Raffaella Cerretti

Haploidentical, unmanipulated, G-CSF–primed bone marrow transplantation for patients with high-risk hematologic malignancies

UNLABELLED Eighty patients with high-risk hematologic malignancies underwent unmanipulated, G-CSF–primed BM transplantation from an haploidentical family donor. Patients were transplanted in first or second complete remission (CR, standard-risk: n =45) or in > second CR or active disease (high-risk: n =35). The same regimen for GVHD prophylaxis was used in all cases. The cumulative incidence (CI) of neutrophil engraftment was 93% 0.1%. The 100-day CIs for II-IV and III-IV grade of acute GVHD were 24% 0.2% and 5% 0.6%, respectively. The 2-year CI of extensive chronic GVHD was 6% 0.1%. The 1-year CI of treatment-related mortality was 36% 0.3%. After a median follow-up of 18 months, 36 of 80 (45%) patients are alive in CR. The 3-year probability of overall and disease-free survival for standard-risk and high-risk patients was 54% 8% and 33% 9% and 44% 8% and 30% 9%, respectively. In multivariate analysis, disease-free survival was significantly better for patients who had standard-risk disease and received transplantations after 2007. We conclude that unmanipulated, G-CSF–primed BM transplantation from haploidentical family donor provides very encouraging results in terms of engraftment rate, incidence of GVHD and survival and represents a feasible, valid alternative for patients with high-risk malignant hematologic diseases, lacking an HLA identical sibling and in need to be urgently transplanted. KEY POINTS Haploidentical, unmanipulated, G-CSF-primed bone marrow transplantation. Haploidentical hematopoietic stem cell transplantation for hematologic malignancies.

Toward Optimization of Postremission Therapy for Residual Disease–Positive Patients With Acute Myeloid Leukemia

PURPOSE Despite the identification of several baseline prognostic indicators, the outcome of patients with acute myeloid leukemia (AML) is generally heterogeneous. The effects of autologous (AuSCT) or allogeneic stem-cell transplantation (SCT) are still under evaluation. Minimal residual disease (MRD) states may be essential for assigning patients to therapy-dependent risk categories. PATIENTS AND METHODS By multiparametric flow cytometry, we assessed the levels of MRD in 142 patients with AML who achieved complete remission after intensive chemotherapy. RESULTS A level of 3.5 x 10(-4) residual leukemia cells (RLCs) after consolidation therapy was established to identify MRD-negative and MRD-positive cases, with 5-year relapse-free survival (RFS) rates of 60% and 16%, respectively (P < .0001) and overall survival (OS) rates of 62% and 23%, respectively (P = .0001). Of patients (n = 77) who underwent a transplantation procedure (56 AuSCT and 21 SCT procedures); 42 patients (55%) were MRD positive (28 patients who underwent AuSCT and 14 patients who underwent SCT) and 35 patients (45%) were MRD negative (28 patients who underwent AuSCT and seven who underwent SCT). MRD-negative patients had a favorable prognosis, with only eight (22%) of 35 patients experiencing relapse, whereas 29 (69%) of 42 MRD-positive patients experienced relapse (P < .0001). In this high-risk group of 42 patients, we observed that 23 (82%) of 28 of those who underwent AuSCT experienced relapse, whereas six (43%) of 14 who underwent SCT experienced relapse (P = .014). Patients who underwent SCT also had a higher likelihood of RFS (47% v 14%). CONCLUSION A threshold of 3.5 x 10(-4) RLCs postconsolidation is critical for predicting disease outcome. MRD-negative patients have a good outcome regardless of the type of transplant they receive. In the MRD-positive group, AuSCT does not improve prognosis and SCT represents the primary option.

Prognostic impact of pre-transplantation transfusion history and secondary iron overload in patients with myelodysplastic syndrome undergoing allogeneic stem cell transplantation: a GITMO study

Background Transfusion-dependency affects the natural history of myelodysplastic syndromes. Secondary iron overload may concur to this effect. The relative impact of these factors on the outcome of patients with myelodysplastic syndrome receiving allogeneic stem-cell transplantation remains to be clarified. Design and Methods We retrospectively evaluated the prognostic effect of transfusion history and iron overload on the post-transplantation outcome of 357 patients with myelodysplastic syndrome reported to the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) registry between 1997 and 2007. Results Transfusion-dependency was independently associated with reduced overall survival (hazard ratio=1.48, P=0.017) and increased non-relapse mortality (hazard ratio=1.68, P=0.024). The impact of transfusion-dependency was noted only in patients receiving myeloablative conditioning (overall survival: hazard ratio=1.76, P=0.003; non-relapse mortality: hazard ratio=1.70, P=0.02). There was an inverse relationship between transfusion burden and overall survival after transplantation (P=0.022); the outcome was significantly worse in subjects receiving more than 20 red cell units. In multivariate analysis, transfusion-dependency was found to be a risk factor for acute graft-versus-host disease (P=0.04). Among transfusion-dependent patients undergoing myeloablative allogeneic stem cell transplantation, pre-transplantation serum ferritin level had a significant effect on overall survival (P=0.01) and non-relapse mortality (P=0.03). This effect was maintained after adjusting for transfusion burden and duration, suggesting that the negative effect of transfusion history on outcome might be determined at least in part by iron overload. Conclusions Pre-transplantation transfusion history and serum ferritin have significant prognostic value in patients with myelodysplastic syndrome undergoing myeloablative allogeneic stem cell transplantation, inducing a significant increase of non-relapse mortality. These results indicate that transfusion history should be considered in transplantation decision-making in patients with myelodysplastic syndrome.

B-Cell Concentration in the Apheretic Product Predicts Acute Graft-Versus-Host Disease and Treatment-Related Mortality of Allogeneic Peripheral Blood Stem Cell Transplantation

Background. The influence of the graft composition on the clinical outcome after allogeneic peripheral blood stem cell (PBSC) transplantation is not well established. Methods. The cellular composition of the apheretic products obtained from 63 human leukocyte antigen–identical siblings was prospectively correlated with the outcome of patients with hematological malignancies undergoing an allogeneic PBSC transplant after myeloablative conditioning. The concentration of nuclear, mononuclear, CD34+, T-cell subsets, B cells, and natural killer cells in the graft has been analyzed. Results. In univariate analysis, acute graft-versus-host disease (GVHD) correlated with the disease (P=0.002), with the phase of disease at transplant (P=0.01), and with the number of CD20+ cells infused (P=0.05). In multivariate analysis, a dose of CD20+ cells in the graft higher than the median dose remained the only factor negatively affecting the incidence of acute GVHD (P=0.01; 95% confidence interval [CI]: 0.12–0.78). In univariate analysis, treatment-related mortality (TRM) correlated with the disease (P=0.04) and was negatively affected by a dose of infused B cells greater than the median value (28% versus 50%; P=0.02). In multivariate analysis, TRM was close to statistical correlation with the dose of CD20+ cells (P=0.06; 95% CI: 0.02–1.05). No other clinical parameter was influenced by the composition of the graft. Conclusions. Our results suggest that the concentration of B cells in the apheretic product may predict the incidence of acute GVHD and TRM in patients undergoing an allogeneic PBSC transplantation and open the way to the new preventive and therapeutic strategies for the management of GVHD.

Haploidentical, G-CSF-primed, unmanipulated bone marrow transplantation for patients with high-risk hematological malignancies: an update

Ninety-seven patients affected by high-risk hematological malignancies underwent G-CSF primed, unmanipulated bone marrow (BM) transplantation from a related, haploidentical donor. All patients were prepared with an identical conditioning regimen including Thiotepa, Busilvex, Fludarabine (TBF) and antithymocyte globulin given at myeloablative (MAC=68) or reduced (reduced intensity conditioning (RIC)=29) dose intensity and received the same GvHD prophylaxis consisting of the combination of methotrexate, cyclosporine, mycofenolate-mofetil and basiliximab. Patients were transplanted in 1st or 2nd CR (early phase: n=60) or in >2nd CR or active disease (advanced phase: n=37). With a median time of 21 days (range 12–38 days), the cumulative incidence (CI) of neutrophil engraftment was 94±3%. The 100-day CI of III–IV grade acute GvHD and the 2-year CI of extensive chronic GvHD were 9±3% and 12±4%, respectively. Overall, at a median follow-up of 2.2 years (range 0.3–5.6), 44 out of 97 (45%) patients are alive in CR. The 5-year probability of overall survival (OS) and disease-free survival (DFS) for patients in early and advanced phase was 53±7 vs 24±8% (P=0.006) and 48±7 vs 22±8% (P=0.01), respectively. By comparing MAC with RIC patient groups, the transplant-related mortality was equivalent (36±6 vs 28±9%) while the relapse risk was lower for the MAC patients (22±6 vs 45±11%), who showed higher OS (48±7 vs 29±10%) and DFS (43±7 vs 26±10%). However, all these differences did not reach a statistical significance. In multivariate analysis, diagnosis and recipient age were significant factors for OS and DFS. In conclusion, this analysis confirms, on a longer follow-up and higher number of patients, our previous encouraging results obtained by using MAC and RIC TBF regimen as conditioning for G-CSF primed, unmanipulated BM transplantation from related, haploidentical donor in patients with high-risk hematological malignancies, lacking an HLA-identical sibling or unrelated donor and in need to be urgently transplanted.

Decision analysis of allogeneic hematopoietic stem cell transplantation for patients with myelodysplastic syndrome stratified according to the revised International Prognostic Scoring System.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) represents the only curative treatment for patients with myelodysplastic syndrome (MDS), but involves non-negligible morbidity and mortality. Crucial questions in clinical decision-making include the definition of optimal timing of the procedure and the benefit of cytoreduction before transplant in high-risk patients. We carried out a decision analysis on 1728 MDS who received supportive care, transplantation or hypomethylating agents (HMAs). Risk assessment was based on the revised International Prognostic Scoring System (IPSS-R). We used a continuous-time multistate Markov model to describe the natural history of disease and evaluate the effect of different treatment policies on survival. Life expectancy increased when transplantation was delayed from the initial stages to intermediate IPSS-R risk (gain-of-life expectancy 5.3, 4.7 and 2.8 years for patients aged ⩽55, 60 and 65 years, respectively), and then decreased for higher risks. Modeling decision analysis on IPSS-R versus original IPSS changed transplantation policy in 29% of patients, resulting in a 2-year gain in life expectancy. In advanced stages, HMAs given before transplant is associated with a 2-year gain-of-life expectancy, especially in older patients. These results provide a preliminary evidence to maximize the effectiveness of allo-SCT in MDS.

The potential role of pre-transplant HBcIgG seroposivity as predictor of clinically relevant cytomegalovirus infection in patients with lymphoma undergoing autologous hematopoietic stem cell transplantation: A study from the Rome Transplant Network

Despite the increased use of intensive immunosuppressive chemo‐immunotherapies in patients with lymphoma observed in the last decade, current data on cytomegalovirus (CMV) infection following autologous stem cell transplantation (Auto‐SCT) are very limited. To address this peculiar aspect, a retrospective study on a cohort of 128 adult patients consecutively transplanted for lymphoma in three Hematology Institutions was performed with the aim to determine the incidence of and the risk factors for CMV symptomatic infection and/or end‐organ disease. Sixteen patients (12.5%) required specific antiviral therapy and 4/16 died (25%); transplant‐related mortality (TRM) was significantly influenced by CMV infection (P = 0.005). In univariate analysis, a pre‐transplant HBcIgG seropositivity, HBV infection according to clinical–virological definitions, a pre‐transplant Rituximab treatment, a diagnosis of B‐cell non‐Hodgkin lymphoma, and age at transplant were significantly associated with the risk of developing a clinically relevant CMV infection. In multivariate analysis, only a pre‐transplant HBcIgG seropositivity (P = 0.008) proved to be an independent predictor of a clinically relevant CMV infection. These results suggest that a pre‐transplant HBcIgG seropositivity could be considered as an independent predictor factor of clinically relevant CMV infection after Auto‐SCT.

Sezary syndrome in relapse after reduced intensity allogeneic transplant successfully treated with donor lymphocyte infusion.

Sezary syndrome in relapse after reduced intensity allogeneic transplant successfully treated with donor lymphocyte infusion

Pre-transplant persistence of minimal residual disease does not contraindicate allogeneic stem cell transplantation for adult patients with acute myeloid leukemia

Despite progress in treatment and supportive therapies, outcome of high-risk adult AML remains dismal with ~ 20% of patients becoming long-term survivors. Since the pretreatment genetics/cytogenetics of AML do not always anticipate the individual outcome, there is a strong rationale to implement laboratory techniques capable of exploring the quality of CR and allowing post-remission therapy to be optimally directed. In this view, minimal residual disease (MRD) assessment promises to be a robust approach. It captures the diversities of the underlying genetic/cytogenetic features of AML and recapitulates other patient heterogeneities regarding drug bioavailability, metabolism and resistance. Multiparametric flow cytometry (MFC) is one of the leading techniques successfully exploited to quantify MRD in AML expressing leukemia-associated immunophenotypes (LAIP). This assay applies to the vast majority of patients after chemotherapy-induced morphologic CR and has been shown to predict the clinical outcome when measured at several time points, potentially prompting prospective treatment adjustments. Recent studies have demonstrated that pretransplant MRD levels negatively affect post-transplant outcome. Years ago, we showed that MRD persistence at the end of consolidation was associated with an unfavorable outcome and that autologous stem cell transplantation (AuSCT) was not able to alter such an unfavorable course. More recently, other authors have extended this observation to either pediatric or adult patients receiving allogeneic stem cell transplantation (ASCT), showing that pretransplant MRD is a major determinant of prognosis, regardless of the occurrence of graft-versus-leukemia (GVL). Nevertheless, whether MRD positivity is an indication or a contraindication to deliver ASCT is still a matter of debate. On the basis of these premises, we analyzed a retrospective series of MRD-positive adults with AML who were submitted to ASCT. Our aim was to evaluate the impact of pretransplant MRD status on overall survival (OS) and DFS. We analyzed 230 consecutive patients achieving CR after the induction cycle of intensive EORTC/GIMEMA protocols and who harbored in their leukemic cells a LAIP suitable for MRD monitoring. The present series represents an extension of a cohort of patients already analyzed for different purposes and reported previously. Following our previous experience, MRD positivity was defined if ⩾ 3.5 × 10 4 (0.035%) residual leukemic cells (RLCs) were detected in the BM upon full hematological recovery after consolidation cycle. According to this definition, 176/230 patients (76.5%) were classified as MRD positive (MRD) and 54/230 (23.5%) as MRD negative (MRD). In the overall series, 84/230 patients (36.5%) received no transplant because of age, poor performance status or insufficient stem cell harvest, 28/230 (12.2%) relapsed before transplant delivery whereas 118/230 (51.3%) underwent ASCT (N= 50) or AuSCT (N= 68) in first CR. For the purpose of the present analysis, we focused on the 81 patients who tested MRD and who were submitted to ASCT (N= 45) or AuSCT (N= 36), respectively. The same analysis was not feasible for MRD patients due to the low numbers in the ASCT group (N= 5), preventing any statistical significance from being demonstrated. The clinico-biological characteristics of the patients are detailed in Table 1. The two groups were balanced regarding white blood cell count (WBCc), ELN risk category, FLT3 and NPM1 mutational status. Karyotypic analysis was available in 77 (95%) out of 81 patients. Intermediate risk category accounted for 78%

Minimal residual disease as biomarker for optimal biologic dosing of ARA-C in patients with acute myeloid leukemia

We assessed by flow cytometry minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) given standard‐dose (SDAC) and high‐dose ARA‐C (HDAC) regimens. Of 163 patients enrolled, 130 (median age, 45 years; range, 18–59 years) qualified for analysis, all achieving complete remission after treatment with SDAC (n = 78) or HDAC (n = 52) plus etoposide and daunorubicin. Consolidation consisted of intermediate‐dose ARA‐C and daunorubicin. MRD negativity was significantly more frequent in the SDAC vs. HDAC arm after both induction (37% vs. 15%, P = 0.007) and consolidation (44% vs. 18%, P = 0.002). Respective median residual leukemic cell counts with SDAC and HDAC use were 1.5 × 10−3 and 4 × 10−3 (P = 0.033) after induction and 5.7 × 10−4 and 2.9 × 10−3 (P = 0.008) after consolidation. Based on ARA‐C schedule and post‐consolidation MRD status, the four patient groups (SDAC‐MRD−, HDAC‐MRD−, SDAC‐MRD+, and HDAC‐MRD+) displayed 5‐year overall survival rates of 60%, 33%, 24%, and 42% (P = 0.007), respectively, with 24%, 35%, 74%, and 48% (P < 0.0001) respective cumulative incidence of relapse estimates. MRD may serve as a biomarker for optimal biologic dosing of ARA‐C, and SDAC regimen appears to yield more frequent MRD negativity. Am. J. Hematol. 90:125–131, 2015.