Liisa Hovi

A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial

BACKGROUND Acute lymphoblastic leukaemia in infants younger than 1 year is rare, and infants with the disease have worse outcomes than do older children. We initiated an international study to investigate the effects of a new hybrid treatment protocol with elements designed to treat both acute lymphoblastic leukaemia and acute myeloid leukaemia, and to identify any prognostic factors for outcome in infants. We also did a randomised trial to establish the value of a late intensification course. METHODS Patients aged 0-12 months were enrolled by 17 study groups in 22 countries between 1999 and 2005. Eligible patients were stratified for risk according to their peripheral blood response to a 7-day prednisone prophase, and then given a hybrid regimen based on the standard protocol for acute lymphoblastic leukaemia, with some elements designed for treatment of acute myeloid leukaemia. Before the maintenance phase, a subset of patients in complete remission were randomly assigned to receive either standard treatment or a more intensive chemotherapy course with high-dose cytarabine and methotrexate. The primary outcomes were event-free survival (EFS) for the initial cohort of patients and disease-free survival (DFS) for the patients randomly assigned to a treatment group. Data were analysed on an intention-to-treat basis. This trial was registered with ClinicalTrials.gov, number NCT 00015873, and at controlled-trials.com, number ISRCTN24251487. FINDINGS In the 482 enrolled patients who underwent hybrid treatment, 260 (58%) were in complete remission at a median follow-up of 38 (range 1-78) months, and EFS at 4 years was 47.0% (SE 2.6, 95% CI 41.9-52.1). Of 445 patients in complete remission after 5 weeks of induction treatment, 191 were randomised: 95 patients to receive a late intensification course, and 96 to a control group. At a median follow-up of 42 (range 1-73) months, 60 patients in the treatment group and 57 controls were disease-free. DFS at 4 years did not differ between the two groups (60.9% [SE 5.2] for treatment group vs 57.0% [5.5] for controls; p=0.81). During the intensification phase, of 71 patients randomly assigned to the treatment group, and for whom toxicity data were available, 35 (49%) had infections, 21 (30%) patients had mucositis, 22 (31%) patients had toxic effects on the liver, and 2 (3%) had neurotoxicity. All types of rearrangements in the (mixed lineage leukaemia) MLL gene, very high white blood cell count, age of younger than 6 months, and a poor response to the prednisone prophase were independently associated with inferior outcomes. INTERPRETATION Patients treated with our hybrid protocol, and especially those who responded poorly to prednisone, had higher EFS than most reported outcomes for treatment of infant ALL. Delayed intensification of chemotherapy did not benefit patients.

Impaired glucose tolerance and dyslipidaemia as late effects after bone-marrow transplantation in childhood

BACKGROUND This follow-up study aimed to assess the frequency of late effects on glucose and lipid metabolism after bone-marrow transplantation in childhood. METHODS 23 long-term survivors (median age 20 years) were studied 3-18 years after bone-marrow transplantation and compared with 23 healthy controls matched for age and sex and with 13 patients in remission from leukaemia. FINDINGS 12 (52%) of the 23 bone-marrow transplantation patients had insulin resistance, including impaired glucose tolerance in six and type 2 diabetes in four. The core signs of the metabolic syndrome (hyperinsulinaemia and hypertriglyceridaemia combined), were found in nine (39%) of the bone-marrow transplantation patients compared with one (8%) of the 13 leukaemia patients and none of the healthy controls (p=0.0015). The frequency of insulin resistance increased with the time since bone-marrow transplantation. Abdominal obesity, but not overweight, was common among the patients with insulin resistance. INTERPRETATION Long-term survivors of bone-marrow transplantation are at substantial risk of insulin resistance, impaired glucose tolerance, and type 2 diabetes even at normal weight and young age. They also develop typical signs of the metabolic syndrome. We advocate measurement of serum lipids, fasting blood glucose, and serum insulin for the follow-up of all patients who undergo transplants in childhood, to be continued regularly and possibly life-long.

Invasive fungal infections in pediatric bone marrow transplant recipients: single center experience of 10 years.

Invasive fungal infections (IFI) with substantial mortality constitute an increasing problem among BMT patients. From 1986 to 1996 148 children underwent BMT, and are included in a retrospective analysis of the incidence, risk factors and outcome of IFI. By histopathology or culture-proven IFI (Candida, 10; Aspergillus, 8) was documented in 12/73 (16%) allogeneic and in 6/75 (8%) autologous BMT patients. Of these 18 patients, 15 subsequently died, and in 12 (66%) IFI was regarded as the main cause of death. In addition to the patients with documented IFI, 48 had suspected and 82 no fungal infection. Invasive candidal infections were more frequent in patients with semiquantitatively estimated abundant candidal colonization as compared with those with no colonization (18% vs 3%, P = 0.015). In the allogeneic group, 50% of those with severe (grades III–IV) aGVHD had IFI as opposed to 8% of those with no or mild aGVHD (P < 0.001). Regarding cGVHD, 57% of those with extensive cGVHD vs 5% of those with absent or limited cGVHD had IFI (P < 0.001). The dose of steroids was associated with IFI: 77% of those who received high-dose steroids (methylprednisolone 0.25–1 g/day for 5 days) vs 5% of those with conventional-dose (prednisone 2 mg/kg/day) had IFI (P < 0.001). Particularly for BMT patients at risk, new, quicker and better diagnostic tests and more effective anti-fungal agents, both for prophylaxis and treatment, are needed. Bone Marrow Transplantation (2000) 26, 999–1004.

Long-term results in children with AML: NOPHO-AML Study Group – report of three consecutive trials

In all, 447 children with acute myeloid leukaemia (AML) have been treated on three consecutive NOPHO studies from July 1984 to December 2001. NOPHO-AML 84 was of moderate intensity with an induction of three courses of cytarabine, 6-thioguanine and doxorubicin followed by four consolidation courses with high-dose cytarabine. The 5-year event-free survival (EFS), disease free survival (DFS) and overall survival (OS) were 29, 37 and 38%. NOPHO-AML 88 was of high intensity with the addition of etoposide and mitoxantrone in selected courses during induction and consolidation. The interval between the induction courses should be as short as possible, that is, time intensity was introduced. The 5-year EFS, DFS and OS were 41, 48 and 46%. In NOPHO-AML 93, the treatment was stratified according to response to first induction course. The protocol utilised the same induction blocks as NOPHO-AML 88, but after the first block, children with a hypoplastic, nonleukaemic bone marrow were allowed to recover before the second block. Consolidation was identical with NOPHO-AML 88. The 5-year EFS, DFS and OS in NOPHO-AML 93 were 48, 52 and 65%. The new NOPHO-AML protocol has been based on experiences from previous protocols with stratification of patients with regard to in vivo response and specific cytogenetic aberrations.

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

Summary. 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 Downs 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.

Improved Outcome in Pediatric Relapsed Acute Myeloid Leukemia: Results of a Randomized Trial on Liposomal Daunorubicin by the International BFM Study Group

PURPOSE In pediatric relapsed acute myeloid leukemia (AML), optimal reinduction therapy is unknown. Studies suggest that liposomal daunorubicin (DNX; DaunoXome; Galen, Craigavon, United Kingdom) is effective and less cardiotoxic, which is important in this setting. These considerations led to a randomized phase III study by the International Berlin-Frankfurt-Münster Study Group. PATIENTS AND METHODS Patients with relapsed or primary refractory non-French-American-British type M3 AML who were younger than 21 years of age were eligible. Patients were randomly assigned to fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) or to FLAG plus DNX in the first reinduction course. The primary end point was status of the bone marrow (BM) sampled shortly before the second course of chemotherapy (the day 28 BM). Data are presented according to intention-to-treat for all 394 randomly assigned patients (median follow-up, 4.0 years). RESULTS The complete remission (CR) rate was 64%, and the 4-year probability of survival (pOS) was 38% (SE, 3%). The day 28 BM status (available in 359 patients) was good (≤ 20% leukemic blasts) in 80% of patients randomly assigned to FLAG/DNX and 70% for patients randomly assigned to FLAG (P = .04). Concerning secondary end points, the CR rate was 69% with FLAG/DNX and 59% with FLAG (P = .07), but overall survival was similar. However, core-binding factor (CBF) AML treated with FLAG/DNX resulted in pOS of 82% versus 58% with FLAG (P = .04). Grade 3 to 4 toxicity was essentially similar in both groups. CONCLUSION DNX added to FLAG improves early treatment response in pediatric relapsed AML. Overall long-term survival was similar, but CBF-AML showed an improved survival with FLAG/DNX. International collaboration proved feasible and resulted in the best outcome for pediatric relapsed AML reported thus far.

Recombinant human granulocyte-macrophage colony-stimulating factor in the treatment of febrile neutropenia: a double blind placebo-controlled study in children.

In a double blind study of 58 episodes of fever and profound neutropenia, children with cancer received either recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) or placebo, combined with identical antimicrobial therapy, i.e. imipenem, on admission. The criteria for discontinuation of therapy were identical. A difference was demonstrated both in the number of hospital days, totaling 252 days in the rhGM-CSF group and 354 in the placebo group, days receiving antibiotics (220 vs. 322), and in the resolution of neutropenia (4.5 days vs. 6.0 days; P < 0.05). The number of episodes requiring antimicrobial therapy for longer than 10 days was 5 of 28 (12%) in the rhGM-CSF group as opposed to 15 of 30 (50%) in the placebo group (P = 0.01). rhGM-CSF was well-tolerated. We conclude that rhGM-CSF was efficacious in accelerating myeloid recovery and reducing the length of hospitalization in febrile neutropenia.

Improved outcome after relapse in children with acute myeloid leukaemia

In the Nordic Society for Paediatric Haematology and Oncology paediatric study acute myeloid leukaemia (AML) 93, event‐free survival was 50% and overall survival was 66%, indicating that many patients were cured following relapse. Factors influencing outcome in children with relapsed AML were investigated. The study included all 146 children in the Nordic countries diagnosed with AML between 1988 and 2003, who relapsed. Data on disease characteristics and relapse treatment were related to outcome. Sixty‐six percentage achieved remission with survival after relapse (5 years) 34 ± 4%. Of 122 patients who received re‐induction therapy, 77% entered remission with 40 ± 5% survival. Remission rates were similar for different re‐induction regimens but fludarabine, cytarabine, granulocyte colony‐stimulating factor‐based therapy had low treatment‐related mortality. Prognostic factors for survival were duration of first complete remission (CR1) and stem cell transplantation (SCT) in CR1. In early relapse (<1 year in CR1), survival was 21 ± 5% compared with 48 ± 6% in late relapse. For children receiving re‐induction therapy, survival in early relapse was 29 ± 6% and 51 ± 6% in late. Patients treated in CR1 with SCT, autologous SCT or chemotherapy had a survival of 18 ± 9, 5 ± 5 and 41 ± 5%, respectively. Survival was 62 ± 6% in 64 children given SCT as part of their relapse therapy. A significant proportion of children with relapsed AML can be cured, even those with early relapse. Children who receive re‐induction therapy, enter remission and proceed to SCT can achieve a cure rate of 60%.

Disturbed root development of permanent teeth after pediatric stem cell transplantation. Dental root development after SCT

Deficient dental root development has been reported after conventional pediatric anticancer therapy, but less information is available on stem cell transplantation (SCT) recipients.

Prevention and monitoring of invasive fungal infections in pediatric patients with cancer and hematologic disorders

The occurrence of invasive fungal infection (IFIs) in a pediatric hematology/oncology unit after renovation of the ventilation system, and initiating routine azole antifungal prophylaxis was monitored. In addition, the value of serial screening for Aspergillus galactomannan (GM) for diagnosing invasive aspergillosis was assessed.