The health impacts of extreme weather and air pollution are expected to worsen into the future. There is growing evidence that vulnerable populations, including pediatric patients with cancer, may be at increased risk. There is limited progress, however, on translating these growing risks into clinical prevention strategies. We describe the utilization of a simple risk communication framework and list resources to help pediatric oncology providers engage in discussion of extreme weather and air pollution with patients to reduce their risk.

Ex-vivo CD34+ selected allogeneic haematopoietic cell transplantation (HCT) provides favourable chronic graft-versus-host disease (GVHD)-free relapse-free survival but is limited by delayed immune reconstitution and early non-relapse mortality. High anti-thymocyte globulin (ATG) exposure after HCT has been associated with delayed CD4+ T-cell immune reconstitution, increased non-relapse mortality, and poor overall survival.

We report the final analysis of a single-centre, phase 2 trial investigating pharmacokinetic model-based ATG (targeting <20 AU × d/mL post-HCT exposure) in participants of any age undergoing ex vivo CD34+ selected allogeneic HCT after myeloablative conditioning for haematological malignancies. Two myeloablative conditioning regimens were used at the discretion of the treating physician: the chemotherapy-based regimen (target cumulative exposure of 65 mg × h/L busulfan, 140 mg/m² melphalan, and 150 mg/m² fludarabine) and a high-dose total-body irradiation-based regimen (included total-body irradiation [1375 cGy], thiotepa [10 mg/kg], and cyclophosphamide [100 mg/kg]). The primary objective was an improvement in CD4+ immune reconstitution (>50 cells per μL at two consecutive timepoints by day +100) in at least 32% of the per protocol population. This study was registered with ClinicalTrials.gov (NCT04872595) and is completed.

Between June 14, 2021, and Nov 28, 2023, we enrolled 59 participants with haematological malignancies. Among evaluable participants (n=56), the median age was 55 years (IQR 30-63), 34 (61%) were male, 22 (39%) were female, 44 (79%) had myeloid malignancies, and 44 (79%) had received chemotherapy-only myeloablative conditioning. The median estimated ATG exposure after HCT was 10 AU × d/mL (IQR 9-11). CD4+ immune reconstitution was reached in 39 (70%) of 56 participants, meeting the study's primary endpoint. The most common grade 3 or worse adverse events were infections (103 [40%] of 259 events) and oral or gastrointestinal events (44 [17%] of 259 events). Grade 5 adverse events occurred in three participants including secondary graft failure (n=1) and multi-organ failure (n=2), with a total of four treatment-related deaths among participants.

These results demonstrate that model-based ATG dosing promotes robust CD4+ immune reconstitution after ex vivo CD34+ selected allogeneic HCT, underscoring the potential of pharmacokinetically guided ATG as a strategy to optimise immune recovery in myeloablative, calcineurin inhibitor-free transplantation for haematological malignancies.

US National Cancer Institute, Memorial Sloan Kettering Cancer Center.

Triplet regimens combining a Bruton's tyrosine kinase inhibitor, B-cell lymphoma 2 inhibitor, and anti-CD20 antibody are among the most effective first-line treatments for chronic lymphocytic leukaemia, but come with substantial toxicity. We investigated whether fixed-duration ibrutinib plus venetoclax, followed by ibrutinib plus obinutuzumab intensification for individuals with residual disease only, could offer a more tailored and less toxic alternative.

HOVON158/NEXT STEP was an open-label, phase 2 study at 17 hospitals in the Netherlands and Denmark. Eligible participants were aged 18 years or older with previously untreated chronic lymphocytic leukaemia, requiring treatment according to the International Workshop on Chronic Lymphocytic Leukemia, with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Participants with complete remission or complete remission with incomplete count recovery and undetectable measurable residual disease (<10^-4 uMRD4) in bone marrow after 15 28-day cycles of oral ibrutinib (420 mg once daily) plus oral venetoclax (5-weekly ramp-up from cycle 4 up to 400 mg once daily) discontinued treatment; all other participants received an additional six cycles of ibrutinib plus obinutuzumab intravenously (1000 mg on days 1, 2, 8, and 15 of cycle 1 and day 1 of cycles 2-6). The primary endpoint was bone marrow uMRD4 complete remission or complete remission with incomplete count recovery 3 months after the end of intensification with ibrutinib plus obinutuzumab in participants who were not in complete remission or who had detectable measurable residual disease (MRD) on ibrutinib plus venetoclax, and analysed according to the modified intention-to-treat principle excluding participants retrospectively deemed ineligible. All participants who received at least one dose of the study drug were included in the safety assessment. This report is the primary endpoint analysis of this trial, which is registered at ClinicalTrials.gov, NCT04639362, and is ongoing.

Between Dec 29, 2020, and Aug 20, 2021, 85 participants were enrolled, 84 of whom were eligible (56 male and 28 female). The intensification group consisted of 55 participants (37 male and 18 female) and the observation group consisted of 17 participants (11 male and six female). 3 months after the end of ibrutinib plus obinutuzumab treatment, 33 (60%; 90% CI 48-71) of 55 participants had bone marrow uMRD4 complete remission or complete remission with incomplete count recovery. The most common grade 3-4 adverse events during ibrutinib plus venetoclax treatment were neutropenia (36 [43%] of 84 participants) and infections (19 [23%] participants), and the most common during ibrutinib plus obinutuzumab treatment were neutropenia and thrombocytopenia (five [10%] of 52 participants) and nervous system disorders (4 [8%] participants). Serious adverse events occurred in 28 (33%) participants receiving ibrutinib plus venetoclax and seven (13%) participants receiving ibrutinib plus obinutuzumab. There were no treatment-related deaths.

An intensification strategy guided by response and MRD deepened remissions in individuals with residual disease and spared early responders further treatment. This approach merits further study as an alternative to fixed-duration triplet therapy.

Janssen.

For the Dutch translation of the abstract see Supplementary Materials section.

A 44-year-old male presented with a 19-year history of urinary calculi and a 1-year history of polydipsia and weight loss. Laboratory tests revealed hyperparathyroidism and evidence of glucagonoma-associated diabetes. Imaging studies identified masses in the pancreatic head and body/tail, suggestive of glucagonoma and a parathyroid adenoma. Furthermore, the patient exhibited hypercalcitoninemia and elevated cortisol and adrenocorticotropic hormone levels. Genetic testing revealed a heterozygous MEN1 mutation [c.65T>G (p.Leu22Arg)], confirming the diagnosis of multiple endocrine neoplasia type 1 (MEN-1). The patient subsequently underwent near-total parathyroidectomy and total pancreatectomy. Postoperative immunohistochemical staining of the pancreatic tail tumor was positive for glucagon and calcitonin. The patient's postoperative hormone levels (calcitonin, glucagon, adrenocorticotropic hormone, cortisol) normalized, suggesting a rare pancreatic neuroendocrine tumor (pNET) that was co-secreting multiple hormones. Postoperative management included pancreatic enzyme supplementation, calcium supplementation, vitamin D supplementation, and insulin for glycemic control. Follow-up evaluations at 10 months demonstrated a stable clinical condition, well-controlled blood glucose and biochemical parameters, and an acceptable quality of life. This case study highlights that the presence of pNETs should be considered in patients with MEN-1 and multiple abnormal hormone levels. Timely surgical management of the involved glands and postoperative complications can effectively improve prognosis.

In 2005, the Chinese Invasive Fungal Infection Working Group published the first guidelines for the diagnosis and treatment of invasive fungal disease (IFD) in patients with hematological disorders and cancers, with the sixth revision released in 2020. Numerous advances in the fields of hematological oncology treatment and the diagnosis and management of IFD have significantly influenced the corresponding strategies. Therefore, the Chinese Invasive Fungal Infection Working Group has reviewed key research advances from 2020 to 2024 and released the seventh revision of the Chinese guidelines. Major revisions include: changes in the epidemiology of IFD; evaluation of novel diagnostic methods (especially PCR and metagenomic next-generation sequencing); updated recommendations on therapeutic drug monitoring and in vitro drug sensitivity test; management of breakthrough IFD; targeted therapy of Pneumocystis jiroveci pneumonia and cryptococcosis; and updated recommendation on the duration of antifungal therapy.