Blinatumomab for First-Line Treatment of Children and Young Persons With B-ALL.

PURPOSE: We tested whether blinatumomab (Blina) is effective as a toxicity-sparing alternative to first-line intensive chemotherapy in children and young persons (CYP) with B-ALL who were chemotherapy-intolerant or chemotherapy-resistant. METHODS: Data were collected for consecutive CYP (age 1-24 years) with Philadelphia chromosome-positive or Philadelphia chromosome-negative B-ALL who received Blina as first-line therapy. Blina was given as replacement for postremission intensive chemotherapy to patients with chemotherapy intolerance or resistance. Blina responders received further chemotherapy (Blin-CT) or first remission hematopoietic stem-cell transplant (Blin-HSCT) if indicated. Event-free survival (EFS) and overall survival (OS) of the Blin-CT group were compared with those of matched controls treated with standard chemotherapy in the UKALL 2003 trial. Events were defined as death, relapse, or secondary cancer. RESULTS: From February 2018 to February 2023, 105 patients were treated, of whom 85 were in the Blin-CT group and 20 were in the Blin-HSCT group. A majority of Blin-CT patients received Blina for chemotherapy intolerance (70 of 85, 82%), and the group had a higher-risk profile than unselected patients with B-ALL. Blina was well tolerated with only one patient having a grade 3/4-related toxicity event, and of the 60 patients who were minimal residual disease-positive pre-Blina, 58 of 60 (97%) responded. At a median follow-up of 22 months, the 2-year outcomes of the 80 matched Blin-CT group patients were similar to those of 192 controls (EFS, 95% [95% CI, 85 to 98] v 90% [95% CI, 65 to 93] and OS, 97% [95% CI, 86 to 99] v 94% [95% CI, 89 to 96]). Of the 20 in the HSCT group, three died because of transplant complications and two relapsed. CONCLUSION: Blina is safe and effective in first-line treatment of chemotherapy-intolerant CYP with ALL.

Bosutinib in Resistant and Intolerant Pediatric Patients With Chronic Phase Chronic Myeloid Leukemia: Results From the Phase I Part of Study ITCC054/COG AAML1921.

PURPOSE: Bosutinib is approved for adults with chronic myeloid leukemia (CML): 400 mg once daily in newly diagnosed (ND); 500 mg once daily in resistant/intolerant (R/I) patients. Bosutinib has a different tolerability profile than other tyrosine kinase inhibitors (TKIs) and potentially less impact on growth (preclinical data). The primary objective of this first-in-child trial was to determine the recommended phase II dose (RP2D) for pediatric R/I and ND patients. PATIENTS AND METHODS: In the phase I part of this international, open-label trial (ClinicalTrials.gov identifier: NCT04258943), children age 1-18 years with R/I (per European LeukemiaNet 2013) Ph+ CML were enrolled using a 6 + 4 design, testing 300, 350, and 400 mg/m2 once daily with food. The RP2D was the dose resulting in 0/6 or 1/10 dose-limiting toxicities (DLTs) during the first cycle and achieving adult target AUC levels for the respective indication. As ND participants were only enrolled in phase II, the ND RP2D was selected based on data from R/I patients. RESULTS: Thirty patients were enrolled; 27 were evaluable for DLT: six at 300 mg/m2, 11 at 350 mg/m2 (one DLT), and 10 at 400 mg/m2 (one DLT). The mean AUCs at 300 mg/m2, 350 mg/m2, and 400 mg/m2 were 2.20 µg h/mL, 2.52 µg h/mL, and 2.66 µg h/mL, respectively. The most common adverse event was diarrhea (93%; ≥grade 3: 11%). Seven patients stopped because of intolerance and eight because of insufficient response. Complete cytogenetic and major molecular response to bosutinib appeared comparable with other published phase I/II trials with second-generation TKIs in children. CONCLUSION: Bosutinib was safe and effective. The pediatric RP2D was 400 mg/m2 once daily (max 600 mg/d) with food in R/I patients and 300 mg/m2 once daily (max 500 mg/d) with food in ND patients, which achieved targeted exposures as per adult experience.

Adjuvant tyrosine kinase inhibitor therapy improves outcome for children and adolescents with acute lymphoblastic leukaemia who have an ABL-class fusion.

Patients with an ABL-class fusion have a high risk of relapse on standard chemotherapy but are sensitive to tyrosine kinase inhibitors (TKI). In UKALL2011, we screened patients with post-induction MRD ≥1% and positive patients (12%) received adjuvant TKI. As the intervention started during UKALL2011, not all eligible patients were screened prospectively. Retrospective screening of eligible patients allowed the outcome of equivalent ABL-class patients who did and did not receive a TKI in first remission to be compared. ABL-class patients who received a TKI in first remission had a reduced risk of relapse/refractory disease: 0% vs. 63% at four years (P = 0·009).

Pharmacokinetics of Nilotinib in Pediatric Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia or Acute Lymphoblastic Leukemia.

PURPOSE: We investigated nilotinib exposure in pediatric patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) resistant to, relapsed on, refractory to, or intolerant of previous treatment. PATIENTS AND METHODS: Fifteen patients (aged 1-<18 years) with CML resistant to or intolerant of imatinib and/or dasatinib (n = 11) or Ph+ ALL relapsed on or refractory to standard therapy (n = 4) enrolled in this phase I study. Nilotinib (230 mg/m2 twice daily; equivalent to the adult 400-mg twice-daily dose) was administered orally in 12 or 24 cycles of 28 days. The primary objective was to characterize the pharmacokinetics of nilotinib in pediatric patients. RESULTS: The area under the concentration-time curve at steady state was slightly lower in pediatric patients versus adults (14,751.4 vs. 17,102.9 ng/h/mL); the geometric mean ratio (GMR; pediatric:adult) was 0.86 [90% confidence interval (CI), 0.70-1.06]. Body surface area-adjusted systemic clearance was slightly higher in pediatric versus adult patients (GMR, 1.30; 90% CI, 1.04-1.62). Nilotinib was generally well tolerated. The most common adverse events were headache, vomiting, increased blood bilirubin, and rash. Three patients with CML achieved major molecular response, and three with Ph+ ALL achieved complete remission. CONCLUSIONS: Nilotinib 230 mg/m2 twice daily in pediatric patients provided a pharmacokinetics and safety profile comparable with the adult reference dose; clinical activity was demonstrated in both CML and Ph+ ALL. This dose is recommended for further evaluation in pediatric patients. The safety profile was consistent with that in adults.

High-dose etoposide and cyclophosphamide in adults and children with primary refractory and multiply relapsed acute leukaemias: The Royal Marsden experience.

INTRODUCTION: For patients with primary refractory and relapsed acute leukaemias allogeneic stem cell transplantation is the only hope for cure, but morphological remission is not always achieved after standard salvage regimens. Here we review the experience with high-dose etoposide and cyclophosphamide (HD-Et/Cy) in relapsed/refractory acute leukaemias at the Royal Marsden Hospital. PATIENTS AND METHODS: Twenty-three patients (15 adults, 8 children) with refractory/relapsed acute myeloblastic (n = 18; 78%), lymphoblastic (n = 4; 17%) or biphenotypic (n = 1; 4%) leukaemia who had failed to respond to at least one previous line of chemotherapy received HD-Et/Cy at our institution between 2006 and 2015. RESULTS: Overall response rate was 21.7% (95%CI 4.0-40.0). Median overall survival was 14.8 months (95%CI 9.1-49.1). Eight (35%) patients (7 AML, 1 biphenotypic leukaemia) proceeded to allogeneic transplant after one cycle of HD-Et/Cy: four of them (50%; 3 adults, 1 child) in complete remission and another four children (50%) with aplastic bone marrow with scattered blasts. Among the transplant recipients, three with AML (38%), ie. one adult (responder) and two children with aplastic bone marrow with scattered blasts, became long-term survivors 9.8, 4.4 and 2.5 years post-HD-Et/Cy, respectively. Toxicity profile was comparable to similar regimens with no treatment-related deaths. The most common grade 3-4 toxicity was febrile neutropenia (96%). CONCLUSIONS: HD-Et/Cy can salvage patients with refractory/relapsed AML who remain candidates for allogeneic stem cell transplantation after failure of standard salvage regimens and do not have access to clinical trials.

Dasatinib in Pediatric Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Phase II Trial.

Purpose Safe, effective treatments are needed for pediatric patients with chronic myeloid leukemia in chronic phase (CML-CP). Dasatinib is approved for treatment of adults and children with CML-CP. A phase I study determined suitable dosing for children with Philadelphia chromosome-positive (Ph+) leukemias. Methods CA180-226/NCT00777036 is a phase II, open-label, nonrandomized prospective trial of patients < 18 years of age receiving dasatinib. There are three cohorts: (1) imatinib-resistant/intolerant CML-CP, (2) imatinib-resistant/intolerant CML in accelerated/blast phase or Ph+ acute lymphoblastic leukemia (n = 17), and (3) newly diagnosed CML-CP treated with tablets or powder for oral suspension. Major cytogenetic response > 30% for imatinib-resistant/intolerant patients and complete cytogenetic response (CCyR) > 55% for newly diagnosed patients were of clinical interest. Results Of 113 patients with CML-CP, 14 (48%) who were imatinib-resistant/intolerant and 61 (73%) who were newly diagnosed remained on treatment at time of analysis. Major cytogenetic response > 30% was reached by 3 months in the imatinib-resistant/intolerant group and CCyR > 55% was reached by 6 months in the newly diagnosed CML-CP group. CCyR and major molecular response by 12 months, respectively, were 76% and 41% in the imatinib-resistant/intolerant group and 92% and 52% in newly diagnosed CML-CP group. Progression-free survival by 48 months was 78% and 93% in the imatinib-resistant/intolerant and newly diagnosed CML-CP groups, respectively. No dasatinib-related pleural or pericardial effusion, pulmonary edema, or pulmonary arterial hypertension were reported. Bone growth and development events were reported in 4% of patients. Conclusion In the largest prospective trial to date in children with CML-CP, we demonstrate that dasatinib is a safe, effective treatment of pediatric CML-CP. Target responses to first- or second-line dasatinib were met early, and deep molecular responses were observed. Safety of dasatinib in pediatric patients was similar to that observed in adults; however, no cases of pleural or pericardial effusion or pulmonary arterial hypertension were reported.

Vocal Cord Palsy in Children With Cancer: A 10-Year Analysis of UK Pediatric Intensive Care Admissions.

Vocal cord palsy (VCP) is a rare but potentially life-threatening complication in children with cancer. This study reviews UK Intensive Care admissions for children with cancer and VCP using data obtained from the Pediatric Intensive Care Audit Network (PICANet) database. 26 children with cancer and VCP were admitted to intensive care from 2002 to 2012. The majority of admissions (23/26) required respiratory intervention (17 invasive ventilation, 8 noninvasive ventilation, and 5 tracheostomy). VCP should be considered early in children with cancer who present with signs of upper airway obstruction, especially in those receiving vinca-alkaloids as VCP is likely to be reversible.

Comparison of Presentation and Outcome in 100 Pediatric Hodgkin Lymphoma Patients Treated at Children Hospital, Lahore, Pakistan and Royal Marsden Hospital, UK.

OBJECTIVE: To compare differences in demographics and outcomes in childhood Hodgkin lymphoma (HL) presenting at the Children's Hospital Lahore (CHL), and Royal Marsden Hospital (RMH), UK. STUDY DESIGN: An observational comparative study. PLACE AND DURATION OF STUDY: From January 2011 to February 2012 at CH, Lahore and from October 2008 to February 2012 at RMH, UK. METHODOLOGY: Consecutive HL patients (50 from each hospital) were inducted. Data regarding age, gender, staging, histopathology and outcome were analysed. Clinical and pathological staging done according to Ann-Arbor and World Health Organization classification. Treatment duration was 6-8 months. They were followed for 6 months post-treatment. Frequencies of variables were noted and compared. Chi-square test was used for determining significance. RESULTS: Patients from Children's Hospital, Lahore were younger (mean 7.9 years) with male predominance (n=42, 84%). Histopathology showed Mixed Cellularity (MC) in 32 (64%), Nodular Sclerosis (NS) in 5 (10%), Lymphocyte Rich in 4 (8%) and lymphocyte depleted in 1 (2%), nodular lymphocyte predominant (NLP) in 1 (2%) each. Majority presented in stage IV (n=25,50%), or stage III (n=20,40%). Constitutional B symptoms were present in 37 (74%). Bone marrow involvement observed in 23 (46%). Remission was achieved in 42 (84%) patients; 2 (4%) relapsed, 4 (8%) expired and 2 (4%) left against medical advice. In contrast, RMH patients were older (mean 11.8 years.) and 30 (60%) were males. NS (n=40,80%) and NLP (n=6,12%) types were predominant. Two (4%) patients were in stage I, 27 (54%) in stage II, 12 (24%) in stage III and 9 (18%) presented in stage IV. Fourteen (28%) had B-symptoms. None had bone marrow disease. Event free survival was 46 (92%). Four (8%) patients relapsed. Three responded to second line therapy and one relapsed postautologous transplant. CONCLUSION: Significant differences were observed in age at presentation, stage, histopathology and extent of bone marrow involvement between the groups. Of interest is the bone marrow involvement in stage IV patients in Pakistan. Delayed diagnosis account for advanced stage but difference in pathological subtype needs further study.

Individualized 131I-mIBG therapy in the management of refractory and relapsed neuroblastoma.

OBJECTIVE: Iodine-131-labelled meta-iodobenzylguanidine (I-mIBG) therapy is an established treatment modality for relapsed/refractory neuroblastoma, most frequently administered according to fixed or weight-based criteria. We evaluate response and toxicity following a dosimetry-based, individualized approach. MATERIALS AND METHODS: A review of 44 treatments in 25 patients treated with I-mIBG therapy was performed. Patients received I-mIBG therapy following relapse (n=9), in refractory disease (n=12), or with surgically unresectable disease despite conventional treatment (n=4). Treatment schedule (including mIBG dose and number of administrations) was individualized according to the clinical status of the patient and dosimetry data from either a tracer study or previous administrations. Three-dimensional tumour dosimetry was also performed for eight patients. RESULTS: The mean administered activity was 11089±7222 MBq and the mean whole-body dose for a single administration was 1.79±0.57 Gy. Tumour-absorbed doses varied considerably (3.70±3.37 mGy/MBq). CTCAE grade 3/4 neutropenia was documented following 82% treatments and grade 3/4 thrombocytopenia following 71% treatments. Further acute toxicity was found in 49% of patients. All acute toxicities resolved with appropriate therapy. The overall response rate was 58% (complete or partial response), with a further 29% of patients having stable disease. CONCLUSION: A highly personalized approach combining patient-specific dosimetry and clinical judgement enables delivery of high activities that can be tolerated by patients, particularly with stem cell support. We report excellent response rates and acceptable toxicity following individualized I-mIBG therapy.

Toxicity and outcome of children and adolescents participating in phase I/II trials of novel anticancer drugs: the Royal Marsden experience.

Early phase trials are crucial in developing new therapies for poor prognosis childhood malignancies. Outcomes and toxicities of children treated on phase I/II trials at the Royal Marsden, one of the largest pediatric oncology early phase trial units in Europe, were examined to provide a baseline dataset and generate hypotheses. All patients recruited over a 10-year period to December 2011 were included. Variables including baseline characteristics, time on study, survival, toxicities, and admissions were collected. Seventy-two patients were recruited to 21 trials (5 phase I, 16 phase II; overall 12 involved molecularly targeted agents). Median age at consent was 12.4 years. Dose-limiting toxicities were rare in phase I trial participants (2 of 15 evaluable patients, 13%); the most common reason for leaving trials was disease progression (76%), rather than drug toxicity (1.7%). Median time on trial was 1.3 months (phase I patients) and 3.3 months (phase II). Early phase trials in children are safe and unexpected toxic side effects are infrequent. Patients and their families are willing to travel to access novel therapies, although the overall prognosis for these individuals is poor. Continued expansion of the portfolio is needed ultimately to improve the outcomes for those with resistant disease.

Dasatinib in children and adolescents with relapsed or refractory leukemia: results of the CA180-018 phase I dose-escalation study of the Innovative Therapies for Children with Cancer Consortium.

PURPOSE: Dasatinib is a potent BCR-ABL inhibitor with proven efficacy in adults with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) and in imatinib-resistant/intolerant disease. This phase I study of the Innovative Therapies for Children with Cancer Consortium assessed dasatinib safety and efficacy in pediatric patients. PATIENTS AND METHODS: Escalating once-daily dasatinib doses (60 to 120 mg/m(2)) were administered to children (n = 58) with (i) imatinib-pretreated CML or Philadelphia chromosome (Ph)-positive acute lymhoblastic leukemia (ALL) and (ii) treatment-refractory Ph-negative ALL or acute myeloid leukemia (AML). RESULTS: Dasatinib safety and efficacy profiles compared favorably with those in adults. The most common drug-related nonhematologic adverse events were nausea (31%, all grades; 2%, grade 3 to 4), headache (22%, 3%), diarrhea (21%, 0%), and vomiting (17%, 2%). Of 17 patients with CML-CP, 14 (82%) achieved complete cytogenetic response (CCyR) and eight (47%) achieved major molecular response. After ≥ 24 months of follow-up, median complete hematologic response (CHR) and major cytogenetic response (MCyR) durations were not reached. Of 17 patients with advanced-phase CML or Ph-positive ALL, six (35%) achieved confirmed CHR and 11 (65%) achieved CCyR. Median MCyR duration was 4.6 months (95% CI, 2.1 to 17.4 months). No patient with Ph-negative ALL or AML responded. Dasatinib pediatric pharmacokinetic parameters were comparable with those in adult studies, showing rapid absorption (time to reach maximum concentration, 0.5 to 6.0 hours) and elimination (mean half-life, 3.0 to 4.4 hours). CONCLUSION: Dasatinib 60 mg/m(2) and 80 mg/m(2) once-daily dosing were selected for phase II studies in children with Ph-positive leukemias.

Outcome of childhood relapsed or refractory mature B-cell non-Hodgkin lymphoma and acute lymphoblastic leukemia.

Patients with childhood relapsed and refractory mature B-cell non-Hodgkin lymphoma (B-NHL) and acute lymphoblastic leukemia (B-ALL) are rare and have a dismal prognosis. The previous UK national analysis of 26 children over a 7-year period prior to 1996 had highlighted the poor outcome, with only three survivors. This 10-year multicenter study evaluated recent data, since 2000. Of 33 children, nine survived (27.3%), with a median follow-up of 4.3 years. On exclusion of six children treated with palliative intent, the survival was one-third (nine of 27; 33.3%). All patients with primary refractory disease (n = 7) and all except one with early relapse (n = 11) died. Administration of four doses of 375 mg/m(2) of rituximab was associated with a longer survival (p = 0.006). Response to reinduction (p < 0.001) and autologous hematopoietic stem cell transplant (auto-HSCT) (p = 0.003) were significant on multivariate analysis. Patients with a time to relapse of at least 6 months are potentially curable and must be offered intensive treatment with salvage chemotherapy, rituximab and auto-HSCT.

Symptomatic severe hypertriglyceridaemia with asparaginase therapy in acute lymphoblastic leukaemia (ALL) and lymphoblastic lymphoma: is rechallenging safe?

Severe hyperlipidaemia with asparaginase therapy is rare. We report six cases, four of which developed significant problems with severe hyperlipidaemia during induction therapy for ALL and lymphoblastic lymphoma. The median triglyceride level was 22.3 mmol/L and the median cholesterol level was 12.3 mmol/L. None of the patients showed signs or symptoms of pancreatitis. Three children were re-exposed with Peg asparaginase, and one with Erwinia asparaginase, without recurrence of hyperlipidaemia or other symptoms. These cases highlight the dilemma in managing such rare cases of symptomatic hypertriglyceridaemia secondary to asparaginase and steroid therapy.

Clinical profile and outcome of urotheliotropic viral haemorrhagic cystitis following haematopoietic stem cell transplantation: a 7-year tertiary centre analysis.

Viral haemorrhagic cystitis (HC) is a significant complication after haematopoietic stem cell transplantation (HSCT), with a potential for major morbidity. The aim of this 7-year analysis of 1160 HSCT patients was to evaluate risk factors for the incidence, severity, toxicity of therapy, clinical course, and outcome of this condition. The overall incidence of HC was 5·8%, with most cases occurring after allogeneic HSCT. Unrelated donors (P = 0·001), non-peripheral blood stem cell source (P = 0·005), myeloablative conditioning (P<0·001), use of alemtuzumab in conditioning (P = 0·001), and severe acute graft versus host disease (P<0·001) were independent risk factors for an increased incidence of HC post-allogeneic transplant on multivariate analysis. Severe forms of HC were associated with grades II-IV acute graft versus host disease and a longer duration of haematuria. Contrary to previous studies which were carried out on smaller patient populations, busulphan, cyclophosphamide, anti-thymocyte globulin, and total body irradiation were not found to independently increase the risk of viral HC, unless used in a myeloablative combination. Neither duration of viriuria nor peak viral load in urine influenced the severity of HC on multivariate analysis. Severe HC contributed to the deaths of two patients. Overall survival was not statistically different between patient subgroups with non-severe and severe HC.

Leukaemia survival trends in children with Down's syndrome in Great Britain, 1971-2000: a population-based study.

BACKGROUND: Children with Down's syndrome (DS) who developed leukaemia have had a worse prognosis than other children with leukaemia in the past. In the 1970s and early 1980s, some children with DS who developed leukaemia received fewer cycles of chemotherapy or were advised not to have treatment. METHODS: In this population-based study, trends in 5-year survival from leukaemia were evaluated for children with and without DS who were diagnosed in Great Britain during 1971-2000 and followed to the end of 2004. RESULTS: For all children, with and without DS, survival has increased dramatically over the 30 year study period. For lymphoid leukaemia, survival in children with DS increased, but remains lower than for other children (5-year survival 59% vs 83% during 1996-2000). For acute non-lymphoblastic leukaemia (ANLL), however, 5-year survival improved substantially for children with DS, from less than 1% in the early 1970s to over 80% in the 1990s. For other children, survival increased from 6% to 64% during the same period. CONCLUSION: Survival for all children diagnosed with leukaemia has improved during the last three decades. For lymphoid leukaemia, the inferior outcome observed on more recent treatment protocols in children with DS remains an area for concern. For ANLL, the improvement in survival for children with DS is due to a number of factors, namely increased recruitment of these children to clinical trials, changes in clinical practice and important differences in the biology of myeloid leukaemia in young children with DS, resulting in a better response to some chemotherapeutic agents.

Relapse of primitive mediastinal lymphoma as a myeloid mass following beam autologous transplant and subsequent refractoriness to matched unrelated umbilical cord blood allograft.

Outlining the treatment for an unclassifiable lymphoid malignancy is often difficult. A highly undifferentiated lymphomatous mass that relapsed in spite of intense chemotherapy and autologous transplant is reported. At relapse, there was differentiation into myeloid lineage. Though remission was achieved with AML-type reinduction chemotherapy, the mass recurred post allogenic cord blood stem cell transplant.

Intracranial hypertension in pediatric patients with acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) remains one of the most common malignancies of childhood. Between April 1999 and August 2004, 9 of 207 patients treated at a Tertiary Oncology Service for ALL presented with Intracranial Hypertension (IH). Seven of the patients met the diagnostic criteria for Idiopathic Intracranial Hypertension (IIH). Four of the patients were treated with cerebrospinal fluid (CSF) drainage alone and four required Acetazolamide. Two of the four patients who were treated with Acetazolamide required subsequently a lumbar-peritoneal (LP) shunt. One patient succumbed to his disease before receiving any specific treatment.