The Bethesda Handbook of Clinical Oncology

Aaron T. Gerds and Mikkael A. Sekeres

INTRODUCTION

Acute leukemia represents a very aggressive, malignant transformation of an early hematologic precursor. The malignant clone is arrested in an immature blast form, proliferates abnormally, and no longer has the ability to undergo maturation. In contrast, the chronic leukemias are characterized by resistance to apoptosis and by accumulation of nonfunctional cells, with the emphasis on proliferation, in contrast to the block in differentiation seen with acute leukemias. Accumulation of the blasts within the bone marrow results in progressive hematopoietic failure, with associated infection, anemia, and thrombocytopenia. These are the complications that often prompt evaluation in newly diagnosed patients.

Acute leukemia continues to be a grave diagnosis because of its rapid clinical course. Patients, particularly those who are younger, require aggressive and urgent evaluation and treatment initiation. As a general rule, treatment is expected to improve quality of life and prolong survival. Unfortunately, many patients present at an advanced age and with comorbid conditions, making cytotoxic approaches difficult. Older or unwell patients who are given the best supportive care survive for a median of only a few months.

The immature, clonally proliferating cells that form blasts are derived from myeloid or lymphoid cell lines. Transformation of granulocyte, RBC, or platelet (myeloid) precursors results in acute myeloid (myelogenous) leukemia (AML). Acute lymphoblastic (lymphocytic) leukemia (ALL) originates from B or T lymphocytes. This general division has implications for different treatment and diagnostic approaches. It is the first step in classifying the leukemic process occurring in the patient.

EPIDEMIOLOGY

Estimated new cases in the United States in 2016 are 19,950 for AML (1.2% of all new cancer cases) and 6,590 for ALL (0.4% of all new cancer cases).

AML accounts for 10,430 deaths and ALL accounts for 1,430 deaths annually in the United States.

The risk of developing AML increases with advanced age, the median age being 67 years.

Seventy-five percent of newly diagnosed patients with AML are older than 60 years.

ALL is more common in children; 60% to 70% are diagnosed in patients younger than 20 years.

TABLE 23.1 Risk Factors for Acute Leukemia

Exposure

Ionizing radiation, benzene, cytotoxic drugs, alkylating agents, cigarette smoking, ethanol use by the mother

Acquired disorders

Myelodysplastic syndrome, paroxysmal nocturnal hemoglobinuria, polycythemia vera, chronic myelogenous leukemia, myeloproliferative disorders, idiopathic myelofibrosis, aplastic anemia, eosinophilic fasciitis, myeloma, primary mediastinal germ cell tumor (residual teratoma elements evolve into myeloid progenitors that evolve into AML years later)

Genetic predisposition

Down syndrome, Fanconi anemia, Diamond-Blackfan anemia, Kostmann syndrome, Klinefelter syndrome, chromosome 21q disorder, Wiskott-Aldrich syndrome, ataxia-telangiectasia, dyskeratosis congenita, combined immunodeficiency syndrome, von Recklinghausen disease, neurofibromatosis 1, Shwachman syndrome

Familial

Nonidentical sibling (1:800), monozygotic twin (1:5), first-degree relative (three times increased risk)

Infection

Human T-cell leukemia virus and T-cell ALL

AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia.

RISK FACTORS

Most patients will have no identifiable risk for developing acute leukemia. Table 23.1 lists the conditions that are associated with an increased risk for developing acute leukemia. Most epidemiologic studies have evaluated the relationship between the risk factors and AML. The conditions that are most commonly associated with AML are chemotherapy or radiation therapy for other cancers (which account for >90% of therapy-related AML), followed by environmental exposures, such as chronic benzene exposure or exposure to ionizing radiation.

Ionizing Radiation Exposure Explored in Atomic Bomb Survivors

Ionizing radiations have a latency period of 5 to 20 years and a peak period of 5 to 9 years in atomic bomb survivors.

They exhibit a 20- to 30-fold increased risk of AML and chronic myelogenous leukemia (CML).

Chemotherapy

Therapy-related AML may account for 10% to 20% of new cases.

Leukemia associated with alkylating agents may be associated with cytogenetic changes of chromosomes 5, 7, and 13. Often there is a multiyear, latent-phase myelodysplastic syndrome preceding the development of AML.

Topoisomerase II agents, often with an abnormal chromosome 11q23 in the blasts, can rapidly evolve after initial therapy, at a median of 2 years following exposure.

Previous, high-dose therapy with autologous transplant leads to a cumulative risk of 2.6% by 5 years, especially with total body irradiation (TBI)-containing regimens.

CLINICAL SIGNS AND SYMPTOMS

Ineffective hematopoiesis: Results from marrow infiltration by the malignant cells and a block in differentiation

Anemia: Pallor, fatigue, and shortness of breath, rarely myocardial infarction or stroke

Thrombocytopenia: Epistaxis, petechiae, and easy bruising

Neutropenia: Fever and pyogenic infection

Infiltration of other organs

Skin: Leukemia cutis in 10%

Gum hypertrophy: Especially in monocytic leukemias

Myeloid (granulocytic) sarcoma: Localized tumor composed of blast cells; <1% will present with prominent extramedullary disease; imparts poorer prognosis; occasionally associated with chromosome 8; 21 translocation; approach to treatment is the same as with overt bone marrow involvement with AML

Enlarged liver, spleen, and lymph nodes: Common in ALL, occasionally in monocytic leukemia

Thymic mass: Present in 15% of ALL in adults

Testicular infiltration: Also a site of relapse for ALL (sanctuary site)

Retinal involvement

Central nervous system (CNS) and meningeal involvement

5% to 10% of ALL cases at diagnosis; <5% AML, associated with inv (16), high blast count, or myeloid sarcoma abutting spine

Cerebrospinal fluid (CSF) analysis and prophylaxis are given in every patient with ALL to decrease CNS relapse

Symptoms: Headache and cranial nerve palsy, but mostly asymptomatic

Disseminated intravascular coagulation (DIC) and bleeding

Common with acute promyelocytic leukemia (APL) or other AML with blasts whose cytoplasms contain granules; the mechanism is related to tissue factor release by granules and fibrinolysis; generally improves with all-trans retinoic acid (ATRA, for APL only), the early initiation of which is imperative

Can be present in AML inv (16) or monocytic leukemias or can be related to sepsis

Patients may present with the medical emergencies of tumor lysis syndrome or leukostasis (reviewed later in this chapter)

DIAGNOSTIC EVALUATION

A complete history and physical examination are an essential part of diagnosis of acute leukemia, including a detailed family history and history of previous chemotherapy or radiation therapy, or of environmental exposures.

Complete blood count (CBC), differential and manual examination of peripheral smear, and peripheral blood flow cytometry are considered when circulating blasts are sufficiently abundant to rapidly establish a diagnosis.

Coagulation tests include prothrombin time (PT), partial thromboplastin time (PTT), d-dimer, and fibrinogen.

Complete metabolic panel with calcium, magnesium, phosphorus, and uric acid. Pseudohyperkalemia, as well as a spuriously low glucose and P_O2 (partial pressure of oxygen) can occur with a high blast count.

Bone marrow biopsy and aspirate (with analysis for morphology), cytogenetics, flow cytometry, and cytochemical stains (Sudan black, myeloperoxidase, acid phosphatase, and specific and nonspecific esterase) are used for diagnosis.

Human leukocyte antigen (HLA) testing of patients who are transplant candidates—the test is performed before the patient becomes cytopenic. Specimen requirements are minimal when DNA-based HLA typing is performed.

Hepatitis B and C, and human immunodeficiency virus antibody titers are obtained.

Pregnancy test (β-human chorionic gonadotropin), if applicable.

Electrocardiogram (ECG) and analysis of cardiac ejection fraction should be done prior to the treatment with anthracyclines only if a patient has symptoms or a history of heart disease.

Lumbar puncture: Performed when signs and symptoms of neurologic involvement are present. Thrombocytopenia and fibrinogen should be corrected prior to the procedure, which should be performed after reduction of peripheral blast count to avoid theoretical inoculation of blasts into uninvolved CSF. Obtain cell count, opening pressure, protein level, and submit cytocentrifuge specimen for cytology or flow cytometry.

Central venous access should be obtained. An implanted port-type catheter is not recommended. Coagulation abnormalities should be corrected if present. It is often possible to initiate induction therapy with normal peripheral veins and await subsidence of coagulopathy to reduce risk of procedural complications.

Supplemental fluorescent in situ hybridization (FISH) or other assay for PML-RARa, or t(15;17), is performed when APL is suspected; and testing for BCR-ABL1, or t(9;22), is performed when CML in blast phase or ALL is suspected.

Cytogenetic (metaphase karyotype) and gene mutation analysis of blasts are essential for risk-stratification and are needed to determine subsequent management.

INITIAL MANAGEMENT

The initial management of acute leukemia involves the following:

Hydration with IV fluids (2 to 3 L/m² per day).

Tumor lysis prophylaxis and relevant laboratory monitoring should be started.

Blood product support: Suggestions for prophylactic transfusions are a hemoglobin level of <8 g/dl and a platelet level of <10,000/uL. Platelet transfusion threshold can be higher in the context of fever or bleeding, cryoprecipitate can be used if fibrinogen level is <normal, and fresh frozen plasma (FFP) can be used to immediately correct significantly elevated levels of PT and PTT. Platelet transfusion threshold should be increased in APL patients to <50,000/uL. The minimum “safe” platelet level required to prevent spontaneous hemorrhage is not known. Additional platelet optimization strategies include avoidance of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, and clopidogrel-like agents. Deep venous thrombosis prophylaxis with anticoagulants or leg compression devices should be avoided.

Blood products should be irradiated and given with a WBC filter (leukopoor).

Episodes of fever require blood and urine cultures, followed by treatment with appropriate antibiotics, particularly in the setting of neutropenia, (see Chapter 37), and imaging.

Therapeutic anticoagulation should be given with extreme caution in patients during periods of extreme thrombocytopenia. Adjustment of prophylactic platelet transfusion thresholds or anticoagulants may be required.

Suppression of menses: High doses of an oral contraceptive pill (containing 35 mcg ethinyl estradiol taken two to four times per day) can be used for heavy or irregular uterine bleeding during chemotherapy. Leuprolide acetate 7.5 mg intramuscularly every 28 days can also be used to suppress menses.

Tumor Lysis Syndrome

Tumor lysis syndrome can be spontaneous or can be induced by chemotherapy.

Risk factors include elevated uric acid, high WBC count, elevated lactate dehydrogenase (LDH), and high tumor burden.

Laboratory tests indicate elevated potassium (or low potassium with monocytic leukemias), LDH, phosphorus, and uric acid, with a resulting decrease in calcium.

Patients should be initiated on allopurinol 300 mg daily until WBC falls to below normal levels.

For hydration, alkalinizing fluids (0.5 NS with 50 mEq sodium bicarbonate, D5W with up to 150 mEq sodium bicarbonate) could be considered to increase solubility of uric acid, minimizing intratubular precipitation. Caution should be taken as alkanizing the urine also promotes calcium–phosphate complex deposition, and normal saline is a viable alternative.

Uricolytic agents (rasburicase) can be considered if the patient has hyperuricemia (>12) and an elevated creatinine on presentation or has hyperuricemia uncontrolled with allopurinol. Prophylactic rasburicase is not necessary with proper uric acid monitoring, due to quick onset of action of rasburicase.

Hemodialysis may be required in refractory cases or urgently in the setting of life-threatening hyperkalemia, or volume overload if oliguric (see Chapter 39).

Leukostasis

Occurs with elevated blast counts.

Symptoms result from capillary plugging by leukemic cells.

Common signs: dyspnea, headache, confusion, chest pain, and/or hypoxia.

Initial treatment includes aggressive hydration, chemotherapy to rapidly lower the circulating blast percentage (e.g., oral hydroxyurea), or leukapheresis if readily available.

Transfusions should be avoided, as these may increase viscosity.

Leukapheresis has not been shown to be superior to chemotherapy for the treatment of leukostasis. If used, it may be repeated daily in conjunction with chemotherapy until the blast count is <50,000. Leukapheresis should not be used for patients with APL, because it may worsen the intrinsic coagulopathy associated with this subtype of leukemia.

CLASSIFICATION

Acute Myeloid Leukemia

Over time, the pathologic classification system from the World Health Organization (WHO) has replaced the French-American-British (FAB) one. The WHO classification system emphasizes recurrent karyotypic and genetic abnormalities over morphology, due to their prognostic relevance (Table 23.2), while still retaining elements of the FAB system to further stratify cases without recurrent genetic abnormalities. Marrow blasts should comprise 20% of the nucleated cells within the aspirate unless t(8;21) or inv(16) is present. The blasts may be characterized as myeloid lineage by the presence of Auer rods; a positive myeloperoxidase, Sudan black, or nonspecific esterase stain; and the immunophenotype shown by flow cytometry. Cell surface markers associated with myeloid cell lines include CD13, CD33, CD34, c-kit (CD117), and HLA-DR. Monocytic markers include CD64, CD11b, and CD14. CD41 (platelet glycophorin) is associated with megakaryocytic leukemia, and glycophorin A is present on erythroblasts. HLA-DR–negative blast phenotype is commonly seen in APL and serves as a rapidly available test corroborating suspicion of this subtype requiring a specific induction therapy.

TABLE 23.2 The World Health Organization (WHO) Classification of Acute Myeloid Leukemia

AML with recurrent genetic abnormalities

AML with t(8;21)(q22;q22.1);RUNX1-RUNX1T1

AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH11

APL with PML-RARA

AML with t(9;11)(p21.3;q23.3);MLLT3-KMT2A

AML with t(6;9)(p23;q34.1);DEK-NUP214

AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM

AML (megakaryoblastic) with t(1;22)(p13.3;q13.3);RBM15-MKL1

Provisional entity: AML with BCR-ABL1

AML with mutated NPM1

AML with biallelic mutations of CEBPA

Provisional entity: AML with mutated RUNX1

AML with myelodysplasia-related changes

Therapy-related myeloid neoplasms

AML, not otherwise specified (NOS)

AML with minimal differentiation (FAB M0)

AML without maturation (FAB M1)

AML with maturation (FAB M2)

Acute myelomonocytic leukemia (FAB M3)

Acute monoblastic/monocytic leukemia (FAB M5)

Pure erythroid leukemia (FAB M6)

Acute megakaryoblastic leukemia (FAB M7)

Acute basophilic leukemia

Acute panmyelosis with myelofibrosis

Myeloid sarcoma

AML, acute myeloid leukemia; FAB, French-American-British.

Acute Lymphoblastic Leukemia

The WHO classification of ALL broadly divides the disease into B-cell, T-cell, and NK-cell leukemias, with subsets being defined by recurrent genetic abnormalities, in particular the presence of BCR-ABL (the Philadelphia chromosome). Immunophenotyping of B-lineage ALL reveals the typical lymphoid markers CD19, CD20, CD10, TdT, and immunoglobulin. T-cell markers include TdT, CD2, CD3, CD4, CD5, and CD7. Burkitt-cell leukemia is characterized by a translocation between chromosome 8 (the c-myc gene) and chromosome 14 (immunoglobulin heavy chain), or between chromosome 8 and chromosomes 2 or 22 (light chain) regions.

PROGNOSTIC GROUPS

Acute Myeloid Leukemia

Patients who are older (>60 years) and those with an elevated blast count at diagnosis (>20,000) have a worse prognosis. Therapy-related AML and those with a prior history of myelodysplastic syndromes (MDS) have a worse chance of obtaining a complete remission (CR) and shorter long-term survival. Table 23.3 illustrates the prognostic groups according to cytogenetics and molecular markers.

TABLE 23.3 Risk Groups in Newly Diagnosed Adult Acute Myeloid Leukemia

Risk Category	Genetic abnormality
Favorable	t(8;21)(q22;q22.1); RUNX1-RUNX1T1
	inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
	Mutated NPM1 without FLT3-ITD or with FLT3-ITD^lowa
	Biallelic mutated CEBPA
Intermediate	Mutated NPM1 and FLT3-ITD^higha
	Wild-type NPM1 without FLT3-ITD or with FLT3-ITD^lowa (without adverse-risk genetic lesions)
	t(9;11)(p21.3;q23.3); MLLT3-KMT2A^b
	Cytogenetic abnormalities not classified as favorable or adverse
Adverse	t(6;9)(p23;q34.1); DEK-NUP214
	t(v;11q23.3); KMT2A rearranged
	t(9;22)(q34.1;q11.2); BCR-ABL1
	inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1)
	−5 or del(5q); −7; −17/abn(17p)
	Complex karyotype,^c monosomal karyotype^d
	Wild-type NPM1 and FLT3-ITD^higha
	Mutated RUNX1^¶
	Mutated ASXL1^¶
	Mutated TP53

a Low, low allelic ratio (<0.5); high, high allelic ratio (≥0.5)

b t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent adverse-risk gene mutations

c Three or more unrelated chromosome abnormalities in the absence of one of the WHO-designated recurring translocations or inversions, that is, t(8;21), inv(16) or t(16;16), t(9;11), t(v;11)(v;q23.3), t(6;9), inv(3) or t(3;3); AML with BCR-ABL1

d Defined by the presence of 1 single monosomy (excluding loss of X or Y) in association with at least 1 additional monosomy or structural chromosome abnormality (excluding, t(8;21), inv(16) or t(16;16))

¶ These markers should not be used as an adverse prognostic marker if they co-occur with favorable-risk AML subtypes

Acute Lymphoblastic Leukemia

As in AML, patients with ALL have a worse prognosis when presenting with advanced age or an elevated WBC count. Burkitt-cell (mature B-cell) leukemia or lymphoma has an improved prognosis with intensive chemotherapy and CNS treatments; it usually has a translocation involving chromosome 8q24. Table 23.4 lists the prognostic groups according to cytogenetic analysis.

TABLE 23.4 Prognostic Groups by Cytogenetics in Adult Acute Lymphoblastic Leukemia

Poor Risk	Good Risk
t(9;22) (Philadelphia (Ph) chromosome)	8q24 translocations
t(4;11)	t(12;21)
Hypodiploid	t(10;14)
t(1;19)	t(7;10)
9p abnormalities (del(9p), add(9p), der(9)t(V;9)(V;p), i(9q))
Intrachromosomal amplification of chromosome 21 (iAMP21)

The presence of t(9;22) (Philadelphia chromosome, Ph, BCR-ABL1 fusion) is the most common abnormality in adults, occurring in 20% to 30% of patients with ALL and in up to 50% of patients in the B-cell lineage. Long-term survival is dismal in this group, if treated by chemotherapy alone. The introduction of tyrosine kinase inhibitors into treatment regimens have improved outcomes, and patients are recommended to undergo allogeneic transplantation if they have a suitable candidate in first CR. Ph-like (also called BCR/ABL1-like) ALL lacks the hallmark BCR-ABL1 oncoprotein; however, it shares a similar gene expression profile and poor prognosis as Ph-positive ALL. This subtype of ALL frequently harbors IKZF1 and CRLF2 alterations; and comprises 10% to 15% of pediatric patients, and 20% to 30% of adolescents and adults with B-cell ALL.

TREATMENT

Acute Myeloid Leukemia (Excluding Acute Promyelocytic Leukemia)

The goal of “induction” chemotherapy is to obtain a remission, which is correlated with improved survival. Complete response (CR) is defined as the elimination of the malignant clone (marrow blasts <5%) and recovery of normal hematopoiesis (absolute neutrophil count [ANC] >1,000/uL and platelet count >100,000/uL). Patients typically have a leukemia cell burden of approximately 10 x10¹² that is reduced to approximately 10 x10⁹ by induction. This residual disease may be undetectable morphologically, but will certainly lead to relapse in a few months if more therapy is not administered. Additional intensive “post-remission” or “consolidation” cycles of chemotherapy are given to further reduce the residual burden in the hope that host immune mechanisms can suppress the residual leukemia population, thereby leading to sustained, maintenance-free remission. The general approach to induction chemotherapy for adults is shown in Table 23.5. All patients should be considered for clinical trials if available.

TABLE 23.5 Standard Induction for Acute Myeloid Leukemia

“7 + 3,” 7 d of infusional cytarabine and 3 d of anthracycline

Cytarabine 100–200 mg/m² daily as continuous infusion × 7 d with

Idarubicin 12 mg/m² daily bolus for 3 d

Daunorubicin 60–90 mg/m² daily bolus for 3 d

In general

Addition of high-dose cytarabine (HiDAC) or etoposide has been evaluated in published regimens for induction, but have not been conclusively been shown to be superior to the backbone of 3 days of an anthracycline and 7 days of cytarabine.

The FLT3-inhibitor midostaurin may be added to chemotherapy and is associated with improved survival in patients whose blasts express this marker.

Bone marrow aspiration should be repeated at approximately day 14 of induction chemotherapy. If significant residual blasts are present (generally defined as >5%), induction chemotherapy should be repeated (“7 + 3,” or can consider “5 + 2” in Table 23.6 for older or frail patients). If significant disease is present (<50% reduction in disease volume), a change in the regimen to age-appropriate HiDAC may be considered.

Older patients (>60 years) may benefit from intensive induction and consolidation treatment. Post-remission cytarabine requires dose reduction due to CNS toxicity.

Older patients or patients who decline intensive induction chemotherapy (i.e., 7 + 3) may be candidates for therapy with low-dose cytarabine or hypomethylating agents (azacitidine or decitabine). These agents have lower CR rates (approximately 10% to 20%) but lower therapy-related mortality, and may be administered in the outpatient setting.

TABLE 23.6 Consolidation for Acute Myeloid Leukemia

Age <60

Cytarabine 3 g/m² infused over 3 h, q12h on days 1, 3, and 5 (six doses)

Creatinine 1.5–1.9 mg/dL: Decrease cytarabine 1.5 g/m² per dose

Age >60

“5 + 2”: Cytarabine 100 mg/m² daily as continuous infusion for 5 d and anthracycline (idarubicin 12 mg/m² or daunorubicin 45–90 mg/m²) bolus daily for 2 d

Intermediate-dose cytarabine: 1–1.5 g/m² q12h on days 1, 3, 5 OR 1–1.5 g/m² daily × 4–5 days

Supportive Care

Infection is a major cause of morbidity and mortality. Prophylactic antibacterials (quinolones), antifungals (itraconazole, fluconazole, or posaconazole), and antivirals (acyclovir) may be given during these periods of prolonged neutropenia. Broad-spectrum antimicrobials are used for neutropenic fever (see Chapter 36).

Growth factors such as granulocyte colony-stimulating factor (G-CSF) can be considered in the setting of neutropenia and severe infection. They may be used rarely to aid in count recovery. Patients should be off growth factors for a minimum of 7 days prior to a bone marrow biopsy that is being used to document remission as it can confound the interpretation of bone marrow morphology.

Steroid eye drops are required during HiDAC infusions to reduce the risk of exfoliative keratitis.

Acute Myeloid Leukemia Postremission Therapy (Excluding Acute Promyelocytic Leukemia)

The consolidation options for those patients who enter CR are shown in Table 23.6. HiDAC especially may benefit those patients with good-risk disease [t(8;21), inv(16), NMP1 mutated/FLT3 wild type]. These good-risk patients should not receive allogeneic transplantation in CR1. Consolidation usually consists of four cycles (the minimum effective dose and the number of cycles are not clear). Older patients do not seem to benefit from more than one to two consolidation cycles of a lower-dosed cytarabine-based regimen. Patients with preceding MDS or poor-risk cytogenetics should receive an allogeneic transplantation in CR1, if possible. Patients with intermediate-risk cytogenetics should be considered for an allogeneic transplant, especially if they have a matched sibling donor, though it remains unclear if this provides an advantage for this sub-population over standard chemotherapy consolidation. Gene mutations may assist in the proper identification of standard-risk patients who would or would not benefit from allogeneic transplant in CR1 (see the Allogeneic Transplantation section).

Acute Promyelocytic Leukemia, t(15;17)

The t(15;17) brings together the retinoic acid receptor-α and the promyelocytic leukemia genes, allowing for transduction of a novel protein (PML-RARα). The protein plays a role in blocking differentiation of the promyelocyte, thereby promoting abnormal accumulation within the marrow space. Because the characteristic translocation occurs in this subgroup of AML, therapy incorporates all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO), which act as differentiating agents. Table 23.7 shows a treatment summary in APL.

TABLE 23.7 Treatment of Acute Promyelocytic Leukemia

	Low to Intermediate Risk	High Risk
Induction	ATRA + ATO	ATRA + anthracycline (idarubicin or daunorubicin) +/- cytarabine
		Or
		ATRA + idarubicin + ATO
Consolidation	ATRA + ATO (28 weeks)	ATRA + anthracycline × 3 cycles +/− cytarabine
		Or
		Arsenic × 2 cycles followed by anthracycline × 2 cycles
Maintenance (2 y)	None	ATRA 45 mg/m² daily for 15 d q3mo + Mercaptopurine 50 mg/m² daily + MTX 15 mg/m² weekly

ATRA, all-trans retinoic acid; ATO, arsenic trioxide; 6-MP, 6-mercaptopurine; MTX, methotrexate.

Therapy with ATRA should be started immediately upon suspicion of APL; therapy can be tailored pending genetic confirmation.

ATRA + ATO is used for low to intermediate risk patients (WBC ≤10 x10⁹/L at presentation) as well as an alternative option for higher-risk patients unable to tolerate anthracyclines.

ATRA + chemotherapy (anthracycline and cytarabine) is used for higher-risk patients (WBC >10 x10⁹/L)

Time to attain remission may be more than 30 days and a bone marrow biopsy is not performed on day 14.

PCR should be followed for PML-RARα: Reinduction therapy or allogenic transplantation should be considered if PCR is still positive postconsolidation (but not postinduction); levels should be followed during the maintenance phase. A return of the transcript to positive heralds relapse.

ATRA (or ATO) syndrome (differentiation syndrome) consists of capillary leak and cytokine release resulting in fever, leukocytosis, respiratory compromise (dyspnea and infiltrates), weight gain, effusions (pleural and pericardial), renal failure, and hypotension. This syndrome occurs in upwards of 25% of patients during induction, with peak occurrences between 1 and 3 weeks into therapy, and is associated with a rapidly rising neutrophil count. Treat with dexamethasone 10 mg IV BID × 3 days, and then taper over 2 weeks. Discontinuation of ATRA can be considered in severe cases. ATRA may still be safely employed in consolidation or maintenance-phase therapy because the ATRA syndrome is limited to the induction-period neutrophilia.

A similar differentiation syndrome, not involving ATRA, is seen with the use of arsenic trioxide.

Prognosis with APL is very good, with >90% of patients attaining a CR and >70% long-term disease-free survival.

Patients are typically classified as high-risk (WBC ≥10,000), intermediate-risk (WBC< 10,000 and platelets ≤40), or low-risk (WBC <10,000 and platelets >40) disease at diagnosis.

Relapsed Disease

ATO 0.15 mg/kg/day until second CR.

Median of 57 days to remission.

Baseline electrolytes (Ca, K, Mg), creatinine, and ECG (for prolonged QT interval).

Monitoring: At least weekly electrolytes and ECG. Keep K >4.0 mEq/L and Mg >2.0 mg/dL and reassess if QTc interval >500.

Patients commonly develop APL differentiation syndrome similar to ATRA.

Eighty-five percent of patients achieve CR.

Arsenic trioxide may be given as consolidation at a dose of 0.15 mg/kg/day, 5 days per week (Monday through Friday) for 25 doses.

Patients achieving CR (PCR negative) should receive consolidation with an autologous transplant, if eligible. Patients with persistent positive PCR results should be considered for an allogeneic transplant.

Relapsed or Refractory Acute Myeloid Leukemia

Relapse of AML after initial CR is common (60% to 80% of all cases). Relapse occurring within 6 months of induction or a patient never attaining remission with induction (refractory disease) complicates many re-induction attempts. The prognosis for long-term survival in this subset of patients is poor with chemotherapy alone, and all patients who are able to tolerate the treatment should be evaluated for allogeneic transplantation. Some treatment approaches are described below.

Reinduction with “7 + 3” or HiDAC.

Reinduction may be an option for those patients who relapse more than 6 to 12 months after initial induction.

Subsequent remissions are usually of shorter duration (<50% of the duration of the preceding remission).

Etoposide, mitoxantrone, ± cytarabine (EM or MEC).

FLAG: fludarabine, cytarabine, and G-CSF (can be combined with idarubicin or mitoxantrone).

Clofarabine +/− cytarabine or cyclophosphamide.

FLT3 inhibitors may have activity (sorafenib, midostaurin, and quizartinib), but are currently investigational in this setting.

In cases of isolated CNS relapse, it should be considered that systemic relapse almost always follows soon and that a systemic therapy is also required.

Acute Lymphoblastic Leukemia

General scheme: induction, consolidation, maintenance, and CNS treatment.

Several strategies exist for the treatment of adult ALL. Table 23.8 illustrates the hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) regimen used at many North American centers. Modification of the Larson regimen reported by Cancer and Leukemia Group B (CALGB, now Alliance for Clinical Trials in Oncology) Study 19802, shown in Table 23.9, is also commonly used. Other options based on the Hoelzer and Linker regimens are also available. Burkitt-cell leukemia (mature-B ALL, FAB L3) can be treated with hyper-CVAD without maintenance therapy but requires aggressive CNS treatment to prevent relapse. Adolescent and young adult patients (age ≤40) with ALL should be treated with a pediatric-like regimen such as CALGB 10403.

TABLE 23.8 The Hyper-CVAD and MTX/HIDAC Regimen

Cycles 1, 3, 5, and 7

Cyclophosphamide 300 mg/m² IV over 3 h q12h days 1–3 (six doses)

Mesna 600 mg/m²/d IV as continuous infusion days 1–3

Vincristine 2 mg IV days 4 and 11

Doxorubicin 50 mg/m² IV day 4

Dexamethasone 40 mg PO daily days 1–4 and 11–14

G-CSF 10 µg/kg/d SQ starting after chemotherapy

Cycles 2, 4, 6, and 8

Methotrexate 200 mg/m² IV over 2 h on day 1, followed by

Methotrexate 800 mg/m² IV over 22 h on day 1

Leucovorin 50 mg starting 12 h after methotrexate completed, followed by leucovorin 15 mg every 6 h × eight doses, dose adjusted on the basis of methotrexate levels

Cytarabine 3 g/m² IV over 2 h every 12 h on days 2 and 3 (four doses)

Methylprednisolone 50 mg IV twice daily days 1–3

G-CSF 10 µg/kg/d SQ starting after chemotherapy

CNS prophylaxis^a

Methotrexate 12 mg intrathecal (IT) on day 2

Cytarabine 100 mg IT on day 8

Maintenance therapy^b (POMP) × 2 y

Mercaptopurine 50 mg PO three times daily

Methotrexate 20 mg/m² PO weekly

Vincristine 2 mg IV monthly

Prednisone 200 mg/d for 5 d each month

Dosage adjustments

Vincristine reduced to 1 mg if bilirubin 2–3 mg/dL (omitted if bilirubin >3 mg/dL)

Doxorubicin decreased to 50% for bilirubin 2–3 mg/dL, decreased to 25% if bilirubin 3–5 mg/dL, and omitted if bilirubin >5 mg/dL

Methotrexate reduced to 50% if creatinine clearance 10–50 mL/min, and a decrease to 50%–75% for delayed excretion, nephrotoxicity, or grade ≥3 mucositis with prior courses

High-dose cytarabine decreased to 1 g/m² if patient ≥60 y, creatinine ≥1.5 mg/dL, or MTX level >20 µmol/L at the completion of the MTX infusion

aDosing interval based on risk stratification (see text).

bMaintenance therapy is not given in Burkitt-cell leukemia/lymphoma.

G-CSF, granulocyte colony-stimulating factor; CNS, central nervous system; MTX, methotrexate.

TABLE 23.9 The Modified Larson Regimen

Modules A1 and A2

Cyclophosphamide 1,000 mg/m² IV day 1^a

Daunorubicin 60 mg/m² IV days 1–3^a

Vincristine 1.5 mg/m² (capped at 2 mg) IV days 1, 8, 15, 22

Prednisone 60 mg/m²/d PO days 1–21^a

L-Asparaginase (Escherichia coli) 6,000 IU/m² SQ/IM days 5, 8, 11, 15, 18, 22

G-CSF 5 µg/kg/d SQ starting day 4

Module B1 and B2

Methotrexate 15 mg intrathecal (IT) day 1

Cyclophosphamide 1,000 mg/m² IV day 1

Cytarabine 2,000 mg/m²/d IV days 1–3

G-CSF 5 µg/kg/d SQ starting day 4

Module C1 and C2

IT Methotrexate 15 mg days 1, 8, 15

Vincristine 1.5 mg/m² (capped at 2 mg) IV days 1, 8, 15

Methotrexate 1,000 mg/m² IV over 4 hours days 1, 8, 15

Methotrexate 25 mg/m² PO q 6 hours x 4 doses beginning 6 hours after initiation of IV methotrexate on days 1, 8, 15

Leukovorin 25 mg /m² IV on days 2, 9, 16; given 30 hours after initiation of IV methotrexate, followed by leukovorin 5 mg/m² PO q 6 hours until methotrexate level is <0.05 uM

Prolonged maintenance (continue until 24 mo after diagnosis)

Vincristine 2 mg IV day 1 of every 4 wk

Prednisone 60 mg/m²/d PO days 1–5 of every 4 wk

6-Mercaptopurine 60 mg/m²/d PO days 1–28

Methotrexate 20 mg/m² PO days 1, 8, 15, 22

aDosage reductions for age >/=60 y: no cyclophosphamide, daunorubicin 60 mg/m² days 1–3, and prednisone 60 mg/m² days 1–7.

CNS, central nervous system.

Supportive Care

The regimens described previously incorporate growth factors to reduce neutropenia and allow more scheduled chemotherapy to proceed. All patients will require blood product support at some point during the treatment. Those patients treated with hyper-CVAD receive prophylactic antimicrobials (i.e., levofloxacin 500 mg daily, fluconazole 200 mg daily, and valacyclovir 500 mg daily).

Central Nervous System Disease

The CNS is a sanctuary site.

CNS disease is diagnosed by the presence of neurologic deficits at diagnosis or by five or more blasts per microliter of CSF.

Therapy for CNS disease is intrathecal (IT), methotrexate (MTX), or cytarabine (Ara-C), often alternating. These will be given twice weekly until disease clears, then weekly for 4 weeks, and then resume the prophylaxis schedule. Radiation (fractionated to 2,400 to 3,000 cGy) can also be considered, being aware of potential late-term cognitive toxicities.

Prophylaxis decreases CNS relapse from 30% to <5%. The prophylactic chemotherapy schedule is dependent on the relapse risk.

In the hyper-CVAD regimen, patients with high-risk disease (i.e., LDH level >2.3 times upper limit of normal or elevated proliferative index) should receive eight prophylactic IT treatments, and those with low-risk disease (no factors) receive six prophylactic IT treatments. Patients with mature B-cell disease or a history of documented CNS involvement will require 16 IT therapies. No prophylactic cranial irradiation is given.

Relapsed Acute Lymphoblastic Leukemia

The bone marrow is the most common site of relapse, but relapse can occur in the testes, eye, and CNS. Patients with late relapse (more than 6 months to 1 year from induction) may respond to reinduction with the original regimen. Early relapse or refractory disease will require changing the treatment plan and evaluation for allogeneic transplantation. Several chemotherapy options are available, including

Blinatumomab

HiDAC with or without idarubicin, mitoxantrone, or fludarabine

Methotrexate, vincristine, asparaginase (not PEG), steroids (MOAD)

Dasatinib, imatinib, or nilotinib (if Ph-positive)

Hyper-CVAD, if not given initially

Vinorelbine with mitoxantrone, fludarabine, steroids, or rituximab

Nelarabine

Clofarabine +/− cytarabine or cyclophosphamide

Liposomal vincristine

Investigational monoclonal antibody agents (e.g., inotuzumab ozogamicin)

Chimeric Antigen Receptor (CAR) T-Cells

Use of Targeted and Immunotherapy in Acute Lymphoblastic Leukemia

1.Blinatumomab (Blincyto)

•Bispecific T-cell engager (BiTE) monoclonal antibody directed at both CD19 on B-cell ALL cells, and CD3 on the patient’s T-cells, which enables the T-cells to recognize the malignant B-cells that express CD19. After the T-cell links with the malignant cell, it is activated and exerts cytotoxic activity on the ALL cell.

•Compared to cytarabine-based therapy, blinatumomab was shown to have an improved CR with full hematologic recovery (34% versus 16%), as well as CR with incomplete hematologic recovery (44% versus 25%), leading to an improved overall survival in a randomized study.

•It is given as a continuous intravenous infusion over 4 weeks, followed by a two-week treatment-free interval; maintenance treatment may continue as 4-week continuous infusions every 12 weeks.

•Unique and serious side effects include cytokine release syndrome and neurological toxicities. Patients are hospitalized for the first 9 days of the continuous infusion to monitor for cytokine release syndrome and neurologic toxicity.

2.Rituximab (Rituxan)

•Anti-CD20 chimeric murine–human monoclonal antibody

•Given in addition to the previously noted regimens in front-line treatment, if CD20+

3.Imatinib, dasatinib, nilotinib, bosutinib, and ponatinib

•Tyrosine kinase inhibitors targeting the Philadelphia chromosome [t(9;22)].

•Dasatinib or imatinib should be considered in addition to previously noted regimens in front-line treatment, if Ph positive.

•Role in maintenance therapy is unknown, but could be considered.

•May be used as treatment or palliation in combination with steroids for patients unable to tolerate aggressive chemotherapy.

•Choice of tyrosine kinase inhibitor agent should be selected based on BCR/ABL mutation analysis.

4.Chimeric Antigen Receptor (CAR) T-cells

•This technology involves collecting a patient’s T-cells, “reprograming” them with a genetically engineered immunoreceptor using a viral vector, expanding them, then reinfusing them into the patient.

•Studies with CD19-directed CAR T-cells are ongoing, and are available only at certain centers with infrastructure for cellular therapy.

•A pilot study evaluated the use of CD19-directed CAR-T cells in 30 children and adults with relapsed or refractory ALL (10% primary refractory, and 60% with relapse after allogeneic transplantation). A CR was seen in 90% of patients with an estimated 6-month event-free survival of 67%, and overall survival of 78%.

•As with blinatumomab, cytokine-release syndrome and neurological toxicities do occur early in the treatment course. Severe cytokine-release syndrome can be treated with the anti-interleukin-6 receptor antibody tocilizumab.

•Relapses were a result of tumor cell evasion of the CAR T-cells (loss of expression of CD19).

•Larger trials with long-term follow-up are needed to verify the efficacy of this treatment.

•Three second-generation CAR T-cell products are in advanced phases of development.

TRANSPLANTATION

Autologous Transplantation

Autologous transplant appears to have minimal benefit in acute leukemia in CR1.

Autologous transplant could be considered for patients achieving CR2, without availability of an allogeneic donor.

It may be performed in older patients (age >60).

Allogeneic Transplantation

Allogeneic transplant has the added benefit of “graft versus leukemia” effect.

In the setting of unrelated donor searches, the prolonged time needed to identify a donor needs to be considered at the time of diagnosis. Referral to a transplant center is preferred as early as possible in the treatment plan.

It is considered for all patients with relapsed or refractory disease, as it is the option that may yield long-term survival.

It is performed in the first CR or early in the course for those patients with poorer-risk cytogenetics or transformation from MDS.

Patients with good-risk AML [t(8;21), inv(16)), NPM1 mutated] or APL [t(15;17)] should not be transplanted in CR1.

Patients with intermediate-risk cytogenetics may be offered allogeneic transplant, especially if they have a sibling donor, though superiority to standard postremission chemotherapy has not been demonstrated prospectively in this group.

Gene mutations may be able to help stratify intermediate-risk patients with normal cytogentics as having a poorer or more favorable outcome, assisting in the decision of the usefulness of transplantation in CR1. Patients with NPM1 and CEBPA mutations (without FLT3-ITD mutations) may have a good prognosis and may not benefit from transplant in CR1. FLT3-ITD mutations are a negative predictor of outcome.

When transplanted in CR1, overall survival is 50% to 60%; it decreases to 25% to 40% when performed for patients in CR2, and is <10% for patients with refractory disease.

Reduced-intensity conditioning transplantation is reasonable for those patients unable to proceed with ablative treatment secondary to comorbidities or advanced age.

In a randomized fashion, BMT-CTN 0901 evaluated the role of reduced-intensity conditioning compared to myeloablative preparative regimens for allogeneic transplant in patients with AML. This study was stopped early because of high relapse incidence with reduced intensity versus myeloablative conditioning (48.3% versus 13.5%). Overall survival was higher with myeloablative regimens, but not significantly. Reduced intensity conditioning resulted in lower complication rates, but due to the higher relapse rates, there was a statistically significant advantage in relapse-free survival with myeloablative conditioning.

PROGNOSIS AND SURVIVAL

Adults with acute leukemia remain at high risk for disease-related and treatment-related complications. In AML, the prognostic characteristics of the disease are associated with survival. Good-risk AML is associated with an 80% to 90% CR rate, and long-term disease-free survival is 60% to 70% in younger patients treated with HiDAC. Poor-risk features are associated with only a 50% to 60% chance of obtaining a CR, and a high risk of relapse is observed in those patients who enter CR. Additionally, gene mutations have been identified as correlating with prognosis in AML, especially in the intermediate-risk group in which cytogenetics cannot guide postremission therapy. In these patients, FLT3-ITD and TP53 mutations confer a poor prognosis. In patients who are FLT3-ITD negative, NPM1 and CEBPA identify a good prognostic subgroup.

CR and long-term outcome have improved for adult patients with ALL who were receiving intensive courses of chemotherapy. With the hyper-CVAD and modified Larson regimens, 85% to 90% of patients will obtain a CR with a median duration of CR of 30 months. Five-year survival is approximately 40%.