Issue Archive

The pathophysiology of erythropoietic protoporphyria and other protoporphyrias is based on disordered heme synthesis, porphyrin transport, and their effects on the skin and liver. Leaf and Dickey provide a comprehensive guide on how to approach the care of patients with these rare inherited diseases and an update on the recent development of novel therapies.

Despite the recent introduction of ruxolitinib and belumosudil into routine practice, management of patients with advanced chronic graft-versus-host disease (cGVHD) represents a major challenge. In this month’s CME article, Koshy et al report on the results of a phase 2 trial evaluating the T-cell immune modulator abatacept in cGVHD, demonstrating an overall response rate of 58% and a 3-year failure-free survival of 66% in patients with a median of 3 prior lines of therapy. Treatment with abatacept is well tolerated and leads to a durable reduction in prednisone dose, arguing for further evaluation of this drug alone and in combination in future studies.

Maintenance therapy is an indispensable element in the treatment strategy for childhood acute lymphoblastic leukemia (ALL) but may need to evolve as induction and consolidation therapies improve. Guolla and colleagues present a systematic review and meta-analysis of published studies of childhood ALL and show that the survival benefit associated with the use of vincristine (VCR)/steroid pulses in maintenance therapy no longer persists in contemporary trials. These data argue for abandoning VCR/steroid pulses in patients with favorable prognoses.

Bramlett and colleagues identify molecular determinants of hematopoietic clonal expansion in response to the mutation of Tet2 by analyzing preleukemic states in an inducible mouse model. Genetic inactivation of Tet2 does not impact hematopoietic clones uniformly, with marked heterogeneity in expansion over time associated with aberrant expression of RNA splicing factors. Repression of RNA splicing factor Rbm25 triggers clonal expansion of Tet2 knockout hematopoietic cells in vitro and in vivo. These data help explain the heterogeneity of outcome observed in patients with TET2-mutated hematopoiesis.

Through in vitro and in vivo studies in mice and humans, Kaiser et al reveal that the GPIIb/Gα13/c-Src/14-3-3ζ signaling axis downstream of the fibrinogen receptor is required for initiation and maintenance of platelet migration. The authors’ data explain how the tyrosine kinase inhibitor dasatinib increases the risk of inflammation-associated mucosal hemorrhage.

Immune thrombotic thrombocytopenic purpura (iTTP) is mediated by severe ADAMTS13 deficiency due to autoantibodies that increase clearance and reduce function, leading to unusually large and extremely adhesive von Willebrand factor (VWF) multimers and platelet clumping in the microcirculation. Halkidis et al reexamine the mechanism of ADAMTS13 inhibition by 3 pathogenic antibodies using enzyme kinetic assays. The authors’ data support a novel model whereby iTTP antibodies induce an allosteric inhibition of the metalloprotease domain, rather than by influencing binding of VWF to ADAMTS13.