Rituximab for posttransplant lymphoproliferative disorder - therapeutic, preemptive, or prophylactic?

To minimize mortality due to posttransplant lymphoproliferative disorder (PTLD), the following strategies have been used: (1) Therapy without EBV Monitoring, i.e., administration of rituximab after PTLD diagnosis, usually by biopsy, in the absence of routine Epstein-Barr virus (EBV) DNAemia monitoring, (2) Prompt Therapy, i.e., monitoring EBV DNAemia, searching for PTLD by imaging when the DNAemia has exceeded a pre-specified threshold, and administration of rituximab if the imaging is consistent with PTLD, (3) Preemptive Therapy, i.e., monitoring EBV DNAemia and administration of rituximab when the DNAemia has exceeded a pre-specified threshold, and (4) Prophylaxis, i.e., administration of rituximab to all transplant recipients. The superiority of one of these strategies over the other strategies has not been established. Here we review the pros and cons of each strategy. Preemptive therapy or prophylaxis may currently be preferred for patients who are at a high risk of dying due to PTLD. However, Therapy without EBV Monitoring may be used for both high- and low-risk patients in the future, if effective and relatively non-toxic therapies for rituximab-refractory PTLD (e.g., EBV-specific T cells) have become easily available.

Outcomes for patients with EBV-positive PTLD post-allogeneic HCT after failure of rituximab-containing therapy.

Epstein-Barr virus-positive (EBV+) post-transplant lymphoproliferative disease (PTLD) is an ultra-rare and aggressive condition that may occur following allogeneic hematopoietic cell transplant (HCT) due to immunosuppression. Approximately half of EBV+ PTLD cases are relapsed or refractory (R/R) to initial rituximab-containing therapy. There are limited treatment options and no standard of care for patients with R/R EBV+ PTLD, and little is known about their treatment history and outcomes. We performed a multinational, multicenter, retrospective chart review of patients with R/R EBV+ PTLD following HCT to describe patients' demographic and disease characteristics, treatment history, and overall survival (OS) from rituximab failure. Among 81 patients who received initial treatment with rituximab as monotherapy (84.0%) or in combination with chemotherapy (16.0%), median time from HCT to PTLD diagnosis was 3.0 months and median OS was 0.7 months. Thirty-six patients received a subsequent line of treatment. The most frequent causes of death were PTLD (56.8%), graft-versus-host disease (13.5%) and treatment-related mortality (10.8%). In multivariate analysis, early PTLD onset and lack of response to initial treatment were associated with mortality. This real-world study demonstrates that the prognosis of patients with R/R EBV+ PTLD following HCT remains poor, highlighting the urgent unmet medical need in this population.

Complete response to donor lymphocyte infusion for primary hemophagocytic lymphohistiocytosis relapse after allogeneic hematopoietic cell transplantation.

Primary hemophagocytic lymphohistiocytosis (HLH) is a hyper-inflammatory disorder characterized by dysregulation of inflammatory cells and cytokine signalling. Although first-line treatment consisting of immunosuppressive therapy and allogeneic hematopoietic cell transplantation (HCT) is often curative, it remains unknown whether any effective therapies exist for disease relapse/progression after HCT. Here we present a case of a 29-year-old male with primary HLH that relapsed after HCT and subsequently achieved durable long disease-free survival following a donor-lymphocyte infusion (DLI). To our knowledge, this represents the first case demonstrating the efficacy of DLI for relapsed primary HLH.

The cancer-associated glycan polysialic acid is dysregulated in systemic sclerosis and is associated with fibrosis.

OBJECTIVE: Systemic sclerosis (SSc) is a rare but deadly disease characterized by autoimmunity, vasculopathy, and fibrosis. Fibrotic complications associated with SSc correlate with severe morbidity and mortality. Previous studies in SSc have identified fibroblasts as the primary drivers of fibrosis; however, the mechanism(s) promoting this are not well understood. Aberrant glycosylation, particularly polysialylation (polySia), has been described as a prominent feature of aggressive cancers. Inspired by this observation, we aimed to determine if polySia is dysregulated in various forms of SSc. METHODS: All patients with SSc met the 2013 ACR/EULAR. Patients were sub-classified into limited cutaneous (lSSc, N = 5 or 46 patients for polySia quantification in the dermis or serum; respectively), diffuse cutaneous (dSSc, N = 11 or 18 patients for polySia quantification in the dermis or serum; respectively), or patients with dSSc treated with an autologous stem cell transplantation (post-ASCT, N = 4 patients for quantification in the dermis). Dermal polySia levels were measured via immunofluorescence microscopy in 10 µm dermal sections, quantified in each group (healthy volunteers (HC), lSSc, dSSc, and post-ASCT) and correlated with skin fibrosis (via the modified Rodnan skin score (mRSS)). Similarly, serum polySia was quantified in each group, and correlated with the mRSS. RESULTS: Dermal polySia levels were highest in patients with dSSc (compared to HC < 0.001), and correlated with the degree of fibrosis in all of the groups (P = 0.008). Serum polySia was higher in all SSc groups (p < 0.001) and correlated with the severity of mRSS (p < 0.0001). CONCLUSION: Polysia is more abundant in the skin and sera from patients with SSc and correlates with the degree of skin fibrosis. The aberrant expression of polySia highlights its potential use as a biomarker in patients with progressive forms of SSc. Dysregulated polySia levels in SSc further emphasizes the cancer-like phenotype present in SSc, which may promote fibrosis and immune dysregulation.

Esophageal motility in systemic sclerosis before and after autologous hematopoietic cell transplantation.

INTRODUCTION: Systemic sclerosis (SSc) is associated with esophageal dysmotility. Autologous hematopoietic cell transplantation (HCT) results in improvement of skin tightness and lung function. Whether esophageal motility improves after HCT is unknown. METHODS: Esophageal motility was studied using high-resolution esophageal manometry in 21 SSc patients before and at multiple time points after autologous HCT. Median posttransplant follow-up was 2 years (range, 6 months to 5 years). RESULTS: Prior to HCT, all 21 patients had abnormal motility-10 (48%) had unmeasurable and 11 (52%) had measurable peristalsis. Manometric diagnosis in the former 10 patients was "absent contractility" and in the latter 11 patients "ineffective esophageal motility (IEM)." After HCT, among the 10 patients with absent contractility, 9 continued to have absent contractility and one demonstrated weak measurable peristalsis. Of the 11 patients with IEM, 5 experienced SSc relapse, and 2 out of these 5 patients developed absent contractility. Among the 6 non-relapsed patients, 4 continued to have IEM, and 2 developed normal motility. CONCLUSIONS: HCT appears to have no beneficial effect on motility in patients with unmeasurable peristalsis. In patients with measurable peristalsis, HCT appears to stabilize and in some normalize motility, unless relapse occurs. Key Points • In patients with systemic sclerosis, esophageal dysmotility is a significant contributor to morbidity and so far, there has been no data describing the effects of hematopoietic cell transplantation on esophageal motility. • Our work demonstrated that in patients with systemic sclerosis and unmeasurable esophageal peristalsis prehematopoietic cell transplantation, there was no measurable beneficial effect of transplantation on esophageal motility. • In patients with systemic sclerosis and measurable peristalsis prehematopoietic cell transplantation, esophageal motility stabilized, except in relapsed patients.

Corticosteroids as graft-versus-host disease prophylaxis for allogeneic hematopoietic cell transplant recipients with calcineurin inhibitor intolerance.

BACKGROUND AIMS: Although calcineurin inhibitors (CNIs) have a well-established role in the prevention of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT), their use can be limited by significant toxicities, which may result in premature treatment discontinuation. The optimal management of patients with CNI intolerance is unknown. The objective of this study was to determine the effectiveness of corticosteroids as GVHD prophylaxis for patients with CNI intolerance. METHODS: This retrospective single-center study included consecutive adult patients with hematologic malignancies who underwent myeloablative peripheral blood allogeneic HCT with anti-thymocyte globulin, CNI, and methotrexate GVHD prophylaxis in Alberta, Canada. Multivariable competing-risks regression was used to compare cumulative incidences of GVHD, relapse, and non-relapse mortality between recipients of corticosteroid versus continuous CNI prophylaxis, and multivariable Cox proportional hazards regression was applied to compare overall survival, relapse-free survival (RFS) and moderate-to-severe chronic GVHD and RFS. RESULTS: Among 509 allogeneic HCT recipients, 58 (11%) patients developed CNI intolerance and were switched to corticosteroid prophylaxis at median 28 days (range 1-53) after HCT. Compared with patients who received continuous CNI prophylaxis, recipients of corticosteroid prophylaxis had significantly greater cumulative incidences of grade 2-4 acute GVHD (subhazard ratio [SHR] 1.74, 95% confidence interval [CI] 1.08-2.80, P = 0.024), grade 3-4 acute GVHD (SHR 3.22, 95% CI 1.55-6.72, P = 0.002), and GVHD-related non-relapse mortality (SHR 3.07, 95% CI 1.54-6.12, P = 0.001). There were no significant differences in moderate-to-severe chronic GVHD (SHR 0.84, 95% CI 0.43-1.63, P = 0.60) or relapse (SHR 0.92, 95% CI 0.53-1.62, P = 0.78), but corticosteroid prophylaxis was associated with significantly inferior overall survival (hazard ratio [HR] 1.77, 95% CI 1.20-2.61, P = 0.004), RFS (HR 1.54, 95% CI 1.06-2.25, P = 0.024), and chronic GVHD and RFS (HR 1.46, 95% CI 1.04-2.05, P = 0.029). CONCLUSIONS: Allogeneic HCT recipients with CNI intolerance are at increased risks of acute GVHD and poor outcomes despite institution of corticosteroid prophylaxis following premature CNI discontinuation. Alternative GVHD prophylaxis strategies are needed for this high-risk population.

Long-term follow-up demonstrates curative potential of autologous stem cell transplantation for relapsed follicular lymphoma.

Although autologous stem cell transplantation (ASCT) can achieve durable responses in eligible patients with follicular lymphoma (FL), long-term follow-up is needed to determine if it has curative potential. This retrospective, multicenter study included 162 patients who received ASCT for relapsed FL in Alberta, Canada. With a median (range) follow-up time of 12.5 years (0.1-27.9), the 12-year time-to-progression (TTP) was 57% (95% confidence interval [CI] 49%-65%), time-to-next-treatment was 61% (95% CI 52%-69%), progression-free survival was 51% (95% CI 42%-59%) and overall survival was 69% (95% CI 60%-76%). A plateau emerged on the TTP curve at 57% starting 9 years after ASCT with no relapses occurring beyond this timepoint. Ten patients remained in remission 20 years or more after ASCT. Patients undergoing ASCT at first or second relapse had superior outcomes compared to third or later relapse (12-year TTP 61% vs. 34%), as did patients without progression of disease within 24 months (POD24) of frontline treatment versus those with POD24 (12-year TTP 67% vs. 50%). ASCT achieves high rates of durable remission in relapsed FL, with long-term follow-up revealing that more than 50% of transplanted patients may be functionally cured of their lymphoma. The optimal timing to consider ASCT is at first or second relapse, regardless of POD24 status.

Autologous hematopoietic stem cell transplant for the treatment of refractory myasthenia gravis with anti-muscle specific kinase antibodies.

INTRODUCTION/AIMS: Up to 25% of patients with myasthenia gravis (MG) have refractory disease despite trials of multiple immunosuppressants. Several case series describe acetylcholine receptor antibody-positive (AChR) MG patients treated with autologous hematopoietic stem cell transplant (HSCT). In this report, we describe three patients with anti-muscle-specific kinase (MuSK) MG treated with HSCT. METHODS: We included all patients who had undergone HSCT with anti-MuSK myasthenia gravis identified through the records of the Alberta Blood and Marrow Transplant Program. We collected demographic and clinical data including validated MG scales as well as questionnaire data. RESULTS: All 3 patients had severe disease (Myasthenia Gravis Foundation of America score IVb-V) and were refractory to multiple treatments, including rituximab. All patients improved with no clinical manifestations or mild symptoms and remained as such for 2, 3.5, and 5.5 y. Adverse events ranged from treatable infections and transient dyspnea to persistent fatigue and premature menopause. The average worst Myasthenia Gravis Activities of Daily Living (MG-ADL) scores improved from 14.7 before to 0.3 after HSCT. The mean worst Myasthenia Gravis Quality of Life Questionnaire (MG-QoL15) scores improved from 26.7 to 0. All patients reported they would undergo transplant again for their MG. DISCUSSION: We describe three patients with anti-MuSK MG treated with HSCT, all of whom became symptom free from MG with a tolerable side effect profile. In patients with severe refractory anti-MuSK MG, it may be reasonable to consider HSCT.

Rituximab Toxicity after Preemptive or Therapeutic Administration for Post-Transplant Lymphoproliferative Disorder.

Rituximab is commonly used as prevention, preemption, or therapeutically for post-transplant lymphoproliferative disorder (PTLD) after hematopoietic cell transplantation (HCT). Although it is generally assumed that rituximab toxicity (ie, infections resulting from hypogammaglobulinemia and neutropenia) is negligible in relation to mortality due to PTLD, limited evidence supports the validity of this assumption. We sought to determine the impact of rituximab on immunoglobulin levels, neutrophil count, infection density, and mortality outcomes. This study retrospectively analyzed 349 HCT recipients, 289 of whom did not receive rituximab and 60 of whom received rituximab preemptively or therapeutically at a median of 55 days post-transplantation. IgM, IgG, and IgA levels at 6 months and 12 months post-transplantation were lower in patients who received rituximab compared with those who did not (significant at P < .05 for IgM and IgA at 6 months and for IgM and IgG at 12 months). Rituximab recipients also had a higher incidence of severe neutropenia (<.5/nl) between 3 and 24 months (subhazard ratio [SHR], 2.3; P = .020). Regarding non-Epstein-Barr viral infections/PTLD, the rituximab group had a higher infection density between 3 and 24 months compared with the no-rituximab group (3.8 versus 1.6 infections per 365 days at risk; incidence rate ratio, 2.2; P < .001). The rituximab group also had a higher incidence of fatal infections (SHR, 3.1; P = .026), higher nonrelapse mortality (SHR, 2.4; P = .006), and higher overall mortality (hazard ratio, 1.7; P = .033). There were no significant between-group differences in the incidence of clinically significant graft-versus-host disease, graft failure, or relapse. Based on this study, rituximab given for PTLD is associated with substantial morbidity and mortality. Whether the benefit of preemptive rituximab outweighs the risk remains to be determined. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Donor Genetic Predisposition to High Interleukin-10 Production Appears Protective against Acute Graft-Versus-Host Disease.

The persistence of graft-versus-host disease (GVHD) as the principal complication of allogeneic hematopoietic cell transplantation (HCT) demonstrates that HLA matching alone is insufficient to prevent alloreactivity. We performed molecular and functional characterization of 22 candidate cytokine genes for their potential to improve matching in 315 myeloablative, 10/10 HLA-matched donor−recipient pairs. Recipients of a graft carrying the -1082GG IL10 gene promoter region variant had a three-fold lower incidence of grade II−IV acute GVHD compared to IL10-1082AA graft recipients (SHR = 0.25, p = 0.005). This was most evident in matched unrelated donor (MUD) transplants, where the greatest alloreactivity is expected. IL10-1082GG transplants did not experience an increased incidence of relapse, and, consequently, overall survival was two-fold higher in IL10-1082GG MUD transplants (HR = 0.17, p = 0.023). Longitudinal post-transplant measurements demonstrated that -1082GG is a high-IL10-producing and -expressing genotype with attenuated CD8+ T-cell reconstitution. High post-transplant donor chimerism in T- and myeloid-cells (>95%) confirmed a predominant donor, rather than recipient, genotype effect on immune function and aGVHD. To date, this is the first study to report corroborating genome-to-cellular evidence for a non-HLA donor immunogenetic variant that appears to be protective against GVHD. The incorporation of IL10 variants in donor selection criteria and clinical-management decisions has the potential to improve patient outcomes.

Hematopoietic Cell Transplantation for Systemic Sclerosis-A Review.

Systemic sclerosis (SSc) is an autoimmune, multi-organ, connective tissue disease associated with significant morbidity and mortality. Conventional immunosuppressive therapies demonstrate limited efficacy. Autologous hematopoietic stem cell transplantation (HCT) is more efficacious but carries associated risks, including treatment-related mortality. Here, we review HCT as a treatment for SSc, its efficacy and toxicity in comparison to conventional therapies, and the proposed mechanisms of action. Furthermore, we discuss the importance of and recent developments in patient selection. Finally, we highlight the knowledge gaps and future work required to further improve patient outcomes.

Incomplete chimerism following myeloablative and anti-thymocyte globulin-conditioned hematopoietic cell transplantation is a risk factor for relapse and chronic graft-versus-host disease.

BACKGROUND AIMS: The value of routine chimerism determination after myeloablative hematopoietic cell transplantation (HCT) is unclear, particularly in the setting of anti-thymocyte globulin (ATG)-based graft-versus-host disease (GVHD) prophylaxis. METHODS: Blood samples were collected at 3 months post-HCT from 558 patients who received myeloablative conditioning and ATG-based GVHD prophylaxis. Chimerism was assessed using multiplex polymerase chain reaction of short tandem repeats in sorted T cells (CD3+) and leukemia lineage cells (CD13+CD33+ for myeloid malignancies and CD19+ for B-lymphoid malignancies). ATG exposure was determined using a flow cytometry-based assay. The primary outcomes of interest were relapse and chronic GVHD (cGVHD). RESULTS: Incomplete (<95%) T-cell chimerism and leukemia lineage chimerism were present in 17% and 4% of patients, respectively. Patients with incomplete T-cell chimerism had a significantly greater incidence of relapse (36% versus 22%, subhazard ratio [SHR] = 2.03, P = 0.001) and lower incidence of cGVHD (8% versus 25%, SHR = 0.29, P < 0.001) compared with patients with complete chimerism. In multivariate modeling, patients with high post-transplant ATG area under the curve and any cytomegalovirus (CMV) serostatus other than donor/recipient seropositivity (non-D+R+) had an increased likelihood of incomplete T-cell chimerism. Patients with incomplete leukemia lineage chimerism had a significantly greater incidence of relapse (50% versus 23%, SHR = 2.70, P = 0.011) and, surprisingly, a greater incidence of cGVHD (45% versus 20%, SHR = 2.64, P = 0.003). CONCLUSIONS: High post-transplant ATG exposure and non-D+R+ CMV serostatus predispose patients to incomplete T-cell chimerism, which is associated with an increased risk of relapse. The increased risk of cGVHD with incomplete B-cell/myeloid chimerism is a novel finding that suggests an important role for recipient antigen-presenting cells in cGVHD pathogenesis.

Genomic instability in early systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) is associated with secondary malignancies. Previous studies have suggested that mutated cancer proteins, such as RNA polymerase III, are autoantigens promoting an inflammatory response in SSc. However, it has never been previously investigated whether non-neoplastic tissue in SSc harbors mutations which may play a role in SSc pathogenesis. METHODS: Skin biopsies were obtained from 8 sequential patients with a progressive form of early stage SSc (with severe skin and/or lung involvement). Areas of dermal fibrosis were microdissected and analyzed with deep, whole exome sequencing. Gene mutation patterns were compared to autologous buccal mucosal cells as a control. RESULTS: SSc skin biopsies were hypermutated with an average of 58 mutations/106 base pairs. The mutational pattern in all samples exhibited a clock-like signature, which is ubiquitous in cancers and in senescent cells. Of the 1997 genes we identified which were mutated in at least two SSc patients, 39 genes represented cancer drivers (i.e. tumor suppressor genes or oncogenes) which are commonly found in gynecological, squamous and gastrointestinal cancer signatures. Of all the mutations, the most common mutated genes were important in regulating pathways related to epigenetic histone modifications, DNA repair and genome integrity. CONCLUSIONS: Somatic hypermutation occurs in fibrotic skin in patients with early progressive SSc. Cancer driver gene mutations may potentially play a fundamental role in the pathogenesis of SSc.

Toward optimization of cyclosporine concentration target to prevent acute graft-versus-host disease following myeloablative allogeneic stem cell transplant.

INTRODUCTION: Despite the common use of cyclosporine (CsA) for acute graft-versus-host disease (aGVHD) prophylaxis following allogeneic stem cell transplant, the optimal CsA trough target remains unknown. MATERIALS AND METHODS: Here, we report on outcomes of adult patients following myeloablative conditioning to identify an optimal CsA trough target and characterize the most relevant timeframe post-transplant for CsA trough targeting to minimize aGVHD. We retrospectively reviewed 399 consecutive patients who underwent first peripheral blood allogeneic stem cell transplant for hematological malignancies between January 2009 and December 2018. RESULTS: In the unadjusted and adjusted analyses, the incidence of grades 2-4 aGVHD was significantly higher among patients with an average CsA trough concentration <250 mcg/L compared to patients with an average CsA trough concentration ≥250 mcg/L during days 15-28 post-transplant (31.5% versus 18.8%, P = 0.037), with an odds ratio (OR) of 1.97 (95% confidence interval 1.04-3.71). In contrast, no correlations between CsA trough concentration and relapse, non-relapse mortality and overall survival was found. CONCLUSION: In conclusion, early post-transplant CsA trough concentrations are an important factor in the prophylaxis against aGVHD. Our findings suggest that CsA trough concentrations should be maximized between days 15-28 post-myeloablative transplant.

Case Report: Chemotherapy-Associated Systemic Sclerosis: Is DNA Damage to Blame?

Systemic sclerosis, also known as scleroderma, is an autoimmune disease characterized by cutaneous and visceral fibrosis, immune dysregulation, and vasculopathy. Generally, the degree of skin fibrosis is associated with an increased likelihood of visceral organ involvement. Its pathogenesis is poorly understood; however, it is clear that changes in both the innate and adaptive immune responses are associated with fibroblast dysfunction and vascular damage. Further, DNA damage has been postulated as one of the triggering factors in systemic sclerosis, although the association of DNA damage with the progression of this disease is more poorly established. Recently, abnormal DNA damage response repair pathways have also been identified in patients with systemic sclerosis, suggesting that cells from patients with this disease may be more susceptible to DNA damaging agents. Chemotherapeutic drugs and other DNA damaging agents have been associated with the development of systemic sclerosis, as these agents may provide additional "hits" that promote abnormal DNA damage responses and subsequent inflammatory changes. Herein, we present the case of a 39-year-old female who developed scleroderma after the treatment of her breast cancer with chemotherapeutic agents. Her scleroderma was subsequently successfully treated with autologous hematopoietic stem cell transplantation. We also completed a literature review for previously published cases of chemotherapy associated with systemic sclerosis and highlighted a role of DNA damage in promoting the disease. Our case is the first case of chemotherapy associated with systemic sclerosis treated with hematopoietic stem cell transplantation.

Lymphocyte subset abnormalities in early severe scleroderma favor a Th2 phenotype and are not altered by prior immunosuppressive therapy.

OBJECTIVES: The Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial compared hematopoietic stem cell transplant to CYC treatment in patients with early SSc with progressive skin and lung or kidney involvement. Here we describe lymphocyte phenotype abnormalities at study entry and the relation to prior DMARD therapy. METHODS: Lymphocyte subsets (n = 26) measured by flow cytometry were compared in 123 heathy controls and 71 SCOT participants, including those given (n = 57) or not given (n = 14) DMARDs within 12 months of randomization. RESULTS: Compared with healthy controls, individuals with SSc showed significant reductions in central memory CD8 T cells, activated total and CD4 T cells, γ/δ T cells, memory B cells, myeloid and plasmacytoid dendritic cells and FOXP3+CD25+ Treg cells and increases in naïve CD4 T cells, effector memory CD4 T cells and effector CD8 T cells. A greater bias towards a IL-4+ Th2/T cytotoxic 2 (Tc2) phenotype based on the Th2:Th1 CD4 ratio and Tc2:Tc1 CD8 T cells was also found. Notably, no difference in any lymphocyte subset was observed between those given or not given prior DMARDs. CONCLUSIONS: In patients with early, severe SSc, significant lymphocyte subset abnormalities were observed. Prior treatment with immunosuppressive therapy did not impact the immunophenotype, suggesting that lymphocyte disturbances in scleroderma appeared to be due to the disease itself. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov), NCT00114530.

Cumulative incidence of subsequent malignancy after allo-HCT conditioned with or without low-dose total body irradiation.

Subsequent malignancies (SMs) present a significant burden of morbidity and are a common cause of late mortality in survivors of allogeneic hematopoietic cell transplant (allo-HCT). Previous studies have described total body irradiation (TBI) as a risk factor for the development of SMs in allo-HCT survivors. However, most studies of the association between TBI and SM have examined high-dose TBI regimens (typically ≥600 cGy), and thus little is known about the association between low-dose TBI regimens and risk of SMs. Our goal, therefore, was to compare the cumulative incidence of SMs in patients of Alberta, Canada, who received busulfan/fludarabine alone vs busulfan/fludarabine plus 400 cGy TBI. Of the 674 included patients, 49 developed a total of 56 malignancies at a median of 5.9 years' posttransplant. The cumulative incidence of SMs at 15 years' post-HCT in the entire cohort was 11.5% (95% confidence interval [CI], 8.5-15.6): 13.4% (95% CI, 9.1-19.3) in the no-TBI group and 10.8% (95% CI, 6.6-17.4) in the TBI group. In the multivariable model, TBI was not associated with SMs, whereas there was an association with number of pre-HCT cycles of chemotherapy. The standardized incidence ratio for the entire cohort, compared with the age-, sex-, and calendar year-matched general population, was 1.75. allo-HCT conditioning that includes low-dose TBI does not seem to increase risk of SMs compared with chemotherapy-alone conditioning.