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.

We studied 459 consecutive patients with hematologic malignancies, median age 44 years (range, 15 to 71 years), who underwent transplantation with grafts from identical sibling donors (SIB; n = 176), matched unrelated donors (MUD; n = 43), mismatched unrelated donors (mmUD; n = 43), unrelated cord blood (UCB; n = 105) or HLA-haploidentical family donors (HAPLO; n = 92). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate in the SIB recipients; antithymocyte globulin for the MUD, mmUD, and UCB recipients; and post-transplantation cyclophosphamide, cyclosporine, and mycophenolate in the HAPLO recipients. Conditioning regimens were mostly myeloablative (69%). Advanced disease phase was more frequent, but not significantly so, in the HAPLO and mmUD groups (P = .08). Acute GVHD grade II-IV was significantly less frequent in the HAPLO, UCB, and MUD groups (14% to 21%) compared with the SIB (31%) and mmUD (42%) groups (P < .001), and there was a trend toward less moderate-severe chronic GVHD in the HAPLO and UCB groups (P = .053). The proportion of patients off cyclosporine at 1 year ranged from 55% for the SIB group to 81% for the HAPLO group (P < .001). Transplantation-related mortality at 2 years was lower in the HAPLO and SIB groups (18% to 24%) compared with the MUD, mmUD, and UCB groups (33% to 35%; P = .10). Relapse rate was comparable in the 5 groups (P = .80). The 4-year actuarial survival was 45% in the SIB group, 43% in the MUD group, 40% in the mmUD group, 34% in the UCB group, and 52% in the HAPLO group (P = .10). In multivariate analysis, advanced disease was a negative predictor of survival (hazard ratio [HR], 2.4; P < .0001), together with a diagnosis of acute leukemia (HR, 1.8; P = .0001); HAPLO grafts were comparable to SIB (P = .80), whereas UCB had inferior survival (P = .03). In conclusion, unmanipulated haploidentical family donor transplants are an additional option for patients lacking a matched sibling donor.

Twenty-six patients with advanced Hodgkin's disease received a related HLA haploidentical unmanipulated BMT, following a nonmyeloablative conditioning with low-dose TBI, proposed by the Baltimore group; GvHD prophylaxis consisted of high-dose posttransplantation CY (PT-CY), mycophenolate and a calcineurin inhibitor. All patients had received a previous autograft, and 65% had active disease at the time of BMT. Sustained engraftment of donor cells occurred in 25 patients (96%), with a median time to neutrophil recovery (40.5 Â 10 9 /L) and platelet recovery (420 Â 10 9 /L) of þ 18 and þ 23 days from BMT. The incidence of grade II-IV acute GVHD and of chronic GVHD was 24% and 8%, respectively. With a median follow-up of 24 months (range 18-44) 21 patients are alive, 20 disease free. The cumulative incidence of TRM and relapse was 4% and 31%, respectively. The actuarial 3-year survival is 77%, the actuarial 3-year PFS is 63%. In conclusion, we confirm that high-dose PT-CY is effective as prophylaxis of GVHD after HLA haploidentical BMT, can prevent rejection and does not appear to eliminate the allogeneic graft versus lymphoma effect.

This is a report of 148 patients with hematologic malignancies who received an unmanipulated haploidentical bone marrow transplant (BMT), followed by post-transplant high-dose cyclophosphamide (PT-CY). All patients received a myeloablative conditioning consisting of thiotepa, busulfan, fludarabine (n = 92) or TBI, fludarabine (n = 56). The median age was 47 years (17-74); 47 patients were in first remission (CR1), 37 in second remission (CR2) and 64 had an active disease; all patients were first grafts. The diagnosis was acute leukemia (n = 75), myelodisplastic syndrome (n = 24), myelofibrosis (n = 16), high-grade lytmphoma (n = 15) and others (n = 18). GVHD prophylaxis consisted in PT-CY on days +3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1). The median day for neutrophil engraftment was day +18 (13-32). The cumulative incidence of grades II-IV acute GVHD was 24%, and of grades III-IV GVHD 10%. The incidence of moderate-severe chronic GVHD was 12%. With a median follow-up for the surviving patients of 313 days (100-1162), the cumulative incidence of transplant-related mortality (TRM) is 13%, and the relapse-related death is 23%. The actuarial 22 months overall survival is 77% for CR1 patients, 49% for CR2 patients and 38% for patients grafted in relapse (P o0.001). Major causes of death were relapse (22%), GVHD (2%) and infections (6%). We confirm our initial results, suggesting that a myeloablative conditioning regimen followed by unmanipulated haploidentical BMT with PT-CY, results in a low risk of acute and chronic GVHD and encouraging rates of TRM and overall survival, also for patients with active disease at the time of transplant.Bone Marrow Transplantation (2015) 50, S37-S39; doi:10.1038/bmt.2015.93 PATIENTS AND METHODSClinical characteristics are outlined in Table 1. All patients received a myeloablative regimen with post-transplant cyclophosphamide, between august 2010 and January 2014. A total of 64 patients had an active disease at transplant; 46 were in first remission (CR1) and 39 in second remission (CR2) hematologic remission. The most common diagnosis was acute leukemia (n = 76 ), 48 AML (27% with active disease) and 24 ALL (32% with active disease). Most of the patients with non-Hodgkin lymphoma (60%) also had advanced disease, as well as patients with myelofibrosis. DonorsAll donor/patient pairs were genotypically haplomismatched. A single patient, because of HLA homozigosity, had 0 mismatches in the graft vs host direction and three mismatched in the host vs graft direction. Conditioning regimenThe myeloablative conditioning regimen was based either on chemotherapy-thiotepa, busulfan, fludarabine-or TBI and fludarabine: 92 patients received the thiotepa, busulfan, fludarabine regimen which included thiotepa 5 mg/kg on days − 6 and − 5 (total dose 10 mg/kg), fludarabine 50 mg/m 2 on days − 4, − 3 and − 2 (total dose 150 mg/m 2 ), and busulfan 3,2 mg/kg IV on days − 4, − 3, − 2 (total dose 9,6 mg/kg). Fifty-six patients received the TBI and fludarabine regimen, which incl...

SummaryWe assessed WT1 expression (expressed as messenger copies/10 4 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 < 0Á0001). Similarly, actuarial 5-year survival (OS) was 40% vs. 63%, respectively (P = 0Á03). In multivariate Cox analysis, WT1 expression post-HSCT was the strongest predictor of relapse (Hazard Ratio [HR] 4Á5, P = 0Á0001), independent of disease phase (HR 2Á3, P = 0Á002). 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 = 0Á004). 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.

HBsAg-negative/HBcAb-positive haematopoietic stem cell transplant (HSCT) recipients are at high risk of hepatitis B virus (HBV) reactivation. Allogeneic HSCT recipients from years 2000 to 2010 were evaluated in order to study the impact of being HBsAg-negative/HBcAb-positive in this population. Overall, 137 of 764 patients (18%) were HBsAg-negative/HBcAb-positive before HSCT. Overall survival, non-relapse mortality (NRM), acute and chronic graft-vs.-host disease were similar in HBcAb-positive and HBcAb-negative patients. Reactivation occurred in 14 patients (10%) within a median of 19 months after HSCT (range 9-77). Cause-specific hazard for reactivation was decreased in the case of an HBV-immune/exposed donor (HRadjusted = 0.12; 95% CI, 0.02-0.96; p 0.045) and increased in patients who received rituximab treatment (HRadjusted = 2.91; 95%CI, 0.77-10.97; p 0.11). Competing risk analyses documented a protective role of an HBV-immune/exposed donor (p 0.041) and an increased probability associated with the length of treatment with cyclosporine (p <0.001) and treatment with rituximab (but not with low-dose rituximab prophylaxis, p <0.001 at each landmark point). No differences in overall survival and NRM were found between patients with and without HBV reactivation. The donor's immunity was independently and consistently associated with a decreased risk of HBV reactivation, while rituximab and cyclosporine treatments increased the probability.

Viral respiratory tract infections (VRTI) are an important cause of morbidity and mortality in haematology patients, particularly after haematopoietic stem cell transplantation (HSCT). The incidence, clinical presentation and outcome of symptomatic and asymptomatic VRTI in HSCT outpatient unit were prospectively evaluated during a single influenza season (January-March 2011). Pharyngeal swabs were performed at the first visit and if new symptoms were present. Molecular multiplex assay for 12 respiratory viruses was performed by the regional reference laboratory. Among 264 swabs from 193 outpatients, 58 (22 %) resulted positive for 61 viruses (influenza, n = 20; respiratory syncytial virus [RSV], n = 21; rhinovirus, n = 12; coronavirus, n = 4; adenovirus, n = 3; parainfluenza, n = 1). VRTI were detected more frequently in the presence of symptoms than in asymptomatic patients: 49 out of 162 (30 %) vs. 9 out of 102 (9 %), p < 0.001. Influenza-like illness syndrome (ILI) was significantly associated with a VRTI if compared to other presentations (42 %), while the European Centre for Disease Prevention and Control definition was not (30 %). Positive predictive value (PPV) of ILI for influenza was 17 %. Influenza and RSV peak periods were contemporary. Influenza prophylaxis was given to 25 patients following exposure. Low rate of progression from upper to lower respiratory tract infection (approximately 5 % for influenza and RSV), no nosocomial epidemics and no VRTI-related deaths were observed. VRTI are very frequent in high-risk haematology outpatients, but symptoms are aspecific and PPV of ILI is low. Symptoms of influenza and RSV overlap. Thus, microbiological diagnosis and contact preventive measures are crucial. Rather than universal influenza prophylaxis, prompt diagnosis and treatment of only documented infections could be pursued.

BackgroundImatinib mesylate is the first line treatment for chronic myeloid leukemia. In patients with advanced phase of the disease, the advent of imatinib significantly increased survival. However, few long-term data, based on large, prospective and controlled trials are available on the outcome of these patients. Design and MethodsWe conducted a phase II trial of imatinib 600 mg daily in patients with chronic myeloid leukemia in blast crisis. The return to chronic phase was defined as <15% blasts and <30% blasts plus promyelocytes in blood or bone marrow and <20% peripheral basophils. A complete hematologic response required the normalization of platelet and white cell differential counts and absence of extramedullary involvement. Cytogenetic response was assessed by the standard banding technique and rated as usual. ResultsNinety-two patients were enrolled (20 with lymphoid blast crisis and 72 with myeloid blast crisis). Forty-six patients (50%) returned to chronic phase, and 24 patients (26%) achieved also a complete hematologic response. Sixteen patients (17%) had a cytogenetic response (9 complete, 1 partial, and 6 minor or minimal). The complete cytogenetic response was subsequently lost by all but two patients between 2 and 12 months after first having achieved it: the median duration of complete cytogenetic response was 7 months. All responses were sustained for a minimum of 4 weeks. The median survival of all the patients was 7 months. After a median observation time of 66 months, seven (8%) patients are alive. Three of these patients are on imatinib treatment (1 in complete hematologic remission, 1 in partial cytogenetic response and 1 in complete cytogenetic remission). Three patients are in complete remission after allogeneic stem cell transplantation. One patient is alive in blast crisis, on therapy with a second-generation tyrosine kinase inhibitor. ConclusionsImatinib was effective and safe in the short-term treatment of chronic myeloid leukemia in blast crisis, but longer-term outcome was not significantly influenced (ClinicalTrials.gov identifier: NCT00514969). Key words: chronic myeloid leukemia, blast crisis, imatinib, outcome, long-term.Citation: Palandri F, Castagnetti F, Testoni N, Luatti S, Marzocchi G, Bassi S, Breccia M, Alimena G, Pungolino E, Rege-Cambrin G, Varaldo R, Miglino M, Specchia G, Zuffa E, Ferrara F, Bocchia M, Saglio G, Pane F, Alberti D, Martinelli G, Baccarani M, and Rosti G on follow-up. Haematologica 2008; 93:1792-1796 This is an open-access paper.Chronic myeloid leukemia in blast crisis treated with imatinib 600 mg: outcome of the patients alive after a 6-year follow-up © F e r r a t a S t o r t i F o u n d a t i o n IntroductionBlast crisis (BC) is the terminal phase of chronic myeloid leukemia (CML), a clonal myeloproliferative disease characterized by a reciprocal t(9;22)(q34;q11) chromosomal translocation, which creates the Philadelphia chromosome (Ph) and leads to the expression of the BCR-ABL fusion protein, whose deregulated constitutive tyrosi...