Improved disease-free survival of children with acute lymphoblastic leukemia at high risk for early relapse with the New York regimen--a new intensive therapy protocol: a report from the Childrens Cancer Study Group

An intensive multimodal therapy was developed for the treatment of a subpopulation of children with acute lymphoblastic leukemia (ALL) who had a predicted event-free survival of less than 40% on previously reported therapeutic regimens (at high risk for early relapse). Induction with multiagent chemotherapy and radiotherapy to bulky disease-bearing areas (peripheral lymph nodes and mediastinum) was followed by consolidation, CNS prophylaxis, and cyclical remission maintenance therapy. Ninety-six (96%) of 100 previously untreated patients, 1 to 17 years of age, attained a complete remission. Seven patients received other maintenance therapy or a bone marrow transplant in remission. Sixty-six of the remaining 89 (74%) are in continuous complete remission at 22+ to 72+ months (median, 44+ months). Marrow relapse occurred in 15 (17%), CNS relapse in 5 (6%), and testicular relapse in one. Sixty-six of the 93 evaluable patients (71%) (including the induction failures) are event-free survivors. Two patients died of infection during the induction phase. No patient died during consolidation or maintenance without recurrent disease. The patients spent a median of 19, 0, and 0 days hospitalized during induction, consolidation, and maintenance, respectively. The most common complications were bacteremia and mucositis during induction and mucositis and fever during periods of neutropenia in consolidation. Maintenance was well tolerated. We conclude that the treatment protocol is intensive, but the inherent toxicities are manageable with adequate supportive care. The life table--projected event-free survival of 69% +/- 5% 48 months from diagnosis is encouraging.     

Treatment of acute lymphoblastic leukemia in Hong Kong children: HKALL 93 study

A population-based multicentre study for childhood acute lymphoblastic leukemia (ALL) was conducted in Hong Kong from 1993 to 1997. One hundred and forty-five newly diagnosed ALL patients were treated by the HKALL 93 protocol. Patients were stratified into three risk groups according to age, presenting white cell count, immunophenotyping and cytogenetic study. The patients received the same induction and early and late intensification at week 5 and week 20. Fifty-eight standard risk (SR) patients received regular intrathecal methotrexate as CNS preventive therapy, while 49 intermediate risk (IR) patients received high dose intravenous methotrexate and regular intrathecal methotrexate. Thirty-eight high risk (HR) patients were treated with prophylactic cranial irradiation and an additional intensification block at week 35. The induction remission rate was 97.2% with 2% induction death. Two patients died during first complete remission. Relapse occurred in 20.7, 42.9 and 42.1% of SR, IR and HR patients respectively. By multivariate logistic regression, age> or =10 years and white cell count> or =100 x 10(9)/l were the two significant variables accounting for mortality. The 5-year overall and event-free survival of the whole group was 81.3 and 62.6% respectively. According to risk groups, the event-free survival was 79, 49 and 61% for SR, IR and HR patients respectively, while the overall survival was 96, 73 and 68% for SR, IR and HR patients respectively. In conclusion, the treatment protocol had low treatment-related mortality but was associated with a rather high relapse rate, especially in IR patients. Salvage therapy achieved sustained second remission in some patients. More intensive treatment especially a late intensification is required to improve the outcome.     

Multiagent chemotherapy in relapsed acute lymphoblastic leukemia in children

Twenty-seven evaluable children with early first bone marrow relapse of acute lymphoblastic leukemia were treated with an intensive induction/consolidation and ongoing maintenance therapy. Induction therapy consisted of a 35-day course of daunomycin, vincristine, and prednisone, immediately followed by teniposide, cytosine arabinoside (Ara-C), and L-asparaginase. Intrathecal methotrexate, hydrocortisone, and Ara-C were given through the induction/consolidation phase. Twenty-three of 27 patients achieved remission by the end of induction/consolidation. Maintenance with the same drugs in a modified dosage schedule continued for approximately 2 years. A small subgroup of patients who were M3 at day 35 but M1 at day 56 (end of induction/consolidation) and had a cumulative event-free survival (EFS) of only 0.40 at 6 months, all had relapsed by 15 months. However, the EFS for M1 patients by day 35 and maintained on chemotherapy was 0.64 at 12 months and 0.32 at 30, 36, and 48 months, respectively. Although good reinduction and remission duration rates at 12 to 24 months were achieved and an apparent plateau in survival occurs at 30 months, fall-off in survival would not be unexpected with probably less than 20% alive after 5 years.     

HiC-COM: a 2-month intensive chemotherapy regimen for children with stage III and IV Burkitt's lymphoma and B-cell acute lymphoblastic leukemia

We designed a protocol that included 2 months of intensive Cytoxan (cyclophosphamide; Bristol-Myers Co, Evansville, IN), high-dose methotrexate (MTX), high-dose cytarabine (ara-C), and vincristine (HiC-COM) to improve event-free survival (EFS) for patients with advanced-stage Burkitt's lymphoma and B-cell acute lymphoblastic leukemia (ALL). We also wished to test the feasibility of rapidly cycling Cytoxan and high-dose ara-C based on signs of early marrow recovery. Twenty patients including 12 with stage III Burkitt's lymphoma and eight with stage IV Burkitt's lymphoma or B-cell ALL were entered onto this pilot study. The rate of complete remission was 95%. Four patients have relapsed. The 2-year actuarial EFS was 75% (median follow-up, 37 months). Two of the initial five patients developed transverse myelitis, which we believe may have been secondary to the concomitant administration of intrathecal (IT) and high-dose systemic ara-C. We conclude that this short but intensive regimen is highly effective for patients with advanced Burkitt's lymphoma and B-cell ALL. EFS has improved over previous less intensive regimens, and is comparable to regimens of longer duration.     

Improved survival of children with isolated CNS relapse of acute lymphoblastic leukemia: a pediatric oncology group study .

PURPOSE: Isolated meningeal relapse in children with acute lymphoblastic leukemia (ALL) usually has been followed by bone marrow relapse and limited survival. The purpose of this study was to prevent marrow relapse by administering intensive therapy before delayed craniospinal radiation. PATIENTS AND METHODS: Eighty-three patients with ALL in first bone marrow remission with an isolated CNS relapse were treated with systemic chemotherapy known to enter into the CSF and intrathecal chemotherapy for 6 months. Craniospinal irradiation (24 Gy cranial/15 Gy spinal) was then administered, followed by 1.5 years of maintenance chemotherapy. RESULTS: All 83 patients achieved a second remission. The 4-year event-free survival (EFS) rate was 71.1% +/- 5.3%. There was a fourfold increased risk of relapse for children whose initial remission was less than 18 months. The 4-year EFS rate for patients with a first complete remission >/= 18 months was 83.3% +/- 5.3%, and for those with a first complete remission less than 18 months, it was 46.2% +/- 10.2% (P =.0002.) There was a low incidence of neurologic toxicity and an unexpectedly high rate of allergic reactions to L-asparaginase. Five patients developed secondary malignancies: two with acute nonlymphoblastic leukemia during therapy, one with myelodysplasia after therapy, and two with brain tumors 1.5 to 2 years after cessation of therapy. CONCLUSION: For children with ALL and an isolated CNS relapse, treatment that delays definitive craniospinal irradiation by 6 months to allow for more intensive systemic and intrathecal chemotherapy results in better EFS than has been previously reported. Using this approach, the long-term prognosis for children with first complete remission >/= 18 months is comparable to that at the time of original diagnosis of ALL.     

Imatinib Treatment Alone in Philadelphia-Positive Acute Lymphoblastic Leukemia: Is It Enough?

BCR-ABL fusion gene t(9;22)(q34;q11) occurs in only 3% of pediatric acute lymphoblastic leukemia (ALL) cases. Previously, less than 40% of Philadelphia-positive ALL patients were cured with intensive chemotherapy. The use of imatinib (340 mg/m(2)/day) added to an intensive chemotherapy regimen has improved the outcome in this population at 3 years to an event-free survival of 80%. Imatinib treatment alone was administered after remission induction chemotherapy to a patient with Philadelphia-positive ALL who presented with serious chemotherapy toxicity, so that intensive chemotherapy could not be maintained. This is the only patient in the literature who survived remission for more than 2.5 years with imatinib treatment only.     

Methotrexate Pharmacology and Resistance in Childhood Acute Lymphoblastic Leukemia

Impressive gains have been made in the therapy of childhood acute lymphoblastic leukemia (ALL) in recent years such that remissions today are commonly achieved in up to 95% of patients and long term disease-free survival rates approach 70%. Methotrexate is a key component in ALL consolidation and maintenance therapies and is administered intrathecally in the prophylaxis and treatment of central nervous system leukemia. Critical determinants of methotrexate sensitivity and resistance (di-hydrofolate reductase levels, methotrexate membrane transport, methotrexate polyglutamylation) previously described in cultured cells have recently been identified in lymphoblasts from children with ALL. Heterogenous expressions of increased dihydrofolate reductase or impaired methotrexate transport can be detected in both diagnostic and relapsed ALL specimens by flow cytometry with fluorescent methotrexate analogues. Lymphoblasts from children with ALL synthesize long chain polyglutamates and correlations have been established between the accumulation of methotrexate polyglutamates in ALL blasts and characteristic patient prognostic features. Variations in methotrexate polyglutamate accumulation may reflect changes in polyglutamate synthetic or degradative enzymes, or may be secondary to changes in methotrexate influx or dihydrofolate reductase levels. Other critical elements in treatment response to methotrexate include the dose and route of methotrexate administration, its catabolism to 7-hydroxymethotrexate, and the rate of methotrexate plasma clearance. A unique relationship exists between chromosome 21 and ALL leukemogenesis, and response to treatment including methotrexate. A better understanding of the molecular bases of methotrexate response and the development of methotrexate resistance in childhood ALL should facilitate further improvements in the effectiveness of methotrexate-based chemotherapy for this disease.     

Adult acute lymphoblastic leukaemia: a study of prognostic features and response to treatment over a ten year period

Between 1974 and 1984 69 adults with acute lymphoblastic leukaemia (ALL) were treated with two different protocols. Fifty-four (78%) of the patients entered complete remission (CR); 27 of these then received a consolidation protocol consisting of daunorubicin, cytosine arabinoside and 6-thioguanine, followed by two courses of intravenous methotrexate 500 mg m-2 with folinic acid rescue. All patients received intrathecal methotrexate and cranial irradiation (24 Gy) followed by maintenance therapy with 6-mercaptopurine and methotrexate for at least 2 years. The median survival for all patients was 23 months from the time of presentation with an actuarial 5-year survival of 21%. The actuarial chance of surviving 5 years in CR for patients receiving the consolidation protocol was 38% compared to 19% for patients receiving no consolidation (P = NS). Only patient age and white cell count at presentation were found to influence the chance of achieving CR and the chance of overall survival. The presence or absence of c-ALL antigen did not influence prognosis. Patients younger than 35 years with low white cell counts at presentation (less than 10 X 10(9)1(-1] had a particularly good prognosis but no patient with T-ALL and no patient older than 50 years old at diagnosis survived more than 18 months.     

Long-term follow-up of the United Kingdom Medical Research Council protocols for childhood acute lymphoblastic leukaemia, 1980-1997. Medical Research Council Childhood Leukaemia Working Party.

Results of three consecutive completed UK trials (1980-1997) for childhood lymphoblastic leukaemia are presented. National accrual has progressively increased so that over 90% of all the country's ALL cases were treated on the latest trial reported, UKALLXI. From 1980 to 1990, event-free and overall survival progressively improved, following adoption of an American therapy template and use of two post-remission intensification modules. Since 1990 despite demonstration of the benefit of a third intensification module overall event-free survival (EFS) has not improved further. Survival remains high due to a good retrieval rate especially for those relapsing off treatment after receipt of two intensification pulses. Possible reasons for the plateau in event-free survival (including type and dose of induction steroid, dropping of induction anthracycline, type and dose of asparaginase, gaps early in therapy following intensification, and overall lack of compliance in maintenance) are being explored in the latest protocol ALL '97. Cranial irradiation had been successfully replaced by a long course of intrathecal methotrexate injections for the majority of patients. Age (<1 year >10 years) sex (male) and white count >50 x 10(9)/l plus slow initial bone marrow clearance were consistently the most important independent prognostic indicators during this time period. Rome/NCI criteria accurately predict standard and high-risk groups for B cell lineage, but not consistently for T cell disease. This international collaborative venture might help us to define those truly at highest risk, and how we can optimise therapy for specific subgroups including T-ALL and those with unfavourable cytogenetics.     

Treatment of acute lymphoblastic leukemia in adults: results of the L-10 and L-10M protocols

Two successive protocols (L-10 and L-10M) employing multidrug induction therapy with vincristine, prednisone, and doxorubicin (Adriamycin) plus an intensive consolidation phase and maintenance program have led to a significant improvement in the prognosis of adult acute lymphoblastic leukemia (ALL). The complete remission (CR) rates for the 34 patients entered on the L-10 protocol and the 38 patients entered on the L-10M protocol were 85% and 84%, respectively. The median duration of remission has not yet been reached for either the L-10 (median follow-up, 5.5 years; range, 3.5-7.5 years) or the L-10M protocol (median follow-up, 2.5 years; range, 1-3.5 years). The median survival time has not yet been reached for the L-10M protocol. Central nervous system prophylaxis with intrathecal methotrexate alone was effective in preventing central nervous system relapse. An analysis of possible prognostic factors indicated that patients less than 25 years of age had a higher CR rate than older patients (p = 0.02). Patients with an initial leukocyte count below 15,000/microL experienced longer remissions than patients with a leukocyte count above 15,000/microL (p = 0.008), and patients who achieved CR within the first month of therapy were in remission longer than those requiring a longer time to achieve CR (p = 0.04). Patients with T cell ALL did not have a poorer prognosis than other patients treated on these protocols. The L-10 and L-10M protocols were well tolerated with minimal morbidity.     

Outcome of adult acute lymphoblastic leukemia with BFM protocol in a resource-constrained setting

Cure rates for adult acute lymphoblastic leukemia (ALL) in developing countries are significantly lower because of problems unique to these countries. We assessed some of the problems in adult ALL patients (>12 years of age) in a tertiary care hospital of northwest India with modified BFM regimen. The diagnosis of ALL was made according to FAB criteria. The protocol consisted of Phase I & II induction, consolidation, reinduction and maintenance phases. CNS prophylaxis was administered with 24 Gy radiation and intrathecal methotrexate. One hundred and eighteen patients (72.9% males), aged 12-68 years (median 23 years) were treated from January 1997 till December 2003. Follow-up of patients was done till December 2005. Complete remission (CR) was achieved in 85.6% patients after induction therapy and 40% patient relapsed. Most patients (23.7%) relapsed during the maintenance phase or after completion of chemotherapy. At least 15% of patients (15/101) after successful induction abandoned the treatment because of financial constraints, prolonged travel time to treatment facility and switching over to alternative medicines. Fatal infectious complications occurred in 19.5% of patients. The 3-year and 5-year event free survival rates were 29.8% and 21.6% respectively. In conclusion, modified BFM regimen resulted in high induction rates but relatively poor 5-year event free survival. Infections related death and post induction abandonment of treatment were the main reasons for poor overall results.     

Combination therapy with arsenic trioxide, all-trans retinoic acid, and chemotherapy in acute promyelocytic leukemia patients with various relapse risks

To improve the recovery rate of high-risk patients with acute promyelocytic leukemia (APL), we used all-trans retinoic acid (ATRA)/arsenic trioxide (ATO)/daunorubicin combination in remission induction, daunorubicin and cytarabine in consolidation, and ATRA/ATO/methotrexate ± 6-mercaptopurine in maintenance treatment of APL patients with various risks for relapse. Our results showed a high complete remission rate of 95.3%. Excluding the cases of early-death, no significant differences in event-free survival were observed between the intermediate-risk and high-risk group (p = 0.393) and the low-risk and high-risk group (p = 0.162). In addition, there were no significant differences between the groups in cumulative incidence of central nervous system relapse. In conclusion, our results suggest that APL patients benefit from combination ATO/ATRA/chemotherapy, and that this regimen is especially beneficial for patients with high-risk prognostic factors.     

Comparison of the L10M consolidation regimen to an alternative regimen including escalating methotrexate/L-asparaginase for adult acute lymphoblastic leukemia: a Southwest Oncology Group Study.

The effectiveness of intensive post-remission chemotherapy regimens for adult patients with acute lymphoblastic leukemia (ALL) is limited by both a high rate of disease recurrence and a substantial incidence of treatment toxicity. To evaluate a potentially more effective and less toxic approach, we conducted a multicenter phase III trial of consolidation therapies comparing the standard L10M regimen with one combining the brief, intensive L17M regimen and escalating methotrexate (MTX) and L-asparaginase (L-asp). Patients over age 15 with previously untreated ALL were eligible. Induction therapy included vincristine, prednisone, doxorubicin, cyclophosphamide and intrathecal methotrexate administered over 36 days. Patients who achieved complete remission (CR) were randomized to receive consolidation with either the L10M regimen or with DAT (daunomycin, cytosine arabinoside, 6-thioguanine) and escalating MTX and L-asp. The randomization was stratified by age, WBC and Ph chromosome status. Maintenance therapy was the same in both arms. Of 353 eligible patients, 218 (62%) achieved CR and 195 were randomized. The treatment arms did not differ significantly with respect to disease-free survival (DFS; P= 0.46) or overall survival (P= 0.39). Estimated DFS at 5 years was 32% (95% confidence interval (CI) 23-42%) in the L10M arm and 25% (95% CI 16-33%) in the DAT/MTX/L-asp arm. In each arm, 4% of patients died of toxicities (infection in all but one case). Infections and nausea/vomiting were somewhat more common in the L10M arm (occurring in 68% and 53% of patients respectively) than the DAT/MTX/L-asp arm (56% and 33%). The DAT/MTX/L-asp consolidation regimen was associated with some reduction in nonfatal toxicities, but no significant improvement in DFS, overall survival or non-relapse mortality when compared to the standard L10M regimen.     

Intensified and shortened cyclical chemotherapy for adult acute lymphoblastic leukemia.

PURPOSE: To assess the efficacy and toxicity of a new treatment program of intensified and shortened cyclical chemotherapy (protocol 8707) in adults with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Previously untreated adults < or = 60 years old with ALL were treated with a four-agent induction chemotherapy regimen. This was followed by cyclical postremission therapy with high-dose cytarabine/etoposide; high-dose methotrexate/6-mercaptopurine; and daunorubicin, vincristine, prednisone, and asparaginase. Maintenance chemotherapy with oral methotrexate and 6-mercaptopurine was continued for 30 months. CNS prophylaxis was given with intrathecal methotrexate in addition to the systemic chemotherapy indicated above. RESULTS: Seventy-eight of 84 patients (93%) achieved complete remission. With a median follow-up of 5.6 years, 5-year event-free survival (EFS) of all remission patients is 52%. Patients with high-risk features including adverse cytogenetics, failure to achieve remission with the first cycle of chemotherapy, and B-precursor disease with WBC counts more than 100,000/microL all relapsed unless taken off study for transplantation. For patients without these high-risk features, 5-year EFS was 60%. Compared with our previous treatment regimen, results appear to be improved for patients with standard-risk B-precursor disease (5-year EFS, 66% v 34%; P =.01). CONCLUSION: Intensified and shortened chemotherapy may improve the outcome for patients with ALL with B-precursor disease lacking high-risk features. Further trials of this regimen are warranted.     

Biochemical interactions between methotrexate and 1-β-d-arabinofuranosylcytosine in hematopoietic cells of children: a Pediatric Oncology Group study

Summary Children with acute lymphocytic leukemia (ALL) in remission were treated with overlapping sequential infusions of methotrexate (MTX) and 1--d-arabinofuranosylcytosine (araC) as part of continuation therapy. The doses and the sequence were chosen to mimic conditions that produced greater than additive antineoplastic activity with these two drugs in preclinical studies. To assess the potential for the drug combination to exhibit greater than additive effect in vivo, we investigated several biochemical parameters that had been associated with synergism in vitro. Because the patients were in remission, the intracellular parameters could only be measured in cytologically normal hematopoietic cells. We observed that (1) the mean plasma concentrations of MTX and araC were above those required to obtain a greater than additive cytotoxicity with the two drugs in tissue culture; (2) MTX did not have a significant antipurine effect in bone marrow mononuclear cells; (3) the mean intracellular concentration of deoxycytidine triphosphate (dCTP) was significantly lower after treatment with the drug combination than after therapy with araC alone; and (4) the ratio of araC triphosphate (araCTP) to dCTP was 2.6 times higher after treatment with the combination than after araC alone. These results indicate that it is possible to achieve in patients the biochemical conditions associated with the greater than additive antineoplastic activity of MTX and araC in vitro.Abbreviations ALL acute lymphocytic leukemia - araC 1--d-arabinofuranosyluracil - araCTP araC triphosphate - araU 1--d-arabinofuranosyluracil - dNTPs deoxyribonucleoside triphosphates - MTX methotrexate - TCA trichloroacetic acid Supported in part by grants from the National Cancer Institute, National Institutes of Health (CA-38 053; CA-33572, CA-32278, CA-38 859, CA-29 691, and CA-30 969). Preliminary reports on the biochemical data were published by E. M. N., A. M. T., and D. P. inProc Am Assoc Cancer Res 24: 133 (1983) and those on the clinical data, by R. A K., E. M. N., D. P. R. B. R., M. B. H., Y. R., and A. I. F. inProc Am Soc Clin Oncol 3: 201 (1984)     

Results of Dana-Farber Cancer Institute Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1981-1995).

The Dana-Farber Cancer Institute (DFCI) ALL consortium has been conducting clinical trials in childhood acute lymphoblastic leukemia (ALL) since 1981. The treatment backbone has included intensive, multi-agent remission induction, early intensification with weekly, high-dose asparaginase, cranial radiation for the majority of patients, frequent vincristine/ corticosteroid pulses during post-remission therapy, and for high-risk patients, doxorubicin during intensification. Between 1981 and 1995, 1,255 children with newly diagnosed ALL were evaluated on four consecutive protocols: 81-01 (1981-1985), 85-01 (1985-1987), 87-01 (1987-1991) and 91-01 (1991-1995). The 5-year event-free survival (EFS) rates (+/- standard error) for all patients by protocol were as follows: 74 +/- 3% (81-01), 78 +/- 3% (85-01), 77 +/- 2% (87-01) and 83 +/- 2% (91-01). The 5-year EFS rates ranged from 78 to 85% for patients with B-progenitor phenotype retrospectively classified as NCI standard-risk, 63-82% for NCI high-risk B-progenitor patients, and 70-79% for patients with T cell phenotype. Results of randomized studies revealed that neither high-dose methotrexate during induction (protocol 87-01) nor high-dose 6-mercaptopurine during intensification (protocol 91-01) were associated with improvement in EFS compared with standard doses. Current studies continue to focus on improving efficacy while minimizing acute and late toxicities.     

Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience.

PURPOSE: T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10% to 15% of newly diagnosed cases of childhood acute lymphoblastic leukemia (ALL). Historically, T-ALL patients have had a worse prognosis than other ALL patients. PATIENTS AND METHODS: We reviewed the outcomes of 125 patients with T-ALL treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium trials between 1981 and 1995. Therapy included four- or five-agent remission induction; consolidation therapy with doxorubicin, vincristine, corticosteroid, mercaptopurine, and weekly high-dose asparaginase; and cranial radiation. T-ALL patients were treated the same as high-risk B-progenitor ALL patients. Fifteen patients with T-cell lymphoblastic lymphoma were also treated with the same high-risk regimen between 1981 and 2000. RESULTS: The 5-year event-free survival (EFS) rate for T-ALL patients was 75% +/- 4%. Fourteen of 15 patients with T-cell lymphoblastic lymphoma were long-term survivors. There was no significant difference in EFS comparing patients with T-ALL and B-progenitor ALL (P =.56), although T-ALL patients had significantly higher rates of induction failure (P <.0001), and central nervous system (CNS) relapse (P =.02). The median time to relapse in T-ALL patients was 1.2 years versus 2.5 years in B-progenitor ALL patients (P =.001). There were no pretreatment characteristics associated with worse prognosis in patients with T-ALL. CONCLUSION: T-ALL patients fared as well as B-progenitor patients on DFCI ALL Consortium protocols. Patients with T-ALL remain at increased risk for induction failure, early relapse, and isolated CNS relapse. Future studies should focus on the identification of and treatment for T-ALL patients at high risk for treatment failure.     

Stage 4 neuroblastoma: sequential hemi-body irradiation or high-dose chemotherapy plus autologous haemopoietic stem cell transplantation to consolidate primary treatment

The aim of the present study was to evaluate the effectiveness of two consecutive nonrandomised treatment programs applied between 1989 and 1999 at the Istituto Nazionale Tumori of Milan in an unselected cohort of 59 children over the age of one with stage 4 neuroblastoma. Both treatment programs consisted of two phases, the induction of the remission phase and the consolidation phase. The induction of the remission phase consisted of intensive chemotherapy, and remained the same throughout the study period. The consolidation phase consisted of sequential hemi-body irradiation (HBI) (10 Gy per session, 6 weeks apart) in the first period (1988-June 1994) and sequential high-dose cyclophosphamide, etoposide, mitoxantrone+L-PAM and autologous haemopoietic stem cell transplantation in the second (July 1994-1999). Intention-to-treat analysis revealed a significantly better outcome for patients treated with the second program, the 5-year event-free survival probability being 0.12 for program 1 and 0.31 for program 2 (P=0.03). This finding led us to conclude that sequential HBI is useless as consolidation treatment. The high-dose chemotherapy adopted in the second program enabled a proportion of patients to obtain long-term survival but, since the clinical results remain unsatisfactory, new treatment strategies are warranted.     

Molecular and Cellular Correlates of Methotrexate Response in Childhood Acute Lymphoblastic Leukemia

The improved outlook for children diagnosed today with acute lymphoblastic leukemia (ALL) over that 40 years ago is remarkable. With modem therapies and supportive care, complete remissions are achieved in up to 95% of patients and long-term disease-free survival rates approach 80%. Methotrexate is a key component in ALL consolidation and maintenance therapies and is administered intrathecally in the prophylaxis and treatment of central nervous system leukemia. Recent reports have significantly extended the results of preclinical studies of methotrexate response and resistance to patients with ALL. The application of new and sensitive molecular biology techniques makes it possible to study specific chromosomal and genetic alterations[t(12;21), hyperdiploidy, deletions or methylation of p15^INK4B and p16^INK4A] which potentially contribute to methotrexate response and resistance in childhood ALL. Studies of the relationships between genetic alterations and ALL progression, methotrexate pharmacology, and long term event-free-survivals may lead to the better identification of subgroups of patients who exhibit unique levels of sensitivity or resistance to chemotherapy including methotrexate. Further, by characterizing the roles of translocation-generated fusion genes (TEL-AML1) and tumor suppressor genes (p15^INK4B and p16^INK4A) in treatment response, it may be possible to identify new and selective targets and/or treatment strategies for both children and adults with ALL who are refractory to current therapies.     

Post-remission therapy in acute myeloblastic leukemia. A randomized trial comparing early consolidation plus maintenance versus maintenance therapy alone

During a 5-year period 203 previously untreated patients with acute myeloblastic leukemia entered an intensive induction chemotherapy regimen with daunorubicin, cytosine arabinoside, 6-thioguanine, vincristine and prednisone (DATOP). The complete remission rate was 64%. Patients in complete remission were randomly assigned to 3 courses of early consolidation with DATOP at lower dosage followed by maintenance chemotherapy, or to the same maintenance regimen in the absence of any consolidation courses. No significant differences were found between these options concerning disease-free survival (median 7.0 vs. 9.8 months; p greater than 0.10) or survival (median 15.8 vs. 19.4 months; p greater than 0.10). This study, in addition to the few previously reported randomized trials, suggests that early low-dose consolidation adds no benefit to maintenance chemotherapy in acute myeloblastic leukemia once complete remission has been achieved.