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Prediction of Coronary Heart Disease Events in Blood or Marrow Transplantation Recipients
Gangaraju, R., Chen, Y., Hageman, L., Landier, W., Balas, N., Ross, E., Francisco, L., Bosworth, A., Te, H. S., Wong, F. L., et al
JACC. CardioOncology. 2023;5(4):504-517
Abstract
BACKGROUND The long-term risk of coronary heart disease (CHD) and clinical models that predict this risk remain understudied in blood or marrow transplantation (BMT) recipients. OBJECTIVES This study sought to examine the risk of CHD after BMT and identify the associated risk factors. METHODS Participants included patients transplanted between 1974 and 2014 at City of Hope, University of Minnesota, or University of Alabama at Birmingham and those who survived ≥2 years after BMT. Multivariable logistic regression models assessed CHD risk in BMT survivors compared with a sibling cohort. A self-reported questionnaire and medical records provided information regarding sociodemographics, comorbidities, and therapeutic exposures, which were used to develop a CHD risk prediction nomogram. RESULTS Overall, 6,677 BMT recipients participated; the mean age at BMT was 43.9 ± 17.7 years, 58.3% were male, and 73.3% were non-Hispanic Whites. The median length of follow-up was 6.9 years (range: 2-46.2 years) from BMT. CHD was reported in 249 participants, with a 20-year cumulative incidence of 5.45% ± 0.39%. BMT survivors had a 1.6-fold greater odds of CHD compared with a sibling cohort (95% CI: 1.09-2.40). A nomogram was then developed to predict the risk of CHD at 10 and 20 years after BMT including age at BMT (HR: 1.06/y; 95% CI: 1.04-1.08), male sex (HR: 1.89; 95% CI: 1.15-3.11), a history of smoking (HR: 1.61; 95% CI: 1.01-2.58), diabetes (HR: 2.45; 95% CI: 1.23-4.89), hypertension (HR: 2.02; 95% CI: 1.15-3.54), arrhythmia (HR: 1.90; 95% CI: 0.89-4.06), and pre-BMT chest radiation (yes vs no: HR: 2.83; 95% CI: 1.20-6.67; unknown vs no: HR: 0.88; 95% CI: 0.34-2.28). The C-statistic was 0.77 in the test set (95% CI: 0.70-0.83). CONCLUSIONS This study identified BMT recipients at high risk for CHD, informing targeted screening for early detection and aggressive control of risk factors.
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Risk of COVID-19 Infection in Long-term Survivors of Blood or Marrow Transplantation: A BMTSS Report
Johnston, E. E., Meng, Q., Hageman, L., Wu, J., Ross, E. S., Lim, S., Balas, N., Bosworth, A. K., Te, H. S., Francisco, L., et al
Blood advances. 2023
Abstract
There is limited information regarding COVID-19 in long-term blood or marrow transplant (BMT) survivors. We leveraged the BMT Survivor Study (BMTSS) to address this gap. BMTSS included patients who underwent BMT at one of three US sites between 1974 and 2014 and survived ≥2 years after BMT. A sibling cohort serves as a non-BMT comparison group. Participants (2,430 BMT survivors; 780 non-BMT participants) completed the BMTSS survey between 10/2020 and 11/2021 about COVID-19 testing, risk mitigation behaviors, morbidity, and healthcare utilization. Median age at BMT was 46 years (range: 0-78 years) and median follow up since BMT was 14 years (6-46 years); 76% were non-Hispanic white, 54% had received allogeneic BMT. The risk of COVID-19 infection was comparable for BMT survivors vs non-BMT participants (15-month cumulative incidence: 6.5% vs. 8.1%; adjusted odd ratio [aOR]=0.93, 95%CI=0.65-1.33, p=0.68). Among survivors, being unemployed (aOR=1.90, 95%CI=1.12-3.23, p=0.02; reference: retired) increased the odds of infection; always wearing a mask in public was protective (aOR=0.49, 95%CI=0.31-0.77. p=0.002; reference: not always masking). When compared with COVID positive non-BMT participants, COVID positive BMT survivors had higher odds of hospitalization (aOR=2.23, 95%CI=0.99-5.05, p=0.05); however, the odds of emergency department visits were comparable (aOR=1.60, 95%CI=0.71-3.58, p=0.25). COVID-19 infection status did not increase the odds of hospitalization among BMT survivors (aOR=1.32, 95%CI=0.89-1.95, p=0.17, but did increase the odds of ED visits (aOR=2.63, 95%CI=1.74-3.98, p=<0.0001). These findings inform healthcare providers about the management of long-term BMT survivors during the ongoing pandemic.
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Risky Health Behaviors and Subsequent Late Mortality after Blood or Marrow Transplantation: a BMTSS Report
Balas, N., Richman, J., Landier, W., Shrestha, S., Bruxvoort, K., Hageman, L., Meng, Q., Ross, E. S., Bosworth, A. K., Te, H. S., et al
Blood advances. 2023
Abstract
We examined the association between risky healthy behaviors (smoking, heavy-alcohol consumption, and lack of vigorous-physical activity) and all-cause and cause-specific late mortality after blood or marrow transplantation (BMT) to understand the role played by potentially modifiable risk factors. Study participants were drawn from the BMT Survivor Study (BMTSS), and included patients transplanted between 1974 and 2014, who had survived ≥2 years post BMT and were age ≥18 at study cohort entry. Survivors provided information on sociodemographic characteristics, chronic health conditions and health-behaviors. National Death Index was used to determine survival and cause of death. Multivariable regression analyses determined the association between risky health behaviors and all-cause mortality (Cox regression) and non-recurrence related mortality [NRM] (sub-distribution hazard regression) after adjusting for relevant sociodemographic, clinical variables and therapeutic exposures. Overall, 3,866 participants completed the BMTSS survey and were followed for a median of 5 years to death or December 31, 2021; 856 participants died (22.1%) after survey completion. Risky health behaviors were associated with increased hazard of all-cause mortality (adjusted hazard ratio [aHR] former smoker=1.2, aHR current smoker=1.7, ref: non-smoker; aHR heavy drinker=1.4; ref: non-heavy drinker; and aHR no vigorous activity=1.2, ref: vigorous activity) and NRM (aHR former smoker=1.3, aHR current smoker=1.6, ref: non-smoker; aHR heavy drinker=1.4; ref: non-heavy drinker; and aHR no vigorous activity=1.2, ref: vigorous activity). The association between potentially modifiable risky health behaviors and late mortality offers opportunities for development of interventions to improve both the quality and quantity of life after BMT.
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4.
Clonal Hematopoiesis and Cardiovascular Disease in Patients With Multiple Myeloma Undergoing Hematopoietic Cell Transplant
Rhee, J. W., Pillai, R., He, T., Bosworth, A., Chen, S., Atencio, L., Oganesyan, A., Peng, K., Guzman, T., Lukas, K., et al
JAMA cardiology. 2023
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Abstract
IMPORTANCE There is a paucity of information on the association between clonal hematopoiesis of indeterminate potential (CHIP) and cardiovascular disease (CVD) in patients with cancer, including those with multiple myeloma (MM) undergoing hematopoietic cell transplant (HCT), a population at high risk of developing CVD after HCT. OBJECTIVE To examine the association between CHIP and CVD in patients with MM and to describe modifiers of CVD risk among those with CHIP. DESIGN, SETTING, AND PARTICIPANTS This was a retrospective cohort study of patients with MM who underwent HCT between 2010 and 2016 at City of Hope Comprehensive Cancer Center in Duarte, California, and had pre-HCT mobilized peripheral blood stem cell (PBSC) products cryopreserved and accessible for CHIP analyses. The study team performed targeted panel DNA sequencing to detect the presence of CHIP (variant allele frequency 2% or more). MAIN OUTCOMES AND MEASURES The primary end point was the 5-year cumulative incidence and risk for developing de novo CVD (heart failure, coronary artery disease, or stroke) after HCT. RESULTS Of 1036 consecutive patients with MM (580 male [56%]; median age, 60.0 years) who underwent a first autologous HCT, 201 patients had at least 1 CHIP variant (19.4%) and 35 patients had 2 or more variants (3.4%). The 5-year incidence of CVD was significantly higher in patients with CHIP (21.1% vs 8.4%; P < .001) compared with those without CHIP; the 5-year incidence among those with 2 or more variants was 25.6%. In the multivariable model, CHIP was associated with increased risk of CVD (hazard ratio [HR], 2.72; 95% CI, 1.70-4.39), as well as of individual outcomes of interest, including heart failure (HR, 4.02; 95% CI, 2.32-6.98), coronary artery disease (HR, 2.22; 95% CI, 1.06-4.63), and stroke (HR, 3.02; 95% CI, 1.07-8.52). Patients who had both CHIP and preexisting hypertension or dyslipidemia were at nearly 7-fold and 4-fold increased risk of CVD, respectively (reference: no CHIP, no hypertension, or dyslipidemia). CONCLUSION AND RELEVANCE CHIP was significantly and independently associated with risk of CVD in patients with MM undergoing HCT and may serve as a novel biologically plausible biomarker for CVD in this cohort. Patients with MM and both CHIP and cardiovascular risk factors had an exceptionally high risk of CVD. Additional studies are warranted to determine if cardiovascular preventive measures can reduce CHIP-associated CVD risk.
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Malignant Neoplasms of the Gastrointestinal Tract After Blood or Marrow Transplant
McDonald, A., Dai, C., Meng, Q., Hageman, L., Richman, J., Wu, J., Francisco, L., Ross, E., Balas, N., Bosworth, A., et al
JAMA oncology. 2023
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Abstract
IMPORTANCE Survivors of blood or marrow transplant (BMT) are at increased risk of subsequent malignant neoplasms (SMNs). Cancers of the gastrointestinal (GI) system are of special interest because their clinical behavior is often aggressive, necessitating early detection by increasing awareness of high-risk populations. OBJECTIVE To describe the risk of SMNs in the GI tract after BMT. DESIGN, SETTING, AND PARTICIPANTS A cohort study of 6710 individuals who lived at least 2 years after BMT performed between January 1, 1974, and December 31, 2014, at City of Hope, University of Minnesota, or University of Alabama at Birmingham. End of follow-up was March 23, 2020. Data analysis was performed between September 1, 2022, and September 30, 2022. EXPOSURES Demographic and clinical factors; therapeutic exposures before or as part of BMT. MAIN OUTCOMES AND MEASURES Development of SMNs in the GI tract after BMT. Participants self-reported SMNs in the GI tract; these were confirmed with pathology reports, medical records, or both. For deceased patients, death records were used. Standardized incidence ratios determined excess risk of SMNs in the GI tract compared with that of the general population. Fine-Gray proportional subdistribution hazard models assessed the association between risk factors and SMNs in the GI tract. RESULTS The cohort of 6710 individuals included 3444 (51.3%) autologous and 3266 (48.7%) allogeneic BMT recipients. A total of 3917 individuals (58.4%) were male, and the median age at BMT was 46 years (range, 0-78 years). After 62 479 person-years of follow-up, 148 patients developed SMNs in the GI tract. The standardized incidence ratios for developing specific SMNs ranged from 2.1 for colorectal cancer (95% CI, 1.6-2.8; P < .001) to 7.8 for esophageal cancer (95% CI, 5.0-11.6; P < .001). Exposure to cytarabine for conditioning (subdistribution hazard ratio [SHR], 3.1; 95% CI, 1.5-6.6) was associated with subsequent colorectal cancer. Compared with autologous BMT recipients, allogeneic BMT recipients with chronic graft-vs-host disease were at increased risk for esophageal cancer (SHR, 9.9; 95% CI, 3.2-30.5). Conditioning with etoposide (SHR, 2.0; 95% CI, 1.1-3.5) and pre-BMT anthracycline exposure (SHR, 5.4; 95% CI, 1.3-23.4) were associated with an increased risk of liver cancer compared with no exposure to the respective agents. CONCLUSIONS AND RELEVANCE The findings of this cohort study are relevant for oncologists and nononcologists who care for the growing number of survivors of transplant. Awareness of subgroups of survivors of BMT at high risk for specific types of SMNs in the GI tract may influence recommendations regarding modifiable risk factors, as well as individualized screening.
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Association of pre-transplant vancomycin resistant enterococcus colonization status on long-term outcomes of allogeneic-hematopoietic cell transplantation
Salhotra, A., Sandhu, K. S., Yang, D., Mokhtari, S., O'Hearn, J., Tegtmeier, B., Al Malki, M. M., Abella, J., Meguro, A., Dickter, J., et al
Bone marrow transplantation. 2022
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Burden of Long-Term Morbidity Borne by Survivors of Acute Myeloid Leukemia Treated With Blood or Marrow Transplantation: The Results of the BMT Survivor Study
Armenian, S. H., Chen, Y., Hageman, L., Wu, J., Landier, W., Bosworth, A., Francisco, L., Schlichting, E., Bhatia, R., Salzman, D., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2022;:Jco2102829
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Editor's Choice
Abstract
PURPOSE Blood or marrow transplantation (BMT) is an integral part of consolidation and/or salvage therapy for patients with acute myeloid leukemia (AML). With the growing population of AML survivors, there is a need to understand the quality of their survival. MATERIALS AND METHODS This multisite study included 1,369 2-year survivors who underwent BMT for AML between 1974 and 2014 at age ≥ 21 years and 1,310 siblings. Using Common Terminology Criteria for Adverse Events, severe/life-threatening and fatal chronic health conditions were identified. Multivariable regression analysis was used to compare the risk of severe/life-threatening conditions and health status between survivors and siblings, and to identify risk factors for health conditions among BMT survivors. RESULTS The prevalence of severe/life-threatening conditions was 54.9% in BMT survivors compared with 28.5% in siblings (P < .001), yielding 3.8-fold higher odds of severe/life-threatening conditions (95% CI, 3.1 to 4.7) among the BMT survivors. The most prevalent conditions included subsequent neoplasms, diabetes, cataracts, venous thromboembolism, and joint replacement. Survivors were more likely to report poor general health (odds ratio [OR], 3.8; 95% CI, 2.8 to 5.1), activity limitation (OR, 3.7; 95% CI, 3.0 to 4.5), and functional impairment (OR, 2.9; 95% CI, 2.3 to 3.6). Among BMT recipients, the 20-year cumulative incidence of severe/life-threatening/fatal conditions was 68%. History of chronic graft-versus-host disease was associated with a higher risk of pulmonary disease (hazard ratio [HR], 3.1; 95% CI, 1.0 to 9.3), cataract (HR, 2.6; 95% CI, 1.4 to 3.8), and venous thromboembolism (HR, 2.3; 95% CI, 1.3 to 4.7). Relapse-related mortality (RRM) plateaued at 30%, whereas non-RRM increased to 50% at 30 years. CONCLUSION The burden of severe/life-threatening conditions is substantially higher in BMT recipients when compared with an unaffected comparison group, contributing to an increasing incidence of non-RRM over time. Chronic graft-versus-host disease was an important risk factor for severe/life-threatening/fatal conditions among BMT recipients, informing the need for close monitoring to anticipate and manage morbidity.
PICO Summary
Population
People who were treated for acute myeloid leukaemia (AML) between 1974 and 2014 and their siblings (n=2679)
Intervention
Single bone marrow transplant at 21 years or younger and surviving at least 2 years (BMT surviviors, n=1369)
Comparison
Nearest age siblings of the cohort of transplant survivors (siblings, n=1310)
Outcome
The prevalence of severe/life-threatening conditions was 54.9% in BMT survivors compared with 28.5% in siblings, yielding 3.8-fold higher odds of severe/life-threatening conditions (95% CI, 3.1 to 4.7) among the BMT survivors. The most prevalent conditions included subsequent neoplasms, diabetes, cataracts, venous thromboembolism, and joint replacement. Survivors were more likely to report poor general health (odds ratio [OR], 3.8; 95% CI, 2.8 to 5.1), activity limitation (OR, 3.7; 95% CI, 3.0 to 4.5), and functional impairment (OR, 2.9; 95% CI, 2.3 to 3.6). Among BMT recipients, the 20-year cumulative incidence of severe/life-threatening/fatal conditions was 68%. History of chronic graft-versus-host disease was associated with a higher risk of pulmonary disease (hazard ratio [HR], 3.1; 95% CI, 1.0 to 9.3), cataract (HR, 2.6; 95% CI, 1.4 to 3.8), and venous thromboembolism (HR, 2.3; 95% CI, 1.3 to 4.7). Relapse-related mortality (RRM) plateaued at 30%, whereas non-RRM increased to 50% at 30 years.
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Social vulnerability and risk of non-relapse mortality after allogeneic hematopoietic cell transplantation
Bhandari, R., The, J. B., He, T., Nakamura, R., Artz, A. S., Jankowska, M. M., Forman, S. J., Wong, F. L., Armenian, S. H.
Journal of the National Cancer Institute. 2022
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Abstract
BACKGROUND Risk of non-relapse mortality (NRM) after hematopoietic cell transplantation (HCT) is high. Patient-level clinical prediction models such as the HCT-comorbidity index (HCT-CI) help identify those at increased risk for NRM, but the independent contribution of social determinants of health on HCT outcomes is not well characterized. METHODS This study included 1,602 patients who underwent allogeneic HCT between 2013-2019 at City of Hope. Census tract-level social vulnerability was measured using the Social Vulnerability Index (SVI). Fine-Gray multivariable regression evaluated the association between SVI and 1-year NRM. Subgroup analysis examined risk of NRM across combined SVI and HCT-CI categories, and by race and ethnicity. RESULTS Cumulative incidence of 1-year NRM after HCT was 15.3% (95% confidence interval [CI] 13.6-17.1). In multivariable analysis, patients in the highest SVI tertile (highest social vulnerability) had a 1.4-fold risk (subdistribution hazard ratio [sHR]=1.36, 95%CI 1.04-1.78) of NRM compared to individuals in the lower tertiles; patients in the highest SVI tertile who also had elevated (≥3) HCT-CI scores had the highest risk (sHR = 1.81, 95%CI 1.26-2.58) of 1-year NRM (reference: lower SVI tertiles and HCT-CI <3). High social vulnerability was associated with risk of 1-year NRM in Asian (sHR = 2.03, 95%CI 1.09-3.78) and Hispanic (sHR = 1.63, 95%CI 1.04-2.55), but not non-Hispanic White patients. CONCLUSIONS High social vulnerability independently associated with 1-year NRM after HCT, specifically among minority populations and those with a high comorbidity burden at HCT. These findings may inform targeted approaches for needs assessment during and after HCT, allowing for timely interventions to improve health outcomes in at-risk patients.
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Outcomes of Allogeneic Hematopoietic Cell Transplantation in Adults with Fusions Associated with Ph-like ALL
Aldoss, I., Yang, D., Tomasian, V., Mokhtari, S., Jackson, R., Gu, Z., Telatar, M., Yew, H., Al Malki, M. M., Salhotra, A., et al
Blood advances. 2022
Abstract
Allogenic hematopoietic cell transplantation (alloHCT) is a well-established curative modality for adults with high-risk ALL; yet large data describing alloHCT outcomes in Philadelphia (Ph)-like ALL is lacking. We retrospectively analyzed archived DNA samples from consecutive adults with B-cell Ph-negative ALL who underwent alloHCT in complete remission (CR) (n= 127) at our center between 2006 and 2020. Identification of fusions associated with Ph-like were performed using accumulative results from RNAseq, conventional cytogenetics, FISH, and whole genome array studies. Fusions associated with Ph-like were detected in 56 (44%) patients, of whom 38 were carrying CRLF2r; and the rest (n=18) were non-CRLF2r. Compared to other non-Ph-like (n=71), patients with fusions associated with Ph-like ALL were more frequently Hispanic (P=0.008), less frequently carried high-risk cytogenetics (P<0.001), and more likely to receive blinatumomab prior to HCT (P=0.019). With the median follow-up of 3.5 years, patients with Ph-like ALL fusions had comparable post-transplant outcomes compared to other B-cell ALL: 3-year relapse-free survival (RFS) [41% vs. 44%, P=0.36], overall survival (OS) [51% vs. 50%, P=0.59] and relapse [37% vs. 31%, P=0.47]. In multivariable analysis, age (P= 0.023), disease status at the time of transplant (P<0.001), and donor type (P=0.015) influenced OS. RFS (primary endpoint) was significantly influenced by disease status (P<0.001) and conditioning regimen intensity (P=0.014). Relapse rate was associated with disease status (P=0.028) and conditioning regimen intensity (P=0.028). In conclusion, our data suggest that alloHCT consolidation results in similarly favorable survival outcomes in adult patients with Ph-like fusions and other high-risk B-cell ALL.
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10.
Treatment of Allosensitized Patients Receiving Allogeneic Transplantation
Ciurea, S. O., Al Malki, M. M., Kongtim, P., Zou, J., Aung, F. M., Rondon, G., Chen, J., Taniguchi, M., Otoukesh, S., Nademanee, A., et al
Blood advances. 2021
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Editor's Choice
Abstract
Donor-specific anti-HLA antibodies (DSA) are a major cause of engraftment failure in patients receiving haploidentical stem cell transplantation (HaploSCT). Effective treatments are needed for these patients who often have no other donor options and/or are in need to proceed urgently to transplantation. We studied a multimodality treatment with alternate day plasma exchange, rituximab, intravenous gamma globulin (IvIg) and an irradiated donor buffy coat for patients with DSA at two institutions. Thirty-seven patients with a median age of 51 years were treated with this desensitization protocol. Treatment outcomes were compared with a control group of HaploSCT patients without DSA (N=345). Majority of patients in the DSA group were females (83.8% vs. 37.1% in controls, p<0.001) and received stem cells from a child as donor (67.6% vs. 44.1%, p=0.002). Mean DSA level before and after desensitization was 10,198 and 5,937 MFI, respectively with mean differences of 4,030 MFI. Fourteen of 30 tested patients (46.7%) had C1q positivity while 8 of 29 tested patients (27.6%) remained positive after desensitization. In multivariable analysis, patients with initial DSA >20,000 MFI and with persistent C1q+ after desensitization had a significantly lower engraftment rate, resulted in a significantly higher non-relapse mortality (NRM) and worse overall survival (OS) than controls whereas graft outcome and survivals of patients with initial DSA <20,000 MFI and those with negative C1q after treatment were comparable with controls. In conclusion, treatment with plasma exchange, rituximab, IvIg and donor buffy coat is effective in promoting engraftment in patients with DSA up to 20,000 MFI.
PICO Summary
Population
Patients with donor specific antibodies (DSAs) from two US centres, receiving allogeneic transplantation (DSA group, n=37)
Intervention
Desensitisation protocol: alternate day plasma exchange, rituximab, intravenous gamma globulin (IvIg) and an irradiated donor buffy coat (n=37)
Comparison
Patients without DSAs undergoing haploidentical transplantation (Control, n=345)
Outcome
The majority of patients in the DSA group were female (83.8% vs 37.1% in controls,) and received stem cells from a child as the donor (67.6% vs 44.1%). Mean DSA level before and after desensitization was 10 198 and 5937 mean fluorescence intensity (MFI), respectively, with mean differences of 4030 MFI. Fourteen of 30 tested patients (46.7%) had C1q positivity, while 8 of 29 tested patients (27.6%) remained positive after desensitization. In multivariable analysis, patients with initial DSA > 20 000 MFI and persistent positive C1q after desensitization had a significantly lower engraftment rate, which resulted in significantly higher non-relapse mortality and worse overall survival (OS) than controls, whereas graft outcome and survival of patients with initial DSA < 20 000 MFI and those with negative C1q after treatment were comparable with controls.