Issue Archive

This Review Series highlights the transformative impact of tyrosine kinase inhibitors (TKIs) on therapy for chronic myeloid leukemia (CML) in the last 25 years. Brian J. Druker introduces the series by providing a Perspective that recalls the initial presentation at the 1999 American Society of Hematology annual meeting, revealing a 100% response rate at effective doses of imatinib in the phase 1 study. Guilhot and Hehlmann review long-term outcomes of patients with CML treated with TKIs in major studies and note that survival of patients with CML now approaches that of the general population. Hughes et al address the issue of treatment-free remission and explore the criteria for safely discontinuing TKIs for select patients. Finally, Cruz-Rodriguez and Deininger discuss mechanisms of resistance, emerging therapeutic strategies, and the promise of BCR::ABL1 degraders and TKI combinations.

Modakafusp alfa is a new immunocytokine-based immunotherapy composed of humanized anti-CD38 immunoglobulin G4 antibody and 2 interferon alfa-2b molecules designed to target delivery of interferon alfa to CD38⁺ immune and myeloma cells. Vogl et al report the results of a first-in-human study of modakafusp alfa in patients with relapsed or refractory multiple myeloma with ≥3 prior lines of treatment and show feasibility and safety with an overall response rate of 43.3%, a median duration of response of 15.1 months and median progression-free survival of 5.7 months. Although clinical development of this agent has been halted, its dual mechanism directly affecting myeloma cells while simultaneously enhancing immune effector activity suggests potential utility in combination strategies.

Although CD19 chimeric antigen receptor (CAR) T-cell therapies have impressive response rates, a significant number of patients relapse. Koh and colleagues show that cotreatment with anti-CD19 antibody induced rapid detachment of anti-CD19 CAR T and natural killer (NK) cells from target cells, mitigating trogocytosis and thereby improving their serial-killing capacity and overall antitumor activity. This study adds to the growing evidence that competition for CD19 binding can modulate CAR T-cell activation and enhance functionality, but clinical testing is needed to investigate optimized antibody clones and dosing strategies.

Neutrophil gelatinase-associated lipocalin (NGAL) is a protein primarily secreted by immune cells, including neutrophils, macrophages, and dendritic cells, in response to inflammation and is associated with cardiovascular disease. Xue et al show that NGAL is a mediator of hypercoagulability, promoting clot formation through multiple mechanisms and that NGAL deficiency in mice results in a hemophilia phenotype with reduced thrombosis. These findings suggest that modulating NGAL levels could potentially help balance thrombotic and hemorrhagic risks.

A clinical challenge is distinguishing whether hypercalcemia in monoclonal gammopathy of undetermined significance (MGUS) signals progression to multiple myeloma (MM) or is due to other unrelated conditions. Jónsdóttir and colleagues leveraged the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study, a large population-based cohort with rigorous ongoing longitudinal data collection. The authors showed that hypercalcemia in MGUS, in the absence of other end-organ damage (anemia, renal failure, osteolytic bone lesions), was rarely due to progression to MM. Therefore, in the absence of other MM-related features, isolated hypercalcemia in MGUS should be evaluated and treated like hypercalcemia in the general population.

This Review Series highlights the transformative impact of tyrosine kinase inhibitors (TKIs) on therapy for chronic myeloid leukemia (CML) in the last 25 years. Brian J. Druker introduces the series by providing a Perspective that recalls the initial presentation at the 1999 American Society of Hematology annual meeting, revealing a 100% response rate at effective doses of imatinib in the phase 1 study. Guilhot and Hehlmann review long-term outcomes of patients with CML treated with TKIs in major studies and note that survival of patients with CML now approaches that of the general population. Hughes et al address the issue of treatment-free remission and explore the criteria for safely discontinuing TKIs for select patients. Finally, Cruz-Rodriguez and Deininger discuss mechanisms of resistance, emerging therapeutic strategies, and the promise of BCR::ABL1 degraders and TKI combinations.

This Review Series highlights the transformative impact of tyrosine kinase inhibitors (TKIs) on therapy for chronic myeloid leukemia (CML) in the last 25 years. Brian J. Druker introduces the series by providing a Perspective that recalls the initial presentation at the 1999 American Society of Hematology annual meeting, revealing a 100% response rate at effective doses of imatinib in the phase 1 study. Guilhot and Hehlmann review long-term outcomes of patients with CML treated with TKIs in major studies and note that survival of patients with CML now approaches that of the general population. Hughes et al address the issue of treatment-free remission and explore the criteria for safely discontinuing TKIs for select patients. Finally, Cruz-Rodriguez and Deininger discuss mechanisms of resistance, emerging therapeutic strategies, and the promise of BCR::ABL1 degraders and TKI combinations.

This Review Series highlights the transformative impact of tyrosine kinase inhibitors (TKIs) on therapy for chronic myeloid leukemia (CML) in the last 25 years. Brian J. Druker introduces the series by providing a Perspective that recalls the initial presentation at the 1999 American Society of Hematology annual meeting, revealing a 100% response rate at effective doses of imatinib in the phase 1 study. Guilhot and Hehlmann review long-term outcomes of patients with CML treated with TKIs in major studies and note that survival of patients with CML now approaches that of the general population. Hughes et al address the issue of treatment-free remission and explore the criteria for safely discontinuing TKIs for select patients. Finally, Cruz-Rodriguez and Deininger discuss mechanisms of resistance, emerging therapeutic strategies, and the promise of BCR::ABL1 degraders and TKI combinations.