Maarten Egeler

Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group

PURPOSE Outcome of childhood acute lymphoblastic leukemia (ALL) improved greatly by intensifying chemotherapy for all patients. Minimal residual disease (MRD) levels during the first months predict outcome and may select patients for therapy reduction or intensification. METHODS Patients 1 to 18 years old with ALL were stratified on the basis of MRD levels after the first and second course of chemotherapy. Thereafter, therapy was substantially reduced in patients with undetectable MRD (standard risk) and intensified in patients with intermediate (medium risk) and high (high risk) levels of MRD. Seven hundred seventy-eight consecutive patients were enrolled. The method of analysis was intention-to-treat. Outcome was compared with historical controls. RESULTS In MRD-based standard-risk patients, the 5-year event-free survival (EFS) rate was 93% (SE 2%), the 5-year survival rate was 99% (SE 1%), and the 5-year cumulative incidence of relapse rate was 6% (SE 2%). The safety upper limit of number of observation years was reached and therapy reduction was declared safe.MRD-based medium-risk patients had a significantly higher 5-year EFS rate (88%, SE 2%) with therapy intensification (including 30 weeks of asparaginase exposure and dexamethasone/vincristine pulses) compared with historical controls (76%, SE 6%). Intensive chemotherapy and stem cell transplantation in MRD-based high-risk patients resulted in a significantly better 5-year EFS rate (78%, SE 8% v 16%, SE 8% in controls). Overall outcome improved significantly (5-year EFS rate 87%, 5-year survival rate 92%, and 5-year cumulative incidence of relapse rate 8%) compared with preceding Dutch Childhood Oncology Group protocols. CONCLUSION Chemotherapy was substantially reduced safely in one-quarter of children with ALL who were selected on the basis of undetectable MRD levels, without jeopardizing the survival rate. Outcomes of patients with intermediate and high levels of MRD improved with therapy intensification.

Will Post-Transplantation Cell Therapies for Pediatric Patients Become Standard of Care?

Although allogeneic hematopoietic stem cell transplantation (HSCT) is a curative approach for many pediatric patients with hematologic malignancies and some nonmalignant disorders, some critical obstacles remain to be overcome, including relapse, engraftment failure, graft-versus-host disease (GVHD), and infection. Harnessing the immune system to induce a graft-versus-tumor effect or rapidly restore antiviral immunity through the use of donor lymphocyte infusion (DLI) has been remarkably successful in some settings. Unfortunately, however, the responses to DLI can be variable, and GVHD is common. Thus, manipulations to minimize GVHD while restoring antiviral immunity and enhancing the graft-versus-tumor effect are needed to improve outcomes after allogeneic HSCT. Cellular therapies, defined as treatment modalities in which hematopoietic or nonhematopoietic cells are used as therapeutic agents, offer this promise for improving outcomes post-HSCT. This review presents an overview of the field for pediatric cell therapies in the transplant setting and discusses how we can broaden applicability beyond phase I.

Chest health surveillance utility in the early detection of bronchiolitis obliterans syndrome in children after allo-SCT.

To prospectively assess whether periodic chest health surveillance is beneficial for the early detection of bronchiolitis obliterans syndrome (BOS) in children after allo-SCT. Children up to 18 years of age receiving allo-SCT from September 2009 to September 2011 were included. Surveillance consisted of the following: a 7-item respiratory system questionnaire of cough, wheeze and shortness of breath; focused physical examination; and pulmonary function test (PFT) conducted before SCT and at 1, 3, 6, 9, 12, 18 and 24 months after SCT. Thirty-nine patients were enrolled. Five children developed BOS at a median time of 192 days (range 94–282). Positive response comparisons between the BOS group vs the non-BOS group were NS for history questionnaire (P=0.2), heart rate (P=0.3), respiratory rate (P=0.3) and oxygen saturation monitoring (P=0.8). Differences between the two groups for chest auscultation and PFT were statistically significant (P=0.03 and P=0.01, respectively). However, chest auscultation in the BOS group was only positive after BOS diagnosis. PFT reduction was evident in the asymptomatic phase (BOS group 33%; non-BOS group 4.5%, P=0.01). Changes in PFT, but not history/physical examination, allow the early detection of BOS in children after SCT. Our study is limited by the small sample size.

Severe lung injury and lung biopsy in children post-hematopoietic stem cell transplantation: The differences between allogeneic and autologous transplantation.

To review outcome of children post‐allogeneic (allo) and autologous (auto) SCT with severe lung injury who had lung biopsy and to determine whether the diagnoses provided by lung biopsy had an impact on outcome. Retrospective study was carried out from January 2000 to June 2010. Nine hundred and eighteen children (0–18 yr) received SCT (allo 476, auto 442), and 59 biopsies were performed in 48 patients. Most common result of lung biopsy was non‐infectious inflammation and recurrent disease in allo‐ and autorecipients, respectively. In a multivariate analysis, survival of allorecipients who had management change was inferior (p = 0.002; HR: 3.12). These patients were extremely sick, and management change was the last attempt to stabilize their respiratory status. There was a trend toward superior survival for children who had biopsy after 100 days following SCT (p = 0.09; HR: 0.55) and a trend toward inferior survival for those with proven infections within two wk of biopsy (p = 0.07; HR: 2.14). Only 31% of allorecipients and 25% of autorecipients survived. There were no biopsy‐related complications. Lung biopsy itself appears to be well tolerated, although requiring a biopsy seems to carry a poor prognosis; this seems to be due to different causes, auto (relapse), allo (non‐infectious inflammation).

The yield of monitoring for HSV and VZV viremia in pediatric hematopoietic stem cell transplant patients

Reactivation of HSV and VZV is common following HSCT. Consensus guidelines do not support the use of routine screening for viremia following HSCT in adults, but no such clear guidelines exist in pediatrics. In our center, routine practice was to screen patients weekly for HSV and VZV viremia until engraftment in autologous transplant patients and up to day +100 in allogeneic transplant patients. We conducted a retrospective study of over 500 patients to establish whether this screening identified any patients with HSV or VZV viremia who would not have been identified by clinical signs or symptoms. Over a 4.5‐yr period, routine screening identified three cases of HSV viremia and one case of VZV viremia. Two patients had persistent, unexplained fever and two patients had skin or mucosal lesions suggestive of HSV/VZV. We conclude that routine screening for HSV and VZV viremia in pediatric HSCT patients has a very low yield and that viremia can be reliably identified by targeted testing in patients with vesicular skin lesions, oral or genital ulceration, unexplained fever, neurological symptoms, or unexplained abnormal liver transaminases.

Acute gut GVHD in children: does skin involvement matter?

Gut GVHD (G-GVHD) is frequently the most severe and difficult to treat compared with skin GVHD. It is unknown if skin involvement with G-GVHD has prognostic significance. To compare the prognosis of acute isolated G-GVHD vs acute gut and skin GVHD (GS-GVHD) in children following allo-SCT. Allo-SCT recipients from Jan 2000–Dec 2009 were included and patients who underwent endoscopy and gut biopsy for G-GVHD were identified. Four hundred and fifty children (0–18 years) underwent allo-SCT during the study period. Seventy-nine (17.5%) patients underwent endoscopy and biopsy. At least stage II was required for skin involvement. Forty nine patients had G-GVHD and 30 had combined, GS-GVHD. The majority of patients received CsA and MTX for GVHD prophylaxis. Sixty-seven percent of patients with GS-GVHD had grade III–IV while only 31% had grade III–IV in the G-GVHD group. Median follow-up was 6.3 years (range 3.6–11.9 years). Relapse rate was similar in both the groups. However, children with G-GVHD had a significantly higher risk of dying from GVHD related complications (37% vs 16%) resulting in superior survival for those with skin involvement (79% vs 49% P=0.02). Extension of G-GVHD to the skin may suggest a better outcome.

Bisphosphonate Therapy in Langerhans Cell Histiocytosis: An International Retrospective Descriptive Study

1Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada, 2Department of Endocrinology & Diabetes, Hellenic Airforce & VA General Hospital, Athens, Greece, 3Department of Pathophysiology, National University of Athens, Athens, Greece, 4Department of Pediatric Oncology, Emma Childrens Hospital/Academic Medical Center, Amsterdam, The Netherlands, 5Division of Hematology-Oncology, Department of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada

Pediatric Allogeneic Bone Marrow and Stem Cell Transplantation in Alberta, Canada |[dagger]| 754

Introduction: Bone marrow and peripheral stem cell transplantantation (BMT and PSCT) are treatment modalities used for a variety of diseases. These procedures are expensive and not without morbidity. It is therefore important to continue evaluating outcome. Here, we report on outcome of BMT and PSCT in children from a single provincial program.

Autologous Peripheral Blood Stem Cell Transplantation (PBSCT) for Children with Recurrent or Poor Risk Solid Tumors |[dagger]| 755

Introduction: Administration of chemotherapeutic agents with maximal dose intensity followed by autologous stem cell transplantation has become an important consideration in the design of treatment regimens for poor prognosis childhood malignancies.