Thiotepa,Busulfan, and Fludarabine Conditioning Regimen in T Cell-Replete HLA-Haploidentical Hematopoietic Stem Cell Transplantation

We report the outcomes of 51 patients who underwent unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post-transplantation cyclophosphamide (PT-Cy) and antithymocyte globulin (ATG), from peripheral blood stem cells (PBSCs) or bone marrow, after receipt of a TBF (thiotepa, busulfan, and fludarabine) conditioning regimen. Their median age was 55 years (range, 16 to 72 years). Hematologic diagnoses included acute leukemias (n = 31), lymphoid neoplasm (n = 12), myeloproliferative neoplasm (n = 5), and myelodysplastic syndromes (n = 3). Thirty-seven patients (73%) were in complete remission. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate for all patients, associated with ATG in 39 patients (76.5%). The median time to neutrophil engraftment was 17 days (range, 12 to 34 days). The cumulative incidences of grade II-IV and grade III-IV acute GVHD were 27.5% and 14%, respectively. In patients receiving a PBSC graft and ATG prophylaxis, grade II-IV aGVHD occurred in 16% of patients. The use of ATG and a lower thiotepa dose (5 mg/kg versus 10 mg/kg) were associated with a reduced cumulative incidence of grade II-IV acute GVHD (P = .03 and .005, respectively). The 2-year cumulative incidence of chronic GVHD was 29% and was significantly reduced to 13% with the lower thiotepa dose (P = .002). After a median follow-up of 25 months (range, 12 to 62 months), the cumulative incidences of nonrelapse mortality, relapse, overall survival (OS), disease-free survival (DFS), and GVHD-free, relapse-free survival (GFRFS) were 20%, 22.5%, 67%, 58%, and 51%, respectively. Pretransplantation disease status (complete remission versus others) was the main factor associated with OS, DFS, and GFRFS. In conclusion, the TBF conditioning regimen is an appealing platform in the haplo-HSCT setting with PT-Cy in terms of engraftment rate, toxicity, and disease control. We found no benefit of a thiotepa dose of 10 mg/kg compared with a dose of 5 mg/kg. ATG reduced the risk of acute GVHD without comprising outcomes.     

Addition of Thiotepa to Total Body Irradiation and Cyclophosphamide Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Acute Lymphoblastic Leukemia

Total body irradiation (TBI)/cyclophosphamide (CY) is a standard-of-care conditioning regimen in allogeneic hematopoietic stem cell transplant (HSCT) for pediatric acute lymphoblastic leukemia (ALL). This study sought to identify whether the addition of thiotepa (TT) to TBI/CY improves HSCT outcomes for pediatric patients with ALL. A retrospective analysis was performed on 347 pediatric ALL patients who underwent HSCT between 1995 and 2015, with 242 receiving TBI/CY/TT and 105 patients receiving TBI/CY. There were no statistical differences in age, donor source, or complete remission status between the 2 groups. Comparison of the TBI/CY/TT versus TBI/CY groups demonstrated no difference in transplant-related mortality at 1 (11% versus 11%), 5 (13% versus 16%), or 10 years (16% versus 16%). There was lower relapse in the TBI/CY/TT group at 1 (14% versus 26%), 5 (24% versus 36%), 10 (26% versus 37%), and 15 years (26% versus 37%) (P= .02) but was not statistically significant on multivariate analysis. The TBI/CY/TT group showed a trend toward improved disease-free survival (DFS) at 5 (59% versus 47%), 10 (56% versus 46%), and 15 years (49% versus 40%) (P = .05) but was not statistically significant on multivariate analysis. Comparing overall survival at 5 (62% versus 53%), 10 (57% versus 50%), and 15 years (50% versus 44%) demonstrated no statistical difference between the 2 groups. The addition of thiotepa to TBI/CY demonstrated no increase in transplant-related mortality for pediatric ALL HSCT but was unable to demonstrate significant benefit in disease control. Minimal residual disease status remained the key risk factor impacting both relapse and DFS. More studies are warranted to better clarify the benefits of using thiotepa in conditioning for ALL HSCT.     

Cord Haploidentical Non-In Vitro T Cell Depletion Allogeneic Hematopoietic Stem Cell Transplantation Reduces Relapse of Refractory Acute Leukemia

Whether a graft-versus-graft (GVG) response in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) is associated with an enhanced graft-versus-leukemia (GVL) effect remains highly controversial. Furthermore, it is unknown if the GVG response overwhelms the impact of refractory acute leukemia. We aimed to compare the characteristics and therapeutic outcomes between patients undergoing a modified haploidentical cord blood (cord-haplo) HSCT protocol (n?=?97) and those undergoing haploidentical HSCT (n?=?42) for refractory acute leukemia. A reliable and stable predominant haploidentical donor chimerism was established. The 2-year relapse rate was more favorable in patients undergoing cord-haplo HSCT than in those undergoing haploidentical HSCT (25.9% versus 53.2%; P = .007), as was progression-free survival (PFS; 35.5% versus 17.9%; P = .049). Meanwhile, nonrelapse mortality at 2 years was not significantly different (38.0% versus 24.6%; P = .367). We also found that a higher number of mutual haploidentical donor-mismatched antigens, a concept similar to HLA mismatching, was associated with better disease control. Multivariate analysis identified cord-haplo HSCT as an independent significant predictor of reduced relapse (hazard ratio [HR], .44; P = .028) and improved PFS (HR, .58; P = .033), as was chronic graft-versus-host disease (GVHD) (relapse: HR, .42; P ?= .013; PFS: HR, .63: P = .052). However, the incidences of neutrophil and platelet engraftment, GVHD, and virus reactivation were comparable in the 2 groups. This study demonstrates that cord-haplo HSCT significantly enhances the GVL effect and improves PFS, providing a reliable and efficient therapeutic platform for patients with refractory acute leukemia.     

Allogeneic Transplants in Follicular Lymphoma: Higher Risk of Disease Progression after Reduced-Intensity Compared to Myeloablative Conditioning

Reduced-intensity conditioning (RIC) regimens have been increasingly used for allogeneic hematopoietic stem cell transplantation (HSCT) in follicular lymphoma (FL). We compared traditional myeloablative conditioning regimens to RIC in FL. Outcomes of HLA-identical sibling HSCT for FL in 208 recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 1997 and 2002 were studied. Conditioning regimens were categorized as myeloablative (N = 120) or RIC (N = 88). Use of RIC regimens increased from <10% of transplants in 1997 to >80% in 2002 signaling a major shift in practice. Patients receiving RIC were older and had a longer interval from diagnosis to transplant. These differences did not correlate with outcomes. Median follow-up of survivors was 50 months (4-96 months) after myeloablative conditioning versus 35 months (4-82 months) after RIC (P < .001). At 3 years, overall survival (OS) for the myeloablative and RIC cohorts were 71 (63%-79%) and 62 (51%-72%; P = .15) and progression free survival (PFS), 67 (58%-75%) and 55 (44%-65%; P = .07), respectively. Lower Karnofsky performance score (KPS) and resistance to chemotherapy were associated with higher treatment-related mortality (TRM) and lower OS and PFS. On multivariate analysis, an increased risk of lymphoma progression after RIC was observed (relative risk = 2.97, P = .04). RIC has become the de facto standard in allogeneic HSCT for FL, and appears to result in similar long-term outcomes. Although disease-free survival (DPS) is similar compared to myeloablative conditioning, an increased risk of late disease progression after RIC is concerning.     

Intravenous Busulfan Compared with Treosulfan-Based Conditioning for Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia: A Study on Behalf of the Acute Leukemia Working Party of European Society for Blood and Marrow Transplantation

Dose intensity of the conditioning regimen has significant impact on the outcomes after stem cell transplantation (SCT) for acute myeloid leukemia. Most studies have shown more relapse, less nonrelapse mortality (NRM), and similar overall survival after reduced-intensity and myeloablative conditioning. There are limited data on the dose equivalence and expected outcomes of treosulfan-based compared with busulfan-based conditioning. We compared SCT outcomes after fludarabine with either intravenous busulfan at a myeloablative dose (FB4, 12.8?mg/kg, n?=?1265) or a reduced dose (FB2, 6.4?mg/kg, n?=?1456) or treosulfan at 42 g/m² (FT14, n?=?403) or 36 g/m² (FT12, n?=?168). Median patient age was 48, 60, 57, and 60 years in the FB4, FB2, FT14, and FT12 groups, respectively (P?<?.0001). Two-year overall survival was 58%, 53%, 53%, and 51%, respectively (P?=?.25). Multivariate analysis identified advanced age, advanced disease status, and secondary leukemia to be associated with worse survival. Relapse rate was 30%, 35%, 34%, and 40%, respectively. Relapse was more common after FB2, advanced age and disease status, secondary leukemia, and sibling donors. NRM was 17%, 18%, 21%, and 16%, respectively. NRM was least common after FT12 and more common with advanced age and disease status and unrelated donors. Treosulfan-based regimens were associated with lower rates of graft-versus-host disease. There was no difference in any outcome among patients in first complete remission at transplantation. However, there was better survival with treosulfan-based conditioning in advanced leukemia. In conclusion, survival is determined mostly by disease biology and is similar after various regimens. Treosulfan-based conditioning is more similar to myeloablative than to reduced-intensity conditioning but can be administered safely in older patients, with lower rates of graft-versus-host disease and possibly better outcomes in patients with active leukemia.     

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%).     

Reduced-Intensity Hematopoietic Cell Transplantation for Patients with Primary Myelofibrosis: A Cohort Analysis from the Center for International Blood and Marrow Transplant Research

We evaluated outcomes and associated prognostic factors in 233 patients undergoing allogeneic hematopoietic cell transplantation (HCT) for primary myelofibrosis (MF) using reduced-intensity conditioning (RIC). The median age at RIC HCT was 55 yr. Donors were a matched sibling donor (MSD) in 34% of RIC HCTs, an HLA well-matched unrelated donor (URD) in 45%, and a partially matched/mismatched URD in 21%. Risk stratification according to the Dynamic International Prognostic Scoring System (DIPSS) was 12% low, 49% intermediate-1, 37% intermediate-2, and 1% high. The probability of survival at 5 yr was 47% (95% confidence interval [CI], 40% to 53%). In a multivariate analysis, donor type was the sole independent factor associated with survival. Adjusted probabilities of survival at 5-yr were 56% (95% CI, 44% to 67%) for MSD, 48% (95% CI, 37% to 58%) for well-matched URD, and 34% (95% CI, 21% to 47%) for partially matched/mismatched URD (P = .002). The relative risk (RR) for NRM was 3.92 (P = .006) for well-matched URD and 9.37 (P < .0001) for partially matched/mismatched URD. Trends toward increased NRM (RR, 1.7; P = .07) and inferior survival (RR, 1.37; P = .10) were observed in DIPSS intermediate-2/high-risk patients compared with DIPSS low/intermediate-1 risk patients. Our data indicate that RIC HCT is a potentially curative option for patients with MF, and that donor type is the most important factor influencing survival in these patients.     

Allogeneic Hemopoietic Stem Cell Transplants in Patients with Acute Myeloid Leukemia (AML) Prepared with Busulfan and Fludarabine (BUFLU) or Thiotepa,Busulfan, and Fludarabine (TBF): A Retrospective Study

This is a multicenter retrospective comparison of 2 myeloablative conditioning regimens in 454 patients with acute myeloid leukemia (AML) in remission: busulfan (4 days) and fludarabine (BUFLU) versus thiotepa, busulfan, and fludarabine (TBF). Eligible for this study were patients allografted between January 2008 and December 2018 in 10 transplant centers, with AML in first or second remission: 201 patients received BUFLU, whereas 253 received TBF. The 2 groups (BUFLU and TBF) were comparable for age (P = .13) and adverse AML risk factors (P = .3). The TBF group had more second remissions and more haploidentical grafts. The donor type included HLA-identical siblings, unrelated donors, and family haploidentical donors. The 5-year cumulative incidence of nonrelapse mortality (NRM) was 19% for BUFLU and 22% for TBF (P = .8), and the 5-year cumulative incidence of relapse was 30% and 15%, respectively (P = .0004). The 5-year actuarial survival was 51% for BUFLU and 68% for TBF (P = .002). In a multivariate Cox analysis, after correcting for confounding factors, the use of TBF reduced the risk of relapse compared with BUFLU (P = .03) and the risk of death (P = .03). In a matched pair analysis of 108 BUFLU patients matched with 108 TBF patients, with the exclusion of haploidentical grafts, TBF reduced the risk of relapse (P = .006) and there was a trend for improved survival (P = .07). Superior survival of patients receiving TBF as compared with BUFLU is due to a reduced risk of relapse, with comparable NRM. The survival advantage is independent of donor type and AML risk factors.     

Pharmacoeconomic Analysis of Palifermin to Prevent Mucositis among Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation

Trials have shown benefits of palifermin in reducing the incidence and severity of oral mucositis in patients with hematological malignancies undergoing autologous hematopoietic stem cell transplantation (HSCT) with total body irradiation (TBI)-based conditioning regimens. Similar outcome data are lacking for patients receiving non-TBI–based regimens. We performed a retrospective evaluation on the pharmacoeconomic benefit of palifermin in the setting of non-TBI–based conditioning and autologous HSCT. Between January 2002 and December 2010, 524 patients undergoing autologous HSCT for myeloma (melphalan 200 mg/m²) and lymphoma (high-dose busulfan, cyclophosphamide, and etoposide) as preparative regimen were analyzed. Use of patient-controlled analgesia (PCA) was significantly lower in the palifermin-treated groups (myeloma: 13% versus 53%, P < .001; lymphoma: 46% versus 68%, P < .001). Median total transplant charges were significantly higher in the palifermin-treated group, after controlling for inflation (myeloma: $167,820 versus $143,200, P < .001; lymphoma: $168,570 versus $148,590, P < .001). Palifermin treatment was not associated with a difference in days to neutrophil engraftment, length of stay, and overall survival and was associated with an additional cost of $5.5K (myeloma) and $14K (lymphoma) per day of PCA avoided. Future studies are suggested to evaluate the cost-effectiveness of palifermin compared with other symptomatic treatments to reduce transplant toxicity using validated measures for pain and quality of life.     

A Phase I/II,Open-Label,Prospective, Multicenter Study to Evaluate the Efficacy and Safety of Lower Doses of Bortezomib Plus Busulfan and Melphalan as a Conditioning Regimen in Patients with Multiple Myeloma Undergoing Autologous Peripheral Blood Stem Cell Transplantation: The KMM103 Study

A phase I/II trial was conducted to explore the safety and activity of the addition of bortezomib on days -6, -3, and +1 relative to the day of autologous stem cell transplantation (ASCT) to a conditioning regimen with busulfan and melphalan (BuMel; 3.2 mg/kg/day busulfan on days -5 to -3 and 140 mg/m²/day melphalan on day -2) in patients with multiple myeloma (MM) following bortezomib-based induction chemotherapy. In phase I, doses of bortezomib (.7, 1.0, and 1.3 mg/m²) with BuMel were administered to groups of 3 patients each. No dose-limiting toxicities were observed. The maximum tolerated dose of bortezomib was 1.3 mg/m²/day. A subsequent cohort with 41 patients was analyzed in a phase II trial to identify safety and efficacy. The phase II trial showed a 75% response rate, including very good partial response (VGPR) or better, and a 55% rate of complete response (CR) at 3 months; For post-transplantation best response, an 83% rate of VGPR or better (68% CR) was observed. With a median follow-up of 31.4 months, the median progression-free survival (PFS) was 26.8 months. The probability of 2 year-PFS was 56.5%, and median overall survival (OS) could not calculated. Specifically, high-risk cytogenetics were associated with adverse survival outcomes compared with standard-risk cytogenetics (median PFS, 12.2 months versus 35.7 months, P = .039; median OS, 26.7 months versus 73.3 months; P = .086). With a median of 11 days to neutrophil engraftment and 10 days for platelet engraftment, no graft failure or delayed engrafting were observed. The most common grade 3 or severe nonhematologic adverse events included neutropenic fever (73.2%) and stomatitis (14.6%). Except for 3 patients with transplantation-related mortality due to sepsis, other adverse events were manageable. These findings demonstrate that bortezomib is safe and has a potential role in conditioning regimens in combination with BuMel for patients with transplantation-eligible MM.     

Busulfan Dose Intensity and Outcomes in Reduced-Intensity Allogeneic Peripheral Blood Stem Cell Transplantation for Myelodysplastic Syndrome or Acute Myeloid Leukemia

Comparisons of myeloablative conditioning versus reduced-intensity conditioning (RIC) have demonstrated a tradeoff between relapse and toxicity. Dose intensity across RIC regimens vary and may affect treatment outcomes. In this retrospective analysis, we investigated the effect of i.v. busulfan dosing (total dose 3.2 mg/kg versus 6.4 mg/kg) in RIC regimens that combined fludarabine and busulfan on outcomes in patients who were undergoing hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). A total of 217 consecutive patients with MDS or AML underwent first busulfan and fludarabine RIC peripheral blood stem cell transplantation from well-matched related or unrelated donors at our institutions between 2004 and 2009. Of the 217 patients, 135 patients received Bu1 (3.2 mg/kg of busulfan) and 82 patients received Bu2 (6.4 mg/kg of busulfan), both with daily fludarabine (30 mg/m²/day for 4 days). The choice of RIC regimen was based on temporal institutional standard, enrollment on protocols, and physician choice. Patients had similar characteristics with a few notable differences: Patients who received Bu1 were younger (median age 61 versus 64 years, P < . 001), received more single-antigen mismatched unrelated grafts (14.1% versus 1.2%, P < . 001), received more sirolimus-based graft-versus-host disease (GVHD) prophylaxis regimens (63% versus 45%, P < .0001), received less antithymocyte globulin for GVHD prophylaxis (0% versus 22%, P < .001), and had less enrollment on a clinical trial that used prophylactic rituximab for the prevention of chronic GVHD (2.2% versus 11.0%, P = .011). Clinical disease status was similar between the groups. Median follow-up for survivors was 4.4 years for Bu1 and 3.2 years for Bu2. Because of the differences in characteristics, the 2 groups were compared with the adjustment of a propensity score that predicted Bu2 to account for measured differences. The day +200 cumulative incidence rates of grades II to IV acute GVHD (Bu1, 17%, versus Bu2, 8.5%; hazard ratio [HR], .56; 95% confidence interval [CI], .22 to 1.41; P = .22) or grades III to IV acute GVHD (Bu1, 6.7%, versus Bu2, 4.9%) were not different. The 2-year cumulative incidence of chronic GVHD was not significantly different between Bu1 and Bu2 (41.5% versus 28%, respectively; HR, .70; CI, .42 to 1.17; P = .09). Two-year nonrelapse mortality rates were similar for Bu1 and Bu2 (8.9% versus 9.8%, respectively; HR, .80; CI, .29 to 2.21; P = .67). Two-year progression-free survival and overall survival were also similar between Bu1 and Bu2 (progression-free survival: 40.6% versus 39.3%, respectively; HR, .82; CI, .57 to 1.30; P = .33; and overall survival: 47.4% versus 48.8%, respectively; HR, .96; CI, .64 to 1.44; P = .85). Subset analysis defined by clinical disease and cytogenetic risk with the propensity risk score applied suggest that in patients with high clinical disease risk and nonadverse cytogenetics, the higher dose busulfan RIC regimen may be of marginal benefit (2-year progression-free survival: HR, .54; CI, .29 to 1.03; P = .062). For the majority of patients with MDS or AML undergoing busulfan and fludarabine RIC peripheral blood stem cell transplantation, however, the dose of busulfan (3.2 mg/kg versus 6.4 mg/kg) is not associated with significant differences in overall outcomes.     

Pretransplant Neutropenia Is Associated with Poor-Risk Cytogenetic Features and Increased Infection-Related Mortality in Patients with Myelodysplastic Syndromes

A retrospective cohort analysis was performed to determine the impact of neutropenia on the outcome of hematopoietic cell transplantation (HSCT) in patients with myelodysplasia (MDS). Among 291 consecutive patients, 178 (61%) had absolute neutrophil counts (ANCs) <1500/μL and 113 (39%) had ANCs ≥1500/μL within 2 weeks before HSCT. Neutropenic patients more often had poor-risk karyotypes (34% versus 12%, P < .0001) and high-risk International Prognostic Scoring System scores (37% veresus 18%, P = .0006). After HSCT, the rate of infections caused by Gram-positive bacteria and invasive fungal infections was significantly increased among neutropenic patients (rate ratio [RR] 1.77, P = .02 and RR = 2.56, P = .03, respectively), whereas infections caused by Gram-negative bacteria were not affected (RR 1.33, P = .53). The hazards of nonrelapse mortality (NRM) (hazard ratio [HR] = 1.62 [1.1-2.4], P = .01), overall mortality (HR = 1.55 [1.1-2.1], P = 0.007), and infection-related mortality (HR = 2.22 [1.2-4.2], P = .01) were increased in neutropenic patients, whereas relapse, engraftment, and graft-versus-host-disease were not affected. After adjusting for cytogenetic risk and marrow myeloblast percentages, neutropenic patients remained at significant hazard for infection-related mortality (HR = 1.94 [1.0-3.8], P = .05), but not for overall mortality or NRM. We propose that intensified strategies to prevent infections should be implemented in MDS patients with preexisting neutropenia who undergo HSCT.     

Reduced-Toxicity (BuFlu) Conditioning Is Better Tolerated but Has a Higher Second Transplantation Rate Compared to Myeloablative Conditioning (BuCy) in Children with Inherited Metabolic Disorders

Hematopoietic stem cell transplantation (HCT) is a primary treatment for various inherited metabolic disorders (IMDs). Achieving stable and sustained engraftment while minimizing transplantation-related morbidity and mortality is critical to optimizing outcomes for IMDs. Traditional regimens have used myeloablative approaches, primarily busulfan and cyclophosphamide (BuCy), which is associated with significant regimen-related toxicity. Alternatively, reduced-toxicity regimens, such as busulfan and fludarabine (BuFlu), have been proposed to offer similar efficacy with reduced toxicities. We compared transplantation-related outcomes with BuCy-based and BuFlu-based conditioning in patients with IMDs. We retrospectively analyzed the University of Minnesota's transplantation database for patients with IMDs who underwent HCT using a BuCy (with alemtuzumab) or BuFlu (with antithymocyte globulin) preparative regimen between March 2008 and September 2017. Overall survival (OS), event-free survival (EFS), and incidence of neutrophil and platelet recovery were determined using standard definitions. Complications such as graft failure, sinusoidal obstruction syndrome, hemorrhagic cystitis, and respiratory failure were compared. Graft failure includes primary and secondary aplastic graft failure with and without autologous recovery. The incidence of viral infections post-transplantation in the 2 regimens was also determined. A total of 99 patients underwent HCT for IMDs during the study period. Sixty-four patients received BuCy conditioning, and the other 35 received BuFlu. Hurler syndrome (46%) and adrenoleukodystrophy (43%) were the most common IMDs, and umbilical cord blood was the most common graft source (74%). One-year OS was similar in the 2 groups (81.2% in BuCy versus 85.5% in BuFlu; P = .8), with an EFS of 75% versus 63%, respectively. The 2 groups also had similar incidences of grade III-IV acute GVHD (9% versus 6%; P = .5) and chronic GVHD (9% versus 7%; P = .67). Neutrophil and platelet recovery were similar in the 2 groups, with a significantly shorter duration of hospital stay noted in the BuFlu cohort (median, 21 days versus 34 days; P = .002). The cumulative incidence of graft failure was significantly higher in the BuFlu group (29% versus 14%; P = .08), as was the rate of second HCT (27% versus 3%; P = .001). The incidences of adenoviral infection (14% versus 0%; P = .02) and hemorrhagic cystitis (23% versus 3%; P = .01) were higher in the BuCy group. T cell engraftment occurred significantly sooner with BuCy conditioning until 1-year post-transplantation, but donor myeloid engraftment was similar in the 2 groups. Our data indicate that reduced-toxicity conditioning is associated with lower rates of infection and other transplantation-related complications but is concerning for a higher rate of graft failure in patients with IMDs. Alternate immunosuppressive agents and novel techniques should be considered to minimize toxicities and reduce complications.     

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.     

Phase II Study of Yttrium-90-Ibritumomab Tiuxetan as Part of Reduced-Intensity Conditioning (with Melphalan,Fludarabine ± Thiotepa) for Allogeneic Transplantation in Relapsed or Refractory Aggressive B Cell Lymphoma: A GELTAMO Trial

We designed a phase II clinical trial including Y-90 ibritumomab-tiuxetan as part of a reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (AlloSCT) in high-risk non-Hodgkin lymphoma (Clinical Trials Identifier: NCT00644371). Eligible patients had high-risk relapsed/refractory aggressive lymphoma. The conditioning regimen consisted of rituximab 250?mg (days ?21 and ?14), Y-90 ibritumomab IV (.4?m Ci/kg, day ?14), fludarabine 30?mg/m² i.v. (days ?3 and ?2) plus melphalan 70?mg/m² i.v. (days ?3 and ?2) or 1 dose of melphalan and thiotepa 5?mg/kg (day ?8). Donors were related. Eighteen patients were evaluable. At the time of transplantation, responses were complete remission (CR) (n = 7, 39%), partial remission (n = 6, 33%) or refractory disease (n = 4, 28%). Y-90-ibritumomab infusions were well tolerated, with no adverse reactions. Nonrelapse mortality at 1 year was 28%. Median follow-up was 46 (range, 39 to 55) months. Estimated 1-year progression-free survival (PFS) was 50%, and 4-year overall survival (OS) and PFS were both 44.4%. CR at the moment of AlloSCT had significant impact on PFS (71% versus 27%, P?=?.046) and OS (71% versus 27%, P?=?.047). Our results show that Y-90-ibritumomab-tiuxetan as a component of RIC for AlloSCT is feasible in patients with high-risk B cell lymphoma. Development of phase III clinical trials is needed to clarify the contribution of radioimmunotherapy to RIC AlloSCT.     

Reduced-Intensity Conditioning with Fludarabine,Melphalan, and Total Body Irradiation for Allogeneic Hematopoietic Cell Transplantation: The Effect of Increasing Melphalan Dose on Underlying Disease and Toxicity

Disease relapse and toxicity are the shortcomings of reduced-intensity conditioning (RIC) for allogeneic hematopoietic cell transplantation (alloHCT). We hypothesized that adding total body irradiation (TBI) to and decreasing melphalan (Mel) from a base RIC regimen of fludarabine (Flu) and Mel would increase cytoreduction and improve disease control while decreasing toxicity. We performed a phase II trial of Flu 160 mg/m², Mel 50 mg/m², and TBI 400 cGy (FluMelTBI-50, n?=?61), followed by a second phase II trial of Flu 160 mg/m², Mel 75 mg/m², and TBI 400cGy (FluMelTBI-75, n?=?94) as RIC for alloHCT. Outcomes were compared with a contemporaneous cohort of 162 patients who received Flu 125 mg/m² and Mel 140 mg/m². Eligibility criteria were equivalent for all 3 regimens. All patients were ineligible for myeloablative/intensive conditioning. The median (range) follow-up for all patients was 51 (15 to 103) months. Day 100 donor lymphoid chimerism and transplant-related mortality, neutrophil and platelet engraftment, acute and chronic graft versus host disease incidence, overall survival (OS), and progression-free survival (PFS) were equivalent between FluMel, FluMelTBI-50, and FluMelTBI-75. Stomatitis wasdecreased for FluMelTBI versus FluMel (P < .01). PFS for patients not in complete remission on alloHCT was improved for FluMelTBI-75 versus FluMel (P?=?.03). On multivariate analysis, OS (P?=?.05) and PFS (P?=?.05) were significantly improved for FluMelTBI-75 versus FluMel. FluMelTBI-75 is better tolerated than FluMel, with improved survival and disease control.     

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.     

Synergistic Cytotoxic Effect of Busulfan and the PARP Inhibitor Veliparib in Myeloproliferative Neoplasms

Patients with high-risk myeloproliferative neoplasms (MPNs), and in particular myelofibrosis (MF), can be cured only with allogeneic hematopoietic stem cell transplantation (HSCT). Because MPNs and JAK2^V617F-mutated cells show genomic instability, stalled replication forks, and baseline DNA double-strand breaks, DNA repair inhibition with poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors represents a potential novel therapy. Because the alkylating agent busulfan is integral in conditioning regimens for HSCT and leads to stalled replication forks through DNA strand cross-linking, we hypothesized that PARP inhibition with veliparib in combination with busulfan may lead to synergistic cytotoxicity in MPN cells. We first treated 2 MPN cell lines harboring the JAK2^V617F mutation (SET2 and HEL) with veliparib at increasing concentrations and measured cell proliferation. SET2 and HEL cells were relatively sensitive to veliparib (IC₅₀ of 11.3 μM and 74.2 μM, respectively). We next treated cells with increasing doses of busulfan in combination with 4 μM veliparib and found that the busulfan IC₅₀ decreased from 27 μM to 4 μM in SET2 cells and from 45.1 μM to 28.1 μM in HEL cells. The mean combination index was .55 for SET2 cells and .40 for HEL cells. Combination treatment of SET2 cells caused G2M arrest in 53% of cells, compared with 30% with veliparib alone and 35% with busulfan alone. G2M arrest was associated with activation of the ATR-Chk1 pathway, as shown by an immunofluorescence assay for phosphorylated Chk1 (p-Chk1). We then tested in vivo the effect of combined low doses of busulfan and veliparib in a JAK2^V617F MPN-AML xenotransplant model. Vehicle- and veliparib-treated mice had similar median survival of 39 and 40 days, respectively. Combination treatment increased median survival from 47 days (busulfan alone) to 50 days (P = .02). Finally, we tested the combined effect of busulfan and veliparib on CD34⁺ cells obtained from the bone marrow or peripheral blood of 5 patients with JAK2^V617F-mutated and 2 patients with CALR-mutated MF. MF cells treated with the combination of veliparib and busulfan showed reduced colony formation compared with busulfan alone (87% versus 68%; P = .001). In contrast, treatment of normal CD34⁺ cells with veliparib did not affect colony growth. Here we show that in vivo confirmation that treatment with the PARP-1 inhibitor veliparib and busulfan results in synergistic cytotoxicity in MPN cells. Our data provide the rationale for testing novel pretransplantation conditioning regimens with combinations of PARP-1 inhibition and reduced doses of alkylators, such as busulfan and melphalan, for high-risk MPNs or MPN-derived acute myelogenous leukemia.     

Comparison of Two Doses of Antithymocyte Globulin in Patients Undergoing Matched Unrelated Donor Allogeneic Stem Cell Transplantation

Antithymocyte globulin (ATG) as part of conditioning regimens is known to reduce the incidence and severity of acute and chronic graft-versus-host disease (aGVHD, cGVHD). The influence of ATG on transplant-related mortality (TRM) and disease-free survival (DFS) is controversial, and may depend on the dose and timing of ATG. We retrospectively compared 2 doses of ATG-Fresenius (ATG-F) in patients undergoing matched unrelated donor allogeneic hematopoetic stem cell transplantation (HSCT) for hematologic malignancies. A dose of 60 mg/kg body weight has previously been recommended for ATG-F. All patients received cyclosporine A and short course methotrexate. ATG-F was administered at a dose of 30 mg/kg on day –1 (ATG-30 group, n = 34) or 20 mg/kg/day on days –3 to –1 (ATG-60 group, n = 49). There was no difference in time to leukocyte and platelet engraftment in the 2 groups. The incidence of aGVHD grade II-IV (50% versus 53%, P = .83) and grade III-IV (27 versus 20%, P = .60) was similar in the ATG-30 versus ATG-60 groups, respectively. There was a trend to a higher incidence of cGVHD in the ATG-30 group (59% versus 40%, P = .14). The estimated 3-year incidence of relapse was similar in the ATG-30 and ATG-60 groups (15% versus 16%, P = .84) whereas the 2-year TRM was lower for the ATG-30 group (12% versus 33%, P = 0.02), mainly because of a higher incidence of fatal infections in the ATG-60 group. This resulted in a better DFS (73% versus 51%, P = .07) for the ATG-30 group. ATG-F (30 mg/kg) administered as a single dose on day –1 may lead to better outcome in patients undergoing unrelated donor allogeneic HSCT compared to 60 mg/kg given in 3 equivalent doses. A prospective randomized study comparing these 2 doses of ATG-F is warranted.     

Unmanipulated Haploidentical Bone Marrow Transplantation and Posttransplantation Cyclophosphamide for Hematologic Malignancies after Myeloablative Conditioning

Fifty patients with high-risk hematologic malignancies, underwent an unmanipulated haploidentical bone marrow transplantation (BMT), followed by posttransplantation high-dose cyclophosphamide (PT-CY): the myeloablative (MA) conditioning consisted of thiotepa, busulfan, fludarabine (n = 35), or total body irradiation (TBI), fludarabine (n = 15). The median age was 42 years (range, 18-66 years); 23 patients were in remission, 27 had active disease, and 10 patients were receiving a second allograft. Graft-versus-host disease (GVHD) prophylaxis consisted in PT-CY on day +3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1). Three patients died before engraftment, and 2 patients had autologous recovery: 45 patients (90%) had full-donor chimerism on day +30. The median day for neutrophil engraftment was day +18 (range, 13-30 days). The cumulative incidence of grade II-III acute GVHD (aGVHD) was 12%, and of moderate chronic GVHD (cGVHD) 10%. With a median follow-up for surviving patients of 333 days (range, 149-623 days), the cumulative incidence of transplantation-related mortality (TRM) was 18%, and the rate of relapse was 26%. The actuarial 22-month disease-free survival (DFS) rate was 68% for patients in remission and 37% for patients with active disease (P < .001). Causes of death were pneumonia (n = 3), hemorrhage (n = 3), sepsis (n = 3), and relapse (n = 7). In conclusion, an MA conditioning regimen followed by haploidentical BMT with PT-CY results in a low risk of aGVHD and cGVHD and encouraging rates of TRM and DFS.