Reduced-intensity Conditioning Allogeneic Hematopoietic Stem Research Articles

Outcomes After Donor Lymphocyte Infusion in Patients With Hematological Malignancies: Donor Characteristics Matter

In the context of T-cell depletion, failing to achieve full donor chimerism (FDC) entails higher risk of graft loss and disease relapse. Donor lymphocyte infusion (DLI) is an adoptive immunotherapy for mixed chimerism (MC) or relapsed disease after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (HSCT). Nevertheless, little is known of factors associated with attaining FDC or disease remission. We carried out a retrospective study with 100 adult patients to identify patient and donor factors that can predict achievement of FDC and disease remission and describe complications after DLI. Indications for DLI were T-cell MC in 61 patients and relapsed disease in 39 patients. Forty patients (65.6%) with MC attained T-full donor chimerism (T-FDC), with higher responses seen in patients whose donors were female (81.5% versus 52.9%, P = .004) and cytomegalovirus negative (76.5% versus 52%, P = .004). However, only patients with younger donors (<30 years old) compared to older donors (94.4% versus 53.5%, P = .013) and those attaining unfractionated whole blood (UWB) FDC after DLI (76.6% versus 28.6%, P < .001) had a survival benefit and subsequently a better graft-versus-host disease (GvHD)–free/relapse-free survival. Nineteen of 39 patients (48.7%) with relapsed disease achieved remission after DLI. In this cohort, attaining T-FDC impacted favorably in disease control (76.7% versus 12.5%, P = .012) and improved survival (45.5% versus 12.5%, P = .007). In the whole population, the cumulative incidence of acute GvHD (aGvHD) at day 100 after DLI was 23%, and chronic GvHD (cGvHD) at 1 year after DLI was 22%. In the whole population, donor age was also a determining factor for aGvHD, because patients with younger donors had a lower incidence of aGvHD (8% versus 36%, P = .021). The cGvHD was more likely to occur in patients who converted to T-FDC (34% versus 10.3%, P = .025). Donor characteristics are increasingly considered when deciding approaches for HSCT. Donor age should be considered when planning HSCT, as well as doses and scheduling of DLI. As per our experience, this should be done alongside T/UWB chimerism to achieve the maximal clinical benefit with less associated toxicity. Selection of younger male donors from stem cell registries can minimize the risk of GvHD and improve survival.

Total Skin Electron Beam Therapy in Patients with Advanced Cutaneous T Cell Lymphoma Undergoing Allogeneic Stem Cell Transplantation: A Single Centre Experience

Introduction: Total skin electron beam (TSEB) therapy represents a valid treatment option in the management of patients with cutaneous T-Cell lymphoma (CTCL) with diffuse skin involvement. While the efficacy of TSEB for palliative treatment is well established, its inclusion as a debulking strategy before reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been only recently reported. Due to the lack of hematopoietic toxicity, TSEB may also be effectively administered in patients relapsing after allo-HSCT. With this study we aimed to retrospectively investigate the use of TSEB among patients who underwent to allo-HSCT in our Center for advanced CTCL. Patients &amp; Methods: As of July 2019, 45 CTCL patients (26 M and 19 F, median age 54 years, range 19-66) all having stage IIB to IV refractory Mycosis Fungoides (MF, n=33) or Sézary Syndrome (SS, n=12) underwent allo-HSCT from HLA-identical sibling (n=18), unrelated donors (n=23) or haploidentical related donors (n=4). Median time from diagnosis to HSCT was 46 months and median number of previous treatment lines was 6. Source of stem cells was peripheral blood in 40 patients, bone marrow in 4 patients and cord blood in 1 patient. Conditioning regimens included FC/TBI200, pentostatin/TBI200, fludarabine/melphalan and TT/CTX/Fluda/TBI200. Outcomes at 5-years were: OS 51% (33%-66%), DFS 40% (20%-50%), NRM 15% (4%-27%) and relapse incidence 48% (32%-65%). Clinical charts of the whole series of patients were extensively reviewed to collect information on the use of TSEB from diagnosis to the last follow up date. Results: Overall 21 patients of the series received TSEB with dose fractionation of 2 Gy in 2 days administered with the Stanford Technique as part of their treatment strategy. In six cases it was included among the lines of treatment administered over the disease course preceding transplant referral, with a total dose of 36 Gy in all of them. In 13 patients TSEB was part of the debulking strategy for patients with chemorefractory disease just prior to allo-HSCT with a median total dose of 24 Gy (range 10.8- 36). In 4 patients TSEB was administered after transplantation: as a salvage treatment for skin relapse during early post tranplant intense immunosuppression phase in 3 cases (12, 36, 21.6 Gy respectively) and as palliative treatment for disease progression in one case (36 Gy). Among patients who received TSEB as a bridge to transplant strategy, CR was achieved in 5 cases: at the last follow up visit (median time from transplantation 23 months, range 6-80) 4 were alive with persistent CR, whereas 1 patient who experienced graft failure died from disease progression 31 months after transplantation. Partial remission (PR) was documented in 7 (very good in 2): at the last follow up visit (median time from transplantation 14 months, range 6-52) 2 patients were alive in CR and 5 died: 3 from disease progression, 1 from GVHD and 1 from myocardial infarction 42 months after transplantion. In 1 patient, who only showed minimal response to TSEB therapy, death from disease progression occurred 9 months after an autologous-allogeneic tandem transplant strategy. All the 3 patients receiving TSEB after allo-HSCT for early relapse achieved a new and durable CR maintained at the last follow up date (42, 21 and 10 months after transplant respectively), suggesting the occurrence of a durable graft-versus-lymphoma effect following TSEB. As far as safety is concerned, only grade 1 skin toxicity (erythematous reactions) was observed in a minority of patients, while no case of haematological toxicity was documented. Conclusions: Our experience confirmed TSEB as a particularly safe and potentially effective treatment strategy in CTCL patients, both to induce remission prior to allo-HSCT and to rescue early post transplant relapse occurring before immunosuppression withdrawal. Disclosures No relevant conflicts of interest to declare.

Comparison of Two Doses of Antithymocyte Globulin in Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation.

The appropriate dose of antithymocyte globulin (ATG) to be used in reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT) is yet to be determined. We retrospectively analyzed the outcomes of patients who underwent unrelated or mismatch related RIC allo-HSCT for hematologic malignancies and received r-ATG (4.5 mg/kg, 141 patients) versus R-ATG (6 mg/kg, 216 patients). There was a higher incidence of cytomegalovirus (P < .001) and Epstein-Barr virus viremia (P =.03) in the R-ATG group than in the r-ATG group. The cumulative incidences of acute graft-versus-host disease (aGVHD) grades II to IV at day 180 in the r-ATG and R-ATG groups were 59% and 44% (P = .006) and grades III to IV 20% and 12% (P = .029), respectively. In multivariable models adjusting for disease diagnosis, the risk of aGVHD grades III to IV did not reach statistical significance (P = .087). The respective cumulative incidences of chronic GVHD in the r-ATG and R-ATG groups were 26% and 15% (P = .10), respectively. There were no significant differences in relapse rate (P = .24), nonrelapse mortality (P = .96), progression-free survival (P = .24), overall survival (P = .70), and GVHD-free relapse-free survival (P = .24). In this retrospective analysis, aGVHD incidence was higher in those treated with r-ATG compared with R-ATG, but this did not translate into significant differences of clinical outcome. Given the increasing use of RIC allo-HSCT for treating malignant hematologic conditions, the correct dose and schedule of ATG administration should be defined by prospective randomized controlled trials.

Effect of Sirolimus Exposure on the Need for Preemptive Antiviral Therapy for Cytomeglovirus Infection after Allogeneic Hematopoietic Stem Cell Transplantation.

The current study evaluates the clinical effect of sirolimus exposure on the occurrence of cytomegalovirus (CMV) DNAemia necessitating preemptive antiviral therapy. A total of 167 consecutive recipients of reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT) who received sirolimus- and tacrolimus-based graft-versus-host disease (GVHD) prophylaxis and whose CMV serostatus was positive for donors and/or recipients were included in this multicenter retrospective study. A parametric model with consecutive sirolimus blood levels describing the time to CMV DNAemia-RAT was developed using NONMEM version 7.4. Overall, 122 of 167 patients (73%) were allografted from an unrelated donor, and the donor CMV-serostatus was negative in 51 cases (31%). Fifty-six recipients (34%) developed CMV DNAemia necessitating preemptive therapy, with a cumulative incidence of 36% at a median follow-up of 25 months. Time to CMV DNAemia necessitating preemptive therapy was best described using a Gompertz function. CMV DNAemia necessitating preemptive therapy-predicting factors were antithymocyte globulin-based conditioning regimen (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.1 to 4.1; P < .01) and sirolimus concentration (HR, .94; 95% CI, .87 to .99; P < .01). The risk of CMV DNAemia-RAT decreased by 6% for each 1 ng/mL increase in sirolimus trough concentration. In conclusion, we provide evidence on the association between sirolimus blood concentration and incidence of CMV DNAemia necessitating preemptive therapy in allo-HSCT recipients. Moreover, this study presents the first predictive model describing the time to CMV DNAemia necessitating preemptive antiviral therapy as a function of sirolimus drug concentration.

Outcomes of reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation for 10 patients with myelofibrosis

目的评价减低强度预处理异基因造血干细胞移植（allo-HSCT）治疗骨髓纤维化患者的疗效。方法回顾性分析接受减低强度预处理allo-HSCT的10例骨髓纤维化患者的临床资料。结果全部10例患者中男6例、女4例，中位年龄为28.5（22~54）岁。采用以氟达拉滨/白消安+全身照射为主的预处理方案。9例患者移植后获得造血重建，中性粒细胞、血小板的中位植入时间分别为13.5（10~22）、16.5（13~40）d。4例患者发生急性移植物抗宿主病，5例患者发生慢性移植物抗宿主病。中位随访时间17（6~109）个月，预期3年总生存率为（90.0±8.5）%。1例患者死亡。结论以氟达拉滨/白消安+全身照射为主的减低强度预处理allo-HSCT是骨髓纤维化的有效治疗方法。

Sequential Intensified Conditioning Regimen Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Intermediate- or High-Risk Acute Myeloid Leukemia in Complete Remission: A Study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

Post-transplant relapse is the leading cause of treatment failure in acute myeloid leukemia (AML) patients after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (allo-HSCT). To improve their outcome, we evaluated the outcome of a sequential intermediate-intensity conditioning regimen combining fludarabine, cytosine arabinoside, amsacrine, cyclophosphamide, and either total body irradiation or busulfan (FLAMSA) in patients with intermediate or high-risk AML in first or second complete remission (CR). A total of 265 patients (median age, 55 years; range, 19 to 76) with AML who underwent allo-HSCT using a FLAMSA regimen were included. At the time of transplant, 216 (81.5%) were in CR1 and 49 (18.5%) in CR2. Cytogenetic was intermediate in 114 (43%) and poor in 42 (15.8%) patients, whereas 109 patients (41.1%) had a secondary AML. With a median follow-up of 46 months (range, 1 to 145), the Kaplan-Meier estimate of overall and leukemia-free survival at 2 years were 56.1% (95% CI, 49.7% to 62.6%) and 52.8% (95% CI, 46.4% to 59.2%), respectively. At 2 years, the cumulative incidences of relapse and nonrelapse mortality were 22.8% (95% CI, 17.6% to 28.4%) and 24.0% (95% CI, 18.8% to 29.5%), respectively. In multivariate analysis, patient age and cytogenetics were the only parameters with a significant impact on overall survival. These data suggest that the FLAMSA sequential intermediate conditioning regimen provides an efficient disease control in intermediate- and high-risk AML patients, including those in CR2 and with secondary AML.

Cytomegalovirus Status and the Outcome of T Cell–Replete Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation

Cytomegalovirus (CMV) serostatus of donor and recipient are frequently used in algorithms of donor selection, whereas the impact of CMV reactivation on transplantation-related mortality, leukemia control, and overall survival (OS) remains controversial. Therefore, we retrospectively studied the impact of latent or active CMV infections on the outcome and occurrence of graft-versus-host disease (GVHD) after reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (SCT) in 294 patients during the period from 2004 to 2010. CMV viral load was routinely monitored in plasma using a quantitative PCR. Preemptive antiviral therapy was initiated when the viral load in plasma exceeded a predefined threshold. In a proportional hazards model, a seropositive recipient was significantly associated with increased occurrence of acute GVHD. However the CMV serostatus of both recipient and donor and the presence of active CMV infection was not associated with the occurrence of relapses, chronic GVHD, or OS. We conclude that in the presence of viral load monitoring and preemptive treatment, latent or active CMV infection does not substantially affect the OS after T cell–replete RIC allogeneic SCT.

Does quality of life impact the decision to pursue stem cell transplantation for elderly patients with advanced MDS?

The factors that influence utilization of reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (HCT) among medically fit older patients with advanced myelodysplastic syndromes (MDS) are largely unknown. The MDS Transplant-Associated Outcomes (MDS-TAO) study is an ongoing prospective observational study at the Dana-Farber Cancer Institute and Massachusetts General Hospital that enrolls transplant-eligible fit patients aged 60-75 years with advanced MDS and follows them through RIC HCT vs non-HCT treatment. In this analysis of 127 patients enrolled from May 2011 to June 2014, we examined the influence of age, gender, cytogenetics, International Prognostic Scoring System (IPSS) category, performance status, distance from HCT center and baseline patient-reported quality of life (QOL) from the EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire) on the likelihood of receiving RIC HCT using competing risk regression modeling. With a median follow-up of 16 months, 44 patients (35%) had undergone RIC HCT. In multivariable analyses, age (hazard ratio (HR) 0.87 per year, 95% confidence interval (CI): 0.81-0.92, P<0.001) and higher IPSS (intermediate-2/high; HR 2.29, 95% CI: 1.25-4.19, P=0.007) were significantly predictive of receipt of RIC HCT; neither global QOL score nor any QOL subscales scores were predictive. These data suggest that baseline patient-reported QOL has little influence on the decision to undergo RIC HCT for older patients with advanced MDS.

Research progress of reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation in treatment of myelodysplastic syndrome

Allogeneic hematopoietic stem cell transplantation(allo-HSCT) is likely to be the optimum method to cure international prognostic scoring system (IPSS) intermediate and high-risk patients with myelodysplastic syndrome(MDS). However, patients suffered with MDS are usually too old to undergo myeloablative conditioning allogeneic stem cell transplantation(MAC-HSCT). On account of its advantages of higher efficiency and lower toxicity, reduced intensity conditioning allogeneic stem cell transplantation(RIC-HSCT) is widely applied in the treatment of MDS patients. Currently, fludarabine plus alkylating regimens are widely applied, but the clinical outcomes are different from each regimen. Although RIC-HSCT has unique advantages in treating intermediate and high-risk elder MDS compared with MAC-HSCT and non-HSCT therapy, whether the outcome is influenced by factors such as tumor burden, recipient age, IPSS risk stratification, type of allo-HSCT, and comorbidity before transplantation is still unclear. In this article, we review literatures on RIC-HSCT in treatment of MDS. Key words: Myelodysplastic syndrome; Transplantation conditioning; Hematopoietic stem cell transplantation

Prognostic value of pretransplant serum C-reactive protein in patients receiving reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation.

The impact of pre-transplant serum C-reactive protein (CRP) level on the outcome of reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (RIC allo-SCT) is unclear. This study retrospectively investigated 78 patients who underwent RIC allo-SCT between 2005 and 2013. The conditioning regimen consisted of fludarabine and melphalan with/without total body irradiation. The 3-year overall survival of high CRP (43.6 % of all patients) patients was significantly worse than that of normal CRP patients in whom CRP was ≤0.3 mg/dl (26.7 vs. 74.1 %, P < 0.001). Both the CRP level before transplantation and disease risk status were independent prognostic factors for overall survival by multivariate analysis. CRP was not a significant predictor of NRM by multivariate analysis (hazard ratio 3.2, 95 % confidence interval 0.8-13.1, P = 0.100). These results suggest that measuring the CRP level before transplantation can be useful to predicting the outcome of RIC allo-SCT.

Comparison of Two Doses of Antithymocyte Globulin (ATG) in Reduced Intensity Conditioning (RIC) Allogeneic Hematopoietic Stem Cell Transplant (alloHSCT)

Introduction: The appropriate dose of antithymocyte globulin (ATG) to be used in reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT) is yet to be determined. In our previous retrospective analysis we compared two dosing schedules of ATG (7.5 mg/kg vs 6 mg/kg) in 136 patients who had undergone RIC allo-HSCT, and found no significant differences in the incidence of acute or chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM), relapse, progression-free survival (PFS) or overall survival (OS). As of October 2013, our ATG dosing was lowered from 6.5 to 4.5 mg/kg. We now compare the outcomes of patients who received ATG at a dose of 4.5 mg/kg (r-ATG) to 6 mg/kg (R-ATG)Methods: We retrospectively analyzed the outcomes of patients who underwent unrelated or mismatch related RIC allo HSCT for hematologic malignancies and received r-ATG (40 patients) vs R-ATG (216 patients) at The Ohio State University Comprehensive Cancer Center between October 2007 and September 2014. Cumulative incidences of GVHD, infection, NRM, and relapse were analyzed using Gray's test, accounting for competing risks. PFS and OS were analyzed using the log-rank test.Results: Patients with hematologic malignancies included AML/MDS (53%), NHL/Hodgkin's (19%), CLL (12%), and other hematologic malignancies including ALL (16%). There was a significant association between disease group and ATG dose (p<0.001), with none of the patients diagnosed with CLL receiving r-ATG and a higher percentage of those with other malignancies receiving r-ATG vs R-ATG than expected. Secondary to the imbalance in disease groups, those receiving r-ATG were younger (median 50 vs 59 yrs, p=0.01) and more likely to have bone marrow stem cell source (18% vs 5%, p=0.008). There were no significant differences in recipient or donor sex, degree of HLA match, prior autografts, comorbidity index, donor/recipient CMV status and CD34 cell dose between the two groups. The cumulative incidences of acute GVHD grade II-IV at day 180 in the r-ATG and R-ATG groups were 63% and 44% (p=0.009), and of grade III-IV 18% and 11% (p=0.25) respectively (Figure 1A and B). When controlling for differences in underlying disease, the estimated risk of acute GVHD grade II-IV was 1.6 times higher with r-ATG (p=0.04). The respective cumulative incidences at 6 months of chronic GVHD were 14% and 16% (p=0.65), and of extensive chronic GVHD 14% and 13% (p= 0.29). With limited follow-up in patients receiving r-ATG (median 10 months), significant differences were not observed in longer-term outcomes between the two groups including relapse rate (p=0.83), NRM (p=0.91), PFS (p=0.92), and OS (p=0.996). The incidence of CMV reactivation at day 180 was lower in the r-ATG group (5% vs 26%, p=0.005), though the incidence of competing risks including GVHD, relapse and death prior to documented reactivation was higher in the r-ATG group (p<0.0001). No statistically significant differences were seen in Epstein-Barr virus reactivation (p=0.74), BK-virus associated hemorrhagic cystitis (p=0.79), bacterial infections (p=0.11), or Clostridium Difficile infections (p=0.22).ConclusionsWhile there was an increase in grade II-IV acute GVHD with r-ATG, there was no significant difference in acute GVHD grade III-IV, relapse, NRM, PFS and OS between the two cohorts. r-ATG resulted in a lower proportion of CMV reactivation, but in a higher proportion of other competing risks. Given the increasing use of RIC allo-HSCT for treating malignant hematologic conditions, the correct dose and schedule of ATG administration should be defined by prospective randomized controlled trials. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Lower dose of antithymocyte globulin does not increase graft-versus-host disease in patients undergoing reduced-intensity conditioning allogeneic hematopoietic stem cell transplant

The appropriate dose of antithymocyte globulin (ATG) to be utilized in reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplant (alloHSCT) is as yet unknown. We retrospectively compared patients who received 7.5 mg/kg (R-ATG, 39 patients) and 6 mg/kg (r-ATG, 97 patients). The cumulative incidences of acute graft-versus-host disease (aGVHD) grade II–IV at 180 days were 46% and 41% and of aGVHD grade III–IV were 11% and 18% in r-ATG and R-ATG, respectively (p > 0.30). The respective estimated cumulative incidences at 24 months of cGVHD were 42% and 44% (p > 0.30). There was no significant difference in non-relapse mortality (p = 0.22), cumulative incidence of relapse (p = 0.53), progression-free survival (p = 0.69) or overall survival (p = 0.95). In conclusion, a decreased ATG dose of 6 mg/kg was associated with a similar proportion of GVHD to 7.5 mg/kg ATG. Given the increasing number of RIC HSCTs performed worldwide, the correct dose and preparation of ATG should be defined by prospective randomized trials.

Host Lymphocyte Depletion as a Strategy to Facilitate Early Full Donor Chimerism after Reduced-Intensity Allogeneic Stem Cell Transplantation

Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (RIC-alloHSCT) is associated with lower toxicity but higher rates of prolonged mixed chimerism than myeloablative conditioning. Decreased pretransplantation host T cell numbers are associated with less graft rejection and early full donor chimerism. To compensate for variability in pretransplantation host lymphocyte numbers and facilitate the achievement of rapid full donor chimerism, we tested a strategy of targeted lymphocyte depletion (TLD) using chemotherapy at conventional doses to provide cytoreduction and lymphocyte depletion before RIC-alloHSCT. In our study, 111 patients with advanced hematologic malignancies received 1 to 3 cycles of conventional-dose chemotherapy to reduce circulating lymphocytes to a predetermined level. Patients then underwent RIC-alloHSCT from HLA-matched siblings. Patients received a median of 2 cycles of TLD chemotherapy, resulting in a median 71% decline in CD4+ count. All patients engrafted; there were no late graft failures. By day +14, median CD3+ chimerism was 99% donor and was significantly associated with lower post-TLD CD4+ counts (P = .012). One- and 5-year treatment-related mortality were 15% and 21%, respectively. At 1-year follow-up, 66% of patients had achieved complete remission (CR) of which 92% were not in CR at the time of transplantation. Overall survival at 1 and 5 years post transplantation were 66% and 47%, respectively.

Autologous CLL cell vaccination early after transplant induces leukemia-specific T cells

Patients with advanced hematologic malignancies remain at risk for relapse following reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT). We conducted a prospective clinical trial to test whether vaccination with whole leukemia cells early after transplantation facilitates the expansion of leukemia-reactive T cells and thereby enhances antitumor immunity. We enrolled 22 patients with advanced chronic lymphocytic leukemia (CLL), 18 of whom received up to 6 vaccines initiated between days 30 and 45 after transplantation. Each vaccine consisted of irradiated autologous tumor cells admixed with GM-CSF-secreting bystander cells. Serial patient PBMC samples following transplantation were collected, and the impact of vaccination on T cell activity was evaluated. At a median follow-up of 2.9 (range, 1-4) years, the estimated 2-year progression-free and overall survival rates of vaccinated subjects were 82% (95% CI, 54%-94%) and 88% (95% CI, 59%-97%), respectively. Although vaccination only had a modest impact on recovering T cell numbers, CD8+ T cells from vaccinated patients consistently reacted against autologous tumor, but not alloantigen-bearing recipient cells with increased secretion of the effector cytokine IFN-γ, unlike T cells from nonvaccinated CLL patients undergoing allo-HSCT. Further analysis confirmed that 17% (range, 13%-33%) of CD8+ T cell clones isolated from 4 vaccinated patients by limiting dilution of bulk tumor-reactive T cells solely reacted against CLL-associated antigens. Our studies suggest that autologous tumor cell vaccination is an effective strategy to advance long-term leukemia control following allo-HSCT. Clinicaltrials.gov NCT00442130. NCI (5R21CA115043-2), NHLBI (5R01HL103532-03), and Leukemia and Lymphoma Society Translational Research Program.

Emerging immunotherapies in older adults with acute myeloid leukemia

We summarize recent advances for acute myeloid leukemia (AML) in older patients, with a focus on immunotherapeutics. Although the recently updated US SEER data still show that the majority of older AML patients do not receive any therapy, this reality is slowly changing. Advances in our understanding of the biology of AML and in the field of immunology are facilitating the development of alternative therapeutic options for patients, affording more and novel opportunities for potentially curative treatment. Data from multiple cooperative groups show that older patients benefit from the incorporation of gemtuzumab ozogamicin, an anti-CD33 mAb toxin, into induction regimens. The first prospective study for reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation in older AML patients was reported at the American Society of Hematology Annual Meeting, 2012; the approach was feasible and improved disease-free survival over conventional chemotherapy. Proof-of-concept trials targeting specific antigens such as WT1 or novel unique leukemia-associated antigens are currently underway, as well as other trials using chimeric antigen receptor T cells or (natural killer/effector cells in nontransplantation settings. Wider application of immunotherapies such as allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning have altered the landscape and offer potential for cure of an increasing number of older AML patients.

Optimal positioning of hematopoietic stem cell transplantation for older patients with myelodysplastic syndromes

This review examines reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (HSCT) for older patients (age ≥60 years) with myelodysplastic syndromes (MDS), focusing on how to choose candidates for HSCT as well as data on the comparative effectiveness of RIC HSCT versus other treatment approaches. For some older patients with MDS, there may be a survival advantage for RIC HSCT compared with nontransplantation approaches. Health service approaches suggest that optimal treatment choice varies with MDS risk. For those with low/intermediate-1 International Prognostic Scoring System (IPSS) risk, non-HSCT treatments may be preferred, but for intermediate-2/high IPSS patients, RIC HSCT may be better, even after adjusting for quality of life (QoL). The optimal positioning of HSCT for older patients with MDS is evolving. Available data suggest that for older patients with higher risk MDS, if their QoL is affected and they are medically fit, RIC HSCT may lead to more favourable outcomes. Prospective trials in older patients with MDS are necessary to confirm the putative benefit of RIC HSCT.

Long-term remission in patients with plasma cell myeloma after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation:

Long-term remission in patients with plasma cell myeloma after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation:

Reduced-Intensity Conditioning Allogeneic Stem Cell Transplantation in Pediatric Patients and Subsequent Supportive Care

To determine if children undergoing reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (RIC-AlloHSCT) have lower incidence of acute toxicities and, subsequently, require less supportive care than is required with myeloablative conditioning (MAC)-AlloHSCT. An additional purpose is to examine later outcomes by comparing 100-day transplantation-related mortality (TRM). Retrospective chart and electronic medical records review. A pediatric care center in the northeastern United States. 86 patients who underwent AlloHSCT from January 2004 through March 2008. Charts were retrospectively reviewed. The comparison between groups was done by t test (continuous variables) and chi-square test (categorical variables). The logistic regressions, Kaplan-Meier product-limit estimator, log rank test, and Cox proportional hazards model were used. Days requiring total parenteral nutrition (TPN), patient-controlled analgesia (PCA), incidence of mucositis, days with fevers, number of infections, transfers to pediatric intensive care unit (PICU), blood product infusions, and 100-day TRM, all for 30 days post-transplantation. When comparing pediatric patients undergoing RIC-AlloHSCT (n = 43) versus MAC-AlloHSCT (n = 43) in the first 30 days post-transplantation, a statistically significant decreased incidence was noted for mucositis, infections, transfers to PICU, days on TPN and PCA, and days with fever, as well as 100-day TRM. For pediatric patients, RIC-AlloHSCT is associated with significantly lower acute post-transplantation toxicities and TRM than MAC-AlloHSCT. For nurses to correctly educate their patients and family members, and to aid nurses in anticipating patient's needs, an understanding of the potential different acute toxicities and supportive care between pediatric patients undergoing RIC- versus MAC-AlloHSCT is vital.

Comparable outcomes between unrelated and related donors after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation in patients with high-risk multiple myeloma

The purpose of this study was to assess the results of allogeneic stem cell transplantation (allo-SCT) after reduced-intensity conditioning (RIC) from matched related donors (MRD) and unrelated donors (URD) in 40 patients with high-risk multiple myeloma (MM) in a single centre. Seventeen (43%) (Group 1) and 23 patients (57%) (Group 2) had URD and MRD, respectively. Thirty-nine patients (98%) received one or more autologous transplantation. The median follow-up was 22 months (1-49). None of our patient experienced a graft rejection. The cumulative incidence of grade II-IV acute GVHD was higher (47%) for the URD vs. (17%) for the MRD (P = 0.092). The cumulative incidence of chronic GVHD was no different between the two groups (24% vs. 30%, respectively). At 2 yr, the TRM probabilities were lower in the unrelated group 12% vs. 22% in the related group (P = 0.4). Also at 2 yrs, for patients receiving unrelated transplantation overall and progression-free survivals, 59% and 42%, respectively compared to patients with related donor transplantation, 66% and 44% (P = 0.241). In conclusion, these results suggest that URD in MM is feasible. The small number of patients with URD emphasizes the need to delineate indications and perform prospective protocols.

Degree of mucositis and duration of neutropenia are the major risk factors for early post‐transplant febrile neutropenia and severe bacterial infections after reduced‐intensity conditioning

Whether the intensity of the conditioning regimen affects febrile neutropenia (FN) and severe bacterial infections (SBIs) is not well established. We analyzed the risk factors (RFs) for the development of FN and SBI in the first 100d post-transplant in 195 consecutive adult recipients of a reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (RIC-allo). The RIC regimens consisted of fludarabine plus melphalan (62%) or busulphan (38%) (FluMel or FluBu). SBIs include pneumonia, urinary tract infections, and bacteremia. FN occurred in 141 patients (72%), always in the first 30d post-allo-RIC. However, a SBI occurred in only 27 patients (14%) during this early post-transplant period (<day +30), while 29 evaluable patients (15%) developed a SBI in the intermediate post-transplant period (days +31 to +100). In multivariate analysis, RFs for the development of FN included onset of neutropenia before day +5 after allo-RIC (P<0.02) and NCI CTC grade III-IV mucosal damage in the first 10d post-transplantation (P=0.03). RFs identified to SBI by multivariate analysis included corticosteroid therapy before day +100 (P<0.01), mycophenolate mofetil-based graft-versus-host disease (GVHD) prophylaxis (P<0.01), and previous SBI before day +30 (P<0.01). The rate of SBI from day +30 to +100 varied according to the number of RFs; thus, the rate of SBI was 1% in patients without any RF, 17% in patients with one RF, 29% with one RFs, and 53% in those with all three RFs. After an RIC-allo, FN and early SBI occurred mostly in patients with severe mucositis and early-onset neutropenia, while postengraftment high-dose steroid therapy for acute GVHD was the major RF.