In this episode, Prof. Robin Foà and Prof. Filippo Milano are joined by Dr. Joshua A. Hill, infectious disease specialist at Fred Hutchinson Cancer Center in Seattle, to take on one of the most clinically relevant challenges of contemporary hematology: the immune deficiency and infectious risk that accompany increasingly effective cancer therapies. From allogeneic stem cell transplantation to CAR-T cells and bispecific antibodies, the conversation examines how progress in disease control has brought new questions about how to protect patients over the long term. The discussion opens with the evolution of infection prevention in transplantation. Historically, infections, particularly cytomegalovirus (CMV), were a leading cause of early mortality after hematopoietic stem cell transplant, and antiviral prophylaxis with agents such as letermovir has dramatically reduced severe CMV reactivations. The speakers then turn to post-transplant cyclophosphamide (PTCy), which has substantially lowered the incidence of graft-versus-host disease (GVHD) but also affects T-cell function. Registry data from the CIBMTR point to higher rates of viral, bacterial, respiratory,and fungal infections, prompting clinical research into reduced-dose cyclophosphamide, for example from 50 mg/kg to 25 mg/kg, to preserve GVHD protection while limiting immune toxicity. A second axis of the conversation compares prophylaxis strategies across the Atlantic. In the United States, antibacterial prophylaxis with levofloxacin and antifungal prophylaxis with fluconazole are used more systematically, and in centers withlow local resistance, such as Seattle, they can reduce febrile episodes and bacteremia in neutropenic patients. European practice, reflected in the ECIL guidelines, is more conservative: given high rates of bacterial resistance, including to fluoroquinolones, routine antibiotic prophylaxis is consideredineffective and potentially harmful, with a risk of further resistance and disruption of the microbiota. The episode then moves to CAR-T cells and bispecific antibodies, which cause secondary immune deficiency and prolonged cytopenias. Infections account for roughly half of non-relapse deaths and remain relevant up to five years after treatment.With CAR-T, infectious risk is highest early after infusion and then tends to stabilize, whereas with bispecific antibodies repeated dosing may lead to T-cell exhaustion and a viral risk that grows over time. The speakers also discuss a randomized trial of monthly intravenous immunoglobulin (IVIG), started before CAR-T and continued for four months versus placebo, which looks at infection rates and at any effect on CAR-T persistence and efficacy. They further address the “antibiotic dilemma”: broad-spectrum antibiotics before infusion are associated with reduced gut microbiota diversity, more relapses, and poorer survival in lymphoma and myeloma, yet about 75% of CAR-T patients develop fever after infusion, mostly from low-grade cytokine release syndrome, while true bacteremia occurs in only 1–2% of cases. Developing precisionmarkers to separate inflammatory from infectious fever is an important goal. The conversation closes with a historical reflection: diseases such as chronic lymphocytic leukemia, hairy cell leukemia, and multiple myeloma carry intrinsic immune alterations, and these persist even as modern therapies extend survival and spare patients conventional chemotherapy. A thoughtful conversation on why infectious risk must be continually reassessed as hematologic treatment evolves.
