Acute lymphoblastic leukemia (ALL) is a malignant (clonal) disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow. ALL is a heterogeneous disease, both in terms of its pathology and the populations that it affects.
Prognostic Factors and Risk Categories
Several factors determine the prognosis of ALL in adults. These most important variables include initial white blood cell count, age at diagnosis, immunophenotype, genetic subset, extramedullary disease, and early treatment response/minimal residual disease.
35 years appears to be a clear prognostic cut-off. Age older than 35 years decreases the chance of remission as well as increases the risk of relapse in patients given conventional chemotherapy. Presenting white cell count (>30 × 109/L for B-cell disease and >100 × 109/L for T-cell disease) is a poor prognostic factor. Immunophenotype: T-cell disease has a better outcome than B-cell disease in adults.
Ph chromosome, t(4;11), t(8:14), complex karyotype (defined as 5 or more chromosomal abnormalities), or low hypodiploidy/near triploidy are also poor prognostic factors too. The presence of the Ph chromosome affects the chance of remission after induction, as well as the risk of relapse, when using conventional chemotherapy.
Minimal residual disease (MRD) in adult ALL could be detected by both molecular and immunophenotypic methods, which can reliably detect the presence of residual ALL at levels of less than 0.01%. The presence of detectable MRD by molecular methods after completion of both phases of induction predicts for a poor prognosis even in patients with standard-risk group. One study reported that patients with standard-risk ALL who had a rapid decline in MRD within the first month of therapy had a 0% 3-year relapse rate while those with molecular persistence of ALL by week 16 of therapy had a 94% 3-year relapse rate. Another study showed that > 8 weeks to CR1 was associated with a poor survival. In the MRC-ECOG UKALLXII/EC2993 trial time to attain CR > 4 weeks is defined as a high risk criteria.
However, the significance of many prognostic factors changes with improvements in treatment. For example, the outcome for both children and adults with Ph+ ALL has improved substantially with the addition of tyrosine kinase inhibitors to the treatment. Recently, children with Ph+ genotyp treated with chemotherapy and imatinib (without allo-SCT) had a 3-year event-free survival (EFS) of over 80%. If the favorable outcome is confirmed with longer follow-up, the Ph chromosome may join a long list of other factors such as male sex and African-American ethnicity that have lost adverse prognostic impact with improved treatment in childhood ALL.
More recently, the application of microarray-based, genome-wide analysis of gene expression and DNA copy number, complemented by transcriptional profiling, re-sequencing and epigenetic approaches, has identified specific genetic alterations with biologic and therapeutic implication.
Table 1 Prognostic Factors Used in Pediatric and Adult Clinical Trials
Of note that there are no “low risk” group in ALL. Instead, there are standard risk group and adverse risk group.
Molecular Monitoring For MRD
Several investigators have introduced more sensitive molecular techniques such as clonal immunoglobulin or T-cell receptor gene rearrangements to detect MRD that can accurately predict relapse in patients with ALL. Pediatricians have recognized that molecular persistence of residual ALL at the end of induction chemotherapy or afterward effectively predicted relapse independent of other risk factors.
Molecular marker monitoring has been used less extensively in adult ALL but appears to be an extremely powerful tool that has yet to be exploited.
Update from Medscape on Sep 19th 2013
Multiparameter flow cytometry and real-time quantitative polymerase chain reaction (qPCR) are two coming techniques that might make routinely monitoring for MRD possible. (Original from http://www.medscape.com/viewarticle/808782?nlid=32288_330&src=wnl_edit_medn_honc&uac=180112PN&spon=7)
Treatment Strategies for ALL
Contrary to the excellent results achieved in pediatric patients, the outcomes for ALL in adult patients are disappointing. While in recent multicenter trials more than 90% of adult patients with ALL younger than 60 years attain CR, conventional chemotherapy is a long arduous process and will result in long-term survival in only one-third of patients.
Treatment of ALL involves some of the most complex chemotherapy combinations and treatment schedules used in oncology. Induction chemotherapy is used first to reduce the burden of lymphoblasts in the bone marrow and to restore normal hematopoietic funtion. Consolidation therapy (also termed intensification) is used with the intention of clearing any drug-resistant leukemia cells that have survived induction therapy and to eliminate minimal residual disease (MRD). Maintenance chemotherapy consists of 2 to 3 years of low-dose antineoplastic drugs designed to prevent leukemia relapse during the crucial few years after remission induction and consolidation. Finally, central nervous system (CNS) prophylaxis is necessary to treat sanctuary sites that are shielded from systemic thearpy by the blood-brain barrier.
The induction chemotherapy is determined according to Ph status. For Ph-negative ALL patients, regimens comprise steroid, vincristine, and L-asparaginase, usually with anthracycline (up to 2 to 3 times the dose given in pediatric protocols) and often with the addition of cyclophosphamide and cyarabine. Comparable rates of complete remission (CR) of approximately 85% to 95% and treatment-related mortality (TRM) are seen in all published regimens, which is between 5% and 10% —— much higher than the <1% in children.
25% of all adults are Ph+ chromosome ALL. For Ph-positive patients with ALL, the induction therapy dose not differ from that for Ph-negative patients, except the addition of tyrosine kinase inhibitor (TKIs) imatinib. Studies show imatinib has improved the CR rate to >90% and makes more patients eligible for transplant. One studieMust to mention that in the latest NCCN guideline for ALL, the addition of one of TKIs to induction therapy, consolidation therapy, and maintenance therapy, respectively, has been the standard of care.
An alternative induction therapy is the hyper-CVAD regimen comprising hyper-fractionated cyclophosphamide, vincristine, doxorubicin (that is adriamycin), and dexamethasone, which reported a CR rate in excess of 90%.
Table 3 Common Chemotherapy Regimen for ALL
|BFM/COG||vincristine, anthracycline, corticosteroid, L-asparaginase|
|CALGB||vincristine, anthracycline, corticosteroid, L-asparaginase+cyclophosphamide|
|hyper-CVAD A||hyper-fractionated cyclophosphamide, vincristine, dexorubicin, dexamethasone|
|hyper-CVAD B||high-dose methotrexate, cytarabine|
For adolescents young adults (AYA) with ALL, there are increasing data that suggests that this group of patients treated with adult ALL protocols have a worse outcome than similar patients treated on pediatric protocols (two studies, the age of enrolled patients are 15-21, 16-20, respectively). A “pediatric” approach to therapy gives superior survival than an adult approach in adolescents with ALL. According to a study published in the May issue of the American Journal of Hematology, Ron Ram et al. found that adolescent and young adult patients with acute lymphoblastic leukemia (ALL) who were treated with pediatric-inspired regimens exhibit lower all-cause mortality, higher complete remission and event-free survival rates, and lower relapse rates compared with those treated with conventional adult-chemotherapy regimens. Some results of certain trials are listed in Table 2.
However, definition of the age range that encompasses the AYA patient is itself controversial, because the age range described in the literature for this population varies depending on the study. In recent studies, the age range was set up to 30 yrs or even up to 40 yrs. Of note, the latest NCCN guideline for ALL suggests that the age of 40 is the cut-off between AYA and “older” adults.
Consolidation/maintenance therapy for adults is based on that used in pediatric regimens. No randomized studies usefully address the benefits of the number or composition of consolidation cycles in adult ALL. Consolidation/intensification with high-dose methotrexate 1.5 to 3 g/m2, somethimes in conjunction with L-asp (L-asparaginase), is commonly used and is an important component of central nervous system (CNS)-directed therapy.
Maintenance therapy remains obligatory in those not undergoing allo-SCT. Daily mercaptopurine, weekly methotrexate and pluses of monthly vincristine and steroids for 18 to 24 months after consolidation is standard.
CNS involvement occurs in 5% of adults at diagnosis and although it impacts on survival (29% vs 38%; P = .03), it is unclear how much prophylactic CNS-directed therapy is required. Most protocols do not now give CNS irradiation, and 4 to 6 intrathecal doses of chemotherapy and high-dose methotrexate seem to be adequate to prevent CNS relapse. However, there are no data on the most efficacious drug or drug combination in adults to CNS-directed therapy. For patients proceeding to TBI-containing allograft regimens, intrathecal chemotherapy alone is sufficient. More prophylaxis may be required with RIC regimens, but this remains untested. CNS involvement is more common with high WBCs, T-cell disease, and a mediastinal mass.
The role of cranial irradiation in providing CNS-directed prophylaxis in adults is difficult to gauge. In the pediatric group, cranial irradiation is now used very infrequently. CNS relapse is now sufficiently infrequent as to render the numbers of patients required to evaluate this in a randomized manner pragmatically impossible.
Hematopoietic Stem Cell Transplantation
The decision to proceed to transplant for adult patients with acute lymphoblastic leukemia is not clear-cut. Relapse and nonrelapse mortality continue to plague the outcome of hematopoietic stem cell transplantation (HSCT) even when undertaken in CR. Those considered to be at high risk for relapse often are considered for HSCT in CR1 while those at lower risk may not be referred until they have relapsed, when their chances for cure are very poor.
During the past 14 years the MRC/ECOG study has assigned allo-SCT to all adult patients, including those with standard-risk ALL, who had an HLA-compatible sibling. The final data were recently reported and showed an unequivocal benefit for HLA-compatible sibling transplantation for patients with standard-risk ALL over other forms of conventional therapy, whether this is consolidation or maintenance therapy or an auto-SCT. The transplantation was performed as soon as possible after successful induction.
Table 4 Recommedations for HSCT of ALL Patients
However, there is a consideration that all standard-risk patients in MRC/ECOG trial were treated with a typical adult regimen rather than a pediatric-like regimen, so the benefit of allo-SCT for AYA group after indcution therapy of a pediatric-like regimen remains open. However, the data recently reported by Dana-Farber Cancer Institute in Boston, Massachusetts, for 51 adolescent patients aged 15 to 18 years showed a remarkable event-free survival of 78% in this population. This is clearly better than anything else that has been reported to date, and, if such data are confirmed in an unselected population, there clearly will be no role for an allogeneic transplantation in this age group.
Impact of Age to allo-HSCT
Although the risk of relapse decreases with allo-SCT, the concomitant treatment-related mortality (TRM) might eliminate the potential survival benefit under some conditions. TRM among “high-risk” patients was sufficient in magnitude to abrogate a survival advantage in this group despite the evident anti-leukemia activity of the procedure indicated by the reduction in relapse risk.
The UKALLXII/ECOG2993 study found that patients with sibling donors who were Ph-negative had an 8% higher chance of survival at 5 years, irrespective of risk status, but the benefit of allo-HSCT was apparently confined to those with “standard risk” disease. The reason for this might be that since one of the criteria for “high-risk” is age greater than 35 years and given that advancing age also confers the highest risk of TRM, this is probably the main reason for lack of survival advantage in the “high-risk” group. To date, the threshold at which TRM exceeds reduction in relapse risk may be as low as 35 to 40 years of age.
For high-risk Ph– patients (age < 35 to 40) without sibling donor, whether the benefits of using a sibling-matched allogeneic HSCT can be extended to un-related donor allogeneic HSCT is still open and need more investigation.
Table 5 MRC-ECOG Trial: Outcome after allo-HSCT in Ph– Patients
Allo-HSCT: Matched Unrelated Donor
Allo-HSCT is particularly effective in Ph+ patients.
Accumulated evidence of the very poor results of treating this disease with chemotherapy alone, accompanied by reports from retrospective series of allo-HSCT suggest that myeloablative therapy, with a TBI-based conditioning regimen followed by sibling allo-HSCT, represents the current best available treatment option for appropriately aged patients with Ph+ ALL in CR1. The MRC-ECOG UKALLXII/EC2993 trial for Ph-positive ALL patients undergoing URD allo-HSCT showed that at 5 years there was no statistically significant difference in OS or in cause of death between those receiving sibling allo-HSCT and those receiving matched unrelated donor allo-HSCT.
Reduced-intensity Conditioned allo-HSCT
There are few publish large-scale data about the efficacy of reduced-intensity allografting for older patients with ALL. The success of RIC allo-HSCT is likely to be disease burden dependent; absence of MRD at the time of transplant may be of crucial importance although this has not been formally studied. Preliminary, retrospective data do not provide sufficient basis for recommending RIC allografts in older or more infirm patients with ALL in CR1. This approach merits consideration, but careful prospective study is still requried to define its role.
The MRC-ECOG UKALLXII/E2993 trial compared 446 CR1 patients randomized to undergo either an autologous HSCT (N = 233) or 2.5 years of maintenance therapy (N = 223). EFS was statistically superior for the chemotherapy-treated patients, 42% versus 33% (P = .02). While OS also was improved in the chemotherapy group (47% versus 37%), in which the evidence showed that autografting in CR1 is inferior to continuous maintenance chemotherapy. An analysis of > 300 patients in three French trials also found no advantage for autografting. Therefore, routine use of autologous HSCT in adult patients with ALL is not recommended.
Table 5 Response Criteria for Acute Lymphoblastic Leukemia