Canadian cancer trials group LY.17: A randomized phase II study evaluating novel salvage therapy pre-autologous stem cell transplant in relapsed/refractory diffuse large B-cell lymphoma-outcome of rituximab-dose-intensive cyclophosphamide, etoposide, cisplatin (R-DICEP) versus R-GDP.

The Canadian Cancer Trials Group (CCTG) LY.17 is an ongoing multi-arm randomized phase II trial evaluating novel salvage therapies compared with R-GDP (rituximab, gemcitabine, dexamethasone and cisplatin) in autologous stem cell transplantation (ASCT)-eligible patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL). This component of the LY.17 trial evaluated a dose-intensive chemotherapy approach using a single cycle of inpatient R-DICEP (rituximab, dose-intensive cyclophosphamide, etoposide and cisplatin) to achieve both lymphoma response and stem cell mobilization, shortening time to ASCT. This report is the result of the protocol-specified second interim analysis of the 67 patients who were randomized to either 1 cycle of R-DICEP or to 3 cycles of R-GDP. The overall response rate (ORR) was 65.6% for R-DICEP and 48.6% for R-GDP. The ASCT rate was 71.9% versus 54.3%, and 1-year progression-free survival rate was 42% versus 32%, respectively, for R-DICEP versus R-GDP. Although the improvement in ORR for R-DICEP versus R-GDP exceeded the pre-specified 10% threshold to proceed to full accrual of 64 patients/arm, higher rates of grade 3-5 toxicities, and the need for hospitalization led to the decision to stop this arm of the study. CCTG LY.17 will continue to evaluate different salvage regimens that incorporate novel agents.

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.

Impact of FLT3 internal tandem duplication and NPM1 mutations in acute myeloid leukemia treated with allogeneic hematopoietic cell transplantation.

BACKGROUND AIMS: The internal tandem duplication of FLT3 (FLT3ITD) and NPM1 mutations (NPM1mut) are well-established prognostic factors in cytogenetically intermediate-risk acute myeloid leukemia (AML) when treated with chemotherapy alone. However, their prognostic value in the setting of allogeneic hematopoietic cell transplantation (HCT) is controversial. METHODS: FLT3 and NPM1 mutational status was determined at diagnosis using single-gene polymerase chain reaction or next-generation sequencing in 247 adult patients with cytogenetically intermediate-risk AML who underwent myeloablative HCT. Multivariate Fine-Gray and Cox regression was used to analyze the cumulative incidence of relapse (CIR), relapse-free survival (RFS) and overall survival (OS). RESULTS: FLT3ITD and NPM1mut were present in 74 of 247 (30%) and 79 of 247 (32%) patients, respectively. There was no significant difference between patients without a FLT3ITD or NPM1mut (FLT3NONITD/NPM1WT) and patients with a FLT3ITD mutation alone (FLT3ITD/NPM1WT) with regard to CIR (P = 0.60), RFS (P = 0.91) or OS (P = 0.66). Similarly, there was no significant difference between FLT3NONITD/NPM1WT and FLT3NONITD/NPM1mut patients with regard to CIR (P = 0.70), RFS (P = 0.75) or OS (P = 0.95). The presence of a concurrent mutation in NPM1 did not appear to modify the impact of having a FLT3ITD mutation. CONCLUSIONS: In contrast to chemotherapy-only treatment, FLT3 and NPM1 mutational status does not appear to predict outcomes in patients with cytogenetically intermediate-risk AML following HCT. These results suggest that HCT may ameliorate the poor prognostic effect of FLT3ITD mutation and that HCT should be considered over chemotherapy-only treatment in FLT3ITD-mutated AML.

Outcomes of Consecutively Diagnosed Primary Central Nervous System Lymphoma Patients Using the Alberta Lymphoma Clinical Practice Guideline Incorporating Thiotepa-Busulfan Conditioning for Transplantation-Eligible Patients.

While no widely accepted standard treatment regimen exists for primary central nervous system lymphoma (PCNSL), growing evidence supports an approach that incorporates autologous stem cell transplantation (ASCT) as consolidative therapy when feasible. In November 2011, the Alberta Hematology Tumor Team established a new clinical practice guideline (CPG) for PCNSL involving high-dose methotrexate (HDMTX)/cytarabine-based induction followed by ASCT for eligible patients using a thiotepa and busulfan (TBu) conditioning regimen that omitted cyclophosphamide from the regimen that was used before 2011. This retrospective study analyzed all 64 patients with PCNSL diagnosed consecutively in 3 Canadian centers between November 2011 and December 2017 to evaluate adherence to the 2011 CPG and associated outcomes. Of the 64 patients with PCNSL, 38 were initiated on the transplantation-eligible protocol, of whom 30 underwent successful ASCT, and 26 were deemed transplantation-ineligible, of whom only 7 completed the transplantation-ineligible HDMTX-based protocol. For the transplantation-eligible and -ineligible cohorts, the projected 3-year overall survival (OS) rates were 83.8% and 14.3% and progression-free survival (PFS) rates were 78.1% and 0%, respectively. For the 30 patients who underwent TBu/ASCT, the 3-year OS and PFS rates were 92.7% and 88.9%, respectively, with no treatment-related mortality or significant neurotoxicity. These real-world results highlight the efficacy and tolerability of TBu/ASCT consolidation for PCNSL in patients young and fit enough for an intensive treatment program, along with the significant need for improved therapies for older or less fit patients with PCNSL.

Establishing a target exposure for once-daily intravenous busulfan given with fludarabine and thymoglobulin before allogeneic transplantation.

A combination of fludarabine (Flu) and daily i.v. busulfan (Bu) is well tolerated and effective in patients undergoing allogeneic hematopoietic stem cell transplantation. Although there is some evidence that Bu exposures exceeding 6000 µM.min [corrected] may lead to excessive toxicity, there is little information on the effect of exposures below this level on outcomes. We studied Bu exposure, as measured by area under the concentration-time curve (AUC), in 158 patients with various hematologic malignancies in an attempt to identify an optimal range for targeted therapy. The preparative chemotherapy regimen comprised Flu 50 mg/m(2) on days -6 to -2 and i.v. Bu 3.2 mg/kg on days -5 to -2 inclusive. Graft-versus-host disease (GVHD) prophylaxis included methotrexate, cyclosporin A, and antithymocyte globulin. Patients with Bu exposures below the median AUC of 4439 µM.min [corrected] were at increased risk for acute GVHD grade II-IV (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.19 to 4.49; P = .014). Those in the highest and lowest Bu exposure quartiles (daily AUC <3814 µM.min and >4993 µM.min) [corrected] had an increased risk of nonrelapse mortality (subdistribution HR, 3.32; 95% CI, 1.46 to 7.54; P = .004), as well as worse disease-free survival (HR, 1.81; 95% CI, 1.09 to 2.99; P = .021) and overall survival (HR, 1.94; 95% CI, 1.12 to 3.37; P = .018). Bu exposures between 4440 and 4993 µM/min were accompanied by the lowest risk of both nonrelapse mortality and acute GVHD.

Consolidative Autotransplantation Achieves High Cure Rates in Adverse-Risk Large B Cell Lymphoma.

There remains an unmet need to optimize the first-line treatment of patients with high-risk large B cell lymphoma (LBCL), particularly those with a high International Prognostic Index (IPI) score or a positive interim positron emission tomography (PET) scan who experience poor outcomes with R-CHOP. This study was conducted to evaluate the real-world effectiveness of consolidative autologous stem cell transplantation (ASCT) among patients with high-risk LBCL. This retrospective study included consecutive patients with LBCL and IPI score 4 or 5 who underwent consolidative ASCT as part of first-line therapy in Alberta, Canada. Progression-free survival (PFS), overall survival (OS), and disease-specific survival (DSS) were determined using the Kaplan-Meier method. The study cohort comprised 114 patients with median age of 60 years (range, 18 to 73 years), of whom 81 (71%) had an IPI score of 4 and 33 (29%) had an IPI score of 5. With a median follow-up of 5.6 years, the 5-year PFS was 72% (95% confidence interval [CI], 62% to 79%), 5-year OS was 74% (95% CI, 64% to 81%), and 5-year DSS was 80% (95% CI, 71% to 87%). There was no significant difference in PFS among patients with and patients without positive interim PET scans (n = 24), MYC and BCL2 and/or BCL6 rearrangements (n = 26), or central nervous system involvement (n = 15). Consolidative ASCT is associated with high cure rates and favorable survival outcomes in patients with high-risk LBCL and may overcome the adverse prognostic impact of a positive interim PET scan.

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.

Fludarabine, busulfan, antithymocyte globulin, and total body irradiation for pretransplantation conditioning in acute lymphoblastic leukemia: excellent outcomes in all but older patients with comorbidities.

Hematopoietic stem cell transplantation (SCT) is routinely offered to suitable candidates with high-risk or advanced acute lymphoblastic leukemia (ALL). In this report, we update our experience with SCT in patients with ALL with a novel conditioning regimen. A total of 44 patients with high-risk or advanced (greater than first complete remission) ALL in remission underwent SCT after myeloablative conditioning with fludarabine + busulfan + total body irradiation. The median follow-up of surviving patients was 4.3 years (range, 1.0-9.0 years). The cohort consists of 32 patients with high-risk disease (median age, 40 years; range, 19-64 years) and 12 patients with advanced disease (median age, 25 years; range, 19-65 years) who underwent SCT: 25 with a related donor (21 fully matched) and 19 with an unrelated donor (16 fully matched). The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 53.2%, and that of grade III-IV acute GVHD was 20.6%. The incidence of chronic GVHD was 55%. The 100-day nonrelapse mortality was 13.6%. Five-year progression-free survival was 56.7%, and 5-year overall survival was 66.0%. Nine patients (20%) died in remission, 6 (14%) died after relapse, and 2 survived after a second SCT for relapsed disease. Outcomes were inferior in older patients with comorbidities compared with other patients.

Development and validation of a test dose strategy for once-daily i.v. busulfan: importance of fixed infusion rate dosing.

Intravenous (i.v.) busulfan (Bu) administered once daily in myeloablative transplant regimens is convenient, effective, and relatively well tolerated. Therapeutic drug monitoring is recommended as nonrelapse mortality increases when daily exposure, as determined by the area under the plasma concentration versus time curve (AUC), exceeds 6000 µM·min. We describe sequential studies to achieve accurate prediction of treatment doses of Bu based on the kinetics of a smaller test dose. A total of 335 patients with hematologic malignancies were given daily i.v. Bu 3.2 mg/kg × 4 and fludarabine 50 mg/m(2) × 5. Pharmacokinetic monitoring was conducted for both the test dose and first treatment dose of Bu (day -5). Three different test dose schedules were evaluated: 12 mg Bu administered over 20 minutes, 0.8 mg/kg over 3 hours, and 0.8 mg/kg infused at 80 mg/h. The 3.2 mg/kg treatment doses were infused over a fixed time of 3 hours for the first 2 test dose trials and at a fixed rate of 80 mg/h for the final protocol. All test dose infusions were on day -7. In the first 2 schedules, Bu administered over a fixed time had significantly higher clearance for the test dose compared with the treatment dose. However, when both the test and the treatment doses were administered at the same infusion rate, clearance of the drug between the 2 dosing days was equivalent. Predicted day -5 AUC (AUC(-5)) showed a high linear correlation (r(2) = 0.74) to the actual AUC(-5). The error of these predictions was <20% in 98% of patients and <10% in 80%. In 24 individuals, the test dose predicted an AUC >5500 µM·min; therefore, the first Bu treatment dose was reduced to a desired target AUC. All adjusted doses fell within 20% of the targeted exposure. We conclude that a test dose strategy for therapeutic drug monitoring of daily i.v. Bu is accurate if the test and treatment doses are infused at the same rate. This approach allows targeting of therapeutic doses of Bu to desired levels and the potential for improved safety and efficacy.

Improving the outcomes of secondary CNS lymphoma with high-dose thiotepa, busulfan, melphalan, rituximab conditioning and autotransplant.

Secondary central nervous system lymphoma (SCNSL) affects approximately 5% of patients with aggressive large B-cell lymphoma (LBCL) and is associated with poor outcomes. This retrospective, multicenter study included 62 consecutive patients with SCNSL intended for transplant with high-dose methotrexate (HD-MTX)-based induction followed by high-dose thiotepa, busulfan, melphalan, rituximab (TBMR) conditioning and autologous stem cell transplantation (ASCT). Median age was 58 years (range 20-75) and 52 (84%) patients had ECOG performance status >1 at diagnosis of SCNSL. Fifty-two (84%) patients completed induction and proceeded to TBMR/ASCT. With median follow-up 5.7 years, 5-year progression-free and overall survival rates were 53% (95% CI 39-65%) and 65% (95% CI 51-76%) for all patients and 62% (95% CI 45-74%) and 73% (95% CI 57-84%) for those undergoing TBMR/ASCT, respectively. Despite a historically poor prognosis, HD-MTX-based induction followed by TBMR/ASCT has the potential to achieve long-term survival in a substantial proportion of patients with SCNSL.

Real-World Eligibility for Second-Line Chimeric Antigen Receptor T Cell Therapy in Large B Cell Lymphoma: A Population-Based Analysis.

The ZUMA-7 trial demonstrated the superiority of second-line chimeric antigen receptor (CAR) T cell therapy over standard of care chemotherapy with or without autologous stem cell transplantation (ASCT) for relapsed/refractory (r/r) large B cell lymphoma (LBCL). We conducted a retrospective population-based analysis to determine eligibility for second-line CAR-T cell therapy in the real-world setting. Among 125 patients with r/r LBCL between 2015 and 2019, 82% progressed within 12 months of first-line chemoimmunotherapy (CIT), 40% were treated with intention-to-transplantation, 22% underwent ASCT, and 7% achieved a durable remission after ASCT. With a median follow-up of 2.8 years, the median overall survival (OS) was 5.1 months, and 3-year OS was 15% (95% confidence interval [CI], 7% to 20%) for all patients and 10% (95% CI, 5% to 17%) for those progressing within 12 months of CIT. Although only 14% of patients met all the ZUMA-7 study inclusion criteria, as many as 65% of patients progressing within 12 months of CIT had adequate performance status to be considered potentially eligible for second-line CAR T cell therapy. Whereas the current standard of care results in poor outcomes for most patients with r/r LBCL, the use of CAR T cell therapy in second-line therapy could substantially increase the proportion of patients able to receive curative-intent treatment at first progression of LBCL.

The role of allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia: A review.

Although the use of allogeneic hematopoietic cell transplantation (HCT) for chronic lymphocytic leukemia (CLL) has declined with the development of novel targeted agents, it continues to play an important role for eligible patients with high-risk or heavily pretreated CLL who lack other treatment options. CLL is susceptible to a potent graft-versus-leukemia (GVL) effect which produces long-lasting remissions in 30-50% of transplanted patients. While allogeneic HCT is associated with significant risks of graft-versus-host disease (GVHD), infection, and non-relapse mortality (NRM), improvements in patient and donor selection, reduced intensity conditioning (RIC), GVHD prophylaxis, and supportive care have rendered this an increasingly safe and effective procedure in the current era. In this review, we discuss recent advances in allogeneic HCT for CLL, with a focus on the optimal evidence-based strategies to maximize benefit and minimize toxicity of this potentially curative cellular therapy.

Favorable Outcomes with R-CHOP Induction and Consolidative Autologous Stem Cell Transplantation for Double-Hit Lymphoma.

Double-hit lymphoma (DHL) is an aggressive large B cell lymphoma associated with a poor prognosis with R-CHOP chemotherapy. The optimal treatment is unknown, but outcomes might be improved with intensive induction regimens or consolidative high-dose chemotherapy and autologous stem cell transplantation (HDT/ASCT). The purpose of this study was to determine the real-world outcomes of patients with DHL treated with primarily R-CHOP induction and consolidative HDT/ASCT. This retrospective, multicenter study included consecutive patients age 18 to 70 years with newly diagnosed DHL intended for consolidative HDT/ASCT in Alberta, Canada. Progression-free survival (PFS) and overall survival (OS) were determined using the Kaplan-Meier method. The cohort comprised 58 patients with a median age of 59.5 years (range, 30 to 69 years). High-risk features at diagnosis included International Prognostic Index score 3 to 5 in 45 patients (78%), transformed indolent lymphoma in 25 (43%), and central nervous system involvement in 3 (5%). Forty-six patients (79%) patients received R-CHOP induction, and 45 (78%) proceeded to consolidative HDT/ASCT. With a median follow-up of 4.6 years, the 4-year PFS and OS rates were 67% (95% confidence interval [CI], 53% to 78%) and 68% (95% CI, 54% to 79%), respectively, for all patients and 86% (95% CI, 72% to 93%) and 88% (95% CI, 73% to 95%) for those undergoing HDT/ASCT. R-CHOP induction and consolidative HDT/ASCT result in excellent outcomes for patients with chemosensitive DHL, whereas patients with primary refractory disease might benefit from alternative strategies, such as earlier use of chimeric antigen receptor T cell therapy.

A Canadian Perspective on the Treatment of Waldenström Macroglobulinemia.

Waldenström macroglobulinemia (WM) is a slowly progressing B-cell non-Hodgkin lymphoma characterized by monoclonal IgM gammopathy in the blood and infiltration of the bone marrow by clonal lymphoplasmacytic cells. As an incurable disease, the goals for therapy for WM are to relieve symptoms, slow disease progression, prevent organ damage, and maintain quality of life. However, given the rarity of WM, clinical trials comparing treatments for WM are limited and there is no definitive standard of care. The selection of first-line WM therapy is thus based on patient factors, disease characteristics, and drug access, with bendamustine-rituximab and Bruton's tyrosine kinase (BTK) inhibitor therapy considered preferred treatments. Other treatments such as proteasome inhibitor- or purine analogue-based therapy, alternative chemoimmunotherapy, and autologous stem cell transplantation are generally reserved for the relapsed setting but may be used in rare circumstances in earlier lines of therapy. This paper summarizes the efficacy and safety of these WM therapies and discusses considerations for treatment from a Canadian perspective.

Prolonged SARS-CoV-2 infection following rituximab treatment: clinical course and response to therapeutic interventions correlated with quantitative viral cultures and cycle threshold values.

BACKGROUND: Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA is completed through reverse transcriptase-PCR (RT-PCR) from either oropharyngeal or nasopharyngeal swabs, critically important for diagnostics but also from an infection control lens. Recent studies have suggested that COVID-19 patients can demonstrate prolonged viral shedding with immunosuppression as a key risk factor. CASE PRESENTATION: We present a case of an immunocompromised patient with SARS-CoV-2 infection demonstrating prolonged infectious viral shedding for 189 days with virus cultivability and clinical relapse with an identical strain based on whole genome sequencing, requiring a multi-modal therapeutic approach. We correlated clinical parameters, PCR cycle thresholds and viral culture until eventual resolution. CONCLUSIONS: We successfully demonstrate resolution of viral shedding, administration of COVID-19 vaccination and maintenance of viral clearance. This case highlights implications in the immunosuppressed patient towards infection prevention and control that should consider those with prolonged viral shedding and may require ancillary testing to fully elucidate viral activity. Furthermore, this case raises several stimulating questions around complex COVID-19 patients around the role of steroids, effect of antiviral therapies in absence of B-cells, role for vaccination and the requirement of a multi-modal approach to eventually have successful clearance of the virus.

Risk Factors for the Incidence of and the Mortality due to Post-Transplant Lymphoproliferative Disorder after Hematopoietic Cell Transplantation.

Post-transplant lymphoproliferative disorder (PTLD) is a potentially serious complication that occurs following hematopoietic cell transplantation (HCT), in which B cells transformed by Epstein-Barr virus (EBV) proliferate uncontrollably. It is unknown whether risk factors for the incidence of PTLD are identical to those for mortality due to PTLD, a clinically more important outcome. We sought to determine the risk factors influencing the incidence of PTLD and those influencing mortality due to PTLD in a cohort of 1184 allogenic HCT recipients. All patients were predisposed to PTLD, because their graft-versus-host disease (GVHD) prophylaxis included antithymocyte globulin. The overall PTLD incidence was 9.0%, and mortality due to PTLD was 1.1%. In multivariate analysis, risk factors for PTLD incidence include donor+/recipient- (D+/R-) EBV serostatus (subhazard ratio [SHR], 3.3; P = .002), use of a donor other than an HLA-matched sibling donor (non-MSD) (SHR, 1.7; P = .029), receipt of total body irradiation (TBI; SHR, 3.3; P = .008), and the absence of GVHD (SHR, 3.3; P < .001). The sole risk factor for mortality due to PTLD among all patients was D+/R- serostatus (SHR, 5.8; P = .022). Risk factors for mortality due to PTLD among patients who developed PTLD were use of a bone marrow (BM) graft (compared with peripheral blood stem cells [PBSCs]; SHR, 22.8; P < .001) and extralymphatic involvement (SHR, 14.6; P < .001). Interestingly, whereas the absence of GVHD was a risk factor for PTLD incidence, there was a trend toward the presence of GVHD as a risk factor for PTLD mortality (SHR, 4.2; P = .093). Likewise, whereas use of a BM graft was a risk factor for PTLD mortality, there was a trend toward use of a PBSC graft as a risk factor for PTLD incidence (SHR, 0.44; P = .179). Some risk factors for the incidence of PTLD are identical to the risk factors for mortality due to PTLD (ie, D+/R- serostatus), whereas other risk factors are disparate. Specifically, TBI was identified as a risk factor for PTLD incidence but not for PTLD mortality; the absence of GVHD was a risk factor for PTLD incidence, whereas the presence of GVHD was possibly a risk factor for PTLD mortality; and receipt of a PBSC graft was possibly a risk factor for PTLD incidence, whereas receipt of a BM graft was a risk factor for PTLD mortality.

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.

Recognition of Hematopoietic Stem Cell Transplantation and Cellular Therapy Expertise to Promote Care Accessibility: A Formally Credentialed Area of Focused Competence in Canada.

Hematopoietic stem cell transplantation (HSCT) and cellular therapy (CT) exploit the therapeutic potential of manipulated or unmanipulated hematopoietic cells to treat diseases. While initially dedicated to the treatment of hematologic malignancies and disorders, the use of these therapies in several diseases and cancers is currently under investigation. Indications are currently booming. In the midst of this expansion, both the American Society for Transplantation and Cellular Therapy (ASTCT) and the European Society for Blood and Marrow Transplantation (EBMT) have highlighted the global shortage of hematologists adequately trained in this field of high expertise. This shortage in transplant physicians and cellular therapists can significantly impact patients' access to cell-based therapy. To address this unmet need and attract aspiring hematologists to the field of cellular therapy, as well as to standardize training, anticipating this trend, a Canadian national task force aiming to develop a structured academic program in HSCT and CT was created. Workshops were organized to identify and establish the fundamentals of the practice in HSCT and CT. These workshops followed a rigorous process in developing the competency-based training program established by the Royal College. The program begins with the development of the main tasks associated with the practice of the discipline and the evidence that trainees must provide to demonstrate that they can perform these tasks independently (the competence portfolio). It continues with the development of training requirements that summarize the knowledge, skills, and aptitudes required to perform these tasks, followed by specific exposure during training (milestones) essential to demonstrate the acquisition of these skills. HSCT and CT together is now formally recognized as an Area of Focused Competence (AFC) by the Royal College of Physicians and Surgeons of Canada, a national organization that provides oversight of the medical education of specialists in Canada. AFCs are areas of specialty medicine that address a legitimate societal and patient population need previously unmet by the system of primary and subspecialty disciplines. The AFC designation for HSCT and CT provides a standardized curriculum, training experience, and accreditation process to attract young hematologists and promote expertise and quality care to meet the needs of both patients and society. A critical number of highly qualified hematologists will ensure continuing expansion of accessibility to HSCT and CT.