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Complications of Autologous Stem Cell Transplantation in Multiple Myeloma: Results from the CALM Study
Waszczuk-Gajda, A., Penack, O., Sbianchi, G., Koster, L., Blaise, D., Reményi, P., Russell, N., Ljungman, P., Trneny, M., Mayer, J., et al
Journal of clinical medicine. 2022;11(12)
Abstract
BACKGROUND The main goal of this post hoc analysis of the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study was to evaluate the rate of short- and long-term infectious and non-infectious complications occurring after ASCT in patients with multiple myeloma (MM). METHODS The analysis included all patients with MM from the CALM study who underwent ≥1 ASCT. The primary endpoint of the analysis was to determine the rate of infectious and non-infectious complications after ASCT and to compare them in three time periods: 0-100 days, 101 days-1 year, and >1 year after the first transplant. RESULTS The analysis included a total of 3552 patients followed up for a median of 56.7 months (range 0.4-108.1). Complication rates decreased with the time from ASCT with 24.85 cases per 100 patient-years from day 0 to 100 days after the transplant, and <2.31 cases per 100 patient-years from the 101st day. At 100 days after ASC T, 45.7% of patients had complications, with infectious events being twice as frequent as non-infectious complications. Bacterial infections (6.5 cases per 100 patient-years, 95% CI: 6.1-7.0) and gastrointestinal complications (4.7 cases per 100 patient-years, 95% CI: 4.3-5.1) were the most common early events. The pattern of complications changed with time from ASCT. The presence of complications after ASCT was not associated with overall survival. CONCLUSIONS Our data provide a solid basis for comparing ASCT-related complications to those caused by emerging treatments in multiple myeloma, such as CAR T-cell therapy and other immunotherapies.
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Vaccination against tick-borne encephalitis (TBE) after autologous and allogeneic stem cell transplantation
Einarsdottir, S., Nicklasson, M., Veje, M., Bergström, T., Studahl, M., Lisak, M., Olsson, M., Johansson, B., Andreasson, B., Piauger, B., et al
Vaccine. 2021
Abstract
INTRODUCTION Our aim was to assess response and side effects of 4 doses of TBE vaccine to patients (pts) after allo- and autologous stem cell transplantation (SCT). PATIENTS Included were 104 pts with leukaemia, myeloma and lymphoma, median age 61 yrs. METHODS Vaccine (FSME-Immun®) was given at 9, 10, 12, and 21 months post-transplant. Serum samples were obtained before and after vaccinations. Healthy controls (n = 27) received 3 vaccinations. Assessments of TBE specific IgG antibodies were performed by Enzygnost anti-TBE ELISA test (Siemens, Sweden). RESULTS Antibody levels (>12 U/mL; "seropositivity") were seen in 77% and 80% of pts after allo- and autoSCT; IgG levels; 89 vs 94 U/mL. Ongoing chronic GvHD and immunosuppression (n = 29) was associated with sero-negativity in the last sample (p = 0.007). All controls (n = 27) developed protective antibody levels. CONCLUSIONS TBE vaccination was safe, and 4 doses starting 9 months post-SCT, induced seropositivity in a vast majority of pts.
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Allogeneic hematopoietic stem cell transplantation for chronic myelomonocytic leukemia: Clinical and molecular genetic prognostic factors in a Nordic population
Wedge, E., Hansen, J. W., Dybedal, I., Creignou, M., Ejerblad, E., Lorenz, F., Werlenius, O., Ungerstedt, J., Holm, M. S., Nilsson, L., et al
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND Chronic myelomonocytic leukemia (CMML) is an aggressive disease in which survival after allogeneic hematopoietic stem cell transplantation (HCT) remains relatively poor. An assessment of prognostic factors is an important part of treatment decision-making and has the potential to be greatly improved by the inclusion of molecular genetics. However, there is a significant knowledge gap in the interpretation of mutational patterns. OBJECTIVE This study aimed to describe outcomes from allogeneic HCT in CMML in relation to clinical and molecular genetic risk factors. STUDY DESIGN This retrospective study included 64 patients with CMML who underwent allogeneic HCT between 2008 and 2018, with a median follow-up of 5.4 years. Next-generation sequencing using targeted myeloid panels was carried out on saved material from 51 patients from the time of transplantation. Kaplan-Meier and Cox regression were used for analysis of overall survival whilst cumulative incidence with competing risks and Fine and Gray models were used for analysis of relapse and non-relapse mortality (NRM). RESULTS Mutations were detected in 48 patients (94%) indicating high levels of minimal residual disease (MRD) positivity at transplantation, even amongst those in complete remission (CR) (n=18), 89% of whom had detectable mutations. The most commonly mutated genes were ASXL1 (37%), TET2 (37%), RUNX1 (33%), SRSF2 (26%) and NRAS (20%). Risk stratification using the CPSS-mol score resulted in 45% of patients moving to a higher risk group compared to the CPSS. High leucocyte count (= 13?×?10(9)/L), transfusion requirement, and previous intensive chemotherapy were associated with higher relapse incidence. Being in CR was not linked to better outcomes. Neither ASXL1 nor RUNX1 mutations were associated with a difference in overall survival (OS), relapse, or NRM, despite being high-risk in the non-transplant setting. TET2 mutations were associated with a significantly higher OS (73 vs. 40% at 3 years, p=0.039). CONCLUSIONS Achieving MRD negative CR was rare in this CMML cohort, which may explain why we did not observe better outcomes for those in CR. This merits further investigation. Our analyses suggest that the negative impact of ASXL1 and RUNX1 mutations can be overcome by allogeneic HCT. However, risk stratification is complex in CMML and requires larger cohorts and multivariate models, presenting an ongoing challenge in this rare disease.
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Second allogeneic transplants for multiple myeloma: a report from the EBMT Chronic Malignancies Working Party
Hayden, P. J., Eikema, D. J., de Wreede, L. C., Koster, L., Kröger, N., Einsele, H., Minnema, M., Dominietto, A., Potter, M., Passweg, J., et al
Bone marrow transplantation. 2021
Abstract
The EBMT Chronic Malignancies Working Party performed a retrospective analysis of 215 patients who underwent a second allo-HCT for myeloma between 1994 and 2017, 159 for relapse and 56 for graft failure. In the relapse group, overall survival (OS) was 38% (30-46%) at 2 years and 25% (17-32%) at 5 years. Patients who had a HLA-identical sibling (HLAid-Sib) donor for their first and second transplants had superior OS (5 year OS: HLAid-Sib/HLAid-Sib: 35% (24-46%); Others 9% (0-17%), p?0.001). There was a significantly higher incidence of acute grade II-IV GvHD in those patients who had also developed GvHD following their initial HLA-identical sibling allo-HCT (HLAid-Sib/HLAid-Sib: 50% (33-67%); Other 22% (8-36%), p?=?0.03). More as opposed to fewer than 2 years between transplants was associated with superior 5-yr OS (31% (21-40%) vs. 10% (1-20%), P?=?0.005). On multivariate analysis, consecutive HLA-identical sibling donor transplants conferred a significant OS advantage (0.4 (0.24-0.67), p?0.001). In the graft failure group, OS was 41% at 2 years. In summary, a second allo-HCT using a HLA-identical sibling donor, if available, provides the best transplant outcomes for relapsed myeloma in this setting.
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Long-term results and GvHD after prophylactic and preemptive donor lymphocyte infusion after allogeneic stem cell transplantation for acute leukemia
Schmid, C., Labopin, M., Schaap, N., Veelken, H., Brecht, A., Stadler, M., Finke, J., Baron, F., Collin, M., Bug, G., et al
Bone marrow transplantation. 2021
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Editor's Choice
Abstract
We report on 318 patients with acute leukemia, receiving donor lymphocyte infusion (DLI) in complete hematologic remission (CHR) after allogeneic stem cell transplantation (alloSCT). DLI were applied preemptively (preDLI) for minimal residual disease (MRD, n?=?23) or mixed chimerism (MC, n?=?169), or as prophylaxis in high-risk patients with complete chimerism and molecular remission (proDLI, n?=?126). Median interval from alloSCT to DLI1 was 176 days, median follow-up was 7.0 years. Five-year cumulative relapse incidence (CRI), non-relapse mortality (NRM), leukemia-free and overall survival (LFS/OS) of the entire cohort were 29.1%, 12.7%, 58.2%, and 64.3%. Cumulative incidences of acute graft-versus-host disease (aGvHD) grade II-IV°/chronic GvHD were 11.9%/31%. Nineteen patients (6%) died from DLI-induced GvHD. Age =60 years (p?=?0.046), advanced stage at transplantation (p?=?0.003), shorter interval from transplantation (p?=?0.018), and prior aGvHD =II° (p?=?0.036) were risk factors for DLI-induced GvHD. GvHD did not influence CRI, but was associated with NRM and lower LFS/OS. Efficacy of preDLI was demonstrated by decreasing MRD/increasing blood counts in 71%, and increasing chimerism in 70%. Five-year OS after preDLI for MRD/MC was 51%/68% among responders, and 37% among non-responders. The study describes response and outcome of DLI in CHR and helps to identify candidates without increased risk of severe GvHD.
PICO Summary
Population
Patients with acute leukaemia in complete remission after allogeneic transplant (n=318)
Intervention
Donor lymphocyte infusion (DLI) for minimal residual disease (MRD, n=23) or mixed chimerism (MC, n=169), or as prophylaxis in high-risk patients with complete chimerism and molecular remission (proDLI, n=126).
Comparison
None
Outcome
Median interval from alloSCT to DLI1 was 176 days, median follow-up was 7.0 years. Five-year cumulative relapse incidence (CRI), non-relapse mortality (NRM), leukemia-free and overall survival (LFS/OS) of the entire cohort were 29.1%, 12.7%, 58.2%, and 64.3%. Cumulative incidences of acute graft-versus-host disease (aGvHD) grade II-IV°/chronic GvHD were 11.9%/31%. Nineteen patients (6%) died from DLI-induced GvHD. Age >/=60 years, advanced stage at transplantation, shorter interval from transplantation, and prior aGvHD =II° were risk factors for DLI-induced GvHD. GvHD did not influence cumulative relapse incidence, but was associated with NRM and lower LFS/OS. Efficacy of preDLI was demonstrated by decreasing MRD/increasing blood counts in 71%, and increasing chimerism in 70%. Five-year OS after preDLI for MRD/MC was 51%/68% among responders, and 37% among non-responders
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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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Treosulfan conditioning for allogeneic transplantation in multiple myeloma - improved overall survival in first line haematopoietic stem cell transplantation - a large retrospective study by the Chronic Malignancies Working Party of the EBMT
Gran, C., Wang, J., Nahi, H., Koster, L., Gahrton, G., Einsele, H., Niittyvoupio, R., Edinger, M., Beelen, D., Ciceri, F., et al
British journal of haematology. 2020
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Allogeneic stem cell transplantation for blast crisis chronic myeloid leukemia in the era of tyrosine kinase inhibitors - A retrospective study by the EBMT Chronic Malignancies Working Party
Radujkovic, A., Dietrich, S., Blok, H. J., Nagler, A., Ayuk, F., Finke, J., Tischer, J., Mayer, J., Koc, Y., Sora, F., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
The prognosis of patients with blast crisis (BC) chronic myeloid leukemia (CML) is still dismal. Allogeneic stem cell transplantation (alloSCT) represents the only curative treatment option, but data on transplant outcomes are scarce. We therefore conducted a retrospective, registry based study of adult patients allografted for BC CML focusing on patients with active disease at transplant and pre-transplant prognostic factors. A total of 170 patients allografted for BC CML after tyrosine kinase inhibitor pre-treatment between 2004 and 2016 were analyzed. Prior to transplant, 95 patients were in remission, whereas 75 patients had active BC. In multivariable analysis of the entire cohort, active BC at transplant was the strongest factor associated with decreased overall survival (OS, HR 1.87, P=0.010) and shorter leukemia-free survival (LFS, HR 1.69, P=0.017). For patients with BC in remission at transplant, advanced age (≥45 years), lower performance status (≤80%), longer interval from diagnosis BC to transplant (>12 months), myeloablative conditioning, and unrelated donor (UD) transplant were risk factors for inferior survival. In patients with active BC, only UD transplant was significantly associated with prolonged LFS and trended towards improved OS. In summary, survival of patients allografted for BC CML was strongly dependent on the pre-transplant remission status. In patients with remission of BC, conventional prognostic factors remained the major determinants of outcome, whereas in those with active BC at transplant, UD transplantation was associated with prolonged LFS in our study.
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EBMT prospective observational study on allogeneic hematopoietic stem cell transplantation in T-prolymphocytic leukemia (T-PLL)
Wiktor-Jedrzejczak, W., Drozd-Sokolowska, J., Eikema, D. J., Hoek, J., Potter, M., Wulf, G., Sellner, L., Ljungman, P., Chevallier, P., Volin, L., et al
Bone marrow transplantation. 2019
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Editor's Choice
Abstract
Preliminary data suggest that allogeneic stem cell transplantation (allo-SCT) may be effective in T-prolymphocytic leukemia (T-PLL). The purpose of the present observational study was to assess the outcome of allo-SCT in patients aged 65 years or younger with a centrally confirmed diagnosis of T-PLL. Patients were consecutively registered with the EBMT at the time of transplantation and followed by routine EBMT monitoring but with an extended dataset. Between 2007 and 2012, 37 evaluable patients (median age 56 years) were accrued. Pre-treatment contained alemtuzumab in 95% of patients. Sixty-two percent were in complete remission (CR) at the time of allo-SCT. Conditioning contained total body irradiation with 6 Gy or more (TBI6) in 30% of patients. With a median follow-up of 50 months, the 4-year non-relapse mortality, relapse incidence, progression-free (PFS) and overall survival were 32, 38, 30 and 42%, respectively. By univariate analysis, TBI6 in the conditioning was the only significant predictor for a low relapse risk, and an interval between diagnosis and allo-SCT of more than 12 months was associated with a lower NRM. This study confirms for the first time prospectively that allo-SCT can provide long-term disease control in a sizable albeit limited proportion of patients with T-PLL.
PICO Summary
Population
Allo-SCT in patients aged 65 years or younger with a centrally confirmed diagnosis of T-PLL.
Intervention
Observational study
Comparison
None
Outcome
With a median follow-up of 50 months, the 4-year non-relapse mortality was 32%, relapse incidence 38%, progression-free (PFS) 30% and overall survival 42%. By univariate analysis, TBI6 in the conditioning was the only significant predictor for a low relapse risk, and an interval between diagnosis and allo-SCT of more than 12 months was associated with a lower NRM.
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Death after hematopoietic stem cell transplantation: changes over calendar year time, infections and associated factors
Styczynski, J., Tridello, G., Koster, L., Iacobelli, S., van Biezen, A., van der Werf, S., Mikulska, M., Gil, L., Cordonnier, C., Ljungman, P., et al
Bone marrow transplantation. 2019
Abstract
Information on incidence, and factors associated with mortality is a prerequisite to improve outcome after hematopoietic stem cell transplantation (HSCT). Therefore, 55'668 deaths in 114'491 patients with HSCT (83.7% allogeneic) for leukemia were investigated in a landmark analysis for causes of death at day 30 (very early), day 100 (early), at 1 year (intermediate) and at 5 years (late). Mortality from all causes decreased from cohort 1 (1980-2001) to cohort 2 (2002-2015) in all post-transplant phases after autologous HSCT. After allogeneic HSCT, mortality from infections, GVHD, and toxicity decreased up to 1 year, increased at 5 years; deaths from relapse increased in all post-transplant phases. Infections of unknown origin were the main cause of infectious deaths. Lethal bacterial and fungal infections decreased from cohort 1 to cohort 2, not unknown or mixed infections. Infectious deaths were associated with patient-, disease-, donor type, stem cell source, center, and country- related factors. Their impact varied over the post-transplant phases. Transplant centres have successfully managed to reduce death after HSCT in the early and intermediate post-transplant phases, and have identified risk factors. Late post-transplant care could be improved by focus on groups at risk and better identification of infections of "unknown origin".