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Association of donor IFNL4 genotype and non-relapse mortality after unrelated donor myeloablative haematopoietic stem-cell transplantation for acute leukaemia: a retrospective cohort study
Gadalla, S. M., Wang, Y., Wang, T., Onabajo, O. O., Banday, A. R., Obajemu, A., Karaesman, E., Sucheston-Campbell, L., Hahn, T., Sees, J. A., et al
The Lancet. Haematology. 2020;7(10):e715-e723
Abstract
BACKGROUND The interferon lambda 4 gene (IFNL4) regulates immune responses by controlling the production of IFN?4, a type III interferon. We hypothesised that IFN?4 could play a role in infection clearance or alloreactivity in patients with acute leukaemia who received a myeloablative 10/10 HLA-matched haematopoietic stem-cell transplantation (HSCT). Therefore, we aimed to assess the association between recipient and donor IFNL4 genotype with post-HSCT survival outcomes in patients with acute leukaemia. METHODS We did a two-stage retrospective cohort study using the Center for International Blood and Marrow Transplant Research (CIBMTR) repository and database, in which nearly all patients underwent the procedure in the USA. We included patients with acute myeloid leukaemia or acute lymphocytic leukaemia, who received a HSCT at any age from an unrelated 10/10 HLA-matched donor, with a myeloablative conditioning regimen, between Jan 1, 2000, and Dec 31, 2008, and had a pre-HSCT recipient or donor blood sample available. The discovery dataset included patients from an existing National Cancer Institute (NCI) cohort of the CIBMTR database, in which donor and recipient IFNL4 polymorphisms (rs368234815, rs12979860, and rs117648444) were genotyped with TaqMan assays. According to their genotype, donors and recipients were categorised into IFNL4-positive, if they had at least one copy of the allele that supports the production of IFN?4, or IFNL4-null for the analyses. The findings were independently validated with patients from the DISCOVeRY-BMT cohort (validation dataset) with existing Illumina array genotype data. We also did a combined analysis using data from patients included in both the NCI and DISCOVeRY-BMT cohorts. FINDINGS We assessed 404 patients (who had a HSCT from Jan 9, 2004, to Dec 26, 2008) in the discovery dataset and 1245 patients in the validation dataset (HSCT Jan 7, 2000, to Dec 26, 2008). The combined analysis included 1593 overlapping participants in both cohorts. Donor, but not recipient IFNL4-positive genotype was associated with increased risk of non-relapse mortality (HR 1·60, 95% CI 1·23-2·10; p=0·0005 in the discovery dataset; 1·22, 1·05-1·40; p=0·0072 in the validation dataset; and 1·27, 1·12-1·45; p=0·0001 in the combined dataset). Associations with post-HSCT overall survival were as follows: HR 1·24, 95% CI 1·02-1·51; p=0·034 in the discovery dataset; 1·10, 0·98-1·20; p=0·10 in the validation dataset; and 1·11, 1·02-1·22; p=0·018 in the combined dataset. INTERPRETATION Prioritising HSCT donors with the IFNL4-null genotype might decrease non-relapse mortality and improve overall survival without substantially limiting the donor pool. If these findings are validated, IFNL4 genotype could be added to the donor selection algorithm. FUNDING The National Cancer Institute Intramural Research Program. For full funding list see Acknowledgments.
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Long-term survival benefit after allogeneic hematopoietic cell transplantation in chronic myelomonocytic leukemia
Gagelmann, N., Bogdanov, R., Stölzel, F., Rautenberg, C., Panagiota, V., Becker, H., Radujkovic, A., Luft, T., Christopeit, M., Finke, J., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
The critical question in the management of chronic myelomonocytic leukemia (CMML) is which patients may benefit from allogeneic hematopoietic cell transplantation (allo-HCT). Using ad hoc statistical analysis, we designed a multicenter retrospective study to determine outcomes in 261 patients =70 years at diagnosis who received allo-HCT (n=119) compared with patients who did not (n=142) according to the current CMML-specific prognostic scoring system (CPSS). Categorizing patients as lower (CPSS low/intermediate-1) and higher risk (intermediate-2/high) showed significantly improved outcome after transplant in higher risk patients, with a 37% reduced hazard for death. However, while higher CPSS was associated with worse outcome in the nontransplant group, the score was of limited utility for posttransplant risk stratification. This study may further support the potentially beneficial role of allo-HCT in terms of long-term survival in higher risk patients but also underlines the need for transplant-specific risk assessment. Recognizing limitations of retrospective comparisons, larger and prospective comparisons are needed to further refine the indication for allo-HCT and thus counseling of CMML patients.
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Upfront stem cell transplantation for newly diagnosed multiple myeloma with del(17p) and t(4;14): a study from the CMWP-EBMT
Gagelmann, N., Eikema, D. J., de Wreede, L. C., Rambaldi, A., Iacobelli, S., Koster, L., Caillot, D., Blaise, D., Remémyi, P., Bulabois, C. E., et al
Bone marrow transplantation. 2020
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Editor's Choice
Abstract
We analyzed newly diagnosed multiple myeloma patients with del(17p) and/or t(4;14) undergoing either upfront single autologous (auto), tandem autologous (auto-auto) or tandem autologous/reduced-intensity allogeneic (auto-allo) stem cell transplantation. 623 patients underwent either auto (n?=?446), auto-auto (n?=?105), or auto-allo (n?=?72) between 2000 and 2015. 46% of patients had t(4;14), 45% had del(17p) while 9% were reported having both abnormalities. Five-year overall survival (OS) was 51% (95% confidence interval [CI], 45-58%) for single auto, 60% (95% CI, 49-72%) for auto-auto, and 67% (95% CI, 53-80%) for auto-allo (p?=?0.187). Five-year progression-free survival (PFS) was 17% (95% CI, 12-22%), 33% (95% CI, 22-43%), and 34% (95% CI, 21-38%; p?=?0.048). Five-year relapse rate was 82, 63, and 56%, while non-relapse mortality was 1, 4, and 10%. In multivariable analysis, in t(4;14) with single auto as reference, auto-auto (hazard ratio [HR], 0.44; p?=?0.007) and auto-allo (HR, 0.45; p?=?0.018) were associated with better PFS. In terms of t(4;14) and OS, auto-auto appeared to improve outcome compared with single auto (HR, 0.49; p?=?0.096). In del(17p), outcome in PFS was similar between single auto and auto-auto, while auto-allo appeared to improve PFS (HR, 0.65; p?=?0.097). No significant difference in OS was identified between the groups in patients with del(17p).
PICO Summary
Population
Patients with newly diagnosed myeloma with del(17p) and/or t(4;14) (n=623)
Intervention
Autologous transplant (auto, n=446), tandem autologous (auto-auto, n=105)
Comparison
tandem autologous/reduced intensity allogeneic transplant (auto-allo, n=72)
Outcome
Five-year overall survival (OS) was 51% for single auto, 60% for auto-auto, and 67% for auto-allo Five-year progression-free survival (PFS) was 17%, 33%, and 34%. Five-year relapse rate was 82, 63, and 56%, while non-relapse mortality was 1, 4, and 10%. In multivariable analysis, in t(4;14) with single auto as reference, auto-auto (hazard ratio [HR], 0.44) and auto-allo (HR, 0.45) were associated with better PFS. In terms of t(4;14) and OS, auto-auto appeared to improve outcome compared with single auto (HR, 0.49;). In del(17p), outcome in PFS was similar between single auto and auto-auto, while auto-allo appeared to improve PFS (HR, 0.65).
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The role of novel agents for consolidation after autologous transplantation in newly diagnosed multiple myeloma: a systematic review
Gagelmann, N., Kröger, N.
Annals of hematology. 2020
Abstract
Despite the increasing inclusion of novel agents within the multiple myeloma (MM) treatment sequence, their role for posttransplant consolidation therapy remains unclear. We systematically reviewed studies evaluating the efficacy of novel agent consolidation. We identified 11 citations on 12 prospective comparative studies, and 5 citations were single-arm or comparative studies with preliminary results. Nine different regimens were evaluated in 5905 patients. Risk assessment yielded serious risk of bias and heterogeneity across study designs was high. Irrespective of the regimen, deepened responses after consolidation were seen and improvements were more pronounced with multi-agent consolidation. Bortezomib, thalidomide, and dexamethasone improved long-term survival versus duplet consolidation, including in patients with high-risk cytogenetics. The addition of daratumumab to triplet regimens yielded modestly improved responses with significantly increased rates of minimal residual disease negativity but survival results were limited by short follow-up. In high-risk MM, responses were not different, whereas progression-free survival appeared to be improved with consolidation therapy, challenging the association of response and overall outcome in this subgroup. Our findings highlight the necessity of longer follow-up and consistent reporting to ensure comparability of studies to enable better evidence assessment and to identify patients benefitting from consolidation therapy.
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Clinical Outcomes in Patients With FLT3-ITD-Mutated Relapsed/Refractory Acute Myeloid Leukemia Undergoing Hematopoietic Stem Cell Transplant After Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial
Ganguly, S., Cortes, J. E., Krämer, A., Levis, M. J., Martinelli, G., Perl, A. E., Russell, N. H., Arunachalam, M., Santos, C. D., Gammon, G., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
Despite the substantial clinical activity of fms-related tyrosine kinase 3 (FLT3) inhibitors in relapsed or refractory (R/R) FLT3-ITD?positive acute myeloid leukemia (AML), durable remissions and prolonged survival in this population require allogeneic hematopoietic stem cell transplant (allo-HSCT). Quizartinib, a once-daily, oral, highly potent and selective FLT3 inhibitor, significantly prolonged overall survival (OS) and improved clinical benefit compared with salvage chemotherapy (median OS, 6.2 vs 4.7 months; hazard ratio [HR], 0.76 [95% CI, 0.58-0.98]; P?=?0.018; composite complete remission [CRc] rate, 48% vs 27%; median duration of CRc, 2.8 vs 1.2 months; mortality rates, 0.8% vs 14% [by day 30], 7% vs 24% [by day 60]) in patients with R/R FLT3-ITD AML in the phase 3 QuANTUM-R trial. In this post hoc analysis, we described the characteristics of and clinical outcomes in patients who underwent an on-study HSCT in QuANTUM-R per investigator discretion and institutional practices. Of 367 randomized patients, 78 (32%) in the quizartinib arm and 14 (11%) in the salvage chemotherapy arm underwent an on-study allo-HSCT without any intervening therapy for AML after quizartinib or study-specified salvage chemotherapy. Pooled data of patients from both treatment arms showed a longer median OS in transplanted patients vs those treated without a transplant (12.2 vs 4.4 months; HR, 0.315 [95% CI, 0.233-0.427]). Pooled data also showed a longer median OS in patients with a last recorded response of CRc before allo-HSCT vs patients without a CRc (20.1 vs 8.8 months; HR, 0.506 [95% CI, 0.296-0.864]). By treatment arm, the median OS was 25.1 months with quizartinib and 20.1 months with salvage chemotherapy in patients with a last recorded response of CRc prior to allo-HSCT. Forty-eight patients in the quizartinib arm continued quizartinib treatment after allo-HSCT. In the 31 patients with a last recorded response of CRc prior to allo-HSCT who continued quizartinib after allo-HSCT, median OS was 27.1 months. Continuation of quizartinib after allo-HSCT was tolerable and no new safety signals were identified. These results suggest that post-transplant survival following salvage chemotherapy and quizartinib treatment are similar. However, quizartinib response occurs more frequently than with salvage chemotherapy, potentially allowing more patients to undergo transplant and achieve durable clinical benefit. Additionally, post-HSCT quizartinib was found to be tolerable and may be associated with prolonged survival in some patients, highlighting its potential value in the management of patients with FLT3-ITD R/R AML.
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Effect of rhG-CSF Combined With Decitabine Prophylaxis on Relapse of Patients With High-Risk MRD-Negative AML After HSCT: An Open-Label, Multicenter, Randomized Controlled Trial
Gao, L., Zhang, Y., Wang, S., Kong, P., Su, Y., Hu, J., Jiang, M., Bai, H., Lang, T., Wang, J., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2020;:Jco1903277
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Abstract
PURPOSE Relapse is a major cause of treatment failure after allogeneic hematopoietic stem-cell transplantation (allo-HSCT) for high-risk acute myeloid leukemia (HR-AML). The aim of this study was to explore the effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) combined with minimal-dose decitabine (Dec) on the prevention of HR-AML relapse after allo-HSCT. PATIENTS AND METHODS We conducted a phase II, open-label, multicenter, randomized controlled trial. Two hundred four patients with HR-AML who had received allo-HSCT 60-100 days before randomization and who were minimal residual disease negative were randomly assigned 1:1 to either rhG-CSF combined with minimal-dose Dec (G-Dec group: 100 µg/m(2) of rhG-CSF on days 0-5 and 5 mg/m(2) of Dec on days 1-5) or no intervention (non-G-Dec group). The primary outcome was relapse after transplantation, and the secondary outcomes were chronic graft-versus-host disease (cGVHD), safety of the treatment, and survival. RESULTS The estimated 2-year cumulative incidence of relapse in the G-Dec group was 15.0% (95% CI, 8.0% to 22.1%), compared with 38.3% (95% CI, 28.8% to 47.9%) in the non-G-Dec group (P < .01), with a hazard ratio (HR) of 0.32 (95% CI, 0.18 to 0.57; P < .01). There was no statistically significant difference between the G-Dec and non-G-Dec groups in the 2-year cumulative incidence of cGVHD without relapse (23.0% [95% CI, 14.7% to 31.3%] and 21.7% [95% CI, 13.6% to 29.7%], respectively; P = .82), with an HR of 1.07 (95% CI, 0.60 to 1.92; P = .81). After rhG-CSF combined with minimal-dose Dec maintenance, increasing numbers of natural killer, CD8+ T, and regulatory T cells were observed. CONCLUSION Our findings suggest that rhG-CSF combined with minimal-dose Dec maintenance after allo-HSCT can reduce the incidence of relapse, accompanied by changes in the number of lymphocyte subtypes.
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Prognostic significance of SET-NUP214 fusion gene in acute leukemia after allogeneic hematopoietic stem cell transplantation
Gao, M. G., Hong, Y., Qin, Y. Z., Chang, Y. J., Wang, Y., Zhang, X. H., Xu, L. P., Huang, X. J., Zhao, X. S.
Medicine. 2020;99(50):e23569
Abstract
The SET nuclear proto-oncogene (SET)-nucleoporin (NUP) 214 fusion gene (SET-NUP214) is a rare leukemia fusion gene. Due to the limited number of samples with SET-NUP214 fusion gene in previous studies, the significance of SET-NUP214 for measurable residual disease (MRD) monitoring in patients with acute leukemia (AL) is still unclear. Our study aimed to observe the dynamic changes in SET-NUP214 expression before and after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and analyzed whether SET-NUP214 could be used to evaluate MRD status. Our study included 24 AL patients who were newly diagnosed with SET-NUP214 fusion gene and they all received allo-HSCT. Their MRD was evaluated by monitoring SET-NUP214 fusion gene and leukemia-associated immunophenotype (LAIP). The median follow-up time was 501 days (56-2208 days). Of the enrolled patients, 6 (25%) patients died, including 3 (12.5%) patients died of leukemia relapse. Total 5 (20.8%) patients experienced hematological relapse at a median of 225 days (56-1057 days) post-transplantation. The SET-NUP214 median expression level at diagnosis was 405.1% (14.6%-1482.4%). SET-NUP214 gene expression generally became positive prior to flow cytometry results. In addition, the Kaplan-Meier survival curves analysis showed that those who had SET-NUP214 positive (SET-NUP214+) post-transplantation had a higher 2-year cumulative incidence of leukemia relapse (CIR) of 43.7?±?18.8% (P?.05). However, there was no significant difference between SET-NUP214 positive and SET-NUP214 negative patients with regard to their 2-year overall survival (OS) (82.5?±?11.3 vs 64.6?±?17.5%, respectively, P?=?.271). ROC curve analysis turned out that the area under the ROC curve (AUC) was 0.916 (95% CI: 0.784-1.0; P?=?.005). In conclusion, SET-NUP214 fusion gene determined by real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) could be used to evaluate MRD status after allo-HSCT. Patients with positive SET-NUP214 expression after transplantation will have a poor prognosis.
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What Multiple Myeloma With t(11;14) Should Be Classified Into in Novel Agent Era: Standard or Intermediate Risk?
Gao, W., Du, J., Liu, J., Zhou, H., Zhang, Z., Jian, Y., Yang, G., Wang, G., Tian, Y., Li, Y., et al
Frontiers in oncology. 2020;10:538126
Abstract
OBJECTIVE To investigate the prognostic value of t(11;14) for de novo multiple myeloma (MM) patients in novel agent era. METHODS A total of 455 patients with fluorescence in situ hybridization (FISH), before treatments from three hospitals in China, were included in the study. All patients received autologous stem cell transplantation (ASCT) after induction therapy as consolidation. High risk (HR) cytogenetics were defined as t(4;14), t(14;16), and/or del 17p. RESULTS A total of 152 patients were in the HR group. Of patients without HR cytogenetics, 55 were in the t(11;14) group, and 248 were in the standard risk (SR) group without t(11;14). Gain in 1q21 was observed in 38.9% patients with t(11;14). There were no differences in median progression free survival (PFS) and overall survival (OS), respectively, between patients in the t(11;14) group and those in the SR group. Patients in the t(11;14) group had the longer median PFS and OS, respectively, compared with those in the HR group. Regardless of coexisting with 1q21 gain or not, patients in the t(11;14) group still had similar median PFS and OS compared to those in the SR group. Finally, multivariate analysis indicated that including 1q21 gain and bone marrow plasma cell with CD20 expression, no variables were found to predict the outcome of the t(11;14) group in our cohort. CONCLUSIONS These results confirm that outcomes of t(11;14) MM are similar to standard risk patients when they receive novel agent induction therapy consolidated by ASCT. Gain of 1q21 coexists with t(11;14) frequently. In addition, both bone marrow plasma cell with CD20 expression and 1q21 gain have no impact on median PFS or OS for patients with t(11;14).
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Gain of 1q21 is an adverse prognostic factor for multiple myeloma patients treated by autologous stem cell transplantation: A multicenter study in China
Gao, W., Jian, Y., Du, J., Li, X., Zhou, H., Zhang, Z., Yang, G., Wang, G., Tian, Y., Li, Y., et al
Cancer medicine. 2020;9(21):7819-7829
Abstract
BACKGROUND Autologous stem cell transplantation (ASCT) has been recommended as a standard approach for young multiple myeloma (MM) patients for decades, even in the era of novel agents. Gain of chromosome 1q21 is a common cytogenetic abnormality in MM, while its clinical prognostic value is still controversial. METHODS In this multicenter study, we retrospectively analyzed 1q21 gain in 446 newly diagnosed MM patients who received at least one ASCT from three large myeloma centers in China. RESULTS Of the all 446 patients, 1q21 gain was an adverse predictor of progression-free survival (PFS) (34 vs 56 months, P = .005) and overall survival (OS) (69 vs 100 months, P = .002). Gain of 1q21 was more likely to coexist with t(4;14), t(14;16), and del(13q). Nevertheless, isolated 1q21 gain still exhibited unfavorable effects on PFS (35 vs 66 months, P = .045) and OS (61 vs 100 months, P = .026). The coexistence of 1q21 gain and high-risk cytogenetics (HRCs) [del(17p), t(4;14),and/or t(14;16)] showed poor prognosis on both PFS and OS, while no additional adverse effect could be identified when compared with HRCs alone. Moreover, when coexisting with t(11;14), patients with 1q21 gain showed a comparable survival to those without 1q21 gain. For patients treated with novel induction regimens followed by ASCT, 1q21 gain also conferred an inferior prognosis. Multivariate analysis further confirmed 1q21 gain could independently predict shorter PFS and OS. CONCLUSION In conclusion, 1q21 gain is an adverse prognostic factor for MM patients received ASCT.
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10.
Risk factors and associations with clinical outcomes of cytomegalovirus reactivation after haploidentical versus matched-sibling unmanipulated PBSCT in patients with hematologic malignancies
Gao, X. N., Lin, J., Wang, L. J., Li, F., Li, H. H., Wang, S. H., Huang, W. R., Gao, C. J., Yu, L., Liu, D. H.
Annals of hematology. 2020
Abstract
In allogeneic hematopoietic stem cell transplantation recipients, cytomegalovirus (CMV) infection can cause overt CMV-associated disease, which is a main cause of transplantation-associated mortality. CMV infection correlates closely with donor's type. We therefore examined whether risk factors of CMV reactivation and clinical endpoints in patients with hematologic malignancies after allogeneic peripheral blood stem cell transplantation (PBSCT) differed between using matched-sibling donors (MSD-SCT) and haploidentical donors (HID-SCT). In this retrospective cohort study, we enrolled in 200 consecutive patients received an unmanipulated G-CSF-mobilized allogeneic PBSCT. Ninety (45%) patients received MSD-SCT and 110 (55%) received HID-SCT. Quantitative PCR was used for monitoring of CMV reactivation after transplantation. One-year cumulative incidence of CMV DNAemia was 55.0%, ranging from 23.5% in MSD-SCT group to 81.0% in HID-SCT group (p < 0.001). Although univariate analyses showed that non-myeloid malignancies, disease in complete remission status at transplantation, pretreatment with antithymocyte globulin, HLA-haploidentical donors, male donors, previous Epstein-Barr virus DNAemia, and absolute lymphocyte count on day 30 < 0.6 x 10(9)/L were respectively associated with CMV reactivation after transplantation in total cohort of recipients (all p < 0.05), haploidentical donors were found to be the only independent predictor in multivariate analyses (Hazard ratio = 6.4, p < 0.001). Furthermore, univariate analyses revealed that non-myeloid malignancies and previous Epstein-Barr virus DNAemia were respectively associated with CMV reactivation in MSD-SCT recipients, and female was associated with CMV reactivation in HID-SCT recipients (all p < 0.05). In HID-SCT recipients, but not MSD-SCT recipients, previous CMV DNAemia was associated with a lower cumulative incidence of acute graft-versus-host disease (49.2% vs. 72.6%, p < 0.001). CMV DNAemia did not play a role in the relapse rate, but it was strongly associated with an increased risk of non-relapse mortality either in total cohort of recipients (30.5% vs. 13.7%; p = 0.003) or in the HID-SCT subgroup (36.0% vs. 16.7%; p = 0.030). Relapse-free survival and overall survival in total cohort of recipients with CMV DNAemia were both inferior to those without CMV DNAemia (45.3% vs. 57.6% and 54.8% vs. 65.8%, respectively; both p < 0.05). However, in subgroup analysis according to donor's type, neither relapse-free survival nor overall survival was impacted by CMV status (both p > 0.05). This study addressed differences in incidence, risk factors, and associations with clinical outcomes of CMV reactivation after haploidentical versus matched-sibling PBSCT.