Chapter 47: The Chronic Myelogenous Leukemias

• BCR-ABL-positive chronic myelogenous leukemia (CML) results from a somatic mutation in a pluripotential lymphohematopoietic cell.

• CML is characterized by granulocytic leukocytosis, granulocytic immaturity, basophilia, anemia, and often thrombocytosis in the blood, intense leukemic granulocytic precursor expansion in the marrow, and splenomegaly.

• The natural history of the disease is to evolve into an accelerated phase in which cytopenias develop and response to chronic phase therapy is lost; it often terminates in acute leukemia.

• Exposure to high-dose ionizing radiation increases the incidence of CML, with a mode of increased incidence that ranges from 4 to 11 years in different exposed populations.

Genetic Abnormality

• CML is the result of an acquired genetic abnormality that induces a malignant transformation of a single pluripotential lymphohematopoietic cell.

• The proximate cause is a translocation between chromosome 9 and 22 [t(9;22)]. This alteration juxtaposes a portion of the ABL protooncogene from chromosome 9 to a portion of the BCR gene on chromosome 22.

• The resulting gene fusion, BCR-ABL, creates an oncogene that encodes an elongated protein tyrosine phosphokinase (usually p210) that is constitutively expressed. This mutant protein disrupts cell signal pathways and results in the malignant transformation.

• The genetic alteration is present in erythroid, neutrophilic, eosinophilic, basophilic, monocytic, megakaryocytic, and marrow B- and T-lymphocytic cells, consistent with its origin in a pluripotential cell.

• The Philadelphia (Ph) chromosome specifically refers to chromosome 22 with a shortened long arm and is evident by light microscopy of cell metaphase preparations in approximately 90 percent of cases. Fluorescence in situ hybridization (FISH) can identify the fusion BCR-ABL gene in approximately 95 percent of cases.

Hematopoietic Abnormalities

• There is a marked expansion of granulocytic progenitors and a decreased sensitivity of the progenitors to regulation resulting in an inexorable increase in white cell count.

• Megakaryocytopoiesis is often expanded. Erythropoiesis is usually moderately deficient.

• Function of the neutrophils and platelets is nearly normal; infection and bleeding are not a feature of the chronic phase.

• CML accounts for approximately 15 percent of all cases of leukemia and approximately 3 percent of childhood leukemias.

• Males are affected at approximately 1.5 times the rate of females.

• The age-specific incidence rate increases exponentially from late teen age (0.2 cases/100,000) to octogenarians (10 cases/100,000).

• Familial occurrence is vanishingly rare, and there is no concordance in identical twins.

• Neither chemical agents, including benzene, cytotoxic drugs, nor combusted tobacco smoke have a causal relationship with CML.

• Approximately 30 percent of patients are asymptomatic at the time of diagnosis. The disease is discovered coincidentally when an elevated white count is noted at a medical evaluation.

• Symptoms are gradual in onset and may include easy fatigability, malaise, anorexia, abdominal discomfort and early satiety, weight loss, and excessive sweating.

• Less frequent symptoms are those of hypermetabolism, such as night sweats, heat intolerance, and weight loss, mimicking hyperthyroidism; gouty arthritis; priapism, tinnitus, or stupor from leukostasis as a consequence of hyperleukocytosis; left upper-quadrant and left shoulder pain because of splenic infarction; diabetes insipidus; and urticaria as a result of histamine release.

• Physical signs may include pallor, splenomegaly, and sternal tenderness.

Blood Findings

• The hemoglobin concentration is decreased in most patients at the time of diagnosis. Occasional nucleated red cells can be seen on the stained blood film. Rare patients may have a normal or slightly increased hematocrit at the time of presentation.

• The leukocyte count is elevated, usually above 25 × 10⁹/L, and often above 100 × 10⁹/L (see Fig. 47–1). Granulocytes at all stages of development are present in the blood, but segmented and band neutrophils predominate (see Table 47–1 and Fig. 47–2). Hypersegmented neutrophils are often present.

• An increase in the absolute basophil count is found in virtually all patients. Basophils usually comprise less than 10 percent of leukocytes in the chronic phase, but occasionally make up a higher proportion. The absolute eosinophil count may also be increased.

• The platelet count is normal or increased at diagnosis but may increase during the course of the chronic phase, sometimes reaching 1000 × 10⁹/L and uncommonly as high as 5000 × 10⁹/L (see Fig. 47–1).

• Neutrophil alkaline phosphatase activity is low or absent in over 90 percent of patients. It may also be low in paroxysmal nocturnal hemoglobinuria, hypophosphatasia, with androgen therapy, and in about 25 percent of patients with primary myelofibrosis. It has been largely replaced as a diagnostic marker by cytogenetic and molecular analysis (see below).

• Whole blood histamine is markedly increased (mean = 5000 ng/mL) compared with normal levels (mean = 500 ng/mL) and is correlated with the absolute basophil count. Occasional cases of pruritus, urticaria, and gastric hyperacidity occur.

Marrow Findings and Cytogenetics

• The marrow is markedly hypercellular, primarily because of granulocytic hyperplasia. Megakaryocytes may be increased in number. Occasionally, sea-blue histiocytes and macrophages engorged with glucocerebroside from exaggerated cell turnover may be present. The latter cells mimic the appearance of Gaucher cells (pseudo-Gaucher cells).

• Reticulin fibrosis rarely is prominent in the marrow and is correlated with the expansion of megakaryocytes.

• The Ph chromosome is present in metaphase preparations of marrow cells in approximately 90 percent of patients. Some of the remaining patients have variant or cryptic translocations (see Fig. 47–3). FISH identification of BCR-ABL fusion and reverse transcriptase polymerase chain reaction (RT-PCR) to detect BCR-ABL mRNA transcripts are the two most sensitive diagnostic tests used.

• Molecular evidence of the BCR-ABL fusion gene is present in the blood and marrow cells of virtually all patients (95%) with apparent CML. The remainder has a phenotype indistinguishable from CML but no evidence of BCR-ABL (see later section "Philadelphia Chromosome-Negative CML").

Serum Findings

• Hyperuricemia and hyperuricosuria are frequent.

• Serum lactic acid dehydrogenase activity is elevated.

• Serum vitamin B₁₂-binding protein and serum vitamin B₁₂ levels are increased in proportion to the total leukocyte count.

• Pseudohyperkalemia may be a result of the release of potassium from granulocytes in clotted blood, and spurious hypoxemia and hypoglycemia may result from cellular utilization in blood under laboratory analysis.

Hyperleukocytosis

• Approximately 15 percent of patients present with leukocyte counts of 300 × 10⁹/L (see Fig. 47–1) or higher and may have signs and symptoms of leukostasis from impaired microcirculation in the lungs, brain, eyes, ears, or penis.

• Patients may have tachypnea, dyspnea, cyanosis, dizziness, slurred speech, delirium, stupor, visual blurring, diplopia, retinal vein distention, retinal hemorrhages, papilledema, tinnitus, impaired hearing, or priapism.

Ph Chromosome-Positive or BCR-ABL-Positive Thrombocythemia

• Some patients (approximately 5%) present with the features of essential thrombocythemia (elevated platelet count and megakaryocytosis in marrow without significant change in hemoglobin or white cell count) but have the Ph chromosome and BCR-ABL fusion gene or no Ph chromosome but a BCR gene rearrangement.

• These patients later develop clinical CML or blast crisis. This presentation is considered a forme fruste of CML.

Neutrophilic CML

• This is a rare variant of BCR-ABL-positive CML in which the leukocytosis is composed of mature neutrophils.

• The white cell count is lower on average (30 to 50 × 10⁹/L), blood basophilia and myeloid immaturity are absent, and splenic enlargement may not be evident.

• These patients have an unusual breakpoint in the BCR gene between exons 19 and 20, which leads to a larger BCR-ABL fusion oncoprotein (230kDa compared to the classic 210 kDa fusion protein).

• This variant tends to have an indolent course, perhaps because of the very low levels of p230 in the cells.

Minor-BCR Breakpoint-Positive CML

• This variant of CML has the BCR breakpoint at the first intron, resulting in a 190 kDa BCR-ABL fusion protein compared with the classic 210 kDa fusion protein. In this variant, the white cell count is lower on average, monocytosis is seen, and basophilia and splenomegaly are less prominent.

• This variant usually progresses to acute leukemia more rapidly on average than in classical CML.

• The diagnosis of CML is made on the basis of neutrophilic granulocytosis with some immature cells (promyelocytes, myelocytes), basophilia, and splenomegaly, coupled with detection of the Ph chromosome and/or the BCR-ABL fusion gene.

• Polycythemia vera is usually distinguished by the elevated hemoglobin concentration, white cell count less than 25 × 10⁹/L, and absence of myeloid immaturity in the blood film.

• Primary myelofibrosis has distinctive red cell morphologic changes (poikilocytosis, anisocytosis, and teardrop red cells), invariable splenomegaly, and usually intense reticulin fibrosis on marrow biopsy.

• Essential thrombocythemia rarely has a white cell count greater than 25 × 10⁹/L.

• In each of the other chronic clonal myeloid diseases, the absence of BCR rearrangement is a key distinction from CML.

• Extreme reactive leukocytosis (leukemoid reaction) may occur in patients with an inflammatory disease, cancer, or infection but is not associated with basophilia, significant granulocytic immaturity, or splenomegaly. The clinical setting usually distinguishes a leukemoid reaction. BCR gene rearrangement is absent.

Hyperuricemia

• Most patients have massive expansion and turnover of blood cells with accompanying hyperuricemia or the risk of hyperuricemia with therapeutic cytoreduction.

• Patients can receive allopurinol, 300 mg/day orally, and adequate hydration before and during therapy to control exaggerated hyperuricemia and hyperuricosuria. It takes several days to lower the uric acid level. Discontinue the drug when uric acid is under control to minimize toxicity, especially skin rashes.

• Rasburicase, a recombinant urate oxidase, is effective in hours but is given intravenously and is more expensive. The manufacturer recommends 5 days of use but that is usually unnecessary to lower the uric acid sufficiently. If the uric acid is very high (e.g., > 9 mg/dL), a single dose of 0.2 mg/kg of ideal body weight can be used with allopurinol on successive days for about 36 hours.

Hyperleukocytosis

• If the white cell count is very high > 300 × 10⁹/L and especially if signs of hyperleukocytosis are present, hydroxyurea, 1 to 6 mg/day depending on the height of the white cell count may be used initially. The dose is decreased as the count decreases and is usually at about 1 g/day when the leukocyte count reaches 20 × 10⁹/L.

• If needed, maintenance doses should be adjusted to keep the total white count at about 5 to 10 × 10⁹/L.

• Blood counts should be followed and the drug should be stopped if the white count falls to 5 × 10⁹/L or less.

• The major side effect of hydroxyurea is suppression of hematopoiesis, often with megaloblastic erythropoiesis.

• Hyperleukocytosis usually responds rapidly to hydroxyurea but, if necessary, because of compelling signs of hyperleukocytosis (e.g., stupor, priapism), leukapheresis can be instituted simultaneously. Leukapheresis removes large numbers of cells minimizing the metabolic effects of tumor lysis (e.g., exaggerating hyperuricemia, hyperphosphatemia) while hydroxyurea is killing and retarding production of leukemic cells.

Thrombocytosis

• In the uncommon circumstance in which thrombocytosis is so prominent that early platelet reduction therapy is warranted, hydroxyurea or anagrelide can be used.

Tyrosine Kinase Inhibitor Therapy

• Recent studies indicate either nilotinib or dasatinib has a significant, approximately 15 percent, increase in cytogenetic and molecular response and a more rapid response on average when compared to imatinib mesylate. Either of these two drugs has become favored as initial therapy. If a patient has had an excellent molecular response on imatinib mesylate it is reasonable to continue that therapy. It is too early to be absolutely certain that the long-term results will mimic that of imatinib but the probability is sufficiently high to use these second generation agents as initial therapy because of their improved initial effects.

• Patients with newly diagnosed CML should be started on a tyrosine kinase inhibitor (TKI). Three choices are approved by the FDA at this time. Dasatinib, 100 mg/day orally, nilotinib, 300 mg every 12 hours, orally, or imatinib mesylate (imatinib) 400 mg/day, orally. In cases with hyperleukocytosis, white cell reduction should precede start of a TKI to lower the risk of tumor lysis syndrome (see above "Hyperleukocytosis")

• The efficacy of a TKI is measured by three indicators of response: hematologic, cytogenetic, and molecular (see Table 47–2).

• The criteria for assessing the response to a TKI are shown in Table 47–3.

• As long as a patient is having continued reduction in the size of the leukemic clone as judged by cytogenetic or molecular measurements, the TKI is continued at the same dose.

• If the patient stops responding before a complete cytogenetic or complete molecular remission occurs, the dose may be increased and/or an alternative second generation TKI should be considered (nilotinib or dasatinib).

• Imatinib is generally well tolerated. The main side effects are fatigue, edema, nausea, diarrhea, muscle cramps, and rashes. Severe periorbital edema is occasionally observed. Hepatotoxicity occurs in about 3 percent of patients. There are numerous other uncommon side effects. The principal side effects of dasatinib include cytopenias and fluid retention, notably pleural effusion. The side effects of nilotinib include rash, hypergylcemia, increased serum lipase and amylase (pancreatitis), transaminitis, and hypophospatemia.

• Neutropenia and thrombocytopenia may occur early in TKI use. Dose reduction for side effects is not recommended. If absolutely necessary, cessation may be required. Often, the mild cytopenias improve with continued therapy.

• Guidelines to judge the response to a TKI based on duration of treatment is shown in Table 47–3. Continued response can be quite prolonged, stretching over several years.

• TKIs may be teratogenic. Women in the child-bearing age group can (a) use contraception during therapy, (b) use interferon-α until delivery if pregnant when diagnosed and then be placed on a TKI, or (c) if in a complete molecular remission, could have TKI therapy stopped until she conceives and be restarted after delivery.

• Leukapheresis may be useful as sole treatment in patients in early pregnancy when it may be necessary to control the white cell count and splenic enlargement without chemotherapy.

• In the case of TKI intolerance or resistance, the alternative second generation TKI can be tried: dasatinib, 100 mg/day, or nilotinib, 400 mg twice per day.

• Failure of TKI therapy during the course of the disease is often the result of a mutation in the ABL portion of BCR-ABL, which interferes with drug action.

• There are several mutations than can induce TKI resistance. Thus, PCR is impractical as a tool to find mutations. It is possible to sequence ABL and, by comparing the results to known mutations, determine the likelihood that a dasatinib-sensitive or nilotinib-sensitive mutation may be present.

• If the T315I ABL mutation is found, allogeneic hematopoietic stem cell transplantation should be considered for eligible patients because that mutation is resistant to imatinib, nilotinib, and dasatinib. Third generation TKI inhibitors entering trial may be available for this situation in the future.

Other Drugs

• Under special circumstances several other second-line drugs can be considered: interferon-α, homoharringtonine, cytarabine, busulfan, and others. These are discussed in Williams Hematology, 8th ed, Chap. 90, p. 1348.

Allogeneic Hematopoietic Stem Cell Transplantation

• Transplantation has decreased markedly in frequency in chronic phase CML because of the very favorable prognosis of those treated with tyrosine kinase inhibitors who achieve a complete cytogenetic remission.

  — Should be considered in patients (a) who are eligible after all signs of continued improvement on tyrosine kinase inhibitors have stopped and a complete cytogenetic remission has not been achieved, (b) who are intolerant to tyrosine kinase inhibitors, or (c) who show progression of disease after using several tyrosine kinase inhibitors.

  — The early mortality rate in younger patients (younger than 40 years of age) without comorbid conditions is approximately 15 percent.

  — Engraftment and 5-year survival can be achieved in approximately 60 percent of patients in chronic phase, and some patients are cured. In patients over 50 years of age, the 5-year survival is somewhat decreased.

  — Some patients die of severe graft-versus-host disease and opportunistic infection in the first 5 years after transplant.

  — There is a 20 percent chance of relapse of CML in the 6 years after apparently successful transplant.

  — Donor T lymphocytes play an important role in successful suppression of the leukemia by initiating a graft-versus-leukemia reaction.

  — Disease status can be monitored by FISH (BCR-ABL fusion) or RT-PCR (BCR-ABL mRNA transcripts).

  — Donor lymphocyte infusion can produce remission in transplanted patients who have relapse of their disease. Ten million mononuclear cells/kg body weight may be sufficient to induce a graft-versus-leukemia effect and a remission. Response rates to this treatment may be as high as 80 percent.

Radiation or Splenectomy

• Patients with marked splenomegaly and splenic pain or encroachment on the gastrointestinal tract who do not respond to drug therapy may benefit transiently from splenic radiation. Marked splenomegaly usually associated with acute transformation of the disease.

• Patients with focal extramedullary myeloid sarcomas with pain may benefit from local radiation.

• Splenectomy is of limited value but may be helpful in some patients, such as those with thrombocytopenia and massive splenomegaly, refractory to therapy. Postoperative complications are frequent.

• The median survival has been greatly prolonged with tyrosine kinase inhibitors.

• As many as 90 percent of patients tolerant to TKIs may achieve a complete cytogenetic remission after 5 years of treatment.

• In a major study, the 7-year overall survival was 86 percent in those able to be maintained on imatinib. This finding may be improved with the use of second generation TKIs, nilotimib and dasatinib. Third generation TKIs are entering trials.

• Table 47–4 provides guidelines for monitoring patients in chronic phase of CML being treated with tyrosine kinase inhibitors.

• Table 47–5 provides the relative 5-year survival by age at diagnosis.

• A report of patients in CMR treated with imatinib with undetectable BCR-ABL transcripts (>5 log reduction) in whom imatinib therapy was stopped indicated that approximately 40 percent may have enduring remissions off TKI treatment. Importantly, those that relapsed were successfully retreated with imatinib.

• The natural history of CML is for patients to eventually become resistant to therapy at which point the disease enters a more aggressive phase characterized by severe dyshematopoiesis, refractory splenomegaly, extramedullary tumors, and, often, development of a clinical picture of acute leukemia—the "blast crisis."

• Although this evolution occurs in patients who are resistant or intolerant to tyrosine kinase inhibitors, the frequency per unit time has decreased markedly as a result of the prolonged remissions induced by these agents. It may take another decade to determine the rate of this event in persons who enter a complete cytogenetic remission after imatinib or its congeners and whether the nature of the accelerated phase mimics the one we have observed over the last 150 years.

• The Ph chromosome and BCR gene rearrangement persist in myeloid or lymphoid blasts in the accelerated phase, but additional chromosomal abnormalities often develop, such as trisomy 8, trisomy 19, isochromosome 17, or gain of a second Ph chromosome, and characteristic molecular genetic changes have been identified.

Clinical Features

• Unexplained fever, night sweats, weight loss, malaise, arthralgias.

• Development of new extramedullary sites of disease containing Ph chromosome-positive blast cells.

• Diminished responsiveness to previously effective drug therapy.

Laboratory Findings

Blood Findings

• Progressive anemia with increasing anisocytosis and poikilocytosis, increased numbers of nucleated red cells.

• An increasing proportion of blasts in the blood or marrow, which may reach 50 to 90 percent at the time of blastic crisis.

• Increase in the percentage of basophils (occasionally to levels of 30 to 80 percent).

• Appearance of hyposegmented neutrophils (acquired Pelger-Huët abnormality).

• Thrombocytopenia.

Marrow Findings

• Marked dysmorphic changes may be seen in any or all cell lineages, or florid blastic transformation may occur.

Blast Crisis

• Extramedullary blast crisis is the first sign of the accelerated phase in about 10 percent of patients. Lymph nodes, serosal surfaces, skin, breast, gastrointestinal or genitourinary tracts, bone, and the central nervous system are most often involved.

• Central nervous system involvement is usually meningeal. Symptoms and signs are headache, vomiting, stupor, cranial nerve palsies, and papilledema. The spinal fluid contains cells, including blasts, and the protein level is elevated.

• Acute leukemia develops in most patients in the accelerated phase. It is usually myeloblastic or myelomonocytic, but may be of any cell type.

• About one-third of patients develop acute lymphoblastic leukemia (ALL), with blast cells that contain terminal deoxynucleotidyl transferase, an enzyme characteristic of ALL, and surface markers typical of B cells.

Treatment of Patients with AML Phenotype

• Acute myelogenous leukemic transformation (any subtype can occur) is essentially incurable with chemotherapy presently available.

• The strategy that is most likely to result in a prolonged remission is allogeneic hematopoietic stem cell transplantation, albeit with a low long-term remission rate. Thus, drug therapy, in patients eligible for transplantation, is focused on a remission sufficiently long to accomplish transplantation in that state.

• One can start with dasatinib, 140 mg/day or 70 mg q 12 h or nilotinib, 400 mg q 12 hours, and then the alternative drug if the response is inadequate. Reports of good remissions with one but not another tyrosine kinase inhibitor have been observed. Remission or reversion to chronic phase usually are short-lived and allogeneic hematopoietic stem cell transplantation from a histocompatible donor should be urgently considered for eligible patients.

• Tyrosine kinase therapy can be combined with mitoxantrone plus etoposide or cytarabine (an AML drug protocol) depending on patient's ability to tolerate such an approach (see Chap. 46).

Treatment of Patients with Acute Lymphocytic Leukemia Phenotype

• Start with dasatinib, 140 mg/day or 70 mg q 12 h or nilotinib, 400 mg q 12 h. If remission ensues, consider allogeneic stem cell transplantation if patient is eligible and a donor is available. These TKIs can induce remissions in the lymphoblastic acute leukemia crisis.

• If relapse after a TKI, consider ALL drug protocol such as vincristine sulfate, 1.4 mg/m² (to a maximum of 2 mg/dose) intravenously once per week, and prednisone, 60 mg/m² per day orally. A minimum of 2 weeks of therapy should be given to judge responsiveness.

• About one-third of patients will reenter the chronic phase with this treatment, but the median duration of remission is about 4 months, and relapse should be expected. Since acute lymphocytic blast crisis occurs in about 30 percent of cases, a 30 percent response represents about 9 percent of all patients entering ALL blast crisis.

• The response rate may be improved by more intensive therapy, similar to that used in de novo ALL, but not dramatically so. Most patients do not respond to repeat therapy.

• Allogeneic hematopoietic stem cell transplantation from a histocompatible donor may lead to prolonged remission in blast crisis. Thus, eligible patients who enter remission with therapy should be strongly considered for transplantation.

• Philadelphia chromosome-positive AML appears, in some cases, to be instances of CML, presenting in myeloid blast crisis, while other cases appear to be unrelated to CML.

• Philadelphia chromosome-positive ALL represents about 3 percent of cases of childhood ALL and 20 percent of cases of adult ALL.

• In both adults and children, the prognosis is worse for those patients with leukemic cells containing the Ph chromosome.

• Some Ph chromosome-positive ALL patients have the same size BCR-ABL fusion oncoprotein (p210) that characterize CML and are believed to be patients with CML presenting in lymphoid blast crisis. The remaining patients have a p190 fusion protein and are thought to have de novo ALL.

• Treatment generally combines a tyrosine kinase inhibitor, as used for CML blast crisis, with intensive therapy for AML or ALL as described in Chaps. 46 and 55, respectively.

Chronic Myelomonocytic Leukemia

• Approximately 75 percent of cases are over 60 years of age at onset (Table 47–6).

• Male:female ratio 1.4:1.

• Onset insidious with weakness, exaggerated bleeding, fever, and infection most common.

• Hepatomegaly and splenomegaly occur in about 50 percent.

• Usually anemia and monocytosis (>1.0 × 10⁹/L) are present; less than 10 percent of cells in blood are myeloblasts.

• White cell count may be decreased, normal, or elevated and can reach levels of over 200 × 10⁹/L.

• Marrow is hypercellular, with granulomonocytic hyperplasia.

• Myeloblasts and promyelocytes are increased but are less than 30 percent of cells in marrow.

• Approximately one-third of patients have an overt cytogenetic abnormality (e.g., monosomy 7, trisomy 8).

• Plasma and urine lysozyme concentrations are nearly always elevated.

• RAS gene mutations are frequent.

• Includes most cases of so-called Philadelphia chromosome-negative, BCR rearrangement-negative CML.

• A small percentage of patients have a translocation fusing the PDGFR-β gene with one of several gene partners (e.g., TEL). These cases may be associated with prominent eosinophilia.

• Several prognostic variables have been identified. Among the most compelling are height of blast cell count, severity of anemia, serum LDH, and spleen size at time of diagnosis.

• Median survival is approximately 12 months with a range of 1 to 60.

• Approximately 20 percent of patients progress to overt AML.

Treatment

• No standard or highly successful therapy has been developed. See Williams Hematology, 8th ed, Chap. 90, p.1356.

• Low-dose cytosine arabinoside, hydroxyurea, etoposide may induce occasional partial remissions for short periods of time (~0.5–1 year, usually).

• 5-Azacytidine or decitabine has resulted in improvement in some patients.

• Occasional patients with PDGFR-partner fusion oncogenes may respond to imatinib, 400 mg/day, orally.

• Other cytotoxic drugs, maturation-enhancing agents, interferons, and growth factors have been used.

• Marrow transplantation has yielded more favorable results than other therapies but the afflicted population has a median age of 70 years, making transplantation for most problematic.

Chronic Eosinophilic Leukemia

• A BCR-ABL negative chronic clonal myeloid disease manifest by prolonged exaggerated blood eosinophilia unexplained by parasitic or allergic disease.

• Fever, cough, weakness, easy fatigability, abdominal pain, maculopapular rash, cardiac symptoms, signs of heart failure, and a variety of neurologic symptoms may coexist in some combination.

• Eosinophilia is a constant finding. Anemia is often present. Platelet counts are normal or mildly decreased. Total white cell counts are normal or elevated in relationship to the degree of eosinophilia, which may be as high as 100 × 10⁹/L.

• Marrow examination reveals markedly increased eosinophilic myelocytes and segmented eosinophils. Reticulin fibrosis may be present.

• Many different cytogenetic abnormalities can be found. Notably a high frequency of translocations involving chromosome 5 occur.

• Immunophenotyping and PCR do not show evidence of clonal T-cell population or T-cell receptor rearrangement.

• Pulmonary function studies may be consistent with fibrotic lung disease.

• Echocardiography may detect mural thrombi, thickened ventricular walls, and valvular dysfunction

• Skin, neural, brain biopsy, if indicated, shows intense eosinophilic infiltrates.

• A subset of patients with elevated serum tryptase (> 11.5 ng/mL), intensely hypercellular marrow eosinophilia with a high proportion of immature eosinophils, high serum B₁₂ and IgE levels, more prone to pulmonary and endocardial fibrosis, the FIL1L1-PDGFR-α oncogene, are responsive to tyrosine kinase inhibitors (e.g., imatinib).

• In patients who are unresponsive to imatinib mesylate or its second generation congeners, should be considered for allogeneic hematopoietic stem cell transplantation if eligible and with an available donor.

• Other patients may be treated with glucocorticoids, hydroxyurea, anti-IL-5 antibodies in an effort to decrease the eosinophil count and ameliorate the eosinophil-induced deleterious tissue effects.

• If the patient is not imatinib-sensitive or eligible for transplantation, chronic eosinophilic leukemia is difficult to control. Occasional patients may progress to acute eosinophilic or myelogenous leukemia. Cardiac, pulmonary, and neurologic manifestations, if not stabilized, contribute to morbidity and mortality.

Juvenile Chronic Myelomonocytic Leukemia

• Occurs most often in children younger than 4 years of age.

• Twenty percent of patients have RAS mutations.

• Ten percent have neurofibromatosis and NF1 mutations.

• Infants have failure to thrive; children present with fever, malaise, persistent infection, and skin and nasal bleeding.

• Fifty percent of patients have eczematoid or maculopapular skin lesions.

• Nearly all patients have splenomegaly.

• Anemia, thrombocytopenia, and leukocytosis are common.

• The blood contains monocytes up to 100 × 10⁹/L; immature granulocytes, including blast cells; and nucleated red cells.

• Fetal hemoglobin concentration is increased in about two-thirds of the patients.

• The marrow shows granulocytic hyperplasia, with an increase in monocytes and leukemic blast cells.

• The disease has been refractory to chemotherapy. Four to six drug combinations have induced partial remissions in some patients and may extend survival although median survival is usually less than 36 months.

• Allogeneic hematopoietic stem cell transplantation can prolong survival, but cures, even with this approach, are few and far between.

• The median survival is less than 2 years, but occasional patients (usually infants) or massively treated patients survive for longer periods with the disease.

Chronic Neutrophilic Leukemia

• Characterized by a leukocyte count of 25,000 to 50,000/μL, with about 90 to 95 percent mature neutrophils.

• Neutrophil alkaline phosphatase activity is increased.

• Marrow shows granulocytic hyperplasia usually with a normal proportion of blasts.

• Ph chromosome and BCR gene rearrangement are absent.

• JAK2(V617F) mutation is present in a small proportion (~15 to 20%) of these patients.

• Liver and spleen are enlarged and are infiltrated with immature myeloid cells and megakaryocytes.

• There have been no systematic studies of treatment.

• Busulfan and hydroxyurea have been used with transient benefit.

• May terminate in typical AML.

• Median survival is 2 to 3 years.

Philadelphia Chromosome-Negative CML

• About 4 percent of patients with a phenotype indistinguishable from BCR-ABL-positive CML, do not have the Ph chromosome or BCR gene rearrangement on assiduous search.

• Median age is 66 years and ranges from 25 to 90 years.

• Median white cell count is lower (approximately 40 × 10⁹/L) but the range is wide (11 to 296 × 10⁹/L).

• The morphologic features in blood and marrow are characteristic of classic CML.

• Splenomegaly in only 50 percent at diagnosis.

• Disease progression marked by cytopenias. Median survival is 2 years and only 7 percent survive for more than 5 years.

• One-third of patients monitored until death developed AML.

• Occasional patients have extended complete responses to interferon-α. Hydroxyurea is often used to control the white cell count or decrease splenomegaly (palliative therapy).