Case study 4.1
A 20-year-old male patient presents with a 2-week history of dyspnea on exertion and fatigue. A chest radiograph reveals a large mediastinal mass that is confirmed by computed tomography (CT) scan. The presenting leukocyte count is 20 × 109/L with 58% lymphoblasts. He also has a hemoglobin level of 12.3 g/dL and a platelet count of 110 × 109/L. A bone marrow aspirate reveals 70% lymphoblasts with an immunophenotype positive for CD34, TdT, cytoplasmic CD3, CD1a, CD5, and CD7. The blasts were negative for myeloperoxidase and other B-cell and myeloid markers. The cytogenetics revealed a normal 46XY karyotype. The findings are consistent with T-cell acute lymphoblastic leukemia (T-cell ALL, or T-ALL). The patient inquires as to what is the most appropriate therapy.
• What is the most appropriate therapy for adult patients with T-ALL?
The intensification of the induction regimen, such as those developed by the Cancer and Leukemia Group B (CALGB), has resulted in a significant improvement in complete remission (CR) rates, with greater than 80% of adult patients achieving a CR. Induction therapy is built on a backbone of vincristine and a glucocorticoid (prednisone or dexamethasone). Most regimens add asparaginase and an anthracycline (daunorubicin or doxorubicin), which has resulted in improved CR rates ranging from 72% to 92%. Pioneered in the treatment of pediatric ALL, the contributions of asparaginase to response rates and duration of response in adults are not clear as there are no randomized studies supporting its use in adult patients. The toxicities of asparaginase in adults include pancreatitis, hepatotoxicity, and coagulopathy. An analysis CALGB 8811 study showed a marginal benefit in disease-free survival (DFS) at 3 years for patients who received all prescribed doses of asparaginase (55% vs. 48%). Eighty-five percent of the 197 patients in that trial achieved CR after induction. Ongoing trials by the German Multicenter ALL (GMALL) group of the long-acting asparaginase, polyethylene glycol–asparaginase, suggest a potential survival benefit in older adults with ALL when the drug is administered at slightly lower doses than have been used by pediatricians.
An alternative treatment regimen known as hyper-CVAD was developed at the MD Anderson Cancer Center and uses hyperfractionated cyclophosphamide, dexamethasone, vincristine, and doxorubicin without asparaginase during induction and high-dose cytarabine and methotrexate during consolidation. The CR rate of hyper-CVAD is 91% with 3- and 5-year DFS rates of 50% and 38%, respectively.
The goal of using granulocyte colony-stimulating factor (G-CSF) is to shorten the period of neutropenia to prevent possibly fatal infections, and previous studies demonstrate the utility of this drug with induction regimens for ALL. In the Leucémie Aigüe Lymphoblastique de l’Adulte (LALA)-94 trial, patients were randomized to receive G-CSF, granulocyte-macrophage CSF (GM-CSF), or no CSF. When given on day 4 of induction until the return of an absolute neutrophil count of 1000/μL, patients receiving G-CSF had significantly shorter hospital stays, less time to neutrophil recovery, and fewer severe infections compared with patients who did not receive G-CSF. The CALGB 9111 trial highlighted the benefit of using this drug in patients prone to difficulty with hematologic recovery, specifically older patients. The study observed a trend toward increased CR rates in patients 60 years of age or older in the G-CSF arm compared with the placebo arm.
• What is the most appropriate therapy for young adult patients with T-ALL?
Increasing age is one of the most important poor prognostic factors of outcome in newly diagnosed patients with ALL. The 5-year DFS is approximately 80% for children and 40% for adults with ALL. Recent retrospective data suggest that younger patients between the ages of 16 and 21 years fare better when treated according to intensive pediatric ALL treatment regimens rather than conventional adult regimens. Despite slight differences in treatment approaches across the different cooperative groups, many retrospective studies have demonstrated significantly better outcome for the patients when they are treated in pediatric studies, where survival has been reported to be in the range of 60% to 65%. In contrast, when the same age group is treated in adult cooperative-group ALL treatment trials, survival has been only 30% to 40%.
From these retrospective studies, it appears that the major differences in treatment between the adult and pediatric regimens are the more intensive use of the nonmyelosuppressive agents (glucocorticoids, asparaginase, and vincristine), earlier and more intensive central nervous system (CNS)-directed therapy, and more prolonged maintenance therapy used in the pediatric regimens. In addition to the obvious treatment differences between adult and pediatric trials, there has been much debate about the potential differences in adherence to therapy protocols among pediatric and adult medical hematologists and the patients who they treat.
Several prospective European and American studies that administered pediatric regimens to younger adults have confirmed improved outcomes for patients aged 16 to 30 years, with DFS rates of 60% to 65%. The Dana-Farber consortium has also presented preliminary results applying this pediatric approach to adults up to the age of 50 years, with an event-free survival rate of 63% with short follow-up. The US Intergroup recently completed a large phase II trial (CALGB 10403) for younger adults up to age 40 years that tested the successful approach used by the Children’s Oncology Group for treatment of high-risk adolescents with ALL. Older adults (over the age of 45 years) may not benefit from this approach due, in part, to their inability to tolerate the intensive asparaginase, glucocorticoid, and vincristine dosing upon which these regimens are based.
• Is CNS-directed therapy critical for patients with T-ALL?
Although less than 10% of adults with ALL will present with CNS involvement, CNS relapse will occur in 35% to 75% of patients at 1 year if prophylactic CNS-directed therapy is not incorporated into treatment. A lumbar puncture at the time of ALL diagnosis is always performed in pediatric studies, but this is typically delayed in most adult ALL regimens. Unless a patient has CNS symptoms, the CALGB regimens perform an initial lumbar puncture at the start of consolidation (postremission) chemotherapy. Symptoms may include headache, meningismus, fever, or cranial nerve palsies. However, some patients are asymptomatic. If symptomatic CNS disease is present at diagnosis, such as focal cranial nerve palsies, concurrent radiation therapy and intrathecal chemotherapy are administered.
Initially, CNS-directed therapy included the use of intrathecal methotrexate and 24 Gy of cranial radiation in the pediatric population. Although in children it is known that combination treatment can result in toxicities that include seizures, early dementia, cognitive dysfunction, slow growth, and second cancer, the long-term effects on adults are less clear. Combined radiation and intrathecal chemotherapy in adults can cause substantial acute toxicities that may delay postremission consolidation treatment. Therefore, lower doses of cranial radiation are currently being explored. An alternative combination strategy that uses intrathecal chemotherapy without radiation has also been investigated. This treatment regimen includes a so-called triple therapy that uses intrathecal methotrexate, cytarabine, and corticosteroids without radiation.
CNS relapse rates as low as 5% have been achieved without radiation by using combination intrathecal treatment in conjunction with high-dose systemic treatment that can penetrate the cerebrospinal fluid. However, the German GMALL investigators have reported higher CNS relapse rates of 9% versus 5% when CNS-directed radiation was postponed. Therefore, although CNS-directed prophylactic therapy is required in ALL treatment, there is no single modality or combination that has been proven to be superior. Of note, the pediatric groups generally still recommend cranial irradiation as part of CNS prophylaxis for high-risk T-ALL, as do the German study groups.
< div class='tao-gold-member'>
13: Hematopoietic Cell Transplantation in Acute Myeloid Leukemia
11: Minimal Residual Disease in Acute Myeloid Leukemia
71: Secondary Brain and Spinal Cord Tumors
