Summary
CD19‐directed chimeric antigen receptor (CAR) T‐cell therapy is an important therapy for relapsed or refractory acute lymphoblastic leukaemia, but its use carries the risk of immune effector ...cell‐associated neurotoxicity syndrome (ICANS). In children, severe ICANS is almost universally reported in association with cytokine release syndrome and is reversible. We describe two cases of severe, intractable neurotoxicity following CAR T‐cell therapy in children with pre‐existing central nervous system (CNS) vulnerabilities. The cases were atypical in their delayed onset and independence from cytokine release syndrome and did not respond to standard therapies.
Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the ...latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.
BCL2 overexpression is a hallmark of chronic lymphocytic leukemia (CLL). The novel BH3 mimetic navitoclax (ABT-263) specifically inhibits BCL2 and related proteins BCL-x(l) and BCL-w, potently ...inducing apoptosis of CLL cells in vitro. A phase I trial in patients with CLL was conducted to evaluate the safety, pharmacokinetics, and biologic activity of oral navitoclax.
Twenty-nine patients with relapsed or refractory CLL received daily navitoclax for 14 days (10, 110, 200, or 250 mg/d; n = 15) or 21 days (125, 200, 250, or 300 mg/d; n = 14) of each 21-day cycle. Dose escalation decisions were informed by continual reassessment methodology.
Lymphocytosis was reduced by more than 50% in 19 of 21 patients with baseline lymphocytosis. Among 26 patients treated with navitoclax ≥ 110 mg/d, nine (35%) achieved a partial response and seven maintained stable disease for more than 6 months. Median treatment duration was 7 months (range, 1 to ≥ 29 months). Median progression-free survival was 25 months. Activity was observed in patients with fludarabine-refractory disease, bulky adenopathy, and del(17p) CLL. Thrombocytopenia due to BCL-x(l) inhibition was the major dose-limiting toxicity and was dose-related. Low MCL1 expression and high BIM:MCL1 or BIM:BCL2 ratios in leukemic cells correlated with response. We determined that the navitoclax dose of 250 mg/d in a continuous dosing schedule was optimal for phase II studies.
BCL2 is a valid therapeutic target in CLL, and its inhibition by navitoclax warrants further evaluation as monotherapy and in combination in this disease.
The clinical success of the BCL-2-selective BH3-mimetic venetoclax in patients with poor prognosis chronic lymphocytic leukemia (CLL) highlights the potential of targeting the BCL-2-regulated ...apoptotic pathway in previously untreatable lymphoid malignancies. By selectively inhibiting BCL-2, venetoclax circumvents the dose-limiting, BCL-XL-mediated thrombocytopenia of its less selective predecessor navitoclax, while enhancing efficacy in CLL. We have previously reported the potent sensitivity of many high-risk childhood acute lymphoblastic leukemia (ALL) xenografts to navitoclax. Given the superior tolerability of venetoclax, here we have investigated its efficacy in childhood ALL. We demonstrate that in contrast to the clear dependence of CLL on BCL-2 alone, effective antileukemic activity in the majority of ALL xenografts requires concurrent inhibition of both BCL-2 and BCL-XL. We identify BCL-XL expression as a key predictor of poor response to venetoclax and demonstrate that concurrent inhibition of both BCL-2 and BCL-XL results in synergistic killing in the majority of ALL xenografts. A notable exception is mixed lineage leukemia–rearranged infant ALL, where venetoclax largely recapitulates the activity of navitoclax, identifying this subgroup of patients as potential candidates for clinical trials of venetoclax in childhood ALL. Conversely, our findings provide a clear basis for progressing navitoclax into trials ahead of venetoclax in other subgroups.
•Venetoclax demonstrates potent in vitro and in vivo single-agent activity in MLL-rearranged ALL xenografts.•Clinically efficacious BH3-mimetic therapy for other high-risk ALL subtypes is likely to require concurrent BCL-2 and BCL-XL inhibition.
New therapeutic targets are needed to address the poor prognosis of patients with high-risk multiple myeloma. Myeloma cells usually express a range of the prosurvival BCL2 proteins. To define the ...hierarchy of their relative importance for maintaining the survival of myeloma cells, we targeted each of them in a large panel of cell lines, using pharmacological inhibitors or gene editing or by peptide-based approaches, alone or in combination. The majority of well-established immortalized cell lines (17/25) or low-passage myeloma cell lines (5/7) are readily killed when MCL1 is targeted, even including those cell lines sensitive to BCL2 inhibition. Targeting MCL1 also constrained the growth of myeloma in vivo. We also identified a previously unrecognized subset of myeloma that is highly BCLXL-dependent, and has the potential for cotargeting MCL1 and BCLXL. As MCL1 is pivotal for maintaining survival of most myelomas, it should be prioritized for targeting in the clinic once high-quality, validated inhibitors become available.
•Only a minority of myeloma cell lines are killed when the prosurvival BCL2 or BCLXL are selectively inhibited with BH3 mimetic compounds.•In contrast, targeting MCL1 readily killed ∼70% of the myeloma cell lines tested, including both low-passage and well-established ones.
Background
CD19‐directed chimeric antigen receptor T‐cell (CAR‐T) therapy is transforming care for pediatric patients with relapsed or refractory B‐cell acute lymphoblastic leukemia (B‐ALL). There ...are limited pediatric‐specific data concerning the infection risks associated with CD19 CAR‐T therapy and the adequacy of current antimicrobial prophylaxis guidelines for these patients.
Methods
We describe the antimicrobial prophylaxis used and the types of infectious occurring in the first 100 days following CAR‐T therapy for relapsed or refractory B‐cell ALL in children and adolescents (≤18 years) at our centre.
Results
Twenty‐seven patients received their first CAR‐T infusion (CTI) during the study period. Almost all patients (96%) had a comprehensive Infectious Diseases review prior to CTI, which informed a personalised prophylaxis or fever/sepsis plan in six (22%). Overall, six (22%) patients had one or more infections during the study period including five (19%, 0.9 per 100 days‐at‐risk) from days 0–30 and three (n = 20, 15%, 0.6 per 100 days‐at‐risk) from days 31–100. Bacterial blood stream infections were the most common type of infection encountered during both time periods, and one patient had probable pulmonary aspergillosis. There were no infection‐related deaths.
Conclusion
Our study contributes important information on the spectrum of infections encountered in pediatric patients with B‐ALL post CAR‐T therapy. Overall, the burden of infectious complications post CAR‐T therapy in our cohort is lower than previously reported in the literature. Results suggest that our prophylaxis recommendations are effective in this population.
Background
Antibiotics, while an essential component of supportive care in allogeneic hematopoietic cell transplantation (allo‐HCT), can have adverse effects and select for antibiotic resistance. ...Understanding of patterns of use will inform antimicrobial stewardship (AMS) interventions.
Methods
Retrospective, single‐center cohort of children undergoing first allo‐HCT (n = 125). Antibiotic prescription and infection data were included from the date conditioning was commenced until 30 days post allo‐HCT. Antibiotic use was reported as length of therapy (LOT) (number of days a patient received an antibiotic) and days of therapy DOT (aggregating all antibiotics prescribed per day). Infections were classified as microbiologically documented infection (MDI) or clinically documented infections.
Results
At least one course of antibiotics was administered to 124 (99%) patients. The LOT was 636 per 1000 patient days and DOT was 959 per 1000 patient days. The median duration of cumulative antibiotic exposure per patient was 24 days (interquartile range IQR 20–30 days). There were 131 days of fever per 1000 patient days with patients febrile for a median of 4 days (IQR 1–7 days). Piperacillin–tazobactam was used for 116 (94%) of patients with an LOT of 532 per 1000 patient days. A total of 119 MDI episodes occurred in 74 (59%) patients, including blood stream infection in 30 (24%) and a proven/probable invasive fungal infection in 4 (3%).
Conclusion
Pediatric HCT patients receive prolonged courses of broad‐spectrum antibiotics relative to the frequency of fever and bacterial infections. This study has identified opportunities for AMS intervention to improve outcomes for our HCT patients.
We report on the Australian experience of blinatumomab for treatment of 24 children with relapsed/refractory precursor B‐cell acute lymphoblastic leukaemia (B‐ALL) and high‐risk genetics, resulting ...in a minimal residual disease (MRD) response rate of 58%, 2‐year progression‐free survival (PFS) of 39% and 2‐year overall survival of 63%. In total, 83% (n = 20/24) proceeded to haematopoietic stem cell transplant, directly after blinatumomab (n = 12) or following additional salvage therapy (n = 8). Four patients successfully received CD19‐directed chimeric antigen receptor T‐cell therapy despite prior blinatumomab exposure. Inferior 2‐year PFS was associated with MRD positivity (20%, n = 15) and in KMT2A‐rearranged infants (15%, n = 9). Our findings highlight that not all children with relapsed/refractory B‐ALL respond to blinatumomab and factors such as blast genotype may affect prognosis.
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