Chapter 46: The Chronic Myelogenous Leukemias

• BCR-ABL1–positive chronic myelogenous leukemia (CML) results from a somatic mutation in a pluripotential lymphohematopoietic cell, yielding a fusion oncogene (BCR-ABL1).

• 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; either the chronic or accelerated phase can undergo further clonal evolution to acute leukemia.

• This natural history has been modified significantly by the introduction of inhibitors of the constitutive kinase activity of the BCR-ABL1 oncoprotein.

• Exposure to high-dose ionizing radiation increases the incidence of BCR-ABL1–positive CML, with a mode of increased incidence that ranges from 4 to 11 years in different exposed populations.

• Obesity may be an endogenous risk factor.

Genetic Abnormality

• BCR-ABL1–positive 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 proto-oncogene from chromosome 9 to a portion of the BCR gene on chromosome 22.

• The resulting gene fusion, BCR-ABL1, 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 lymphohematopoietic cell.

• The designation Philadelphia (Ph) chromosome specifically refers to chromosome 22 with a shortened long arm (22q-) and is evident by light microscopy of cell metaphase preparations in approximately 90% of cases. Fluorescence in situ hybridization (FISH) can identify the fusion BCR-ABL1 gene in approximately 96% of cases. Approximately 4% of cases with a blood and marrow phenotype indistinguishable from BCR-ABL1 CML do not have rearrangement in the BCR gene.

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 and decrease in hemoglobin concentration.

• 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.

• BCR-ABL1–positive CML accounts for approximately 15% of all cases of leukemia and approximately 3% of childhood leukemias in the United States.

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

• The age-specific incidence rate increases exponentially from late adolescence (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 has a causal relationship with CML.

• Approximately 30% of patients are asymptomatic at the time of diagnosis. The disease is discovered coincidentally when an elevated white cell 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 Figure 46–1). Granulocytes at all stages of development are present in the blood, but segmented and band neutrophils predominate (see Table 46–1 and Figure 46–2). Hypersegmented neutrophils are often present.

• An increase in the absolute basophil count is found in virtually all patients. Basophils usually constitute less than 10% 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 Figure 46–1).

• Neutrophil alkaline phosphatase activity is low or absent in more than 90% of patients. It may also be low in paroxysmal nocturnal hemoglobinuria, hypophosphatasia, with androgen therapy, and in about 25% 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% of patients. Some of the remaining patients have variant or cryptic translocations (see Figure 46–3). FISH identification of BCR-ABL1 fusion and reverse transcriptase polymerase chain reaction (RT-PCR) to detect BCR-ABL1 mRNA transcripts are the two most sensitive diagnostic tests used.

• Molecular evidence of the BCR-ABL1 fusion gene is present in the blood and marrow cells of virtually all patients (96%) with apparent CML. The remainder has a phenotype indistinguishable from CML but no evidence of BCR-ABL1 (see “Philadelphia Chromosome–Negative CML,” below).

Serum Findings

• Hyperuricemia (and hyperuricosuria) are frequent.

• Serum lactic acid dehydrogenase (LDH) 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% of patients present with leukocyte counts of 300 × 10⁹/L (see Figure 46–1) 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.

Philadelphia Chromosome–Positive or BCR-ABL1–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-ABL1 fusion gene or no Ph chromosome but a BCR-ABL1 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-ABL1–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-ABL1 fusion oncoprotein (230-kDa 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-ABL1 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-ABL1 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. Virtually all patients have a mutation in the JAK2 gene (see Chap. 41).

• Primary myelofibrosis has distinctive red cell morphologic changes (poikilocytosis, anisocytosis, and teardrop red cells), invariable splenomegaly, and usually reticulin fibrosis on marrow biopsy. Mutations in JAK2, CALR, or MPL are present in 85% of patients (see Chap. 47).

• Essential thrombocythemia rarely has a white cell count greater than 25 × 10⁹/L. JAK2 mutations are found in approximately 50% of patients and BCR-ABL1 is absent (see Chap. 42).

• In each of the other chronic clonal myeloid diseases, the absence of BCR-ABL1 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-ABL1 oncogene 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 should receive allopurinol, 300 mg/d 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 (eg, > 9 mg/dL), a single dose of 0.2 mg/kg of ideal body weight can be used with allopurinol on successive days for approximately 36 hours, dependent on response.

Hyperleukocytosis

• If the white cell count is very high (> 300 × 10⁹/L), especially if signs of hyperleukocytosis are present, hydroxyurea, 1 to 6 mg/d, 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 0.5 to 1 g/d 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 (eg, stupor, priapism), leukapheresis can be instituted simultaneously. Leukapheresis removes large numbers of cells minimizing the metabolic effects of tumor lysis (eg, 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. Plateletpheresis and hydroxyurea can be combined if there are acute vascular problems.

Tyrosine Kinase Inhibitor Therapy

• Any of three established tyrosine kinase inhibitors (TKIs) can be used for the initial treatment of CML: imatinib mesylate (imatinib), dasatinib, or nilotinib. These are administered orally. Although the latter two agents have a significant, approximately 15%, increase in cytogenetic and molecular response and a more rapid response on average when compared to imatinib mesylate, an advantage of the latter two agents, as judged by overall survival, has not been established. If a patient has had an excellent molecular response on imatinib, it is reasonable to continue that therapy. Because of the advantages projected for dasatinib or nilotinib, they are often used for initial therapy. A table summarizing the comparative features of imatinib, nilotinib, and dasatinib are shown in Table 46–2.

• Patients with newly diagnosed CML should be started on one of the TKIs. Dasatinib, 100 mg/d orally, nilotinib, 300 mg every 12 hours, orally, or imatinib 400 mg/day, orally, are approved by the US Food and Drug Administration. In cases with hyperleukocytosis, white cell reduction should precede the start of a TKI to lower the risk of tumor lysis syndrome (see “Hyperleukocytosis,” above).

• The efficacy of a TKI is measured by three indicators of response: hematologic, cytogenetic, and molecular (see Table 46–3).

• The guidelines for the tests used to measure the response to TKI therapy are shown in Table 46–4.

• The criteria for assessing the response to a TKI are shown in Table 46–5.

• 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 to a TKI before a complete cytogenetic or complete molecular remission occurs, the dose may be increased and/or an alternative TKI should be considered (eg, 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% 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, hyperglycemia, increased serum lipase and amylase (pancreatitis), transaminitis, and hypophosphatemia (see Table 46–2).

• 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.

• The definition of the response to TKI therapy is shown in Table 46–5. Duration of response may extend over years or decades.

• TKIs may be teratogenic. Women in the childbearing age group can (1) use contraception during therapy; (2) use interferon-α until delivery, if pregnant when diagnosed, and then be placed on a TKI; or (3) if in a complete molecular remission, could have TKI therapy stopped until conception and then be restarted after delivery.

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

• In the case of TKI intolerance or resistance, an alternative TKI can be tried.

• Failure of TKI therapy during the course of the disease is often the result of a mutation in the ABL portion of BCR-ABL1, which interferes with drug action.

• There are several mutations that 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 TKI-sensitive mutation may be present.

• If the T315I ABL mutation is found, ponatinib may be considered (see Table 46–2). Allogeneic hematopoietic cell transplantation, also, should be considered for eligible patients.

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, 9th ed, Chap. 89.

Allogeneic Hematopoietic 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.

  — It should be considered in patients (1) who are eligible after all signs of continued improvement on TKIs have stopped and a complete cytogenetic remission has not been achieved, (2) who are intolerant to TKIs, or (3) who show progression of disease after using several TKIs.

  — Patients younger than 70 years of age with an identical twin, a histocompatible sibling, or a histocompatible unrelated donor (matched using molecular methods) can be transplanted after intensive cyclophosphamide and fractionated total body radiation or a combination of busulfan and cyclophosphamide.

  — Older patients may be transplanted with reduced-intensity conditioning regimens.

  — Engraftment and 5-year survival can be achieved in approximately 60% of patients in chronic phase, and some patients are cured. In patients older than 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% 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-ABL1 fusion) or RT-PCR (BCR-ABL1 mRNA transcripts).

  — Donor lymphocyte infusion (DLI) 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% and can be durable. Graft-versus-host disease and severe myelosuppression are the principal toxic risks.

  — Post-transplant TKI therapy can be useful for patients who relapse, in patients in whom DLI does not provide benefit, and in patients felt to be at high-risk of relapse after transplantation because of advanced disease at time of transplant.

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 palliative splenic radiation. Marked splenomegaly is 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% 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% in those able to be maintained on imatinib. This finding may be improved with the use of second-generation TKIs, nilotinib and dasatinib.

• Table 46–6 provides the relative 5-year survival by age at diagnosis.

• Patients in CMR treated with imatinib with undetectable BCR-ABL1 transcripts (more than five log reduction) in whom imatinib therapy was stopped indicated that some 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 enter a more aggressive phase of disease characterized by severe dyshematopoiesis, increasing 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 TKIs, 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 treatment with a TKI and whether the nature of the accelerated phase mimics the one we have observed over the past 150 years.

• The Ph chromosome and BCR-ABL1 oncogene 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, and arthralgias occur.

• New extramedullary sites of disease containing Ph chromosome-positive blast cells may develop.

• There is a diminished responsiveness to previously effective drug therapy.

Laboratory Findings

Blood Findings

• There is progressive anemia with increasing anisocytosis and poikilocytosis and increased numbers of nucleated red cells.

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

• The percentage of basophils increases (occasionally to levels of 30%–80%).

• Hyposegmented neutrophils appear (acquired Pelger-Huët abnormality).

• Thrombocytopenia occurs.

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% 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 leukemic 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 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 imatinib, 600 mg/d; dasatinib, 140 mg/d or 70 mg q12h; or nilotinib, 400 mg q12h. Then one should use the alternative drug if the response is inadequate. Good remissions with one but not another TKI have been observed. Remission or reversion to chronic phase usually is short-lived, and allogeneic hematopoietic cell transplantation from a histocompatible donor should be urgently considered for eligible patients.

• TKI 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. 45).

Treatment of Patients with Acute Lymphoblastic Leukemia Phenotype

• Start with dasatinib, 140 mg/d, or 70 mg q12h or nilotinib, 400 mg q12h. These TKIs can induce a remission in patients with an ALL phenotype. If remission ensues, consider allogeneic stem cell transplantation if patient is eligible and a donor is available.

• If relapse occurs 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 (see Chap. 54).

• 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. Because acute lymphocytic blast crisis occurs in about 30% of cases, a 30% response represents about 9% 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 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.

• Ph 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.

• Ph chromosome-positive ALL represents about 3% of cases of childhood ALL and 20% 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-ABL1 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 TKI, as used for CML blast crisis, with intensive therapy for AML or ALL, as described in Chaps. 45 and 54, respectively.

(Table 46–7)

Chronic Myelomonocytic Leukemia

• Approximately 75% of patients are older than 60 years of age at onset.

• The male-to-female ratio is 1.4:1.

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

• Hepatomegaly and splenomegaly occur in about 50% of cases.

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

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

• Marrow is hypercellular, with granulomonocytic hyperplasia.

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

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

• Plasma and urine lysozyme concentrations are nearly always elevated.

• Thirty-five percent of patients have N-RAS or K-RAS gene mutations.

• Thirty percent to 50% of patients have a SRSF2 mutation. The latter mutation frequently coincident with TET2 or EZH2 mutations.

• Other gene mutations include RUNX1, IDH1/2, CBL, JAK2, TET2, EZH2, and several more.

• The Ph chromosome and BCR-ABL1 are absent.

• More than 90% of patients have an identifiable mutated gene.

• A small percentage of patients have a translocation fusing the PDGFR-α gene with one of several gene partners (eg, 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% of patients progress to overt AML.

Treatment

• No standard or highly successful therapy has been developed. See Williams Hematology, 9th ed, Chap. 89.

• Low-dose cytosine arabinoside, hydroxyurea, etoposide may induce occasional partial remissions for short periods of time, measured in months usually.

• 5-Azacytidine or decitabine has resulted in improvement in a minority of patients.

• Occasional patients with PDGFR-partner fusion oncogenes can respond to imatinib, 400 mg/d, orally or an alternative TKI. A TKI may result in a hematological, cytogenetic, and molecular remission.

• 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

• This BCR-ABL1–negative chronic clonal myeloid disease is manifested 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. Occasional Charcot-Leyden crystals may be found. In patients with the FIP1L1-PDGFR-α mutation, spindle-shaped (neoplastic) mast cell aggregates are invariably present.

• Many different cytogenetic abnormalities can be found. Notably a high frequency of translocations involving chromosome 5 occur; for example, t(1;5) t(2;5), t(5;12), t(6;11), 8p11, trisomy 8, and infrequently others can be present. PDGFR-α, present on chromosome 5, is sometimes involved in the translocation.

• 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 dysfunctions.

• Skin, neural, and 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, and the FIL1L1-PDGFR-α oncogene, are responsive to TKIs (eg, imatinib).

  — This mutation can be found in approximately 15% of patients with eosinophilia unrelated to parasitic or allergic diseases. This mutation may be responsive to imatinib mesylate or its congeners.

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

• Other patients may be treated with glucocorticoids, hydroxyurea, or 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

• This occurs most often in infants and children younger than 4 years of age.

• Twenty percent of patients have RAS mutations.

• Ten percent have type 1 neurofibromatosis (400 times the expected frequency) and NF1 mutations.

• Somatic mutation in the PTPN11 gene occurs in one-third of affected children and chromosome abnormalities such as -7, del(7q) occur in approximately 20% of patients.

• The disease appears to be related, in part, to an increase in sensitivity of myeloid cells to the proliferative effects of granulocyte-monocyte colony-stimulating factor.

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

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

• Café-au-lait spots (neurofibromatosis type 1) may occur.

• Nearly all patients have splenomegaly, sometimes massive.

• Anemia, thrombocytopenia, and leukocytosis are common.

• The blood contains monocytosis of 1.0 to 100 × 10⁹/L, with immature granulocytes, including a low percentage of blast cells, and nucleated red cells.

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

• The marrow is hypercellular as a reflection of granulocytic hyperplasia, with an increase in monocytes and leukemic blast cells. Erythroblasts and megakaryocytes are decreased.

• The disease is refractory to chemotherapy. Four to six drug combinations (eg, cytarabine, etoposide, vincristine, and isotretinoin) have induced partial remissions in some patients and may extend survival, although median survival has been less than 30 months.

• Allogeneic hematopoietic cell transplantation can prolong survival, but cures, even with this approach, are difficult to achieve.

• A rapid search for a suitable donor (matched-related, matched-unrelated) is important.

• Allogeneic hematopoietic cell transplantation can achieve 5-year survivals of up to 50% in children up to 1 year of age and approximately 30% in children older than 1 year of age.

• Monosomy 7 is a poor prognostic indicator of transplantation results.

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

• A minority of children have a smoldering course and survive for approximately 2 to 4 years, with rare exceptions for as long as a decade.

• The disease may undergo clonal evolution to acute leukemia, usually myelogenous type.

Chronic Neutrophilic Leukemia

• A leukocyte count of 25 to 50 × 10⁹/L, with about 90% to 95% mature neutrophil is characteristic.

• Neutrophil alkaline phosphatase activity is increased.

• Serum vitamin B₁₂ and vitamin B₁₂-binding protein are markedly increased.

• Marrow shows granulocytic hyperplasia usually with a very low proportion of blasts (1%–3%). Rarely, dysmorphic features of neutrophils are evident (acquired Pelger-Hüet nuclear shape).

• Ph chromosome and BCR gene rearrangement are absent.

• Approximately 25% of patients have random clonal cytogenetic abnormality (eg, trisomy 9 or 21 or del(20q)).

• CSF3R and SETBP1 gene mutations, either, alone or combined, occur in 60% of patients. A JAK2 V617F mutation is present in about 10% of patients.

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

• A concordance with essential monoclonal gammopathy or myeloma has been noted.

• The neoplasm is rare, and no systematic studies of treatment are available.

• Hydroxyurea and cytarabine have been used with transient benefit.

• An inhibitor of JAK2 (eg, ruxolitinib) may be useful in cases with either a JAK2 mutation or a CSF3R T618I mutation, and a TKI (eg, dasatinib) may be useful in those with a CSF3R S783Fs mutation.

• Allogeneic hematopoietic cell transplantation may be curative.

• The condition may terminate in typical AML.

• Survival is usually 0.5 to 6.0 years (median 2.5 years).

Philadelphia Chromosome–Negative CML

• About 4% of patients with a phenotype indistinguishable from BCR-ABL1–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% at diagnosis.

• Disease progression marked by cytopenias. Median survival is 2 years, and only 7% 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).

Atypical Myeloproliferative Disease (Atypical CML)

• This disorder usually occurs in older patients (60 to 90 years).

• It does not meet the criteria for a classical myeloproliferative disease (eg, CML, CMML, polycythemia vera, essential thrombocythemia, myelodysplastic syndrome).

• It does not have classical translocation such as that involving BCR, PDGFRα, and so on.

• Hepatomegaly or splenomegaly are infrequent.

• Serum LDH may be elevated.

• Anemia and granulocytosis are very common, including a low proportion of immature granulocytes, but with a very low blast count (< 5.0%). Monocytes are not increased.

• Marrow is usually hypercellular with a low blast count (typically < 10%).

• Neutrophilic dysmorphia may be present (eg, acquired Pelger-Hüet anomaly).

• Clonal cytogenetic abnormalities, if present, are random (eg, trisomy 8, del(20q); assorted others).

• There is no specific therapy. Azacytidine or hydroxyurea (if hyperproliferative) may be used with variable results. Red cell and platelet transfusion are necessary as required.

• In a suitable patient with an appropriate donor, allogeneic hematopoietic cell transplantation can be considered (nonmyeloablative or ablative).

• Median survival is approximately 18 months, but longer survival with palliative therapy can occur.

• Clonal evolution to acute myelogenous leukemia can occur.