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1.
Nature ; 612(7941): 787-794, 2022 12.
Article in English | MEDLINE | ID: mdl-36450980

ABSTRACT

Medulloblastoma (MB) is the most common malignant childhood brain tumour1,2, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella3-5 have not fully defined the compositional heterogeneity of MBs. Here we undertook single-cell profiling of freshly isolated human fetal cerebella to establish a reference map delineating hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group 3 and metastatic tumours. Single-cell multi-omics revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in group 3 MBs. Genomic and Hi-C profiling identified de novo long-range chromatin loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group 3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group 3 MB growth. Our integrated single-cell atlases of human fetal cerebella and MBs show potential cell populations predisposed to transformation and regulatory circuitries underlying tumour cell states and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.


Subject(s)
Brain Neoplasms , Cell Transformation, Neoplastic , Fetus , Medulloblastoma , Humans , Brain Neoplasms/pathology , Cell Transformation, Neoplastic/pathology , Cerebellar Neoplasms/pathology , Cerebellum/cytology , Cerebellum/pathology , Fetus/cytology , Fetus/pathology , Medulloblastoma/pathology , Neural Stem Cells/cytology , Neural Stem Cells/pathology , Prognosis
2.
Br J Haematol ; 2024 Jul 31.
Article in English | MEDLINE | ID: mdl-39082439

ABSTRACT

Venetoclax (VEN) combined with hypomethylating agents (HMA) decitabine or azacitidine is used for adult acute myeloid leukaemia (AML), but its application in paediatric, adolescent and young adult (AYA) AML lacks prospective studies. We performed a retrospective chart review of paediatric and AYA AML patients treated with HMA + VEN at Cincinnati Children's Hospital Medical Centre. Twenty-seven patients received 30 HMA + VEN treatment courses for relapsed/refractory (R/R, n = 21) or newly diagnosed (n = 9) AML due to ineligibility for intensive chemotherapy. The R/R cohort had high-risk cytomolecular genetic alterations and prior extensive treatments, with 50% (n = 9) of relapse patients (n = 18) having undergone haematopoietic stem cell transplantation (HSCT). Venetoclax treatment using the 400 mg adult exposure-equivelant dosing (AED) had a median duration of 21 days (range 7-30 days). Grade 3-4 toxicities included neutropenia (90%), anaemia (64%), thrombocytopenia (64%) and febrile neutropenia (44%). The overall complete remission (CR)/CR with incomplete blood count recovery (CRi) rate was 73% (77% minimal residual disease [MRD] negativity <0.1%), with 60% undergoing HSCT. Among newly diagnosed patients (n = 9), 89% achieved CR/CRi (78% MRD negativity) and 78% proceeded to HSCT. The R/R cohort (n = 21) showed a 67% CR/CRi rate (71% MRD negativity), with 52% undergoing HSCT. These findings support the safety and efficacy of HMA + VEN in paediatric/AYA AML, indicating it as a viable option for patients unfit for intensive chemotherapy. Further studies are necessary to determine optimal venetoclax dosing, chemotherapy combinations and pharmacokinetics in this population.

3.
Pediatr Blood Cancer ; 70(4): e30214, 2023 04.
Article in English | MEDLINE | ID: mdl-36694431

ABSTRACT

Multiagent immunochemotherapy affords excellent outcomes in pediatric non-Hodgkin lymphoma (NHL); however, scarce data exist for patients unfit for intensive treatment. Rituximab, gemcitabine, and oxaliplatin (R-GemOx) is well tolerated and efficacious in elderly adults with NHL; however, its use has not been described in pediatrics. In this retrospective, single-center study, six children with mature B-cell NHL and significant comorbidities received anti-CD20 therapy with GemOx (rituximab or obinutuzumab or ofatumumab with gemcitabine and oxaliplatin [R/O-GemOx]). R/O-GemOx was well tolerated and resulted in complete response in two of three patients with newly diagnosed NHL and one of three patients with primary refractory NHL. R/O-GemOx is a viable treatment option for children with NHL who cannot tolerate intensive therapy.


Subject(s)
Gemcitabine , Lymphoma, Non-Hodgkin , Adult , Humans , Child , Adolescent , Aged , Rituximab , Oxaliplatin , Retrospective Studies , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Non-Hodgkin/drug therapy , Deoxycytidine , Treatment Outcome
4.
Pediatr Blood Cancer ; 70(3): e30186, 2023 03.
Article in English | MEDLINE | ID: mdl-36602026

ABSTRACT

BACKGROUND: Adherence promotion is a critical component of adolescent and young adult (AYA) cancer care, but predictors of nonadherence that could be targeted in intervention efforts remain largely unknown. The purpose of this multi-site longitudinal observational study was to examine the relationship between barriers and medication adherence among AYAs with cancer. PROCEDURE: Sixty-five AYAs (ages 15-24 years; mean age = 18.97 years, SD = 2.51; Mmean time since diagnosis = 1.42 years, SD = 1.95) with newly diagnosed or relapsed cancer completed self-report measures of barriers and adherence at quarterly study visits and used an electronic adherence monitoring device for 12 months. Longitudinal mixed effects models were used to examine our primary hypothesis that greater barriers are related to lower adherence over time. Descriptive statistics were used to explore our secondary aim of describing the frequency and patterns of barriers endorsed by AYAs with cancer. RESULTS: After controlling for covariates (time, medication type, race, ethnicity, diagnosis, time since diagnosis), a greater number of barriers was associated with lower electronically monitored (ß = -5.99, p = .005) and self-reported (ß = -1.92, p < .001) adherence. The specific barriers endorsed by AYAs differed across participants, and the majority of AYAs endorsed an entirely different pattern of barriers than any other AYA in the study. CONCLUSION: Barriers are associated with nonadherence and may be a promising target for intervention. Individual variability across barriers, however, suggests that tailoring may be necessary, and a promising next step is to explore personalized approaches to adherence promotion.


Subject(s)
Neoplasms , Humans , Adolescent , Young Adult , Adult , Neoplasms/drug therapy , Self Report , Longitudinal Studies , Chronic Disease , Medication Adherence
5.
Pediatr Blood Cancer ; 70(2): e30128, 2023 02.
Article in English | MEDLINE | ID: mdl-36495256

ABSTRACT

In this commentary, we highlight the central role that data standards play in facilitating data-driven efforts to advance research in pediatric oncology. We discuss the current state of data standards for pediatric oncology and propose five steps to achieve an improved future state with benefits for clinicians, researchers, and patients.


Subject(s)
Neoplasms , Child , Humans , Neoplasms/therapy , Medical Oncology , Forecasting , Patients , Oncology Nursing
6.
Pediatr Blood Cancer ; 68(8): e29126, 2021 08.
Article in English | MEDLINE | ID: mdl-34019326

ABSTRACT

No guidelines exist for which intensive chemotherapy regimen is best in pediatric or young adult patients with high-risk posttransplant lymphoproliferative disorder (PTLD). We retrospectively reviewed patients with PTLD who received interval-compressed short-course etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (SC-EPOCH) regimens at our institution. Eight patients were included with median age of 12 years. All patients achieved a complete response with a manageable toxicity profile. Two patients developed second, clonally unrelated, EBV-positive PTLD and one patient had recurrence at 6 months off therapy. No graft rejection occurred during therapy. All eight patients are alive with median follow-up of 29 months.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoproliferative Disorders , Organ Transplantation/adverse effects , Child , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Etoposide/therapeutic use , Humans , Lymphoproliferative Disorders/drug therapy , Lymphoproliferative Disorders/etiology , Postoperative Complications , Prednisone/therapeutic use , Prognosis , Retrospective Studies , Vincristine/therapeutic use , Young Adult
7.
Pediatr Blood Cancer ; 68(4): e28833, 2021 04.
Article in English | MEDLINE | ID: mdl-33336845

ABSTRACT

Data for visual acuity (VA) after treatment of neurofibromatosis type 1-associated optic pathway gliomas (NF1-OPGs) are limited. We retrospectively collected VA, converted to logMAR, before and after targeted therapy with everolimus for NF1-OPG, and compared to radiologic outcomes (14/18 with NF1-OPG, 25 eyes [three without quantifiable vision]). Upon completion of treatment, VA was stable in 19 eyes, improved in four eyes, and worsened in two eyes; visual and radiologic outcomes were discordant. In summary, the majority of children with NF1-OPG exhibited stabilization of their VA after everolimus treatment. A larger, prospective study will help delineate visual outcomes after targeted therapy.


Subject(s)
Antineoplastic Agents/therapeutic use , Everolimus/therapeutic use , Neurofibromatosis 1/drug therapy , Optic Nerve Glioma/drug therapy , Visual Acuity/drug effects , Adolescent , Adult , Child , Child, Preschool , Female , Humans , Infant , Male , Neurofibromatosis 1/physiopathology , Optic Nerve Glioma/physiopathology , Retrospective Studies , Treatment Outcome , Young Adult
8.
J Pediatr Hematol Oncol ; 43(4): 152-154, 2021 05 01.
Article in English | MEDLINE | ID: mdl-32496443

ABSTRACT

Infants with KMT2A-rearranged acute lymphoblastic leukemia (ALL) have historically poor outcomes despite maximal intensification of chemotherapy. Chimeric antigen receptor (CAR) T-cell therapy has revolutionized our approach to pediatric patients with relapsed/refractory ALL. Unfortunately, infants were excluded from early CAR T-cell trials due to concerns regarding the feasibility of T-cell collection and expansion. Here, we report the use of tisagenlecleucel in an infant with chemotherapy-refractory KMT2A-rearranged ALL. While CAR T-cell therapy was not curative for this patient, collection and expansion of T-cells proved feasible despite prior chemotherapy, he achieved minimal residual disease negative remission with excellent quality of life, and it facilitated a delay in hematopoietic stem cell transplantation.


Subject(s)
Antigens, CD19/immunology , Immunotherapy, Adoptive/methods , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Receptors, Antigen, T-Cell/therapeutic use , Gene Rearrangement , Histone-Lysine N-Methyltransferase/genetics , Humans , Infant , Male , Myeloid-Lymphoid Leukemia Protein/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology
9.
Pediatr Blood Cancer ; 65(1)2018 Jan.
Article in English | MEDLINE | ID: mdl-28792686

ABSTRACT

BACKGROUND: While viral surveillance of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus using PCR is routine in patients undergoing hematopoetic stem cell transplant and solid organ transplant, the utility in the nontransplant pediatric leukemia population is unknown. Our institution screens patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) for viral DNAemia by PCR as part of clinical care. PROCEDURE: This retrospective chart review included patients treated for newly diagnosed or relapsed AML or ALL between April 2010 and September 2014. We retrieved data for viral PCR screening, detection and quantification, duration of positivity, and prophylaxis or treatment. RESULTS: One hundred eleven patients were included in analyses. Forty (36.0%) had at least one blood PCR positive for EBV, CMV, or adenovirus. Patients with ALL had significantly higher rates of persistent viral detection and treatment than those with AML (P < 0.02, P < 0.01, respectively). International patients had significantly higher rates of viral detection (P < 0.01), persistence (P < 0.01), any treatment (P < 0.03), and antiviral treatment (P < 0.01); 16.9% of patients who received intravenous immunoglobulin (IVIG) prophylactically had viral detection compared to 63% of patients who did not receive prophylactic IVIG (P = 0.0008). CONCLUSIONS: Patients with ALL were more susceptible than those with AML to viral reactivation that was persistent or resulted in treatment. Patients with relapsed ALL, refractory ALL, or infantile ALL are most likely to benefit from asymptomatic screening for CMV and adenovirus. International patients are at higher risk for reactivation and may merit screening. EBV reactivation was not significant and does not warrant screening.


Subject(s)
DNA Virus Infections/blood , DNA Viruses , DNA, Viral/blood , Leukemia, Myeloid, Acute , Polymerase Chain Reaction/methods , Adolescent , Adult , Child , Child, Preschool , DNA Virus Infections/prevention & control , Female , Humans , Immunoglobulins, Intravenous/administration & dosage , Infant , Infant, Newborn , Leukemia, Myeloid, Acute/blood , Leukemia, Myeloid, Acute/virology , Male
10.
Br J Clin Pharmacol ; 83(5): 1097-1107, 2017 05.
Article in English | MEDLINE | ID: mdl-28000286

ABSTRACT

AIMS: Temsirolimus is an inhibitor of the mammalian target of rapamycin (mTOR). Pharmacokinetic (PK) characterization of temsirolimus in children is limited and there is no paediatric temsirolimus population PK model available. The objective of this study was to simultaneously characterize the PK of temsirolimus and its metabolite sirolimus in paediatric patients with recurrent solid or central nervous system tumours and to develop a population PK model. METHODS: The PK data for temsirolimus and sirolimus were collected as a part of a Children's Oncology Group phase I clinical trial in paediatric patients with recurrent solid tumours. Serial blood concentrations obtained from 19 patients participating in the PK portion of the study were used for the analysis. Population PK analysis was performed by nonlinear mixed effect modelling using NONMEM. RESULTS: A three-compartment model with zero-order infusion was found to best describe temsirolimus PK. Allometrically scaled body weight was included in the model to account for body size differences. Temsirolimus dose was identified as a significant covariate on clearance. A sirolimus metabolite formation model was developed and integrated with the temsirolimus model. A two-compartment structure model adequately described the sirolimus data. CONCLUSION: This study is the first to describe a population PK model of temsirolimus combined with sirolimus formation and disposition in paediatric patients. The developed model will facilitate PK model-based dose individualization of temsirolimus and the design of future clinical studies in children.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Models, Biological , Neoplasms/drug therapy , Sirolimus/analogs & derivatives , Adolescent , Antineoplastic Agents/administration & dosage , Child , Child, Preschool , Dose-Response Relationship, Drug , Female , Humans , Infant , Male , Neoplasm Recurrence, Local , Neoplasms/pathology , Nonlinear Dynamics , Sirolimus/administration & dosage , Sirolimus/pharmacokinetics , TOR Serine-Threonine Kinases/antagonists & inhibitors , Young Adult
12.
Pediatr Blood Cancer ; 64(11)2017 Nov.
Article in English | MEDLINE | ID: mdl-28449393

ABSTRACT

BACKGROUND: The c-Met receptor tyrosine kinase is dysregulated in many pediatric cancers. Tivantinib is an oral small molecule that inhibits the c-Met receptor tyrosine kinase. A phase 1 and pharmacokinetic (PK) trial evaluating tivantinib was conducted in children with relapsed/refractory solid tumors. METHODS: Oral tivantinib capsules were administered twice daily with food, continuously in 28-day cycles. Dose levels 170, 200, and 240 mg/m2 /dose were evaluated using a rolling-six design (Part A). In Part B, subjects received tivantinib powder sprinkled on food at the recommended phase 2 dose (RP2D) from Part A. PK, CYP2C19 genotyping, and baseline tumor tissue c-Met expression were analyzed. RESULTS: Thirty-six patients were enrolled: 20 in Part A, 6 in a PK expansion cohort, and 10 in Part B. Fifteen patients had primary central nervous system tumors and 21 had solid tumors. In Part A, there were no dose-limiting toxicities. One grade 4 intracranial hemorrhage occurred in a patient with a progressive brain tumor in the expanded PK cohort (240 mg/m2 ). PK analysis showed marked interpatient variability (20-fold) in the Cmax and AUC0-8h across all dose levels. Sprinkling tivantinib powder over food did not alter exposure. Membranous and total c-Met expression was moderate (2), low (4), or not detected (26). Two patients had stable disease as the best response. CONCLUSIONS: The RP2D of tivantinib given with food in children with refractory solid tumors is 240 mg/m2 /dose. PK of tivantinib in children demonstrated high variability. Objective responses were not observed in this phase 1 trial.


Subject(s)
Drug Resistance, Neoplasm/drug effects , Neoplasm Recurrence, Local/drug therapy , Neoplasms/drug therapy , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyrrolidinones/pharmacology , Quinolines/pharmacology , Salvage Therapy , Adolescent , Adult , Child , Child, Preschool , Female , Humans , Infant , Male , Maximum Tolerated Dose , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Neoplasms/pathology , Pilot Projects , Prognosis , Pyrrolidinones/pharmacokinetics , Quinolines/pharmacokinetics , Tissue Distribution , Young Adult
13.
Pediatr Blood Cancer ; 62(10): 1739-46, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26153194

ABSTRACT

PURPOSE: To evaluate BSO-mediated glutathione (GSH) depletion in combination with L-PAM for children with recurrent or refractory high-risk neuroblastoma (NB) as a means to enhance alkylator sensitivity. PROCEDURE: This pilot study (NCI #T95-0092) administered L-S,R-buthionine sulfoximine (BSO) as a bolus followed by 72 hr continuous infusion of either 0.75 g/m(2)/hr (level 1) or 1.0 g/m(2)/hr (level 2) and melphalan (L-PAM) (15 mg/m(2) bolus at hour 48 of BSO infusion). GSH in blood mononuclear cells and bone marrow was measured by enzymatic assay, BSO in plasma by HPLC. RESULTS: Thirty two patients received 58 courses of therapy (median 1, range 1-4 courses). Blood mononuclear cell GSH decreased (48 hr) to 47% ± 15.7%. Level 2 mean steady-state concentration (Css) for BSO = 524 ± 207 µM and peak L-PAM concentration = 3.32 ± 1.2 µM. Grade 3-4 leukopenia and thrombocytopenia were common. There were two deaths from CNS toxicity and acute tubular necrosis; one had a large, intracranial mass, both were receiving cephalosporin antibiotics. No other significant toxicities were seen. There were six responses (five partial and, one mixed) representing an 18% response rate; four/six responses occurred in patients that relapsed following myeloablative therapy and included a 98% reduction in volume (cm(3)) of a pelvic mass, and three/five patients with >3 log reduction of tumor in marrow as measured by immunocytology (sensitivity 1/10(5)). CONCLUSIONS: BSO/L-PAM has activity against recurrent high-risk NB. Exclusion of cephalosporin antibiotics in future clinical trials of BSO may diminish the potential for serious renal and CNS toxicity.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Neuroblastoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Buthionine Sulfoximine/administration & dosage , Buthionine Sulfoximine/adverse effects , Child , Chromatography, High Pressure Liquid , Female , Glutathione/analysis , Glutathione/drug effects , Humans , Infusions, Intravenous , Injections, Intravenous , Male , Melphalan/administration & dosage , Melphalan/adverse effects , Pilot Projects
14.
Cancer ; 120(16): 2482-9, 2014 Aug 15.
Article in English | MEDLINE | ID: mdl-24771494

ABSTRACT

BACKGROUND: The discovery of new, effective non-anthracycline-based reinduction regimens for children with recurrent acute myeloid leukemia (AML) is critical. In this phase 1/2 study, the tolerability and overall response rate of clofarabine in combination with cytarabine was investigated in children with recurrent/refractory AML. METHODS: AAML0523 enrolled 49 children with AML in first recurrence or who were refractory to induction therapy. The study consisted of a dose-finding phase (9 patients) and an efficacy phase (40 patients). Two children received clofarabine at a dose of 40 mg/m(2)/day and 47 children at a dose of 52 mg/m(2)/day. RESULTS: Toxicities typical for intensive chemotherapy regimens were observed at all doses of clofarabine. The recommended pediatric phase 2 dose of clofarabine in combination with cytarabine was 52 mg/m(2)/day for 5 days. Of 48 evaluable patients, the overall response rate (complete remission plus complete remission with partial platelet recovery) was 48%. Four patients met conventional criteria for complete remission with incomplete count recovery. Twenty-one of 23 responders subsequently underwent hematopoietic stem cell transplantation. The overall survival rate at 3 years was 46% for responders compared with 16% for nonresponders (P < .001). Patients found to have no minimal residual disease at the end of the first cycle by flow cytometric analysis had superior overall survival after 1 year (100% vs 38%; P = .01). CONCLUSIONS: The combination of clofarabine and cytarabine yielded an acceptable response rate without excess toxicity in children with recurrent AML. The nearly 50% survival rate reported in responders is highly encouraging in these high-risk patients and suggests that this combination is an effective bridge to hematopoietic stem cell transplantation.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Adenine Nucleotides/administration & dosage , Adenine Nucleotides/adverse effects , Adolescent , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Arabinonucleosides/administration & dosage , Arabinonucleosides/adverse effects , Child , Child, Preschool , Clofarabine , Cytarabine/administration & dosage , Cytarabine/adverse effects , Dose-Response Relationship, Drug , Female , Humans , Male , Young Adult
15.
Blood ; 120(4): 800-11, 2012 Jul 26.
Article in English | MEDLINE | ID: mdl-22692505

ABSTRACT

Despite the introduction of tyrosine kinase inhibitor therapy, the prognosis for p190-BCR-ABL(+) acute lymphoblastic leukemia remains poor. In the present study, we present the cellular and molecular roles of the Rho GTPase guanine nucleotide exchange factor Vav in lymphoid leukemogenesis and explore the roles of Vav proteins in BCR-ABL-dependent signaling. We show that genetic deficiency of the guanine nucleotide exchange factor Vav3 delays leukemogenesis by p190-BCR-ABL and phenocopies the effect of Rac2 deficiency, a downstream effector of Vav3. Compensatory up-regulation of expression and activation of Vav3 in Vav1/Vav2-deficient B-cell progenitors increases the transformation ability of p190-BCR-ABL. Vav3 deficiency induces apoptosis of murine and human leukemic lymphoid progenitors, decreases the activation of Rho GTPase family members and p21-activated kinase, and is associated with increased Bad phosphorylation and up-regulation of Bax, Bak, and Bik. Finally, Vav3 activation only partly depends on ABL TK activity, and Vav3 deficiency collaborates with tyrosine kinase inhibitors to inhibit CrkL activation and impair leukemogenesis in vitro and in vivo. We conclude that Vav3 represents a novel specific molecular leukemic effector for multitarget therapy in p190-BCR-ABL-expressing acute lymphoblastic leukemia.


Subject(s)
B-Lymphocytes/pathology , Cell Transformation, Neoplastic/pathology , Fusion Proteins, bcr-abl/metabolism , Lymphoid Progenitor Cells/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Proto-Oncogene Proteins c-vav/physiology , Animals , B-Lymphocytes/metabolism , Cell Transformation, Neoplastic/metabolism , Cells, Cultured , Female , Fetal Blood/cytology , Fetal Blood/metabolism , Humans , Lymphoid Progenitor Cells/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Phosphorylation , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Survival Rate , Tumor Stem Cell Assay , rac GTP-Binding Proteins/physiology , RAC2 GTP-Binding Protein
16.
Pediatr Blood Cancer ; 61(10): 1754-60, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24976003

ABSTRACT

BACKGROUND: This Phase 2 study tested the tolerability and efficacy of bortezomib combined with reinduction chemotherapy for pediatric patients with relapsed, refractory or secondary acute myeloid leukemia (AML). Correlative studies measured putative AML leukemia initiating cells (AML-LIC) before and after treatment. PROCEDURE: Patients with <400 mg/m(2) prior anthracycline received bortezomib combined with idarubicin (12 mg/m(2) days 1-3) and low-dose cytarabine (100 mg/m(2) days 1-7) (Arm A). Patients with ≥400 mg/m(2) prior anthracycline received bortezomib with etoposide (100 mg/m(2) on days 1-5) and high-dose cytarabine (1 g/m(2) every 12 hours for 10 doses) (Arm B). RESULTS: Forty-six patients were treated with 58 bortezomib-containing cycles. The dose finding phase of Arm B established the recommended Phase 2 dose of bortezomib at 1.3 mg/m(2) on days 1, 4, and 8 with Arm B chemotherapy. Both arms were closed after failure to meet predetermined efficacy thresholds during the first stage of the two-stage design. The complete response (CR + CRp) rates were 29% for Arm A and 43% for Arm B. Counting additional CRi responses (CR with incomplete neutrophil recovery), the overall CR rates were 57% for Arm A and 48% for Arm B. The 2-year overall survival (OS) was 39 ± 15%. Correlative studies showed that LIC depletion after the first cycle was associated with clinical response. CONCLUSION: Bortezomib is tolerable when added to chemotherapy regimens for relapsed pediatric AML, but the regimens did not exceed preset minimum response criteria to allow continued accrual. This study also suggests that AML-LIC depletion has prognostic value.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Adolescent , Animals , Boronic Acids/administration & dosage , Boronic Acids/adverse effects , Bortezomib , Child , Child, Preschool , Cytarabine/administration & dosage , Cytarabine/adverse effects , Dose-Response Relationship, Drug , Etoposide/administration & dosage , Etoposide/adverse effects , Female , Humans , Idarubicin/administration & dosage , Idarubicin/adverse effects , Infant , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute/mortality , Male , Neoplasm Recurrence, Local/drug therapy , Pyrazines/administration & dosage , Pyrazines/adverse effects , Rabbits , Salvage Therapy/methods , Treatment Outcome , Young Adult
17.
Pediatr Blood Cancer ; 61(7): 1246-51, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24664955

ABSTRACT

BACKGROUND: We report results of a phase I trial designed to estimate the maximum tolerated dose (MTD), describe dose-limiting toxicities (DLT), and characterize the pharmacokinetic profile of MK-2206, an AKT inhibitor, in children with refractory or recurrent malignancies. PROCEDURE: MK-2206 was administered either every other day (Schedule 1), or once a week (Schedule 2) in a 28-day cycle. Dose escalations in increments of ∼30% were independently made in each part using the rolling-six design. Serial pharmacokinetic (PK) studies were obtained. Biological studies include analysis of PI3K/PTEN/AKT-cell signaling pathway in pre and post-therapy in PBMC and in tumors at diagnosis or recurrence. RESULTS: Fifty patients (26 males, median age 12.6 years [range, 3.1-21.9]) with malignant glioma (16), ependymoma (4), hepatocellular carcinoma (3), gliomatosis cereberi (2), or other tumors (22) were enrolled; 40 were fully evaluable for toxicity (Schedule 1, n = 23; Schedule 2, n = 17). Schedule 1 DLTs included: grade 3 dehydration in 1/6 patients at 28 mg/m(2) ; grade 4 hyperglycemia and neutropenia in 1/6 patients at 45 mg/m(2) ; and grade 3 rash in 3/6 patients at dose level 4 (58 mg/m(2) ). Schedule 2 DLTs included: grade 3 alkaline phosphatase in 1/6 patients at 90 mg/m(2) ; grade 3 rash in 1/6 patients at 120 mg/m(2) ; and grade 3 rash in 2/6 patients at 155 mg/m(2) . CONCLUSIONS: The recommended pediatric phase 2 dose of MK-2206 is 45 mg/m(2) /dose every other day or 120 mg/m(2) /dose weekly. PK appeared linear over the dose range studied.


Subject(s)
Heterocyclic Compounds, 3-Ring/administration & dosage , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Maximum Tolerated Dose , Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacokinetics , Adolescent , Adult , Child , Child, Preschool , Heterocyclic Compounds, 3-Ring/adverse effects , Humans , Infant , Neoplasms/enzymology , PTEN Phosphohydrolase/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Protein Kinase Inhibitors/adverse effects , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/metabolism
18.
Semin Radiat Oncol ; 34(3): 351-364, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38880544

ABSTRACT

The "FLASH effect" is an increased therapeutic index, that is, reduced normal tissue toxicity for a given degree of anti-cancer efficacy, produced by ultra-rapid irradiation delivered on time scales orders of magnitude shorter than currently conventional in the clinic for the same doses. This phenomenon has been observed in numerous preclinical in vivo tumor and normal tissue models. While the underlying biological mechanism(s) remain to be elucidated, a path to clinical implementation of FLASH can be paved by addressing several critical translational questions. Technological questions pertinent to each beam type (eg, electron, proton, photon) also dictate the logical progression of experimentation required to move forward in safe and decisive clinical trials. Here we review the available preclinical data pertaining to these questions and how they may inform strategies for FLASH cancer therapy clinical trials.


Subject(s)
Neoplasms , Translational Research, Biomedical , Humans , Neoplasms/radiotherapy , Animals , Radiation Oncology/methods , Clinical Trials as Topic
19.
Br J Haematol ; 161(3): 406-10, 2013 May.
Article in English | MEDLINE | ID: mdl-23432727

ABSTRACT

Low-dose decitabine has encouraging activity and tolerability in adults with acute myeloid leukaemia (AML), but paediatric experience is lacking. We report our retrospective experience with decitabine in eight children and young adults (median age 4 years) with refractory/relapsed AML, who had failed multiple regimens or were not candidates for standard retrieval regimens due to prior toxicities. Three of eight patients (38%) had complete response (CR; 1 each of CR, CR with incomplete platelet recovery and CR with incomplete count recovery). Best responses were observed after a median of 2.5 cycles (range 1-4 cycles). Four patients received subsequent allogeneic stem cell transplant, and two remain in long-term CR.


Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Azacitidine/analogs & derivatives , Leukemia, Myeloid, Acute/drug therapy , Adolescent , Adult , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/adverse effects , Azacitidine/administration & dosage , Azacitidine/adverse effects , Azacitidine/therapeutic use , Bone Marrow/chemistry , Child , Child, Preschool , Combined Modality Therapy , DNA (Cytosine-5-)-Methyltransferase 1 , DNA (Cytosine-5-)-Methyltransferases/analysis , Decitabine , Drug Evaluation , Female , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/surgery , Male , MicroRNAs/analysis , Neoplasm Proteins/analysis , Neutropenia/chemically induced , RNA, Neoplasm/analysis , Remission Induction , Salvage Therapy , Stem Cell Transplantation , Transplantation, Homologous , Treatment Outcome
20.
Pediatr Blood Cancer ; 60(6): 964-71, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23255301

ABSTRACT

For the 365 children diagnosed with acute myeloid leukemia in the US annually, 5-year survival for patients on COG trials with low, intermediate, and high risk disease is 83%, 62%, and 23%, respectively. Recent advances include improved therapeutic stratification, improved survival with dose intensification, and further elucidation of the heterogeneity specific to childhood AML. These discoveries now guide current strategy incorporating targeted agents to pathways specific to childhood AML as well as evaluating methods to increase the sensitivity of the leukemic stem cell, first in Phase II feasibility trials followed by Phase III efficacy trials of the most promising agents. Acute myeloid leukemia in children, though with similar subgroups to adults, remains uniquely different based upon quite different prevalence of subtypes as well as overall response to therapy. The Children's Oncology Group's research agenda builds upon earlier efforts to better elucidate the leukemogenic steps distinct to childhood AML in order to more scientifically develop and test novel therapeutic approaches to the treatment and ultimate cure for children with this disorder. Pediatr Blood Cancer 2013; 60: 964-971. © 2012 Wiley Periodicals, Inc.


Subject(s)
Antineoplastic Agents/therapeutic use , Clinical Trials as Topic , Leukemia, Myeloid, Acute/drug therapy , Humans , Research
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