OBJECTIVE:High-intensity conditioning autologous hematopoietic stem cell transplantation (AHSCT) is standard of care for patients with advanced systemic sclerosis (SSc). The role of reduced-intensity conditioning (RIC) before AHSCT in this population remains unclear. We conducted this study to determine the long-term outcomes of RIC AHSCT in patients with SSc and cardiac involvement. METHODS:We evaluated 42 participants who sequentially underwent RIC AHSCT 5 years after the last participant was treated. Progression was defined as reinitiation of disease-modifying antirheumatic drugs or worsening end-organ failure. We determined overall survival (OS) and progression-free survival (PFS) by the Kaplan-Meier method and identified pretransplant characteristics associated with OS or PFS by multivariable Cox regression. RESULTS:All participants had evidence of SSc with cardiac involvement. Ninety-five percent of participants had interstitial lung disease. The median percent predicted forced vital capacity and diffusing capacity of the lungs for carbon monoxide was 62% and 45%, respectively. The 5-year OS was 75% (95% confidence interval [CI] 63%-90%), and 5-year PFS was 59% (95% CI 46%-76%). Pretransplant supplemental oxygen use (hazard ratio [HR] 7.88, P < 0.01) and elevated B-type natriuretic peptide (BNP; HR 1.005 per pg/mL, P < 0.01]) were associated with mortality. Anti-Scl-70 antibody positivity (HR 3.03, P = 0.02) was associated with progression. Twenty-four participants (57%) who did not use supplemental oxygen and had BNP <100 pg/mL pretransplant had a 5-year OS of 91% (95% CI 80%-100%). CONCLUSION:RIC AHSCT is safe for patients with severe manifestations from SSc. Supplemental oxygen use, elevated BNP, and anti-Scl-70 antibody positivity were risk factors for worse outcomes after RIC AHSCT.

ObjectiveTwo randomized trials for patients with diffuse systemic sclerosis (SSc) demonstrated an overall survival (OS) and event-free survival (EFS) advantage of autologous hematopoietic stem cell transplantation (AHSCT) using CD34+ selected peripheral blood stem cells (PBSCs) compared with monthly cyclophosphamide (CY). We asked if an unmodified PBSC graft followed by maintenance mycophenolate mofetil (MMF) after AHSCT, instead of a CD34+ selected graft, could provide comparable AHSCT outcomes.MethodsTwenty patients with high-risk SSc were enrolled in a prospective, single-arm trial with CY 200 mg/kg and horse antithymocyte globulin (ATG; CY200/ATG), followed by unmanipulated autologous PBSC, and then MMF maintenance starting at 2 months after AHSCT.ResultsPoint estimates of OS and EFS at 5 years after AHSCT were 85% (95% confidence interval [CI] 60.4%-94.9%) and 75% (95% CI 50%-88.7%), respectively. Median follow-up was 7.5 years (range 5.6-11.6) after transplant for living patients. Eight patients (40%) required intensive care unit treatment early after transplant. Early transplant-related mortality occurred in two patients (10%). Five patients developed relapse/progression of SSc after AHSCT. Four of nine patients with anti-RNA polymerase III antibodies had prior scleroderma renal crisis and the lowest quartile of estimated glomerular filtration rate (eGFR) on study entry; all four patients developed prolonged organ failure/death early after transplant.ConclusionWe observed favorable OS and EFS after AHSCT for patients with SSc, using CY200/ATG, unmanipulated PBSCs, and MMF posttransplant maintenance, which was comparable to trials with CD34+ graft selection. We identified a possible risk factor, pretransplant low eGFR, for adverse outcomes after AHSCT.

Background & aims: Durable remissions of Crohn's Disease (CD) have followed myeloablative conditioning therapy and allogeneic marrow transplantation. For patients with treatment-refractory disease, we used reduced-intensity conditioning to minimize toxicity, marrow from donors with low Polygenic Risk Scores for CD as cell sources, and protracted immune suppression to lower the risk of graft-versus-host disease (GVHD). Our aim was to achieve durable CD remissions while minimizing transplant-related complications. Methods: DNA from patients and their HLA-matched unrelated donors was genotyped and Polygenic Risk Scores calculated. Donor marrow was infused following non-myeloablative conditioning. Patient symptoms and endoscopic findings were documented at intervals after transplant. Results: We screened 807 patients, 143 of whom met eligibility criteria; 2 patients received allografts. Patient 1 had multiple complications and died at day 332 from respiratory failure. Patient 2 had resolution of CD symptoms until day 178 when CD recurred, associated with persistent host chimerism in both peripheral blood and intestinal mucosa. Withdrawal of immune suppression was followed by dominant donor immune chimerism in peripheral blood and resolution of CD findings. Over time, mucosal T-cells became donor-dominant. At 5 years after allografting, Patient 2 remained off all medications but had mild symptoms related to a jejunal stricture that required stricturoplasty at 6 years. At 8 years, she remains stable off medications. Conclusions: The kinetics of immunologic chimerism after allogeneic marrow transplantation for CD patients depends on the intensity of the conditioning regimen and the magnitude of immune suppression. One patient achieved durable improvement of her previously refractory CD only after establishing donor immunologic chimerism in intestinal mucosa. Her course provides proof-of-principal for allografting as a potential treatment for refractory CD, but an immunoablative conditioning regimen should be considered for future studies.(ClinicalTrials.gov, NCT01570348)

Abstract Objective Myasthenia gravis (MG) is an autoantibody‐mediated neuromuscular junction disorder involving the acetylcholine receptors on the motor endplate. The safety and response to high‐dose chemotherapy (HDIT) and autologous hematopoietic cell transplantation (HCT) were assessed in a patient with severe refractory MG. Methods As part of a pilot study of HDIT/HCT for patients with treatment‐resistant autoimmune neurological disorders, a patient with severe refractory MG underwent treatment. After mobilization of hematopoietic stem cells with rituximab, prednisone, and G‐CSF, the patient had HDIT consisting of carmustine, etoposide, cytarabine, melphalan, and rabbit antithymocyte globulin, followed by autologous HCT. The effect of treatment on the autoantibody to the acetylcholine receptor (AChR) was assessed. Results The patient had been diagnosed with AChR antibody‐positive MG 14 years before HDIT/HCT and had failed thymectomy, therapeutic plasma exchange, and multiple immunomodulatory agents. The Myasthenia Gravis Foundation of America (MGFA) clinical classification was IVb before HDIT/HCT. She tolerated HDIT/HCT well and started to improve clinically within days of treatment. At both 1 and 2 years after HDIT/HCT, patients remained symptom‐free. After HDIT/HCT, AChR‐binding autoantibodies persisted, and the relative frequency of immune cell subtypes shifted. Interpretation HDIT/HCT induced a complete response of disease activity in a patient with severe refractory MG. This response may suggest that a cell‐mediated etiology may be a significant contributing factor in refractory MG cases. A phase 2 clinical trial is warranted to establish if HDIT/HCT can be an effective therapy for severe refractory MG and to gain a further understanding of disease pathogenesis.

Introduction Fanconi anemia (FA) is an inherited disorder of impaired DNA repair, associated with progressive bone marrow failure (BMF), leukemia, and cancer predisposition. Hematopoietic cell transplantation (HCT) may be curative for FA associated BMF, and changes in HCT practice over the past decades may have impacted outcomes in FA patients. Methods We used CIBMTR database to perform a retrospective cohort study of children and adults undergoing first allogeneic HCT for FA BMF (patients with MDS/AML excluded) from 2000-2018. We hypothesized that contemporary HCT approaches, including decreases in radiation and increase in use of serotherapy and ex-vivo graft manipulation, would associate with improved outcomes in FA patients receiving HCT. The primary endpoints were overall survival (OS) and early subsequent malignant neoplasm (SMN; by 5 yr post-HCT). Secondary endpoints included event free survival (EFS; death, SMN or graft failure), treatment related mortality (TRM), graft failure, and acute (grade II-IV) and cGVHD. Univariate and multivariate Cox regression models were created to evaluate the impact of conditioning, donor and graft source, treatment era, and patient characteristics on outcomes, adjusting for other significant covariates. Due to confounding factors, we were not able to create a single multivariate model that included radiation, ex-vivo graft manipulation, and donor and graft source; therefore, we performed subgroup univariate analysis for patients receiving unrelated donor bone marrow (BM) or peripheral blood stem cell (PBSC) HCT. Results We analyzed 652 HCTs from 2000-07 (n=353) and 2008-18 (n=293). 223 (35%) patients had a matched related donor (MRD) with any graft type, 244 (38%) had an unrelated donor BM or PBSC grafts, 123 (19%) had an unrelated cord blood graft, and 44 (7%) had a related haploidentical donor with any graft type. Between the two treatment eras, 5-yr OS has dramatically improved (78.8% 2008-18 v 62.5% 2000-07, p<0.01; figure 1) driven by lower 5-yr TRM (15.2% v 25.5%, p=0.004) and lower rates of primary (7.9% v 12.9% at 42 days, p=0.038) and secondary (4.1% v 8.9% at 1 year, p=0.014) graft failure. No statistically significant change was observed for aGVHD, cGVHD, or early SMN. Assessing the entire cohort, use of total body irradiation (TBI) >300cGy was associated with lower OS (HR=1.75, 95% CI 1.24-2.47) and increased TRM (HR=3.36, 95% CI 1.54-7.34; figure 2) on multivariable analysis. For patients that received unrelated BM or PBSC HCT, use of TBI was associated with inferior OS survival (HR=1.93, 95% CI 1.18-3.17), EFS (HR=1.78, 95% CI 1.13-2.80), and TRM (HR=2.31, 95% CI 1.20-4.46) on univariate analysis. Among all patients, CD34 selection or T-cell depletion ( ex vivo depletion) were not associated with better OS (95% HR=1.014, 95% CI 0.84-1.56), EFS (HR=1.163, 95% CI 0.86-1.58), or TRM (HR=0.79, 95% CI 0.52-1.19) but was associated with less aGVHD (HR=0.35 95% CI 0.22-0.57) and lower but not-statistically significant cGVHD (HR=0.54, 95% CI 0.29-1.01) on multivariable analysis. Within the unrelated donor setting, univariate analysis showed reduced aGVHD (HR=0.39 95% CI 0.23-0.68) and cGVHD (HR=0.47 95% CI 0.28-0.79) but did not have a significant effect on OS, EFS, or TRM. Early SMN occurred in 3.2% of participants by 5-years post-HCT and was associated with cGVHD occurrence (HR=2.14, 95% CI 1.06-4.33) and older age (>18 v <9 years, HR=6.35, 95% CI 2.66-15.14), but not ex-vivo depletion or use of ATG or alemtuzumab. Early SMN risk was not impacted by the use of TBI (HR=1.60, 95% CI 0.77-3.34), but secondary analysis demonstrated a trend towards a relationship with doses >300 cGy (HR=2.24, 95% CI 0.99-5.08). Conclusions Outcomes for patients with FA BMF have improved significantly in more recent HCT eras, driven by reductions in TRM and graft failure risk. Although radiation doses >300cGy were associated with greater toxicity, doses of 100-300cGy were not associated with inferior outcomes in our cohort. Use of CD34 selection or T-cell depletion may reduce the risk of GVHD in transplant FA patients, but does not appear to impact 5-yr OS. Risk for early SMN development in FA patients receiving HCT associates with older age and cGVHD.

The present work addresses the effect of three high-temperature deformation modes, namely, torsion, uniaxial compression, and plane strain compression, on flow stress vs. strain curves, as well as on post-dynamic and static recrystallization of 316Nb austenitic stainless steel. Using a Hosford criterion instead of the classical von Mises criterion enables a unified description of the stress–strain curves obtained under different loading modes. This work also revealed that the loading mode had no significant effect on post-dynamic and static recrystallization phenomena. The amount of niobium atoms in solid solution might be preponderant in the control of recrystallization of 316Nb.

Background: Allogeneic hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis (HLH) disorders is associated with substantial morbidity and mortality. Objective: The effect of conditioning regimen groups of varying intensity on outcomes after transplantation was examined to identify an optimal regimen or regimens for HLH disorders. Methods: We studied 261 patients with HLH disorders transplanted between 2005 and 2018. Risk factors for transplantation outcomes by conditioning regimen groups were studied by Cox regression models. Results: Four regimen groups were studied: (1) fludarabine (Flu) and melphalan (Mel) in 123 subjects; (2) Flu, Mel, and thiotepa (TT) in 28 subjects; (3) Flu and busulfan (Bu) in 14 subjects; and (4) Bu and cyclophosphamide (Cy) in 96 subjects. The day 100 incidence of veno-occlusive disease was lower with Flu/Mel (4%) and Flu/Mel/TT (0%) compared to Flu/Bu (14%) and Bu/Cy (22%) (P < .001). The 6-month incidence of viral infections was highest after Flu/Mel (72%) and Flu/Mel/TT (64%) compared to Flu/Bu (39%) and Bu/Cy (38%) (P < .001). Five-year event-free survival (alive and engrafted without additional cell product administration) was lower with Flu/Mel (44%) compared to Flu/Mel/TT (70%), Flu/Bu (79%), and Bu/ Cy (61%) (P = .002). The corresponding 5-year overall survival values were 68%, 75%, 86%, and 64%, and did not differ by conditioning regimen (P = .19). Low event-free survival with Flu/Mel is attributed to high graft failure (42%) compared to Flu/Mel/TT (15%), Flu/Bu (7%), and Bu/Cy (18%) (P < .001). Conclusions: Given the high rate of graft failure with Flu/Mel and the high rate of veno-occlusive disease with Bu/Cy and Flu/Bu, Flu/Mel/TT may be preferred for HLH disorders. Prospective studies are warranted.

Background: Brain volume loss (BVL) is commonly observed after high-dose immunosuppression and autologous hematopoietic cell transplantation (HDIT/HCT) for treatment of multiple sclerosis (MS). To better understand the mechanisms of underlying BVL associated with this treatment, we characterized the time courses of wholebrain (WB), grey-matter (GM) and white-matter (WM) volume loss in relapsing-remitting MS (RRMS) patients who received BEAM-based HDIT/HCT. Methods: We used Jacobian integration to measure MRI-based WB, GM and WM volume changes up to 5 years after transplant in twenty-four RRMS participants who underwent BEAM-based HDIT/HCT. Using a twopiecewise mixed-effects model, we estimated the short-term (baseline to 1 year) and long-term (beyond 1 year) rates of BVL after HDIT/HCT. We also compared the rates based on the presence of gadolinium-enhancing lesions at baseline, and the maintenance of event-free survival during follow-up. Results: On average, accelerated short-term BVL of -1.37% (SE: 0.21), -0.86% (SE: 0.28) and -2.18% (SE: 0.26) occurred in WB, GM and WM, respectively. Baseline T1-weighted MRI WM lesion volume was a significant predictor in the WB (short-term) and the WM (short-term and long-term). The average rates of BVL after the initial acceleration were -0.22%/y (SE: 0.10), -0.13%/y (SE: 0.11) and -0.36%/y (SE: 0.11) in the WB, GM and WM, respectively. Participants with gadolinium-enhancing lesions at baseline had significantly higher short-term rates of GM (-1.56% vs. -0.27%, p = 0.01) and WB volume loss (-1.94% vs. -0.81%, p = 0.006) at 1 year follow-up as compared to those without gadolinium-enhancing lesions. WM volume loss was not significantly different (-2.59% vs. -1.66%, p = 0.16). Participants who maintained event-free survival had similar rates of BVL compared to those who did not.

We have used a non-myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation for the past twenty years. During that period, changes in clinical practice have been aimed at reducing morbidity and mortality from infections, organ toxicity, and graft-versus-host disease. We hypothesized that improvements in clinical practice led to better transplantation outcomes over time. From 1997-2017, 1,720 patients with hematologic malignancies received low-dose total body irradiation +/- fludarabine or clofarabine before transplantation from HLA-matched sibling or unrelated donors, followed by mycophenolate mofetil and a calcineurin inhibitor ± sirolimus. We compared outcomes in three cohorts by year of transplantation: 1997 +/- 2003 (n=562), 2004 +/- 2009 (n=594), and 2010 +/- 2017 (n=564). The proportion of patients ≥60 years old increased from 27% in 1997 +/- 2003 to 56% in 2010-2017, and with scores from the Hematopoietic Cell Transplantation Comborbidity Index of ≥3 increased from 25% in 1997 +/- 2003 to 45% in 2010 +/- 2017. Use of unrelated donors increased from 34% in 1997 +/- 2003 to 65% in 2010-2017. When outcomes from 2004 +/- 2009 and 2010-2017 were compared to 1997 +/- 2003, improvements were noted in overall survival (P=.0001 for 2004-2009 and P <.0001 for 2010-2017), profression-free survival (P=.002 for 2004-2009 and P <.0001 for 2010 +/- 2017), non-relapse mortality (P<.0001 for 2004 +/- 2009 and P <.0001 for 2010 +/- 2017), and in rates of grades 2 +/- 4 acute and chronic graft-vs.-host disease. For patients with hematologic malignancies who underwent transplantation with non-myeloablative conditioning, outcomes have improved during the past two decades. Trials reported are registered under ClinicalTrials.gov identifiers: NCT00003145, NCT00003196, NCT00003954, NCT00005799, NCT00005801, NCT00005803, NCT00006251, NCT00014235, NCT00027820, NCT00031655, NCT00036738, NCT00045435, NCT00052546, NCT00060424, NCT00075478, NCT00078858, NCT00089011, NCT00104858, NCT00105001, NCT00110058, NCT00397813, NCT00793572, NCT01231412, NCT01252667, NCT01527045.

Introduction: Inborn errors of immunity such as hemophagocytic lymphohistiocytosis (HLH) and chronic granulomatous disease (CGD) are characterized by hyperinflammation. Hematopoietic cell transplantation (HCT) in the setting of hyperinflammation leads to high morbidity and mortality. Consequently, there is increasing use of less intense conditioning regimens, which can increase risk of mixed chimerism or graft failure. We sought to study the effect of common regimens on outcomes after HCT using data reported to the Center for International Blood and Marrow Transplant Research. Methods : 365 patients aged <21 years with HLH (n=263) and CGD (n=102) were transplanted in the US between 2005-2018. Included are recipients of HLA-matched sibling (n=58; 16%) and HLA-matched (n=149; 41%) and mismatched unrelated (n=158; 43%) donor HCT. The analysis considered 3 conditioning regimen intensity groups: 1) fully myeloablative conditioning with busulfan (Bu; median dose 16 mg/kg [IQR 13-17]), cyclophosphamide (Cy) ± anti-thymocyte globulin (ATG) or alemtuzumab, n=142; 2) reduced intensity conditioning consisting of fludarabine (Flu), melphalan (Mel; 140mg/m2 [60%], 100 mg/m2 [40%]) ± alemtuzumab or ATG, n=131; and 3) reduced toxicity myeloablative conditioning consisting of either Flu, Mel (140mg/m2 [75%], 100 mg/m2 [25%]), and thiotepa (TT; 8 mg/kg or 10 mg/kg), or Flu, Bu (12mg/kg, IQR 9-15) ± alemtuzumab or ATG, n=92. The cumulative incidence rates of veno-occlusive disease (VOD) and infections were calculated. The probabilities of overall survival and event-free survival were calculated using Kaplan-Meier estimator. For event-free survival, an event was defined as the first occurrence of any of the following: primary graft failure, secondary graft failure, cellular product intervention for mixed chimerism, donor chimerism <5%, second transplant, or death. The Fine and Gray method for acute and chronic GVHD and Cox regression analysis for event-free and overall survival were used to determine factors affecting outcomes. Results : Patient demographics were similar across the three treatment groups. Patients with HLH were more likely to receive the Flu/Mel regimen. Although unrelated donor HCTs were predominant across the treatment groups, cord blood graft was more common in the Bu/Cy group. Conditioning regimens changed over the study period with most Flu/Mel/TT and Flu/Bu regimens used after 2010. Consequently, outcomes were censored 2-years post-HCT to account for differences in follow-up. The day-100 incidence of VOD was higher with Bu/Cy (18%) compared to Flu/Mel (4%) and Flu/Mel/TT or Flu/Bu (7%) regimens (p<0.001). The 6-month incidence of bacterial infection was higher after Bu/Cy (50%) and Flu/Mel (58%) compared to Flu/Mel/TT or Flu/Bu (43%) regimens (p=0.013). Viral infections were higher in Flu/Mel group (72%) compared to Bu/Cy (44%) and Flu/Mel/TT or Flu/Bu (56%), p<0.001. There were no differences in overall survival (Figure 1A), but event-free survival (Figure 1B) was lowest with the Flu/Mel regimen, after adjusting for donor type (Table 1). Compared to matched sibling, survival was lower with matched (HR 2.41, p=0.05) and mismatched (HR 2.89, p=0.01) unrelated donor HCT. Chronic GVHD but not grade II-IV acute GVHD was lower with Flu/Mel regimen. Table 2 shows the results of multivariate analysis for HLH disorders and findings consistent with the main analysis. Conclusion : The data does not support the use of a reduced intensity Flu/Mel regimen for hyperinflammatory inborn errors of immunity. Although we did not observe differences in event-free survival between Bu/Cy and Flu/Mel/TT or Flu/Bu regimens, lower incidences of VOD and bacterial infections favor Flu/Mel/TT or Flu/Bu regimens. Disclosures Pulsipher: Bellicum: Honoraria; Jasper: Honoraria; Novartis: Honoraria; Miltenyi: Honoraria, Research Funding; Mesoblast: Honoraria; Adaptive: Research Funding. Stenger:ISCT: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Research Funding.

Although autologous hematopoietic cell transplantation (AHCT) is standard therapy for patients with lymphoma and multiple myeloma (MM), few studies have addressed late effects and quality of life (QoL) in long-term survivors after AHCT. Using long-term follow-up (LTFU) annual questionnaires with self-reported outcomes, we surveyed 665 patients who were at ≥5 years after AHCT for the diagnosis of lymphoma or MM. Three-hundred and eighty-nine patients completed the questionnaire (58% response rate) at a median of 11 years (range, 5-30 years) after AHCT. The median patient age was 63 years (range, 22-88 years) in the 268 patients with lymphoma and 69 years (range, 34-84 years) in the 121 patients with multiple myeloma. The most commonly reported medical conditions (>10% incidence) were sexual dysfunction, history of shingles, cataracts, osteoporosis or osteopenia, joint replacement, and skin cancer. Current medication use was more frequent in the patients with MM for infection prevention/treatment (19% for MM versus 5% lymphoma; P < .001), hypertension (41% versus 26%; P = .004), osteoporosis (23% versus 10%; P < .001), and pain (32% versus 11%, P < .001). Treated hypothyroidism was more common in lymphoma patients. In multivariate analysis combining lymphoma and MM, worse physical functioning was associated with older age, shorter interval since AHCT, comorbidities, relapse, and treatment for depression and/or pain. Worse mental functioning was associated with younger age and treatment for anxiety, depression, or pain. In conclusion, AHCT survivors report generally good QoL but many late effects and symptoms that are potentially amenable to intervention.

Effective treatment for severe aplastic anemia (SAA) is either allogeneic bone marrow transplantation (BMT) [1Bacigalupo A. How I treat acquired aplastic anemia.Blood. 2017; 129: 1428-1436Crossref PubMed Scopus (219) Google Scholar, 2Georges G.E. Storb R. Hematopoietic cell transplantation for aplastic anemia.in: Forman SJ Negrin RS Antin JH Appelbaum FR Thomas' Hematopoietic Cell Transplantation. 5th ed. John Wiley & Sons, Chichester, United Kingdom2016: 517-536Crossref Scopus (3) Google Scholar] or nontransplant immunosuppressive therapy (IST) containing antithymocyte globulin (ATG) [3Frickhofen N. Heimpel H. Kaltwasser J.P. Schrezenmeier H. Antithymocyte globulin with or without cyclosporin A: 11-year follow-up of a randomized trial comparing treatments of aplastic anemia.Blood. 2003; 101: 1236-1242Crossref PubMed Scopus (278) Google Scholar, 4Townsley D.M. Scheinberg P. Winkler T. et al.Eltrombopag added to standard immunosuppression for aplastic anemia.N Engl J Med. 2017; 376: 1540-1550Crossref PubMed Scopus (299) Google Scholar]. Both treatment approaches have advanced over the recent decades to achieve significantly improved outcomes. Considering that allogeneic BMT is a more durable treatment with a reduced risk of long-term complications and improved overall survival compared with IST, there is widespread consensus that BMT is the preferred first-line therapy for younger patients with SAA who have an HLA-matched sibling donor [1Bacigalupo A. How I treat acquired aplastic anemia.Blood. 2017; 129: 1428-1436Crossref PubMed Scopus (219) Google Scholar]. Younger has been generally defined as patients <40years of age. There is also recent evidence that if an HLA-matched unrelated donor can be rapidly identified (with an urgent, fast-track search), younger patients with SAA also have improved long-term survival if unrelated donor BMT is used as first-line therapy [5Dufour C. Veys P. Carraro E. et al.Similar outcome of upfront-unrelated and matched sibling stem cell transplantation in idiopathic paediatric aplastic anaemia. A study on behalf of the UK Paediatric BMT Working Party, Paediatric Diseases Working Party and Severe Aplastic Anaemia Working Party of EBMT.Br J Haematol. 2015; 171: 585-594Crossref PubMed Scopus (115) Google Scholar]. Based on previous registry data and clinical trials, older patients (generally >40 or 50 years of age) with SAA had poor survival outcomes with allogeneic BMT, and IST was recommended as first-line therapy for older patients [6Bacigalupo A. Giammarco S. Sica S. Bone marrow transplantation versus immunosuppressive therapy in patients with acquired severe aplastic anemia.Int J Hematol. 2016; 104: 168-174Crossref PubMed Scopus (36) Google Scholar]. Twenty years ago, the question of whether allogeneic BMT should even be offered to older patients who had failed IST (with relapse of SAA) was considered controversial [7Doney K. Leisenring W. Storb R. Appelbaum F.R. Primary treatment of acquired aplastic anemia: outcomes with bone marrow transplantation and immunosuppressive therapy.Ann Intern Med. 1997; 126: 107-115Crossref PubMed Scopus (153) Google Scholar]. However, over the past decade, less toxic conditioning regimens, improved selection of patients and donors, and improved control of both acute and chronic graft-versus-host disease (GVHD) have significantly decreased treatment-related mortality for older patients with SAA undergoing allogeneic BMT [8Sangiolo D. Storb R. Deeg H.J. et al.Outcome of allogeneic hematopoietic cell transplantation from HLA-identical siblings for severe aplastic anemia in patients over 40years of age.Biol Blood Marrow Transplant. 2010; 16: 1411-1418Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 9Maury S. Bacigalupo A. Anderlini P. et al.Improved outcome of patients older than 30years receiving HLA-identical sibling hematopoietic stem cell transplantation for severe acquired aplastic anemia using fludarabine-based conditioning: a comparison with conventional conditioning regimen.Haematologica. 2009; 94: 1312-1315Crossref PubMed Scopus (96) Google Scholar]. Despite this progress, there was a dearth of recent registry data that focused on the outcome of allogeneic BMT for older patients with SAA. In this issue, Rice et al. [10Rice C, Eikema DJ, Marsh JCW, et al. Allogeneic hematopoietic cell transplantation in patients aged 50years or older with severe aplastic anemia [e-pub ahead of print]. Biol Blood Marrow Transplant. doi:10.1016/j.bbmt.2018.08.029. Accessed 1 February 2019.Google Scholar] provide a comprehensive analysis on the outcome of 499 SAA patients ≥50 years old (median age, 57.8; range, 50 to 77) who underwent hematopoietic cell transplantation between 2005 and 2016 from an HLA-matched sibling or unrelated donor at a median of 10 months (range, <1 to 29.7 years) since diagnosis. This was a retrospective combined European Group for Blood and Marrow Transplantation/Center for International Blood and Marrow Transplant Research registry study. Multivariate analysis indicted higher mortality risk for patients with performance scores <90 and recipients of unrelated donor grafts. The 3-year probability of overall survival for patients with performance scores of 90 to 100 and after HLA-matched sibling and unrelated donor transplant was 66% and 57%, respectively. For patients with performance scores <90 and after HLA-matched sibling and unrelated donor transplant, the 3-year overall survival was 57% and 48%, respectively. These data support the rationale for performing allogeneic BMT in older patients with SAA, especially after failure of first-line therapy with IST. Although there are several shortcomings with a retrospective combined registry analysis, the overall conclusions and observations are important and highly relevant for clinical practice. First, based on the favorable survival data for older patients with SAA, all patients who experience failure of first-line IST must be considered for allogeneic BMT as second-line therapy. Compared with published results for a second course of IST for refractory SAA [11Desmond R. Townsley D.M. Dumitriu B. et al.Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug.Blood. 2014; 123: 1818-1825Crossref PubMed Scopus (277) Google Scholar, 12Scheinberg P. Cooper J.N. Sloand E.M. Wu C.O. Calado R.T. Young N.S. Association of telomere length of peripheral blood leukocytes with hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia.JAMA. 2010; 304: 1358-1364Crossref PubMed Scopus (153) Google Scholar], and the risk of progression to myelodysplastic syndrome or acute myeloid leukemia [13Kulasekararaj A.G. Jiang J. Smith A.E. et al.Somatic mutations identify a subgroup of aplastic anemia patients who progress to myelodysplastic syndrome.Blood. 2014; 124: 2698-2704Crossref PubMed Scopus (177) Google Scholar, 14Yoshizato T. Dumitriu B. Hosokawa K. et al.Somatic mutations and clonal hematopoiesis in aplastic anemia.N Engl J Med. 2015; 373: 35-47Crossref PubMed Scopus (402) Google Scholar], the outcome for allogeneic BMT is superior. Even for select patients with performance status <90, an unrelated donor BMT may be more appropriate than a second attempt at IST. The unanswered question is whether an older patient with excellent performance status (90 to 100) and an HLA-matched donor should proceed to allogeneic BMT as first-line treatment for SAA. The case can be made that for the appropriately informed older patient, allogeneic BMT should be considered as first-line therapy [15Georges G.E. Doney K. Storb R. Severe aplastic anemia: allogeneic bone marrow transplantation as first-line treatment.Blood Adv. 2018; 2: 2020-2028Crossref PubMed Scopus (61) Google Scholar]. A weakness of the current study is the lack of adequate recognition that either ATG or alemtuzumab in the conditioning regimen reduces the incidence of both graft failure and GVHD (acute and chronic), and that the inclusion of ATG/alemtuzumab in the conditioning regimen may be a more important predictor of GVHD than some of the alternate versions of post-transplant GVHD prophylaxis regimens. Based on the well-documented superiority of conditioning regimens that contain ATG for SAA [16Bacigalupo A. Socie G. Hamladji R.M. et al.Current outcome of HLA identical sibling versus unrelated donor transplants in severe aplastic anemia: an EBMT analysis.Haematologica. 2015; 100: 696-702Crossref PubMed Scopus (114) Google Scholar, 17Storb R. Etzioni R. Anasetti C. et al.Cyclophosphamide combined with antithymocyte globulin in preparation for allogeneic marrow transplants in patients with aplastic anemia.Blood. 1994; 84: 941-949Crossref PubMed Google Scholar], it was somewhat surprising that for some categories of GVHD prophylaxis (calcineurin inhibitor + mycophenolate mofetil and calcineurin inhibitor + methotrexate), >50% of patients received regimens that did not contain ATG or alemtuzumab. In this study, several patient outcomes were analyzed based on the category of a specific chemotherapy/radiation regimen ± ATG, meaning that recipients of non-ATG-containing regimens were not analyzed separately. Limitations such as these suggest that interpretation of the optimal GVHD prophylaxis regimen and the analysis of graft source (peripheral blood stem cells versus bone marrow) may be incomplete. In addition, definitive conclusions cannot be drawn regarding the risk factor analysis for acute or chronic GVHD. For older patients with SAA, the use of a more effective conditioning regimen will very likely lead to superior overall survival when compared with the registry outcomes. For example, an optimal conditioning regimen consists of cyclophosphamide, fludarabine, ATG (or alemtuzumab), and, for unrelated donor transplants, 2 Gray total body irradiation [9Maury S. Bacigalupo A. Anderlini P. et al.Improved outcome of patients older than 30years receiving HLA-identical sibling hematopoietic stem cell transplantation for severe acquired aplastic anemia using fludarabine-based conditioning: a comparison with conventional conditioning regimen.Haematologica. 2009; 94: 1312-1315Crossref PubMed Scopus (96) Google Scholar, 18Marsh J.C. Pearce R.M. Koh M.B. et al.Retrospective study of alemtuzumab vs ATG-based conditioning without irradiation for unrelated and matched sibling donor transplants in acquired severe aplastic anemia: a study from the British Society for Blood and Marrow Transplantation.Bone Marrow Transplant. 2014; 49: 42-48Crossref PubMed Scopus (63) Google Scholar, 19Anderlini P. Wu J. Gersten I. et al.Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1-2 dose de-escalation study.Lancet Haematol. 2015; 2: e367-e375Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar]. Additionally, the use of bone marrow for the hematopoietic cell source [20Schrezenmeier H. Passweg J.R. Marsh J.C. et al.Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired aplastic anemia.Blood. 2007; 110: 1397-1400Crossref PubMed Scopus (227) Google Scholar, 21Bacigalupo A. Socie G. Schrezenmeier H. et al.Bone marrow versus peripheral blood as the stem cell source for sibling transplants in acquired aplastic anemia: survival advantage for bone marrow in all age groups.Haematologica. 2012; 97: 1142-1148Crossref PubMed Scopus (147) Google Scholar] and 2-drug post-transplant GVHD prophylaxis (e.g., calcineurin inhibitor + methotrexate) are important factors contributing to an optimal transplant outcome [22Gallo S. Woolfrey A.E. Burroughs L.M. et al.Marrow grafts from HLA-identical siblings for severe aplastic anemia: does limiting the number of transplanted marrow cells reduce the risk of chronic GvHD?.Bone Marrow Transplant. 2016; 51: 1573-1578Crossref PubMed Scopus (11) Google Scholar, 23Burroughs L.M. Woolfrey A.E. Storer B.E. et al.Success of allogeneic marrow transplantation for children with severe aplastic anemia.Br J Haematol. 2012; 158: 120-128Crossref PubMed Scopus (21) Google Scholar]. The bottom line is that despite any of the potential shortcomings of this retrospective registry analysis, this study is an important contribution to the field. The report by Rice et al. [10Rice C, Eikema DJ, Marsh JCW, et al. Allogeneic hematopoietic cell transplantation in patients aged 50years or older with severe aplastic anemia [e-pub ahead of print]. Biol Blood Marrow Transplant. doi:10.1016/j.bbmt.2018.08.029. Accessed 1 February 2019.Google Scholar] confirms the efficacy of allogeneic BMT for the treatment of older patients with SAA. Despite the recent progress in IST with combined ATG, cyclosporine, and eltrombopag [4Townsley D.M. Scheinberg P. Winkler T. et al.Eltrombopag added to standard immunosuppression for aplastic anemia.N Engl J Med. 2017; 376: 1540-1550Crossref PubMed Scopus (299) Google Scholar], this report demonstrates the long-term value of allogeneic BMT for SAA. Financial disclosure: The author has nothing to disclose. Conflict of interest: There are no conflicts of interest to report.

Multiple sclerosis (MS) is a chronic, disabling, immune-mediated, demyelinating and degenerative disease of the central nervous system. Approved disease-modifying therapies may be incompletely effective in some patients with highly active relapsing disease and high risk of disability. The use of immunoablative or myeloablative therapy followed by autologous hematopoietic cell transplantation (AHCT) has been investigated in retrospective studies, clinical trials, and meta-analyses/systematic reviews as an approach to address this unmet clinical need. On behalf of the American Society for Blood and Bone Marrow Transplantation (ASBMT), a panel of experts in AHCT and MS convened to review available evidence and make recommendations on MS as an indication for AHCT. A review of recent literature identified 8 retrospective studies, 8 clinical trials, and 3 meta-analyses/systematic reviews. In aggregate, these studies indicate that AHCT is an efficacious and safe treatment for active relapsing forms of MS to prevent clinical relapse, magnetic resonance imaging-detectable lesion activity, and worsening disability and to reverse disability without unexpected adverse events. Based on the available evidence, the ASBMT recommends that treatment-refractory relapsing MS with high risk of future disability be considered a "standard of care, clinical evidence available" indication for AHCT. Collaboration of neurologists with expertise in treating MS and transplantation physicians with experience performing AHCT for autoimmune disease is crucial for ensuring appropriate patient selection and optimizing transplantation procedures to improve patient outcomes. Transplantation centers in the United States and Canada are strongly encouraged to report baseline and outcomes data on patients receiving AHCT for multiple sclerosis to the Center for International Blood and Marrow Transplant Research.

The hot deformation behavior and associated microstructural evolution of a coarse-grained Nb-bearing austenitic stainless steel (316Nb) has been investigated by the means of torsion tests at high temperature [1223 K to 1423 K (950 °C to 1150 °C)] followed by microstructural characterization. The starting microstructure was varied by applying prior annealing. Except for strains below 10 pct, the resistance to viscoplastic flow is not sensitive to the starting microstructure. On the other hand, prior annealing at higher temperatures increases the resistance to incipient viscoplastic flow and strongly impedes dynamic and post-dynamic recrystallization by delaying the grain boundary bulging phenomenon. It also affects the static recrystallization behavior during further annealing. The influence of the amount of available niobium atoms, in particular close to grain boundaries, is discussed.

Which is better, myeloablative chemotherapy–based conditioning or total body irradiation (TBI)-based conditioning for younger (<60 years) and medically fit patients with hematologic malignancies in preparation for allogeneic hematopoietic cell transplant (HCT)? For this recurring question, why has a universally accepted answer been elusive despite more than 30 years of mainly multicenter, retrospective analyses and a handful of prospective trials? Let us review the relevant data, beginning with observational studies. A 2018 observational, retrospective, single-center analysis from colleagues in Boston addressed the following question: Is fludarabine/busulfan (FLU/BU) or cyclophosphamide (CY)/TBI conditioning optimal for allogeneic HCT [1Gooptu M. Kim H.T. Ho V.T. et al.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.Biol Blood Marrow Transplant. 2018; 24: 1733-1740Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]? We do not believe they succeeded in definitively answering the question. The authors compared outcomes in 229 patients given CY/TBI conditioning with 158 patients given FLU/BU conditioning before allogeneic HCT. Because of its retrospective nature, this study was fraught with both uncontrolled and unknown variables, including a variety of hematologic malignancies for which HCT was carried out, some of which were preferentially directed to 1 regimen. For example, only 6 patients (3.8%) with acute lymphoblastic leukemia (ALL) received FLU/BU yet 58 (25%) received CY/TBI. In addition, patients received grafts from related and unrelated 8/8 and 7/8 HLA antigen-matched donors; marrow or peripheral blood as graft source; a variety of graft-versus-host disease (GVHD) prophylactic regimens; at least 2 TBI doses, 1200 and 1400 cGy, respectively, but unknown TBI dose rate, unknown lung shielding, and unknown patient numbers per TBI dose and schedules and no explanation why 1 TBI dose was chosen over the other; lack of information on why some patients received a TBI-based regimen and others FLU/BU; and why 35 additional patients, not included in the analysis, were conditioned with a BU/CY regimen. The authors adjusted for imbalances, and after doing so they concluded the results suggested that patients given CY/TBI experienced a higher nonrelapse mortality (NRM) and worse overall survival (OS) and progression-free survival compared with patients conditioned with FLU/BU. Have other studies comparing TBI-based with chemotherapy-based conditioning regimens concurred with these conclusions? Results have been conflicting, both those derived from observational studies and prospective clinical trials (including some trials where different BU-based regimens were compared with each other). It is worthwhile to review these results and consider the evidence. A large, retrospective, nonrandomized European Society for Blood and Marrow Transplantation (EBMT) registry analysis compared BU/CY with CY/TBI conditioning among 1659 patients transplanted for acute myeloid leukemia (AML) in first or second remission [2Nagler A. Rocha V. Labopin M. et al.Allogeneic hematopoietic stem-cell transplantation for acute myeloid leukemia in remission: comparison of intravenous busulfan plus cyclophosphamide (Cy) versus total-body irradiation plus Cy as conditioning regimen—a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation.J Clin Oncol. 2013; 31: 3549-3556Crossref PubMed Scopus (118) Google Scholar]. Donors were HLA-identical siblings. Both marrow (∼30%) and peripheral blood (∼70%) served as graft source. TBI doses ranged from 750 to 1440 cGy with unknown dose rates and schedules. Median follow-up was longer for CY/TBI-treated patients (33 versus 20 months). Most patients received methotrexate/cyclosporine (MTX/CSP) for GVHD prophylaxis, but other prophylaxis regimens were also used including antithymocyte globulin (ATG). After adjustment, the authors found less acute GVHD and less chronic GVHD, a higher rate of relapse (unadjusted 2-year estimates of 26% versus 21%), and comparable NRM (12% versus 15%) in the BU/CY arm as well as comparable 2-year leukemia-free survival (unadjusted 2-year estimates of 61% versus 64%) and OS (unadjusted 2-year estimates of 68% versus 69%) among patients in the 2 treatment arms [2Nagler A. Rocha V. Labopin M. et al.Allogeneic hematopoietic stem-cell transplantation for acute myeloid leukemia in remission: comparison of intravenous busulfan plus cyclophosphamide (Cy) versus total-body irradiation plus Cy as conditioning regimen—a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation.J Clin Oncol. 2013; 31: 3549-3556Crossref PubMed Scopus (118) Google Scholar]. A multicenter cohort study from the Center for International Blood and Marrow Transplant Research (CIBMTR) compared TBI-based regimens (CY/TBI or etoposide [VP16]/TBI) with those containing BU (either BU/CY or FLU/BU) in 1483 patients with AML, chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS) at various disease stages [3Bredeson C. Lerademacher J. Kato K. et al.Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation.Blood. 2013; 122: 3871-3878Crossref PubMed Scopus (106) Google Scholar]. TBI doses ranged from 550 to 1440 cGy, given either in fractions or as a single dose with information on dose rates or lung shielding not provided. Donors of marrow or peripheral blood–derived hematopoietic cells (PBSCs) included HLA-matched related and unrelated individuals and HLA-mismatched individuals. Patients received a variety of GVHD prophylaxis regimens, and a number of patients were given ATG or Campath as part of the conditioning regimen (14% of TBI-treated versus 29% of BU-treated patients). They found that 2-year OS was better for patients given BU-based regimens (56% versus 48%), with comparable rates of relapse (34% versus 39%) and NRM (18% versus 19%) [3Bredeson C. Lerademacher J. Kato K. et al.Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation.Blood. 2013; 122: 3871-3878Crossref PubMed Scopus (106) Google Scholar]. Of note, there were no statistically significant differences in outcomes between FLU/BU- and BU/CY-conditioned patients. Another retrospective, multicenter CIBMTR report analyzed data from 1230 patients with AML in first remission who were conditioned with either CY/TBI (n = 586 at 117 centers) or BU/CY (n = 640) [4Copelan E.A. Hamilton B.K. Avalos B. et al.Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI.Blood. 2013; 122: 3863-3870Crossref PubMed Scopus (122) Google Scholar]. Multiple TBI regimens were used with total doses ranging from 550 to 1500 cGy, given either as a single dose or in fractions, but no further information was given. BU was given either orally (n = 408 at 86 centers) or intravenously (n = 236 at 80 centers). Again, as in the study by Bredesen et al. [3Bredeson C. Lerademacher J. Kato K. et al.Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation.Blood. 2013; 122: 3871-3878Crossref PubMed Scopus (106) Google Scholar], donors were either related or unrelated and HLA-matched or partially HLA-matched, grafts were either marrow (∼ 40%) or PBSCs (∼ 60%), and a variety of GVHD prophylaxis regimens were used. The authors reported superior survival among patients who were conditioned with the intravenous (but not with oral) BU-based regimen compared with those conditioned with TBI-based regimens [4Copelan E.A. Hamilton B.K. Avalos B. et al.Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI.Blood. 2013; 122: 3863-3870Crossref PubMed Scopus (122) Google Scholar]. Are the conclusions drawn in these studies valid or flawed? One would prefer that comparative studies be done in the context of a randomized trial. As our Boston colleagues stated with respect to multicenter observational analyses [1Gooptu M. Kim H.T. Ho V.T. et al.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.Biol Blood Marrow Transplant. 2018; 24: 1733-1740Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar], "These registry analyses incorporate patients from multiple centers, and are inherently susceptible to center effects and biases due to varying transplantation practices in different institutionsp.367-368". When discussing their own single-center, retrospective analysis, the same authors then stated, "There have been no RCTs [randomized, controlled trials] performed comparing chemotherapy-only regimens with TBI-based regimensp.367-368". Although this statement is true for chemotherapy-only regimens that contain intravenous BU, a number of randomized trials have compared BU-containing with TBI-containing regimens, in addition to 4 trials comparing BU/FLU with BU/CY. The results from these trials need to be carefully considered before drawing conclusions from observational studies. In the 1990s results of 4 prospective, randomized trials were reported in the journal Blood comparing BU/CY conditioning with CY/TBI conditioning. The CY/TBI regimen used was first described by the Seattle team in 1975 [5Thomas E.D. Storb R. Clift R.A. et al.Bone-marrow transplantation (first of two parts).N Engl J Med. 1975; 292: 832-843Crossref PubMed Scopus (1422) Google Scholar], whereas the BU/CY regimen was reported by Santos et al. from Johns Hopkins in 1983 [6Santos G.W. Tutschka P.J. Brookmeyer R. et al.Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide.N Engl J Med. 1983; 309: 1347-1353Crossref PubMed Scopus (665) Google Scholar]. Two of the 4 randomized trials were from the multicenter French Marrow Transplant Group [7Devergie A. Blaise D. Attal M. et al.Allogeneic bone marrow transplantation for chronic myeloid leukemia in first chronic phase: a randomized trial of busulfan-cytoxan versus cytoxan-total body irradiation as preparative regimen: a report from the French Society of Bone Marrow Graft (SFGM).Blood. 1995; 85: 2263-2268Crossref PubMed Google Scholar, 8Blaise D. Maraninchi D. Archimbaud E. et al.Allogeneic bone marrow transplantation for acute myeloid leukemia in first remission: a randomized trial of a busulfan-cytoxan versus cytoxan-total body irradiation as preparative regimen. A report from the Groupe d'Etudes de la Greffe de Moelle Osseuse.Blood. 1992; 79: 2578-2582Crossref PubMed Google Scholar], the third was a multicenter Nordic group trial [9Ringdén O. Ruutu T. Remberger M. et al.A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia: a report from the Nordic Bone Marrow Transplantation Group.Blood. 1994; 83: 2723-2730Crossref PubMed Google Scholar, 10Ringdén O. Remberger M. Ruutu T. et al.Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation: long-term results of a randomized trial in allogeneic marrow recipients with leukemia.Blood. 1999; 93: 2196-2201Crossref PubMed Google Scholar], and the fourth was a single-center study from the Fred Hutchinson Cancer Research Center (Fred Hutch) in Seattle [11Clift R.A. Buckner C.D. Thomas E.D. et al.Marrow transplantation for chronic myeloid leukemia: a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide.Blood. 1994; 84: 2036-2043Crossref PubMed Google Scholar, 12Clift R.A. Radich J. Appelbaum F.R. et al.Long-term follow-up of a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide for patients receiving allogeneic marrow transplants during chronic phase of chronic myeloid leukemia [Letter to Editor].Blood. 1999; 94: 3960-3962Crossref PubMed Google Scholar]. All patients in these trials had HLA-identical sibling marrow donors, and all were given a short course of MTX and an extended course of CSP for GVHD prophylaxis [13Storb R. Deeg H.J. Whitehead J. et al.Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia.N Engl J Med. 1986; 314: 729-735Crossref PubMed Scopus (1190) Google Scholar], although a number of French patients received, in addition, treatment with an anti-IL-2 receptor antibody. All 120 patients in 1 of the French trials and all 142 patients in the Fred Hutch study had CML in first chronic phase, whereas the other French study treated 101 patients with AML in first morphologic remission, and the Scandinavian trial included 167 patients with a wide spectrum of hematologic malignancies. Unfortunately, center effects and varying transplant practices invoked by our Boston colleagues already were a problem in those early years. One example of this was TBI protocols in the French and Nordic Group trials with dosing, dose rates, dose schedules, and lung shielding varying from center to center. Close linkage between total TBI doses and toxicities had already been well documented in 2 earlier, prospective, controlled Fred Hutch trials, also published in Blood, 1 in patients with AML in first remission and the other in patients with CML in first chronic phase [14Clift R.A. Buckner C.D. Appelbaum F.R. et al.Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens.Blood. 1990; 76: 1867-1871Crossref PubMed Google Scholar, 15Clift R.A. Buckner C.D. Appelbaum F.R. et al.Allogeneic marrow transplantation in patients with chronic myeloid leukemia in the chronic phase: a randomized trial of two irradiation regimens.Blood. 1991; 77: 1660-1665Crossref PubMed Google Scholar]. Also, targeting BU blood levels was as yet not widely used, and actual drug levels may have fluctuated considerably. The French AML study [8Blaise D. Maraninchi D. Archimbaud E. et al.Allogeneic bone marrow transplantation for acute myeloid leukemia in first remission: a randomized trial of a busulfan-cytoxan versus cytoxan-total body irradiation as preparative regimen. A report from the Groupe d'Etudes de la Greffe de Moelle Osseuse.Blood. 1992; 79: 2578-2582Crossref PubMed Google Scholar] concluded that 2-year outcomes after CY/TBI conditioning were significantly better than after BU/CY conditioning (survival, 75% versus 51%; disease-free survival, 72% versus 47%; relapse, 14% versus 34%; NRM, 8% versus 27%, respectively). In contrast, the French CML study [7Devergie A. Blaise D. Attal M. et al.Allogeneic bone marrow transplantation for chronic myeloid leukemia in first chronic phase: a randomized trial of busulfan-cytoxan versus cytoxan-total body irradiation as preparative regimen: a report from the French Society of Bone Marrow Graft (SFGM).Blood. 1995; 85: 2263-2268Crossref PubMed Google Scholar] showed comparable survival with the 2 regimens (62.9% for CY/TBI versus 60.6% for BU/CY; disease-free survival, 55% versus 59.1%). These authors concluded that BU/CY conditioning was an acceptable alternative to CY/TBI in patients with CML in first chronic phase. The Nordic group trial included patients with a variety of hematologic malignancies with a broad range of disease stages [9Ringdén O. Ruutu T. Remberger M. et al.A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia: a report from the Nordic Bone Marrow Transplantation Group.Blood. 1994; 83: 2723-2730Crossref PubMed Google Scholar, 10Ringdén O. Remberger M. Ruutu T. et al.Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation: long-term results of a randomized trial in allogeneic marrow recipients with leukemia.Blood. 1999; 93: 2196-2201Crossref PubMed Google Scholar]. The investigators saw more grades III to IV acute GVHD among BU/CY-conditioned patients, whereas relapse rates were comparable. Three-year survival was 76% among CY/TBI-treated patients compared with 62% among BU/CY-treated patients (P < .03). The report concluded that CY/TBI was the conditioning of choice, especially in patients with more advanced disease. Researchers at Fred Hutch in Seattle published early results of a controlled, prospective, randomized trial in patients with CML in first chronic phase in 1994 [11Clift R.A. Buckner C.D. Thomas E.D. et al.Marrow transplantation for chronic myeloid leukemia: a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide.Blood. 1994; 84: 2036-2043Crossref PubMed Google Scholar], with an update in 1999 [12Clift R.A. Radich J. Appelbaum F.R. et al.Long-term follow-up of a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide for patients receiving allogeneic marrow transplants during chronic phase of chronic myeloid leukemia [Letter to Editor].Blood. 1999; 94: 3960-3962Crossref PubMed Google Scholar]. The patients' ages ranged from 6 to 55 years (mean, 38). They were enrolled on study between October 1988 and November 1992. All received marrow grafts from HLA-identical sibling donors, and all were given a short course of MTX and at least 180 days of CSP [13Storb R. Deeg H.J. Whitehead J. et al.Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia.N Engl J Med. 1986; 314: 729-735Crossref PubMed Scopus (1190) Google Scholar]. For conditioning, all patients received CY, 60 mg/kg/day i.v. for 2 days. They were randomized to receive either 1200 cGy TBI delivered in six 200-cGy fractions over 6 days at 6 to 7 cGy/min from 2 opposing cobalt-60 sources without lung shielding after CY or BU at 4 mg/kg/day p.o. for 4 days, preceding CY. Fever days, acute GVHD, and hospital days were significantly more common in the CY/TBI group compared with the BU/CY group. Figure 1 summarizes the trial outcomes with updates as of July 1999 (left) and February 2019 (right). CY/TBI-conditioned patients experienced slightly more relapse, slightly more NRM, and slightly worse OS and event-free survival than BU/CY-conditioned patients; however, none of the comparisons was statistically significantly different. Twenty-year survival for BU/CY-treated patients was 63% compared with 58% for CY/TBI-treated patients, and corresponding event-free survivals were 45% and 41%, respectively. Some of the late deaths were age-related, which was not surprising given that a number of patients were 50 years and older at study entry in the late 1980s and early 1990s. The team concluded that BU/CY was better tolerated than CY/TBI and was associated with survival, relapse, and NRM probabilities that compared favorably with the CY/TBI regimen. Since the findings of this tightly controlled trial were published, BU/CY conditioning has been standard practice at Fred Hutch, not only for patients with CML in first chronic phase but also for those with AML in remission and with MDS. Additional support for this decision, which was made in 1994, was provided by later reports describing lesser rates of subsequent malignancies in BU/CY-conditioned patients compared with their CY/TBI-conditioned counterparts [16Baker K.S. Leisenring W.M. Goodman P.J. et al.Total body irradiation dose and risk of subsequent neoplasms following allogeneic hematopoietic cell transplantation.Blood. 2019; 133: 2790-2799Crossref PubMed Scopus (48) Google Scholar, 17Bhatia S. Bhatia R. Subsequent malignant neoplasms after hematopoietic cell transplantation.in: Forman S.J. Negrin R.S. Antin J.H. Appelbaum F.R. Thomas' Hematopoietic Cell Transplantation. 5th ed. John Wiley & Sons, Chichester, UK2016: 1275-1289Crossref Scopus (4) Google Scholar]. A prospective trial conducted by a Korean cooperative group randomized 126 patients with various hematologic malignancies at various disease stages to receive either FLU/BU or BU/CY conditioning before HCT from either HLA-matched sibling or unrelated donors (4.7% and 11.3%, respectively, of the donors were HLA mismatched) [18Lee J.H. Joo Y.D. Kim H. et al.Randomized trial of myeloablative conditioning regimens: busulfan plus cyclophosphamide versus busulfan plus fludarabine.J Clin Oncol. 2013; 31: 701-709Crossref PubMed Scopus (84) Google Scholar]. Other variables, apart from center effects, included bone marrow, peripheral blood, or unrelated cord blood as graft source and either CSP alone or MTX/CSP for GVHD prophylaxis. The study showed similar NRM in the 2 arms; however, the BU/CY arm had significantly better OS, relapse-free survival, and event-free survival at 2 years (67.4% versus 41.4%, 74.4% versus 54.9%, and 60.7% versus 36.0%, respectively). The authors concluded that BU/FLU conditioning was not a suitable replacement for BU/CY conditioning in young adults who were eligible for myeloablative allogeneic HCT. A prospective trial from Peking University randomized patients to receive BU/CY or FLU/BU, each regimen also containing hydroxyurea, cytarabine, and semustine [19Liu D.H. Xu L.P. Zhang X.H. et al.Substitution of cyclophosphamide in the modified BuCy regimen with fludarabine is associated with increased incidence of severe pneumonia: a prospective, randomized study.Int J Hematol. 2013; 98: 708-715Crossref PubMed Scopus (12) Google Scholar]. The trial was intended to randomize 178 patients but was terminated early (after 105 patients) because of an increased risk of severe pneumonia in the FLU/BU group (19.2% versus 5.7%; with further follow-up, severe pneumonia was observed in 26.9% and 9.4% of patients, respectively). Patients included those with AML (37%), ALL (28%), CML (25%), or MDS (10%). Despite the apparent increase in severe pneumonia seen with FLU/BU, both OS and leukemia-free survival were similar in the 2 groups but with numerically less relapse in the FLU/BU group. Contrasting with the conclusions of the Korean and Chinese trials are results of 2 other prospective trials comparing BU/CY with FLU/BU. One trial was conducted by 25 Italian centers of the Gruppo Italiano Trapianto di Midollo Osseo and 1 Israeli center [20Rambaldi A. Grassi A. Masciulli A. et al.Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial.Lancet Oncol. 2015; 16: 1525-1536Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar]. The authors randomized 252 patients with AML, predominantly in first remission, between 2 conditioning regimens. Donors included HLA-matched related and unrelated individuals, and some donors were HLA mismatched. All recipients were given MTX/CSP for GVHD prevention; however, unrelated recipients received, in addition, ATG. Marrow or peripheral blood was allowed as graft source. The authors found less NRM, slightly more relapse, better leukemia-free survival, and comparable OS (2-year OS, 64.2% versus 62.4%) among FLU/BU-treated patients and recommended that FLU/BU should be the standard of care. The other trial that contrasts with the conclusions of the trials that favor BU/CY was another Chinese study [21Liu H. Zhai X. Song Z. et al.Busulfan plus fludarabine as a myeloablative conditioning regimen compared with busulfan plus cyclophosphamide for acute myeloid leukemia in first complete remission undergoing allogeneic hematopoietic stem cell transplantation: a prospective and multicenter study.J Hematol Oncol. 2013; 6: 15Crossref PubMed Scopus (78) Google Scholar]. In this study 108 patients with AML in first complete remission were randomized to receive BU/CY or FLU/BU. Efficacy outcomes were similar between groups (5-year estimates of relapse, 16.5% versus 16.2%; disease-free survival, 67.4% versus 75.3%; OS, 72.3% versus 81.9%). Grades 3 to 4 regimen-related toxicity was less in the FLU/BU group (0% versus 16.7%), and 5-year NRM was 18.8% with BU/CY versus 9.9% with FLU/BU. A meta-analysis of 15 reports (including the 4 randomized studies above, with 11 observational studies) comparing BU/FLU with BU/CY conditioning before allogeneic HCT [22Ben-Barouch S. Cohen O. Vidal L. Avivi I. Ram R. Busulfan fludarabine vs busulfan cyclophosphamide as a preparative regimen before allogeneic hematopoietic cell transplantation: systematic review and meta-analysis.Bone Marrow Transplant. 2016; 51: 232-240Crossref PubMed Scopus (48) Google Scholar] concluded that both regimens had similar efficacy profiles, whereas toxicity was lower with the BU/FLU regimen. The authors concluded that BU/FLU was not inferior to BU/CY as a myeloablative preparative regimen and may be associated with lower early NRM. However, they further argued that well-controlled randomized trials that assess the BU/FLU regimen among specific subgroups are warranted. The randomized trials summarized above comparing BU/CY with CY/TBI were somewhat conflicting, with 2 studies overall favoring BU/CY and 2 favoring CY/TBI. One of the trials [9Ringdén O. Ruutu T. Remberger M. et al.A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia: a report from the Nordic Bone Marrow Transplantation Group.Blood. 1994; 83: 2723-2730Crossref PubMed Google Scholar] that favored CY/TBI was conducted among a variety of hematologic malignancies, roughly 25% of which were lymphoid. Moreover, the advantage purported for CY/TBI was in comparison with oral drug in the BU/CY regimen as opposed to intravenous drug. We consider the conclusions from the randomized trials comparing BU/CY with CY/TBI cited above to be largely in favor of using BU/CY rather than CY/TBI for myeloid malignancies, and the observational studies summarized above are consistent with this conclusion. Taken together, we consider these data to be in support of BU-based regimens for most patients with myeloid malignancies with relatively low tumor burden. Whether this conclusion holds true for patients with high tumor burden, say, AML in relapse or CML in myeloid blast crisis, is not clear. The same uncertainty holds true for patients with minimal residual disease at the time of HCT. Well-controlled comparisons to address this question have not been done, and some centers have intuitively continued using CY/TBI in such patients. However, among the 4 randomized clinical trials that have addressed the question of what is preferable, FLU/BU or BU/CY, 2 have favored FLU/BU and 2 have favored BU/CY. The 2 trials that favored BU/CY contained a variety of hematologic malignancies (AML, ALL, CML, MDS), whereas the 2 that favored FLU/BU were conducted solely in AML (either in first complete remission exclusively or predominantly). These results support the conclusion of the meta-analysis cited above, where the authors suggested that additional well-controlled randomized trials were needed in specific subgroups of patients. So, are myeloablative TBI-based regimens history and have they been replaced by BU-based regimens? Not so fast. Let us look at HCT for ALL and other lymphoid malignancies. The situation is even more unsettled when the focus is on ALL. A small, randomized, multicenter study in pediatric patients with ALL compared BU/CY/VP16 with 1200 cGy TBI (6 fractions in 3 days)/CY/VP16 [23Bunin N. Aplenc R. Kamani N. Shaw K. Cnaan A. Simms S. Randomized trial of busulfan vs total body irradiation containing conditioning regimens for children with acute lymphoblastic leukemia: a Pediatric Blood and Marrow Transplant Consortium study.Bone Marrow Transplant. 2003; 32: 543-548Crossref PubMed Scopus (149) Google Scholar]. Donors were either related or unrelated. Marrow was the predominant graft source, and GVHD prevention consisted mainly of MTX/CSP. The authors concluded that the BU-based regimen was inferior to the TBI-based regimen in pediatric patients with ALL (3-year event-free survival, 29% versus 58%; P = .03). A randomized International Pediatric ALL Forum 2012 study in more than 400 patients had randomization suspended, and ultimately closed, after an interim analysis showed a survival benefit among patients conditioned with TBI/VP16 over those conditioned with either FLU/thiotepa/treosulfan or FLU/thiotepa/i.v. BU (88% versus 71% 2-year OS). Although transplant-related mortality was comparable among the groups, there was a large increase in relapse rates among chemotherapy-treated patients compared with TBI-treated patients. This carefully controlled randomized trial is the most definitive statement for a continued role of TBI for patients with ALL undergoing allogeneic HLA-matched HCT (https://clinicaltrials.gov/ct2/show/study/NCT01949129). A retrospective EBMT analysis of 601 patients with T cell ALL compared outcomes after BU/CY with those after TBI-based regimens [24Cahu X. Labopin M. Giebel S. et al.Impact of conditioning with TBI in adult patients with T-cell ALL who receive a myeloablative allogeneic stem cell transplantation: a report from the acute leukemia working party of EBMT.Bone Marrow Transplant. 2016; 51: 351-357Crossref PubMed Scopus (47) Google Scholar]. As in other registry analyses, TBI doses and schedules varied and detailed information was not given. Unrelated and related donors were lumped, as were marrow and PBSCs as graft sources, and multiple GVHD prophylaxis regimens, including ATG, were used. The analysis concluded that TBI-based conditioning gave superior results compared with BU/CY (5-year leukemia-free survival rate of 50% versus 18%). Another retrospective EBMT analysis included patients with ALL in remission and with active disease, of whom 180 received thiotepa conditioning and 540 received CY/TBI conditioning (TBI doses and dose schedules not provided) [25Eder S. Canaani J. Beohou E. et al.Thiotepa-based conditioning versus total body irradiation as myeloablative conditioning prior to allogeneic stem cell transplantation for acute lymphoblastic leukemia: a matched-pair analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.Am J Hematol. 2017; 92: 997-1003PubMed Google Scholar]. B cell ALL and T cell ALL patients were included, of whom some were Philadelphia chromosome positive (Ph+) in first complete remission, although in most patients this information was unknown. Marrow or PBSC grafts were from HLA-matched related or unrelated donors. Information on GVHD prophylaxis was not provided, although apparently some patients received ATG or Campath in the conditioning. Patients conditioned with CY/TBI had less relapse, comparable NRM, and marginally better event-free survival at 2 years in multivariate analysis (39% versus 33%; P = .06). A recent retrospective study [26Kebriaei P. Anasetti C. Zhang M.J. et al.Intravenous busulfan compared with total body irradiation pretransplant conditioning for adults with acute lymphoblastic leukemia.Biol Blood Marrow Transplant. 2018; 24: 726-733Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar] compared outcomes of ALL patients (approximately 75% in first remission and 25% in second remission; 83% B cell lineage) given CY/TBI or VP16/TBI conditioning (TBI doses ranging from 1200 to 1600 cGy—no information on dose schedules or rates or lung shielding) with BU/FLU, BU/clofarabine, BU/melphalan, or BU/CY. The TBI-based cases (n = 819) and 67 BU-based cases were from the CIBMTR database, which included results from 504 transplant centers. The remaining 232 BU-based cases were from the MD Anderson Cancer Center and Moffitt Cancer Center. This kind of selection, of course, introduced a considerable bias from the start. Also, it was not clear how patients were chosen to receive CY/TBI versus VP16/TBI or, say, BU/FLU versus the remaining 3 BU-based regimens. Marrow or PBSCs were transplanted. Approximately half of the donors were HLA-identical siblings and half were HLA-matched unrelated donors. TBI-based cases had a median follow-up of 63 months versus 43 months for BU-based patients. More BU-based Ph+ patients received post-transplant tyrosine kinase inhibitors than TBI-based Ph+ cases. The authors reported a 3-year NRM of 19% for BU-treated patients versus 25% for TBI-treated patients. Corresponding percentages for relapse, disease-free survival, and OS were 37% versus 28%, 45% versus 48%, and 57% versus 53%, respectively. Having compared the experience of 4 BU-based regimens, which was largely generated at 2 transplant centers, with that of 2 TBI regimens used at 504 other centers, the authors concluded that BU-based regimens were better tolerated than TBI-based regimens. Fred Hutch investigators have generally preferred using TBI-based over BU-based conditioning regimens for allogeneic HCT in patients with ALL and other lymphoid disorders, although this practice was not based on randomized, prospective, clinical trials. The rationale for this preference goes back to extensive preclinical animal studies that uniformly showed little effect of BU on B cell and T cell function, whereas comparably intense TBI nearly completely suppressed the immune function. We reasoned that drug and irradiation effects on normal immune cells were representative of their respective effects on malignant B and T cells. In 1958 Elson et al. [27Elson L.A. Galton D.A. Till M. The action of chlorambucil (CB. 1348) and busulphan (myleran) on the haemopoietic organs of the rat.Br J Haematol. 1958; 4: 355-374Crossref PubMed Scopus (43) Google Scholar] already noticed that "the lymphoid organs after BU administration (in rats) showed no changes throughout the experiment," whereas "from 8 to 14 days [when] depletion of normoblasts, granulocytes, and granulopoietic cells (in marrow) was maximal." Studies in dogs given highest tolerated doses of i.v. BU showed profound depletion of marrow and peripheral blood neutrophil and platelet counts. However, primary antibody responses to sheep RBCs, bacteriophage ΦX174, and allogeneic buffy coat cells were little or not at all affected [28Kolb H.J. Storb R. Weiden P.L. et al.Immunologic, toxicologic and marrow transplantation studies in dogs given dimethyl myleran.Biomedicine. 1974; 20: 341-351PubMed Google Scholar]. Also, dog leukocyte antigen (DLA)-mismatched marrow grafts were all rejected [28Kolb H.J. Storb R. Weiden P.L. et al.Immunologic, toxicologic and marrow transplantation studies in dogs given dimethyl myleran.Biomedicine. 1974; 20: 341-351PubMed Google Scholar], and sustained engraftment of dog leukocyte antigen (DLA)-identical littermate grafts was only seen in 50% of recipients after BU [29Storb R. Weiden P.L. Graham T.C. Lerner K.G. Nelson N. Thomas E.D. Hemopoietic grafts between DLA-identical canine littermates following dimethyl myleran. Evidence for resistance to grafts not associated with DLA and abrogated by antithymocyte serum.Transplantation. 1977; 24: 349-357Crossref PubMed Scopus (53) Google Scholar]. Of note, complete engraftment was achieved when BU was combined with ATG. Similarly, Santos and Tutschka [30Santos G.W. Tutschka P.J. Effect of busulfan on antibody production and skin allograft survival in the rat.J Natl Cancer Inst. 1974; 53: 1775-1780PubMed Google Scholar] treated both Lewis and Sprague-Dawley rats with single LD50 doses of BU and saw no effect on antibody production against sheep RBCs and on allogeneic skin graft rejection. Buckner et al. [31Buckner C.D. Dillingham L.A. Giddens Jr., W.E. Thomas E.D. Toxicologic and marrow transplantation studies in rhesus monkeys given dimethyl myleran.Exp Hematol. 1975; 3: 275-288PubMed Google Scholar] failed to achieve allogeneic marrow engraftment in monkeys given the highest tolerated doses of i.v. BU. More recently, Kang et al. [32Kang E.M. Hsieh M.M. Metzger M. et al.Busulfan pharmacokinetics, toxicity, and low-dose conditioning for autologous transplantation of genetically modified hematopoietic stem cells in the rhesus macaque model.Exp Hematol. 2006; 34: 132-139Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar] confirmed that hematologic effects of BU in rhesus monkeys were most profound in the myeloid compartment, resulting in profound declines of neutrophils and platelets, whereas lymphocytes were less affected. In contrast to the only marginal effect of BU on B and T cell compartments, equitoxic doses of TBI completely suppressed antibody production to sheep RBCs and bacteriophage ΦX174 [33Ochs H.D. Storb R. Thomas E.D. et al.Immunologic reactivity in canine marrow graft recipients.J Immunol. 1974; 113: 1039-1057Google Scholar] and enabled sustained marrow engraftment. Taken together, we consider these results (both preclinical and clinical) to provide a compelling rationale for continuing the use of TBI-based conditioning for HCT in patients with lymphoid-based disorders. The lone outlier to this conclusion comes from the study where the overwhelming majority of BU-based patients were from 2 centers and compared with registry patients who received TBI. It is virtually impossible to separate institutional effects from treatment effects in such a study, and we therefore view these results with great caution. Results of a few retrospective multicenter studies and a single small, randomized trial in pediatric patients are consistent with the compelling preclinical findings and suggest that BU-based conditioning is inferior to TBI-based conditioning in patients with ALL. The single retrospective analysis that suggested BU-based conditioning was approximately equivalent to TBI for patients with ALL was heavily influenced by selection bias. The interim analysis results from the ALL SCTped 2012 FORUM randomized trial (NCT01949129) showed superior survival for patients treated with TBI-based regimen. Until future randomized, prospective trials indicate otherwise, the current data support the use of TBI-based regimens for ALL. BU-based conditioning for ALL remains experimental and cannot be considered an equivalent substitute for TBI. Although randomized clinical trials are the accepted gold standard to obtain the most definitive assessment of treatment effect in clinical research, quality results from a randomized trial are only obtainable if the trial is well designed. Moreover, if there are subgroups of patients who have differential treatment effects, the overall treatment effect cannot and should not be generalized to the entire population. Also, well-controlled, prospective, randomized trials may end up showing differences in primary endpoints that are small and fail to reach statistical significance, but secondary endpoints may point in the same direction or statistically favor 1 arm, leading to the preference of the arm that is not statistically significantly better for the primary outcome. An example of such a trial is the Fred Hutch study in patients with CML, reviewed above, that compared BU/CY with CY/TBI. Even after nearly 30 years of follow-up, NRM, relapse, event-free survival, and OS were only slightly but not statistically significantly in favor of BU/CY. However, during the conduct of that trial it became apparent that BU/CY had a more favorable toxicity profile than CY/TBI. It was this finding that made BU/CY the regimen of preference for patients with myeloid malignancies. Another such example is the Blood and Marrow Transplant Clinical Trials Network trial comparing bone marrow versus PBSCs as the source of stem cells from unrelated donors [34Anasetti C. Logan B.R. Lee S.J. et al.Peripheral-blood stem cells versus bone marrow from unrelated donors.N Engl J Med. 2012; 367: 1487-1496Crossref PubMed Scopus (635) Google Scholar]. The 2-year estimates of OS in this study were 46% and 51%, respectively (P = .29). The estimates of chronic GVHD were 41% and 53%, respectively (P = .01). A long-term follow-up study from the same randomized trial showed superior quality of life in the bone marrow arm (higher mean Mental Health Inventory Psychological Well-Being score, 78.9 versus 72.2; P = .01) and lower mean Lee Chronic Graft-versus-Host Disease Symptom scores (13.1 versus 19.3, p = .004) [35Lee S.J. Logan B. Westervelt P. et al.Comparison of patient-reported outcomes in 5-year survivors who received bone marrow vs peripheral blood unrelated donor transplantation: long-term follow-up of a randomized clinical trial.JAMA Oncol. 2016; 2: 1583-1589Crossref PubMed Scopus (78) Google Scholar]. The totality of these results led to the recommendation that bone marrow is the preferred stem cell choice among recipients of unrelated allografts. If such subtle differences are seen in well-controlled trials, it may not come as a surprise that conflicting findings can be observed in larger, retrospective registry analyses.

Importance Autologous hematopoietic stem cell transplantation (AHSCT) may be effective in aggressive forms of multiple sclerosis (MS) that fail to respond to standard therapies. Objective To evaluate the long-term outcomes in patients who underwent AHSCT for the treatment of MS in a large multicenter cohort. Design, Setting, and Participants Data were obtained in a multicenter, observational, retrospective cohort study. Eligibility criteria were receipt of AHSCT for the treatment of MS between January 1995 and December 2006 and the availability of a prespecified minimum data set comprising the disease subtype at baseline; the Expanded Disability Status Scale (EDSS) score at baseline; information on the administered conditioning regimen and graft manipulation; and at least 1 follow-up visit or report after transplant. The last patient visit was on July 1, 2012. To avoid bias, all eligible patients were included in the analysis regardless of their duration of follow-up. Data analysis was conducted from September 1, 2014 to April 27, 2015. Exposures Demographic, disease-related, and treatment-related exposures were considered variables of interest, including age, disease subtype, baseline EDSS score, number of previous disease-modifying treatments, and intensity of the conditioning regimen. Main Outcomes and Measures The primary outcomes were MS progression-free survival and overall survival. The probabilities of progression-free survival and overall survival were calculated using Kaplan-Meier survival curves and multivariable Cox proportional hazards regression analysis models. Results Valid data were obtained from 25 centers in 13 countries for 281 evaluable patients, with median follow-up of 6.6 years (range, 0.2-16 years). Seventy-eight percent (218 of 281) of patients had progressive forms of MS. The median EDSS score before mobilization of peripheral blood stem cells was 6.5 (range, 1.5-9). Eight deaths (2.8%; 95% CI, 1.0%-4.9%) were reported within 100 days of transplant and were considered transplant-related mortality. The 5-year probability of progression-free survival as assessed by the EDSS score was 46% (95% CI, 42%-54%), and overall survival was 93% (95% CI, 89%-96%) at 5 years. Factors associated with neurological progression after transplant were older age (hazard ratio [HR], 1.03; 95% CI, 1.00-1.05), progressive vs relapsing form of MS (HR, 2.33; 95% CI, 1.27-4.28), and more than 2 previous disease-modifying therapies (HR, 1.65; 95% CI, 1.10-2.47). Higher baseline EDSS score was associated with worse overall survival (HR, 2.03; 95% CI, 1.40-2.95). Conclusions and Relevance In this observational study of patients with MS treated with AHSCT, almost half of them remained free from neurological progression for 5 years after transplant. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline EDSS score were factors associated with better outcomes. The results support the rationale for further randomized clinical trials of AHSCT for the treatment of MS.

Although AHCT is an increasingly used therapy for patients (pts) with lymphoma (Lym) and multiple myeloma (MM), few studies have addressed late effects and QoL for survivors after AHCT. This study population included pts who were ≥5 years after AHCT for Lym or MM. Patient self-reported outcomes were surveyed by LTFU annual questionnaires (7/2015 to 9/2017) with a 60.5% response rate; median age (years, range) of responders was 65 (22-87), and 62 (31-83) for non-responders. Among 385 respondents (252 Lym, 133 MM), gender distribution and incidence of relapse did not differ between Lym vs. MM. High-dose TBI conditioning was more frequent in Lym (31% Lym vs. 2% MM), p < .001. Median age (range), was lower in Lym, 64 (22-87), vs. MM, 68 (33-83), p < .001. Years since AHCT, median (range), was greater in Lym, 11 (5-30.1), compared to MM, 7.2 (5-25), p < .001. After AHCT for Lym, more frequent late effects were post-traumatic stress disorder (7% Lym vs. 2% MM, P = .027) and hypothyroidism requiring treatment (41% Lym vs. 22% MM, p < .001). After AHCT for MM, more frequent late effects were bone fracture/compression (5% Lym vs. 20% MM, p < .001), and osteopenia/ osteoporosis (21% Lym vs. 32% MM, P = .022). Some notable medical conditions/behaviors that were not different between Lym and MM pts included pulmonary embolism/clots (9% vs 11%) and smoking/ chewing tobacco (10% vs. 10%). We did not observe any differences in other late effects. Current medication use (Rx) was more frequent in MM pts for: infection prevention/treatment (6% Lym vs. 20% MM, p < .001), hypertension (24% Lym vs. 42% MM, p < .001), depression (11% Lym vs. 20% MM, P = .013), osteoporosis (11% Lym vs. 22% MM, P = .002), and pain (12% Lym vs. 33% MM, p < .001). Predictors of physical and mental health were determined by multivariate analysis (MVA) of SF-36 physical and mental component summary data (PCS/MCS, see Table). Younger age, longer time since AHCT, no comorbidities, no relapse and no Rx for depression and/or pain were associated with better physical functioning. Older age and no Rx for anxiety, depression or pain, were associated with better mental functioning. None of the MVA outcomes differed between Lym and MM pts. In conclusion, LTFU annual surveys after AHCT indicated several key differences and similarities in late effects and QoL between Lym and MM pts. At a median of 10 (range, 5-30) years after AHCT, we have identified important QoL and late effects to be addressed that are potentially amenable to intervention. Tabled 1MVA of SF-36PCSMCSVariableParameter Estimate (PE)P-valuePEP-valueAge-.10.043.20<.001Female-1.06.307.68.496Years since AHCT.18.048.10.249Comorbidity (>0)-4.32<.001-1.30.253Relapse-4.18.013-.27.866MM vs. Lym-.05.9631.68.14Rx for anxiety.28.866-4.95.002Rx for depression-3.79.037-5.50.002Rx for insomnia-1.75.169-1.27.300Rx for pain-8.92<.001-2.90.026 Open table in a new tab

BACKGROUND Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma. METHODS We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score. RESULTS In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P = 0.01). In the per-protocol population (participants who received a transplant or completed >= 9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P = 0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P = 0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P = 0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group. CONCLUSIONS Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials. gov number, NCT00114530.)