In addition to reduction of systemic disease burden, another key goal of post-induction therapy is the prevention of CNS disease. Introduction of prophylactic cranial radiation was a historic milestone in averting CNS relapse, which otherwise occurred in over half of patients following induction of remission. However, it has been largely replaced by alternative approaches in recent decades because of the substantial associated morbidity of acute neurotoxicity, long-term neurocognitive deficits, growth impairment, second malignancies, endocrinopathies, and obesity.
The St. Jude Children's Research Hospital group recently reported that a regimen omitting cranial radiation for all patients with newly diagnosed ALL (of whom 9 of 498 had overt CNS disease) produced 5-year event-free and overall survival figures that did not differ significantly between cases and historical controls. However, most cooperative groups currently use cranial radiation for between 2% and 20% of patients who have significant risk factors for CNS relapse—eg, CNS2 and CNS3 involvement at diagnosis (see Table 2 for definitions), hyperleukocytosis, T-cell immunophenotype, BCR-ABL1 positivity, MLL rearrangement, or hypodiploidy. Typically, radiation doses of 12 to 18 Gy are used for prevention, and doses of 18 to 24 Gy are used for treatment of CNS3 disease. Recently, the Dana-Farber Cancer Institute Consortium reported that hyperfractionated (twice-daily) delivery of cranial radiation does not improve late neuropsychologic function and may actually decrease antileukemic efficacy, compared to conventionally fractionated (daily) radiation.
Other effective approaches to the control and/or prevention of CNS disease include intensive intrathecal therapy and the use of systemic chemotherapy regimens with CNS penetration, such as dexamethasone(Drug information on dexamethasone), high-dose methotrexate, high-dose cytarabine, and intensive asparaginase. The relative benefit of triple intrathecal therapy (methotrexate, cytarabine, and hydrocortisone(Drug information on hydrocortisone)) versus single-agent intrathecal methotrexate(Drug information on methotrexate) in ALL remains unclear. A recent CCG study reported that triple intrathecal therapy decreased CNS relapses but unexpectedly led to inferior overall survival due to increased bone marrow and testicular relapses. However, the systemic therapy used in this protocol, administered from 1996 to 2000, was substantially less intensive than most current regimens. When triple intrathecal therapy is combined with a backbone of intensive systemic therapy, the outcomes appear to be excellent.
Maintenance or continuation therapy, which consists of approximately 2 to 3 years of primarily oral antimetabolites, is a unique feature of ALL treatment. Presumably, maintenance therapy eradicates MRD, perhaps by inducing leukemia progenitor differentiation. The cornerstone of ALL maintenance is oral weekly methotrexate and daily mercaptopurine. Methotrexate potentiates mercaptopurine by reducing de novo purine synthesis, which leads to greater incorporation of thiopurines into DNA and RNA. Interestingly, evening dosing of mercaptopurine appears to be more efficacious. Maintaining dose intensity of methotrexate and mercaptopurine during maintenance is significantly positively associated with EFS; however, excessive dose escalation is to be avoided, since periodic suspension because of neutropenia has a negative impact on EFS. Host genotype for thiopurine methyltransferase (TPMT), the enzyme responsible for mercaptopurine metabolism, significantly affects drug activity. Homozygosity for a mutant allele occurs in approximately 1 in 300 persons and results in very high thioguanine levels, profound myelosuppression, and an increased risk of second malignancies at standard mercaptopurine doses; heterozygosity occurs in 10% of the population and results in moderately elevated levels and toxicities. Some groups therefore employ prospective TPMT genotyping to guide mercaptopurine dosing.
Several studies have compared thioguanine and mercaptopurine during maintenance.[44-46] Both are prodrugs that require conversion to active metabolites, thioguanine nucleotides, with thioguanine requiring fewer steps and also demonstrating greater CNS penetration. However, despite the superior bioavailability of thioguanine, all three studies demonstrated serious adverse effects—primarily hepatotoxicity (vaso-occlusive disease and chronic portal hypertension)—that have led to rejection of its prolonged use during maintenance therapy. Also, intravenous mercaptopurine has not been shown to be more advantageous than oral mercaptopurine during maintenance therapy.
The optimal duration of maintenance is likely regimen-dependent but appears to fall somewhere between 2 and 3 years of total treatment. The Tokyo Children's Cancer Study Group reported a 5-year EFS of 60% for patients who received a total of 12 months of treatment, demonstrating that a sizeable number of patients do achieve cure with this short duration, but that an unacceptable proportion, distributed across all risk groups, relapse. The BFM Study Group further demonstrated that 24 months of treatment resulted in fewer relapses than did 18 months. Thus, somewhere between 2 and 3 years of treatment appears to be optimal, with shorter durations increasing relapses and longer durations increasing remission deaths. Some groups use a longer duration of therapy in boys while others do not; whether increased treatment duration ameliorates their survival disadvantage remains unclear.
The benefit of vincristine and dexamethasone pulses during maintenance therapy is uncertain and regimen-dependent. Some studies have shown benefit,[49,50] while others have not.[51,52] In general, the benefit of maintenance pulses appears to be most significant in older treatment regimens that did not utilize dexamethasone and an intensive reinduction phase.
Hematopoietic Stem-Cell Transplant and Relapse
Hematopoietic stem-cell transplantation (HSCT) is considered in first remission for a subset of very high-risk childhood ALL cases, such as those that involve induction failure, severe hypodiploidy, and the Philadelphia chromosome (Ph). Management of Ph-positive ALL has become more controversial as treatment with chemotherapy combined with imatinib and later-generation tyrosine kinase inhibitors has demonstrated excellent early outcomes, comparable or superior to HSCT. Indications for HSCT in adult ALL are also controversial. Traditionally, HSCT in a first complete remission was considered the best curative option in general for adult ALL, but recent studies have yielded conflicting data regarding the relative benefit of chemotherapy versus HSCT in both standard- and high-risk disease.[54,55]
Although significant survival gains have been made in ALL, relapsed ALL is still the fourth most common childhood malignancy, and survival following relapse remains poor in both children and adults. Moreover, progress in treating relapsed ALL has been halting; in a recent retrospective review of nearly 10,000 children treated in COG trials between 1988 and 2002, there was no improvement in survival from early- to late-era trials within this period. The single most important positive prognostic factor is duration of first remission (see Figure 2). Prognosis is best in those patients with late relapse (over 36 months from diagnosis), followed by those with intermediate relapse (18 to 36 months from diagnosis), and finally those with early relapse (less than 18 months from diagnosis). Other significant positive prognostic factors include isolated extramedullary relapse, B-cell rather than T-cell immunophenotype, female gender, younger age at diagnosis, and MRD negativity following reinduction and prior to HSCT.
Second remission can generally be achieved in 70% of early relapses and in 95% of late relapses using intensive conventional chemotherapy, but duration is often brief, leading to poor EFS rates of approximately 30% to 40% overall. Both remission and EFS rates following second or greater relapse are dismal. HSCT does not necessarily improve outcomes compared to chemotherapy, and it is often not an option—eg, for patients who lack a suitable donor, those whose remission is not sustained, or those who have active infection or compromised organ function. Generally, HSCT is recommended for early bone marrow relapse, whereas chemotherapy is preferred in late bone marrow relapse and any isolated extramedullary relapse. The generally poor EFS rates in relapsed ALL, whether treated with chemotherapy or HSCT, indicate the need for novel therapeutic approaches. Several promising novel agents currently advancing in clinical trials are listed in Table 3.
Survival in ALL has improved dramatically as a result of sophisticated classification schemas that tailor therapy according to multiple risk factors, optimal combinations of chemotherapeutic agents, and delivery of effective CNS prophylaxis that obviates the need for radiation for the majority of patients. Nevertheless, significant challenges remain. Outcomes remain poor in several subgroups, including infants, MRD-positive patients, and patients who carry adverse genetic features. Severe toxicities have complicated the delivery of effective therapy in particular subgroups—eg, infections in patients with Down syndrome, and avascular necrosis in adolescents. Achieving further advances through clinical trials has become more challenging as the number of prognostic factors multiplies and patients are carved into ever-smaller categories. Despite these challenges, novel approaches continue to yield new insights into disease pathogenesis and treatment, and progress continues toward the goal of cure for ALL.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.