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1.
Severity of Chronic Graft-versus-Host Disease and Late Effects Following Allogeneic Hematopoietic Cell Transplantation for Adults with Hematologic Malignancy
Lee, C. J., Wang, T., Chen, K., Arora, M., Brazauskas, R., Spellman, S. R., Kitko, C., MacMillan, M. L., Pidala, J. A., Badawy, S. M., et al
Transplantation and cellular therapy. 2023
Abstract
PURPOSE Our aim was to determine the association of chronic graft-versus-host disease (cGVHD) diagnosis and severity with the development of subsequent neoplasms (SN) and non-malignant late effects (NM-LE) in 2-year disease-free adult survivors following hematopoietic cell transplantation (HCT) for a hematologic malignancy. METHODS We conducted a retrospective analysis of 3884 survivors of HCT for hematologic malignancy in the Center of International Blood and Marrow Transplant Research (CIBMTR) database. A landmark analysis was conducted at the 2-year post-transplant date. We compared first SN and NM-LE in survivors with and without cGVHD. The cumulative incidences (CI) of SN and NM-LE were estimated through 10 years after HCT in both groups, with death or disease relapse as a competing risk. Cox proportional hazards models were used to evaluate the association of cGVHD and its related characteristics with the development of SN and NM-LE. RESULTS The estimated 10-year CI of SN in patients with (N=2669) and without cGVHD (N=1215) was 15% (95% CI, 14%-17%) vs. 9% (7.2%-11%), respectively (P<.001). Chronic GVHD by 2 years post-HCT was independently associated with SN (HR 1.94, 95% CI, 1.53-2.46, P<.0001) with a standardized incidence ratio of 3.2 (95% CI, 2.9-3.5, P<.0001). Increasing severity of cGVHD was associated with risk of SN. The estimated 10-year cumulative incidence of first NM-LE in patients with and without cGVHD was 28 (95% CI, 26-30%) vs. 13% (95% CI, 11%-15%), respectively (P<.001). Chronic GVHD by 2 years post-HCT was independently associated with NM-LE (HR 2.23, 95% CI, 1.81-2.76, P<.0001). Multivariate analysis of cGVHD-related factors showed that increasing severity of cGVHD, extensive grade, having both mucocutaneous and visceral involvement and receiving cGVHD treatment for more than 12 months were associated with the highest magnitude of risk for NM-LE. CONCLUSION Chronic GVHD appeared closely associated with both SN and NM-LE in adult survivors of HCT for hematologic malignancy. Patients identified as having more severe involvement and both mucocutaneous and visceral organ involvement may warrant enhanced monitoring and screening for SNs and NM-LEs. However, caution in interpreting these results is warranted as patients with cGVHD may have more vigilant post-transplant health care and surveillance for late effects.
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2.
Association of Chronic Graft-versus-Host Disease with Late Effects Following Allogeneic Hematopoietic Cell Transplantation for Children with Hematologic Malignancy
Lee, C. J., Wang, T., Chen, K., Arora, M., Brazauskas, R., Spellman, S. R., Kitko, C., MacMillan, M. L., Pidala, J. A., Auletta, J. J., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Chronic graft-versus-host disease (cGVHD) occurs in up to 25% of children following allogeneic hematopoietic cell transplantation (HCT) and continues to be a major cause of late morbidity and poor quality-of-life among long-term survivors of pediatric HCT. Late effects of HCT are well documented in this population and cGVHD has been reported as a risk factor for subsequent neoplasms (SN) and several non-malignant late effects. However, the correlation between cGVHD and late effects varies between studies. OBJECTIVE We compared late effects occurring ≥ 2 years following childhood HCT for a hematologic malignancy in 2-year disease-free survivors with and without cGVHD and further evaluated the association of cGVHD features on the development of late effects. STUDY DESIGN This was a systematic retrospective analysis using data from the Center of International Blood and Marrow Transplant Research (CIBMTR) on a large and representative cohort of 1260 survivors of pediatric HCT for hematologic malignancy to compare first malignant and non-malignant late effects following a diagnosis of cGVHD versus those who never developed cGVHD. The cumulative incidence (CI) of any first LE, subsequent neoplasm (SN), and non-malignant LE (NM-LE) was estimated at 10 years after HCT, with death as a competing risk for patients with cGVHD vs. no cGVHD. Cox proportional hazards models were used to evaluate the impact of cGVHD and its related characteristics on the development of first late effects. RESULTS The estimated 10-year cumulative incidence of any late effect in patients with and without cGVHD was 43% (95% CI, 38%-48.2%) vs. 32% (95% CI, 28.5%-36.3%) (P<0.001), respectively. The development of cGVHD by 2 years post-HCT was independently associated with any late effect (HR 1.38, 95% CI, 1.13-1.68, P=.001) and non-malignant late effects (HR 1.37, 95% CI, 1.10-1.70, P=.006), but not SN (HR 1.30, 95% CI, 0.73-2.31, P=.38). Chronic GVHD-related factors linked with the development of a non-malignant late effect included having extensive grade (HR 1.60, 95% CI 1.23 - 2.08, P=.0005), severe cGVHD (HR 2.25, 95% CI 1.60 - 3.17, P<.0001), interrupted onset type (HR 1.57, 95% CI 1.21 - 2.05, P=.0008), and both mucocutaneous and visceral organ involvement (HR 1.59, 95% CI 1.24 - 2.03, P=.0002). No significant association between cGVHD-specific variables and SN was identified. Lastly, duration of cGVHD treatment with systemic immunosuppression was not significantly associated with SN or non-malignant late effects. CONCLUSIONS cGVHD was more closely associated with non-malignant late effects than SN amongst survivors of pediatric HCT for hematologic malignancy. In this analysis, the development of SN was strongly associated with myeloablative total body irradiation. Chronic GVHD-related characteristics consistent with a state of higher immune dysregulation were more closely linked to non-malignant late effects.
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3.
Planned granulocyte-colony stimulating factor adversely impacts survival after allogeneic hematopoietic cell transplantation performed with Thymoglobulin for myeloid malignancy
Orfali, N., Zhang, M. J., Allbee-Johnson, M., Boelens, J. J., Artz, A. S., Brunstein, C. G., McNiece, I. K., Milano, F., Abid, M. B., Chee, L., et al
Transplantation and cellular therapy. 2021
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Editor's Choice
Abstract
BACKGROUND The in vivo depletion of recipient and donor T-lymphocytes using anti-thymocyte globulin (ATG) is widely adopted in allogeneic hematopoietic stem cell transplantation (HCT) to reduce the incidence of both graft failure and graft versus host disease (GVHD). However excess toxicity to donor lymphocytes may hamper immune reconstitution, compromising anti-tumour effects and increasing infection. Granulocyte-colony stimulating factor (G-CSF) administered early after HCT may increase ATG-mediated lympho-toxicity. OBJECTIVE Our study objective was to investigate the effect of an interaction between ATG and post-transplant G-CSF on allogeneic transplant outcomes, using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. STUDY DESIGN We studied patients aged =18 years with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) who received thymoglobulin-containing preparative regimens for HLA-matched sibling/unrelated or mismatched unrelated donor HCT from 2010-2018. The effect of planned G-CSF that was started between pre-transplant day 3 and post-transplant day 12 was studied in comparison to transplantations that did not include G-CSF. Cox regression models were built to identify risk factors associated with outcomes 1 year after transplantation. RESULTS 874 patients met study eligibility criteria; 459 (53%) received planned G-CSF. HCTs with planned G-CSF significantly increased risk for non-relapse mortality (HR 2•03, p<0•0001; 21% vs. 12%) compared to HCTs without G-CSF. The 6-month incidence of viral infections was higher with G-CSF (56% vs. 47%, p=0•007), with a particular increase in EBV infections (19% vs. 11%, p=0•002). The observed higher non-relapse mortality with planned G-CSF led to lower overall survival (HR 1•52, p=0•0005; 61% vs. 72%). There was no difference in GVHD risk between treatment groups. We include two sub-group analyses showing our findings held true (i) in patients aged =50 years and (ii) in centers where G-CSF was used in some but not all patients. CONCLUSION In allogeneic peripheral blood HCT performed with Thymoglobulin for AML and MDS, G-CSF administered early post-transplant results in a two-fold increase in non-relapse mortality and a 10% absolute decrement in survival. The use of planned G-CSF in the early post-transplant period should be carefully considered on an individual patient basis, weighing any perceived benefits against these risks.
PICO Summary
Population
Adult patients with acute myeloid leukaemia or myelodysplastic syndrome reported to the CIBMTR registry from 2010-2018 (n=874)
Intervention
Allogeneic transplant (HCT) with planned granulocyte-colony stimulating factor (G-CSF) administration (n=459)
Comparison
Allogeneic transplant with no planned granulocyte-colony stimulating factor (G-CSF) administration (n=415)
Outcome
HCTs with planned G-CSF significantly increased risk for non-relapse mortality (HR 2.0 ; 21% vs. 12%) compared to HCTs without G-CSF. The 6-month incidence of viral infections was higher with G-CSF (56% vs. 47%), with a particular increase in EBV infections (19% vs. 11%). The observed higher non-relapse mortality with planned G-CSF led to lower overall survival (HR 1.52, 61% vs. 72%). There was no difference in GVHD risk between treatment groups. We include two sub-group analyses showing our findings held true (i) in patients aged >/=50 years and (ii) in centres where G-CSF was used in some but not all patients.
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The European Society for Blood and Marrow Transplantation (EBMT) consensus recommendations for donor selection in haploidentical hematopoietic cell transplantation
Ciurea, S. O., Al Malki, M. M., Kongtim, P., Fuchs, E. J., Luznik, L., Huang, X. J., Ciceri, F., Locatelli, F., Aversa, F., Castagna, L., et al
Bone marrow transplantation. 2019
Abstract
The number of HLA-haploidentical hematopoietic cell transplants continues to increase worldwide due to recent improvements in outcomes, allowing more patients with hematological malignancies and non-malignant disorders to benefit from this procedure and have a chance to cure their disease. Despite these encouraging results, questions remain as multiple donors are usually available for transplantation, and choosing the best HLA-haploidentical donor for transplantation remains a challenge. Several approaches to haploidentical transplantation have been developed over time and, based on the graft received, can be grouped as follows: T-cell depleted haploidentical transplants, either complete or partial, or with T-cell replete grafts, performed with post-transplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis, or G-CSF-primed bone marrow graft and enhanced GVHD prophylaxis. Carefully selecting the donor can help optimize transplant outcomes for recipients of haploidentical donor transplants. Variables usually considered in the donor selection include presence of donor-specific antibodies in the recipient, donor age, donor/recipient gender and ABO combinations, and immunogenic variables, such as natural killer cell alloreactivity or KIR haplotype. Here we provide a comprehensive review of available evidence for selecting haploidentical donors for transplantation, and summarize the recommendations from the European Society for Blood and Marrow Transplantation (EBMT) on donor selection for different transplant platforms.
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A unique schedule of palonosetron, ondansetron, and dexamethasone for the prevention of delayed nausea and vomiting in patients receiving myeloablative chemotherapy
LaPorte, J., Leone, K., Zhang, X., Holland, K., Morris, L., Bashey, A., Solh, M., Solomon, S.
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2018;:1078155218790345
Abstract
Myeloablative chemotherapy administered prior to autologous stem cell transplantation (auto-SCT) is associated with a significant amount of chemotherapy-induced nausea and vomiting (CINV). We conducted a phase II trial to assess the safety, efficacy, and impact on quality of life when palonosetron (PAL) 0.25 mg combined with dexamethasone were given on the final or only day of myeloablative chemotherapy for auto-SCT. The primary end point of this study was the incidence of achieving a delayed CINV complete response defined as no emetic episode and no use of rescue medications during the 24-120 h period post chemotherapy. Eighty-five patients were enrolled in the study and received PAL. A delayed CINV complete response was achieved in 15% of patients. A multivariate analysis demonstrated no associated differences between age, gender, diagnosis, or regimen. By day 5 after PAL, the mean nausea severity was 0.91 +/- 2.45 vs. 0.09 +/- 1.58 at baseline (p = 0.012). Quality of life measurements demonstrated similar quality of life between baseline and day 3. By day 6 however, nausea alone had a statistically significant impact on quality of life. In our study, PAL controlled nausea severity and sustained quality of life, but further strategies are needed to control delayed CINV associated with the auto-SCT process.
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Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for High-Risk Acute Lymphoblastic Leukemia
Srour, S. A., Milton, D. R., Bashey, A., Karduss-Urueta, A., Al Malki, M. M., Romee, R., Solomon, S., Nademanee, A., Brown, S., Slade, M., et al
Biology of Blood & Marrow Transplantation. 2017;23(2):318-324
Abstract
Haploidentical transplantation performed with post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis has been associated with favorable outcomes for patients with acute myeloid leukemia and lymphomas. However, it remains unclear if such approach is effective for patients with acute lymphoblastic leukemia (ALL). We analyzed outcomes of 109 consecutively treated ALL patients 18 years of age and older at 5 institutions. The median age was 32 years and the median follow-up for survivors was 13 months. Thirty-two patients were in first complete remission (CR1), while the rest were beyond CR1. Neutrophil engraftment occurred in 95% of the patients. The cumulative incidences of grades II to IV and III and IV acute GVHD at day 100 after transplantation were 32% and 11%, respectively, whereas chronic GVHD, nonrelapse mortality, relapse rate, and disease-free survival (DFS) at 1 year after transplantation were 32%, 21%, 27%, and 51%, respectively. Patients in CR1 had 52% DFS at 3 years. These results suggest that haploidentical transplants performed with PTCy-based GVHD prophylaxis provide a very suitable alternative to HLA-matched transplantations for patients with ALL.