Treatment stratification based on initial in vivo response in acute myeloid leukaemia in children without Down's syndrome: results of NOPHO-AML trials

Three consecutive protocols for childhood acute myeloid leukaemia (AML) have been used in the Nordic countries since 1984: the Nordic Society for Paediatric Haematology and Oncology (NOPHO)-AML84 was of moderate intensity, NOPHO-AML88 of high intensity with upfront loading and aggressive consolidation. NOPHO-AML93 utilized the same treatment blocks as NOPHO-AML88, but after the first block those children with a hypoplastic non-leukaemic bone marrow were allowed to recover from aplasia. Poor responders received intensified induction therapy. Between January 1993 and December 2000, 219 children without Down's syndrome were entered on NOPHO-AML93. Compared with NOPHO-AML88, the event-free survival (EFS) at 7 years increased from 41% to 49% (P = 0.06) and 7-year overall survival increased from 47% to 64% (P < 0.01). Toxic death during induction was reduced from 10% to 3%. Survival was similar in patients receiving stem cell transplantation or chemotherapy only in first remission. The major prognostic factors in NOPHO-AML93 were response to therapy and cytogenetics. A total of 67% of patients achieved remission after the first induction course and showed an EFS of 56% compared with 35% in those not in remission (P < 0.01). Cytogenetic results were obtained in 95% of patients. Patients with t(9;11) (p22;q23) (n = 16) experienced a significantly better EFS (86%) than other cytogenetic groups. The overall outcome was improved by employing the previous toxic protocol with different timings, and through individualizing therapy according to the initial response of the patient.     

Randomized use of cyclosporin A (CsA) to modulate P-glycoprotein in children with AML in remission: Pediatric Oncology Group Study 9421

Relapse is a major obstacle in the cure of acute myeloid leukemia (AML). The Pediatric Oncology Group AML Study 9421 tested 2 different strategies to improve event-free survival (EFS) and overall survival (OS). Patients were randomized to receive standard-dose DAT (daunorubicin, cytarabine, and thioguanine) or high-dose DAT during induction. To interfere with P-glycoprotein (P-gp)-dependent drug efflux, the second randomization tested the benefit of cyclosporine (CsA) added to consolidation chemotherapy. Of the 282 children randomly assigned to receive standard DAT induction, 248 (87.9%) achieved remission compared to 253 (91%) of the 278 receiving high-dose DAT (P = ns). Children with HLA-identical sibling donors who achieved a complete remission received an allogeneic bone marrow transplant as consolidation. For the 83 patients receiving a matched related donor bone marrow transplantation (BMT), the 3-year disease-free survival (DFS) is 67%. Of the 418 children who achieved remission and went on to consolidation with and without CsA, the DFS was 40.6% and 33.9%, respectively (P = .24). Overexpression of P-gp was infrequent (14%) in this pediatric population. In this study, intensifying induction with high-dose DAT and the addition of CsA to consolidation chemotherapy did not prolong the durations of remission or improve overall survival for children with AML.     

The value of the MDR1 reversal agent PSC-833 in addition to daunorubicin and cytarabine in the treatment of elderly patients with previously untreated acute myeloid leukemia (AML), in relation to MDR1 status at diagnosis

To determine whether MDR1 reversal by the addition of the P-glycoprotein (P-gp) inhibitor PSC-833 to standard induction chemotherapy would improve event-free survival (EFS), 419 untreated patients with acute myeloid leukemia (AML) aged 60 years and older were randomized to receive 2 induction cycles of daunorubicin and cytarabine with or without PSC-833. Patients in complete remission were then given 1 consolidation cycle without PSC-833. Neither complete response (CR) rate (54% versus 48%; P = .22), 5-year EFS (7% versus 8%; P = .53), disease-free survival (DFS; 13% versus 17%; P = .06) nor overall survival (OS; 10% in both arms; P = .52) were significantly improved in the PSC-833 arm. An integrated P-gp score (IPS) was determined based on P-gp function and P-gp expression in AML cells obtained prior to treatment. A higher IPS was associated with a significantly lower CR rate and worse EFS and OS. There was no significant interaction between IPS and treatment arm with respect to CR rate and survival, indicating also a lack of benefit of PSC-833 in P-gp-positive patients. The role of strategies aimed at inhibitory P-gp and other drug-resistance mechanisms continues to be defined in the treatment of patients with AML.     

Infant acute lymphoblastic leukemia with MLL gene rearrangements: outcome following intensive chemotherapy and hematopoietic stem cell transplantation

Forty-four infants with acute lymphoblastic leukemia (ALL) characterized by MLL gene rearrangements were treated on a protocol of intensive chemotherapy followed by hematopoietic stem cell transplantation (HSCT) between November 1998 and June 2002. The remission induction rate was 91.0%, and the 3-year overall survival and event-free survival (EFS) rates, with 95% confidence intervals, were 58.2% (43.5%-72.9%) and 43.6% (28.5%-58.7%), respectively. Univariate analysis of EFS by presenting features indicated a poorer outcome in patients younger than 6 months of age with high white blood cell counts (>/= 100 x 10(9)/L; EFS rate, 9.4% versus 55.1% for all others, P = .0036) and in those with central nervous system invasion (EFS rate, 10.0% versus 56.9% for all others, P = .0073). The 3-year posttransplantation EFS rate for the 29 patients who underwent HSCT in first remission was 64.4% (46.4%-82.4%). In this subgroup, only the timing of HSCT (first remission versus others) was a significant risk factor by multivariate analysis (P < .0001). These results suggest that early introduction of HSCT, possibly with a less toxic conditioning regimen, may improve the prognosis for infants with MLL(+) ALL. Identification of subgroups or patients who respond well to intensified chemotherapy alone should have a high priority in future investigations.     

Induction chemotherapy followed by allogeneic bone marrow transplantation or aggressive consolidation chemotherapy in childhood acute myeloblastic leukemia: A prospective study from the French Society of Pediatric Hematology and Immunology (SHIP)

In the LAME89/91 protocol, children with acute myeloid leukemia (AML) who achieved complete remission (CR) after induction chemotherapy, were treated either with allogeneic bone marrow transplantation (BMT) if they had an HLA-compatible related donor or with chemotherapy including high-dose cytarabine. The objectives of this study were to describe the overall results of this strategy and to compare the two post-remission arms. Two hundred and thirty-one children were enrolled in the protocol. Induction chemotherapy consisted of a combination of cytarabine and mitoxantrone. A CR was achieved in 204 children (88%). Fifty-one of them had an HLA-identical sibling donor and were eligible for BMT. These 51 patients, as well as two additional children who had a one antigen HLA-mismatched father, received BMT during first CR. Consequently, 53 patients were analysed in the BMT group and 151 in the chemotherapy group. With a mean follow up duration in the study of 38 ± 2 months, overall event-free survival (EFS) was 47 ± 7% at 4 years for the 231 patients entered into the protocol. The 4-year disease-free survival (DFS) was 53 ± 8% for the 204 patients who achieved complete remission after induction therapy. The 4-year probability of relapse was 28 ± 14% in the BMT group and 47 ± 9% in the chemotherapy group (p = 0.02). The risk of therapy-related death was 6.2% for BMT and 8.1% for chemotherapy. DFS was 68 ± 14% in the BMT group and 48 ± 9% in the chemotherapy group (p = 0.02). We conclude that allogeneic BMT from a matched sibling donor is the treatment of choice for reducing the relapse risk and for increasing DFS in children with AML in first CR.     

Results of consecutive trials for children newly diagnosed with acute myeloid leukemia from the Australian and New Zealand Children's Cancer Study Group

Despite improvements in the treatment of acute myeloid leukemia (AML), approximately 50% of children die of the disease. Clinical trials in adult patients with AML indicate that idarubicin may have superior efficacy when compared to daunorubicin in the remission-induction phases of chemotherapy. We conducted consecutive clinical trials in children with newly diagnosed AML in which daunorubicin (group 1, n = 102) or idarubicin (group 2, n = 160) was used during the remission-induction (RI) and the early consolidation phases of chemotherapy. Idarubicin was given at a dose of either 10 mg/m(2) (group 2A, n = 106) or 12 mg/m(2) (group 2B, n = 53). A high rate of RI was achieved for all groups (95% group 1, 90% group 2A, 94% group 2B). There were no significant differences in 5-year event-free survival (EFS) or in overall survival (OS) when the 3 groups were compared (group 1: EFS 50%, OS 56%; group 2A: EFS 50%, OS 60%; group 2B: EFS 34%, OS 50%). RI deaths resulting from treatment toxicity were low-2% for group 1 and 5% for group 2. More gastrointestinal, pulmonary, and renal toxicity but fewer infections were observed in patients receiving idarubicin (P <.001, P =.04, P =.03, respectively). Following RI chemotherapy, all patients received 3 to 4 more courses of identical chemotherapy and then underwent either autologous (n = 156) or an allogeneic bone marrow transplantation (BMT) (n = 35). OS was higher in allogeneic BMT patients than in autologous BMT patients (79% vs 63%; P =.23). We conclude that daunorubicin is as effective as idarubicin for remission-induction therapy for childhood AML and has reduced toxicity.     

Identification of two risk groups in childhood acute myelogenous leukemia after therapy intensification in study AML-BFM-83 as compared with study AML-BFM-78. AML-BFM Study Group

The main difference between the two cooperative studies on therapy of childhood acute myelogenous leukemia AML-BFM-78 and AML-BFM-83 was the addition of an 8-day ADE (cytosine arabinoside, daunorubicin, etoposide) induction treatment in the second study. Due to this intensification, the relapse rate, but not the rate of induction failures, was reduced. The probability of a 6-year event-free survival increased from 38%, SD 4%, in study AML-BFM-78 to 49%, SD 4%, in study AML-BFM-83, P = .08. The improvement of the 6-year event-free interval (EFI) was significant in the second study (61%, SD 4%, versus 47%, SD 5%, P less than .05); it was restricted to the FAB types M1 through M4 (EFI: 67%, SD 5%, versus 45%, SD 5%, P less than .01). The difference in EFI seen in FAB M5 was not statistically significant (EFI: 40%, SD 10%, versus 63%, SD 11%, NS). According to the results of the second study, two different risk groups (low and high) could be identified by combinations of predominantly pretherapeutic parameters. The low risk group, comprising 37% of the patients who achieved complete remission, included the FAB types with granulocytic differentiation and specific additional features: FAB M1 with Auer rods, FAB M2 with white blood cell count of less than 20,000/microL, FAB M3 all patients, and FAB M4 with eosinophilia. The 6-year Kaplan-Meier estimation of EFI is 91%, SD 4%, compared with 42%, SD 6% in the high risk group. In future studies based on the AML-BFM-83 treatment, bone marrow transplantation in first remission should be mandatory only for children of the high risk group.     

Superior outcome of infant acute myeloid leukemia with intensive chemotherapy: results of the Japan Infant Leukemia Study Group.

This study analyzed data on 35 infants with acute myeloid leukemia (AML) who were treated with intensive chemotherapy between 1995 and 1998 in Japan. The incidence of boys, younger age (< 6 months old), and hyperleukocytosis at onset was high in patients with the M4/M5 subtype (n = 23) in the French-American-British classification, compared with the non-M4/M5 subtype (n = 12). Thirteen (56%) and 16 (70%) patients with the M4/M5 subtype also showed 11q23 translocations and MLL gene rearrangements, respectively, whereas only one patient with the non-M4/M5 subtype had this rearrangement. All 35 patients were treated with the ANLL91 protocol consisting of etoposide, high-dose cytarabine, and anthracyclines. Overall survival and the event-free survival (EFS) rates at 3 years of all patients were 76% (95% confidence interval [CI], 61.3%-90.7%) and 72% (95% CI, 56.4%-87.9%), respectively. EFS showed no significant difference between 2 subgroups divided by age, gender, presence of the MLL gene rearrangements, and white blood cell count at onset; EFS in patients with the M4/M5 subtype tended to be better than those with the non-M4/M5 subtype. Although all 6 patients who underwent allogeneic stem cell transplantation (SCT) have been in complete remission, no benefit of SCT was confirmed. These findings suggest that the intensive chemotherapy with the ANLL91 protocol might have been responsible for the observed good outcome of infant AML, even without SCT. The presence of the MLL gene rearrangements or the age at onset had no impact on the outcome of infant AML.     

Comparison of high-dose cytarabine and timed-sequential chemotherapy as consolidation for younger adults with AML in first remission: the ALFA-9802 study

To assess the value of administering timed-sequential chemotherapy (TSC; 2 therapeutic sequences separated by a 4-day interval-free chemotherapy) or high-dose cytarabine (HDAraC) cycles in consolidation therapy for acute myeloid leukemia (AML), 459 patients 15 to 50 years of age were enrolled in the prospective randomized Acute Leukemia French Association-9802 trial. Complete remission was achieved in 89%. A total of 237 patients were then randomized to either TSC consolidation (120 patients) or HDAraC consolidation cycles (117 patients). Overall, there was no significant difference between the 2 consolidation arms (5-year event-free survival [EFS]: 41% for HDAraC vs 35% for TSC), or cumulative incidence of relapse, or treatment-related mortality. Cytogenetically normal AML NPM1(+) or CEBPA(+) and FLT3-ITD(-) had the same outcome as those with favorable cytogenetics. When considering favorable and unfavorable risk groups, the trend was in favor of HDAraC. However, the difference became significant when considering intermediate cytogenetics (5-year EFS: 49% vs 29%; P = .02), especially cytogenetically normal AML (5-year EFS: 48% vs 31%; P = .04), which was related to lower relapse rate and less toxicity. This study demonstrates that TSC did not produce any benefit when used as consolidation therapy in younger adults compared with HDAraC. This trial was registered at www.clinicaltrials.gov as #NCT00880243.     

Biology and outcome of childhood acute megakaryoblastic leukemia: a single institution's experience

To describe the clinical and biologic features of pediatric acute megakaryoblastic leukemia (AMKL) and to identify prognostic factors, experience at St Jude Children's Research Hospital was reviewed. Of 281 patients with acute myeloid leukemia treated over a 14-year period, 41 (14.6%) had a diagnosis of AMKL. Six patients had Down syndrome and AMKL, 6 had secondary AMKL, and 29 had de novo AMKL. The median age of the 22 boys and 19 girls was 23.9 months (range, 6.7-208.9 months). The rate of remission induction was 60.5%, with a 48% rate of subsequent relapse. Patients with Down syndrome had a significantly higher 2-year event-free survival (EFS) estimate (83%) than did other patients with de novo AMKL (14%) or with secondary AMKL (20%; P < or =.038). Among patients who had de novo AMKL without Down syndrome, 2-year EFS was significantly higher after allogeneic bone marrow transplantation (26%) than after chemotherapy alone (0%; P =.019) and significantly higher when performed during remission (46%) than when performed during persistent disease (0%; P =.019). The 5-year survival estimates were significantly lower for de novo AMKL (10%) than for other forms of de novo AML (42%; P <.001). Treatment outcome is very poor for patients with AMKL in the absence of Down syndrome. Remission induction is the most important prognostic factor. Allogeneic transplantation during remission offers the best chance of cure; in the absence of remission, transplantation offers no advantage over chemotherapy alone. (Blood. 2001;97:3727-3732)     

Intensive treatment of children with acute lymphoblastic leukemia according to ALL-BFM-86 without cranial radiotherapy: results of Dutch Childhood Leukemia Study Group Protocol ALL-7 (1988-1991).

In The Netherlands from July 1988 to October 1991, children (0 to 16 years of age) with de novo acute lymphoblastic leukemia (ALL) were treated according to protocol ALL-7 of the Dutch Childhood Leukemia Study Group (DCLSG). In this protocol, chemotherapy and treatment stratification were identical to the ALL-BFM-86 protocol (Reiter et al, Blood 84:3122, 1994), but cranial irradiation was restricted to patients with initial central nervous system (CNS) involvement. Patients were stratified into 3 risk groups, based on leukemia cell mass and response to initial treatment: standard-risk group (SRG), risk group (RG), and experimental group (EG). As in ALL-BFM-86, a randomized study on late intensification (protocol S) was performed in RG patients, and during the study (since October 1990), early reinduction treatment (protocol II) was introduced for SRG patients. Treatment duration for all patients was 18 months. Two hundred eighteen children entered the study: 74 SRG, 127 RG, and 17 EG patients. The overall complete remission (CR) rate was 98%. The 5-year event-free survival (EFS) for all DCLSG ALL-7 patients was 65. 3% (standard error [SE] 3.2%), which was significantly different from the 73% (SE 1%) 5-year EFS achieved in the ALL-BFM-86 study (P =.02, Z-test). However, restricting the analysis to SRG patients receiving protocol II with a total duration of treatment of 18 months, the 5-year EFS rates were 64.6% (SE 4.0%) and 67% (SE 4%), respectively, and no significant difference could be established (P =.67, Z-test). The 5-year EFS rates for SRG, RG, and EG patients were 63.5% (SE 5.6%), 66.6% (SE 4.2%), and 63.3% (SE 12.0%), respectively. SRG patients receiving protocol II fared better than patients not receiving protocol II (5-year EFS 76.7% [SE 7.7] and 54. 5% [SE 7.5], respectively). No difference in 5-year EFS was observed in RG patients randomized to receive or not to receive late intensification with protocol S. The overall CNS relapse rate at 5 years was 5.5%. The incidence rate at 5 years was 11.4% in SRG patients not receiving protocol II, whereas no CNS relapses occurred in SRG patients receiving protocol II. Six children died in first complete remission and 2 children developed a second malignancy (thyroid carcinoma and acute nonlymphoblastic leukemia). Systemic high-dose methotrexate (MTX) and intrathecal chemotherapy is a safe and effective method of CNS prophylaxis in the context of BFM-oriented treatment for all children with ALL, regardless of the risk group (with the possible exception of T-ALL patients with high white blood cell counts). The results of the DCLSG ALL-7 study confirm those of the ALL-BFM-86 study showing that early reinduction with protocol II is essential in the treatment of SRG patients and that late intensification with protocol S does not improve the prognosis for RG patients.     

Favorable effect of priming with granulocyte colony-stimulating factor in remission induction of acute myeloid leukemia restricted to dose escalation of cytarabine

The clinical value of chemotherapy sensitization of acute myeloid leukemia (AML) with G-CSF priming has remained controversial. Cytarabine is a key constituent of remission induction chemotherapy. The effect of G-CSF priming has not been investigated in relationship with variable dose levels of cytarabine. We randomized 917 AML patients to receive G-CSF (456 patients) or no G-CSF (461 patients) at the days of chemotherapy. In the initial part of the study, 406 patients were also randomized between 2 cytarabine regimens comparing conventional-dose (199 patients) versus escalated-dose (207 patients) cytarabine in cycles 1 and 2. We found that patients after induction chemotherapy plus G-CSF had similar overall survival (43% vs 40%, P = .88), event-free survival (37% vs 31%, P = .29), and relapse rates (34% vs 36%, P = .77) at 5 years as those not receiving G-CSF. However, patients treated with the escalated-dose cytarabine regimen benefited from G-CSF priming, with improved event-free survival (P = .01) and overall survival (P = .003), compared with patients without G-CSF undergoing escalated-dose cytarabine treatment. A significant survival advantage of sensitizing AML for chemotherapy with G-CSF was not apparent in the entire study group, but it was seen in patients treated with escalated-dose cytarabine during remission induction. The HOVON-42 study is registered under The Netherlands Trial Registry (www.trialregister.nl) as #NTR230.     

Autologous hematopoietic stem cell transplantation for adults with acute myeloid leukemia in complete remission: the Edouard Herriot Hospital experience

We retrospectively assess the long-term outcome and determined prognostic factors correlated with outcomes in adults with acute myeloid leukemia (AML) undergoing autologous hematopoietic stem cell transplantation (HSCT) in our institution over a 19-year period. A total of 78 adults who received autologous HSCT for AML in first complete remission (CR) and of 21 adults in further CR were included in the study. Bone marrow (n = 14) or peripheral blood stem cells (PBSC) (n = 85) transplantation was performed at a median of 2.9 months from CR. Hematologic recovery was significantly reduced in the PBSC group. Five-year cumulative incidences of relapse were 56 and 49%, respectively. Corresponding 5-year probabilities of event-free survival (EFS) were 33 and 35%, while those of overall survival (OS) were 38 and 49%, respectively. In multivariate analyses, cytogenetics was the main prognostic factor for outcome. Treatment-related mortality (TRM) was of 15% at 5 years, but higher in females as compared to males (p = 0.04). We confirmed that long-term EFS can be achieved after autologous HSCT in adult patients with AML. Results in adults who experience a relapse after conventional chemotherapy support the use of autologous HSCT as salvage therapy if such patients achieve a subsequent CR.     

Prognostic significance of chromosome analysis in childhood acute lymphoblastic leukemia. Children's Cancer and Leukemia Study Group (CCLSG)

We analyzed the prognostic significance of chromosomal findings in children with acute lymphoblastic leukemia (ALL), treated according to the Children's Cancer and Leukemia Study Group protocols between 1987 and 1993. Patients were classified into 5 groups according to chromosome number. The patients with a hyperdiploid(> 50) karyotype(13%) had the best prognosis [4-year event-free survival (EFS): 83 +/- 6%], while those with a pseudodiploid karyotype (24%) had the worst prognosis(4-year EFS: 52 +/- 6%) (log-rank, p = 0.03). However, multivariate analysis revealed that the ploidy classification had no prognostic significance in terms of EFS. When patients were classified according to chromosome abnormalities, those with any type of translocation had a worse outcome (4-year EFS: 33 +/- 9%) than those with hyperdiploidy(> 50), normal diploidy, and other abnormalities(log-rank, p < 0.0001). Multivariate analysis revealed that chromosome abnormalities were an independent prognostic factor (relative risk 3.98; p < 0.0001). Patients with t(1; 19) had an EFS similar to that of patients with chromosome abnormalities other than translocations or normal diploidy. We conclude that chromosomal findings have prognostic significance, although some chromosome abnormalities lost their statistical significance after modern intensified chemotherapy. Childhood ALL should be further stratified according to chromosome classification.     

Burkitt's and Burkitt-like lymphoma in children and adolescents: a review of the Children's Cancer Group experience

Historically, the survival of children and adolescents with Burkitt's and Burkitt-like lymphoma had been poor. Recently, short and intensive chemotherapy appears to have improved disease outcome. We therefore reviewed the results of four successive Children's Cancer Group trials conducted on 470 children with disseminated Burkitt's and Burkitt-like lymphoma. Of the patients studied, the median age was 8 years (0-21 years), the male:female ratio was 4:1, 58% had lactate dehydrogenase (LDH) > or = 500 IU/l, 23% had M2 or M3 bone marrow (BM), and 12% demonstrated central nervous system involvement. In a multivariate analysis, the 4-year event-free survival (EFS) in patients > or = 15-years-old compared with < 15-year-old was 34 +/- 7 versus 59 +/- 2% (P < 0.05), the 4-year EFS of M2/M3 compared with M1 BM was 38 +/- 5 versus 63 +/- 3% (P < 0.001), and the 4-year EFS with LDH > or = 500 IU/l compared with LDH < 500 IU/l was 49 +/- 3 versus 71 +/- 4% (P < 0.001). Furthermore, patients treated on the most recent protocol, which was short and more intensive, had a significantly improved survival compared with those on previous trials (4-year EFS 80 +/- 6 versus 54 +/- 2%, P < 0.001). In summary, the outcome for childhood Burkitt's and Burkitt-like lymphoma has recently improved with the use of short and intensive B-cell non-Hodgkin's lymphoma-directed therapy.     

A phase II clinical trial of intensive chemotherapy followed by consolidative stem cell transplant: long-term follow-up in newly diagnosed mantle cell lymphoma

Mantle cell lymphoma (MCL) is associated with high relapse rates and poor survival when treated with conventional chemotherapy, with or without rituximab. We report the long-term follow-up of a phase II clinical trial using a new intensive multiagent chemotherapeutic regimen [cyclophosphamide, teniposide, doxorubicin and prednisone (CTAP) alternating with vincristine and high-dose methotrexate and cytarabine (VMAC)] in newly diagnosed MCL. Following 4–6 cycles of CTAP/VMAC induction, patients aged ≤65 years proceeded to consolidative autologous haematopoietic stem cell transplantation (auto-HSCT), while patients ≤55 years who had a HLA-identical sibling received allogeneic-HSCT (busulfan/cyclophosphamide conditioning for both). Twenty-five untreated MCL patients enrolled on the protocol between 1997 and 2002. Among evaluable patients, overall response rate (ORR) was 74% following induction chemotherapy. Seventeen patients received HSCT (autologous-13/allogeneic-4). On intent-to-treat analysis, ORR for patients who received consolidative HSCT was 100% (complete remission 76%). Therapy was well-tolerated with 4% treatment-related mortality (including HSCT). The 5-year event-free-survival (EFS) and overall survival (OS) for all patients was 35% and 50% respectively. Furthermore, at 66-months median follow-up, the 5-year EFS and OS for patients who received consolidative auto-HSCT was 54% and 75% respectively. Patients who received auto-HSCT had improved outcomes compared to no auto-HSCT (EFS P  = 0·001; OS P  = 0·0002). CTAP/VMAC induction followed by consolidative auto-HSCT for newly diagnosed MCL is associated with high ORR and durable survival.     

Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group

Trial ALL-BFM 90 was designed to improve outcome in patients with childhood acute lymphoblastic leukemia (ALL) by using a reduced treatment regimen. Patients were stratified into a standard-risk group (SRG), a medium-risk group (MRG), both defined by adequate early treatment response; and a high-risk group (HRG), defined by inadequate response to the cytoreductive prednisone prephase, induction failure, or Philadelphia-chromosome-positive ALL. Four treatment modifications were evaluated: dose intensification in induction by a more rapid drug sequence; administration of L-asparaginase during consolidation therapy in the MRG (randomized); enforced consolidation by rotational elements in the HRG; and reduction in the dose of anthracyclines and use of only 12-Gy preventive cranial radiotherapy in the MRG and HRG, with the aim of avoiding toxicity. Among all 2178 patients (相似文献   

Total therapy 2 without thalidomide in comparison with total therapy 1: role of intensified induction and posttransplantation consolidation therapies

Patients with myeloma, treated on the thalidomide arm of total therapy 2 (TT2), had a higher complete response (CR) rate and improved event-free survival (EFS) but not overall survival (OS). To evaluate the benefit of TT2's posttandem autotransplant consolidation chemotherapy and dexamethasone maintenance, outcomes were compared on TT2 without thalidomide (n = 345; median follow-up, 3.5 years) and on predecessor trial TT1 (n = 231; median follow-up, 11.5 years). CR rates were similar (43% vs 41%); however, 5-year estimates of continuous CR (45% vs 32%, P < .001) and 5-year EFS (43% vs 28%, P < .001) were superior with TT2, with a trend for improved OS (62% vs 57%; P = .11). OS was also superior among patients achieving CR and receiving the second transplantation early after the first transplantation. Superior EFS and OS with TT2 versus TT1 was noted in the two thirds presenting without cytogenetic abnormalities (CAs); 4-year posttandem transplantation OS for patients with CAs was 47% with TT1 and 76% with TT2 when combination chemotherapy rather than DEX was applied for consolidation (P = .040). Thus, TT2 (without thalidomide) improved OS of patients without CAs; those with CAs benefited from posttransplantation consolidation chemotherapy. The favorable effects of CR and rapidly sequenced second transplantation attest to the validity of a melphalan dose-response effect in myeloma.     

Low-dose versus high-dose methotrexate during remission induction in childhood acute lymphoblastic leukemia (Protocol 81-01 update).

We evaluated event-free survival (EFS) and leukemia-free interval (LFI) of children treated for acute lymphoblastic leukemia (ALL). Patients were randomized to receive either a low dose or high dose of methotrexate (MTX) as a single agent at the time of diagnosis. Five days later, multidrug therapy was begun. We assessed the early antileukemic efficacy of the two doses of MTX, as well as toxicity and long-term efficacy. An increase in cell kill, as indicated by a larger decrease in the percentage of viable cells in the bone marrow between days 0 and 5, was observed for the high-dose MTX group when compared with the low-dose MTX group (P = .04). At 7.1 years of median follow-up, the 38 children randomized to receive high-dose MTX had a better EFS and LFI compared with the 39 patients randomized to receive low-dose MTX. The 7-year percentages (+/- SE) for EFS were 82% +/- 6% for high-dose MTX and 69% +/- 7% for low-dose MTX (P = .13). The 7-year percentages for LFI were 91% +/- 5% and 69% +/- 7%, respectively (P = .01). We recommend that high-dose MTX be considered as an effective addition to induction therapy in childhood ALL.     

Induction chemotherapy followed by allogeneic bone marrow transplantation or aggressive consolidation chemotherapy in childhood acute myeloblastic leukemia: A prospective study from the French Society of Pediatric Hematology and Immunology (SHIP)

In the LAME89/91 protocol, children with acute myeloid leukemia (AML) who achieved complete remission (CR) after induction chemotherapy, were treated either with allogeneic bone marrow transplantation (BMT) if they had an HLA-compatible related donor or with chemotherapy including high-dose cytarabine. The objectives of this study were to describe the overall results of this strategy and to compare the two post-remission arms. Two hundred and thirty-one children were enrolled in the protocol. Induction chemotherapy consisted of a combination of cytarabine and mitoxantrone. A CR was achieved in 204 children (88%). Fifty-one of them had an HLA-identical sibling donor and were eligible for BMT. These 51 patients, as well as two additional children who had a one antigen HLA-mismatched father, received BMT during first CR. Consequently, 53 patients were analysed in the BMT group and 151 in the chemotherapy group. With a mean follow up duration in the study of 38 ± 2 months, overall event-free survival (EFS) was 47 ± 7% at 4 years for the 231 patients entered into the protocol. The 4-year disease-free survival (DFS) was 53 ± 8% for the 204 patients who achieved complete remission after induction therapy. The 4-year probability of relapse was 28 ± 14% in the BMT group and 47 ± 9% in the chemotherapy group (p = 0.02). The risk of therapy-related death was 6.2% for BMT and 8.1% for chemotherapy. DFS was 68 ± 14% in the BMT group and 48 ± 9% in the chemotherapy group (p = 0.02). We conclude that allogeneic BMT from a matched sibling donor is the treatment of choice for reducing the relapse risk and for increasing DFS in children with AML in first CR.Research grant support: Supported by lAssociation pour la Recherche contre le Cancer (ARC)