Simona Geroldi

Unmanipulated Haploidentical Bone Marrow Transplantation and Posttransplantation Cyclophosphamide for Hematologic Malignancies after Myeloablative Conditioning

Fifty patients with high-risk hematologic malignancies, underwent an unmanipulated haploidentical bone marrow transplantation (BMT), followed by posttransplantation high-dose cyclophosphamide (PT-CY): the myeloablative (MA) conditioning consisted of thiotepa, busulfan, fludarabine (n = 35), or total body irradiation (TBI), fludarabine (n = 15). The median age was 42 years (range, 18-66 years); 23 patients were in remission, 27 had active disease, and 10 patients were receiving a second allograft. Graft-versus-host disease (GVHD) prophylaxis consisted in PT-CY on day +3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1). Three patients died before engraftment, and 2 patients had autologous recovery: 45 patients (90%) had full-donor chimerism on day +30. The median day for neutrophil engraftment was day +18 (range, 13-30 days). The cumulative incidence of grade II-III acute GVHD (aGVHD) was 12%, and of moderate chronic GVHD (cGVHD) 10%. With a median follow-up for surviving patients of 333 days (range, 149-623 days), the cumulative incidence of transplantation-related mortality (TRM) was 18%, and the rate of relapse was 26%. The actuarial 22-month disease-free survival (DFS) rate was 68% for patients in remission and 37% for patients with active disease (P < .001). Causes of death were pneumonia (n = 3), hemorrhage (n = 3), sepsis (n = 3), and relapse (n = 7). In conclusion, an MA conditioning regimen followed by haploidentical BMT with PT-CY results in a low risk of aGVHD and cGVHD and encouraging rates of TRM and DFS.

Allogeneic hemopoietic SCT for patients with primary myelofibrosis: a predictive transplant score based on transfusion requirement, spleen size and donor type

A total of 46 patients with primary myelofibrosis (PMF) (median age 51 years), underwent an allogeneic hemopoietic SCT (HSCT) after a thiotepa-based reduced-intensity conditioning regimen. The median follow-up for surviving patients is 3.8 years. In multivariate analysis, independent unfavorable factors for survival were RBC transfusions >20, a spleen size >22 cm and an alternative donor—24 patients had 0–1 unfavorable predictors (low risk) and 22 patients had 2 or more negative predictors (high risk). The overall actuarial 5-year survival of the 46 patients is 45%. The actuarial survival of low-risk and high-risk patients is, respectively, 77 and 8% (P<0.0001); this is because of a higher TRM for high-risk patients (RR, 6.0, P=0.006) and a higher relapse-related death (RR, 7.69; P=0.001). In multivariate Cox analysis, the score maintained its predictive value (P=0.0003), even after correcting for donor–patient age and gender, Dupriez score, IPSS (International Prognostic Scoring System) score pre-transplant and splenectomy. In conclusion, PMF patients undergoing an allogeneic HSCT may be scored according to the spleen size, transfusion history and donor type; this scoring system may be useful to discuss transplant strategies.

In vivo B-cell depletion with rituximab for alternative donor hemopoietic SCT

We retrospectively analyzed 55 patients given a fixed dose of rituximab (200 mg) on day+5 after an alternative donor transplant, to prevent EBV DNA-emia; 68 alternative transplants who did not receive prophylactic rituximab served as controls. The two groups were comparable for donor type, and all patients received anti-thymocyte globulin in the conditioning regimen. Rituximab patients had a significantly lower rate of EBV DNA-emia 56 vs 85% (P=0.0004), a lower number of maximum median EBV copies (91 vs 1321/105 cells, P=0.003) and a significantly lower risk of exceeding 1000 EBV copies per 105cells (14 vs 49%, P=0.0001). Leukocyte and lymphocyte counts were lower on day +50 and+100 in rituximab patients, whereas Ig levels were comparable. The cumulative incidence of grade II–IV acute GvHD was significantly reduced in rituximab patients (20 vs 38%, P=0.02). Chronic GvHD was comparable. There was a trend for a survival advantage for patients receiving rituximab (46 vs 40%, P=0.1), mainly because of lower transplant mortality (25 vs 37%, P=0.1). Despite the drawback of a retrospective study, these data suggest that a fixed dose of rituximab on day +5 reduces the risk of a high EBV load, and also reduces acute GvHD.

Leukaemia relapse after allogeneic transplants for acute myeloid leukaemia: predictive role of WT1 expression

We assessed WT1 expression (expressed as messenger copies/104 ABL1) from marrow cells of 122 patients with acute myeloid leukaemia (AML), before and after an unmanipulated allogeneic haemopoietic stem cell transplant (HSCT). The median age was 44 years (15–69), 59% were in first remission, 74% received a myeloablative conditioning regimen and the median follow up was 865 d (34–2833). Relapse was higher in 67 patients with WT1 expression, at any time post‐HSCT, exceeding 100 copies (54%), as compared to 16%, for 55 patients with post‐HSCT WT1 expression <100 copies (P < 0·0001). Similarly, actuarial 5‐year survival (OS) was 40% vs. 63%, respectively (P = 0·03). In multivariate Cox analysis, WT1 expression post‐HSCT was the strongest predictor of relapse (Hazard Ratio [HR] 4·5, P = 0·0001), independent of disease phase (HR 2·3, P = 0·002). Donor lymphocyte infusions (DLI) were given to 17 patients because of increasing WT1 levels: their OS was 44%, vs. 14% for 21 patients with increasing WT1 expression who did not receive DLI (P = 0·004). In conclusion, WT1 expression post‐HSCT is a strong predictor of leukaemia relapse and survival in AML; WT1 may be used as a marker for early interventional therapy.

Systemic lupus erythematosus complicated with thymoma and pure red cell aplasia (PCRA). CR of both complications following thymectomy and allogeneic haematopoietic SCT (HSCT), but persistence of antinuclear antibodies (ANA)

Systemic lupus erythematosus complicated with thymoma and pure red cell aplasia (PCRA). CR of both complications following thymectomy and allogeneic haematopoietic SCT (HSCT), but persistence of antinuclear antibodies (ANA)

Impact of HLA Disparity in Haploidentical Bone Marrow Transplantation Followed by High-Dose Cyclophosphamide

We studied the impact of HLA mismatching on the outcome of 318 consecutive patients who received an unmanipulated haploidentical bone marrow transplant, followed by post-transplant cyclophosphamide (PTCy). The number of HLA-mismatched antigens was tested for its impact on overall survival (OS) and nonrelapse mortality (NRM), whereas HLA mismatches in the graft-versus-host (GVH) direction were tested for prediction of graft-versus-host disease (GVHD and relapse. Finally, we studied whether graft rejection correlated with the number of HLA mismatched antigens in host-versus-graft (HVG) direction. Two hundred thirty-one donor-recipient pairs (72%) had 4/8 mismatches at the -A, -B, -C, -DRB1 HLA loci. HLA mismatches did not predict the 2-year OS (hazard ratio, .83; P = .58) and NRM (subhazard ratio, 1.08; P = .93). The cumulative incidence of acute GVHD (P = .13), 1-year chronic GVHD (P = .84), and relapse rate (P = .26) did not correlate with univectorial GVH mismatches. Similarly, no correlation was observed between the amount of HLA mismatch in the HVG direction and graft rejection. In multivariate analysis advanced disease at transplant was the strongest predictor of survival, NRM, relapse, and graft rejection. In conclusion, the degree of HLA mismatching should not be used as a criterion to select family haploidentical donors when using bone marrow as stem cell source and PTCy for GVHD prophylaxis.