Adam Gassas

Early lymphocyte recovery post-allogeneic hematopoietic stem cell transplantation is associated with significant graft-versus-leukemia effect without increase in graft-versus-host disease in pediatric acute lymphoblastic leukemia

To study the effect of early lymphocyte recovery post-allogeneic hematopoietic stem cell transplantation (HSCT) on outcome in pediatric ALL, we reviewed 136 consecutive pediatric patients with ALL who received allogeneic HSCT between 1994 and 2005 at the Hospital for Sick Children, Toronto, Canada. Patients with an absolute lymphocyte count (ALC) <0.3 × 109 per liter at day 21 (n=104) had more than five times risk of relapse compared to those with ALC >0.3 × 109 per liter (n=32) (hazard ratio (HR) 5.3; P=0.002) and had inferior 3-year event-free survival, (EFS), 0.42 (95% confidence interval (CI) 0.32, 0.51) compared to 0.66 (95% CI 0.48, 0.82; P=0.02). Similarly, patients with an ALC <0.3 × 109 per liter (n=48) at day 30 were more than twice as likely to relapse compared to those with an ALC >0.3 × 109 per liter (n=88) (HR 2.2; P=0.01) and had an inferior 3-year EFS, 0.30 (95% CI 0.18, 0.45) compared to 0.57 (95% CI 0.46, 0.68; P=0.0001). Interestingly, increasing ALC at days 21 and 30 was not associated with increased incidence of acute or chronic GVHD or transplant-related mortality (TRM). Early lymphocyte recovery post-HSCT is associated with a significant GVL without increase in GVHD.

Atypical Teratoid or Rhabdoid Tumors: Improved Outcome With High-dose Chemotherapy

Purpose To retrospectively review an institutional experience in managing atypical teratoid/rhabdoid tumors (AT/RT) of the Central Nervous System with high-dose chemotherapy in infants and children less than 4 years old. Materials/Methods Eight AT/RT patients were identified during the study period 2003 to 2008. Tumor location was supratentorial in 3 cases, infratentorial in 3 cases, and multifocal in 2 patients. Five patients presented with leptomeningeal dissemination. Two of these patients did not receive any active therapy. After surgery, the 6 remaining patients received induction therapy followed by sequential high-dose chemotherapy with autologous stem cell rescue. Two patients receive focal irradiation. Results At a median follow-up of 52 months, 4 patients are alive without evidence of tumor. Three of these patients, including 2 with metastatic disease were not irradiated. However, all surviving patients exhibit neuro-cognitive impairment, either at baseline assessment or upon follow-up. Conclusions This experience confirms that a subset of young AT/RT patients may achieve long-term survival with intensive and high-dose chemotherapy. The role of radiotherapy is still unclear. However, evidence of neuro-cognitive impairment even in the absence of radiotherapy in this young population suggests that systematic introduction of radiotherapy in current protocols should be carefully assessed.

Predictors of Viridans Streptococcal Shock Syndrome in Bacteremic Children With Cancer and Stem-Cell Transplant Recipients

PURPOSE To describe episodes of viridans streptococcal bacteremia (VSB) in a cohort of children with cancer and stem-cell transplant (SCT) recipients and to determine predictors of viridans streptococcal shock syndrome (VSSS) in this group of children. PATIENTS AND METHODS For this retrospective review, we included episodes of VSB isolated between March 1997 and September 2002, in children (<or= 18 years) with a diagnosis of cancer or SCT patients. The primary outcome was VSSS, defined as hypotension requiring intravascular volume expansion or inotropic support and/or respiratory insufficiency necessitating assisted ventilation. RESULTS Eighty-eight episodes of VSB occurred in 79 children. The mean age of the children was 6.7 years (range, 0.6 to 18.0 years). The most common underlying diagnosis was acute myelogenous leukemia (AML) in 31 (35%) of 88 episodes, and 38 (43%) of 88 had undergone SCT. VSSS occurred in 16 (18%) of 88 episodes, and two children died from VSSS. Two variables were predictive of VSSS, namely peak temperature at presentation (odds ratio [OR], 6.3; 95% CI, 2.1 to 19.0; P =.001) and inpatient status (OR, 5.9; 95% CI, 1.3 to 28.0; P =.02). Diagnosis of AML (OR, 1.1; 95% CI, 0.4 to 3.5; P =.8), receipt of SCT (OR, 1.9; 95% CI, 0.6 to 5.7; P =.2), high-dose cytarabine (OR, 0.6; 95% CI, 0.1 to 3.2; P =.6), and mucositis (OR, 0.8; 95% CI, 0.3 to 2.6; P =.7) were not predictive of VSSS. CONCLUSION VSSS occurred in 18% of episodes of VSB in children with cancer or SCT recipients. Peak temperature before antibiotic therapy and inpatient status were predictive of VSSS.

Graft-versus-leukemia effect in hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia : significantly lower relapse rate in unrelated transplantations

To determine graft-versus-leukemia (GVL) effect after hematopoietic stem cell transplantation (HSCT), we studied the outcome of consecutive children with acute lymphoblastic leukemia (ALL) who received fully matched marrow allografts comparing relapse rate post HSCT between matched sibling donor (MSD) and matched unrelated donor (MUD) recipients. Furthermore, we estimated event-free survival (EFS) on the basis of the occurrence of acute graft-versus-host disease (aGVHD). Between 1998 and 2006 we performed 37 fully MSD and 36 fully MUD HSCTs. All patients received identical conditioning regimens with cyclophosphamide/total body irradiation and dual GVHD prophylaxis with cyclosporine (CSA) and methotrexate (MTX). Three-year cumulative incidence of relapse for the MSD and MUD groups were 55.6±12.3 and 22.0±8.1%, respectively (P=0.03). Three-year EFS according to aGVHD was 32.7±12.2% for no aGVHD, 61.2±10.0% for grade I–II aGVHD and 66.7±11.1% for grade III–IV aGVHD. Three-year EFS and overall survival (OS) were 40.5±11.6, 49.1±9.5% for the MSD group, and 60.5±8.7, 62.3±8.4% for the MUD group. In children with ALL receiving dual GVHD prophylaxis, relapse rate is significantly higher among recipients of MSD compared to MUD transplantation, which may in part be attributed to a better GVL effect with the unrelated graft.

Does consolidation with autologous stem cell transplantation improve the outcome of children with metastatic or relapsed Ewing sarcoma

To evaluate the role of high‐dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) as consolidation therapy for children with high‐risk Ewing sarcoma (ES) treated at The Hospital for Sick Children (SickKids), Toronto.

Inferior outcomes for overweight children undergoing allogeneic stem cell transplantation

This retrospective cohort study aimed at determining whether overweight children undergoing allogeneic stem cell transplantation (SCT) had inferior overall survival compared with children who were not overweight. Children ≥2 years of age who received allogeneic SCT were included. Overweight was defined as a body mass index ≥ 95th percentile; 54/325 (17%) children were overweight. Overall survival at 5 years was significantly inferior at 46·6 ± 7·3% in the overweight group compared with 59·5 ± 3·2% in the non‐overweight group (P = 0·02). Our study demonstrated that overweight children who undergo allogeneic SCT had inferior survival compared with children who were not overweight.

Comparative outcome of hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia following cyclophosphamide and total body irradiation or VP16 and total body irradiation conditioning regimens

To compare the outcome of hematopoietic stem cell transplantation (HSCT) in pediatric acute lymphoblastic leukemia (ALL) conditioned with two different regimens: (1) single dose of VP16 (60 mg/kg over 4 h) and total body irradiation (TBI; 1200 cGy, in six fractions) or (2) Cyclophosphamide 50 mg/kg over 1 h daily for 4 days followed by the same dose of TBI. One hundred and seven children with ALL received fully matched HSCT from 1990 to 2003 in the Hospital for Sick Children, Toronto. All received cyclosporin A and a short course of methotrexate for graft-versus-host disease (GVHD) prophylaxis. The VP16 group, there were 36 matched related donor transplants (MRD) and 26 matched unrelated donor transplants (MUD), and in the cyclophosphamide group there were 23 MRD and 22 MUD transplants. Neutrophil engraftment occurred at a median of 18 and 17 days for the VP16/TBI and the CY/TBI groups, respectively. The 3 year event-free survival and overall survival were 47±7 and 55±7% for those receiving VP16/TBI, and 51±8 and 53±8% for the CY/TBI group. There were no significant differences in the prevalence of acute or chronic GVHD and transplant-related mortality between the two groups. Both VP16/FTBI and CY/FTBI regimen are equally effective regimens.

Life-threatening pulmonary hemorrhages post bone marrow transplantation in Hurler syndrome. Report of three cases and review of the literature.

Summary:Hurler syndrome (MPS-IH) is an autosomal recessive mucopolysaccharide storage disorder caused by deficiency of lysosomal alpha-L-iduronidase (IDU) enzyme activity. This results in accumulation of heparan sulfate and dermatan sulfate substances. Untreated children develop progressive developmental deterioration and multisystem morbidity with a median survival of 5 years. Allogeneic bone marrow transplantation (BMT) is the only long-lasting treatment that ameliorates or halts the aggressive course of the disease. Pulmonary hemorrhage (PH) is an unusual complication of BMT and has not been previously reported in MPS-IH post-BMT. We report three children with MPS-IH with life-threatening PH around the time of engraftment. All needed intensive-care support and one child developed recurrent PH that required prolonged ventilation.

IV Busulfan Dose Individualization in Children undergoing Hematopoietic Stem Cell Transplant: Limited Sampling Strategies

We currently calculate area under the busulfan concentration time curve (AUC) using 7 plasma busulfan concentrations (AUC7) drawn after the first of 16 i.v. busulfan doses given as a 2-hour infusion every 6 hours. The aim of this study was to develop and validate limited sampling strategies (LSSs) using 3 or fewer busulfan concentration values with which to reliably calculate AUC in children undergoing hematopoietic stem cell transplant (HSCT). Children in the development group (44) received i.v. busulfan at Sick Kids; the validation group consisted of 35 children who received care at CHU Ste-Justine. Busulfan doses given and subsequent plasma busulfan concentrations were recorded. LSSs using 1 to 3 concentration-time points were developed using multiple linear regression. LSS were considered to be acceptable when adjusted r(2) > 0.9, mean bias <15% and precision <15%. Extent of agreement between the AUC7 values and the LSS AUC was assessed by the intraclass correlation coefficient (ICC) and Bland-Altman (BA) analysis. Agreement was considered to be excellent when the lower limit of the 95% confidence limit of the ICC exceeded 0.9 and when the limits of agreement in the BA analysis were +/-15% for both AUC and dose. Administration of the theoretic adjusted busulfan doses based on each LSS was simulated and cases where the resulting AUC was >1500 or <900 microM x min were noted. LSSs using 1, 2, or 3 plasma busulfan concentrations were developed that showed excellent agreement with AUC7 and adjusted busulfan doses. In the validation sample, only the 2- and 3-point LSSs demonstrated acceptable precision and lack of bias. LSSs using 2 or 3 plasma busulfan concentrations can be used to reliably estimate busulfan AUC after IV administration in children undergoing HSCT.

Reliability and construct validity of the oral mucositis daily questionnaire in children with cancer

BACKGROUND The objective of this study was to examine the test-retest reliability and construct validity of parent-reported Oral Mucositis Daily Questionnaire (OMDQ) in children receiving intensive chemotherapy. METHODS Parents of children with cancer receiving intensive chemotherapy for leukaemia/lymphoma or undergoing stem cell transplantation (SCT) were asked to complete OMDQ daily for 21 d after chemotherapy. Other measures of mucositis obtained concurrently with OMDQ included the World Health Organization (WHO) Mucositis Scale, pain Visual Analogue Scale (VAS) and the Functional Assessment of Cancer Therapy Esophageal Cancer Sub-scale (FACT-ECS). RESULTS Parents of 59 children (median age = 5.62) provided complete OMDQ data for inclusion in analysis. The majority of children (73%) received SCT. Test-retest reliability of OMDQ exceeded the expected moderate reliability threshold established a priori and in particular, was good to excellent when mucositis was expected. In general, items of OMDQ that relate to pain, swallowing, drinking, eating and talking demonstrated moderate correlations with WHO, VAS and FACT-ECS indices with correlation coefficients ≥ 0.5. CONCLUSIONS Parent-report of a modified version of OMDQ is reliable and the questions relating to mouth and throat pain, as well as effect on function display construct validity for this population of children receiving intensive chemotherapy.