Optimal management of patients with ALL requires careful attention to supportive care, including immediate treatment or prevention of metabolic and infectious complications (Chap. 24) and rational use of blood products (Chaps. 138 and 139). Other important supportive care measures, such as use of indwelling catheters, amelioration of nausea and vomiting, pain control, and continuous psychosocial support for the patient and family, are essential.
Hyperuricemia and hyperphosphatemia with secondary hypocalcemia are frequently encountered at diagnosis, even before chemotherapy is initiated, especially in patients with B-cell or T-cell ALL or precursor B-cell leukemia with high leukemic cell burden.98 Patients should be given intravenous fluids; allopurinol or rasburicase (recombinant urate oxidase) to treat hyperuricemia; and a phosphate binder, such as aluminum hydroxide, calcium carbonate (if the serum calcium concentration is low), lanthanum carbonate, or sevelamer to treat hyperphosphatemia. Allopurinol, a relatively inexpensive drug, is usually used if the uric acid is less than 7 mg/dL. Allergic skin reactions occur in approximately 10 percent, and allopurinol should be stopped as soon as the risk of hyperuricemia from the destruction of a large leukemic cell burden has passed. By inhibiting de novo purine synthesis in leukemic blast cells, allopurinol can reduce the peripheral blast-cell count before chemotherapy.99 Allopurinol can decrease both the anabolism and catabolism of mercaptopurine by depleting intracellular phosphoribosyl pyrophosphate and by inhibiting xanthine oxidase. If mercaptopurine and allopurinol are given together orally, the dosage of mercaptopurine must be reduced.
Rasburicase works very rapidly and is extremely effective, especially for very elevated uric acid levels (>7 mg/dL), often with one infusion (a far smaller dose than the manufacturer recommends). Rasburicase breaks down uric acid to allantoin, a readily excreted metabolite that is five to 10 times more soluble than uric acid. Rasburicase is more effective than allopurinol, and it facilitates phosphorus excretion, partly because of rasburicase’s potent uricolytic effect (which obviates the need to alkalinize urine) and partly because of improved renal function with its use.100 However, rasburicase is contraindicated in patients with glucose-6-dehydrogenase deficiency because hydrogen peroxide, a by-product of uric acid breakdown, can cause methemoglobinemia or hemolytic anemia.
For patients with extreme leukocytosis (leukocyte count >400 × 109/L), either leukapheresis or exchange transfusion (in small children) can be used to reduce the burden of leukemic cells. In theory, either treatment should reduce the complications associated with leukostasis, but the short- and long-term benefits of the procedures are questionable.70 Emergency cranial irradiation, once advocated by some leukemia therapists, probably has no role in the treatment of these patients. Preinduction therapy with low-dose glucocorticoids, with addition of vincristine and cyclophosphamide in cases of B-cell ALL, is a favored means of ameliorating hyperleukocytosis. This method, when used in conjunction with urate oxidase, has largely eliminated tumor lysis syndrome and the need for hemodialysis in patients with mature B-cell ALL.
Infections are common in febrile patients with newly diagnosed ALL. Therefore, any patient presenting with fever, especially a patient with neutropenia, should be given broad-spectrum antibiotics until infection is excluded. Remission induction therapy can increase susceptibility to infection by exacerbating myelosuppression, immunosuppression, and mucosal breakdown. At least 50 percent of patients undergoing induction therapy experience infections. Special precautions should be taken to reduce the risk of infection during this critical phase of treatment, including protective contact isolation and air filtration; elimination of contact with people with infections; refraining from eating certain food products, such as raw cheese, uncooked vegetables, or unpeeled fruits; and use of antiseptic mouthwash or sitz baths, especially for patients with mucositis. Good hand washing practices and the use of alcohol-based cleansers are important. Administration of granulocyte colony-stimulating factor can hasten recovery from neutropenia and reduce the complications of intensive chemotherapy, but does not improve the EFS rate for children or adults.101,102 One study suggested growth factor increased the risk of therapy-related acute myeloid leukemia in the context of epipodophyllotoxin-based therapy.103 Intensified remission induction regimens, especially in combination with high-dose glucocorticoids, have resulted in an increased risk of disseminated fungal infection and death. Antifungal prophylaxis is commonly given.
All nonallergic patients with ALL are given trimethoprim-sulfamethoxazole, 2 to 3 days per week, as prophylactic therapy for Pneumocystis carinii (Pneumocystis jiroveci) pneumonia. Prophylaxis is started after 2 weeks of remission induction and continues for several months after completion of all chemotherapy. Alternative treatments for patients who cannot tolerate trimethoprim-sulfamethoxazole include aerosolized pentamidine, dapsone, and atovaquone.104 Live-virus vaccines should not be administered during immunosuppressive therapy. Siblings and other children who have frequent contact with patients can receive routine immunizations, including inactivated poliomyelitis vaccine. Susceptible patients exposed to varicella virus should receive zoster immunoglobulin within 96 hours of exposure together with acyclovir. Such treatment usually prevents or mitigates the clinical manifestations of varicella.
ALL and its treatment leads to pancytopenia. Hemorrhagic manifestations are common but usually are limited to the skin and mucous membranes. Although rare, bleeding in the CNS, lungs, or gastrointestinal tract can be life-threatening. Patients with extremely high leukocyte counts (>400 × 109/L) at diagnosis are more likely to develop such complications.70 Coagulopathy attributable to disseminated intravascular coagulation, hepatic dysfunction, or chemotherapy is usually mild.76 Patients receiving l-asparaginase and a glucocorticoid have a hypercoagulable state. Platelet transfusions should be given therapeutically for overt bleeding and may be used prophylactically when platelet counts are less than 10 × 109/L.105 Anticoagulants and antiplatelet agents such as aspirin must be avoided. Children generally do not have active bleeding during remission induction therapy with prednisone, vincristine, and l-asparaginase, even when platelet counts are less than 10 × 109/L. A higher threshold for prophylactic platelet transfusions should be considered for active toddlers and patients with fever or infection. Transfusion of packed leukocyte-poor red cells is indicated in patients with anemia and marrow suppression but should be delayed until the leukocyte count is reduced in patients with extreme hyperleukocytosis. Transfusions should be given slowly in patients with profound but chronic anemia to prevent development of congestive heart failure. Granulocyte transfusions are rarely needed, but should be considered for patients with absolute neutropenia and documented Gram-negative septicemia or disseminated fungal infection that is responding poorly to antimicrobial treatment alone. All blood products should be irradiated to prevent transfusion-related graft-versus-host disease.
Because ALL is a heterogeneous disease with many distinct subtypes, there is no uniform approach to therapy. Increasingly, treatment is targeted to biologically distinct subgroups. The best results have been reported from experienced treatment centers using well-designed and rigorously applied protocols.106,107,108,109 No consensus exists on the risk criteria and the terminology for defining prognostic subgroups. Usually, childhood ALL cases are divided into standard-risk, high- (intermediate- or average-) risk, and very-high-risk groups, although the United States’ Children’s Oncology Group advocates four categories, including low risk, to accommodate patients with a very low risk of relapse. Adult cases are generally divided into two risk groups. Often infant and elderly ALL are considered special subgroups of ALL that require different treatment, primarily related to intolerance. One study showed improved outcome for infant ALL, using a hybrid treatment protocol with elements to treat both ALL and acute myeloid leukemia, and reducing dose intensity in the very young infants.110 Few studies have been performed in those older than 60 years of age and their management remains a therapeutic challenge.111,112 Some successes have been achieved with the use of dose-reduced regimens and the addition of imatinib or dasatinib for patients with Philadelphia chromosome–positive ALL.113,114 Because cure is not common in patients older than age 70 years, maintenance of a good quality of life is a major goal for this age group.
Mature B-Cell Acute Lymphoblastic Leukemia (Burkitt-Type)
The most effective contemporary treatment regimens for mature B-cell (Burkitt-type) ALL are drug combinations that include cyclophosphamide and/or ifosfamide given over a relatively short time (3 to 6 months). The first major breakthrough in this disease was reported by French investigators, who achieved a 68 percent EFS rate in their LMB84 study featuring high-dose cyclophosphamide, high-dose methotrexate, vincristine, doxorubicin, and conventional doses of cytarabine. In the LMB89 study, the same group reported a cure rate of 87 percent, which was achieved by using increased doses of methotrexate (to 8 g/m2 per dose) and cytarabine (3 g/m2 per dose) and by adding etoposide for patients with a large leukemia cell burden.115 This excellent result has been confirmed in a randomized international study.116 Successful treatments also have been developed by the Berlin-Frankfurt-Münster consortium, which uses a multiagent regimen that incorporates cyclophosphamide, high-dose methotrexate (1 g/m2 per dose), etoposide, ifosfamide, doxorubicin, dexamethasone, and cytarabine (3 g/m2 per dose).117 These intensive pediatric protocols have been translated into adult treatment regimens that are completed in as little as 18 weeks.118,119,120 Because of its demonstrated efficacy in B-cell lymphoma, rituximab (anti-CD20) has been incorporated in frontline clinical trials for adults with B-cell ALL.118,120 Maintenance or continuation therapy is not needed. The remission rate is very high, and most remissions are durable. B-cell ALL rarely, if ever, reoccur after the first year.
Effective CNS therapy is an essential component of successful regimens for B-cell ALL and generally consists of methotrexate and cytarabine administered both systematically and intrathecally. Cranial irradiation does not appear to be necessary even for patients presenting with CNS leukemia.116,120
Precursor B-Cell and T-Cell Acute Lymphoblastic Leukemia
Treatment for leukemias affecting the precursor B-cell and T-cell lineages consists of three standard phases: remission induction, intensification (consolidation), and prolonged continuation (maintenance) therapy.121 CNS-directed therapy, which overlaps other treatments, is started early and is given for different lengths of time, depending on the patient’s risk of relapse and the intensity of the primary systemic regimen.
Remission Induction The first goal of therapy is inducing a complete remission and restoring normal hematopoiesis. The induction regimen typically includes a glucocorticoid (prednisone, prednisolone, or dexamethasone), vincristine, and l-asparaginase for children or an anthracycline for adults.17,67,106,107,108 Children with high- or very-high-risk ALL, and nearly all young adults with ALL, receive four or more drugs (daunorubicin, vincristine, glucocorticoid, and l-asparaginase) during remission induction in contemporary clinical trials. Improvements in chemotherapy and supportive care have resulted in complete remission rates of approximately 98 percent for children and 85 to 90 percent for adults. When a complete clinical remission is induced, patients have various degrees of residual leukemia.122 Because the extent of residual disease is well correlated with long-term outcome,83,123,124,125,126,127,128,129 the concept of a “molecular” or “immunologic” remission, defined as leukemia less than 0.01 percent of nucleated marrow cells,122 is beginning to supplant the traditional perception of remission, which is based solely on microscopic criteria.129 Prospective trials are needed to demonstrate that outcomes will improve when interventions to change therapy are based on measurements of residual disease.
Attempts have been made to intensify induction therapy based on the premise that more rapid and complete reduction of the leukemia cell burden forestalls the development of drug resistance. However, several studies have suggested intensive induction therapy is unnecessary for children with standard-risk ALL, provided patients receive postinduction intensification therapy.107 Intensive induction can lead to increased early morbidity and mortality. More intensive induction regimens with additional cyclophosphamide, high-dose cytarabine, or high-dose anthracycline also have been tested in adults with ALL and have yielded no clear benefit, partly because of the low tolerance of adults to drug toxicity.130,131 However, in one study, the use of high-dose dexamethasone (10 mg/m2 per day) instead of prednisone (60 mg/m2 per day) during remission induction significantly improved treatment outcome for children with ALL, especially those with T-cell ALL and good prednisone response, despite a higher induction death rate.121,132 Conceivably, intensified remission induction with other relatively nonmyelosuppressive drugs can also improve treatment outcome. Dexamethasone provided better control of systemic and CNS disease than did prednisone in two randomized studies of childhood ALL.133,134
The pharmacodynamics of asparaginase differ by formulation and three forms are available: one derived from Erwinia chrysanthemi, another prepared from Escherichia coli, and a third made of a polyethylene glycol form of the E. coli product (pegaspargase).135,136 In terms of leukemic control, the dose intensity and duration of asparaginase treatment (i.e., the amount of asparagine depletion) are far more important than the type of asparaginase used. The dosages of the three preparations are based on their half-lives. Pegaspargase, which has the longest half-life, usually is administered at 2500 IU/m2 every other week for one to two doses in cases of newly diagnosed ALL. By contrast, the Erwinia preparation, which has the shortest half-life, is administered at 20,000 IU/m2 three times per week for 6 to 12 doses. The doses of E. coli l-asparaginase range from 5000 to 10,000 IU/m2, administered two to three times per week for 6 to 12 doses. Because of lower immunogenicity, improved efficacy, and less-frequent administration, pegaspargase has replaced the native product as the first-line treatment for children and adults in the United States, and is also increasingly used in other ALL trials around the world.137,138,139,140 None of the various anthracyclines (daunorubicin, doxorubicin, idarubicin, and mitoxantrone) given to adults with ALL has proven superior to any other; daunorubicin is used most commonly.
Intensification (Consolidation) Therapy After normal hematopoiesis is restored, patients in remission become candidates for intensification therapy. Such treatment, administered shortly after remission induction, refers to readministration of the induction regimen or to high doses of multiple agents not used during the induction phase. Although there is no dispute on the importance of this treatment in childhood ALL, there is no consensus on the best regimen and duration of treatment. More commonly used regimens for childhood ALL include high-dose methotrexate with or without mercaptopurine, high-dose l-asparaginase given for an extended period, or a combination of dexamethasone, vincristine, l-asparaginase, and doxorubicin, followed by thioguanine, cytarabine, and cyclophosphamide.107,108,121,137,141,142 This phase of therapy has improved outcomes, even for patients with low-risk ALL.143 Patients with ETV6-RUNX1 have an especially good outcome in clinical trials featuring intensive postremission treatment with glucocorticoids, vincristine, and asparaginase.144,145 A very high dose of methotrexate (5 g/m2) appears to improve the treatment outcome of patients with T-cell ALL.141,146 This finding is consistent with data indicating T-cell blasts accumulate methotrexate polyglutamates (active metabolites of the parent compound) less avidly than do B-cell precursors; consequently, higher serum levels of the drug are needed for an adequate therapeutic effect.147,148 The conventional dose of methotrexate (1 g/m2) may be too low for many patients with B-cell precursor ALL. Among B-lineage ALL, blasts with either ETV6-RUNX1 or TCF3-PBX1 gene fusion accumulate significantly lower methotrexate polyglutamates compared to those with hyperdiploidy or other genetic abnormalities.149 This finding suggested that patients with ETV6-RUNX1 or TCF3-PBX1 gene fusion would also benefit from a higher dose of methotrexate.
Based on pediatric studies, intensive consolidation therapy has become a standard in the treatment of adult ALL even though early studies failed to show the benefit of this phase of treatment. Various drugs have been used for intensification, including high-dose methotrexate, high-dose cytarabine, cyclophosphamide, and asparaginase.67,102,150,151,152,153 Increasingly, intensification treatment is risk-adapted and subtype specific. In the German 06/93 study, high-dose methotrexate was used for patients with standard-risk B-cell precursor ALL, high-dose methotrexate and high-dose cytarabine for high-risk B-cell precursor ALL, and cyclophosphamide for T-cell ALL. The hyper-CVAD (cyclophosphamide, vincristine, Adriamycin, dexamethasone) regimen of the MD Anderson Cancer Center alternates the combination of cyclophosphamide, vincristine, doxorubicin (Adriamycin), and dexamethasone, with high-dose methotrexate and high-dose cytarabine for four courses each. More recently, rituximab has been added for patients with CD20 expression on lymphoblasts.150,151 In adults, methotrexate dose should probably be limited to 1.5 to 2.0 g/m2 because higher doses may lead to excessive toxicities, delayed subsequent treatment, and reduced compliance. In a Cancer and Leukemia Group B study, a five-drug remission induction was followed by early and late intensification courses with eight drugs.67 These studies and others suggested the benefit of early intensive consolidation therapy, especially in young adults. In adult T-cell ALL, benefit is derived from cyclophosphamide and cytarabine.67,102 In other adult cases of standard-risk and high-risk ALL, the benefit is derived from high-dose cytarabine. Two German multicenter trials using high-dose cytarabine, mitoxantrone, and allogeneic hematopoietic stem cell transplantation showed markedly improved results in cases bearing the t(4;11), which generally confers an adverse prognosis.154 Several ongoing trials are testing the efficacy of asparaginase during intensification in young adult ALL137 because this drug clearly improves outcome in childhood ALL and is better tolerated during consolidation treatment than during remission induction.
Patients diagnosed with ALL between the ages of 16 and 39, often considered together as adolescents and young adults, are commonly treated by either adult or pediatric hematologists. Several retrospective comparative analyses have reported that adolescents and young adults with ALL treated on pediatric protocols have had superior event-free and overall survival rates when compared with similar patients enrolled on adult ALL trials. Preliminary data suggest that these patients have better outcomes when treated with pediatric-inspired regimens, and that excess toxicity is not observed.153,155,156,157,158,159,160,161,162
Continuation Therapy Although unnecessary for cure of mature B-cell leukemia, continuation therapy for 2 to 3 years is an integral part of pediatric and adult ALL regimens. Attempts to shorten the duration of treatment have led to inferior outcomes in both childhood and adult ALL,163 although as many as two-thirds of childhood cases might be cured with only 12 months of treatment.164 However, which subgroups of childhood ALL can be cured with abbreviated therapy is unclear. In a meta-analysis of 42 trials, a third year of continuation therapy reduced the likelihood of relapse during the third year, but no advantage to prolonging treatment beyond 3 years was observed.165 Early studies demonstrated that the third year of continuation therapy benefits boys but not girls.166,167 Hence, most studies discontinue all therapy for girls after 2 to 2.5 years of treatment. It is uncertain whether with improved contemporary treatment boys still require prolonged continuation treatment. Whether adults with ALL benefit from prolonged continuation therapy is also unclear. In most adult trials, continuation therapy is given for 2 years from diagnosis.
Methotrexate administered weekly and mercaptopurine administered daily constitute the usual continuation regimen for ALL. Accumulation of higher intracellular concentrations of the active metabolites of methotrexate and mercaptopurine and administration of this combination to the limits of tolerance (as indicated by low leukocyte counts) have been associated with improved clinical outcome.168,169 Many investigators advocate that drug dosage be adjusted to maintain leukocyte counts below 3 × 109/L and neutrophil counts between 0.5 and 1.5 × 109/L to ensure adequate dose intensity during the continuation treatment in childhood ALL.2 In one study, the dose intensity of mercaptopurine was the most important pharmacologic factor influencing treatment outcome.170 Mercaptopurine is most effective when it is given orally on a daily basis. However, overzealous use of mercaptopurine is counterproductive, as such use results in neutropenia and interruption of chemotherapy, reducing overall dose intensity. The effect of mercaptopurine is better when the drug is administered in the evening.171 Mercaptopurine should not be given with milk or milk products containing xanthine oxidase, which can degrade the drug.172 Antimetabolite treatment should not be withheld because of isolated increases of liver enzymes since such liver function abnormalities are tolerable and reversible.173
A few patients (one in 300) have an inherited homozygous deficiency of thiopurine S-methyltransferase, the enzyme that catalyzes the S-methylation (inactivation) of mercaptopurine. In these patients, standard doses of mercaptopurine have potentially fatal hematologic side effects. The drug should be given in much smaller doses (e.g., 10-fold reduction).174 Approximately 10 percent of patients are heterozygous for the enzyme deficiency and have intermediate levels of thiopurine methyltransferase.175 This subgroup can be treated safely with only moderate reductions in mercaptopurine dosage and appears to have better clinical outcomes than do patients with the homozygous wild-type phenotype. Importantly, patients with this enzyme deficiency are at risk for therapy-related myeloid leukemia and radiation-related brain tumors.176,177,178 Identification of this autosomal codominant trait has been enabled by molecular diagnosis and led to increased emphasis on inherited differences in drug metabolism and disposition resulting from genetic polymorphisms in drug-metabolizing enzymes and in drug transporters, receptors, and targets.1,179,180 Ultimately, therapy can be designed according to the genetic constitution of both the host and the host’s leukemia cells.
Because thioguanine is more potent than mercaptopurine in model systems and leads to higher concentrations of thioguanine nucleotides in cells and cytotoxic concentrations in CSF,181 randomized trials have been performed in children to compare the effectiveness of these two drugs.182 Thioguanine, given at a daily dose of 40 mg/m2 or more, produced superior antileukemic responses to mercaptopurine, but was associated with profound thrombocytopenia, an increased risk of death, and unacceptable rate of hepatic venoocclusive disease.182 Consequently, mercaptopurine, remains the drug of choice for ALL, although thioguanine is still used in short-term courses during the intensification phase of therapy.
Intermittent pulses of vincristine and a glucocorticoid improved the efficacy of antimetabolite-based continuation regimens and have been widely adopted for both childhood and adult ALL.165,183 In older children and adults, prolonged glucocorticoid therapy may lead to increased risk of osteonecrosis.184 Another integral component of many protocols is reinduction therapy introduced relatively soon after the first remission. This treatment, which relies on the same drugs used during the initial phase of induction therapy, has improved outcomes for children and adults with ALL.67,106,107,108 A second reinduction phase during continuation treatment may further improve the outcome of patients with standard- or high-risk ALL.142,185 The benefit of such a double-delayed intensification may result from either the increased dose intensity of other agents such as asparaginase or anthracycline or the timing or scheduling of the intensification regimen.
Therapy of the Central Nervous System The CNS is a common sanctuary for leukemic cells and requires prophylactic or presymptomatic therapy. In the 1970s, the cornerstone of ALL therapy was cranial irradiation (2400 cGy) plus methotrexate administered intrathecally after complete remission was induced. Concerns that cranial irradiation could cause second cancer, late neurocognitive deficits, and endocrinopathy stimulated efforts to replace cranial irradiation with early intensification by intrathecal and systemic chemotherapy. Two early clinical trials tested the feasibility of complete omission of prophylactic cranial irradiation in the treatment of childhood ALL.186,187,188 Although the cumulative risk of an isolated CNS relapse was relatively low (3 to 4 percent), the EFS rates in the two studies were only 68.4 percent and 60.7 percent.186,187,188 In another study, prophylactic cranial irradiation appeared to improve outcome in T-cell ALL with leukocyte counts >100 × 109/L.189 Thus, until recently, virtually all childhood study groups continued to rely on prophylactic cranial irradiation for up to 20 percent of patients.80 A radiation dose of 1200 cGy appeared to provide adequate protection against CNS relapse, even in high-risk patients (e.g., those with T-cell ALL and leukocyte counts >100 × 109/L).141 More recently, a study at St. Jude Children’s Research Hospital again tested the feasibility of total omission of prophylactic cranial irradiation in the context of risk-adapted intrathecal and systemic chemotherapy.190 The 5-year survival rate for the 498 patients enrolled was 93.5 percent and the cumulative risk of an isolated CNS relapse rate was only 2.7 percent, a promising result, suggesting that prophylactic cranial irradiation can be safely omitted in the context of the effective intrathecal and systemic chemotherapy. Another study by the Dutch Childhood Oncology Group also showed that prophylactic cranial irradiation can be safely omitted from children with ALL.191 Preliminary data from additional trials also indicate that prophylactic cranial irradiation is not necessary.
Systemic treatment including high-dose methotrexate, intensive asparaginase, and dexamethasone, as well as optimal intrathecal therapy, is important to control CNS leukemia.80,192 Triple intrathecal therapy with methotrexate, cytarabine, and hydrocortisone is more effective than intrathecal methotrexate in preventing CNS relapse.193 Because the presence of ALL blasts in the CSF, even from traumatic lumbar puncture, is associated with an increased risk of CNS relapse and poor EFS,80,81 intrathecal therapy should be intensified in patients with this feature. With CNS prophylaxis and high-dose systemic therapy most adults with ALL remain free of CNS disease. CNS disease at the time of leukemia relapse in adults occurs in approximately 10 percent of cases. The frequency of CNS recurrence is about the same whether CNS radiation therapy (12 to 24 Gy) is used or whether only intrathecal cytotoxic therapy is used. Systemic high-dose methotrexate and cytarabine add to the CNS therapy. The outcome after CNS relapse is poor. Survival after CNS relapse is usually less than 1 year in adults. Treatment of CNS relapse requires cranial irradiation, intrathecal chemotherapy, typically via an Ommaya shunt, plus reinduction and reconsolidation systemic therapy.
Stem Cell Transplantation Hematopoietic stem cell transplantation during first remission remains controversial.194 In adult ALL, long-term disease-free survival rates range from 35 to 50 percent with chemotherapy alone and from 45 to 60 percent with allogeneic transplantation.195,196 However, interpretation of these results is difficult because of the lack of true randomization. Even so, results from both adult and pediatric studies suggest allogeneic transplantation benefits some high-risk patients.194,196,197 Because of their unfavorable prognosis, patients with the Philadelphia chromosome–positive ALL and those with a poor initial response to induction therapy have been recommended to undergo allogeneic stem cell transplantation during the first remission.194,195,196,198 However, the advent of improved chemotherapy has diminished the survival advantage from transplantation in children with Philadelphia chromosome–positive ALL.199 The use of a tyrosine kinase inhibitor has further improved the early treatment results,200 casting doubt on the benefit from transplantation in first remission in childhood cases.201 Allogeneic transplantation appears to improve the outcome of adults with the t(4;11),154 but not that of children or infants with the same genotype.202
Allogeneic transplantation has not been compared to chemotherapy alone in a true randomized trial, and thus the results of comparative studies are biased by availability of appropriate donors and other factors.194,203,204,205 The more potent antileukemia activity of allogeneic transplantation is balanced against the considerable nonrelapse mortality and long-term consequences of graft-versus-host disease. A meta-analysis involving 3157 patients supports matched sibling donor allogeneic transplantation as the optimal postremission therapy for adults with ALL with a significant reduction in relapses and a significant increase in treatment related mortality. Results may differ depending upon stem cell source, that is, related or unrelated donors or umbilical cord stem cells. A retrospective study of 421 adults who underwent allogeneic cord blood transplantation reported 2-year leukemia-free survival of 39 percent for patients in first complete remission and 31 percent for second remission. In multivariate analysis, factors associated with poor outcomes were age older than 35 years, myeloablative conditioning, and more advanced disease. Reduced intensity-conditioning allografting has yielded lower nonrelapse mortality and higher relapse rates than myeloablative conditioning with no significant differences in leukemia-free survival.206,207 The indications for allogeneic transplantation in first remission should be reevaluated as chemotherapy and transplantation continue to improve. Autologous transplantation failed to improve outcome in adult ALL overall, mainly because of a high rate of relapse.195 Several small studies indicate that autologous stem cell transplantation is feasible and beneficial for adults with Philadelphia chromosome–positive ALL who achieve a molecular remission after combined chemotherapy and imatinib.208,209
Targeted Therapies The best example of targeted therapy is the use of the tyrosine kinase inhibitors imatinib or dasatinib in Philadelphia chromosome–positive ALL.21,113,114,210 Used as single agents or with a glucocorticoid, they can induce complete remission in older patients where this subset of ALL is more common.114,210,211 In combination with chemotherapy, they not only induce a higher complete remission rate but also a high rate of molecular remission in children and adults.200,201,212,213,214,215,216 The duration of these remissions is uncertain, but some have been quite long after additional chemotherapy. Although the need for early transplantation in childhood cases is uncertain, this treatment modality is still a standard for adult cases.206,217 The use of imatinib or dasatinib yields a higher proportion of adult cases suitable for transplantation. The outcome depends on minimal residual disease before and after transplantation.218 In patients with residual disease after transplantation, rapid response to imatinib was associated with a superior survival.219 It is uncertain whether and when to discontinue imatinib or dasatinib after the patient is treated with chemotherapy or transplantation.
Surface expression of CD20 by leukemia cells is associated with an inferior outcome in adult,220 but not childhood, ALL.221 Chemotherapy trials incorporating rituximab, an anti-CD20 antibody, have yielded promising results in adults with CD20-positive B-cell precursor ALL.150,222 Other monoclonal antibodies that bind CD22 and CD19 are in late-stage clinical development.223 Nelarabine is an approved antimetabolite drug that has shown considerable activity in T-cell ALL, both alone and in combination with other chemotherapy.224,225,226