Faculty Bibliography

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with unmanipulated grafts is increasingly adopted for high-risk acute leukemia, with acute graft-versus-host disease (aGVHD) prophylaxis based on antithymocyte globulin (ATG) or posttransplant cyclophosphamide (PTCy) as main platforms. No consensus exists on selection criteria over several haploidentical donors. We evaluated the impact of donor-recipient antigenic and allelic HLA-A, -B, -C, and -DRB1 mismatches on mismatched haplotype on outcomes of 509 unmanipulated haplo-HSCTs performed for acute leukemia under a PTCy (N = 313) or ATG (N = 196) regimen. An antigenic but not allelic mismatch at the HLA-DRB1 locus was an independent risk factor for grade ≥2 aGVHD in PTCy (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.2-4.0; P = .02) but not in ATG regimens (HR, 1.3; 95% CI, 0.4-3.4; P = .6). Moreover, the hazards of aGVHD were significantly associated with other factors influencing alloreactivity, including peripheral blood as stem cell source (HR, 2.2; 95% CI, 1.4-3; P < .01), reduced-intensity conditioning (HR, 0.6; 95% CI, 0.4-0.9; P = .04), and female donors (HR, 1.8; 95% CI, 1-3.2; P = .05), in PTCy but not ATG regimens. No significant associations were found between cumulative number of HLA mismatches and GVHD, or between HLA-matching status and other study end points including transplant-related mortality, disease-free survival, and relapse. Based on these data, the role of HLA mismatching on unshared haplotype appears not to be sufficiently prominent to justify its consideration in haploidentical donor selection. However, the role of HLA matching in haploidentical HSCT might be modulated by GVHD prophylaxis, calling for further investigations in this increasingly relevant field.

Major improvements have been made in the treatment of myeloma. However, all patients, perhaps with some exceptions, eventually relapse, even after autologous stem cell transplantation (ASCT). In that setting, the combinations of new drugs, namely the IMiDs and the proteasome inhibitors along with steroids, give encouraging results in relapsed patients. The median progression-free survival (PFS) is 20 months with lenalidomide plus dexamethasone plus ixazomib and 26 months with lenalidomide plus dexamethasone plus carfilzomib. Monoclonal antibodies have emerged as an additional new treatment option. The antibody anti-SLAMF7, elotuzumab, in combination with lenalidomide plus dexamethasone gives a median PFS of 20 months. The antibody daratumumab, targeting CD38, alone has an outstanding activity in previously heavily treated patients. Its use in combination is ongoing. Transplantation remains a major treatment option. For patients who relapse at least 18 months from the initial ASCT, a second ASCT can be performed with an expected time to progression of 19 months from the time of transplantation. For patients relapsing earlier and/or with high-risk characteristics and who are still chemosensitive, with a suitable donor, an allogeneic transplantation can be considered. The optimal treatment combination and sequence remain to be determined.

Carbapenem resistance has evolved rapidly since 2001 and the distribution of Carbapenemase-producing Klebsiella pneumoniae (CR-Kp) is currently a public health concern worldwide. In the haematological setting, especially in allogenic transplant, CR-KP infections were associated with a mortality up to 65%. Aim of this report is to describe the management of patients colonized by CR-Kp and undergoing allo- HSCT with a multiple-step intervention strategy: the "Turin bundle". Steps included oral gentamicin (GO) within 20 days before allo-HSCT, avoidance of levofloxacin prophylaxis during neutropenia, treatment of febrile neutropenia with tigecycline 100 mg bid and piperacillin-tazobactam at standard dosages and early appropriate combination therapy for patients with severe sepsis. In our small series all patients survived, no resistance to oral gentamicin was observed and 60% of patients had negative rectal swabs after transplant.

Neurologic complications after hematopoietic stem cell transplantation are frequently life-threatening, and their clinical management can be highly challenging. A wide spectrum of causative factors-including drug-related toxicities; infections sustained by virus, bacteria, or invasive molds; metabolic encephalopathy; cerebrovascular disorders; immune-mediated disorders; and disease recurrence-may lead to potentially lethal complications. Moreover, given that some neurologic complications are not uncommonly diagnosed post mortem, their overall incidence is likely to be underestimated. Their prompt recognition and timely treatment are of paramount importance to reduce the risk for transplantation-related death.

Severe graft-versus-host disease is a major barrier for non-T-cell-depleted haploidentical stem cell transplantation. There is no consensus on the optimal graft-versus-host disease prophylaxis. This study compared the two most commonly used graft-versus-host disease prophylaxis regimens (post-transplant cyclophosphamide-based vs. the anti-thymocyte globulin-based) in adults with acute myeloid leukemia reported to the European Society for Blood and Bone Marrow Transplantation. A total of 308 patients were analyzed; 193 received post-transplant cyclophosphamide-based regimen and 115 anti-thymocyte globulin-based regimen as anti-graft-versus-host disease prophylaxis. The post-transplant cyclophosphamide-based regimen was more likely to be associated to bone marrow as graft source (60% vs. 40%; P=0.01). Patients in the post-transplant cyclophosphamide-based regimen group had significantly less grade 3-4 acute graft-versus-host disease than those in the anti-thymocyte globulin-based group (5% vs. 12%, respectively; P=0.01), comparable to chronic graft-versus-host disease. Multivariate analysis showed that non-relapse mortality was lower in the post-transplant cyclophosphamide-based regimen group [22% vs. 30%, Hazard ratio (HR) 1.77(95%CI: 1.09-2.86); P=0.02] with no difference in relapse incidence. Patients receiving post-transplant cyclophosphamide-based regimen had better graft-versus-host disease-free, relapse-free survival [HR 1.45 (95%CI: 1.04-2.02); P=0.03] and leukemia-free survival [HR 1.48 (95%CI: 1.03-2.12); P=0.03] than those in the anti-thymocyte globulin-based group. In the multivariate analysis, there was also a trend for a higher overall survival [HR 1.43 (95%CI: 0.98-2.09); P=0.06] for post-transplant cyclophosphamide-based regimen versus the anti-thymocyte globulin-based group. Notably, center experience was also associated with non-relapse mortality and graft-versus-host disease-free, relapse-free survival. Haplo-SCT using a post-transplant cyclophosphamide-based regimen can achieve better leukemia-free survival and graft-versus-host disease-free, relapse-free survival, lower incidence of graft-versus-host disease and non-relapse mortality as compared to anti-thymocyte globulin-based graft-versus-host disease prophylaxis in patients with acute myeloid leukemia.

Transformed plasma cells in multiple myeloma (MM) are susceptible to natural killer (NK) cell-mediated killing via engagement of tumor ligands for NK activating receptors or "missing-self" recognition. Similar to other cancers, MM targets may elude NK cell immunosurveillance by reprogramming tumor microenvironment and editing cell surface antigen repertoire. Along disease continuum, these effects collectively result in a progressive decline of NK cell immunity, a phenomenon increasingly recognized as a critical determinant of MM progression. In recent years, unprecedented efforts in drug development and experimental research have brought about emergence of novel therapeutic interventions with the potential to override MM-induced NK cell immunosuppression. These NK-cell enhancing treatment strategies may be identified in two major groups: (1) immunomodulatory biologics and small molecules, namely, immune checkpoint inhibitors, therapeutic antibodies, lenalidomide, and indoleamine 2,3-dioxygenase inhibitors and (2) NK cell therapy, namely, adoptive transfer of unmanipulated and chimeric antigen receptor-engineered NK cells. Here, we summarize the mechanisms responsible for NK cell functional suppression in the context of cancer and, specifically, myeloma. Subsequently, contemporary strategies potentially able to reverse NK dysfunction in MM are discussed.