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Impact of age, obesity, and renal impairment on outcomes after autologous stem cell transplantation for patients with newly diagnosed multiple myeloma
Gaffney, K. J., Bakos, J. K., Velayati, A., Davis, J. A., Thurlapati, A., Weeda, E., Maldonado, A., Granger, K., Butcher, C., Herrington, T., et al
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2024;:10781552231224361
Abstract
INTRODUCTION There remains a need to determine whether certain subgroups of newly diagnosed multiple myeloma (NDMM) derive the same benefit from high-dose chemotherapy-autologous stem cell transplant (HDT-ASCT). We describe our institutional experience highlighting the impact of age, obesity, and renal impairment on outcomes after HDT-ASCT for patients with NDMM in a real-world setting. METHODS A total of 449 consecutive patients were included in this retrospective analysis. RESULTS No difference in median progression free survival or overall survival was seen for patients with age > 65, body mass index (BMI) > 30 kg/m(2), or estimated glomerular filtration rate < 60 mL/min/1.73 m(2) when compared to those without these characteristics. From a safety standpoint, there were no differences in the incidence of transplant-related mortality or secondary malignancy among subgroups. CONCLUSION For patients with NDMM undergoing HDT-ASCT, there is no difference in outcomes based on age, BMI, or renal function, and the presence of one or more of these factors should not preclude patients from HDT-ASCT.
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Splenic irradiation for myelofibrosis prior to hematopoietic cell transplantation: A global collaborative analysis
Gagelmann, N., Hobbs, G. S., Campodonico, E., Helbig, G., Novak, P., Schroeder, T., Schneider, A., Rautenberg, C., Reinhardt, H. C., Bosques, L., et al
American journal of hematology. 2024
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Editor's Choice
Abstract
Splenomegaly is the clinical hallmark of myelofibrosis. Splenomegaly at the time of allogeneic hematopoietic cell transplantation (HCT) is associated with graft failure and poor graft function. Strategies to reduce spleen size before HCT especially after failure to Janus kinase (JAK) inhibition represent unmet clinical needs in the field. Here, we leveraged a global collaboration to investigate the safety and efficacy of splenic irradiation as part of the HCT platform for patients with myelofibrosis. We included 59 patients, receiving irradiation within a median of 2 weeks (range, 0.9-12 weeks) before HCT. Overall, the median spleen size prior to irradiation was 23 cm (range, 14-35). Splenic irradiation resulted in a significant and rapid spleen size reduction in 97% of patients (57/59), with a median decrease of 5.0 cm (95% confidence interval, 4.1-6.3 cm). The most frequent adverse event was thrombocytopenia, with no correlation between irradiation dose and hematological toxicities. The 3-year overall survival was 62% (95% CI, 48%-76%) and 1-year non-relapse mortality was 26% (95% CI, 14%-38%). Independent predictors for survival were severe thrombocytopenia and anemia before irradiation, transplant-specific risk score, higher-intensity conditioning, and present portal vein thrombosis. When using a propensity score matching adjusted for common confounders, splenic irradiation was associated with significantly reduced relapse (p = .01), showing a 3-year incidence of 12% for splenic irradiation versus 29% for patients with immediate HCT and 38% for patients receiving splenectomy. In conclusion, splenic irradiation immediately before HCT is a reasonable approach in patients experiencing JAK inhibition failure and is associated with a low incidence of relapse.
PICO Summary
Population
Adults with with primary myelofibrosis, post polycythemia vera, and post-essential thrombocythemia myelofibrosis, identified from centres worldwide (n=171)
Intervention
Splenic irradiation within a median of 2 weeks before transplant (n=59)
Comparison
Matched controls receiving immediate transplant without splenic irradiation (n=56), or who had splenectomy (n=56)
Outcome
Overall, the median spleen size prior to irradiation was 23 cm (range, 14-35). Splenic irradiation resulted in a significant and rapid spleen size reduction in 97% of patients (57/59), with a median decrease of 5.0 cm (95% confidence interval, 4.1-6.3 cm). The most frequent adverse event was thrombocytopenia, with no correlation between irradiation dose and hematological toxicities. The 3-year overall survival was 62% (95% CI, 48%-76%) and 1-year non-relapse mortality was 26% (95% CI, 14%-38%). Independent predictors for survival were severe thrombocytopenia and anemia before irradiation, transplant-specific risk score, higher-intensity conditioning, and present portal vein thrombosis. When using a propensity score matching adjusted for common confounders, splenic irradiation was associated with significantly reduced relapse, showing a 3-year incidence of 12% for splenic irradiation versus 29% for patients with immediate HCT and 38% for patients receiving splenectomy.
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Letermovir for Cytomegalovirus infection in pediatric patients undergoing allogenic hematopoietic stem cell transplantation: a real-life study by the Infectious Diseases Working Group of Italian Association of Pediatric Hematology-Oncology (AIEOP)
Galaverna, F., Baccelli, F., Zama, D., Tridello, G., Masetti, R., Soncini, E., Mura, R., Barzaghi, F., Colombini, A., Prunotto, G., et al
Bone marrow transplantation. 2024
Abstract
Letermovir prophylaxis revolutionized the approach to Cytomegalovirus infection in adult hematopoietic stem cell transplant (HCT), while data in pediatric setting are still lacking. We retrospectively analyzed 87 HCT children transplanted in 11 AIEOP centers receiving letermovir as off-label indication between January 2020 and November 2022. Letermovir was used as primary, secondary prophylaxis or CMV treatment in 39, 26 and 22 cases, respectively; no discontinuation due to toxicity was reported. Median duration was 100 days (14-256) for primary and 96 days (8-271) for secondary prophylaxis, respectively. None of the patients experienced CMV-clinically significant reactivation during Letermovir primary prophylaxis; one patient developed breakthrough infection during secondary prophylaxis, and 10 and 1 patient experienced asymptomatic CMV-reactivation and CMV-primary infection after drug discontinuation, respectively. Median duration of letermovir in CMV treatment was 40 days (7-134), with 4/22 patients suffering CMV-pneumonia, with an overall response rate of 86.4%. With a median follow-up of 10.7 months (8.2-11.8), estimated 1-year overall survival was 86%; no CMV-related deaths were reported in prophylaxis groups. This is the largest report on Letermovir use in pediatric HCT; real-life data confirm an excellent toxicity profile, with high efficacy as CMV prophylaxis; results in CMV-infection treatment should be investigated in larger, prospective trials.
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Risk factors for hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation in a letermovir-exposed CMV-free population receiving PTCy
Galli, E., Metafuni, E., Gandi, C., Limongiello, M. A., Giammarco, S., Mattozzi, A., Santangelo, R., Bacigalupo, A., Sorà, F., Chiusolo, P., et al
European journal of haematology. 2024
Abstract
Hemorrhagic cystitis (HC) is a highly impacting complication in allogeneic hematopoietic stem cell transplantation (HSCT), occurring in 12%-37% of patients. The impact of transplant- and patient-specific variables has been described, with a possible role for JCV and BKV, which may be cooperating with cytomegalovirus (CMV). Here, we analyze 134 letermovir-exposed, CMV-free patients, treated with the same cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis, describing risk factors for HC. The overall incidence of HC was 23%. Patients with HLA mismatched transplant, higher comorbidity score, and receiving three alkylating agents with TBF (thiotepa, busulfan, and fludarabine) conditioning regimen had a higher risk of HC in multivariate analysis (OR: 4.48, 6.32, and 1.32, respectively). A HC-score including male gender, TBF conditioning, and HLA-mismatch stratifies the risk of HC in the first 100 days after HSCT. The role of BKV and JCV was not highly impacting in those patients, suggesting a possible synergistic effect between CMV and JCV in causing HC. HC can be interpreted as the combination of patient-related factors, chemotherapy-related toxicities-especially due to alkylating agents-and immunological elements.
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Allogenic hematopoietic stem cell transplantation outcomes of patients aged ≥ 55 years with acute myeloid leukemia or myelodysplastic syndromes in China: a retrospective study
Gao, L., Yang, L., Zhou, S., Zhu, W., Han, Y., Chen, S., Xue, S., Wang, Y., Qiu, H., Wu, D., et al
Stem cell research & therapy. 2024;15(1):24
Abstract
BACKGROUND Elderly patients with acute myeloid leukemia or myelodysplastic syndromes (AML/MDS) have historically had poor prognoses. However, there has been a recent increase in the use of allogenic hematopoietic stem cell transplantation (allo-HSCT) are in this patient population. Nevertheless, the optimal choice of donor type for the patients remains an unmet need. Limited data exist on the use of allo-HSCT in elderly patients with AML/MDS from China. To better understand and optimize the selection of donor type for the elderly patients, particularly for those with refractory or relapsed disease, in comparison with the previous studies in the US and Europe. METHODS Our retrospective study enrolled 259 patients aged over 55 years who underwent their first allo-HSCT between April 2015 and August 2022. These patients were divided into three groups based on donor type: haploidentical related donor group (haploidentical related donor transplantation [HID], n = 184), matched sibling donor group (matched sibling donor transplantation [MSD], n = 39), and matched unrelated donor group (matched unrelated donor transplantation [MUD], n = 36). Statistics were performed with the chi-square test, the log-rank and Fine-Gray tests. RESULTS The median age of the cohort was 57 years (range: 55-75) and 26.25% of patients were over 60 years old. Younger patients had a higher incidence of acute graft-versus-host disease (HR = 1.942, P = 0.035), faster neutrophil recovery (HR = 1.387, P = 0.012), and better overall survival (HR = 0.567, P = 0.043) than patients aged ≥ 60 years across the entire cohort. Patients with refractory or relapsed (R/R) diseases had delayed neutrophil engraftment (P = 0.010, HR = 0.752) and platelet engraftment (P < 0.001, HR = 0.596), higher incidence of relapses (HR = 2.300, P = 0.013), and inferior relapse-free survival (RFS) (HR = 1.740, HR = 0.016) regardless of donor type. When it came to graft-versus-host-disease-free, relapse-free survival (GRFS), MUDs turned out to be superior to HIDs (HR = 0.472, P = 0.026) according to the multivariable analysis. In contrast, we found MSDs had an inferior GRFS to HIDs in parallel (HR = 1.621, P = 0.043). CONCLUSION The choice of donor type did not significantly affect the outcomes of allo-HSCT. However, when considering the quality of post-transplant life, MUDs or HIDs from younger donors may be the optimal choice for elderly patients.
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Prophylactic maintenance with venetoclax/azacitidine after reduced intensity conditioning allo-transplant for high risk MDS and AML
Garcia, J. S., Kim, H. T., Murdock, H. M., Ansuinelli, M., Brock, J., Cutler, C. S., Gooptu, M., Ho, V. T., Koreth, J., Nikiforow, S., et al
Blood advances. 2024
Abstract
We conducted a phase 1 trial assessing safety and efficacy of prophylactic maintenance therapy with venetoclax and azacitidine (Ven/Aza) in patients with high risk myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) undergoing reduced intensity allogeneic hematopoietic stem cell transplantation following venetoclax and FluBu2-conditioning (Ven/FluBu2 allo-SCT) with tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Among 27 patients who underwent Ven/FluBu2 allo-SCT (55.6% prior venetoclax exposure and 96% molecular measurable residual disease (MRD)-positive), 22 received maintenance therapy with azacitidine 36 mg/m2 intravenously on days 1-5 and venetoclax 400 mg by mouth on days 1-14 on one of two schedules (42-day cycles x 8 or 28-day cycles x 12). During maintenance, the most common grade 3/4 adverse events were leukopenia, neutropenia and thrombocytopenia, which were transient and manageable. Infections were uncommon (n=4, all grade 1-2). The 1-year and 2-year moderate/severe chronic GVHD rates were 4% (95% CI, 0.3-18%) and 22% (95% CI, 9-40%). After a median follow-up of 25-months among survivors, median overall survival (OS) was not reached. In the 22 patients who received Ven/Aza maintenance, the 2-year OS, progression-free survival, non-relapse mortality, and cumulative incidence of relapse rates were 67% (95% CI, 43-83%), 59% (95% CI, 36-76%), 0%, and 41% (95% CI, 20-61%), respectively. Immune monitoring demonstrated no significant impact on T cell expansion, but identified reduced B cell expansion compared to controls. This study demonstrates prophylactic Ven/Aza maintenance can be safely administered in high risk MDS/AML patients, but a randomized study is required to properly assess any potential benefit. (NCT03613532).
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Matched unrelated donor transplantation versus haploidentical transplantation with post-transplant cyclophosphamide in children with acute myeloid leukemia: a PDWP-EBMT study
Ruggeri, A., Santoro, N., Galimard, J. E., Kalwak, K., Algeri, M., Zubarovskaya, L., Czyzewski, K., Skorobogatova, E., Sedlacek, P., Besley, C., et al
Haematologica. 2024
Abstract
In children with acute myeloid leukemia (AML) who lack an HLA identical sibling, the donor can be replaced with an HLA matched unrelated donor (MUD) or a haploidentical donor (haplo). We compared outcomes of patients <18 years with AML in first and second complete remission (CR1 and CR2) undergoing a hematopoietic stem cell transplantation (HCT) either with a MUD with anti-thymocyte globuline (ATG) (n=420) or a haplo HCT with PT-CY (n=96) after a myeloablative conditioning regimen (MAC) between 2011 and 2021, reported to EBMT. A matched pair analysis was performed to adjust for differences among groups. The final analysis was performed on 253 MUD and 95 haplo-HCTs. In the matched cohort, median age at HCT was 11.2 and 10 years and median year of HCT was 2017 and 2018, in MUD and haplo- HCT recipients, respectively. The risk of grade III-IV aGvHD was significantly higher in the haplo group (HR=2.33, 95%CI1.18-4.58, p=0.03). No significant differences were found in 2 years overall survival (OS; 78.4%vs71.5%; HR 1.39, 0.84-2.31, p=0.19), leukemia-free-survival (LFS; 72.7%vs69.5%; HR1.22, 0.76-1.95, p=0.41), CI of relapse (RI; 19.3%vs19.5%; HR=1.14, 0.62-2.08, p=0.68) non-relapse-mortality (NRM; 8%vs11%; HR=1.39, 0.66-2.93, p=0.39) and graft versus host free-relapse free survival (GRFS; 60.7%vs54.5%, HR=1.38, 0.95-2.02, p=0.09) after MUD and haplo-HCT respectively. Our study suggests that haplo-HCT with PT-CY is a suitable option to transplant children with AML lacking a matched related donor.
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Ofatumumab as part of reduced intensity conditioning in high risk B-cell lymphoma patients: final long-term analysis from a prospective multicenter Phase-II Trial
Cabrero, M., López-Corral, L., Jarque, I., de la Cruz-Vicente, F., Pérez-López, E., Valcárcel, D., Sanz, J., Espigado, I., Ortí, G., Martín-Calvo, C., et al
Bone marrow transplantation. 2024
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Full text
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Editor's Choice
Abstract
Curative potential of allogeneic transplantation (AlloSCT) in high-risk non-Hodgkin lymphoma (NHL) could be enhanced by the integration of Ofatumumab (OFA), a 2nd generation anti-CD20 moAb, due to an antitumor effect and a role over graft-versus-host disease (GVHD). In this phase II trial (NCT01613300), we investigated safety and effectiveness of OFA-based reduced intensity conditioning (RIC). High-risk B-cell NHL patients with chemorrefractory disease or post-autologous SCT relapse were eligible. OFA was added to a standard RIC regimen. Primary endpoint was grade 3-4 aGVHD rate, while secondary endpoints included CR and survival rates. Thirty-three patients were included (median age 51; diffuse large B-cell:68%, HLA-identical donor: 74%). No grade >2 OFA toxicity was observed. Acute GVHD affected 77% of patients (16% grade 3-4). Remarkably, GVHD achieved CR in 75% of patients after first-line treatment. Chronic GVHD, primarily mild or moderate, occurred in 54% of patients. NHL CR rate at day +100 was 81%. Relapses occurred in 7 patients after a median of 3 months. Causes of death were lymphoma progression (5), infections (10), and GVHD (2). At 24 months, progression-free and overall survival rates were 50.1 and 51.6% respectively. OFA-RIC regimen is safe and effective, though acute GVHD remains a significant complication. However, data suggest that OFA could mitigate its severity.
PICO Summary
Population
Adults with high-risk B-cell non-Hodgkin lymphoma with either chemorrefractory disease or who relapsed post-autologous transplant, from centres in Spain (n=33)
Intervention
Ofatumumab (OFA), a 2nd generation anti-CD20 moAb, added to a reduced intensity conditioning (RIC) regime
Comparison
None
Outcome
Acute GVHD affected 77% of patients (16% grade 3-4). Remarkably, GVHD achieved CR in 75% of patients after first-line treatment. Chronic GVHD, primarily mild or moderate, occurred in 54% of patients. NHL CR rate at day +100 was 81%. Relapses occurred in 7 patients after a median of 3 months. Causes of death were lymphoma progression (5), infections (10), and GVHD (2). At 24 months, progression-free and overall survival rates were 50.1 and 51.6% respectively.
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Population pharmacokinetics of cyclosporine A in pediatric patients with thalassemia undergoing allogeneic hematopoietic stem cell transplantation
Cai, R., Zhang, L., Wu, T., Huang, Y., Lu, J., Huang, T., Wu, Y., Wu, D., Qi, J., Niu, L., et al
European journal of clinical pharmacology. 2024
Abstract
PURPOSE To establish the population pharmacokinetics (PPK) model of cyclosporine A(CsA) in pediatric patients with thalassemia undergoing allogeneic hematopoietic stem cell transplantation (HSCT), aiming at providing a reference for clinical dose individualization of CsA. METHODS Children with thalassemia who underwent allogeneic HSCT were enrolled retrospectively. The PPK structural model and the random variable model of CsA were established on NONMEN. And goodness of fit plots (GOFs), visual predictive check (VPC), and bootstrap and normalized prediction distribution errors (NPDE) were used to evaluate the final model. RESULTS A one-compartment model with first-order absorption was employed to fit the base model. A total of 74 pediatric patients and 600 observations of whole blood concentration were included. The final model included weight (WT) in clearance (CL), alongside post-operative day (POD), fluconazole (FLUC), voriconazole (VORI), posaconazole (POSA), and red blood cell count (RBC) significantly. All the model evaluations were passed. CONCLUSION In the PPK model based on the pediatric cohort on CsA with thalassemia undergoing allogeneic HSCT, WT, POD, FLUC, VORI, POSA, and RBC were found to be the significant factors influencing CL of CsA. The reliability and robustness of the final model were excellent. It is expected that the PPK model can assist in individualizing dosing strategy clinically.
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Cost-Effectiveness of Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation for Older Patients With High-Risk Myelodysplastic Syndrome: Analysis of BMT CTN 1102
Saber, W., Bansal, A., Li, L., Scott, B. L., Sangaralingham, L. R., Thao, V., Roth, J. A., Wright, W., Steuten, L. M. G., Pidala, J. A., et al
JCO oncology practice. 2024;:Op2300413
Abstract
PURPOSE BMT CTN 1102 was a phase III trial comparing reduced-intensity allogeneic hematopoietic cell transplantation (RIC alloHCT) to standard of care for persons with intermediate- or high-risk myelodysplastic syndrome (MDS). We report results of a cost-effectiveness analysis conducted alongside the clinical trial. METHODS Three hundred eighty-four patients received HCT (n = 260) or standard of care (n = 124) according to availability of a human leukocyte antigen-matched donor. Cost-effectiveness was calculated from US commercial and Medicare perspectives over a 20-year time horizon. Health care utilization and costs were estimated using propensity score-matched cohorts of HCT recipients in the OptumLabs Data Warehouse (age 50-64 years) and Medicare (age 65 years and older). EuroQol 5 Dimension (EQ-5D) surveys of trial participants were used to derive health state utilities. RESULTS Extrapolated 20-year overall survival for those age 50-64 years was 29% for HCT (n = 105) versus 13% for usual care (n = 44) and 31% for HCT (n = 155) versus 12% for non-HCT (n = 80) for those age 65 years and older. HCT was more effective (+2.36 quality-adjusted life-years [QALYs] for age 50-64 years and +2.92 QALYs for age 65 years and older) and more costly (+$452,242 in US dollars (USD) for age 50-64 years and +$233,214 USD for age 65 years and older) than usual care, with incremental cost-effectiveness ratios of $191,487 (USD)/QALY and $79,834 (USD)/QALY, respectively. For persons age 50-64 years, there was a 29% chance that HCT was cost-effective using a willingness-to-pay (WTP) threshold of $150K (USD)/QALY and 51% at a $200K (USD)/QALY. For persons age 65 years and older, the probability was 100% at a WTP >$150K (USD)/QALY. CONCLUSION Among patients age 65 years and older with high-risk MDS, RIC HCT is a high-value strategy. For those age 50-64 years, HCT is a lower-value strategy but has similar cost-effectiveness to other therapies commonly used in oncology.