Clonal hematopoiesis and its emerging effects on cellular therapies

The accumulation of somatic mutations in hematopoietic stem cells during aging, leading to clonal expansion, is linked to a higher risk of cardiovascular mortality and hematologic malignancies. Clinically, clonal hematopoiesis is associated with a pro-inflammatory phenotype of hematopoietic cells and their progeny, inflammatory conditions and a poor outcome for patients with hematologic neoplasms and solid tumors. Here, we review the relevance and complications of clonal hematopoiesis for the treatment of hematologic malignancies with cell therapeutic approaches. In autologous and allogeneic hematopoietic stem cell transplantation native hematopoietic and immune effector cells of clonal origin are transferred, which may affect outcome of the procedure. In chimeric antigen receptor modified T-cell therapy, the effectiveness may be altered by preexisting somatic mutations in genetically modified effector cells or by unmodified bystander cells harboring clonal hematopoiesis. Registry studies and carefully designed prospective trials will be required to assess the relative roles of donor- and recipient-derived individual clonal events for autologous and allogeneic cell therapies and to incorporate novel insights into therapeutic strategies

Half-dose glucarpidase as efficient rescue for toxic methotrexate levels in patients with acute kidney injury

Purpose!#!High-dose methotrexate (HDMTX)-associated acute kidney injury with delayed MTX clearance has been linked to an excess in MTX-induced toxicities. Glucarpidase is a recombinant enzyme that rapidly hydrolyzes MTX into non-toxic metabolites. The recommended dose of glucarpidase is 50 U/kg, which has never been formally established in a dose finding study in humans. Few case reports, mostly in children, suggest that lower doses of glucarpidase might be equally effective in lowering MTX levels.!##!Methods!#!Seven patients with toxic MTX plasma concentrations following HDMTX therapy were treated with half-dose glucarpidase (mean 25 U/kg, range 17-32 U/kg). MTX levels were measured immunologically as well as by liquid chromatography-mass spectrometry (LC-MS). Toxicities were assessed according to National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE) v5.0.!##!Results!#!All patients experienced HDMTX-associated kidney injury (median increase in creatinine levels within 48 h after HDMTX initiation compared to baseline of 251%, range 80-455%) and showed toxic MTX plasma concentrations (range 3.1-182.4 µmol/L) before glucarpidase injection. The drug was administered 42-70 h after HDMTX initiation. Within one day after glucarpidase injection, MTX plasma concentrations decreased by ≥ 97.7% translating into levels of 0.02-2.03 µmol/L. MTX rebound was detected in plasma 42-73 h after glucarpidase initiation, but concentrations remained consistent at < 10 µmol/L.!##!Conclusion!#!Half-dose glucarpidase seems to be effective in lowering MTX levels to concentrations manageable with continued intensified folinic acid rescue

Salvage treatment with plerixafor in poor mobilizing allogeneic stem cell donors: results of a prospective phase II-trial

We conducted a prospective clinical trial to investigate the safety and efficacy of plerixafor (P) in allogeneic peripheral blood stem cells (PBSC) donors with poor mobilization response to standard-dose granulocyte colony-stimulating factor (G-CSF), defined by <2 × 1

MRD dynamics during maintenance for improved prognostication of 1280 patients with myeloma in the TOURMALINE-MM3 and -MM4 trials

Measurable residual disease (MRD) evaluation may help to guide treatment duration in multiple myeloma (MM). Paradoxically, limited longitudinal data exist on MRD during maintenance. We investigated the prognostic value of MRD dynamics in 1280 transplant-eligible and -ineligible patients from the TOURMALINE-MM3 and -MM4 randomized placebo-controlled phase 3 studies of 2-year ixazomib maintenance. MRD status at randomization showed independent prognostic value (median progression-free survival [PFS], 38.6 vs 15.6 months in MRD− vs MRD+ patients; HR, 0.47). However, MRD dynamics during maintenance provided more detailed risk stratification. A 14-month landmark analysis showed prolonged PFS in patients converting from MRD+ to MRD− status vs those with persistent MRD+ status (76.8% vs 27.6% 2-year PFS rates). Prolonged PFS was observed in patients with sustained MRD− status vs those converting from MRD− to MRD+ status (75.0% vs 34.2% 2-year PFS rates). Similar results were observed at a 28-month landmark analysis. Ixazomib maintenance vs placebo improved PFS in patients who were MRD+ at randomization (median, 18.8 vs 11.6 months; HR, 0.65) or at the 14-month landmark (median, 16.8 vs 10.6 months; HR, 0.65); no difference was observed in patients who were MRD−. This is the largest MM population undergoing yearly MRD evaluation during maintenance reported to date. We demonstrate the limited prognostic value of a single–time point MRD evaluation, because MRD dynamics over time substantially impact PFS risk. These findings support MRD− status as a relevant end point during maintenance and confirm the increased progression risk in patients converting to MRD+ from MRD− status. These trials were registered at www.clinicaltrials.gov as #NCT02181413 and #NCT02312258