiation and cytotoxic agents. Populations exposed to ionizing radiation or cytotoxic chemotherapy are not associated with an increased incidence of CLL.
Table 23.1 Chromosomal Abnormalities in Chronic Lymphocytic Leukemia
II. PATHOLOGY AND NATURAL HISTORY
A. Pathology. CLL is characterized by suppression of programmed cell death (apoptosis) of mature B cells. Increased levels of Bcl-2 protein have been identified in cells taken from patients with CLL. Two other BCL-2family gene products may prevent apoptosis of CLL cells. BCL-xL, which is expressed at high levels in CLL, enhances the efforts of Bcl-2, whereas BCL-xS, which is expressed at low levels in CLL cells, is a Bcl-2antagonist. Furthermore, nonclonal CD4+ T cells and cells of the bone marrow stroma may support and sustain survival of the neoplastic B-cell clone.
1. The leukemia cells have low levels of surface immunoglobulin and display a single heavy chain class, typically μ; some cells display both μ and δ; and less commonly, γ, α, or no heavy chain determinant is found. The leukemia cells display either κ or λ light chains, but never both.
2. Surface membrane antigens include the B-cell antigens CD19, CD20, and CD23; CD22 and CD79b are weak or negative. The CD11c and CD25 antigens are found on the cells in half of the cases. CD5 is always present on CLL cells. Expression of CD38 has been associated with an unfavorable prognosis (see Appendix C5, “Discriminatory Immunophenotypes for Lymphocytic Neoplasms”).
3. CLL is associated with low expression of the B-cell receptor (BCR), leading to impaired responses of CLL cells after BCR signaling.
B. Natural history
1. Immunologic abnormalities in CLL
a. Advanced disease is associated with hypogammaglobulinemia and an increased risk of infection with encapsulated bacterial organisms.
b. A variety of in vitro lymphocyte function tests are abnormal. Many studies have suggested decreased helper T-cell functions, and patients may have an inversion of the normal helper T-cell–to–suppressor T-cell ratios.
c. Monoclonal paraproteins are not routinely identified; however, when one uses more sensitive techniques, it appears that most patients with CLL secrete small amounts of paraproteins (usually immunoglobulin M [IgM]). These paraproteins rarely produce symptoms of hyperviscosity.
d. Coombs-positive warm antibody hemolytic anemia occurs in about 10% of patients and immune thrombocytopenia in about 5%. Immune neutropenia and pure red blood cell aplasia are rare.
e. Compared with the general population, the incidence of skin carcinoma is increased eightfold and visceral epithelial cancers twofold in patients with CLL.
2. Clinical course. The natural history of CLL is highly variable. Survival is closely correlated with the stage of disease at the time of diagnosis. Because most patients are elderly, >30% die of diseases unrelated to leukemia.
a. Manifestations. In 25% of patients, CLL is first recognized at routine physical examination or by a routine CBC. Clinical manifestations develop as the leukemia cells accumulate in the lymph nodes, spleen, liver, and bone marrow.
(1) Pulmonary infiltrates and pleural effusions are common late in the course of disease.
(2) Renal involvement is common in CLL, but functional impairment is unusual in the absence of obstructive uropathy, pyelonephritis, or hyperuricemia secondary to tumor lysis from therapy.
(3) Transformation into a diffuse large cell lymphoma (Richter syndrome) or prolymphocytic leukemia occurs in <5% of patients.
(4) Skin involvement is rare.
(5) Osteolytic lesions and isolated mediastinal involvement are unusual and suggest a diagnosis other than CLL.
b. Progressive disease is accompanied by deterioration of both humoral and cell-mediated immunity. As the disease progresses, patients develop progressive pancytopenia, persistent fever, and inanition. During the latter stages of disease, cytotoxic chemotherapy is generally ineffective, and dosages are restricted because of pancytopenia. Death is usually caused by infection, bleeding, or other complications of the disease.
(1) Herpes zoster is the cause of 10% of infections in CLL patients.
(2) Bacterial pathogens associated with hypogammaglobulinemia include Streptococcus pneumoniae, Haemophilus influenzae, and Legionella sp.
(3) Pneumocystis jiroveci may be the causative infectious agent in patients with pulmonary infiltrates.
III. DIAGNOSIS
A. Symptoms and signs. Patients with CLL that was discovered incidentally are usually asymptomatic. Chronic fatigue and reduced exercise tolerance are the first symptoms to develop. Advanced disease and progressive disease are manifested by severe fatigue out of proportion to the degree of the patient’s anemia, fever, bruising, and weight loss.
Lymphadenopathy, splenomegaly, and hepatomegaly should be carefully assessed. Edema or thrombophlebitis may result from obstruction of lymphatic or venous channels by enlarged lymph nodes.
B. Laboratory studies
1. Hemogram
a. Erythrocytes. Anemia may be caused by lymphocyte infiltration of the bone marrow, hypersplenism, autoimmune hemolysis, and other factors. Red blood cells are usually normocytic and normochromic in the absence of prominent hemolysis.
b. Lymphocytes. The absolute lymphocyte count typically ranges from 10,000 to 200,000/μL but may exceed 500,000/μL. Lymphocytes are usually mature appearing with scanty cytoplasm and clumped nuclear chromatin. When blood smears are made, the cells are easily ruptured, producing typical “basket” or “smudge” cells.
c. Granulocytes. Absolute granulocyte counts are normal until late in the disease.
d. Platelets. Thrombocytopenia may be produced by bone marrow infiltration, hypersplenism, or immune thrombocytopenia.
2. Other useful studies that should be obtained in patients with CLL include the following:
a. Biologic markers of the disease, including FISH, ZAP-70 expression, and IgVH gene rearrangement
b. Flow cytometry of the peripheral blood lymphocytes for typical markers of CLL
c. Renal and liver function tests
d. Direct antiglobulin (Coombs) test
e. Serum protein electrophoresis
f. Chest radiographs
g. Computed tomography (CT) scans, which can be used to evaluate mediastinal, retroperitoneal, abdominal, and pelvic lymph nodes
3. Bone marrow examination is usually not necessary to establish the diagnosis in patients with persistent lymphocytosis. The bone marrow of all patients with CLL contains at least 30% lymphocytes. The pattern of bone marrow infiltration is an important prognostic factor (see Section IV.A.2). The indications for bone marrow aspiration and biopsy include the following:
a. Borderline cases of lymphocytosis when the diagnosis is in doubt
b. Thrombocytopenia, to distinguish immune thrombocytopenia from severe bone marrow infiltration
c. Coombs-negative, unexplained anemia
4. Lymph node biopsy in patients with CLL shows malignant lymphoma of the small lymphocytic type. A lymph node biopsy is not indicated in CLL unless the cause of the lymph node involvement is in doubt, particularly when Richter transformation is suspected.
C. Establishing the diagnosis of CLL. The National Cancer Institute (NCI) Working Group on CLL has established useful guidelines for the minimum diagnostic requirements for this disease, which are as follows:
1. Absolute lymphocytosis (5,000/μL or more) with mature-appearing lymphocytes that is sustained
2. Characteristic immunophenotype of monoclonal B cells
a. Expression of pan–B-cell antigens (CD19, CD20, and CD23)
b. Coexpression of CD5 on the leukemic B cells
c. Surface immunoglobulin of low intensity (most often IgM)
D. Differential diagnosis
1. Benign causes of lymphocytosis in adults
a. Viral infections, especially hepatitis, cytomegalovirus, and Epstein-Barr virus (EBV). Lymphadenopathy and hepatosplenomegaly are absent or mild in elderly patients with infectious mononucleosis. The presence of fever, LFTs compatible with hepatitis, and positive EBV serologies should distinguish mononucleosis from CLL.
b. Brucellosis, typhoid fever, paratyphoid, and chronic infections
c. Autoimmune diseases; drug and allergic reactions
d. Thyrotoxicosis and adrenal insufficiency
e. Postsplenectomy
2. Hairy cell leukemia must be differentiated from CLL because management of the two disorders is different. Diagnosis depends on recognizing the pathognomonic hairy cells by immunophenotyping.
3. Cutaneous T-cell lymphomas are suspected if skin involvement is extensive. Differentiation from CLL is made by identifying the convoluted nuclei and helper T cells (with immunohistochemistry and flow cytometry) that are characteristic of this disease.
4. Leukemic phase of non-Hodgkin lymphoma (NHL) is usually distinguished from CLL morphologically and immunologically. NHL cells are often cleaved, whereas CLL cells are never cleaved. In addition, NHL cells demonstrate intense surface immunoglobulins without the CD5 and CD23 antigens, and the opposite is generally true for CLL cells.
5. Prolymphocytic leukemia has large lymphocytes with prominent nucleoli. Lymphadenopathy is minimal; splenomegaly is massive (see Section VI.B).
6. Large granular lymphocytic leukemia/lymphoma (LGLL) has a characteristic morphology with abundant pale to clear, sharply defined cytoplasm and multiple distinct azurophilic granules of varying size. The cells are either T cells or NK cells, and most correspond to natural killer cells. The immunophenotype is positive for CD3, CD8, CD16, and CD57. LGLL is indolent and almost uniformly associated with neutropenia. Rheumatoid arthritis is present in about one-third of patients.
IV. STAGING SYSTEM AND PROGNOSTIC FACTORS
A. Prognostic factors. Routine CBC may detect asymptomatic cases of CLL, but this has no bearing on the overall survival of these patients. If survival has been improved, effective treatment of complicating infections in CLL probably has been responsible for much of the improvement.
1. Clinical staging is helpful for determining prognosis and deciding when to initiate treatment. Anemia and thrombocytopenia adversely affect prognosis when they are due to leukemic infiltration (“packing”) of the bone marrow but not when they are due to autoimmune destruction of red blood cells or platelets.
2. The pattern of bone marrow infiltration also appears to affect prognosis. Patients with nodular or interstitial patterns of bone marrow involvement have longer survival than patients with diffuse (“packed”) involvement.
3. V genes. Two subsets of CLL are defined by the IgVH mutational status. Patients with somatic mutations of the VH genes generally have a better prognosis than those with unmutated VH genes.
4. CD38 expression on CLL cells generally is associated with a poorer prognosis than absent or low-level expression of CD38.
5. Chromosome abnormalities as described in Table 23.1 may predict outcome.
6. Other adverse prognostic factors appear to be a lymphocyte doubling time of <12 months and an elevated serum β2-microglobulin level.
B. Staging system. The modified Rai classification of CLL with median survivals is shown in Table 23.2 (see Section III.C for differences with the NCI Working Group criteria).
Table 23.2 The Modified Rai Classification of Chronic Lymphocytic Leukemia
aExcluding anemia or thrombocytopenia caused by immunologic destruction of cells
V. MANAGEMENT
A. Indications for treatment. CLL is usually indolent. Treatment of asymptomatic stable disease is not warranted. The magnitude of the blood lymphocyte count does not indicate the need to start therapy. The initiation of therapy should be timed according to the clinically assessed pace of disease. Complete remission is not a necessary goal. The indications for instituting therapy in CLL are as follows:
1. Persistent or progressive systemic symptoms (fever, sweats, weight loss)
2. Lymphadenopathy that causes mechanical obstruction or bothersome cosmetic deformities
3. Progressive enlargement of the lymph nodes, liver, or spleen
4. Stage III or IV (high-risk) disease that results from the replacement of bone marrow with lymphocytes
5. Immune hemolysis or immune thrombocytopenia that is treated with prednisone alone
6. Rapid lymphocyte doubling time
B. Chemotherapy. Fludarabine is superior to alkylating agents in its associated complete response rate and duration of response but not in overall survival. Drug dosage schedules for CLL are as follows:
1. Nucleosides. Fludarabine may be the initial treatment of choice for patients who would benefit from a rapid and sustained remission, such as those designated for further aggressive therapy. Prolonged treatment with fludarabine and other nucleoside analogs, such as cladribine or pentostatin, however, are also associated with marked immunosuppression and an increased risk of opportunistic infections and autoimmune hemolysis, and may be associated with myelodysplasia.
a. Fludarabine, 25 to 30 mg/m2 IV daily for 5 consecutive days every 4 weeks
b. Cladribine (2-chlorodeoxyadenosine, 2-CdA), either 0.10 mg/kg daily by continuous IV infusion for 7 days, or 0.14 mg/kg daily IV over 2 hours for 5 consecutive days every 4 to 5 weeks
c. Pentostatin at 4 mg/m2 IV every 2 weeks. Typically, this drug, and the others mentioned above, are combined with an alkylating agent and/or rituximab.
2. Alkylating agents remain useful and effective for palliative therapy.
a. Chlorambucil, 0.1 mg/kg PO daily for 3 to 6 weeks as tolerated; the dose is usually tapered to 2 mg daily until the desired effect is achieved. Alternatively, 15 to 30 mg/m2 PO may be given for 1 day (or divided over 4 days) every 14 to 21 days; the dose is adjusted to tolerance.
b. Cyclophosphamide, 2 to 4 mg/kg PO daily for 10 days; the dose is then adjusted downward for continued therapy until the desired effect is achieved.
c. Bendamustine is a bifunctional alkylating agent with antimetabolite properties. Doses of 100 mg/m2 IV are given over 30 minutes on days 1 and 2 every 28 days for up to 6 cycles. The dose is adjusted for cytopenias.
3. Monoclonal antibodies can be useful for CLL.
a. Rituximab (Rituxan) is an anti-CD20 chimeric monoclonal antibody. The dose of 375 mg/m2 weekly for 4 weeks, as used for non-Hodgkin lymphoma, has minimal activity in previously treated patients with CLL but is quite useful as part of combination therapy in untreated patients. Dose escalation with the weekly schedule or thrice-weekly administration increases the clinical response significantly with minimal toxicity. Unlike alemtuzumab, the remission rate is low. However, rituximab is not associated with myelosuppression and is a better candidate, in terms of immunosuppression, to combine with chemotherapy than alemtuzumab. The primary toxicity associated with rituximab is an infusion-related cytokine release syndrome that is typically associated with the first infusion.
b. Alemtuzumab (Campath-1H) is a humanized anti-CD52 monoclonal antibody whose antigen is expressed on more than 95% of mature B and T lymphocytes and may be used for the treatment of fludarabine-refractory CLL. Alemtuzumab preferentially eliminates CLL cells from the blood, bone marrow, and spleen but is less effective in nodal sites of disease. Approximately one-third of the patients will have a partial response to alemtuzumab; complete responses are rare. Dosing is discussed in Chapter 4, Section VII.B.
Side effects of alemtuzumab include cytokine release syndrome, immunosuppression, and neutropenia. The acute infusion reactions following intravenous administration are markedly reduced with subcutaneous injection. The immunosuppression has resulted opportunistic infections; trimethoprim/sulfamethoxazole (Bactrim) and acyclovir are recommended for prophylaxis.
4. Modern combination therapies have resulted in high response rates (70% to 95%) and high complete response rates (20% to 65%) in previously untreated patients. Variations in the following regimens are in active clinical trials. Prophylaxis with fluconazole, acyclovir, and Bactrim are recommended for all of these therapies.
a. Fludarabine and cyclophosphamide. Fludarabine (25 mg/m2 IV daily on days 1 to 3) and cyclophosphamide (250 mg/m2 IV daily on days 1 to 3) are given every 4 weeks for six cycles (30% to 50% achieve a complete remission, CR).
b. Fludarabine and rituximab. Fludarabine (25 mg/m2 IV daily on days 1 to 5) is given every 4 weeks for six cycles. Rituximab (375 mg/m2) is given on days 1 and 4 of the first cycle and on day 1 of cycles 2 to 6 (50% CR rate).
c. Fludarabine, cyclophosphamide, and rituximab. Fludarabine (25 mg/m2 IV daily on days 1 to 3) and cyclophosphamide (250 mg/m2 IV daily on days 1 to 3) are given every 4 weeks for six cycles. Rituximab is given at a dose of 375 mg/m2 1 day before the first course and increased to 500 mg/m2 on day 1 for cycles 2 to 6 (65% CR rate).
d. Pentostatin and cyclophosphamide. Pentostatin (4 mg/m2 IV) and cyclophosphamide (600 to 900 mg/m2 IV) are given every 3 weeks for six cycles (17% CR in previously treated patients). A newer regimen with rituximab uses lower doses of pentostatin (4 mg/m2) and cyclophosphamide (600 mg/m2).
e. Bendamustine and rituximab. Bendamustine (70 mg/m2 IV over 30 minutes on days 1 and 2) and rituximab (375 mg/m2 for the first course and 500 mg/m2 for subsequent courses). Repeat every 28 days.
5. Treatment of resistant disease is controversial. Clearly, if patients were initially treated with an alkylating agent, then fludarabine or a fludarabine combination (see above) should be initiated. If a patient is resistant to fludarabine, then single-agent alkylators, alemtuzumab, or pentostatin plus cyclophosphamide should be considered. However, if patients have previously responded to fludarabine, then one of the fludarabine combinations should be considered. The role of autologous and allogeneic stem cell transplants is limited in CLL patients, who are typically elderly and poor candidates for transplantation. However, in selected patients, nonmyeloablative allogeneic stem cell transplants can be considered to induce long-term remission.
C. Radiation therapy (RT). Local irradiation is recommended only for reduction of lymph node masses that threaten vital organ function and that respond poorly to chemotherapy. Splenic irradiation may result in improvement of disease elsewhere and may temporarily improve signs of hypersplenism; however, the clinical usefulness of splenic irradiation has not been established. Total-body irradiation remains investigational and potentially dangerous.
D. Surgery. Splenectomy is indicated in CLL patients who have immune hemolytic anemia or immune thrombocytopenia that either fails to respond to corticosteroid therapy or must be treated with corticosteroids chronically. Splenectomy may also be helpful in patients with problematic hypersplenism.
VI. SPECIAL CLINICAL PROBLEMS IN CLL
A. Richter syndrome. About 5% of patients with CLL develop a diffuse large cell lymphoma with rapid clinical deterioration and death occurring within 1 to 6 months. The clinical features include fever, weight loss, increasing localized or generalized lymphadenopathy, lymphocytopenia (as well as other cytopenias), and dysglobulinemia. Combination chemotherapy with CHOP (see Appendix D2, Section II) is usually initiated. The role of postremission autologous or allogeneic transplantation in this setting is unknown.
B. Prolymphocytic leukemia is a rare variant of CLL. The main clinical feature is massive splenomegaly without substantial lymph node enlargement. Leukocytosis usually exceeds 100,000/μL and is characterized by large lymphoid cells with single prominent nucleoli. Tissue sections show almost no mitotic figures despite the immature appearance of the leukemic cells.
1. Eighty percent of cases involve B cells that have different surface markers than typical CLL (the B cells of prolymphocytic leukemia show intense surface immunoglobulin, the CD19 and CD20 B-cell antigens, but typically not the CD5 antigen). Twenty percent of cases are T cell, usually with a T-helper phenotype (CD3 and CD4 positive).
2. A small percentage of CLL patients develop a “prolymphocytoid” transformation, whereby more than 30% of the peripheral blood cells are prolymphocytic. This differs from de novo prolymphocytic leukemia in that the cells maintain the immune features of CLL and the clinical course resembles typical CLL, albeit in a late stage of the disease.
3. Single-agent therapy with fludarabine, cladribine, or alemtuzumab or combination therapy with CHOP may be useful.
HAIRY CELL LEUKEMIA
I. EPIDEMIOLOGY AND ETIOLOGY. Hairy cell leukemia (HCL; leukemic reticuloendotheliosis, lymphoid myelofibrosis) accounts for about 2% of all leukemia. The disease occurs more frequently in men than women by a ratio of 5:1. The median age of patients is 55 years; patients <30 years of age are unusual. The etiology is unknown.
II. PATHOLOGY AND NATURAL HISTORY
A. Pathology. The pathognomonic cells with irregular cytoplasmic projections can be identified in the peripheral blood, bone marrow, liver, and spleen of affected patients. Hairy cells are B lymphocytes in virtually every case (rare T-cell variants have been reported). Requesting specific flow cytometric marker analysis contributes to making the diagnosis.
B. Natural history. The natural history is characterized by neutropenia. The time course can be variable, ranging from a relatively fulminant course to a waxing and waning course of exacerbations and spontaneous improvements, and to prolonged survival measured in decades. Most patients are able to function normally throughout most of their illness.
Patients with HCL usually present with an insidious development of nonspecific symptoms, splenomegaly, neutropenia, and sometimes pancytopenia. Progression of disease is manifested by bleeding because of thrombocytopenia, anemia requiring transfusions, and recurrent infections.
III. DIAGNOSIS
A. Symptoms and signs. Weakness and fatigue are the presenting symptoms in about 40% of cases. Bleeding, recent infection, or abdominal discomfort is present in about 20% of patients.
Splenomegaly occurs in 95% of patients. Hepatomegaly is seen in about 40% of patients. Peripheral lymphadenopathy is rarely present in patients with HCL; however, CT scans of the abdomen may reveal retroperitoneal lymphadenopathy.
B. Preliminary laboratory studies
1. CBC. Anemia and thrombocytopenia occur in 85% of patients. About 60% of patients have granulocytopenia; 20% have increased hairy cells with leukocytosis and absolute granulocytopenia.
2. Blood chemistries. Only 10% to 20% of patients have abnormal liver or renal function tests. Polyclonal hyperglobulinemia or decreased normal immunoglobulin concentrations occurs in 20% of patients.
C. Special diagnostic studies. The diagnosis of HCL is made by identifying the pathognomonic mononuclear cells in the peripheral blood or bone marrow, but an immunophenotype characteristic of HCL is required. The cells have irregular and serrated borders with characteristic slender, hair-like cytoplasmic projections and round, eccentric nuclei with spongy chromatin. The cytoplasm is sky blue without granules.
1. Immune flow cytometry demonstrates a characteristic pattern of CD19, CD20, CD22, CD11c, CD25, and CD103 positivity. Hairy cell variants may be CD25 or CD103 negative and typically do not have a favorable prognosis.
2. Phase-contrast microscopy with supravital staining of fresh preparations is valuable for demonstrating the cellular characteristics because the cytoplasm of hairy cells is often poorly preserved in films mixed with Wright stain.
3. Tartrate-resistant acid phosphatase (TRAP). HCL cells have a strong acid phosphatase activity, which is resistant to inhibition by 0.05 M tartaric acid (due to the presence of isoenzyme 5 of acid phosphatase); the acid phosphatase in leukocytes from most patients with lymphomas and CLL is sensitive to tartrate. A strongly positive TRAP study is present in most patients with HCL but is not required for the diagnosis and can be detected in patients with other lymphoid malignancies. Cytochemical staining for TRAP is often omitted.
4. Bone marrow aspiration frequently is unsuccessful (“dry tap”). Marrow biopsy shows a characteristic loose and spongy arrangement of cells, even with extensive infiltration with hairy cells. Fibrosis of the marrow with reticulin fibers is also characteristic in areas of HCL infiltration and accounts for the high frequency of dry taps.
5. Splenic morphology. The spleen is the most densely infiltrated organ in HCL. The red pulp may contain a unique vascular lesion: pseudosinuses lined by hairy cells.
D. Differential diagnosis. It is important to distinguish HCL from other diseases because management is substantially different. HCL is most often confused with CLL, malignant lymphoma, myelofibrosis, or monocytic leukemia. Differentiation is made by identifying the pathognomonic cell, the characteristic immune profile, usually today without a TRAP test, and pathologic findings of the bone marrow biopsy.
IV. STAGING SYSTEM AND PROGNOSTIC FACTORS. The median survival in the natural history of HCL appears to be 5 to 10 years, but this has been dramatically altered by current therapies.
V. MANAGEMENT
A. The decision to treat. Many cases tend to have an indolent course, and these patients have excellent survival without therapy. Therapy may be deferred for asymptomatic patients until the patient develops symptomatic anemia or clinically worrisome granulocytopenia and/or thrombocytopenia.
B. Cladribine is the treatment of choice for HCL. The drug is given by continuous intravenous infusion once only at a dose of 0.1 mg/kg/d for 7 days. Other regimens have been published, including a 5-day bolus IV treatment. Virtually all patients respond, and 95% achieve complete response. Relapse occurs in 35% of patients, usually after 3 years, and most respond to an additional course of cladribine. Toxicity has been limited to transient fever, usually associated with neutropenia. Survival at 9 years exceeds 95% in patients treated with cladribine.
C. Pentostatin (Nipent) is also highly effective therapy for HCL. Most patients not only have normalization of their CBC but also have a complete response with disappearance of hairy cells from their bone marrow (rarely seen with IFN-α). Complications include skin rash and neurotoxicity. The dosage is 4 mg/m2 IV every 2 weeks for 3 to 6 months.
D. Interferon-α (IFN-α) is a highly effective agent in reversing the pancytopenia and splenomegaly in HCL. Dosages of IFN ranging from 2 to 4 million units daily or three times weekly for 1 year achieve responses in 90% of patients with HCL. Complete response with disappearance of hairy cells from the bone marrow, however, is unusual, and use of this drug for HCL has nearly disappeared.
E. Splenectomy has achieved at least a partial response in 75% of patients and historically had been the standard therapy for HCL but, like interferon therapy, is no longer used as primary therapy.
F. Other therapy. Rituximab has been effective for treatment of HCL in case reports. Immunotoxin therapy, such as that studied with an anti-CD22 immunoconjugate, may be useful in the future.
CHRONIC MYELOGENOUS LEUKEMIA
I. EPIDEMIOLOGY AND ETIOLOGY. Chronic myelogenous leukemia (CML) is a myeloproliferative disorder with a characteristic cytogenetic abnormality and a propensity to evolve from a chronic phase into a blast phase with features similar to acute leukemia.
A. Incidence. CML has an incidence of approximately 1 case in 100,000 population and composes 20% of adult leukemias in Western countries. The median age at onset is in the mid-50s, although children are also affected.
B. Etiology. The cause of most cases of CML is unknown, although radiation exposure is a known risk factor.
II. PATHOGENESIS AND NATURAL HISTORY
A. Clonality. CML is a clonal disease of an abnormal stem cell. Myeloid, erythroid, megakaryocytic, and B-lymphoid cells are involved in the malignant clone.
B. The Philadelphia chromosome (Ph1) is the diminutive chromosome 22 produced by an unbalanced translocation between chromosomes 9 and 22. This translocation, designated t(9;22), fuses the 3′ portion of the c-ABLgene on the long arm of chromosome 9 (band q34) to the 5′ end of the breakpoint cluster (BCR) gene on the long arm of chromosome 22 (band q11). The resultant fusion gene encodes a chimeric protein of 210 kDa (p210) with constitutive tyrosine kinase activity. The BCR-ABL protein stimulates the proliferation and enhances the survival of CML hematopoietic progenitor cells.
1. Atypical (Ph1-negative) CML. Approximately 1% to 2% of cases that appear clinically to be CML are Ph1-negative by bone marrow cytogenetics, FISH, and polymerase chain reaction (PCR) amplification for the BCR-ABL fusion gene. Some cases may have a translocation involving chromosome 5q31–35, which encodes the PDGFRB gene. The clinical course is poorly characterized as many case series were published before availability of FISH and PCR assays, and probably included a majority of cases with occult BCR-ABL translocations. Nevertheless, anemia, thrombocytopenia, and splenomegaly appear to be clinical consequences of this disorder.
Therapy with imatinib may benefit patients with the PDGFRB gene rearrangement. In the absence of this specific abnormality, hydroxyurea would be the myelosuppressive therapy of choice, if required for management of leukocytosis or splenomegaly.
2. Ph1 chromosome in acute leukemia. The Ph1 chromosome can be found in de novo acute leukemia. Approximately 30% of adults with acute lymphoblastic leukemia (ALL) and fewer than 2% of adults with acute myelogenous leukemia (AML) present with the Ph1 chromosome. Some of these cases represent CML in blast crisis that was never diagnosed in the chronic phase; effective treatment may reverse some cases to a chronic phase.
C. Clinical course. Three stages of CML are recognized: chronic phase (CP), accelerated phase (AP), and blast phase (or blast crisis, BP). Approximately 85% of patients are diagnosed while in chronic phase. All stages of disease can present with fatigue, low-grade fevers, night sweats, and early satiety or abdominal pain from splenomegaly. Symptoms tend to be more severe when advanced disease is present. Evolution of accelerated or blast phase from the chronic phase can be suggested by the development of anemia, thrombocytopenia, leukocytosis with immature myeloid cells or basophilia, increasing splenomegaly, or recurrent constitutional symptoms while on therapy. The disease status should be re-evaluated in this setting.
Cytogenetic changes other than the Ph1 abnormality are commonly observed in association with blast crisis evolution. Approximately 70% of blast crises are myeloid, in which the blasts display a phenotype indistinguishable from acute myeloid leukemia. The remaining cases of blast crisis are lymphoid, in which the blasts have immunophenotypic characteristics of pre-B cells, or have biphenotypic features (myeloid and B lymphoid).
III. CLINICAL MANIFESTATIONS
A. Symptoms and signs
1. CML is asymptomatic in approximately 20% of patients and is discovered incidentally by routine blood counts.
2. The excessive numbers of metabolically active myeloid cells can cause fevers and sweats. Fatigue and malaise are also commonly present.
3. Bone pain and tenderness can result from the expanding leukemic mass in the marrow.
4. Splenomegaly is present in the majority of cases, and it may be massive. It can be manifested as early satiety, abdominal fullness, or pain. Hepatomegaly is less common and is usually asymptomatic.
5. Marked leukocytosis (particularly white blood cell counts [WBC] exceeding 100,000/μL) can be associated with symptoms of leukostasis. Manifestations may include visual changes, seizures, cerebral or myocardial infarctions, and priapism. Similar complications can result from severe thrombocytosis.
6. Progression to accelerated phase or blast crisis is suggested by the recurrence of constitutional symptoms, including fevers, sweats, anorexia, fatigue, and bone pain, while on therapy. Recurrent or worsening splenomegaly also suggests disease progression. The development of blast crisis may be accompanied by infection or bleeding due to neutropenia or thrombocytopenia, respectively. Lymphadenopathy can develop in lymphoid blast crisis.
B. Laboratory studies
1. Leukocytes. The WBC usually exceeds 30,000/μL and usually ranges from 100,000 to 300,000/μL at the time of diagnosis. The peripheral blood smear in the chronic phase is often described as appearing like a bone marrow aspirate smear due to presence of all stages of myeloid cell maturation. Myeloblasts constitute <15% of the leukocytes in the peripheral blood, and promyelocytes plus blasts combined compose <30% in the chronic phase. Eosinophil and basophil counts are often elevated, but basophils constitute <20% of the peripheral blood leukocytes in the chronic phase.
2. Platelets. Thrombocytosis is common, and the platelet count may exceed 1,000,000/μL at presentation. Thrombocytopenia is unusual in the chronic phase. Platelet aggregation tests are commonly abnormal.
3. Erythrocytes. The hemoglobin level is usually normal, but a mild normocytic, normochromic anemia can be present. A few nucleated red blood cells can be seen on the peripheral blood smear.
4. Bone marrow aspiration and biopsy should be performed on all patients as part of the diagnostic evaluation. This is necessary to evaluate the stage of disease at presentation. In all cases, the marrow is markedly hypercellular as a result of massive myeloid hyperplasia, resulting in a markedly increased myeloid-to-erythroid ratio. Megakaryocyte numbers are frequently increased. Fibrosis may also be present in variable amounts but is rarely profound in the chronic phase.
5. Cytogenetic analysis should be performed at the time of bone marrow examination on all patients. The characteristic t(9;22) is identified in the majority of patients. However, complex translocations infrequently occur that can mask the BCR-ABL translocation. In this situation, FISH or PCR for BCR-ABL can identify the characteristic abnormality. Cytogenetics are particularly important to determine if additional chromosomal abnormalities associated with advanced disease are present.
6. Fluorescence in situ hybridization (FISH) for the BCR-ABL gene rearrangement can be performed on peripheral blood or bone marrow. This assay does not require dividing cells and is more sensitive than cytogenetics at detecting minimal residual disease during therapy. It can be useful if complex chromosomal translocations are present.
7. Polymerase chain reaction (PCR) is a molecular assay performed on the peripheral blood that identifies the BCR-ABL translocation. The quantitative PCR (Q-PCR) assay is the most sensitive method to follow residual disease during the treatment of CML. A baseline Q-PCR assay should be obtained on all patients so that subsequent measurements during therapy will permit an accurate assessment of response in relation to the pretreatment level of disease. Like the FISH test, the PCR assay is capable of detecting the BCR-ABL rearrangement if complex chromosomal translocations occur.
8. Leukocyte alkaline phosphatase activity in circulating granulocytes is decreased or absent in CML and was previously helpful diagnostically. This test has been supplanted by FISH and PCR assays for BCR-ABL.
9. Uric acid. Hyperuricemia and hyperuricosuria are typically present.
IV. DIAGNOSTIC CRITERIA AND PROGNOSTIC VARIABLES
A. World Health Organization (WHO) diagnostic criteria for chronic-phase (CP) CML include
1. Peripheral blood leukocytosis due to increased numbers of mature and immature neutrophils
2. No significant dysplasia
3. Promyelocytes, myelocytes, and metamyelocytes >10% of WBCs
4. Blasts <2% of WBCs
5. Monocytes usually <3% of WBCs
6. Bone marrow hypercellular with granulocytic proliferation and often expansion of small megakaryocytes with hypolobated nuclei
7. Less than 10% blasts in the bone marrow
B. WHO criteria for diagnosis of accelerated-phase (AP) CML require one or more of the following:
1. Blasts 10% to 19% in the blood or bone marrow
2. Basophils ≥20% of peripheral blood leukocytes
3. Platelets ≥1,000,000/μL unresponsive to therapy or ≤100,000/μL unrelated to therapy
4. Increasing spleen size and/or increasing WBC count unresponsive to therapy
5. Cytogenetic evidence of clonal evolution (cytogenetic abnormalities in addition to the Ph1 chromosome)
C. WHO criteria for diagnosis of blast-phase CML (blast crisis, BP)
1. Blasts ≥20% of bone marrow cells or peripheral WBC
2. Extramedullary blast formation (e.g., osteolyticbonelesions, lymphadenopathy)
D. Differential diagnosis
1. Leukemoid reactions rarely show the full spectrum of myeloid cells (especially myelocytes, promyelocytes, or blasts) in the peripheral blood and lack the BCR-ABL translocation.
2. Other myeloproliferative disorders may present with leukocytosis and thrombocytosis but will not have the BCR-ABL translocation.
3. Chronic neutrophilic leukemia is an exceedingly rare disorder that can be considered when no other cause for persistent, mature neutrophilia (WBC > 25,000/μL with >80% segmented neutrophils and bands) is found. There is no myeloid left shift or increased percentage of myeloblasts in the blood or bone marrow. Cytogenetics are normal, and there is no BCR-ABL translocation or rearrangement of PDGFRA, PDGFRB, or FGFR1.
4. Atypical chronic myeloid leukemia (BCR-ABL negative) is characterized by peripheral blood leukocytosis (WBC ≥13,000/μL) with increased neutrophils and their precursors displaying prominent dysgranulopoiesis. Neutrophil precursors comprise >10% of the leukocytes. Basophils are <20% of leukocytes, and monocytes are <10% of leukocytes. Blasts are <20% of bone marrow cells. There is no BCR-ABL fusion, or translocation of PDGFRA or PDGFRB.Patients can have anemia, thrombocytopenia, and splenomegaly.
E. Prognostic variables. The Sokal score (www.roc.se/Sokal.asp) and Hasford score (www.pharmacoepi.de/cgi-bin/cmiscore.cgi) use variables including age, spleen size, platelet count, peripheral blood blast percentage, and peripheral blood basophil and eosinophil percentages to calculate the likelihood of achieving a remission in chronic-phase patients but are not currently used to select treatment. Ongoing assessment of response during therapy has emerged as a much more important predictor of progression-free survival. Advanced-phase disease, especially blast crisis, conveys an adverse prognosis and warrants referral to a tertiary center capable of transplant evaluation.
V. MANAGEMENT
A. Imatinib (Gleevec) is an inhibitor of BCR-ABL tyrosine kinase activity that is highly active in CML. Long-term progression-free survival of CML patients on imatinib therapy correlates with the depth of response.
1. Imatinib dosing. The standard dose of imatinib is 400 mg/d for chronic phase and 600 mg/d for advanced disease. Suboptimal response (Table 23.3) may warrant a dose increase to 600 or 800 mg/d administered in divided doses as (400 mg b.i.d.). Potential side effects include fluid retention, nausea, diarrhea, muscle cramps, skin rash, fatigue, and myelosuppression. If moderate toxicity warrants dose reduction, re-escalation to a standard dose should be attempted once side effects abate. The minimum dose reliably capable of inducing a cytogenetic response is 300 mg/d. Failure of a patient to tolerate this dose warrants a change in therapy. There is some evidence that second-generation kinase inhibitors, such as dasatinib and nilotinib, may be associated with more rapid achievements of therapeutic milestones.
Table 23.3 European Leukemia Net Guidelines for Response to Imatinib in Newly Diagnosed Chronic-phase CML (2009)
CHR, complete hematologic response; CyR, cytogenetic response; CCyR, complete cytogenetic response; MiCyR, minor cytogenetic response; MMR, major molecular response; PCyR, partial cytogenetic response.
2. Acquired imatinib resistance is defined as loss of a previous hematologic or cytogenetic response. The best understood mechanism of resistance is the development of point mutations in BCR-ABL that impair the binding of imatinib to the kinase domain. BCR-ABL mutation analysis should be sent if acquired resistance develops. CML with most of the common BCR-ABL mutations can be effectively treated by the second-generation kinase inhibitors dasatinib or nilotinib. Clinical case series have suggested that the V299L and F317I mutations confer relative resistance to dasatinib, while the Y253H, E255V/K, and F359V/C mutations are moderately resistant to nilotinib. The T315I mutation is highly resistant to both dasatinib and nilotinib. Patients with the T315I mutation should be referred to a center that is evaluating investigational agents for this mutation. Another mechanism of resistance to all of the tyrosine kinase inhibitors is amplification of BCR-ABL copy number, as detected by FISH.
B. Second-generation BCR-ABL kinase inhibitors, dasatinib and nilotinib, were initially developed and approved to treat CML patients with resistance or intolerance to imatinib. Both agents are more potent inhibitors of the BCR-ABL kinase than imatinib. Randomized trials have subsequently demonstrated the superiority of each drug to imatinib in their ability to induce a CCyR and MMR after a year of therapy. Therefore, they are also FDA-approved as initial therapy for newly diagnosed chronic-phase CML patients. Both agents are active against virtually all BCR-ABL mutations (other than T315I) that confer imatinib resistance, and they are usually well tolerated.
1. Dasatinib (Sprycel) is an SRC and ABL kinase inhibitor that is administered once a day with a meal. Starting dose is 100 mg/d for chronic phase, 140 mg/d for advanced disease. Common side effects include myelosuppression, fluid retention (especially pleural effusion), diarrhea, rash, and bone pain. Dasatinib impairs platelet function and can cause serious gastrointestinal or intracranial bleeding in conjunction with severe thrombocytopenia.
2. Nilotinib (Tasigna) is an imatinib analog administered at a dose of 300 mg twice daily for newly diagnosed patients and 400 mg twice daily after imatinib failure or for AP disease. Patients must fast for 2 hours before and 1 hour after each dose to prevent increased drug absorption, which results in QT prolongation. Nilotinib prolongs the QT interval and sudden deaths were reported in early clinical trials. Common side effects include myelosuppression, arthralgias and myalgias, rash, and nausea. Additional laboratory abnormalities caused by nilotinib include elevated lipase, hyperglycemia, hyperbilirubinemia, and AST/ALT elevations.
C. Efficacy monitoring. Close monitoring of response is essential to optimize patient outcomes. Guidelines for adequacy of response to imatinib as initial therapy for chronic-phase CML have been established by the European Leukemia Net (ELN) and the National Comprehensive Cancer Network (Table 23.3). The second generation tyrosine kinase inhibitors (TKIs) induce more rapid responses than imatinib, but guidelines for adequacy of response have not yet been formulated for dasatinib or nilotinib in this setting. For now, these guidelines must suffice for monitoring all newly diagnosed patients treated with TKIs.
Patients with suboptimal responses to initial therapy should be considered for imatinib dose escalation (if receiving imatinib), therapy with an alternative TKI, or allogeneic bone marrow transplantation. The same considerations are appropriate for patients who experience treatment failure on imatinib, but dose escalation of imatinib is not likely to provide prolonged benefit. Transplantation is typically reserved for patients who do not have an adequate response to second-line therapy. Failure of a second TKI is best defined as lack of an MCyR after 1 year. However, there should be evidence of progressive reduction of disease burden prior to that time point.
1. Complete hematologic response (CHR) is defined as a normalization of the peripheral blood counts and can be expected in >95% of chronic-phase patients. Failure to achieve this end point by 3 months is considered a primary treatment failure and warrants a change in treatment.
2. Cytogenetic responses
a. Minor cytogenetic response (MiCyR) is the presence of the Ph1 chromosome in 36% to 65% of bone marrow metaphases.
b. Partial cytogenetic response (PCyR) is reduction of the Ph1 chromosome to ≤35% of bone marrow metaphases.
c. Complete cytogenetic response (CCyR) is defined as normalization of the bone marrow cytogenetics.
d. Major cytogenetic response (MCyR) combines PCyR and CCyR. Ideally, an MCyR should be observed by 6 months and a CCyR by 1 year. The absence of any cytogenetic response at 6 months, less than an MCyR at 12 months, or less than a CCyR at 18 months should prompt consideration of a change in treatment.
3. Major molecular response (MMR) is a >3-log (1,000-fold) reduction in the level of disease compared to a reference control of untreated patient samples, as measured by quantitative real-time PCR (Q-PCR). Patients who achieve this end point by 1 year have almost no risk of disease progression to AP or BP at 5 years.
4. PCR undetectable (PCR-U) represents a greater than or equal to 5-log (100,000-fold) reduction of disease burden that cannot be measured using the PCR assay. Imatinib-treated patients who maintained a stable PCR-U response for at least 2 years were taken off treatment and monitored closely for relapse. Approximately 40% of patients remained PCR-U without treatment for at least 2 years. Given the limited data relating to this observation, and the lack of harmonization between laboratories performing Q-PCR testing, treatment discontinuation for PCR-U patients is not recommended.
D. Response monitoring should include a bone marrow aspiration and biopsy at baseline and every 3 to 6 months until a complete cytogenetic response is achieved. Although FISH is somewhat more sensitive than routine cytogenetics, and it can be performed on peripheral blood, FISH has not been used to assess response in any clinical trial and it has not been validated prospectively as a surrogate end point for outcome. Therefore, bone marrow cytogenetics remains the gold standard of response assessment. FISH would be of value if an occult translocation, not detectable by cytogenetics, is present. Q-PCR should be performed at baseline and every 3 months. A 10-fold increase in Q-PCR is considered clinically significant but should be repeated to confirm that the change is real. A bone marrow biopsy should be repeated if there is an unexplained progressive increase in the Q-PCR assay (>10-fold).
E. Goals of therapy should be to prevent progression to advanced disease using a dose and schedule of drug with acceptable side effects. Although the achievement of a CCyR conveys a survival advantage, some patients will lose this response and experience disease progression. Patients who achieve an MMR have a near-zero chance of progression, but follow-up of patients receiving imatinib as initial therapy is still <10 years duration, and any residual disease retains the potential to develop drug resistance or to progress.
Therefore, the goal of therapy should be to suppress the disease to the lowest possible level. This is most important in young patients who would be expected to live with their disease for longer than there is outcome data from clinical trials. For older patients or those with multiple comorbidities, less aggressive cytoreduction may be adequate to prevent disease progression during their lives.
F. Safety monitoring is similar for all of the TKIs. At the initiation of therapy, all peripheral blood cells are derived from the CML clone. Therefore, cytopenias are anticipated during the transition to normal hematopoiesis induced by TKI therapy. Most laboratory side effects of the TKIs are observed within the first few weeks after initiating therapy. Close initial monitoring of potential clinical and laboratory abnormalities is recommended.
1. CBC with differential, liver function tests, and electrolyte assessment must be performed before starting therapy and every 2 weeks until blood counts have normalized. Electrolyte abnormalities should be corrected prior to initiating therapy. Indications for holding drug include ANC <1,000/μL, platelets <500,000/μL, AST/ALT greater than fivefold above upper limit of normal (ULN), or bilirubin greater than threefold above ULN.
2. For patients taking dasatinib, physical examinations should routinely evaluate for development of a pleural effusion. This complication can occur after many months on therapy.
3. For patients taking nilotinib, an ECG must be performed prior to initiating therapy. The baseline QTcF should be <450 milliseconds prior to starting drug to minimize the risk of clinically significant QT prolongation. A repeat ECG is done after 1 week of therapy to ensure QTcF is <450 milliseconds on therapy.
4. All of the TKIs are metabolized by the CYP3A4 hepatic microsomal enzyme, so drugs that induce or inhibit this enzyme should be avoided.
5. Pregnancy must be avoided with all the TKIs as they are teratogenic.
G. Bone marrow transplantation (BMT) is the only therapy that is proven to be curative for CML, but its role in the management of this disease has been diminished by the marked success of the TKIs. The disadvantage of transplantation is that there is a 15% to 20% risk of mortality at 1 year in young patients, and the risk increases with the age of the patient. In comparison, the risk of death during the first year on TKI therapy is approximately 2% in patients with a median age of >50 years, and use of imatinib before transplantation does not appear to adversely affect outcome. Therefore, BMT is primarily reserved as a salvage therapy for patients who are at high risk (AP or BP at diagnosis) or who are having suboptimal response or treatment failure on a TKI.
Careful monitoring of response to imatinib using cytogenetics and Q-PCR should permit the prediction of long-term benefit from medical therapy and identification of patients who should be considered for transplantation due to inadequate response. The risks and benefits of ongoing medical therapy versus transplantation must be highly individualized and should be discussed in detail with patients as therapy proceeds. The risk of relapse is unacceptably high if BMT is performed in BP and therefore is not routinely performed. AP disease is also associated with an increased risk of relapse, so when there are clinical indications that medical therapy will be inadequate, transplantation should be considered while the patient is still in chronic phase.
The expected outcomes of BMT for CML include
1. Disappearance of the Ph1 chromosome
2. Long-term (5 to 10 years) disease-free survival is reported in 60% to 80% of patients in chronic-phase CML who are treated with BMT using related donors. Allogeneic transplants using 10/10 matched unrelated donors produce survival results approximately 5% points lower than for patients receiving transplants from matched related donors. Survival rates after BMT appear to plateau after 3 to 7 years.
3. Young patients undergoing BMT face a 15% to 20% probability of transplant-related death within 1 year of the procedure. Significant graft-versus-host disease (GVHD) occurs in 10% to 60% of cases and is the cause of death in 5% to 15% of patients. The risk of severe GVHD and mortality increases with age and with degree of HLA disparity between the donor and recipient.
4. Survival rates decrease by half when using BMT in the accelerated phase and by half again when used in the blast phase.
5. Relapses of CP disease can be effectively treated with lymphocyte infusions from the original donor (donor lymphocyte infusions, or DLI) without additional chemotherapy. CCyR can be expected in approximately 60% of patients with chronic-phase CML treated with DLI. The predominant risk of this therapy is worsening GVHD. Patients who relapse with AP or BP disease should ideally be returned to CP before the use of DLI.
H. Younger patients who are considered good candidates for an allotransplantation should be referred to a transplant center to discuss this option. Human leukocyte antigen (HLA) typing of the patient and siblings should be performed to determine the potential availability of a related donor. Because the therapeutic landscape for CML is still evolving, candid discussions about the risks and benefits of transplantation and tyrosine kinase inhibitors should be undertaken. Close monitoring of response to imatinib is essential, as discussed previously.
I. Management of the accelerated phase (AP) or blast phase (BP). Randomized studies are not available to guide the choice of TKI in these patients. It is suggested that dasatinib 140 mg/d, nilotinib 400 mg b.id., or imatinib 600 mg/d be used as initial therapy in AP patients. Patients who evolve AP on one TKI should be switched to a second-generation agent and be referred to a transplant center. The AP patients who achieve a CCyR can maintain stable benefit from TKI therapy.
Patients who present with or evolve BP would be best managed on a clinical trial or be considered for therapy with combination TKI and chemotherapy. Treatment regimens for Ph1-positive ALL can be used to treat lymphoid blast crisis. AML induction regimens can be combined with a TKI for myeloid blast crisis. Should a second chronic or accelerated phase be achieved, allogeneic stem cell transplantation is the only option that confers a chance of long-term survival.
Side effects of all TKIs are more common and are potentially more severe in patients who present with advanced disease. Patients who experience severe cytopenias (neutrophils < 500/μL or platelets < 20,000/μL) on treatment should have a bone marrow biopsy to determine if the low counts are due to the drug or the disease. If the bone marrow is hypocellular without increased blasts, then treatment should be held until the neutrophils are ≥1,000/μL and the platelets are ≥20,000 to 50,000/μL. If increased numbers of blasts persist in the bone marrow, treatment should be continued, and the bone marrow biopsy should be repeated in 2 to 4 weeks if the cytopenias persist.
J. Other treatment modalities
1. Allopurinol, 300 mg/d PO, is given to all patients at diagnosis and is continued until the WBC normalizes.
2. Leukapheresis rapidly decreases the granulocyte count for short periods of time but is time-consuming and expensive. This procedure is useful in the following circumstances:
a. Patients with central nervous system or pulmonary symptoms from leukostasis, which usually develops when the WBC count exceeds 100,000/μL, especially with significant proportions of blasts. Leukapheresis is implemented emergently in combination with TKI therapy.
b. Patients with priapism
c. Pregnant patients, in whom TKIs and cytotoxic agents are contraindicated
3. Interferon-alpha (IFN-α) can induce hematologic and cytogenetic responses in CML patients and was the standard therapy for many years. However, a landmark randomized clinical trial of imatinib versus IFN-α plus cytarabine demonstrated a markedly higher cytogenetic response rate and much greater tolerability for imatinib than IFN-α–based therapy. There does not currently appear to be any role for IFN-α in the management of CML, except in pregnant patients who require cytoreductive therapy, as it is not believed to be teratogenic.
4. Hydroxyurea (1 to 3 g/d PO) has been used for many years to rapidly reduce the blood counts of CML patients. It is well tolerated, but it does not induce cytogenetic responses. The rapid effectiveness of the TKIs has relegated hydroxyurea to a minor role in therapy. It can be used as a bridge between TKIs to control blood counts, when necessary.
5. Chemotherapy does not have an established role in the management of CML. Historically, lymphoid blast crisis has had a 20% to 40% response rate to ALL-type chemotherapy regimens, whereas myeloid blast crisis has a response rate of <20% to AML induction. The use of chemotherapy plus TKIs may be useful in lymphoid blast crisis, as it has been in Ph1-positive ALL. Because most CML patients currently develop blast crisis while on imatinib, the results of ongoing trials of second-generation TKIs plus chemotherapy may provide guidance for this patient population.
6. Splenic irradiation or splenectomy is not indicated for splenomegaly in CML.
VI. SPECIAL CLINICAL PROBLEMS IN CML
A. False platelet counts. Patients with AP or BP CML may develop severe, refractory thrombocytopenia. Platelet counts that incorrectly show improvement may be found in patients with marked leukocytosis and advancing disease. The false platelet count happens because the granulocytes become disrupted in the test tube, and automatic platelet counting machines enumerate the larger leukocyte granules as platelets. The paradox is resolved by reviewing the peripheral blood smear and estimating platelet numbers.
B. Other false laboratory results. Pseudohyperkalemia, pseudohypoglycemia, and pseudohypoxemia are discussed in Chapter 24, Section II.G, “Comparable Aspects.”
CHRONIC MYELOMONOCYTIC LEUKEMIA
I. TERMINOLOGY. Chronic myelomonocytic leukemia (CMML) is classified as a “myelodysplastic/myeloproliferative syndrome” in the WHO system (Table 25.2). It is divided into two subtypes (CMML-1 and CMML-2), depending on the percentage of blasts in the bone marrow.
II. DIAGNOSIS
A. Clinical features. CMML most commonly affects the elderly. Splenomegaly is commonly present and tends to increase as the disease progresses. Hepatomegaly is uncommon, and lymphadenopathy is rare.
B. Diagnosis according to the WHO classification requires all of the following:
1. A persistent, unexplained monocytosis (>1,000/μL) must be present.
2. The Ph1 chromosome or BCR-ABL fusion gene must be absent.
3. Fewer than 20% blasts (myeloblasts, monoblasts, and promonocytes) must be present in the bone marrow, and dysplasia must involve one or more myeloid lineages.
4. If dysplasia is not evident, there must be a clonal cytogenetic abnormality, the monocytosis must have been present for at least 3 months, and other potential causes of the monocytosis must have been excluded.
C. Additional laboratory abnormalities are commonly observed.
1. Leukocytosis in the range of 11,000 to 50,000/μL (because of increased numbers of both granulocytes and monocytes) is present in most patients, but leukopenia occasionally occurs. The morphology of the leukocytes is characteristically abnormal. Cells with nucleoli in the peripheral blood are uncommon. Eosinophilia is observed in CMML harboring a rearrangement of the PDGFRB gene (see Section II.E.).
2. Mild anemia, often macrocytic
3. Thrombocytopenia is mild in most patients and severe in 15%. Some patients have normal platelet counts. Rarely, thrombocytosis is observed.
4. Serum lysozyme levels are usually elevated.
5. Leukocyte alkaline phosphatase values are variable but rarely as low as those in CML.
D. Bone marrow aspirates in CMML are very hypercellular. Granulocytic hyperplasia with increased numbers of promyelocytes and myeloblasts is prominent. The myeloid series in the marrow often has monocytoid features, but pure monocytic hyperplasia is unusual. Blasts account for <10% of the nucleated cells in CMML-1 and for 10% to 19% in CMML-2. Myelodysplasia is typically present in one or more cell lines.
E. Cytogenetic abnormalities occur in approximately 20% to 40% of cases, but the Ph1 chromosome is absent. It is important to evaluate whether there is rearrangement of the PDGFRB gene on chromosome 5q33 by FISH or PCR. It can partner with ETV6 on chromosome 12p13, HIP1 on chromosome 7q11, RAB5 on chromosome 17p13, and others. The fusion gene created by these translocations encodes a protein in which the tyrosine kinase activity of PDGFRBis constitutively active. Treatment of patients with PDGFRB gene rearrangements with imatinib has induced hematologic and cytogenetic remissions due to the ability of the drug to inhibit the kinase activity of PDGFRB.
F. Molecular abnormalities include point mutations of the KRAS, NRAS ASXL1, CBL, EZH2, TET2, JAK2, and RUNX1 genes, predominantly in patients without cytogenetic abnormalities. These genetic alterations are not unique to CMML, as they are also observed in other myeloproliferative disorders, myelodysplastic syndromes, and AML (Chapter 25). The encoded proteins can be categorized functionally into those involved in growth factor signaling pathways (KRAS, NRAS, ASXL1, CBL, JAK2) and epigenetic DNA regulation (EZH2, TET2).
III. CLINICAL COURSE. Distinguishing CMML from acute myelomonocytic leukemia is essential. CMML-1 often has an insidious onset and an indolent course. Most of these patients live ≥2 years, and many survive >5 years. Patients with CMML-2 have a high risk of AML evolution.
IV. MANAGEMENT
A. Allogeneic stem cell transplantation remains the only curative option for CMML. The criteria for determining the appropriateness of this therapy should be extrapolated from the experience with myelodysplastic syndrome.
B. Imatinib should be administered to patients with rearrangement of the PDGFRB gene on chromosome 5q33. Complete remissions have been observed with imatinib 400 mg/d in this uncommon subset of CMML patients.
C. Hypomethylating agents, including azacitidine or decitabine, have been reported to induce partial or complete remissions in 30% to 60% of CMML patients. An additional 10% to 20% of patients experience some hematologic improvement. The randomized trials of these drugs versus supportive care in MDS patients included small numbers of CMML patients. These studies demonstrated a superior response rate and progression-free survival for study patients treated with hypomethylating agents versus best supportive care.
Indications for treatment include high-risk disease (CMML-2) to prevent AML evolution, or cytopenias that are severe or unresponsive to supportive care measures. The drugs should be dosed as for MDS, and at least three to four cycles should be given before assessing response, unless there is evidence of progressive disease. Treatment is typically continued for as long as there is clinical benefit. There appears to be little long-term toxicity other than myelosuppression.
D. Hydroxyurea can be used to reduce the leukocytosis or splenomegaly in CMML, but it does not induce remissions.
E. Induction chemotherapy, as for acute myeloid leukemia, should be reserved for disease progression as it has not been shown to improve survival.
F. Erythropoiesis-stimulating agents may be considered for patients with low-risk disease (bone marrow blasts <5%) and symptomatic anemia. As in MDS, a serum erythropoietin level of <200 U/L and minimal or absent transfusion requirements are associated with a higher likelihood of response.
G. Blood product transfusions are standard supportive care measures in CMML patients with symptomatic anemia and/or thrombocytopenia.
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