Comparison of Unrelated Cord Blood Transplantation and HLA-Matched Sibling Hematopoietic Stem Cell Transplantation for Patients with Chronic Myeloid Leukemia in Advanced Stage

This is the first report to present a clinical comparison of unrelated cord blood transplantation (CBT) and HLA-matched sibling allogeneic hematopoietic stem cell transplantation for patients with chronic myeloid leukemia (CML) in advanced stage (accelerated phase or blast crisis). A total of 32 consecutive patients with advanced CML received unrelated CBT (n = 16) or HLA-matched sibling allogeneic peripheral blood stem cell or bone marrow transplantation (allo-PBSCT/BMT) (n = 16) between 2002 and 2011. The median day to neutrophil engraftment and the median day to platelet engraftment were longer in the unrelated CBT group. The cumulative incidence of grades 1 to 2 acute graft-versus-host disease (aGVHD), grades 3 to 4 aGVHD, and chronic graft-versus-host disease did not differ significantly between the 2 cohorts. The cumulative incidence of transplantation-related mortality (TRM) at day +180 was higher in CBT group (37.5% versus 12.5%, P = .013). The risk of relapse was lower in CBT patients compared with that of allo-PBSCT/BMT patients (14.2% versus 42.7%, P = .03). The long-term survival in CBT group patients was slightly better than that of allo-PBSCT/BMT group, although the difference did not reach statistical significance: the 5-year overall survival for CBT patients and allo-PBSCT/BMT patients was 62.5% and 48.6%, respectively (P = .10), whereas the 5-year leukemia-free-survival rate was 50% and 40.5%, respectively (P = .12). Our comparisons suggest that patients with advanced CML receiving unrelated CBT had a lower relapse rate, a slightly better long-term survival, but a higher early TRM than those receiving HLA-matched related allo-PBSCT/BMT.     

Fludarabine-Melphalan Conditioning for AML and MDS: Alemtuzumab Reduces Acute and Chronic GVHD without Affecting Long-Term Outcomes

The purpose of this study was to determine the effect of alemtuzumab on treatment-related mortality (TRM), relapse, overall survival (OS), and disease-free survival (DSF) in patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) undergoing reduced intensity conditioning (RIC). We compared the outcome of 95 patients treated at the University of Chicago with fludarabine melphalan (Flu + Mel) + alemtuzumab conditioning and 59 patients treated at the M.D. Anderson Cancer Center with Flu + Mel conditioning. Both groups had similar patient and donor characteristics. There were no significant differences in TRM, relapse, survival, and DFS between the 2 groups. The incidence of acute graft-versus-host disease (aGVHD) grade II-IV (relative risk [RR] 5.5, P < .01) and chronic GVHD (cGVHD) (RR 6.6, P < .01) were significantly lower in patients receiving alemtuzumab. The addition of alemtuzumab to an RIC regimen dramatically reduces the incidence of aGVHD and cGVHD in patients with AML and MDS undergoing allogeneic transplantation. TRM, relapse risk, OS and DFS are not affected.     

Treosulfan-Based Conditioning and Hematopoietic Cell Transplantation for Nonmalignant Diseases: A Prospective Multicenter Trial

Hematopoietic cell transplantation is an effective treatment for patients with nonmalignant diseases and for many is the only known cure. Conventional myeloablative regimens have been associated with unacceptably high early transplant-related mortality (TRM), particularly in patients with comorbid conditions. This prospective multicenter trial was designed to determine the safety and engraftment efficacy of treosulfan-based conditioning in patients with nonmalignant diseases. Thirty-one patients received HLA-matched related (n = 4) or unrelated (n = 27) grafts after conditioning with treosulfan (total dose, 42 g/m²), fludarabine (total dose, 150 mg/m²), ± thymoglobulin (6 mg/kg; n = 22). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. All patients engrafted. Day-100 TRM was 0%. With a median follow-up of 2 years, the 2-year survival was 90%. Three patients died of GVHD, recurrent hemophagocytic lymphohistiocytosis, and a surgical complication, respectively. The cumulative incidences of grades II to IV and III to IV acute GVHD at day 100 and chronic GVHD at 2 years were 62%, 10%, and 21%, respectively. Patients who received thymoglobulin had a significantly lower incidence of grades III to IV acute GVHD (0% versus 33%; P = .005). These results indicate that the combination of treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with low toxicity and improved survival in patients with nonmalignant diseases and support the need for future disease-specific clinical trials.     

A Modified Haploidentical Nonmyeloablative Transplantation without T Cell Depletion for High-Risk Acute Leukemia: Successful Engraftment and Mild GVHD

Severe graft-versus-host disease (GVHD) and graft rejection still remain major complications of haploidentical nonmyeloablative (NMA) stem cell transplantation. Recent studies have shown that bone marrow-derived mesenchymal stem cells (MSCs) possess immunomodulatory capacity and may promote hematopoietic engraftment. The purpose of this study was to observe if the new strategy, which included a haploidentical peripheral blood stem cell transplantation (PBSCT) combined with MSCs, modified NMA conditioning, and GVHD prophylaxis would improve donor engraftment and prevent severe GVHD. The modified conditioning approach consisted of fludarabine (Flu), low-dose total body irradiation (TBI), cyclophosphamide (Cy), cytarabine, and anti-Tcell-lymphocyte globulin, whereas the GVHD prophylaxis consisted of cyclosporin A (CsA), mycophenolate mofetil (MMF), anti-CD25 antibody and intrabone marrow injection of MSCs. Thirty-three patients with high-risk acute leukemia underwent transplantation with PBSC from HLA-haploidentical donors without T cell depletion. All of the patients achieved full donor chimerisms, including 6 who switched to full donor chimerisms from mixed chimerisms in 1 to 2 months after the transplantations. Rapid hematological engraftment was observed with neutrophils >0.5 × 10⁹/L at day 11 and platelets >20 × 10⁹/L at day 14. Fifteen patients (45.5%) developed grade I–IV acute GVHD (aGVHD) and only 2 (6.1%) developed grade III to IV aGVHD. Nine (31%) of 29 evaluable patients experienced chronic GVHD (cGVHD). Upon follow-up for 1.5 to 60 months, 20 (60.6%) patients were alive and well and 6 (18.2%) had relapsed leukemia in the 33 patients. The probability of 3-year survival was 57.2%. The results indicate that this new strategy is effective in improving donor engraftment and preventing severe GVHD, which will provide a feasible option for the therapy of high-risk acute leukemia.     

Excellent Outcome of Allogeneic Hematopoietic Stem Cell Transplantation Using a Conditioning Regimen with Medium-Dose VP-16, Cyclophosphamide and Total-Body Irradiation for Adult Patients with Acute Lymphoblastic Leukemia

We retrospectively evaluated the outcomes of 37 adult patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT) conditioned with medium-dose VP-16 (VP, 30 mg/kg), cyclophosphamide (CY, 120 mg/kg), and fractionated total-body irradiation (TBI, 12 Gy) (medium-dose VP/CY/TBI). The median age of the patients was 26 years. Thirteen patients underwent transplantation from HLA-matched related donors (MRD), 18 patients underwent transplantation from HLA-matched unrelated donors (MUD), and 6 patients underwent transplantation from HLA-mismatched donors (MMD). Thirty-two patients received bone marrow and 4 patients received peripheral blood stem cells. Ten patients were Philadelphia chromosome-positive (Ph⁺) and 35 patients were in complete remission (CR) at transplantation. All of the patients achieved engraftment, and grade 3 organ toxicity before engraftment occurred in 27 patients. Grade II-III acute graft-versus-host disease (GVHD) and chronic GVHD (cGVHD) occurred in 15 and 18 patients, respectively. No patient developed grade IV acute GVHD (aGVHD) or died of GVHD. At median follow-up of 35.1 months, 32 patients were alive and all Ph⁺ patients were alive. Three patients died of relapse and 2 died of transplant-related mortality (TRM). The actuarial 3-year overall survival (OS) rate, relapse rate, and TRM rate were 89.2%, 8.1%, and 5.4%, respectively. Non-CR at transplantation, MRD, and no aGVHD were significant adverse prognostic factors for survival. Medium-dose VP/CY/TBI for adult ALL patients was associated with lower relapse rate and no increase in toxicity, resulting in better survival.     

Double Umbilical Cord Blood Transplantation after Novel Myeloablative Conditioning Using a Regimen of Fludarabine,Busulfan, and Total Lymphoid Irradiation

We conducted a pilot study evaluating double umbilical cord blood transplantation (dCBT) after myeloablative conditioning with fludarabine and busulfan 3.2 mg/kg i.v. × 4, followed by total lymphoid irradiation at 400 cGy (FluBu4/TLI) for any indicated hematological disorder for patients without a suitable donor. Twenty patients with predominantly high-risk disease underwent dCBT according to protocol. The regimen was well tolerated, with mucositis as the primary observed toxicity (n = 19). The cumulative incidence of neutrophil engraftment was 89% (95% confidence interval [CI], 64% to 97%), with a median time to recovery of 16 days (range, 12 to 31 days). All evaluable patients with neutrophil engraftment achieved complete donor chimerism by day 40. The cumulative incidence of grades III and IV acute graft-versus-host disease (GVHD) at day 100 was 10% (95% CI, 2% to 27%), and the cumulative incidence of chronic GVHD was 35% (95% CI, 16% to 55%) by the end of the study. At 1 year, the cumulative incidence of treatment-related mortality (TRM) was 35% (95% CI, 16% to 55%). The leading cause of nonrelapse mortality was acute GVHD (n = 4), followed by graft failure (n = 2) and chronic GVHD (n = 1). TRM was significantly associated with a pretransplantation hematopoietic cell transplantation–specific comorbidity index score ≥ 3 (P = .005). At 1 year, disease relapse occurred in 6 patients and overall survival was 40% (95% CI, 19% to 60%). We conclude that FluBu4/TLI is an adequate preparative regiment before dCBT, providing high engraftment rates and relatively early neutrophil recovery. The best survival outcomes were seen in patients without significant comorbidities before transplantation, and outcomes are comparable to previously published dCBT studies.     

A Modified Post-Transplant Cyclophosphamide Regimen,for Unmanipulated Haploidentical Marrow Transplantation,in Acute Myeloid Leukemia: A Multicenter Study

We report a modified post-transplant cyclophosphamide (PT-CY) regimen, for unmanipulated haploidentical marrow transplants, in 150 patients with acute myeloid leukemia (AML). All patients received a myeloablative regimen, cyclosporine A (CsA) on day 0, mycophenolate on day +1, and PT-CY 50?mg/kg on days +3 and +5. The median age was 51 (range, 17–74) years, 51 (34%) patients had active disease at transplant, and the median follow-up of surviving patients 903 (range, 150-1955) days. The cumulative incidence (CI) of engraftment, acute graft-versus-host disease (GVHD) grade II to IV, and moderate/severe chronic GVHD was 92%, 17%, and 15%, respectively. The 4-year CI of transplant-related mortality (TRM) and relapse was 20% and 24%, respectively. Four-year survival for remission patients was 72% (74% versus 67% for <60 or ≥60 years of age) and 26% for advanced patients (17% versus 41% for <60 or ≥60 years of age). In a multivariate analysis, active disease at transplant was the only negative predictor of survival, TRM and relapse. The original PT-CY regimen can be modified with CsA on day 0, still providing protection against GVHD, low toxicity, and encouraging low relapse incidence in AML patients, also over 60 years of age.     

Adult recipients of matched related donor blood cell transplants given myeloablative regimens including pretransplant antithymocyte globulin have lower mortality related to graft-versus-host disease: a matched pair analysis.

Because pretransplantation anti-thymocyte globulin (ATG) seems to reduce graft-versus-host-disease (GVHD) and treatment-related mortality (TRM) after unrelated donor bone marrow transplantation (BMT), we investigated this agent in matched related donor (MRD) blood cell transplantation (BCT). Fifty-four adults receiving rabbit ATG, cyclosporine A, and methotrexate with myeloablative conditioning and undergoing first MRD BCT were matched for disease and stage with 54 patients not given ATG. Most ATG-treated patients had fludarabine with oral (7) or i.v. busulfan (46) with total body irradiation (TBI) in 10. Control patients largely received TBI with VP16 (28) or oral busulfan with cyclophosphamide (15) or fludarabine (7). The ATG was given at a total dose of 4.5 mg/kg over 3 d, finishing on day 0. Rates of acute GVHD (aGVHD) grade II-IV, aGVHD grade III-IV, and chronic GVHD (cGVHD) were 19 +/- 5% versus 32 +/- 6% (P = .1), 6 +/- 3% versus 13 +/- 5% (P = NS), and 55 +/- 8% versus 96 +/- 3% (P = .002) in the ATG and control groups, respectively. Patients given ATG had fewer sites involved by cGVHD compared with the control group (mean 2.1 +/- 0.2 versus 2.8 +/- 0.2, P = .04). Non-relapse mortality (NRM) with and without ATG, respectively, was 4 +/- 3% versus 17 +/- 5% at 100 d and 9 +/- 4% versus 34 +/- 7% at 4 yr (P = .002). Deaths were GVHD related in 3 ATG-treated patients versus 14 controls (P = .007). Despite a trend to more relapse with ATG (43 +/- 7% versus 22 +/- 7% at 4 yr, P = 0.05), survival was 66 +/- 7% in the patients given ATG versus 50 +/- 7% in the controls (P = 0.046). This study indicates that myeloablative regimens incorporating fludarabine and oral or i.v. busulfan with pretransplantation ATG given to recipients undergoing MRD BCT may result in less cGVHD, lower TRM, and probably improved quality of life in survivors compared with previous protocols.     

Australasian Trends in Allogeneic Stem Cell Transplantation for Myelofibrosis in the Molecular Era: A Retrospective Analysis from the Australasian Bone Marrow Transplant Recipient Registry

To review the updated trends of national practice and outcomes in transplantation to treat myelofibrosis (MF), we retrospectively evaluated 142 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) for primary (n = 94) or secondary (n = 48) MF at an Australian/New Zealand transplantation center between 2006 and 2017. The median duration of follow-up was 51.8 months (range, 3.1 to 148 months). The median age at allo-HSCT was 56 years (range, 26 to 69 years). Fifty-two percent of the patients had HLA-identical sibling donors, and 45% had matched unrelated donors (UD). Conditioning regimens were predominantly reduced intensity (83%). Before transplantation, 16% of the patients had undergone splenectomy or splenic irradiation, and 38% (n = 54) received JAK inhibitor therapy. JAK2 mutation testing was performed in 66.9% of the patients, whereas other mutations (CALR, MPL, ASXL1, SRSF2, U2AF1Q57, EZH2, and IDH1/2) were rarely tested (1.4% to 8.4%). Only 4.2% of patients had next-generation sequencing mutation analysis. The median time to neutrophil engraftment was 19 days (range, 10 to 43 days), and the median time to platelet engraftment was 27 days (range, 13 to 230 days). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 21.4% at 100 days, and that of extensive chronic GVHD (cGVHD) at 5 years was 18.1%. Overall survival (OS) was 67% at 1 year and 57% at 5 years. GVHD-free, relapse-free survival was 54% at 1 year and 42% at 5 years. The cumulative incidence of nonrelapse mortality (NRM) was 16% at 100 days and 25% at 1 year. In multivariate analysis, age ≥65 years and use of an UD were identified as significant unfavorable risk factors for OS and NRM. Use of an UD increased the incidence of aGVHD, whereas administration of antithymocyte globulin/alemtuzumab lowered the risk of both aGVHD and cGVHD. Pretransplantation splenectomy/splenic irradiation had a positive influence on time to engraftment. There have been no improvements in the outcomes of allo-HSCT for MF in Australasia over the last decade, with a low uptake of molecular genomic technology due to limited access to funding.     

A Randomized Phase II Trial of Fludarabine/Melphalan 100 versus Fludarabine/Melphalan 140 Followed by Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Multiple Myeloma

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment for multiple myeloma (MM); however, because of high treatment-related mortality (TRM), its role is not well defined. Patients with newly diagnosed, relapsed, or primary refractory myeloma were enrolled in a randomized phase II trial of 2 reduced-intensity conditioning regimens: fludarabine 120 mg/m² + melphalan 100 mg/m² (FM100) versus fludarabine 120 mg/m² + melphalan 140 mg/m² (FM140) before allo-HCT from related or unrelated donors. Fifty patients underwent allo-HCT using FM100 (n = 23) or FM140 (n = 27) conditioning between April 2002 and 2011. There were no significant differences between FM100 and FM140 in time to neutrophil engraftment (P = .21), acute grade II to IV graft-versus-host disease (GVHD) (P = 1.0), chronic GVHD (P = .24), response rate (P = 1.0), TRM (13% versus 15%, P = 1.0), median progression-free survival (PFS), 11.7 versus 8.4 months, P = .12, and median overall survival (OS), 35.1 versus 19.7 months, P = .38. Cumulative incidence of disease progression in FM100 and FM140 was 43% and 70%, respectively (P = .08). Recurrent disease was the most common cause of death for both FM100 (26%) and FM140 (44%), P = .24. On multivariate analysis, disease status at allo-HCT, complete response or very good partial response (VGPR) was significantly associated with longer PFS (15.6 versus 9.6 months in patients with <VGPR, P = .05). OS was similar across all variables. We conclude that FM100 and FM140 may result in similar patient outcomes after allo-HCT for MM.     

Graft-versus-Host Disease Prophylaxis with Tacrolimus and Mycophenolate Mofetil in HLA-Matched Nonmyeloablative Transplant Recipients Is Associated with Very Low Incidence of GVHD and Nonrelapse Mortality

Incidence of grade II-IV acute graft-versus-host disease (aGVHD) in nonmyeloablative (NMA) transplant recipients remains high. To date, the ideal prophylaxis regimen, which minimizes aGVHD and chronic GVHD (cGVHD), but does not abrogate graft-versus-tumor (GVT) response, has not been described. Because tacrolimus is more potent than cyclosporine (CSA), and because mycophenolate mofetil (MMF) is an effective immunosuppressant that does not lead to mucositis, we hypothesized that a combination of these 2 oral agents may be an effective GVHD prophylactic strategy. We, therefore, designed an outpatient prospective cohort study with a conditioning regimen consisting of fludarabine (Flu) 30 mg/m² daily and cyclophosphamide (Cy) 300 mg/m² daily for 5 days followed by infusion of blood stem cells. Tacrolimus 3 mg twice a day was started on day (D) −8, adjusted to achieve levels 10-15 nmol/L, continued until D +50 and then tapered by D +100 or +180 according to estimated risk of relapse. MMF 1000 mg twice a day was started on D +1 and discontinued on D +50. To date, 131 patients (males/females: 75/56) with a median age of 54 years have received a 6/6 matched sibling transplant using this protocol. Indication for NMA transplant included age >55 years (24%), expected increased risk of toxicity (28%), or participationin a multiple myeloma (MM) sequential protocol (48%). Most common diagnoses included MM (N = 62), non-Hodgkin lymphoma (NHL, N = 46), and acute leukemia (N = 10). Following infusion of 6.8 × 10⁶ CD34⁺ cells/kg (range: 0.30-22.3), neutrophil and lymphocyte engraftment occurred in 95% of patients by D +180. The estimated cumulative incidence of classical grade I-IV aGVHD by D +120 was 11.6% (95% confidence interval [CI]: 7.1-18.5). No grade IV aGVHD was observed. In addition, 15 patients (12%: CI: 7.4-19.2; median D +140) developed an overlap syndrome consisting of clinical and histologic features of both aGVHD and cGVHD simultaneously. The estimated cumulative incidence of extensive cGVHD was 76.1% (95% CI: 67.4-83.9) at 2 years, with clinical features at presentation similar to other reported series. In patients developing extensive cGVHD, the probability of remaining on immunosuppression at 5 years was 34.8% (95% CI: 16.4-57.3). With a median follow-up of 982 days, the estimated probabilities of nonrelapse mortality (NRM) and overall survival (OS) were 15.5% (95% CI: 9.0-26.1) and 62.7% (95% CI: 51.4-72.1). The cumulative incidence of relapse was 30% at 7 years. Following NMA transplant, disease-free survival (DFS) was highest in recipients with follicular NHL (79.8%: 95% CI: 57.6-91.2) and lowest in large cell NHLs (34.3%: 95% CI: 1.6-75.9). From this large group of patients treated with a uniform conditioning and GVHD prophylaxis regimen, we conclude that aGVHD prophylaxis with early use of tacrolimus and MMF is safe, effective, and associated with low NRM. Future strategies will need to focus on decreasing the incidence of extensive cGVHD without increasing the risk of relapse.     

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.     

Retrospective Multicenter Study of Extracorporeal Photopheresis in Steroid-Refractory Acute and Chronic Graft-versus-Host Disease

Extracorporeal photopheresis (ECP) is an established treatment strategy in steroid-refractory graft-versus-host disease (GVHD). This study's main objective was to analyze the clinical response and impact of ECP therapy in steroid dose reduction. A retrospective observational series of 113 patients from 7 transplantation centers was analyzed. Sixty-five patients (58%) had acute GVHD (aGVHD), and 48 (42%) had chronic GVHD (cGVHD). All ECP procedures were performed with the off-line system. The median number of procedures until achievement of initial response was 3 for both patients with aGVHD and those with cGVHD. ECP was the second-line therapy in 48% of the aGVHD cases and in 50% of the cGVHD cases. 71% of the cases of aGVHD were grade III-IV, and 69% of the cases of cGVHD were severe. The overall response rate on day 28 was 53% (complete response [CR] rate, 45%) in the patients with aGVHD and 67% (CR, 23%) in those with cGVHD. Skin was the most frequently involved organ, with a response rate of 58% (CR, 49%) in the patients with aGVHD and 69% (CR 29%) in those with cGVHD. At the end of ECP treatment, 60% of patients treated for aGVHD who responded were able to stop steroid therapy, with a median dose reduction of 100%. Significant differences in overall survival were observed for patients responding to ECP with aGVHD (hazard ratio [HR], 4.3; P < .001) and with cGVHD (HR, 4.8; P = .003). Our data indicate that ECP is a valid therapeutic alternative in patients with steroid-refractory aGVHD and cGVHD, permitting significant steroid dosage reductions.     

Hematopoietic Cell Transplantation from an HLA-Mismatched Familial Donor Is Feasible Without Ex Vivo-T Cell Depletion after Reduced-Intensity Conditioning with Busulfan,Fludarabine, and Antithymocyte Globulin

To extend the use of allogeneic hematopoietic cell transplantation (HCT) to patients without an HLA-matched donor, we investigated HCT from a related donor with 1 fully mismatched HLA-haplotype after conditioning with busulfan in reduced-dose, fludarabine, and antithymocyte globulin. Hematopoietic cells were collected from the donors via leukapheresis after mobilization and infused without further manipulation. Cyclosporin and methotrexate were administered for graft-versus-host disease (GVHD) prophylaxis. Posttransplant engraftment, GVHD, and transplantation-related mortality (TRM) were recorded. Thirty-one patients (age range: 16-69 years) with high-risk acute leukemia/myelodysplastic syndrome (n = 25) or bone marrow failure (n = 6) were enrolled. The donors were either mothers (n = 14), offspring (n = 9), or siblings (n = 8) of these patients. Excluding 3 patients who died or relapsed with leukemia within 3 weeks after HCT, all the remaining 28 patients engrafted with neutrophils (>500/μL) at a median of 16.5 days. Twenty-two of 24 evaluated patients achieved complete donor chimerism (≥95%) 2 weeks after HCT and none experienced graft failure subsequently. The cumulative incidences of grade 2-4 acute GVHD (aGVHD) and moderate-severe chronic GVHD (cGVHD) were 19% (95% confidence interval [CI], 9%-40%) and 20% (95% CI, 10%-41%), respectively. After a median follow-up of 18.2 months (range: 6.3-52.1), 18 patients remained alive (53%). Four patients died without recurrence/progression of underlying diseases giving a TRM of 13% (95% CI, 5%-33%). HCT from an HLA-mismatched family member is feasible without ex vivo T cell depletion when reduced-intensity conditioning containing anti-hymocyte globulin is performed.     

Sirolimus,Tacrolimus, and Low-Dose Methotrexate as Graft-versus-Host Disease Prophylaxis in Related and Unrelated Donor Reduced-Intensity Conditioning Allogeneic Peripheral Blood Stem Cell Transplantation

We assessed the combination of sirolimus, tacrolimus, and low-dose methotrexate as acute graft-versus-host disease (aGVHD) prophylaxis after reduced-intensity conditioning (RIC) allogeneic peripheral blood stem cell (PBSC) transplantation from matched related (MRD, n = 46) and unrelated (URD, n = 45) donors. All patients received fludarabine and intravenous busulfan conditioning followed by transplantation of mobilized PBSC. The median time to neutrophil engraftment was 13 days. The cumulative incidence of grade II-IV and III-IV aGVHD were 16% and 7%, respectively. There was no difference in the incidence of aGVHD between MRD and URD cohorts. Two-year cumulative incidence of extensive chronic GVHD (cGVHD) was 40%. Relapse-free survival (RFS) at 2 years was 34%: 21% in MRD and 45% in URD. Overall survival (OS) at 2 years was 59%: 47% in MRD and 67% in URD. High levels (>90%) of donor derived hematopoiesis were achieved in 59% of patients early after transplantation. The addition of sirolimus to tacrolimus and low-dose methotrexate as GVHD prophylaxis following RIC with fludarabine and low-dose intravenous busulfan is associated with rapid engraftment, low rates of aGVHD, and achievement of high levels of donor chimerism.     

Pilot Study of Prophylactic Ex Vivo Costimulated Donor Leukocyte Infusion After Reduced-Intensity Conditioned Allogeneic Stem Cell Transplantation

Donor leukocyte infusion (DLI) can induce potent graft-versus-leukemia (GVL) activity in patients with relapsed hematologic malignancies after allogeneic hematopoietic stem cell transplantation (HSCT). Unfortunately, except in patients with chronic-phase chronic myelogenous leukemia, responses to DLI have been disappointing. GVL induction is likely to be most effective in the setting of minimal residual disease. Prevention of relapse through the provision of prophylactic DLI to high-risk patients may improve the outcome of allogeneic HSCT. We previously reported that ex vivo costimulated T cell infusion of activated DLI (aDLI) as treatment for relapse is safe and has potent GVL effects. We hypothesized that prophylactic aDLI can be given safely and prevent relapse in high-risk patients after allogeneic HSCT. Eighteen patients with acute myeolgenous leukemia (n = 14), acute lymphoblastic leukemia (n = 3), or myelodysplastic syndrome (n = 1) underwent allogeneic HSCT after a reduced-intensity conditioning (RIC) regimen with alemtuzumab, fludarabine, and busulfan. Graft-versus-host-disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate with a planned early and rapid taper of tacrolimus. Patients without GVHD, off immune suppression, and in remission received aDLI at a dose of 1 × 10⁷ CD3⁺ cells/kg (aDLI 1) at day +120, followed by a second infusion of 1 × 10⁸ CD3 cells/kg (aDLI 2) at day +180. At a median follow-up of 58 months, 5 of the 18 patients (28%) were alive, and 4 patients were in remission. Eleven patients (65%) relapsed, at a median time of 191 days. Twelve of the 18 patients received at least one aDLI, and 6 of these 12 patients also received aDLI 2. Six patients did not receive any aDLI owing to early relapse (n = 2), protocol ineligibility (n = 1), or GVHD (n = 3). Only 2 of the 12 patients who received aDLI 1 developed GVHD. Two out of the 12 patients remain in remission at the time of this report. Disease recurrence was the cause of death in 10 of the 13 patients (77%) who died. Our data indicate that prophylactic ex vivo costimulated CD3/CD28 DLI is safe, feasible, and not associated with significant GVHD. Relapse remains the major cause of treatment failure after RIC HSCT even with rapid withdrawal of immune suppression and the use of prophylactic aDLI, and better strategies to prevent relapse are needed.     

High Serum Level of Antithymocyte Globulin Immediately before Graft Infusion Is Associated with a Low Likelihood of Chronic,But Not Acute,Graft-versus-Host Disease

Rabbit antithymocyte globulin (ATG) is administered during transplant conditioning to decrease the risk of both acute graft-versus-host disease (aGVHD) and chronic graft-versus-host disease (cGVHD). Here we evaluated the relationship between the serum concentration of ATG (capable of binding to lymphocytes) immediately before graft infusion (day 0) or on day +7 or +28 post-transplantation and the development of aGVHD or cGVHD. We studied 180 patients whose conditioning included 4.5 mg/kg antithymocyte globulin (ATG; Thymoglobulin). For aGVHD, we found no association with ATG levels on day 0. Nevertheless, high day +7 and +28 ATG levels were associated with a low likelihood of aGVHD. For cGVHD, high ATG levels at all 3 time points (days 0, +7, and +28) were associated with a low likelihood of cGVHD. In conclusion, high-dose ATG administration at the time of graft infusion appears to inhibit the development of cGVHD, but not aGVHD; however, higher ATG levels on days +7 and +28 are associated with lower rates of both aGVHD and cGVHD.     

Outcomes following HSCT Using Fludarabine,Busulfan, and Thymoglobulin: A Matched Comparison to Allogeneic Transplants Conditioned with Busulfan and Cyclophosphamide

We have reported a lower incidence of acute graft-versus-host disease (aGVHD) with a novel conditioning regimen using low-dose rabbit antithymocyte globulin (ATG; Thymoglobulin [TG]) with fludarabine and intravenous busulfan (FluBuTG). To assess further this single-center experience, we performed a retrospective matched-pair analysis comparing outcomes of adult patients transplanted using the FluBuTG conditioning regimen with matched controls from patients reported to the CIBMTR receiving a first allogeneic hematopoietic stem cell transplant (HCT) after standard oral busulfan and cyclophosphamide (BuCy). One hundred twenty cases and 215 matched controls were available for comparison. Patients receiving FluBuTG had significantly less treatment related mortality (TRM; 12% versus 34%, P < .001) and grades II-IV aGVHD (15% versus 34%, P < .001) compared to BuCy patients. The risk of relapse was higher in the FluBuTG patients (42% versus 20%, P < .001). The risks of chronic GVHD (cGVHD) and disease free survival (DFS) were similar in the cases and controls. These results suggest that the novel regimen FluBuTG decreases the risk of aGVHD and TRM after HLA-identical sibling HSCT, but is associated with an increased risk of relapse, resulting in similar DFS. Whether these conditioning regimens may be more suitable for specific patient populations based on relapse risk requires testing in prospective randomized trials.     

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.