Abstract

The American Society for Transplantation and Cellular Therapy (ASTCT) published its first white paper on indications for autologous and allogeneic hematopoietic cell transplantation (HCT) in 2015. It was identified at the time that periodic updates of indications would be required to stay abreast with state of the art and emerging indications and therapy. In recent years, the field has not only seen an improvement in transplantation technology thus widening the therapeutic scope of HCT, but additionally a whole new treatment strategy using modified immune effector cells including chimeric antigen receptor T-cell (CART-cell) and T-cell receptors (TCRs) has emerged. The guidelines review committee of the ASTCT deemed it optimal to update the ASTCT recommendations for indications for HCT to include new data and to incorporate indications for immune effector cell therapy (IECT) where appropriate. The guidelines committee established multi-stakeholder task force consisting of transplant experts, payer representatives and a patient advocate to provide guidance on indications for HCT and IECT. This manuscript presents the updated recommendations from the ASTCT on indications for HCT and IECT. Indications for HCT/IECT were categorized as (1) Standard of care, where indication is well defined and supported by evidence, (2) Standard of care, clinical evidence available, where large clinical trials and observational studies are not available but has been shown to be effective therapy, (3) Standard of care, rare indication, for rare diseases where demonstrated effectiveness exist but large clinical trials and observational studies are not feasible, (4) Developmental, for diseases where pre-clinical and/or early phase clinical studies show HCT/IECT to be a promising treatment option, and (5) Not generally recommended, where available evidence does not support the routine use of HCT/IECT. The ASTCT will continue to periodically review these guidelines and update them as new evidence becomes available.

Abstract

Anti-thymocyte globulin (ATG) is used to reduce the incidence and severity of graft-versus-host disease (GVHD) with hematopoietic cell transplantation, yet optimum dosing has yet to be determined. We have previously demonstrated that 2.5 mg/kg of ATG in conditioning can reduce the incidence of GVHD in unrelated donor transplants. Recent literature has suggested that ATG dosing based on absolute lymphocyte count (ALC) could lead to more optimum exposure of the drug. We sought to determine if ALC at the time of transplant could impact clinical outcomes. We conducted a retrospective single centre study analyzing all consecutive patients at The Ottawa Hospital who received a matched unrelated donor stem cell transplant with ATG between 2009 and 2014. Patients received rabbit ATG (Thymoglobulin(R)) at 0.5 mg/kg on day -2 and 2.0 mg/kg on day -1. Univariate and multivariate analysis were used to determine if any patient or transplant related factors, including weight, ALC, and total ATG dose given, impacted GVHD, relapse, or mortality. One hundred and eleven patients met inclusion, with a median age of 50 years (range 19-70). The most common diagnoses were AML (43%), MDS/MPN (13%), and lymphoma (12%). The median weight at time of conditioning was 80.3 kg (range 45-216). The median ALC on the first day of ATG administration was 0.1 x 10(9)/L (range 0-190). The median total dose of ATG received was 201 mg (range 112-540). The incidence of acute and chronic GVHD was 35.1% and 21.6% respectively. In multivariate model, the actual dose of ATG given to patients was not associated with GVHD (HR=1.11, 95% CI 0.99-1.25, p=0.07), relapse (HR=1.13, 95% CI 0.98-1.30, p=0.1) or mortality (HR= 1.09, 95% CI 0.92-1.28, p=0.32). Similarly, the pre-transplant ALC was not associated with GVHD (HR=1, p=0.82), relapse (HR=1, p=0.90) or mortality (HR=1, p=0.39). If patients had received ALC based dosing according to previously published work (Admiraal et al., Lancet Haematol 2017), the mean total dose of ATG received would have been 1205 mg, more than five times the mean dose that was actually given based on weight. With GVHD outcomes being similar to that published by Admiraal et al. and ALC not independently associated with outcomes in our study, further studies are still needed to compare standard weight-based dosing to ALC-based dosing of ATG in matched unrelated donor stem cell transplant.

Abstract

There are limited data on the effect of donor body mass index (BMI) on peripheral blood stem cell (PBSC) mobilization response to granulocyte colony-stimulating factor (G-CSF), especially in unrelated donors. Obesity has been associated with persistent leukocytosis, elevated circulating progenitor cells, and enhanced stem cell mobilization. Therefore, we hypothesized that adequate collection of CD34+ cells may be achieved with lower doses (per kilogram of body weight) of G-CSF in donors with higher BMI compared with donors with lower BMI. Using the Center for International Blood and Marrow Transplant Research database, we evaluated the impact of donor BMI on G-CSF-mobilized PBSC yield in healthy unrelated donors. We examined 20 884 PBSC donations collected at National Marrow Donor Program centers between 2006 and 2016. We found significantly higher collection yields in obese and severely obese donors compared with normal and overweight donors. An increase in average daily G-CSF dose was associated with an increase in stem cell yield in donors with normal or overweight BMI. In contrast, an increase in average daily G-CSF dose beyond 780 mug per day in obese and 900 mug per day in severely obese donors did not increase cell yield. Pain and toxicities were assessed at baseline, during G-CSF administration, and postcollection. Obesity was associated with higher levels of self-reported donation-related pain and toxicities in the pericollection and early postdonation recovery periods. This study suggests a maximum effective G-CSF dose for PBSC mobilization in obese and severely obese donors, beyond which higher doses of G-CSF add no increased yield.

Abstract

Importance: Reduced-intensity conditioning and nonmyeloablative conditioning (RIC-NMAC) regimens are frequently used in allogeneic hematopoietic cell transplant (HCT) for non-Hodgkin lymphoma. However, the optimal RIC-NMAC regimen in allogeneic HCT for non-Hodgkin lymphoma is not known. Objective: To investigate whether RIC-NMAC regimens at a higher end of the intensity spectrum are associated with increased nonrelapse mortality and lower overall survival compared with RIC-NMAC regimens at the lower end of the intensity spectrum in patients with non-Hodgkin lymphoma undergoing allogeneic HCT. Design, Setting, and Participants: This cohort study used data from 1823 adult patients with non-Hodgkin lymphoma in the Center for International Blood and Marrow Transplant Research registry. Included patients underwent allogeneic HCT using matched related or unrelated donors between January 2008 and December 2016. Statistical analysis was performed from June 1, 2019, to February 10, 2020. Interventions: Patients received 1 of 4 RIC-NMAC regimens: fludarabine-intravenous busulfan (Flu-Bu), approximately 6.4 mg/kg (n = 458); fludarabine-melphalan (Flu-Mel140), 140 mg/m2 (n = 885); fludarabine-cyclophosphamide (Flu-Cy) (n = 391); or Flu-Cy with 2 Gy total body irradiation (Flu-Cy-2GyTBI) (n = 89). Main Outcomes and Measures: The primary outcome was overall survival. Secondary outcomes were nonrelapse mortality, incidence of relapse, progression-free survival, and the incidence of acute and chronic graft-vs-host disease (GVHD). Results: Of 1823 patients, 1186 (65%) were male, with a mean (SD) age of 54.8 (9.9) years. The 4-year adjusted OS was 58% in the Flu-Bu cohort, 67% in the Flu-Cy-2GyTBI cohort, 49% in the Flu-Mel140 cohort, and 63% in the Flu-Cy cohort (P < .001). After adjustment for age, Karnofsky performance score, HCT comorbidity index, NHL subtype, remission status at HCT, and the use of antithymocyte globulin or alemtuzumab, the regression analysis showed a significantly higher mortality risk associated with Flu-Mel140 compared with Flu-Bu (hazard ratio [HR], 1.34; 95% CI, 1.13-1.59; P < .001). Compared with the Flu-Cy cohort, the Flu-Mel140 cohort had a higher risk of chronic GVHD (HR, 1.38; 95% CI, 1.15-1.65; P < .001). The Flu-Mel140 regimen was associated with a higher nonrelapse mortality risk (HR, 1.78; 95% CI, 1.37-2.31; P < .001) compared with the Flu-Bu regimen. Conclusions and Relevance: The findings suggest that use of the more intense RIC-NMAC regimen, Flu-Mel140, may have a negative association with overall survival and may be associated with higher nonrelapse mortality. The Flu-Bu and Flu-Cy regimens with or without 2GyTBI regimens appeared to provide comparable overall survival.

Abstract

BACKGROUND Evidence about the impact of marital status before hematopoietic cell transplantation (hct) on outcomes after hct is conflicting. METHODS We identified patients 40 years of age and older within the Center for International Blood and Marrow Transplant Research registry who underwent hct between January 2008 and December 2015. Marital status before hct was declared as one of: married or living with a partner, single (never married), separated or divorced, and widowed. We performed a multivariable analysis to determine the association of marital status with outcomes after hct. RESULTS We identified 10,226 allogeneic and 5714 autologous hct cases with, respectively, a median follow-up of 37 months (range: 1-102 months) and 40 months (range: 1-106 months). No association between marital status and overall survival was observed in either the allogeneic (p = 0.58) or autologous (p = 0.17) setting. However, marital status was associated with grades 2-4 acute graft-versus-host disease (gvhd), p < 0.001, and chronic gvhd, p = 0.04. The risk of grades 2-4 acute gvhd was increased in separated compared with married patients [hazard ratio (hr): 1.13; 95% confidence interval (ci): 1.03 to 1.24], and single patients had a reduced risk of grades 2-4 acute gvhd (hr: 0.87; 95% ci: 0.77 to 0.98). The risk of chronic gvhd was lower in widowed compared with married patients (hr: 0.82; 95% ci: 0.67 to 0.99). CONCLUSIONS Overall survival after hct is not influenced by marital status, but associations were evident between marital status and grades 2-4 acute and chronic gvhd. To better appreciate the effects of marital status and social support, future research should consider using validated scales to measure social support and patient and caregiver reports of caregiver commitment, and to assess health-related quality of life together with health care utilization.

Abstract

BACKGROUND In Ontario, no clearly defined standard of care for the management of mantle cell lymphoma (mcl) has been developed, and substantial variability from centre to centre is evident. This guidance document was prompted by the need to harmonize practice in Ontario with respect to first-line, conditioning, and post-transplantation maintenance therapy for patients newly diagnosed with transplantation-eligible mcl. METHODS The medline and embase databases were systematically searched from January 2013 to January 2020 for evidence, and the best available evidence was used to draft recommendations relevant to first-line therapy, autologous stem-cell transplantation, and post-transplantation maintenance in the management of transplantation-eligible newly diagnosed mcl. Final approval of this guidance document was obtained from the Stem Cell Transplant Advisory Committee. RECOMMENDATIONS These recommendations apply to all cases of transplantation-eligible newly diagnosed mcl:¦ Alternating cycles of r-chop (rituximab plus cyclophosphamide-doxorubicin-vincristine-prednisolone) and r-dhap [rituximab plus dexamethasone-high-dose cytarabine-cisplatin] is the recommended first-line treatment for symptomatic patients newly diagnosed with mcl before autologous stem-cell transplantation (asct).¦ Rituximab plus hyperfractionated cyclophosphamide-vincristine-doxorubicin-dexamethasone (r-hypercvad), alternating with methotrexate and cytarabine, is not recommended for the treatment of patients with newly diagnosed mcl.¦ beam (carmustine-etoposide-cytarabine-melphalan), beac (carmustine-etoposide-cytarabine-cyclophosphamide), and total-body irradiation-based regimens are reasonable conditioning options for patients with mcl who have responded to first-line therapy and who are undergoing asct.¦ Maintenance therapy with rituximab is recommended for patients with newly diagnosed mcl who have undergone asct.

Abstract

Myeloablative (MAC) as compared to reduced-intensity conditioning (RIC) is generally associated with lower relapse risk after allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). However, disease specific risk factors in AML/MDS can further inform when MAC vs. RIC may yield differential outcomes. We analyzed HCT outcomes stratified by the disease risk index (DRI) in 4387 adults (age 40-65 years) to identify the impact of conditioning intensity. In the low/intermediate risk DRI cohort, RIC was associated with lower non-relapse mortality (NRM) (HR=0.74, 95% CI 0.62-0.88; p<0.001), but significantly higher relapse risk (HR=1.54, 95% CI 1.35-1.76; p<0.001) and thus inferior disease-free survival (DFS) (HR=1.19, 95% CI 1.07-1.33; p=0.001). In the high/very high risk DRI cohort, RIC resulted in marginally lower NRM (HR=0.83, 95% CI 0.68-1.00; p=0.051), and significantly higher relapse risk (HR=1.23, 95% CI 1.08-1.41; p=0.002) leading to similar DFS using either RIC or MAC. These data support MAC over RIC as the preferred conditioning intensity for AML/MDS with low/intermediate risk DRI, but similar benefit to RIC in high/very high risk DRI. Novel MAC regimens with less toxicity could benefit all, but more potent anti-neoplastic approaches are needed for the high/very high risk DRI group.

Abstract

Malignancy relapse is the most common cause of treatment failure among recipients of hematopoietic cell transplantation (HCT). Conditioning dose intensity can reduce disease relapse, but it is offset by toxicities. Improvements in radiotherapy techniques and supportive care may translate to better outcomes with higher irradiation doses in the modern era. This study compares outcomes of recipients of increasing doses of high dose total body irradiation (TBI) divided into intermediate high dose (IH 13-13.75 Gy) and high dose (HD 14 Gy) to standard dose (SD 12Gy) with cyclophosphamide (Cy). A total of 2,721 patients ages of 18 to 60 with hematologic malignancies receiving HCT from 2001 to 2013 were included. Cumulative incidence of non-relapse mortality (NRM) at 5 years was 28% (95% Cumulative Incidence [CI] 25-30%), 32% (95%CI 29-36%) and 34% (95%CI 28-39%) for SD, IH and HD, respectively (p=0.02). Patients receiving IH-TBI had a 25% higher risk of NRM compared to SD-TBI (12 Gy) (p=0.007). Corresponding cumulative incidence of relapse was 36% (95%CI 34-38%), 32% (95%CI 29-36%) and 26% (95%CI 21-31%) (p=0.001). Hazard ratio for mortality compared to SD were 1.06 (95% 0.94-1.19, p=0.36) for IH and 0.89 (95% CI 0.76-1.05, p=0.17) for HD. The study demonstrates that despite improvements in supportive care, myeloablative conditioning using higher doses of TBI (with Cy) leads to worse non-relapse mortality and offers no survival benefit over SD, despite reducing disease relapse.

Abstract

The combination of a calcineurin inhibitor (cyclosporine [CSA] or tacrolimus [Tac]) and methotrexate (MTX) or mycophenolate mofetil (MMF) are widely used approaches to graft-versus-host disease (GVHD) prevention. There is limited and conflicting data, however, on the comparative effectiveness of MMF compared to MTX. We analyzed data from the CIBMTR for adult patients undergoing first myeloablative hematopoietic cell transplant (HCT) from an HLA-identical matched related (MRD) (N=3979) or matched unrelated donor (URD) (N=4163) using CSA+MMF, CSA+MTX, Tac+MMF or Tac+MTX for GVHD prevention from 2000-2013. Within the MRD cohort, 2252 received CSA+MTX, 1391 Tac+MTX, 114 CSA+MMF, and 222 Tac+MMF. Recipients of CSA+MMF had a higher incidence of acute grade 2-4 (HR 1.65, 95% CI 1.24-2.20, P<0.001) and grade 3-4 (HR 1.92, 95% CI 1.31-2.83, P<0.001) GVHD compared to Tac+MTX. The use of CSA+MMF was also associated with inferior overall survival (OS) (HR 2.31, 95% CI 1.73-3.09, P<0.001) due to higher transplant-related mortality (TRM) (HR 4.03, 95% CI 2.61-6.23, P<0.001) versus Tac+MTX. Within the URD cohort, 974 received CSA+MTX, 2697 Tac+MTX, 68 CSA+MMF, and 424 Tac+MMF. CSA+MMF was again significantly associated with a higher incidence of grade 3-4 acute GVHD (HR 2.31, 95% CI 1.57-3.42, P<0001), worse OS (HR 2.36, 95% CI 1.67-3.35, P<0.001), and higher TRM (HR 3.09, 95% CI 2.00-4.77, P<0.001), compared to Tac+MTX, and other regimens. This large retrospective comparison of MMF versus MTX in combination with CSA or Tac thus demonstrates significantly worse GVHD and survival outcomes with CSA+MMF compared to Tac+MTX.

Abstract

BACKGROUND Follow-up is integral for hematopoietic cell transplant (HCT) care to ensure surveillance and intervention for complications. We characterized the incidence of, and predictors for, being lost to follow-up. METHODS Two-year survivors of first allogeneic (10,367 adults and 3,865 children) or autologous (7,291 adults and 467 children) HCT for malignant/non-malignant disorders from 2002-2013 reported to the Center for International Blood and Marrow Transplant Research were selected. The cumulative incidence of being lost to follow-up (defined as having missed 2 consecutive follow-up reporting periods) was calculated. Marginal Cox models (adjusted for center effect) were fit to evaluate predictors. RESULTS The 10-year cumulative incidence of being lost to follow-up among adult allogeneic and autologous HCT survivors was 13% (95% CI, 12-14) and 15% (95% CI, 14-16), respectively. Among pediatric HCT survivors, estimates were 25% (95% CI, 24-27) and 24% (95% CI, 20-29), respectively. In adult allogeneic HCT survivors, younger age, non-malignant disease, public/no insurance (reference: private), living farther from the HCT center, and being unmarried were associated with being lost to follow-up. For adult autologous HCT survivors, older age and testicular/germ cell tumor (reference: non-Hodgkin lymphoma) were associated with greater risk of being lost to follow-up. Among pediatric allogeneic HCT survivors, older age, public/no insurance (reference: private), and non-malignant disease were associated with being lost to follow-up. Among pediatric autologous HCT survivors, older age was associated with greater risk of being lost to follow-up. CONCLUSION Follow-up focusing on minimizing attrition in high-risk groups is needed to ensure surveillance for late effects.