Faculty Bibliography

Haploidentical stem cell transplantation with T cell-replete grafts and post-transplant cyclophosphamide (PTCy) is increasingly used with encouraging outcome. Natural killer (NK) cell alloreactivity, predicted by missing killer cell immunoglobulin-like receptor (KIR) ligands in the recipient that are present in their donor improves outcome of T cell-depleted haploidentical transplants. We explored the role of KIR ligand mismatching in 444 acute leukemia patients after T cell-replete transplants with PTCy. Thirty-seven percent of all patients had KIR ligand mismatching. Patients were in first remission (CR1) (39%), second remission (CR2) (26%), or active disease (35%). Stem cell source was peripheral blood (PBSC, 46%) or bone marrow (54%). The 2-year relapse, non-relapse mortality (NRM), and survival rates were 36.0% (95% confidence interval (CI), 31.4-40.7), 23.9% (20.0-28.0), and 45.9% (40.8-51.0), respectively. Multivariate analysis identified acute myeloid leukemia compared with acute lymphoblastic leukemia (hazard ratio (HR) 0.55, P = 0.002), female gender (HR 0.72, P = 0.04), and good performance status (HR 0.71, P = 0.04) as factors associated with better survival, while advanced age (HR 1.13, P = 0.04), active disease (HR 3.38, P < 0.0001), and KIR ligand mismatching (HR 1.41, P = 0.03) as associated with worse survival. KIR ligand mismatching was associated with a trend for higher relapse but not with graft-versus-host disease or NRM. The KIR ligand-mismatching effect was more prominent in patients given PBSC. In conclusion, there is no evidence that KIR ligand mismatching results in better outcome in the PTCy setting.

BACKGROUND:T cell-replete haploidentical stem cell transplantation (haplo-SCT) is a valid therapeutic option for adult patients with high-risk acute myeloid leukemia (AML) lacking an HLA-matched sibling or unrelated donor. METHOD:We retrospectively analyzed the outcomes of 912 AML patients ≥45 years of age who had undergone haplo-SCT with either myeloablative conditioning (MAC; n = 373) or reduced intensity conditioning (RIC; n = 539) regimens. RESULTS:The median follow-up was 31.1 and 25.7 months for MAC and RIC, respectively. The incidence of relapse and nonrelapse mortality (NRM) were 25.1% versus 28.7% and 31.0% versus 30.3% for MAC and RIC, respectively; 2-year leukemia-free survival (LFS) was 43.9% for MAC versus 41.0% for RIC. In multivariate analysis, the use of MAC versus RIC was not associated with a difference in the outcomes. Results were confirmed in the propensity score-weighted analysis. Disease status and performance status at transplantation were associated with outcomes. Notably, the use of posttransplantation cyclophosphamide was associated with reduced acute graft-versus-host disease (aGVHD) stage III-IV, and NRM and increased overall survival, LFS, and GVHD-free, relapse-free survival. The use of mobilized peripheral blood stem cells was associated with an increased risk of stage II-IV aGVHD. CONCLUSION:No differences were found between MAC and RIC regimens for haplo-SCT in adults with AML who were ≥45 years of age. The type of GVHD prophylaxis, disease status, and performance status were the major predictors of transplantation outcome. These results may serve as the background for randomized study comparing RIC versus MAC for haplo-SCT in adults with AML.

We previously reported initial results in 102 multiple myeloma (MM) patients treated with sequential high-dose melphalan and autologous hematopoietic cell transplantation followed by 200 cGy total body irradiation with or without fludarabine 90 mg/m² and allogeneic hematopoietic cell transplantation. Here we present long-term clinical outcomes among the 102 initial patients and among 142 additional patients, with a median follow up of 8.3 (range 1.0-18.1) years. Donors included human leukocyte antigen identical siblings (n=179) and HLA-matched unrelated donors (n=65). A total of 209 patients (86%) received tandem autologous-allogeneic upfront, while thirty-five patients (14%) had failed a previous autologous hematopoietic cell transplantation before the planned autologous-allogeneic transplantation. Thirty-one patients received maintenance treatment at a median of 86 days (range, 61-150) after allogeneic transplantation. Five-year rates of overall survival (OS) and progression-free survival (PFS) were 54% and 31%, respectively. Ten-year OS and PFS were 41% and 19%, respectively. Overall non-relapse mortality was 2% at 100 days and 14% at five years. Patients with induction-refractory disease and those with high-risk biological features experienced shorter OS and PFS. A total of 152 patients experienced disease relapse and 117 of those received salvage treatment. Eighty-three of the 117 patients achieved a clinical response, and for those, the median duration of survival after relapse was 7.8 years. Moreover, a subset of patients who became negative for minimal residual disease (MRD) by flow cytometry experienced a significantly lower relapse rate as compared with MRD-positive patients (P=0.03). Our study showed that the graft-versus-myeloma effect after non-myeloablative allografting allowed long-term disease control in standard and high-risk patient subsets. Ultra-high-risk patients did not appear to benefit from tandem autologous/allogeneic hematopoietic cell transplantation because of early disease relapse. Incorporation of newer anti-MM agents into the initial induction treatments before tandem hematopoietic cell transplantation and during maintenance might improve outcomes of ultra-high-risk patients. Clinical trials included in this study are registered at: clinicaltrials.gov identifiers: 00075478, 00005799, 01251575, 00078858, 00105001, 00027820, 00089011, 00003196, 00006251, 00793572, 00054353, 00014235, 00003954.

We report a randomized study comparing fludarabine in combination with busulfan (FB) or thiotepa (FT), as conditioning regimen for hematopoietic stem cell transplantation (HSCT) in patients with myelofibrosis. The primary study endpoint was progression-free survival (PFS). Sixty patients were enrolled with a median age of 56 years and an intermediate-2 or high-risk score in 65%, according to the Dynamic International Prognostic Staging System (DIPSS). Donors were HLA-identical sibling (n = 25), matched unrelated (n = 25) or single allele mismatched unrelated (n = 10). With a median follow-up of 22 months (range, 1 to 68 months), outcomes at 2 years after HSCT in the FB arm versus the FT arm were as follows: PFS, 43% versus 55% (P = .28); overall survival (OS), 54% versus 70% (P = .17); relapse/progression, 36% versus 24% (P = .24); nonrelapse mortality (NRM), 21% in both arms (P = .99); and graft failure, 14% versus 10% (P = .96). A better PFS was observed in patients with intermediate-1 DIPSS score (P = .03). Both neutrophil engraftment and platelet engraftment were significantly influenced by previous splenectomy (hazard ratio [HR], 2.28; 95% confidence interval [CI], 1.16 to 4.51; P = .02) and splenomegaly at transplantation (HR, 0.51; 95% CI, 0.27 to 0.94; P = .03). In conclusion, the clinical outcome after HSCT was comparable when using either a busulfan or thiotepa based conditioning regimen.

Physio-pathologic interrelationships between endothelial layer and graft-versus-host disease (GVHD) have been described leading to assess the entity "endothelial GVHD" as the early step for clinical manifestations of acute GVHD. The availability of the CellSearch system has allowed us to monitor Circulating Endothelial Cells (CEC) changes in allogeneic hematopoietic stem cell transplantation (allo-HSCT) as useful tool to help clinicians in GVHD diagnostic definition. We have compared CEC counts generated by an ad hoc designed polychromatic-flowcytometry (PFC) Lyotube with those of the CellSearch system. CEC were counted in parallel at 5 timepoints in 50 patients with malignant hematologic disorders undergoing allo-HSCT (ClinicalTrials.gov, NCT02064972). Spearman rank correlation showed significant association between CEC values at all time points (p = 0.0001). The limits of agreement was demonstrated by Bland Altman plot analysis, showing bias not significant at T1, T3, T4, while at T2 and T5 resulted not estimable. Moreover, Passing Bablok regression analysis showed not significant differences between BD Lyotube and CellSearch system. We show that CEC counts, generated with either the CellSearch system or the PFC-based panel, have a superimposable kinetic in allo-HSCT patients and that both counting procedures hold the potential to enter clinical routine as a suitable tool to assist clinicians in GVHD diagnosis.