Hematopoietic Stem Cell Transplantation after Reduced Intensity Conditioning in Acute Myelogenous Leukemia Patients Older Than 40 Years

Reduced intensity conditioning (RIC) protocols are increasingly used for allogeneic hematopoietic stem cell transplantation (HSCT) in elderly patients. We analyzed the outcome of RIC HSCT in acute myelogenous leukemia (AML) patients over the age of 40 years. Forty-three AML or high-risk myelodysplastic syndrome (MDS) patients were treated with a fludarabine and low-dose total-body irradiation (TBI)-based pretransplantation regimen. Donors were HLA-compatible sibling (68%) or unrelated volunteers (34%). All but 2 AML patients were in complete remission (CR) at the time of transplantation. Seventy-six percent of patients had a poor risk profile. Hematologic recovery was fast, and primary graft failure occurred in 1 patient. Two patients with active disease at the time of HSCT experienced ongoing relapse. Infections were diagnosed in 9 patients (21%), and 6 patients (14%) were treated for cytomegalovirus (CMV) reactivation. Sixty percent of patients developed acute graft-versus-host disease (aGVHD), which was grade II in 40% and grade III in 12%. The cumulative incidence of chronic graft-versus-host disease (cGVHD) was 33% at 1 and at 2 years. Treatment-related mortality (TRM) was low (9%), total nonrelapse mortality (NRM) was 19%. After a median follow-up of 571 days, 16 patients (37%) experienced relapse. Median disease-free and overall survival (DFS; OS) were 24 and 31 months, respectively. There were no differences in complications and outcome between recipients of sibling and unrelated grafts. In conclusion, fludarabine plus low-dose TBI-based RIC HSCT is effective in AML patients over the age of 40 years without active disease at the time of transplant and is associated with low TRM.     

A Comparison of the Myeloablative Conditioning Regimen Fludarabine/Busulfan with Cyclophosphamide/Total Body Irradiation,for Allogeneic Stem Cell Transplantation in the Modern Era: A Cohort Analysis

With improvement in transplantation practices in the modern era, nonrelapse mortality (NRM) following allogeneic hematopoietic stem cell transplantation (HSCT) has improved, while disease relapse rates have remained unchanged. Survival outcomes are therefore driven by NRM in the modern era. Myeloablative conditioning (MAC) regimens are used to maximize disease control and facilitate engraftment; however, their use is often limited by toxicity. The commonly used MAC regimens incorporate either chemotherapy plus total body irradiation (TBI) or combination chemotherapy. Furthermore, reduced-toxicity myeloablative (RTM) regimens, such as fludarabine/busulfan (FluBu), have emerged as alternatives to traditional MAC and their impact on outcomes in the current era have not been fully investigated. In this study, we compare outcomes following HSCT, using the chemotherapy only RTM MAC regimens FluBu with the chemoradiotherapy regimen cyclophosphamide/TBI (CyTBI), for patients with hematologic malignancies who underwent MAC HSCT at the Dana-Farber Cancer Institute. We hypothesized that the chemotherapy-only regimen would fare better, primarily due to improved NRM. A retrospective cohort analysis was performed on 387 patients with myeloid or lymphoid hematologic malignancies who underwent HLA-matched related (8/8), matched unrelated (8/8), or single-antigen mismatched unrelated (7/8) HSCT following myeloablative conditioning. Patients received FluBu (n?=?158) or CyTBI (n?=?229). The primary outcome was overall survival (OS) and all other outcomes were regarded as secondary. A subset analysis was performed for patients <55 years of age and for acute myelogenous leukemia/myelodysplastic syndrome patients of age?<55 years. For the whole cohort, 3-year OS was similar for FluBu compared with CyTBI in unadjusted analysis. However, in multivariable analysis, FluBu resulted in superior OS compared with CyTBI (3-year adjusted estimate: 65% versus 55%, respectively; HR for death, .62; 95% CI, .40 to .97; P?=?.036). While relapse rates were similar between the 2 regimens, NRM and acute graft-versus-host disease (GVHD) (grade II to IV) were significantly worse with CyTBI compared with FluBu. Rates of chronic GVHD were similar between 2 regimens. These results were consistent in a subset of patients <55 years of age and in acute myelogenous leukemia/myelodysplastic syndrome patients below 55 years of age. The RTM chemotherapy-only regimen FluBu appears to be as effective and more tolerable than the chemoradiotherapy regimen CyTBI, leading to better OS driven by better NRM. The improvement in NRM was attributable chiefly to lower rates of grade II to IV acute GVHD. Relapse rates were not increased with FluBu. In the absence of randomized data, FluBu appears to be the optimal regimen for myeloablative HSCT in patients of all age groups.     

Allogeneic Stem Cell Transplantation with BEAM and Alemtuzumab Conditioning Immediately after Remission Induction Has Curative Potential in Advanced T-Cell Non-Hodgkin's Lymphoma

Patients with relapsed or refractory advanced T cell non-Hodgkin lymphoma have a dismal prognosis and may not even reach allogeneic hematopoietic stem cell transplantation (HSCT) in adequate condition. We present the outcome of 24 consecutive patients (age range 11 to 65 years) treated at a single institution in Kiel within a recent 5.5-year time frame with allogeneic HSCT in a rather uniform approach. Relapsed and refractory T and natural killer cell lymphomas of various subtypes were included. All patients except 1 were in progression or relapse before start of pretransplantation salvage therapy. Five patients had relapsed after autologous HSCT. With intensive remission induction therapy, usually the CLAEG (cladribine, cytosine arabinoside, and etoposide with granulocyte colony-stimulating factor support) protocol, attempts were made to improve disease control and proceed immediately to conditioning with carmustine, etoposide, cytosine arabinoside, melphalan (BEAM), and medium-dose alemtuzumab. Twenty of 21 patients who received CLAEG induction therapy benefited from this protocol and 1 patient appeared to be therapy-resistant. At the time of allogeneic HSCT, 9 patients were in complete remission (CR) (2 in CR1, 5 in CR2, and 2 in CR >2), whereas 50% had never achieved CR. Nineteen transplants were obtained from matched or partially matched unrelated donors and only 5 from siblings. With a median follow-up of 321 days (1252 days for surviving patients), 20 of 22 assessable patients reached CR. Five of these patients had hematologic or molecular relapse. With donor lymphocyte infusions, 1 patient became minimal residual disease MRD negative again and has maintained CR for more than 4 years. The frequency of grades II to IV acute graft-versus-host disease was 25% and chronic graft-versus-host disease, 30%. Intense reinduction therapy followed by reduced-intensity BEAM-alemtuzumab conditioning and allogeneic HSCT is effective and offers curative potential for patients with advanced T cell lymphomas, even for those not in remission.     

Phase I Trial of Maintenance Sorafenib after Allogeneic Hematopoietic Stem Cell Transplantation for Fms-like Tyrosine Kinase 3 Internal Tandem Duplication Acute Myeloid Leukemia

The fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation is associated with a high relapse rate for patients with acute myeloid leukemia (AML) even after allogeneic hematopoietic stem cell transplantation (HSCT). Sorafenib is a tyrosine kinase inhibitor, which inhibits the FLT3 tyrosine kinase and has shown encouraging activity in FLT3-ITD AML. We conducted a phase I trial of maintenance sorafenib after HSCT in patients with FLT3-ITD AML (ClinicalTrials.gov NCT01398501). Patients received a variety of conditioning regimens and graft sources. A dose escalation 3 + 3 cohort design was used to define the maximum tolerated dose (MTD), with an additional 10 patients treated at the MTD. Sorafenib was initiated between days 45 and 120 after HSCT and continued for 12 28-day cycles. Twenty-two patients were enrolled (status at HSCT: first complete remission [CR1], n = 16; second complete remission [CR2], n = 3; refractory, n = 3). The MTD was established at 400 mg twice daily with 1 dose-limiting toxicity (DLT) observed (pericardial effusion). Two patients died of transplantation-related causes, both unrelated to sorafenib. Two patients stopped sorafenib after relapse and 5 stopped because of attributable toxicities after the DLT period. Median follow-up for surviving patients is 16.7 months after HSCT (range, 8.1 to 35.0). There was 1 case of grade II acute graft-versus-host disease (GVHD) after starting sorafenib and the 12-month cumulative incidence of chronic GVHD was 38% (90% confidence interval [CI], 21% to 56%). For all patients, 1-year progression-free survival (PFS) was 85% (90% CI, 66% to 94%) and 1-year overall survival (OS) was 95% (90% CI, 79% to 99%) after HSCT. For patients in CR1/CR2 before HSCT (n = 19), 1-year PFS was 95% (90% CI, 76% to 99%) and 1-year OS was 100%, with only 1 patient who relapsed. Sorafenib is safe after HSCT for FLT3-ITD AML and merits further investigation for the prevention of relapse.     

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in the Era of Tyrosine Kinase Inhibitors: A Registry-Based Study of the Italian Blood and Marrow Transplantation Society (GITMO)

We performed a nationwide registry-based analysis to describe the clinical outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL) who underwent an allogeneic hematopoietic stem cell transplantation (HSCT) after a tyrosine kinase inhibitor (TKI)-based treatmentA total of 441 patients were included in the study. The median age at HSCT was 44 years (range, 18 to 70 years). All 441 patients (100%) received TKI before HSCT (performed between 2005 and 2016). Of these 441 patients, 404 (92%) were in cytologic complete remission (CR), whereas the remaining 37 (8%) had active disease at the time of HSCT. Molecular minimal residual disease (MRD) was negative in 147 patients (36%) at the time of HSCT. The donor was unrelated in 46% of patients. The most prevalent source of stem cells was peripheral blood (70%). The conditioning regimen was myeloablative in 82% of cases (total body irradiation-based in 50%) and included antithymocyte globulin in 51% of patients. With a median follow-up after HSCT of 39.4 months (range, 1 to 145 months), the probability of overall survival (OS) at 1, 2, and 5 years was 69.6%, 61.1% and 50.3%, respectively, with a median OS of 62 months. Progression-free survival (PFS) at 1, 2, and 5 years was 60.2%, 52.1% and 43.7%, respectively. OS and PFS were significantly better in patients who were in CR and MRD-negative at the time of HSCT compared with patients who were in CR but MRD-positive (50% OS not reached versus 36 months; P = .015; 50% PFS not reached versus 26 months, P = .003). The subgroup of MRD-negative patients both at HSCT and at 3 months after HSCT had a better outcome (5-year OS, 70%). Conversely, the 37 patients who underwent a HSCT with active Ph⁺ ALL had a median OS of 7 months and a median PFS of 5 months. The 5-year cumulative incidence of relapse was significantly lower in MRD-negative patients (19.5% versus 35.4%; P = .001). Nonrelapse mortality (NRM) after 1, 2, and 5 years was 19.1% (95% confidence interval [CI], 15.5% to 22.9%), 20.7% (95% CI, 17% to 24.7%), and 24.1% (95% CI, 20% to 28.5%), respectively. NRM was significantly lower with a modified European Society for Blood and Marrow Transplantation (mEBMT) risk score of 0 to 2 compared with ≥3 (15% versus 25%; P = .016). The median OS for Ph⁺ ALL patients who underwent a TKI-based treatment followed by an allogeneic HSCT, in recent years at the GITMO centers, was 62 months. Evaluation of the mEBMT risk score can be useful to predict NRM. Our data confirm that HSCT is a potentially curative treatment for Ph⁺ ALL with an excellent outcome for the subgroup of MRD-negative patients both at HSCT and at 3 months after HSCT (5-year OS, 70%).     

Calcineurin Inhibitor–Free Graft-versus-Host Disease Prophylaxis with Post-Transplantation Cyclophosphamide and Brief-Course Sirolimus Following Reduced-Intensity Peripheral Blood Stem Cell Transplantation

Calcineurin inhibitors (CNIs) form the foundation of current graft-versus-host disease (GVHD) prophylaxis regimens. We hypothesized that a CNI-free regimen consisting of post-transplantation cyclophosphamide (PTCy) and brief-course sirolimus would reduce chronic GVHD and nonrelapse mortality (NRM) after reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation (PBSCT). Twenty-six patients (median age, 61 years) underwent unmanipulated PBSCT from an 8/8 locus-matched donor (matched related donor, n = 17; natched unrelated donor, n = 9). GVHD prophylaxis consisted of PTCy and brief-course sirolimus. Donor engraftment occurred in all patients. The cumulative incidence (CI) of grade II-IV acute GVHD, grade III-IV acute GVHD, and chronic GVHD was 46%, 15%, and 31% respectively. One-year NRM was 4%. The median time to immunosuppression discontinuation was day +138. With a median follow-up of 20 months, the estimated 2-year overall survival was 71%, estimated disease-free survival was 64%, and estimated relapse incidence was 32%. In patients with a lymphoid malignancy (eg, chronic lymphoblastic leukemia, non-Hodgkin lymphoma, Hodgkin disease), 2-year disease-free survival was 100%, and there were no relapses. Good immune reconstitution was evidenced by low cytomegalovirus reactivation rate of 21% (4 of 19 at-risk patients). GVHD prophylaxis with PTCy and sirolimus achieves consistent donor engraftment, low rates of chronic GVHD and NRM, and excellent outcomes in recipients of HLA-identical related and unrelated donor allogeneic PBSCT.     

Reduced-Intensity Conditioning and Dual T Lymphocyte Suppression with Antithymocyte Globulin and Post-Transplant Cyclophosphamide as Graft-versus-Host Disease Prophylaxis in Haploidentical Hematopoietic Stem Cell Transplants for Hematological Malignancies

Haploidentical hematopoietic stem cell transplantation (haploHSCT) with conditioning regimens using post-transplant cyclophosphamide (PTCy) for peripheral blood stem cell (PBSC) grafts is limited by comparably higher rates of acute and chronic graft-versus-host disease (GVHD). Antithymocyte globulin (ATG) may mitigate this risk. We evaluated haploHSCT after reduced-intensity conditioning (RIC) with ATG, PTCy, and cyclosporine to prevent rejection and GVHD. Fifty adults underwent haploHSCT from August 2016 to February 2018. RIC included fludarabine (30 mg/m²/day on days –5 to –2), busulfan (3.2 mg/m²/day on days –3 and –2), and total body irradiation (200 cGy) on day –1. Unmanipulated PBSCs were infused on day 0. GVHD prophylaxis included ATG (4.5 mg/kg over days –3 to –1), PTCy (50 mg/kg/day on days +3 and +4), and cyclosporine from day +5. Median age was 56 years (range, 22 to 70 years); 25 (73.5%) patients were in first complete remission (CR1), 5 (14.7%) were in second complete remission (CR2), and 8 (23.5%) had active disease. Median time to neutrophil engraftment was 16 days (range, 8 to 43 days). At day +100, the cumulative incidence of acute GVHD of any grade, and grades III to IV was 38.3% and 5.2%, respectively. Mild chronic GVHD was seen in 15.5%. Cytomegalovirus (CMV) reactivation occurred in 37 (74%) cases and CMV disease occurred in 4 (11.5%) cases. Epstein-Barr virus (EBV) reactivation occurred in 21 (61.8%) patients. The incidence of histologically confirmed post-transplantation lymphoproliferative disorder (PTLD) was 5.8%. Four patients received rituximab. There were no CMV, EBV, or PTLD-related deaths. Six-month and 1-year overall survival (OS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM) were 73.9%, 10.2%, and 19.4%, respectively, and 48.1%, 16% and 38.2%, respectively. Infection was the most common cause of death (18%). Unmanipulated haploidentical PBSC transplantation following RIC with ATG, PTCy, and cyclosporine as a GVHD prevention strategy results in low rates of acute and chronic GVHD.     

Long-term outcome of unrelated donor transplantation for AML using myeloablative conditioning incorporating pretransplant Alemtuzumab.

The outcome of 55 patients who underwent matched unrelated donor (MUD) transplantation for acute myelogenous leukemia (AML) following a conditioning regimen of cyclophosphamide and total-body irradiation (TBI) with the addition of Alemtuzumab 10 mg/kg/day on days -5 to -1 is described. All patients received graft-versus-host disease (GVHD) prophylaxis with cyclosporine as well as 3 doses of posttransplant methotrexate. Forty-one patients were transplanted in complete remission (CR) (20 in CR1, 20 in CR2, and 1 in CR3), and 14 were not in remission at the time of transplantation as they were refractory to chemotherapy either at induction or at relapse. The group consisted of adult patients with a median age of 37 years. Thirty-five patients were fully matched at HLA-A, -B, -C, and -DRB1. All patients engrafted and there were no cases of graft rejection. Grade II-IV acute GVHD occurred in only 2 patients. Chronic GVHD developed in 30% of patients but was extensive in only 3 cases. The predicted TRM was 11% at day 100 and 26% at 1 year. In multivariate analysis the receipt of an HLA mismatched transplant was associated with a higher transplant-related mortality (TRM) (55% versus 15%). Twelve of the 14 transplant-related deaths were due to infection. The 5-year cumulative incidence of relapse was 36% for the whole group and 28% for patients in CR at transplantation. The 5-year cumulative survival for the whole group was 38% and was 49% for those in remission at transplantation. Seven of the 12 patients transplanted in CR1 with adverse risk cytogenetics remain alive and in remission, and the predicted 5-year overall survival (OS) for this group is 50%. These results support the use of Alemtuzumab for unrelated donor hematopoietic stem cell transplant (HSCT) for poor risk AML in CR1 and for relapsed AML in CR2. The addition of Alemtuzumab is highly effective in preventing both rejection and severe acute and extensive chronic GVHD without an increased relapse risk.     

Haploidentical Transplantation with Post-Transplant Cyclophosphamide versus Unrelated Donor Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

Hematopoietic stem cell transplantation (HSCT) is the standard treatment for patients with high-risk hematologic malignancies. Only approximately 25% of siblings are HLA-matched, and thus alternative donors—unrelated or haploidentical—are usually the only options available. This meta-analysis aimed to compare haploidentical HSCT with post-transplantation cyclophosphamide and unrelated donor (URD) HSCT. We searched the PubMed and Cochrane databases for pertinent studies indexed between 2008 and 2018. Twenty observational studies (with a total of 1783 haploidentical HSCT recipients and 6077 URD HSCT recipients) were included. Results for overall survival, graft-versus-host disease (GVHD), nonrelapse mortality (NRM), and relapse incidence were pooled. Measures of association used were hazard ratios and risk differences. The median age was 51 years for haploidentical transplant recipients and 52 years for URD transplant recipients. Peripheral blood stem cell (PBSC) grafts were more frequent in the URD transplant recipients (85%) than in the haploidentical transplant recipients (31%). Overall survival was not different between the 2 groups. NRM was lower for haploidentical transplantation. All forms of GVHD (acute grades II-IV and III-IV and moderate, severe, and extensive chronic) were lower with haploidentical donor HSCT. The risk of chronic GVHD was fairly proportional to the differential use of PBSC grafts across studies, however. All included studies were retrospective, representing the major limitation of this meta-analysis. In conclusion, haploidentical HSCT for hematologic malignancies achieved the same overall survival as URD HSCT, with a lower incidence of GVHD and NRM. The increased frequency of PBSC use in the unrelated donor group could partially explain the higher cGVHD rate. Haploidentical transplantation with post-transplantation cyclophosphamide should strongly be considered as the first option for adult patients with hematologic malignancies who do not have matched sibling donors in experienced centers. This systematic review has been registered at PROSPERO (65790).     

Long-Term Follow-up of Allogeneic Hematopoietic Stem Cell Transplantation for De Novo Acute Myelogenous Leukemia with a Conditioning Regimen of Total Body Irradiation and Granulocyte Colony-Stimulating Factor-Combined High-Dose Cytarabine

We retrospectively evaluated the efficacy and safety of total body irradiation (TBI) and granulocyte colony-stimulating factor (G-CSF)-combined high-dose cytarabine as a conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in patients with de novo acute myelogenous leukemia (AML). The conditioning regimen consisted of 12 Gy of TBI followed by high-dose cytarabine (3 g/m²) every 12 hours for 4 days in combination with the continuous administration of G-CSF. Stem cell sources included bone marrow or peripheral blood stem cells (PBSC) from human leukocyte antigen (HLA)-identical siblings (n = 24), or bone marrow from HLA serologically matched unrelated donors (n = 26). Fifty patients (median age, 38 years) were evaluated. At HSCT, 35 patients were in the first or second complete remission (CR1/2), and 15 patients were not in remission (n = 14) or in the third CR (n = 1). Thirty-six of 50 patients are currently alive, with a median follow-up period of 5.6 years (range: 1.1-12.1 years). The 5-year estimated overall survival (OS) and disease-free survival (DFS) rates were 85.5% (95% confidence interval [CI], 73.7%-97.3%) and 82.1% (95% CI, 69.0%-95.2%) in patients with AML in the first or second CR, 46.7% (95% CI, 21.4%-72.0%), and 40.0% (95% CI, 15.3%-64.7%) in patients with AML in other stages. The 2-year cumulative incidence of treatment-related mortality (TRM) of all patients was 10.4% (95% CI, 1.8%-18.6%). The only factors affecting the OS and DFS were disease status at transplant and cytogenetics by multivariate analysis. These results suggest that G-CSF-combined high-dose cytarabine could be a promising component of the conditioning regimen for allogeneic HSCT for AML, providing a high DFS and low TRM.     

Nonmyeloablative Conditioning Regimen before T Cell Replete Haploidentical Transplantation with Post-Transplant Cyclophosphamide for Advanced Hodgkin and Non-Hodgkin Lymphomas

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a valid option in patients with refractory lymphomas. HLA haploidentical stem cell transplantation (haplo-SCT) expanded the accessibility to allogeneic hematopoietic cell transplantation. The aims of study were to retrospectively assess the toxicity and efficacy of haplo-SCT using nonmyeloablative conditioning in patients with advanced lymphoma. In total, 147 patients with advanced lymphoma at 2 partner institutions were included. Patients received a uniform nonmyeloablative conditioning regimen and graft-versus-host disease (GVHD) prophylaxis. The primary endpoints were progression-free survival (PFS), overall survival (OS), GVHD, nonrelapse mortality, and GVHD, relapse-free survival (GRFS). Median follow-up was 39 months (range, 6 to 114 months). The median age was 46 years (range, 19 to 71 years). Sixty-five percent of patients were in complete remission (CR) at transplantation. Cumulative incidence of grade II to IV acute GVHD was 30% (95% confidence interval [Cl], 23% to 38%). Two-year cumulative incidence of all grades of chronic GVHD was 13% (95% CI, 8% to 20%). Two-year cumulative incidence of disease relapse was 19% (95% CI, 14% to 27%), with a higher incidence in patients not being in CR at allo-HCT (CR versus not CR: 12% versus 33%, P = .006). Two-year PFS, OS, and GRFS were 66% (95% CI, 59-75), 73% (95% CI, 66-81), and 56% (95% CI, 48-65), respectively. Haplo-SCT with post-transplantation cyclophosphamide may be considered a valid option for patients with aggressive lymphoma and deserves further evaluation.     

Allogeneic Stem Cell Transplantation for Adults with Myelodysplastic Syndromes: Importance of Pretransplant Disease Burden

Allogeneic stem cell transplantation is the only known curative therapy for myelodsyplastic syndromes (MDS). We present the transplant outcomes for 84 adult MDS patients, median age 50 (18-69 years), undergoing allogeneic hematopoietic stem cell transplantation (HSCT) at the University of Minnesota between 1995 and 2007. By WHO criteria 35 (42%) had refractory anemia with excess blasts (RAEB-1 or 2), 23 (27%) had refractory cytopenia with multilineage dysplasia (RCMD) or RCMD and ringed sideroblasts (RCMD-RS), and the remaining 26 (31%) had refractory anemia (RA), myelodysplastic syndrome-unclassifiable (MDS-U), chronic myelomonocytic leukemia (CMML), myelodysplastic/myeloproliferative disease (MDS/MPD), or myelodysplastic syndrome-not otherwise specified (MDS-NOS). Graft source was related in 47 (56%), unrelated donor (URD) marrow in 11 (13%), and unrelated cord blood (UCB) in 26 (31%). The conditioning regimen included total body irradiation (TBI) in 94% of transplantations; 52 (62%) myeloablative (MA) and 32 (38%) nonmyeloablative (NMA) regimens. Cumulative incidence of neutrophil engraftment by day +42, acute graft-versus-host disease (aGVHD) by day +100, and chronic GVHD (cGVHD) by 1 year were 88% (80%-96%, 95% confidence interval [CI]), 43% (36%-50%, 95% CI), and 15% (10%-20%, 95% CI), respectively. One-year treatment-related mortality (TRM), relapse, disease-free survival (DFS), and overall survival (OS) were 39% (28%-50%, 95% CI), 23% (12%-32%, 95% CI), 38% (28%-48%, 95% CI), and 48% (38%-58%, 95% CI) respectively. Cumulative incidence of relapse at 1 year in patients with pre-HCT complete remission (CR) or <5% blasts was improved at 18% (8%-28%, 95% CI) compared to 35% (16%-54%, 95% CI) in patients with 5%-20% blasts (P = .07). Additionally, with MA conditioning, the incidence of relapse at 1 year trended lower at 16% (6%-26%, 95% CI) versus 35% (18%-52%, 95% CI) in NMA (P = .06), and a statistically significant decrease in relapse was noted in patients entering HCT with CR or <5% blasts with an incidence of 9% (0%-18%, 95% CI) (MA) versus 31% (11%-51%, 95% CI) (NMA) (P = 0.04). For those patients with ≥5% blasts, MA conditioning did not significantly decrease relapse rates. One-year TRM was similar between MA and NMA conditioning. For patients entering transplant in CR or with <5% blasts, prior treatment to reach this level did not impact rates of relapse or transplant-related mortality when all patients were analyzed; however, when broken down by conditioning intensity, there was a trend toward improved DFS in those NMA patients who were pretreated. Finally, 1-year DFS was similar using related donor peripheral blood stem cell (PBSC)/marrow, URD marrow, or UCB grafts. These data suggest that (1) blast percentage <5% at HSCT is the major predictor of improved DFS and relapse and prior treatment to reach this disease status may have value in leading to improved DFS; (2) MA conditioning is associated with lower relapse risk, particularly in patients with CR or <5% blasts, but is not able to overcome increased disease burden; (3) NMA conditioning yields equivalent TRM, DFS, and OS, and is reasonable in patients unsuited for MA conditioning; (4) the donor sources tested (PBSC, bone marrow [BM], or UCB) yielded similar outcomes.     

A Phase II Trial of Autologous Stem Cell Transplantation Followed by Mini-Allogeneic Stem Cell Transplantation for the Treatment of Multiple Myeloma: An Analysis of Eastern Cooperative Oncology Group ECOG E4A98 and E1A97

Conventional allogeneic hematopoietic stem cell transplantation (HSCT) for multiple myeloma is associated with high transplantation-related mortality (TRM). Nonmyeloablative allogeneic transplantation (NST) uses the well-known graft-versus-myeloma (GVM) effect to eradicate minimal residual disease. The Eastern Cooperative Oncology Group conducted a Phase II trial of autologous HSCT followed by NST to provide maximal tumor cytoreduction to allow for a subsequent GVM effect. Patients received melphalan 200 mg/m² with autologous HSCT, followed by fludarabine 30 mg/m² in 5 daily doses and cyclophosphamide 1 g/m² in 2 daily doses with matched sibling donor NST. Graft-versus-host disease (GVHD) prophylaxis included cyclosporine and corticosteroids. The primary endpoints were TRM, graft failure, acute GVHD, progression-free survival (PFS), and overall survival (OS). Thirty-two patients were enrolled into the study; 23 patients completed both transplantations (72%). Best responses post-NST were 7 (30%) complete remission (CR), 11 (48%) partial remission (PR), 2 (9%) no response, and 3 (13%) not evaluable. Acute grade III-IV GVHD was observed in 4 patients (17%), and chronic GVHD was seen in 13 patients (57%; 7 limited, 6 extensive). Chronic GVHD resulted in the following responses: 3 (23%) CR, 1 continuing CR, and 6 (46%) PR. Two patients (8.7%) had early TRM. With a median follow up of 4.6 years, the median PFS was 3.6 years, and the 2-year OS was 78%. Our findings indicate that autologous HSCT followed by NST is feasible, with a low early TRM in a cooperative group setting. The overall response rate was 78%, including 30% CR, similar to other reports for autologous HSCT-NST. Because a plateau in PFS or OS was not observed with this treatment approach even in patients achieving CR, we suggest that future studies use posttransplantation maintenance therapy.     

Transplantation in Remission Improves the Disease-Free Survival of Patients with Advanced Myelodysplastic Syndromes Treated with Myeloablative T Cell-Depleted Stem Cell Transplants from HLA-Identical Siblings

From 1985 to 2004, 49 patients with advanced myelodysplastic syndromes (MDS) (≥5% blasts) or acute myeloid leukemia (AML) transformed from MDS underwent T cell depleted bone marrow or peripheral blood hematopoietic stem cell transplantation (HSCT) from HLA-identical siblings following conditioning with a myeloablative regimen that included total body irradiation (44 patients) or busulfan (5 patients). Thirty-six patients received chemotherapy (3 low dose and 33 induction doses) before conditioning, and 13 patients did not receive any chemotherapy. Prior to transplantation, 22 of the 36 treated patients were in hematologic remission; 4 were in a second refractory cytopenia phase (26 responders); 8 had failed to achieve remission; and 2 of the responders had progression or relapse of their MDS (10 failures). No post-transplantation pharmacologic prophylaxis for graft-versus-host disease (GVHD) was given. The median age was 48 yrs (range 13-61). Forty-five of the 49 patients engrafted; 2 had primary graft failure; and 2 died before engraftment. Only 3 patients developed acute GVHD (aGVHD) (grades I and III) and 1 chronic GVHD (cGVHD). At 3 yrs post-transplantation, the overall survival (OS) was 54% in the responders; 31% in the untreated group; and 0% in the failure group (P=.0004). The disease free survival (DFS) was 50%, 15% and 0% in each group respectively (P=.0008). In multivariate analysis, disease status before cytoreduction remained highly correlated with DFS (P<.001). The cumulative incidence (CI) of relapse at 2-yrs post-transplantation for the responders was 23%; for the untreated group was 38%; and for the failures was 50%. The CI of non-relapse mortality at 2-yrs post-transplantation, for the responders was 23%; for the untreated group was 38%; and for the failures was 40%. All survivors achieved a Karnofsky Performance Status (KPS) of ≥90. These results indicate that patients with advanced MDS who achieve and remain in remission or a second refractory cytopenia phase with chemotherapy before conditioning can achieve successful long-term remissions following a myeloablative T cell depleted allogeneic HSCT.     

Role of Antithymocyte Globulin and Granulocyte-Colony Stimulating Factor-Mobilized Bone Marrow in Allogeneic Transplantation for Patients with Hematologic Malignancies

The main obstacle for allogeneic transplantation is delayed hematologic reconstitution and serious graft-versus-host disease (GVHD). The results of 128 patients with hematologic malignancies undergoing HLA-identical (n = 52) or HLA-haploidentical/mismatched (n = 76) hematopoietic stem cell transplantation (HSCT) performed during the same time period were compared. Patients with HLA-identical HSCT received unmanipulated granulocyte-colony stimulating factor-mobilized peripheral blood stem cells (G-PBSCs). Forty-six patients with HLA-haploidentical related HSCT received antithymocyte globulin (ATG) in conditioning regimens followed by the transplantation of the combination of unmanipulated G-PBSCs and granulocyte-colony stimulating factor-mobilized bone marrow (G-BM) and 30 patients with HLA-mismatched unrelated HSCT received ATG in conditioning regimens followed by the transplantation of unmanipulated G-PBSCs. All patients got successful hematopoietic engraftment. The cumulative incidences of grades I to II acute GVHD (aGVHD) on day 100 in the identical, haploidentical related and mismatched unrelated cohorts were 21.2%, 43.5%, and 53.3%, respectively. The cumulative incidences of chronic GVHD (cGVHD) in the identical, mismatched unrelated, and haploidentical related cohorts were 34.6%, 33.3%, and 10.9%, respectively. The 2-year relapse and treatment-related mortality (TRM) rates were 19.2%, 23.9%, 23.3%, and 9.6%, 8.7%, 10% for patients who underwent identical, HLA-haploidentical related, and mismatched unrelated transplantation, respectively. The 2-year probabilities of leukemia-free survival and overall survival were 72.2%, 70.6%, 68.1%, and 76.5%, 77.8%, 70.0% after identical, haploidentical related and mismatched unrelated transplantations, respectively. Multivariate analyses showed that only advanced disease stage and a diagnosis of disease had increased risk of relapse, treatment failure, and overall mortality. In conclusion, it is a feasible approach with acceptable outcomes for patients undergoing HLA-haploidentical related HSCT by the combination of G-PBSCs and G-BM with conditioning regimens including ATG.     

Donor and Recipient CMV Serostatus and Outcome of Pediatric Allogeneic HSCT for Acute Leukemia in the Era of CMV-Preemptive Therapy

In the era of cytomegalovirus (CMV)-preemptive therapy, it is unclear whether CMV serostatus of donor or recipient affects outcome of allogeneic hematopoietic stem cell transplantation (HSCT) among children with leukemia. To investigate, consecutive patients aged 0-18 who underwent primary HSCT for acute leukemia in 1997-2007 (HLA-matched sibling or unrelated donor, myeloablative conditioning, unmanipulated bone marrow or peripheral blood, preemptive therapy, no CMV prophylaxis) were followed retrospectively through January 2008. Treatment failure (relapse or death) was analyzed using survival-based proportional hazards regression. Competing risks (relapse and nonrelapse mortality, NRM) were analyzed using generalized linear models of cumulative incidence-based proportional hazards. Excluding 4 (2.8%) patients lacking serostatus of donor or recipient, there were 140 subjects, of whom 50 relapsed and 24 died in remission. Pretransplant CMV seroprevalence was 55.7% in recipients, 57.1% in donors. Thirty-five (25.0%) grafts were from seronegative donor to seronegative recipient (D−/R−). On univariate analysis, D−/R− grafts were associated with shorter relapse-free survival (RFS) than other grafts (median 1.06 versus 3.15 years, P < .05). Adjusted for donor type, diagnosis, disease stage, recipient and donor age, female-to-male graft, graft source, and year, D−/R− graft was associated with relapse (hazards ratio 3.15, 95% confidence interval 1.46-6.76) and treatment failure (2.45, 1.46-4.12) but not significantly with NRM (2.00, 0.44-9.09). In the current era, children who undergo allogeneic HSCT for acute leukemia have reduced risk of relapse and superior RFS when recipient and/or donor is CMV-seropositive before transplantation. However, no net improvement in RFS would be gained from substituting seropositive unrelated for seronegative sibling donors.     

Outcomes in Patients Age 70 or Older Undergoing Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies

Allogeneic hematopoietic stem cell transplantation (HSCT) can achieve durable remissions in a number of patients with advanced hematologic malignancies. Little is known about the safety of HSCT in patients age 70 or older. Consecutive patients (n = 54) age 70 or older underwent HSCT between 2007 and 2012. Diseases included acute myelogenous leukemia (n = 25), myelodysplastic syndrome (n = 12), chronic lymphocytic leukemia (n = 5), non-Hodgkin lymphoma (n = 4), acute lymphoblastic leukemia (n = 3), myeloproliferative neoplasm (n = 4), and chronic myelogenous leukemia (n = 1). Median follow-up for survivors was 21 months. All patients received reduced-intensity conditioning regimens, primarily busulfan/fludarabine. All patients received unmanipulated peripheral blood stem cell grafts: 44 from 8/8 matched unrelated donors, 8 from matched related donors, and 2 from 7/8 matched unrelated donors. Graft-versus-host disease (GVHD) prophylaxis was calcineurin inhibitor–based in all patients. The median age at transplantation was 71 years (range, 70 to 76); the median HCT comorbidity index score was 1 (range, 0 to 5). Two patients died before hematopoietic recovery (1 with graft failure and 1 with disease progression), and 1 patient relapsed before hematopoietic recovery; otherwise, all engrafted with median donor chimerism of 94% at 1 month. Cumulative incidence of grades II to IV acute GVHD was 13% and of grades III to IV acute GVHD, 9.3%. At 2 years, the cumulative incidence of chronic GVHD was 36%, progression-free survival was 39%, overall survival was 39%, and relapse was 56%. Nonrelapse mortality was 3.7% at day +100 and 5.6% at 2 years. We conclude that allogeneic HSCT is a safe and effective option for carefully selected patients age 70 or older.     

Fludarabine,Campath, and Low-Dose Cyclophosphamide (FCClow) with or without TBI Conditioning Results in Excellent Transplant Outcomes in Children with Severe Aplastic Anemia

Various reduced-intensity conditioning regimens are in use for allogeneic hematopoietic cell transplant (HSCT) in patients with idiopathic severe aplastic anemia (SAA). We describe the use of fludarabine, Campath, and low-dose cyclophosphamide (FCC^low) conditioning in 15 children undergoing related or unrelated donor transplants. Total body irradiation (TBI) of 2 Gy was added for unrelated donor HSCT. At a median follow-up of 2.3 years, the failure-free survival was 100%, with low rates of infection and toxicity. There was no occurrence of grade III to IV acute graft-versus-host disease (GVHD). All patients had full donor myeloid chimerism post-HSCT, even with mixed chimerism in the T cell lineage. The absence of chronic GVHD and long-term stable mixed donor T cell chimerism confirms immune tolerance following FCC^low (± TBI) conditioned transplantation in children with SAA.     

High Incidence of Severe Acute Graft-Versus-Host Disease with Tacrolimus and Mycophenolate Mofetil in a Large Cohort of Related and Unrelated Allogeneic Transplantation Patients

Both acute and chronic graft-versus-host disease (GVHD) are major causes of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). The optimal pharmacological regimen for GVHD prophylaxis is unclear, but combinations of a calcineurin inhibitor (cyclosporin or tacrolimus [Tac]) and an antimetabolite (methotrexate or mycophenolate mofetil [MMF]) are typically used. We retrospectively evaluated the clinical outcomes of 414 consecutive patients who underwent AHSCT from sibling (SD) or unrelated donors (UD) with Tac/MMF combination, between January 2005 and August 2010. The median follow-up was 60 months. Less than one third of the patients received a reduced-intensity chemoregimen. The incidence of grades III and IV acute GVHD was 22.3% and 36.5% in SD and UD groups, respectively (P = .0007). The incidence of chronic GVHD was 47.1% and 52.7% in the SD and UD groups, respectively. Nonrelapse mortality (NRM) at 60 months was 33.3% and 46.5% in the SD and UD groups, respectively (P = .0016). The incidence of relapse was 22.4% for UD and 28.8% for SD. Five-year overall survival was 43% and 34% in the SD and UD groups, respectively (P = .0183). GVHD was the leading cause of death for the entire cohort. Multivariable analysis showed that 8/8 HLA match, patient's age < 60, and low-risk disease were associated with better survival. The use of Tac/MMF for GVHD prophylaxis was associated with a relatively high incidence of severe acute GVHD and NRM in AHSCT from sibling and unrelated donors.     

Reduced-intensity transplantation for patients with myelodysplastic syndrome achieves durable remission with less graft-versus-host disease.

Reduced-intensity allogeneic transplantations for myelodysplastic syndrome (MDS) patients have been limited by significant graft-versus-host disease (GVHD), treatment-related mortality, and disease relapse. We treated 18 MDS patients ineligible for standard allogeneic transplantation with a preparative regimen of photopheresis day -7 and -6, pentostatin 4 mg/m(2) by continuous infusion day -5 and -4, and total body irradiation 600 cGy in 3 fractions day -3 and -2, followed by allogeneic stem cell infusion from 6/6 or 5/6 HLA-matched related donors or 6/6 HLA-matched unrelated donors. GVHD prophylaxis consisted of cyclosporin A and a short course of methotrexate. The median age was 54 years (range, 30-70 years). Diagnoses included refractory anemia (n = 2), refractory anemia with ringed sideroblasts (n = 2), refractory anemia with excess blasts (n = 10), refractory anemia with excess blasts in transformation (n = 3), and chronic myelomonocytic leukemia (n = 1). Sixteen of 18 patients developed full donor chimerism with no day +100 transplant-related mortality. Grade II to IV acute GVHD and extensive chronic GVHD developed in 19% and 18% of patients, respectively. Disease relapse occurred in 2 patients. At a median follow-up of 14 months (range, 1-35 months), the 1-year failure-free and overall survival were 64% and 65%, respectively. Our photopheresis and pentostatin-based reduced-intensity preparative regimen for allogeneic bone marrow transplantation in high-risk MDS patients achieves successful donor engraftment and disease remission with less transplant toxicity and grade II to IV acute GVHD.