More precise treatment strategies are urgently needed to decrease toxicity and improve outcomes for treatment-refractory leukemia. We used ex vivo drug response profiling of high-risk, relapsed, or refractory acute lymphoblastic leukemia (ALL) cases and identified a subset with exquisite sensitivity to small-molecule mimetics of the second mitochondria-derived activator of caspases (SMAC) protein. Potent ex vivo activity of the SMAC mimetic (SM) birinapant correlated with marked in vivo antileukemic effects, as indicated by delayed engraftment, decreased leukemia burden, and prolonged survival of xenografted mice. Antileukemic activity was dependent on simultaneous execution of apoptosis and necroptosis, as demonstrated by functional genomic dissection with a multicolored lentiCRISPR approach to simultaneously disrupt multiple genes in patient-derived ALL. SM specifically targeted receptor-interacting protein kinase 1 (RIP1)-dependent death, and CRISPR-mediated disruption of RIP1 completely blocked SM-induced death yet had no impact on the response to standard antileukemic agents. Thus, SM compounds such as birinapant circumvent escape from apoptosis in leukemia by activating a potent dual RIP1-dependent apoptotic and necroptotic cell death, which is not exploited by current therapy. Ex vivo drug activity profiling could provide important functional diagnostic information to identify patients who may benefit from targeted treatment with birinapant in early clinical trials.
Abstract Recently, studies in adults with acute promyelocytic leukemia (APL) showed high cure rates in low‐risk patients treated with all‐ trans retinoid acid (ATRA) and arsenic trioxide (ATO), while toxicities were significantly reduced compared to the standard treatment with ATRA and chemotherapy. Here we report about first experience with 11 pediatric patients with low‐risk APL treated with ATRA and ATO. All patients stayed in molecular remission. All suffered from hyperleukocytosis. Two patients experienced reversible severe side effects. One suffered from osteonecroses at both femurs, seizures, as well as posterior reversible encephalopathy syndrome, the other patient had an abducens paresis.
Relapsed Acute Lymphoblastic Leukemia (ALL) is among the most common causes of cancer-associated deaths in children. However, little is known about the implications of deviations from ALL treatment protocols on survival rates. The present study elucidates the various characteristics of treatment deviations in children with relapsed ALL included in the ALL-REZ BFM 2002 (i.e., Relapse Berlin-Frankfurt- Münster) trial and determines their prognostic relevance for relapse and death rates. Among 687 patients, 100 were identified with treatment deviations, further classified, and examined by occurrence time, cause and type. Protocol deviation was considered a time-dependent variable and its impact on Disease Free Survival (DFS) and Overall Survival (OS) was examined using the time-dependent model Mantel Byar. Five years after the relapse diagnosis, deviations were significantly related to both inferior DFS (38%) and OS (57%) rates compared to protocol conformed treatment (DFS = 61%; OS = 70%, P < 0.001). Based on multivariate analyses, protocol deviation proved to be an independent adverse prognostic factor of DFS. Moreover, deviations triggered by chemotherapy-induced toxicity were associated with a higher relapse rate compared to deviations due to insufficient response. Therefore, to avoid impairment of results by deviations, future clinical trials, and treatment strategies should focus on less toxic treatments and stricter protocol compliance.
Approximately 10% of cases of childhood cancer arise in the context of a cancer predisposition syndrome (CPS) [1].Among the rare CPS, Li-Fraumeni syndrome (LFS, MIM#151623) is relatively common and estimated to account for >1% of cases of childhood cancer [2].LFS is a dominantly inherited condition caused by pathogenic germline variants in the TP53 tumor suppressor gene [3,4].Children with LFS are predisposed to a range of neoplasms such as osteosarcoma, adrenocortical carcinoma, medulloblastoma, choroid plexus carcinoma, anaplastic rhabdomyosarcoma, and (frequently hypodiploid) acute lymphoblastic leukemia (LFS-ALL) [5,6].Notably,
Abstract Objective Pediatric patients with relapsed or refractory acute lymphoblastic leukemia have a poor prognosis. We here assess the response rates, adverse events, and long‐term follow‐up of pediatric patients with relapsed/refractory acute lymphoblastic leukemia receiving blinatumomab. Methods Retrospective analysis of a single‐center experience with blinatumomab in 38 patients over a period of 10 years. Results The median age at onset of therapy was 10 years (1‐21 years). Seventy‐one percent of patients had undergone at least one hematopoietic stem cell transplantation (HSCT) prior to treatment with blinatumomab. We observed a response to blinatumomab in 13/38 patients (34%). The predominant side effect was febrile reactions, nearly half of the patients developed a cytokine release syndrome. Eight events of neurotoxicity were registered over the 78 cycles (15%). To date, nine patients (24%) are alive and in complete molecular remission. All survivors underwent haploidentical HSCT after treatment with blinatumomab. Conclusions Despite heavy pretreatment of most of our patients, severe adverse events were rare and response rates encouraging. Blinatumomab is a valuable bridging salvage therapy for relapsed or refractory patients to a second or even third HSCT.
PURPOSE: The aim of this study was to investigate whether, in relapsed childhood acute lymphoblastic leukemia (ALL), the frequent genetic feature of TEL-AML1 fusion resulting from the cryptic chromosomal translocation t(12;21)(p13;q22) is an independent risk factor. PATIENTS AND METHODS: A matched-pair analysis was performed within a homogeneous group of children with first relapse of BCR-ABL–negative B-cell precursor (BPC) ALL treated according to relapse trials ALL-Rezidiv (REZ) of the Berlin-Frankfurt-Münster Study Group. A total of 249 patients were eligible for this study: 53 (21%) were positive for TEL-AML1, and 196 (79%) were negative. Positive patients were matched for established most-significant prognostic determinants at relapse, time point, and site of relapse, as well as age and peripheral blast cell count at relapse. RESULTS: Fifty pairs matching the aforementioned criteria could be determined. The probabilities with SE of event-free survival and survival at 5 years for matched TEL-AML1 positives and negatives are 0.63 ± 0.10 versus 0.38 ± 0.10 (P = .09) and 0.82 ± 0.09 versus 0.42 ± 0.19 (P = .10), respectively. These results were confirmed by multivariate analysis, revealing an independent prognostic significance of time point and site of relapse (both P < .001) but not of TEL-AML1 expression (P = .09). CONCLUSION: TEL-AML1 expression does not constitute an independent risk factor in relapsed childhood BCP-ALL after matching for relevant prognostic parameters. It undoubtedly characterizes genetically an ALL entity associated with established favorable prognostic parameters. High-risk therapeutic procedures such as allogeneic SCT should be considered restrictively.
Acute lymphoblastic leukemia (ALL) is the most common cancer in children 1 .Pediatric patients with disease refractory to last chemotherapy, relapse after allogeneic hematopoietic stem-cell transplantation (alloHSCT), or second or further relapse have a particularly poor prognosis 2 .Intensive chemotherapy followed by alloHSCT after achieving remission can result in cure for some patients.However, survival is still low with this approach 3 .Thus, additional treatment modalities with acceptable toxicity are needed to improve long-term survival.Blinatumomab is a bispecific T-cell engager (BiTE) antibody construct that directs CD3-positive effector memory T-cells to CD19-positive target leukemia cells.We previously reported the primary results of a phase 1-2 study of blinatumomab treatment in pediatric patients with relapsed/refractory B-cell precursor ALL (BCP-ALL) 4 .In that report, of the 70 patients who received the recommended phase 2 dose in either phase, 27 patients (39%; 95% confidence interval [CI], 27 to 51%) achieved complete remission (CR) within the first two cycles; of these, 52% attained negative minimal residual disease (MRD).Adverse events of interest included neurologic events (24%), cytokine release syndrome (11%), and transient, clinically non-significant elevation of alanine aminotransferase (19%), aspartate aminotransferase (14%), or bilirubin (6%).The objective of this follow-up analysis is to examine the final results for remission and survival 24 months after blinatumomab treatment.Full study methods have been reported previously 4 .In brief, this open-label, single-arm phase 1-2 study enrolled patients ≤ 18 years of age with relapsed/refractory BCP-ALL and > 25% bone marrow blasts if disease was primary refractory or in refractory first relapse after full standard induction regimen, in second or further relapse, or in any relapse after alloHSCT.Patients in nonrefractory first relapse without prior alloHSCT were not permitted in the study.All patients received blinatumomab as a 4-week continuous intravenous infusion, with a 2-week treatment-free interval after each cycle.On the basis of phase 1 results, the recommended phase 2 dose was 5 µg/m 2 /day for the first week of cycle 1, followed by 15 µg/m 2 /day for the remaining 3 weeks of cycle 1 and for all 4 weeks of the following cycles.Infusions were administered in the hospital during the first week of cycle 1 and the first 2 days of cycle 2, then in an outpatient setting whenever clinically appropriate for a given patient's condition.Bone marrow aspirate for response assessment (or biopsy if aspirate could not be obtained) was performed during screening, on day 15 of cycle 1, and on day 29 of each cycle.Patients achieving hematologic CR within the first 2 cycles could receive up to three additional cycles and/or consolidation chemotherapy and/or alloHSCT at any time per investigator's choice.Central nervous system prophylaxis according to institutional/national standards was administered at ageadjusted doses when bone marrow assessment was performed.Patients who experienced neurologic adverse events requiring medical intervention were given
