THE ACUTE LEUKAEMIAS

THE ACUTE LEUKAEMIAS

Normal haematopoiesis  requires tightly regulated proliferation and differentiation of pluripotent hematopoietic stem cells that become mature peripheral blood cells. Acute leukaemia is the result of a malignant event or events occurring in an early hematopoietic precursor. Instead of proliferating and differentiating normally, the affected cell gives rise to progeny that fail to differentiate but continue to proliferate in an uncontrolled fashion. As a result, immature myeloid cells in acute myeloid leukaemia (AML) or lymphoid cells in acute lymphoblastic leukaemia (ALL)—often called blasts—rapidly accumulate and progressively replace the bone marrow, diminishing the production of normal red cells, white cells, and platelets. This loss of normal marrow function in turn gives rise to the common clinical complications of leukaemia: anaemia, infection, and bleeding. With time, the leukemic blasts pour out into the blood stream and eventually occupy the lymph nodes, spleen, and other vital organs. If untreated, acute leukaemia is rapidly fatal; most patients die within several months after diagnosis. With appropriate therapy, however, the natural history of acute leukaemia can be markedly altered, and many patients can be cured.

Incidence

There were 14,590 new cases of AML and 6075 new cases of acute ALL in the United States in 2013, leading to 10,320 deaths from AML and 1430 deaths from ALL. The incidence of acute leukaemia has remained relatively stable over the past 3 decades. Although acute leukaemia accounts for only about 2% of cancer deaths, the impact of leukaemia is heightened because of the young age of some patients. For example, with a maximum incidence between ages 2 and 10 years, ALL is the most common cancer in children younger than 15 years and accounts for one third of all childhood cancer deaths. The incidence of AML gradually increases with age, without an early peak. The median age at diagnosis of AML is about 60 years.

Determinants

In most cases, acute leukaemia develops for no known reason, but sometimes a possible cause can be identified.

Genetic Predisposition

The concordance rate is virtually 100% in identical twins if one twin develops leukaemia during the first year of life. Single germline mutations in RUNX1, CEBPA, and GATA2cause rare syndromes leading to acute leukaemia without other manifestations. The incidence of acute leukaemia is markedly increased in syndromes involving defective DNA repair, such as Fanconi’s anaemia and Bloom’s syndrome, and in bone marrow failure syndromes associated with ribosomal abnormalities, including Diamond-Blackfan syndrome, Shwachman-Diamond syndrome, and dyskeratosis congenita. Germline mutations in P53 (Li-Fraumeni syndrome) and abnormalities in chromosome number, as in Down and Klinefelter’s syndromes, are also associated with an increased incidence of acute leukaemia.

Radiation

Ionizing radiation is leukaemogenic. The incidence of ALL, AML, and chronic myeloid leukaemia (CML) is increased in patients given therapeutic radiation and among survivors of the atomic bomb blasts at Hiroshima and Nagasaki. The magnitude of the risk depends on the dose of radiation, its distribution in time, and the age of the individual. Greater risk results from higher doses of radiation delivered over shorter periods to younger patients. In areas of high natural background radiation (often from radon), chromosomal aberrations are reportedly more frequent, but an increase in acute leukaemia has not been consistently found. Concern has been raised about the possible leukaemogenic effects of extremely low-frequency nonionizing electromagnetic fields emitted by electrical installations. If such an effect exists at all, its magnitude is small.

Oncogenic Viruses

The search for a viral cause of leukaemia has been pursued intensely, but only two clear associations have been found. Human T-cell lymphotropic virus type I (HTLV-I), an enveloped, single-stranded RNA virus, is considered the causative agent of adult T-cell leukaemia. This distinct form of leukaemia is found within geographic clusters in southwestern Japan, the Caribbean basin, and Africa. Because HTLV-I seropositivity was found with increasing frequency among heavily transfused patients and intravenous drug users, screening of blood products for antibodies to HTLV-I is now routine practice in blood banks in the United States. Epstein-Barr virus, the DNA herpes family virus that causes infectious mononucleosis, is associated with the endemic African form of Burkitt’s lymphoma/leukaemia.

Chemicals and Drugs

Heavy occupational exposure to benzene and benzene-containing compounds such as kerosene and carbon tetrachloride may lead to marrow damage, which can take the form of aplastic anaemia, myelodysplasia, or AML. A link between leukaemia and tobacco use has been reported.

With the increasing use of chemotherapy and radiotherapy to treat other malignancies, as much as 10% of AMLs and a smaller percentage of ALLs are likely the consequence of prior therapy. Prior exposure to alkylating agents such as melphalan and the nitrosoureas is associated with an increased risk for secondary AML, which often manifests initially as a myelodysplastic syndrome, frequently with abnormalities of chromosomes 5, 7, and 8 but with no distinct morphologic features. These secondary AMLs typically develop 4 to 6 years after exposure to alkylating agents, and their incidence may be increased with greater intensity and duration of drug exposure. Secondary AML associated with exposure to topoisomerase II inhibitors, including the epipodophyllotoxins (teniposide or etoposide) and doxorubicin, tends to have a shorter latency period (1 to 2 years), lacks a myelodysplastic phase, has a monocytic morphology, and involves abnormalities of the long arm of chromosome 11 (band q23) or chromosome 21 (band q22). Recently, concern has been raised about an increased risk for second cancers including myeloid malignancies in patients receiving lenalidomide as maintenance therapy in multiple myeloma. Because patients frequently receive combination chemotherapy, it is often difficult to identify a single causative agent.

Clonality and Cell of Origin

The acute leukaemias are clonal disorders, and all leukemic cells in a given patient are descended from a common progenitor. The clonal nature of acute leukaemia suggests that there are leukemic stem cells capable of both self-renewal and proliferation. Leukemic stem cells in AML are rare among the leukemic mass, with a frequency of 0.2 to 10 per 10, and are within the primitive CD342+  CD38– fraction. Less is known about the ALL stem cell.

Classification

The World Health Organization (WHO) classification of acute leukaemias is based on clinical, morphologic, immunophenotypic, cytogenetic, and molecular features.

WORLD HEALTH ORGANIZATION CLASSIFICATION OF ACUTE LEUKEMIAS

CLASSIFICATION SUBTYPES (2008)

Acute Myeloid Leukaemia (AML) and Related Neoplasms

  • AML with recurrent genetic abnormalities
  • AML with t(8;21)(q22;q22); RUNX1-RUNX1T1
  • AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
  • Acute promyelocytic leukaemia (APL) with t(15;17)(q22;q12); PML-RARA
  • AML with t(9;11)(p22;q23); MLLT3-MLL
  • AML with t(6;9)(p23;q34); DEK-NUP214
  • AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1
  • AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1
  • Provisional entity: AML with mutated NPM1
  • Provisional entity: AML with mutated CEBPA
  • AML with myelodysplasia-related changes
  • Therapy-related myeloid neoplasms
  • AML, not otherwise specified
  • AML with minimal differentiation
  • AML without maturation
  • AML with maturation
  • Acute myelomonocytic leukaemia
  • Acute monoblastic/monocytic leukaemia
  • Acute erythroid leukaemia
  • Pure erythroid leukaemia
  • Erythroleukemia, erythroid/myeloid
  • Acute megakaryoblastic leukaemia
  • Acute basophilic leukaemia
  • Acute panmyelosis with myelofibrosis
  • Myeloid sarcoma
  • Myeloid proliferations related to Down syndrome
  • Transient abnormal myelopoiesis
  • Myeloid leukaemia associated with Down syndrome
  • Blastic plasmacytoid dendritic cell neoplasm

B-Lymphoblastic Leukaemia (ALL)/Lymphoma

  • B-lymphoblastic leukaemia/lymphoma, not otherwise specified
  • B-lymphoblastic leukaemia/lymphoma with recurrent genetic abnormalities
  • B-lymphoblastic leukaemia/lymphoma with t(9;22)(q34;q11.2); BCR-ABL1(Philadelphia chromosome–positive ALL)
  • B-lymphoblastic leukaemia/lymphoma with t(v;11q23); MLL rearranged
  • B-lymphoblastic leukaemia/lymphoma with t(12;21)(p13;q22); TEL-AML1 ETV6-RUNX1 )
  • B-lymphoblastic leukaemia/lymphoma with hyperdiploidy
  • B-lymphoblastic leukaemia/lymphoma with hypodiploidy
  • B-lymphoblastic leukaemia/lymphoma with t(5;14)(q31;q32); IL3-IGH
  • B-lymphoblastic leukaemia/lymphoma with t(1;19)(q23;p13.3); TCF3-PBX1

T-Lymphoblastic Leukaemia (ALL)/Lymphoma

ALL = acute lymphoblastic leukaemia.

Leukemic cells in AML are typically 12 to 20 nm in diameter, with discrete nuclear chromatin, multiple nucleoli, and cytoplasm that usually contains azurophilic granules. Auer rods, which are slender, fusiform cytoplasmic inclusions that stain red with Wright-Giemsa stain, are virtually pathognomonic of AML. The French-American-British (FAB) morphologic system divides AML into eight subtypes: M0, M1, M2, and M3 reflect increasing degrees of differentiation of myeloid leukemic cells; M4 and M5 leukaemias have features of the monocytic lineage; M6 has features of the erythroid cell lineage; and M7 is acute megakaryocytic leukaemia. The WHO system also recognizes acute basophilic leukaemia and acute leukaemia with predominant myelofibrosis.

The leukemic cells in ALL tend to be smaller than AML blasts and relatively devoid of granules. ALL can be divided by FAB criteria into L1, L2, and L3 subgroups. L1 blasts are uniform in size, with homogeneous nuclear chromatin, indistinct nucleoli, and scanty cytoplasm with few, if any, granules. L2 blasts are larger and more variable in size and may have nucleoli. L3 blasts are distinct, with prominent nucleoli and deeply basophilic cytoplasm with vacuoles.

Immunophenotyping by multiparameter flow cytometry is used to determine lineage involvement of newly diagnosed acute leukaemias and to detect aberrant immunophenotypes, allowing the measurement of minimal residual disease after therapy. Most cases of AML express antigens seen on normal immature myeloid cells. The most immature forms of AML express CD34, CD117 and HLA-DR, whereas more differentiated forms express CD13 and CD33. CD14, CD15, and CD11b are expressed by AMLs with monocytic features, erythroid leukaemias express CD36 and CD71, and megakaryocytic AMLs express CD41a and CD61. In 10 to 20% of patients, otherwise typical AML blasts also express antigens usually restricted to B- or T-cell lineage. Expression of a single lymphoid antigen by AML cells does not change either the natural history or the therapeutic response of these leukaemias.

Approximately 75% of cases of ALL express B-lineage antigens and can be subdivided into four categories. The most immature group, pro-B ALL, expresses CD19 and/or CD 22 but not CD10 and represents about 10% of cases of ALL. Approximately 50 to 60% of cases of ALL express the early B-cell antigens CD19 and/or CD22 along with the common ALL antigen (CALLA, or CD10), a glycoprotein that is also found occasionally on normal early lymphocytes. CALLA-positive ALL is thought to represent an early pre-B-cell differentiation state. Approximately 10% of cases of ALL have intracytoplasmic immunoglobulin and are termed pre-B-cell ALL. Mature B-cell ALL is signified by the presence of surface immunoglobulin and accounts for less than 5% of cases of ALL. In general, the best therapeutic outcomes among B-cell ALL types are with early pre-B-cell (CALLA positive) ALL. The 25% of cases of ALL that express T-lineage antigens can be separated into three groups: (1) early T-precursor ALL expressing CD7 but not CD1a or CD3, (2) thymic T-ALL expressing CD1a but not surface CD3, and (3) mature T-ALL expressing surface CD3. The prognosis for thymic T-cell ALL is superior to that of the other forms of T-ALL. In about 25% of patients with ALL, the leukemic cells may also express a myeloid antigen, but with current therapies, this does not affect outcome.

Acute leukaemias of ambiguous lineage are rare cases with no evidence of lineage differentiation (i.e., acute undifferentiated leukaemia [AUL]) or those with blasts that express definitive markers of more than one lineage (i.e., mixed phenotype acute leukaemia [MPAL]). MPAL can contain either distinct blast populations of different lineages (bilineal) or a single population expressing features of both lineages (biphenotypic). In general, the prognosis of patients with AUL or MPAL is poor when treated with standard chemotherapy.

In most cases of acute leukaemia, an abnormality in chromosome number or structure is found. These abnormalities are clonal, involving all the malignant cells in a given patient; they are acquired and are not found in the normal cells of the patient; and they are referred to as “non-random” because specific abnormalities are found in multiple cases and are associated with distinct morphologic or clinical subtypes of the disease. These abnormalities may be simply the gain or loss of whole chromosomes, but more often they include chromosomal translocations, deletions, or inversions. When patients with acute leukaemia and a chromosomal abnormality receive treatment and enter into complete remission, the chromosomal abnormality disappears; when relapse occurs, the abnormality reappears. In many cases, these abnormalities have provided clues into the pathobiology of acute leukaemia.

The most common cytogenetic abnormalities seen in AML can be categorized according to their underlying biology and prognostic significance. The translocation t(8;21) and the inversion inv(16) result in abnormalities of a transcription factor made up of core binding factor-α (CBF-α) and CBF-β. The t(8;21) results in the fusion of CBF-α on chromosome 21 with the MTG8 gene on chromosome 8, whereas inv(16) results in the fusion of CBF-β on the q arm of chromosome 16 with the MYH11 gene on the p arm. Both of these “core binding factor” AMLs are characterized by a high complete response rate and relatively favourable long-term survival. An additional translocation with a favourable prognosis, t(15;17), involves two genes, PML and RAR-α (a gene encoding the α-retinoic acid receptor), and is invariably associated with acute promyelocytic leukaemia (APL), the M3 subtype of AML. Translocations involving the MLL gene, located at chromosome band 11q23, are seen in 5-7% of AMLs. MLL is perhaps the most promiscuous oncogene partner in oncology, with more than 30 fusion partners identified. The prognosis of MLL-associated AML depends on the fusion partner, with t(9;11) and t(11;19) predicting an intermediate prognosis and all others considered unfavourable. Trisomy 8 is among the most common non-random cytogenetic abnormalities seen in AML; it accounts for 9% of cases and carries an intermediate prognosis. Trisomies of chromosome 21, chromosome 11, and other chromosomes are sometimes seen as well. Deletions of part or all of chromosome 5 or 7 each account for 6 to 8% of cases of AML. These abnormalities are seen with greater frequency in older patients and in patients with AML secondary to myelodysplasia or prior exposure to alkylating agents, and are associated with an unfavourable prognosis. The presence of multiple (more than three) cytogenetic abnormalities in individual cases of AML defines “complex cytogenetics” and also is associated with an unfavourable prognosis.

The identification of recurrent chromosomal abnormalities in acute leukaemia, including translocations, inversions, and gene duplications, led to the identification and cloning of the involved genes. More recently, directed and genome-wide assays have provided a better understanding of the genomic landscape of AML. AML cells appear to carry, on average, a total of approximately 13 mutations per cell, far less than found in epithelial cancers. Of these, on average 5 mutations are in genes recurrently mutated in AML (so called driver mutations), with the remainder being considered as passenger mutations. Among the recurrently mutated driver mutations, several are of significant prognostic importance and thus are part of the standard evaluation of AML.CEBPA , a gene encoding a leucine zipper transcription factor involved in myeloid differentiation, is mutated in 4 to 15% of cases of AML and is associated with a more favourable prognosis. NPM1 encodes a nucleolar phosphoprotein with multiple functions. Mutations in NPM1 are found in approximately 30% of AML cases and are also associated with a more favourable prognosis. FLT3 is a receptor tyrosine kinase and is mutated in 30 to 35% of AML patients, one fourth of the time as a point mutation and three fourths of the time as an internal tandem duplication. Mutations in FLT3 are associated with a poorer clinical outcome. Other driver mutations recurrently mutated in AML include DNMT3A, IDH 1 and 2, NRAS and KRAS, RUNX1, TET2, and TP53.Although assays of the mutational status of these genes has not yet become standard, increasing numbers of studies are suggesting their possible utility both for prognosis and for treatment selection.

Whole-genome sequencing of paired samples of skin and bone marrow in individuals who transform from myelodysplastic syndromes to secondary AML shows that the genetic evolution of secondary AML is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection. The pre-existing myelodysplastic syndrome−founding clone persists with transformation to AML. With the acquisition of each new set of mutations, all the pre-existing mutations are carried forward, resulting in daughter subclones that contain increasing numbers of mutation during evolution.

The most common cytogenetic abnormality seen in adults with ALL is the Philadelphia (Ph) chromosome, or t(9;22). This translocation results in fusion of the BCR gene on chromosome 22 to the ABL tyrosine kinase gene on chromosome 9. This results in the constitutive activation of ABL , but the precise mechanism by which this activity leads to leukaemia is unclear. The BCR-ABL fusion is associated with both ALL and CML, with a difference in the breakpoint of BCR distinguishing the two. A slightly smaller 190-kD fusion protein is usually found in ALL, whereas a larger 210-kD protein is characteristic of CML. The frequency of t(9;22) in ALL increases with age: it is found in approximately 5% of childhood cases and 25% of adults. Before the development of specific tyrosine kinase inhibitors, ALL with t(9;22) had a poor prognosis; newer regimens combining tyrosine kinase inhibitors with chemotherapy are providing improved outcomes. The most common translocation seen in childhood ALL is t(12;21), which involves the genes TEL and AML1 . Like the AML-associated t(8;21) and inv(16), t(12;21) is thought to result in abnormal DNA transcription by interfering with the normal function of CBF. Although t(12;21) is difficult to diagnose by routine cytogenetics, by molecular studies it has been shown to account for 25% of childhood ALL and 4% of adult ALL and has a favourable prognosis. Partial deletions in 9p, seen in 5 to 7% of adults with ALL, are also associated with a favourable outcome. Other abnormalities sometimes seen in B-cell ALL include t(8;14) and t(8;22), which result in translocation of the MYC gene on chromosome 8 and immunoglobulin enhancer response genes on chromosomes 14 or 22; they are associated with a poor therapeutic outcome. T-cell ALLs are frequently associated with abnormalities of chromosome 7 or 14 at the sites of T-cell receptor enhancer genes on these chromosomes. The leukaemia cells in about 20% of patients with ALL have a propensity to gain chromosomes, sometimes reaching an average of 50 to 60 chromosomes per cell. Patients with such hyperdiploid leukaemias tend to respond well to chemotherapy.

As in AML, directed and genome-wide evaluation of cases of ALL have revealed recurrent mutations in addition to those already identified through cytogenetics. Among the most common are mutations in PAX5 and IKZF1 seen in 30 and 25% of cases of B-cell ALL respectively, and mutations in NOTCH1 seen in 35% of cases of T-cell ALL.

The signs and symptoms of acute leukaemia are usually rapid in onset, developing over a few weeks to a few months at most; they result from decreased normal marrow function and invasion of normal organs by leukemic blasts. Anaemia is present at diagnosis in most patients and causes fatigue, pallor, headache, and, in predisposed patients, angina or heart failure. Thrombocytopenia is usually present, and approximately one third of patients have clinically evident bleeding at diagnosis, usually in the form of petechiae, ecchymoses, bleeding gums, epistaxis, or haemorrhage. Most patients with acute leukaemia are significantly granulocytopenic at diagnosis. As a result, approximately one third of patients with AML and slightly fewer patients with ALL have significant or life-threatening infections when initially seen, most of which are bacterial in origin.

In addition to suppressing normal marrow function, leukemic cells can infiltrate normal organs. In general, ALL tends to infiltrate normal organs more often than AML does. Enlargement of lymph nodes, liver, and spleen is common at diagnosis. Bone pain, thought to result from leukemic infiltration of the periosteum or expansion of the medullary cavity, is a common complaint, particularly in children with ALL. Leukemic cells sometimes infiltrate the skin and result in a raised, nonpruritic rash, a condition termed leukaemia cutis . Leukemic cells may infiltrate the leptomeninges and cause leukemic meningitis, typically manifested by headache and nausea. As the disease progresses, central nervous system (CNS) palsies and seizures may develop. Although less than 5% of patients with ALL have CNS involvement at diagnosis, the CNS is a frequent site of relapse; therefore, CNS prophylaxis is an essential component of ALL therapy. Because the incidence of CNS disease is low in AML, there is no proven benefit to CNS surveillance or prophylaxis. Testicular involvement is seen in ALL, and the testicles are a frequent site of relapse. In AML, collections of leukemic blast cells, often referred to as chloromas or myeloblastomas , can occur in virtually any soft tissue and appear as rubbery, fast-growing masses.

Certain clinical manifestations are unique to specific subtypes of leukaemia. Patients with acute promyelocytic leukaemia (APL) of the M3 type commonly have subclinical or clinically evident disseminated intravascular coagulation (DIC; Chapter 175 ) caused by tissue thromboplastins released by the leukemic cells. Acute monocytic or myelomonocytic leukaemias are the forms of AML most likely to have extramedullary involvement. M6 leukaemia often has a long prodromal phase. Patients with T-cell ALL frequently have mediastinal masses.

Abnormalities in peripheral blood counts are usually the initial laboratory evidence of acute leukaemia. Anaemia is present in most patients. Most are also at least mildly thrombocytopenic, and up to one fourth have severe thrombocytopenia (platelets <20,000/µL). Although most patients are granulocytopenic at diagnosis, the total peripheral white cell count is more variable; approximately 25% of patients have very high white cell counts (>50,000/µL), approximately 50% have white cell counts between 5000 and 50,000/µL, and about 25% have low white cell counts (<5000/µL). In most cases, blasts are present in the peripheral blood, although in some patients the percentage of blasts is quite low or absent.

The diagnosis of acute leukaemia is typically established by marrow aspiration and biopsy, usually from the posterior iliac crest. Marrow aspirates and biopsy specimens are usually hypercellular and contain 20 to 100% blast cells, which largely replace the normal marrow. Occasionally, in addition to the blast cell infiltrate, other findings are present, such as marrow fibrosis (especially with M7 AML) or bone marrow necrosis. Marrow samples should also be evaluated by immunophenotyping and cytogenetics. If AML is suspected, samples should be evaluated for the presence of mutations in FLT3 NPM1 , and CEBPA . A diagnostic lumbar puncture is generally recommended in suspected cases of ALL, but not in asymptomatic cases of AML.

The prothrombin and partial thromboplastin times are sometimes elevated. In APL, reduced fibrinogen and evidence of DIC are often seen. Other laboratory abnormalities frequently present are hyperuricemia, especially in ALL, and increased serum lactate dehydrogenase. In cases of high cell turnover and cell death (e.g., L3 ALL), evidence of tumour lysis syndrome may be noted at diagnosis, including hypocalcaemia, hyperkalaemia, hyperphosphatemia, hyperuricemia, and renal insufficiency. This syndrome, which is more commonly seen shortly after therapy is begun, can be rapidly fatal if untreated.

The diagnosis of acute leukaemia is usually straightforward but can occasionally be difficult. Both leukaemia and aplastic anaemia can manifest with peripheral pancytopenia, but the finding of a hypoplastic marrow without blasts usually distinguishes aplastic anaemia. An occasional patient has hypocellular marrow and a clonal cytogenetic abnormality, which establishes the diagnosis of myelodysplasia or hypocellular leukaemia. A number of processes other than leukaemia can lead to the appearance of immature cells in the peripheral blood. Although other small round cell neoplasms can infiltrate the marrow and mimic leukaemia, immunologic markers are effective in differentiating the two. Leukemoid reactions to infections such as tuberculosis can result in the outpouring of large numbers of young myeloid cells, but the proportion of blasts in marrow or peripheral blood almost never reaches 20% in a leukemoid reaction. Infectious mononucleosis and other viral illnesses can sometimes resemble ALL, particularly if large numbers of atypical lymphocytes are present in the peripheral blood and the disease is accompanied by immune thrombocytopenia or haemolytic anaemia.

With the development of effective programs of combination chemotherapy and advances in hematopoietic cell transplantation, many patients with acute leukaemia can be cured. These therapeutic measures are complex and are best carried out at centres with appropriate support services and experience in treating leukaemia. Because leukaemia is a rapidly progressive disease, specific antileukemic therapy should be started as soon after diagnosis as possible, usually within 72 hours. The goal of initial chemotherapy is to induce a complete remission (CR) with restoration of normal marrow function. In general, induction chemotherapy is intensive and is accompanied by significant toxicities. Therefore, patients should be stabilized to the extent possible before specific antileukemic therapy is begun.

Preparing the Patient for Therapy

Severe bleeding usually results from thrombocytopenia, which can be reversed with platelet transfusions. Once thrombocytopenic bleeding is stopped, continued prophylactic transfusions of platelets is warranted to maintain the platelet count higher than 10,000/µL. Occasionally, patients also have evidence of DIC, usually associated with the diagnosis of M3 AML. If M3 AML is suspected as the cause, all- trans -retinoic acid (ATRA) should be started without waiting for molecular confirmation of the diagnosis; the drug can be discontinued if the diagnosis is not M3 AML. If active bleeding is due to DIC, low doses of heparin (50 U/kg) given intravenously every 6 hours can be of benefit. Platelets and fresh-frozen plasma (or cryoprecipitate) should be transfused to maintain the platelet count higher than 50,000/µL and the fibrinogen level greater than 100 mg/dL until the DIC abates. Whether heparin should be given prophylactically to patients with laboratory evidence of DIC but no active bleeding is an often debated but unsettled question.

Blood cultures should be obtained in patients with fever and granulocytopenia; while awaiting culture results, infection should be assumed and broad-spectrum antibiotics begun empirically. It is preferable to bring an infection under control before starting initial chemotherapy if the patient has an adequate granulocyte count. However, patients often have infection but essentially no granulocytes; in this situation, delaying chemotherapy is unlikely to be beneficial.

Patients with very high blast counts may develop symptoms attributable to the effect of masses of these immature cells on blood flow (leukostasis). Although randomized trials are lacking, many experts suggest immediate leukapheresis and administration of hydroxyurea (3 g/m /day orally for 2 or 3 days) in an effort to rapidly lower counts in asymptomatic patients with AML presenting with while blood cell counts greater than 100,000/µL and for ALL patients presenting with counts greater than 300,000/µL. The most often affected organs are the CNS and lungs. If CNS symptoms occur, immediate whole-brain irradiation (600 cGy in one dose) should be added. If pulmonary symptoms occur, high-dose corticosteroids are often used.

Before treatment, management in all patients should be aimed at preventing the tumour lysis syndrome. Patients should be hydrated and given allopurinol 100 to 200 mg orally or intravenously three times a day before chemotherapy is initiated. Allopurinol prevents the conversion of xanthine and hypoxanthine to uric acid, but does not affect already formed uric acid. Patients presenting with very high white cell counts may have uraemia and anuria secondary to greatly increased serum uric acid levels and intratubular crystallization, even before starting therapy. These patients should be treated with rasburicase 0.20 mg/kg/day for up to 5 days intravenously, given over 30 minutes. Rasburicase promotes the catabolism of already formed uric acid to allantoin. Urinary alkalinisation, a past standard, is no longer recommended because, although it increases uric acid solubility, it also increases the possibility of xanthine and calcium phosphate precipitation in the kidney.

The diagnosis of leukaemia usually comes as a profound psychological shock to the patient and family. Therefore, in addition to stabilizing the patient haematologically and metabolically, it is worthwhile to have at least one formal conference in which the patient and family are advised about the meaning of the diagnosis of leukaemia and the consequences of therapy before treatment is initiated.

Treatment of Acute Lymphoblastic Leukaemia

After the patient’s condition has been stabilized, antileukemic therapy should be started as soon as possible. Treatment of newly diagnosed ALL can be divided into three phases: remission induction, postremission therapy, and CNS prophylaxis.

Remission Induction

The initial goal of treatment is to induce CR, defined as the reduction of leukemic blasts to undetectable levels and the restoration of normal marrow function. A number of different chemotherapeutic combinations can be used to induce remission; all include vincristine and prednisone, and most add l -asparaginase and daunorubicin, administered over a period of 3 to 4 weeks. With such regimens, CR is achieved in 90% of children and 80 to 90% of adults. Because vincristine, prednisone, and l -asparaginase are relatively nontoxic to normal marrow precursors, the disease often enters CR after a relatively brief period of myelosuppression. Failure to achieve CR is usually due to either the leukemic cells’ resistance to the drugs or progressive infection. These two complications occur with approximately equal frequency.

Management of newly diagnosed acute myeloid leukaemia

  1. Induction—daunorubicin 60-90 mg/m /day for 3 days (or idarubicin 10-12 mg/m /day for 3 days) and cytarabine 200 mg/m /day for 7 days
  2. Postremission
  3. Favourable risk—cytarabine 3 g/m over 3 hr q12h on days 1, 3, and 5 every month for 4 mo
  4. Intermediate risk—as for favourable risk; or, if HLA-matched related or unrelated donor exists, allogeneic hematopoietic cell transplantation
  5. Unfavourable risk—proceed to allogeneic transplantation if possible; if not, treat as for intermediate risk

Management of newly diagnosed acute promyelocytic leukaemia

  1. Induction—ATRA 45 mg/m /day until complete remission plus daunomycin 45-60 mg/m /day for 3 days and cytarabine 200 mg/m /day for 7 days
  2. Consolidation #1—arsenic trioxide 0.15 mg/kg/day 5 days/wk for 5 wk; repeat course after 2-wk rest

Consolidation #2—ATRA 45 mg/m /day for 7 days and daunomycin 50 mg/m 2/day for 3 days; repeat course 1 mo later

  1. Maintenance—ATRA 45 mg/m /day for 15 days every 3 mo plus 6-MP 100 mg/m /day and MTX 10 mg/m /wk for 2 yr

Or, if intermediate/good risk, consider:

  1. Induction: Arsenic trioxide 0.15 mg/kg/day plus ATRA 45 mg/m /day until complete remission
    • Consolidation: Arsenic trioxide 0.15 mg/kg/day 5 days/wk, 4 wk on, 4 wk off for 4 cycles

ATRA 45mg/m /day 2 wk on, 2 wk off for 7 cycles

Management of newly diagnosed adult ph-negative acute lymphoid leukaemia

A. Induction (and courses 3, 5, 7)—cyclophosphamide 300 mg/m over 3 hr q12h for 6 doses on days 1, 2, 3; doxorubicin 50 mg/m on day 4; vincristine 2 mg/day on days 4 and 11; and dexamethasone 40 mg/day on days 1-4 and days 11-14

B. Consolidation (courses 2, 4, 6, 8)—MTX 200 mg/m2  over 2 hr, followed by 800 mg/m over 22 hr on day 1; high-dose cytarabine 3 g/m over 2 hr q12h for 4 doses on days 2 and 3

C. Four intrathecal treatments of MTX 12 mg alternating with cytarabine 100 mg are given during the first four courses of systemic therapy

ATRA = all- trans -retinoic acid; HLA = human leukocyte antigen; 6-MP = 6-mercaptopurine; MTX = methotrexate; Ph = Philadelphia chromosome [t(9;22)].

If no further therapy is given after induction of CR, relapse occurs in almost all cases, usually within several months. Chemotherapy after CR can be given in a variety of combinations, dosages, and schedules. The term consolidation chemotherapy refers to short courses of further chemotherapy given at doses similar to those used for initial induction (requiring rehospitalization). Usually, different drugs are selected for consolidation chemotherapy than were used to induce the initial remission. In the case of ALL, such drugs include high-dose methotrexate, cyclophosphamide, and cytarabine, among others. Most regimens include six to eight courses of intensive consolidation therapy. Maintenance involves the administration of low-dose chemotherapy on a daily or weekly outpatient basis for long periods. The most commonly used maintenance regimen in ALL combines daily 6-mercaptopurine and weekly or biweekly methotrexate. The optimal duration of maintenance chemotherapy is unknown, but it is usually given for 2 to 3 years. Maintenance is most beneficial for patients with pro- and pre-B-cell ALL, less so for T-cell ALL, and of no apparent benefit for patients with mature B-cell ALL.

Most chemotherapeutic agents that are given intravenously or orally do not penetrate the CNS well, and if no form of CNS prophylaxis is given, at least 35% of adults with ALL will develop CNS leukaemia. With prophylaxis, relapse in the CNS as an isolated event occurs in less than 10% of patients. Systemic chemotherapy with high-dose methotrexate (e.g., 200 mg/m intravenously over 2 hours, followed by 800 mg/mover 22 hours) and cytarabine (e.g., 3 g/mover 2 hours every 12 hours for four doses) can achieve therapeutic drug levels within the CNS. Alternatives are intrathecal methotrexate, intrathecal methotrexate combined with 2400 cGy radiation to the cranium, or 2400 cGy to the craniospinal axis.

Burkitt-like ALL (also called FAB L3 or mature B-cell ALL) is characterized by the presence of monoclonal surface immunoglobulin, cytogenetics showing t(8;14), and the constitutive expression of the MYC oncogene. Burkitt-like ALL, which accounts for 3 to 5% of adult cases of ALL, responds well to regimens that incorporate short, intensive courses of high-dose methotrexate (1.5 g/m over 24 hours with leucovorin), cytarabine (3 g/m over 2 hours every 12 hours for four doses), and cyclophosphamide (200 mg/m /day for 5 days); this regimen yields high rates of complete response and cures in about 50% of patients. Recent results suggest that the addition of rituximab may further improve outcomes.

Approximately 5% of paediatric cases and 25% of adult cases of ALL have cytogenetics showing t(9;22), the Ph chromosome. Historically, such patients had CR rates slightly lower than those seen in Ph-negative ALL and markedly reduced remission durations, averaging less than a year; few if any such patients were cured with conventional chemotherapy. Therefore, the general recommendation has been that such patients receive an allogeneic transplant during the first remission, if possible. With this approach, approximately 50% of patients can be cured. More recently, the addition of the tyrosine kinase inhibitor imatinib mesylate to conventional chemotherapeutic regimens has increased complete response rates, equalling those seen in Ph-negative ALL, but the impact of the addition of imatinib mesylate on the duration of remission is not yet known. Dasatinib, a second-generation BCR-ABL tyrosine kinase inhibitor, has demonstrated efficacy in relapsed/refractory adult Ph-positive ALL. Therapy with dasatinib and prednisone alone without chemotherapy appears sufficient to allow the majority of older patients with Ph-positive ALL to achieve an initial hematologic remission.

A number of factors are predictive of outcome in ALL, the most important of which are younger age, a lower white cell count at diagnosis, and favourable cytogenetics. With currently available treatment regimens, 80 to 85% of children and 35 to 40% of adults who initially achieve CR maintain that state for more than 5 years, and these patients are probably cured of their disease.

Most relapses occur within 2 years after diagnosis, and most occur in the marrow. Occasionally, relapse is initially found in an extramedullary site such as the CNS or testes. Extramedullary relapse is usually followed shortly by systemic (marrow) relapse and should be considered part of a systemic recurrence. With the use of chemotherapeutic regimens similar to those used for initial induction, 50 to 70% of patients achieve at least a short-lived second remission. A small percentage of patients for whom the initial remission was longer than 2 years may be cured with salvage chemotherapy. If the CNS or testes is the initial site of the relapse, specific therapy to that site is also required, along with systemic retreatment. Because the prognosis of relapsed leukaemia treated with chemotherapy is so poor, hematopoietic stem cell transplantation is usually recommended in this setting. Newer agents active in recurrent ALL include nelarabine for T-cell ALL and the anti-CD19 targeted agent blinatumomab and the anti-CD22 immunoconjugate inotuzumab in B-cell ALL. Complete responses have also recently been reported in early trials using chimeric antigen receptor T cells targeting CD19.

The use of high-dose chemoradiotherapy followed by hematopoietic stem cell transplantation from an HLA-identical sibling can cure 20 to 40% of patients with ALL who fail to achieve an initial remission or who have a relapse after an initial CR; it can cure 50 to 60% of patients who undergo transplantation during a first remission. Although there is still considerable debate, several recent studies have reported improved survival for adults with high-risk or standard-risk ALL who receive a hematopoietic stem cell transplant during a first remission rather than being treated with standard chemotherapy. The major limitations of transplantation are graft-versus-host disease, interstitial pneumonia, and recurrence of disease. If an HLA-identical sibling is not available, transplantation from a matched unrelated donor or transplantation of cord blood from a partially matched unrelated donor can be conducted, with results that approach those seen with matched related donors.

Treatment with a combination of an anthracycline and cytarabine (100 to 200 mg/m /day for 7 days) leads to CR in 60 to 80% of patients with AML. Prospective randomized trials have demonstrated that for patients aged 65 years or less idarubicin (10 to 12 mg/m /day for 3 days) or a higher dose of daunorubicin (60 to 90 mg/m /day for 3 days) is superior to the conventional daunorubicin dose of 45 mg/m /day for 3 days. Profound myelosuppression always follows when these agents are used at doses capable of achieving CR. Failure to achieve CR is usually due to either drug resistance or fatal complications of myelosuppression. In a randomized study of adults with AML, five doses of intravenous gemtuzumab ozogamicin (3 mg/m on days 1, 4, and 7 during induction and day 1 of each of the two consolidation chemotherapy courses) doubled the probability of event-free survival at 2 years.

Intensive consolidation chemotherapy with repeated courses of daunorubicin and cytarabine at doses similar to those used for induction, high-dose cytarabine (1 to 3 g/m /day for 3 to 6 days), or other agents prolongs the average remission duration and improves the chances for long-term disease-free survival. The best results reported to date have generally been achieved with repeated cycles of high-dose cytarabine. Unlike the situation with ALL, low-dose maintenance therapy is of limited benefit after intensive consolidation treatment. In AML, leukemic recurrence occurs less often in the CNS (approximately 10% of cases), most commonly in patients with the M4 or M5 variant. There is no evidence that CNS prophylaxis improves survival in AML.

Among patients in whom CR is achieved, 20 to 40% remain alive in continuous CR for more than 5 years, suggesting a probable cure. As with ALL, younger patients and those with a low white cell count at diagnosis have a more favourable outcome. The European LeukemiaNet recognizes four risk categories of AML based on cytogenetics and molecular testing. The favourable group includes those with t(8;21) or inv(16) and those with normal cytogenetics but mutated CEBPA or mutated NPM1 and wild-type FLT3. Intermediate I patients are those with normal cytogenetics but without mutations in NPM1 and CEBPA , or with mutations in FLT3. Intermediate II includes those with t(9;11), t(11;19), or those with cytogenetics abnormalities not classified as favourable or unfavourable. Finally, the unfavourable group includes those with inv(3), t(6 : 9), −5 or del5, −7 or del7, and those with complex cytogenetics ( Fig. 183-3 ). Patients withDNMT3A and NPM1 mutations and those with MLL translocations appear to selectively benefit from higher dose induction. Patients who have a preleukemic phase before their condition evolves into acute leukaemia and those whose leukaemia is secondary to prior exposure to chemotherapy have a poorer prognosis. Increased expression of the multidrug resistance gene 1 (MDR1) is also associated with a worse outcome.

Patients whose AML recurs after initial chemotherapy can achieve a second remission in about 50% of cases after retreatment with daunorubicin-cytarabine or high-dose cytarabine. The likelihood of achieving a second remission is predicted by the duration of the first remission: 70% in patients whose first remission persisted beyond 2 years, compared with less than 15% in those whose first remission lasted less than 6 months. Older patients may benefit from gemtuzumab ozogamicin (9 mg/m intravenously on days 1 and 15), a form of antibody-targeted chemotherapy. Second remissions tend to be short-lived, however, and few patients in whom relapse occurs after first-line chemotherapy are cured by salvage chemotherapy.

CR can be induced in at least 90% of patients with APL by using ATRA (45 mg/m/day orally until CR is achieved) in combination with an anthracycline. Patients treated with ATRA usually have their coagulation disorders corrected within several days. A unique toxicity of ATRA in the treatment of APL is the development of hyperleukocytosis accompanied by respiratory distress and pulmonary infiltrates. The syndrome responds to temporary discontinuation of ATRA and the addition of corticosteroids. By combining ATRA with anthracyclines for induction and consolidation and then using ATRA as maintenance therapy, approximately 70% of patients can be cured. Arsenic trioxide (0.15 mg/kg/day intravenously until CR is achieved) is effective in patients with recurrent APL and appears to improve overall survival if used as part of consolidation therapy for patients in their first CR. The combination of ATRA plus arsenic trioxide without any chemotherapy has recently been shown to be as effective as the standard ATRA-chemotherapy combination for patients with low- or-intermediate risk APL (i.e., those who present with white blood cell counts <10,000/µL).

For patients with AML in whom an initial remission cannot be achieved or for those who relapse after chemotherapy, hematopoietic stem cell transplantation from an HLA-identical sibling offers the best chance for cure. Fifteen percent of patients with end-stage disease can be saved by this treatment. If the procedure is applied earlier, the outcome is better: approximately 30% of patients who undergo hematopoietic stem cell transplantation at first relapse or second remission are cured, and 50 to 60% of patients are cured if hematopoietic stem cell transplantation is performed during the first remission. A large number of studies have prospectively compared the outcome of allogeneic hematopoietic stem cell transplantation with that of chemotherapy in patients with AML in first remission. The trends in all these studies have been toward higher treatment-related mortality but improved disease-free and overall survival time with allogeneic transplantation. Meta-analyses conclude that survival is improved with allogeneic transplantation from a matched sibling in first remission when compared with continued chemotherapy. This improvement is clearest in patients with unfavourable or intermediate-risk disease and is not seen in those in the favourable-risk category. The major limitations of allogeneic hematopoietic stem cell transplantation are lack of a matched sibling donor, graft-versus-host disease, interstitial pneumonia, and disease recurrence. Because transplant-related toxicities increase with patient age, some centres limit hematopoietic stem cell transplantation to those 65 years of age or younger. However, recent studies of reduced-intensity or nonmyeloablative allogeneic transplantation have shown encouraging results in patients with AML in remission at ages up to 75 years. Allogeneic transplantation using matched unrelated donors results in survival essentially equivalent to that seen using matched siblings, although there is a higher incidence of complications. Autologous hematopoietic stem cell transplantation offers an alternative for patients without matched siblings to serve as donors. In randomized trials, the use of autologous transplantation after consolidation chemotherapy significantly prolonged the duration of disease-free survival for patients with AML in first remission but did not alter overall survival.

The benefits of intensive consolidation chemotherapy in younger patients do not translate to patients older than 65 years, in part because older patients are less able to tolerate therapy, but also because AML in older patients is more often associated with unfavourable cytogenetics (particularly abnormalities of chromosomes 5 and 7) and more often overexpresses P-glycoprotein, resulting in the multidrug resistance phenotype. Accordingly, long-term survival rates of only 10 to 15% are seen with chemotherapy in patients older than 65 years. Otherwise healthy older patients can usually tolerate intensive chemotherapy and should be offered this treatment. However, intensive chemotherapy can cause more harm than good in older patients with poor performance status. In prospective randomized trials, low-dose cytarabine prolonged survival in older patients unfit for intensive therapy. Other alternative therapies for this group of patients include the demethylating agents azacytidine or decitabine or entry onto clinical trials.

Treatment of acute leukaemia, especially AML, is accompanied by a number of complications, the two most serious and frequent being infection and bleeding. During the granulocytopenic period that follows induction and consolidation chemotherapy, the risk for bacterial infection is high. A Cochrane review examined results of antibiotic prophylaxis compared with placebo in afebrile neutropenic patients. Antibiotic prophylaxis significantly decreased infection-related deaths, with the best results seen with quinolones. Despite prophylaxis, many patients are febrile while neutropenic, and patients can still develop important infections. The most common bacterial species vary somewhat from medical centre to medical centre, but Staphylococcus (primarily S. epidermidis ) and Enterococcus species are the most frequent gram-positive organisms, whereas Pseudomonas aeruginosa and enteric organisms such as Escherichia coli and Klebsiella species are the most common gram-negative organisms isolated.

Even if no cause for fever is found, bacterial infection should be assumed, and, in general, all patients with fever and neutropenia should receive broad-spectrum antibiotics. Monotherapy with an intravenous antipseudomonal agent, such as a carbapenem (e.g., imipenem-cilastatin), a cephalosporin (e.g., cefepime), or an antipseudomonal penicillin (e.g., piperacillin-tazobactam), is recommended as empirical therapy. Vancomycin should not be part of standard coverage in most patients but may be used in those with suspected catheter infections or severe mucositis and in patients with hemodynamic instability or altered mental status. Combination therapy with other gram-negative agents (e.g., aminoglycosides) may be needed. Once begun, antibiotics should be continued until patients recover their granulocyte counts, even if they become afebrile first. If documented bacteraemia persists despite appropriate antibiotics, the physician should consider removal of indwelling catheters.

Invasive fungal infections are also common following chemotherapy for acute leukaemia and are associated with significant morbidity and mortality. A review of randomized trials found a significant reduction in death from fungal infection in patients given antifungal prophylaxis. Posaconazole is considered by many to be more effective than fluconazole or itraconazole. In addition to being granulocytopenic, patients undergoing induction chemotherapy for leukaemia have deficient cellular and humoral immunity, at least temporarily, and therefore are subject to infections common in other immunodeficiency states, including Pneumocystis jirovecii (formerly Pneumocystis carinii ) infection and a variety of viral infections. P. jirovecii infection can be prevented by the prophylactic use of trimethoprim-sulfamethoxazole. In cytomegalovirus (CMV) -seronegative patients, CMV-seronegative or leukocyte-reduced blood products should be used to prevent primary infection. Herpes simplex can often complicate existing mucositis and can be prevented with prophylactic acyclovir. Acyclovir is also useful for the prevention and treatment of herpes zoster.

Myeloid growth factors (granulocyte or granulocyte-macrophage colony-stimulating factor), if given shortly after the completion of chemotherapy, shorten the period of severe myelosuppression by, on average, 4 days. In most studies, this accelerated recovery has resulted in fewer days with fever and less use of antibiotics, but it has not improved the complete response rate or altered survival.

The platelet count that signals a need for platelet transfusion has been the subject of debate. Traditionally, platelet transfusions from random donors were used to maintain platelet counts greater than 20,000/µL, but more recently it has been demonstrated that lowering this threshold to 10,000/µL is safe in patients with no active bleeding. In contrast, a no-prophylaxis strategy results in more days with bleeding and a shorter time to first bleeding episode and therefore is not recommended.  In 30 to 50% of cases, patients eventually become alloimmunized and require the use of HLA-matched platelets. Transfusion-induced graft-versus-host disease, manifesting as a rash, low-grade fever, elevated values in liver function tests, and decreasing blood counts, can be prevented by irradiating all blood products before transfusion.

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