Atrial arrhythmias following CAR-chimeric antigen receptor T-cell therapy: Incidence, risk factors and biomarker profile.

Recent reports have raised concerns about the association of chimeric antigen receptor T cell (CAR-T) with non-negligible cardiotoxicity, particularly atrial arrhythmias. First, we conducted a pharmacovigilance study to assess the reporting of atrial arrhythmias following CD19-directed CAR-T. Subsequently, to determine the incidence, risk factors and outcomes of atrial arrhythmias post-CAR-T, we compiled a retrospective single-centre cohort of non-Hodgkin lymphoma patients. Only commercial CAR-T products were considered. Atrial arrhythmias were nearly fourfold more likely to be reported after CAR-T therapy compared to all other cancer patients in the FAERS (adjusted ROR = 3.76 [95% CI 2.67-5.29]). Of the 236 patients in our institutional cohort, 23 (10%) developed atrial arrhythmias post-CAR-T, including 12 de novo arrhythmias, with most (83%) requiring medical intervention. Atrial arrhythmias frequently co-occurred with cytokine release syndrome and were associated with higher post-CAR-T infusion peak levels of IL-10, TNF-alpha and LDH, and lower trough levels of fibrinogen. In a multivariable analysis, risk factors for atrial arrhythmia were history of atrial arrhythmia (OR = 6.80 [2.39-19.6]) and using CAR-T product with a CD28-costimulatory domain (OR = 5.17 [1.72-18.6]). Atrial arrhythmias following CD19-CAR-T therapy are prevalent and associated with elevated inflammatory biomarkers, a history of atrial arrhythmia and the use of a CAR-T product with a CD28 costimulatory domain.

Multilineage involvement in KMT2A-rearranged B acute lymphoblastic leukaemia: cell-of-origin, biology, and clinical implications.

AIMS: B lymphoblastic leukaemia/lymphoma (B-ALL) is thought to originate from Pro/Pre-B cells and the genetic aberrations largely reside in lymphoid-committed cells. A recent study demonstrated that a proportion of paediatric B-ALL patients have BCR::ABL1 fusion in myeloid cells, suggesting a chronic myeloid leukaemia (CML)-like biology in this peculiar subset of B-ALL, although it is not entirely clear if the CD19-negative precursor compartment is a source of the myeloid cells. Moreover, the observation has not yet been extended to other fusion-driven B-ALLs. METHODS AND RESULTS: In this study we investigated a cohort of KMT2A-rearranged B-ALL patients with a comparison to BCR::ABL1-rearranged B-ALL by performing cell sorting via flow cytometry followed by FISH (fluorescence in situ hybridization) analysis on each of the sorted populations. In addition, RNA sequencing was performed on one of the sorted populations. These analyses showed that (1) multilineage involvement was present in 53% of BCR::ABL1 and 36% of KMT2A-rearranged B-ALL regardless of age, (2) multilineage involvement created pitfalls for residual disease monitoring, and (3) HSPC transcriptome signatures were upregulated in KMT2A-rearranged B-ALL with multilineage involvement. CONCLUSIONS: In summary, multilineage involvement is common in both BCR::ABL1-rearranged and KMT2A-rearranged B-ALL, which should be taken into consideration when interpreting the disease burden during the clinical course.

Universal germline genetic testing in patients with hematologic malignancies using DNA isolated from nail clippings.

Not available.

Biomarkers and cardiovascular outcomes in chimeric antigen receptor T-cell therapy recipients.

AIMS: Chimeric antigen receptor T-cell therapy (CAR-T) harnesses a patient's immune system to target cancer. There are sparse existing data characterizing death outcomes after CAR-T-related cardiotoxicity. This study examines the association between CAR-T-related severe cardiovascular events (SCE) and mortality. METHODS AND RESULTS: From a multi-centre registry of 202 patients receiving anti-CD19 CAR-T, covariates including standard baseline cardiovascular and cancer parameters and biomarkers were collected. Severe cardiovascular events were defined as a composite of heart failure, cardiogenic shock, or myocardial infarction. Thirty-three patients experienced SCE, and 108 patients died during a median follow-up of 297 (interquartile range 104-647) days. Those that did and did not die after CAR-T were similar in age, sex, and prior anthracycline use. Those who died had higher peak interleukin (IL)-6 and ferritin levels after CAR-T infusion, and those who experienced SCE had higher peak IL-6, C-reactive protein (CRP), ferritin, and troponin levels. The day-100 and 1-year Kaplan-Meier overall mortality estimates were 18% and 43%, respectively, while the non-relapse mortality (NRM) cumulative incidence rates were 3.5% and 6.7%, respectively. In a Cox model, SCE occurrence following CAR-T was independently associated with increased overall mortality risk [hazard ratio (HR) 2.8, 95% confidence interval (CI) 1.6-4.7] after adjusting for age, cancer type and burden, anthracycline use, cytokine release syndrome grade ≥ 2, pre-existing heart failure, hypertension, and African American ancestry; SCEs were independently associated with increased NRM (HR 3.5, 95% CI 1.4-8.8) after adjusting for cancer burden. CONCLUSION: Chimeric antigen receptor T-cell therapy recipients who experience SCE have higher overall mortality and NRM and higher peak levels of IL-6, CRP, ferritin, and troponin.

Interventions and outcomes of adult patients with B-ALL progressing after CD19 chimeric antigen receptor T-cell therapy.

CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has become a breakthrough treatment of patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, despite the high initial response rate, the majority of adult patients with B-ALL progress after CD19 CAR T-cell therapy. Data on the natural history, management, and outcome of adult B-ALL progressing after CD19 CAR T cells have not been described in detail. Herein, we report comprehensive data of 38 adult patients with B-ALL who progressed after CD19 CAR T therapy at our institution. The median time to progression after CAR T-cell therapy was 5.5 months. Median survival after post-CAR T progression was 7.5 months. A high disease burden at the time of CAR T-cell infusion was significantly associated with risk of post-CAR T progression. Thirty patients (79%) received salvage treatment of post-CAR T disease progression, and 13 patients (43%) achieved complete remission (CR), but remission duration was short. Notably, 7 (58.3%) of 12 patients achieved CR after blinatumomab and/or inotuzumab administered following post-CAR T failure. Multivariate analysis revealed that a longer remission duration from CAR T cells was associated with superior survival after progression following CAR T-cell therapy. In summary, overall prognosis of adult B-ALL patients progressing after CD19 CAR T cells was poor, although a subset of patients achieved sustained remissions to salvage treatments, including blinatumomab, inotuzumab, and reinfusion of CAR T cells. Novel therapeutic strategies are needed to reduce risk of progression after CAR T-cell therapy and improve outcomes of these patients.

A phase 2 biomarker-driven study of ruxolitinib demonstrates effectiveness of JAK/STAT targeting in T-cell lymphomas.

Signaling through JAK1 and/or JAK2 is common among tumor and nontumor cells within peripheral T-cell lymphoma (PTCL). No oral therapies are approved for PTCL, and better treatments for relapsed/refractory disease are urgently needed. We conducted a phase 2 study of the JAK1/2 inhibitor ruxolitinib for patients with relapsed/refractory PTCL (n = 45) or mycosis fungoides (MF) (n = 7). Patients enrolled onto 1 of 3 biomarker-defined cohorts: (1) activating JAK and/or STAT mutations, (2) ≥30% pSTAT3 expression among tumor cells by immunohistochemistry, or (3) neither or insufficient tissue to assess. Patients received ruxolitinib 20 mg PO twice daily until progression and were assessed for response after cycles 2 and 5 and every 3 cycles thereafter. The primary endpoint was clinical benefit rate (CBR), defined as the combination of complete response, partial response (PR), and stable disease lasting at least 6 months. Only 1 of 7 patients with MF had CBR (ongoing PR > 18 months). CBR among the PTCL cases (n = 45) in cohorts 1, 2, and 3 were 53%, 45%, and 13% (cohorts 1 & 2 vs 3, P = .02), respectively. Eight patients had CBR > 12 months (5 ongoing), including 4 of 5 patients with T-cell large granular lymphocytic leukemia. In an exploratory analysis using multiplex immunofluorescence, expression of phosphorylated S6, a marker of PI3 kinase or mitogen-activated protein kinase activation, in <25% of tumor cells was associated with response to ruxolitinib (P = .05). Our findings indicate that ruxolitinib is active across various PTCL subtypes and support a precision therapy approach to JAK/STAT inhibition in patients with PTCL. This trial was registered at www.clincialtrials.gov as #NCT02974647.

Molecular predictors of immunophenotypic measurable residual disease clearance in acute myeloid leukemia.

Measurable residual disease (MRD) is a powerful prognostic factor in acute myeloid leukemia (AML). However, pre-treatment molecular predictors of immunophenotypic MRD clearance remain unclear. We analyzed a dataset of 211 patients with pre-treatment next-generation sequencing who received induction chemotherapy and had MRD assessed by serial immunophenotypic monitoring after induction, subsequent therapy, and allogeneic stem cell transplant (allo-SCT). Induction chemotherapy led to MRD- remission, MRD+ remission, and persistent disease in 35%, 27%, and 38% of patients, respectively. With subsequent therapy, 34% of patients with MRD+ and 26% of patients with persistent disease converted to MRD-. Mutations in CEBPA, NRAS, KRAS, and NPM1 predicted high rates of MRD- remission, while mutations in TP53, SF3B1, ASXL1, and RUNX1 and karyotypic abnormalities including inv (3), monosomy 5 or 7 predicted low rates of MRD- remission. Patients with fewer individual clones were more likely to achieve MRD- remission. Among 132 patients who underwent allo-SCT, outcomes were favorable whether patients achieved early MRD- after induction or later MRD- after subsequent therapy prior to allo-SCT. As MRD conversion with chemotherapy prior to allo-SCT is rarely achieved in patients with specific baseline mutational patterns and high clone numbers, upfront inclusion of these patients into clinical trials should be considered.

Acute febrile neutrophilic dermatosis (Sweet syndrome) in acute myeloid leukemia patients: a 28-year institutional experience.

INTRODUCTION: Sweet syndrome (SS) is well-known to be associated with underlying hematologic malignancies. The incidence and qualities of SS among novel targeted therapies for acute myeloid leukemia (AML) have not yet been described. METHODS: Through retrospective review of 19432 patients diagnosed with acute/chronic leukemia or myelodysplastic syndromes/ myeloproliferative neoplasms (MDS+/-MPN) over 28 years, we calculated the incidence of SS in the setting of select hematologic malignancies and described the clinicopathologic characteristics of SS in patients with onset of SS after initiation of novel AML-targeted therapies. RESULTS: Overall incidence of SS was 0.36% (95% CI: 0.27% - 0.45%), which was significantly higher among patients with AML (50/5248, 0.94%; 95% CI: 0.71% - 1.25%). Nine AML patients were on 4 classes of novel targeted treatments - IDH1/2 inhibitor alone, FLT3 inhibitor, IDH2 and DOT1L inhibitor, and anti-CD33 therapy. In therapies inducing myeloid blast differentiation, SS occurred at later onset following treatment. CONCLUSIONS: In AML patients with fever and unusual skin lesions, physicians may consider SS earlier which may shorten time to diagnosis. Future assessments of SS among patients treated with novel therapies for AML and molecular studies of biopsies may help further explain this dermatologic adverse event with earlier diagnosis and management of neutrophilic dermatoses in these patients.

Outcomes of COVID-19 in patients with CLL: a multicenter international experience.

Given advanced age, comorbidities, and immune dysfunction, chronic lymphocytic leukemia (CLL) patients may be at particularly high risk of infection and poor outcomes related to coronavirus disease 2019 (COVID-19). Robust analysis of outcomes for CLL patients, particularly examining effects of baseline characteristics and CLL-directed therapy, is critical to optimally manage CLL patients through this evolving pandemic. CLL patients diagnosed with symptomatic COVID-19 across 43 international centers (n = 198) were included. Hospital admission occurred in 90%. Median age at COVID-19 diagnosis was 70.5 years. Median Cumulative Illness Rating Scale score was 8 (range, 4-32). Thirty-nine percent were treatment naive ("watch and wait"), while 61% had received ≥1 CLL-directed therapy (median, 2; range, 1-8). Ninety patients (45%) were receiving active CLL therapy at COVID-19 diagnosis, most commonly Bruton tyrosine kinase inhibitors (BTKi's; n = 68/90 [76%]). At a median follow-up of 16 days, the overall case fatality rate was 33%, though 25% remain admitted. Watch-and-wait and treated cohorts had similar rates of admission (89% vs 90%), intensive care unit admission (35% vs 36%), intubation (33% vs 25%), and mortality (37% vs 32%). CLL-directed treatment with BTKi's at COVID-19 diagnosis did not impact survival (case fatality rate, 34% vs 35%), though the BTKi was held during the COVID-19 course for most patients. These data suggest that the subgroup of CLL patients admitted with COVID-19, regardless of disease phase or treatment status, are at high risk of death. Future epidemiologic studies are needed to assess severe acute respiratory syndrome coronavirus 2 infection risk, these data should be validated independently, and randomized studies of BTKi's in COVID-19 are needed to provide definitive evidence of benefit.

Pediatric-inspired chemotherapy incorporating pegaspargase is safe and results in high rates of minimal residual disease negativity in adults up to age 60 with Philadelphia chromosome-negative acute lymphoblastic leukemia.

Administration of pediatric-inspired chemotherapy to adults up to age 60 with acute lymphoblastic leukemia (ALL) is challenging in part due to toxicities of asparaginase as well as myelosuppression. We conducted a multicenter phase II clinical trial (NCT01920737) investigating a pediatric-inspired regimen, based on the augmented arm of the Children's Cancer Group 1882 protocol, incorporating 6 doses of pegaspargase 2000 IU/m2, rationally synchronized to avoid overlapping toxicity with other agents. We treated 39 adults ages 20-60 years (median, 38 years) with newly-diagnosed ALL (n=31) or lymphoblastic lymphoma (n=8). Grade 3-4 hyperbilirubinemia occurred frequently and at higher rates in patients 40-60 (n=18) vs 18-39 (n=21) years (44 vs 10%, p=0.025). However, 8/9 patients re-challenged with pegaspargase did not experience recurrent grade 3-4 hyperbilirubinemia. Grade 3-4 hypertriglyceridemia and hypofibrinogenemia were common (each 59%). Asparaginase activity at 7-days post-infusion reflected levels associated with adequate asparagine depletion, even among those with antibodies to pegaspargase. Complete response (CR)/CR with incomplete hematologic recovery was observed post-induction in 38/39 (97%) patients. Among patients with ALL, rates of MRD negativity by multiparameter flow cytometry were 33% and 83% following Induction Phase I and Phase II, respectively. Event-free and overall survival at 3 years (67.8 and 76.4%) compare favorably to outcomes observed in other series. These results demonstrate pegaspargase can be administered in the context of intensive multi-agent chemotherapy to adults age ≤60 with manageable toxicity. This regimen may serve as an effective backbone into which novel agents may be incorporated in future frontline studies.

Considerations for Use of Hematopoietic Growth Factors in Patients With Cancer Related to the COVID-19 Pandemic.

Hematopoietic growth factors, including erythrocyte stimulating agents (ESAs), granulocyte colony-stimulating factors, and thrombopoietin mimetics, can mitigate anemia, neutropenia, and thrombocytopenia resulting from chemotherapy for the treatment of cancer. In the context of pandemic SARS-CoV-2 infection, patients with cancer have been identified as a group at high risk of morbidity and mortality from this infection. Our subcommittee of the NCCN Hematopoietic Growth Factors Panel convened a voluntary group to review the potential value of expanded use of such growth factors in the current high-risk environment. Although recommendations are available on the NCCN website in the COVID-19 Resources Section (https://www.nccn.org/covid-19/), these suggestions are provided without substantial context or reference. Herein we review the rationale and data underlying the suggested alterations to the use of hematopoietic growth factors for patients with cancer in the COVID-19 era.

Loss of plasmacytoid dendritic cell differentiation is highly predictive for post-induction measurable residual disease and inferior outcomes in acute myeloid leukemia.

Measurable residual disease is associated with inferior outcomes in patients with acute myeloid leukemia (AML). Measurable residual disease monitoring enhances risk stratification and may guide therapeutic intervention. The European LeukemiaNet working party recently came to a consensus recommendation incorporating leukemia associated immunophenotype-based different from normal approach by multi-color flow cytometry for measurable residual disease evaluation. However, the analytical approach is highly expertise-dependent and difficult to standardize. Here we demonstrate that loss of plasmacytoid dendritic cell differentiation after 7+3 induction in AML is highly specific for measurable residual disease positivity (specificity 97.4%) in a uniformly treated patient cohort. Moreover, loss of plasmacytoid dendritic cell differentiation as determined by a blast-to-plasmacytoid dendritic cell ratio >10 was strongly associated with inferior overall and relapse-free survival (RFS) [Hazard ratio 2.79, 95% confidence interval (95%CI): 0.98-7.97; P=0.077) and 3.83 (95%CI: 1.51-9.74; P=0.007), respectively), which is similar in magnitude to measurable residual disease positivity. Importantly, measurable residual disease positive patients who reconstituted plasmacytoid dendritic cell differentiation (blast/ plasmacytoid dendritic cell ratio <10) showed a higher rate of measurable residual disease clearance at later pre-transplant time points compared to patients with loss of plasmacytoid dendritic cell differentiation (blast/ plasmacytoid dendritic cell ratio <10) (6 of 12, 50% vs 2 of 18, 11%; P=0.03). Furthermore pre-transplant plasmacytoid dendritic cell recovery was associated with superior outcome in measurable residual disease positive patients. Our study provides a novel, simple, broadly applicable, and quantitative multi-color flow cytometry approach to risk stratification in AML.

Autologous CD19-Targeted CAR T Cells in Patients with Residual CLL following Initial Purine Analog-Based Therapy.

Patients with residual chronic lymphocytic leukemia (CLL) following initial purine analog-based chemoimmunotherapy exhibit a shorter duration of response and may benefit from novel therapeutic strategies. We and others have previously described the safety and efficacy of autologous T cells modified to express anti-CD19 chimeric antigen receptors (CARs) in patients with relapsed or refractory B cell acute lymphoblastic leukemia and CLL. Here we report the use of CD19-targeted CAR T cells incorporating the intracellular signaling domain of CD28 (19-28z) as a consolidative therapy in 8 patients with residual CLL following first-line chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab. Outpatients received low-dose conditioning therapy with cyclophosphamide (600 mg/m2), followed by escalating doses of 3 × 106, 1 × 107, or 3 × 107 19-28z CAR T cells/kg. An objective response was observed in 3 of 8 patients (38%), with a clinically complete response lasting more than 28 months observed in two patients. Self-limited fevers were observed post-CAR T cell infusion in 4 patients, contemporaneous with elevations in interleukin-6 (IL-6), IL-10, IL-2, and TGF-α. None developed severe cytokine release syndrome or neurotoxicity. CAR T cells were detectable post-infusion in 4 patients, with a longest observed persistence of 48 days by qPCR. Further strategies to enhance CAR T cell efficacy in CLL are under investigation.

CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date.

Adoptive transfer of T cells genetically modified to express chimeric antigen receptors (CARs) targeting CD19 has produced impressive results in treating patients with B-cell malignancies. Although these CAR-modified T cells target the same antigen, the designs of CARs vary as well as several key aspects of the clinical trials in which these CARs have been studied. It is unclear whether these differences have any impact on clinical outcome and treatment-related toxicities. Herein, we review clinical results reflecting the investigational use of CD19-targeted CAR T-cell therapeutics in patients with B-cell hematologic malignancies, in light of differences in CAR design and production, and outline the limitations inherent in comparing outcomes between studies.

Review: Current clinical applications of chimeric antigen receptor (CAR) modified T cells.

The past several years have been marked by extraordinary advances in clinical applications of immunotherapy. In particular, adoptive cellular therapy utilizing chimeric antigen receptor (CAR)-modified T cells targeted to CD19 has demonstrated substantial clinical efficacy in children and adults with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) and durable clinical benefit in a smaller subset of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or B-cell non-Hodgkin lymphoma (B-NHL). Early-phase clinical trials are currently assessing CAR T-cell safety and efficacy in additional malignancies. Here, we discuss clinical results from the largest series to date investigating CD19-targeted CAR T cells in B-ALL, CLL, and B-NHL, including discussion of differences in CAR T-cell design and production and treatment approach, as well as clinical efficacy, nature of severe cytokine release syndrome and neurologic toxicities, and CAR T-cell expansion and persistence. We additionally review the current and forthcoming use of CAR T cells in multiple myeloma and several solid tumors and highlight challenges and opportunities afforded by the current state of CAR T-cell therapies, including strategies to overcome inhibitory aspects of the tumor microenvironment and enhance antitumor efficacy.

Reduced Toxicity Conditioning and Allogeneic Hematopoietic Progenitor Cell Transplantation for Recessive Dystrophic Epidermolysis Bullosa.

Recessive dystrophic epidermolysis bullosa is a severe, incurable, inherited blistering disease caused by COL7A1 mutations. Emerging evidence suggests hematopoietic progenitor cells (HPCs) can be reprogrammed into skin; HPC-derived cells can restore COL7 expression in COL7-deficient mice. We report two children with recessive dystrophic epidermolysis bullosa treated with reduced-toxicity conditioning and HLA-matched HPC transplantation.

A comparison of bronchoalveolar lavage versus lung biopsy in pediatric recipients after stem cell transplantation.

Bronchoalveolar lavage (BAL) has been a useful initial diagnostic tool in the evaluation of pulmonary complications after hematopoietic stem cell transplantation (HSCT); however, the diagnostic sensitivity, prevalence, and outcome after BAL versus lung biopsy (LB) in pediatric HSCT patients remains to be determined. We reviewed 193 pediatric HSCT recipients who underwent a total of 235 HSCTs. Sixty-five patients (34%) underwent a total of 101 BALs for fever, respiratory distress, and/or pulmonary infiltrates on chest radiograph and/or computed tomography scan. The 1-year probability of undergoing BAL was 43.0% after allogeneic stem cell transplantation (alloSCT) and 8.5% after autologous stem cell transplantation (autoSCT) (P = .001). Sixteen of the 193 patients (8%) patients underwent 19 LBs. The probability of undergoing LB at 1 year after HSCT was 9.3%. No grade III or IV adverse events related to either procedure were observed. Of the 101 BALs performed, 40% (n = 40) were diagnostic, with a majority revealing a bacterial pathogen. Among the 19 LBs performed, 94% identified an etiology. In multivariate analysis, myeloablative conditioning alloSCT conferred the highest risk of requiring a BAL (hazard ratio [HR],8.5; P = .0002). The probability of 2-year overall survival was 20.2% in patients who underwent BAL, 17.5% for patients who underwent biopsy, and 67.4% for patients who had neither procedure. In multivariate analysis, only the requirement of a BAL was independently associated with an increased risk of mortality (HR, 2.96; P < .0001). In summary, in this cohort of pediatric HSCT recipients, BAL and LB were used in approximately 35% and 8% of pediatric HSCTs with diagnostic yields of approximately 40% and 94%, respectively, and were both associated with poor long-term outcomes.

Pilot trial of risk-adapted cyclophosphamide intensity based conditioning and HLA matched sibling and unrelated cord blood stem cell transplantation in newly diagnosed pediatric and adolescent recipients with acquired severe aplastic anemia.

BACKGROUND: Cyclophosphamide-based conditioning regimens and allogeneic hematopoietic stem cell transplantation (AlloHSCT) from matched related donors (MRD) has resulted in the highest survival rates in children and adolescents with acquired severe aplastic anemia (SAA). Time to transplant has consistently been associated with decreased overall survival. Reduced toxicity conditioning and AlloHSCT has been used successfully in other pediatric non-malignant diseases. PROCEDURE: We piloted a risk-adapted AlloHSCT approach, using fludarabine and anti-thymocyte globulin based conditioning with high (200 mg/kg) and low (60 mg/kg) dose cyclophosphamide as upfront treatment in newly diagnosed pediatric patients with acquired SAA incorporating alternative donor sources, including cord blood. Average risk for non-engraftment patients with <10 transfusions received low dose cyclophosphamide (60 mg/kg); High Risk, those with ≥10 transfusions received conditioning regimen with higher intensity cyclophosphamide (200 mg/kg). RESULTS: Seventeen patients were enrolled and underwent AlloHSCT including 12 males and 5 females with mean age of 8 years (range 3-16), and median follow-up time of 39 months (range 1-135). Donor sources included MRD BM (6/6 [n = 9], 5/6 [n = 2]) and unrelated CB (5/6 [n = 4], 4/6 [n = 2]). Five year OS was 67.6% (37.9-85.4). Three secondary graft failures (17.6%) occurred in the low dose cyclophosphamide arm. CONCLUSIONS: Upfront treatment with risk-adapted cyclophosphamide conditioning AlloSCT is well tolerated for the management of newly diagnosed pediatric and adolescent patients with acquired SAA. However, the increased risk of graft rejection in the lower dose arm warrants additional research regarding the optimal intensity of cyclophosphamide-based conditioning regimen to reduce toxicity without increasing graft failure.

Rituximab pharmacokinetics in children and adolescents with de novo intermediate and advanced mature B-cell lymphoma/leukaemia: a Children's Oncology Group report.

The ANHL01P1 trial was undertaken to determine pharmacokinetics and safety following the addition of rituximab to French-American-British/Lymphome Malins de Burkitt (FAB/LMB96) chemotherapy in 41 children and adolescents with Stage III/IV mature B-cell lymphoma/leukaemia. Patients received rituximab (375 mg/m(2) ) days -2 and 0 of two induction cycles and day 0 of two consolidation cycles. Highest peak levels were achieved following the second dose of each induction cycle [299 ± 19 and 384 ± 25 µg/ml (Group-B); 245 ± 31 and 321 ± 32 µg/ml (Group-C)] with sustained troughs and t½ of 26-29 d. Rituximab can be safely added to FAB chemotherapy with high early rituximab peak/trough levels and a long t½.