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Defibrotide plus best standard of care compared with best standard of care alone for the prevention of sinusoidal obstruction syndrome (HARMONY): a randomised, multicentre, phase 3 trial
Grupp, S. A., Corbacioglu, S., Kang, H. J., Teshima, T., Khaw, S. L., Locatelli, F., Maertens, J., Stelljes, M., Stepensky, P., Lopez, P., et al
The Lancet. Haematology. 2023
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Editor's Choice
Abstract
BACKGROUND Sinusoidal obstruction syndrome, also known as veno-occlusive disease, is a potentially life-threatening complication of haematopoietic stem-cell transplantation (HSCT). We aimed to compare defibrotide prophylaxis plus best supportive care versus best supportive care alone for sinusoidal obstruction syndrome prevention after HSCT. METHODS This open-label, randomised, multicentre, phase 3 trial was done in 104 centres in 14 countries. Patients who were at least 1 month old, were scheduled to receive allogeneic HSCT (adult [aged >16 years] or paediatric [aged >1 month to ≤16 years] patients) or autologous HSCT (paediatric patients only), and were at high risk or very high risk of developing sinusoidal obstruction syndrome were eligible for inclusion. Patients were randomly assigned (1:1) by an interactive web response system to receive intravenous defibrotide 25 mg/kg per day (four equal doses [6·25 mg/kg per dose]) and best supportive care (determined by individual institutional guidelines; defibrotide prophylaxis group) or best supportive care only (best supportive care group). Randomisation was stratified by sinusoidal obstruction syndrome risk, age, and country. The primary endpoint, sinusoidal obstruction syndrome-free survival at day 30 after HSCT, was assessed by an independent Endpoint Adjudication Committee in the intention-to-treat (ITT) population. Safety was assessed in all patients who received protocol treatment. The trial is registered with ClinicalTrials.gov, NCT02851407. FINDINGS Between Jan 11, 2017, and Oct 20, 2020, 372 patients (172 [46%] women and 200 [54%] men; median age 14·0 years [IQR 4·0-41·0] were randomly assigned to the defibrotide prophylaxis group (n=190) or best supportive care group (n=182; ITT population). On the basis of recommendations from the Independent Data Monitoring Committee following completion of the planned interim analysis in the first 280 recruited patients on April 29, 2020, enrolment was prematurely stopped for presumed futility. At the final analysis, sinusoidal obstruction syndrome-free survival by day 30 after HSCT was 67% (95% CI 58-74) in the defibrotide prophylaxis group and 73% (62-80) in the best supportive care group (HR 1·27 [95% CI 0·84-1·93]; p=0·85). Treatment-emergent adverse events were similar between groups during the randomised prophylaxis phase; most treatment-emergent adverse events were related to the transplantation rather than to study drug. The most common grade 3 or 4 treatment-emergent adverse events were stomatitis (grade 3, 52 [29%] of 181 patients in the defibrotide prophylaxis group and 56 [32%] of 174 patients in the best supportive care group; grade 4, two [1%] in the defibrotide prophylaxis group and two [1%] in the best supportive care group) and febrile neutropaenia (grade 3, 51 [28%] in the defibrotide prophylaxis group and 52 [30%] in the best supportive care group; grade 4, no patients in the defibrotide prophylaxis group and three [2%] in the best supportive care group). Serious treatment-emergent adverse events occurred in 74 (41%) of 181 patients in the defibrotide prophylaxis group and 61 (35%) of 174 patients in the best supportive care group. In the rescue phase, when patients in both treatment groups received defibrotide as rescue treatment, fatal treatment-related adverse events occurred in one (4%) of 25 patients in the defibrotide prophylaxis group (intracranial haemorrhage) and one (3%) of 31 patients in the best supportive care group (sinusoidal obstruction syndrome). INTERPRETATION Defibrotide did not show a benefit in the prophylaxis of sinusoidal obstruction syndrome. Additional studies of carefully selected patients at high risk of sinusoidal obstruction syndrome after HSCT are warranted. FUNDING Jazz Pharmaceuticals.
PICO Summary
Population
Adults and children at least one month old who were scheduled to receive allogeneic transplant or children 1 month – 16 years scheduled to receive autologous transplant, and at high or very high risk of developing sinusoidal obstruction syndrome (n=372)
Intervention
Defibrotide prophylaxis plus best supportive care (n=190)
Comparison
Best supportive care alone (n=182)
Outcome
On the basis of recommendations from the Independent Data Monitoring Committee following completion of the planned interim analysis in the first 280 recruited patients on April 29, 2020, enrolment was prematurely stopped for presumed futility. At the final analysis, sinusoidal obstruction syndrome-free survival by day 30 after HSCT was 67% (95% CI 58-74) in the defibrotide prophylaxis group and 73% (62-80) in the best supportive care group (HR 1·27 [95% CI 0·84-1·93]; p=0·85). Treatment-emergent adverse events were similar between groups during the randomised prophylaxis phase; most treatment-emergent adverse events were related to the transplantation rather than to study drug. Serious treatment-emergent adverse events occurred in 74 (41%) of 181 patients in the defibrotide prophylaxis group and 61 (35%) of 174 patients in the best supportive care group. In the rescue phase, when patients in both treatment groups received defibrotide as rescue treatment, fatal treatment-related adverse events occurred in one (4%) of 25 patients in the defibrotide prophylaxis group (intracranial haemorrhage) and one (3%) of 31 patients in the best supportive care group (sinusoidal obstruction syndrome).
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A randomized phase II study of acyclovir for the prevention of chemotherapy-induced oral mucositis in patients undergoing autologous hematopoietic stem cell transplantation
Hong, J., Park, H. K., Chang, S. H., Byun, J. M., Shin, D. Y., Koh, Y., Yoon, S. S., Choi, Y., Kim, I.
BMC oral health. 2023;23(1):1008
Abstract
OBJECTIVES To prove our hypothesis that acyclovir prophylaxis in autologous hematopoietic stem cell transplantation (AHSCT) recipients with hematologic malignancies (HM) reduces the incidence of chemotherapy-induced oral mucositis (CIOM) by inhibiting the intraoral HSV reactivation during the neutropenic period, we conducted a randomized phase II study of acyclovir for the prevention of CIOM in adult HSV sero-positive AHSCT recipients. METHODS Patients were randomized to either the study group (acyclovir 400 mg PO bid until neutrophil engraftment) or the control group (no prophylaxis) and received AHSCT. Oral examination and sampling for HSV were performed at three timepoints of AHSCT. RESULTS In 54 patients who were randomized (for intention-to-analysis), the incidence of CIOM was 16.0% (4/25 patients) and 58.6% (17/29 patients) in the study group and the control group, respectively (P = 0.001). In 49 patients who completed the study (for per-protocol analysis), the incidence of CIOM was 13.0% (3/23 patients) and 61.5% (16/26 patients) in the study group and the control group, respectively (P = 0.001). In addition, HSV-1 PCR positivity in the study group was significantly lower than that the control group (4.3% vs. 46.2%, P = 0.001). A strong association between the HSV-1 reactivation status and CIOM was reconfirmed. CONCLUSIONS Prophylactic use of oral acyclovir effectively reduced the incidence of CIOM in patients with HM who were undergoing AHSCT. TRIAL REGISTRATIONS This trial was registered at the Clinical Research Information Service in the Republic of Korea under the number KCT0003885 (registration date 03/05/2019).
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Hangeshashinto for prevention of oral mucositis in patients undergoing hematopoietic stem cell transplantation: a randomized phase II study
Yoshimatsu, M., Kawashita, Y., Soutome, S., Murata, M., Sawayama, Y., Kurogi, T., Nakao, N., Miyazaki, Y., Umeda, M., Ukai, T.
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2023;31(12):707
Abstract
PURPOSE Oral mucositis (OM) is a side effect associated with cancer treatment. Hangeshashinto (HST), a Kampo medicine, was originally prescribed to treat diarrhea, gastritis, and stomatitis. Several reports have described the effects of HST for OM induced by chemotherapy in patients with gastric or colorectal cancer. In this study, the effects of HST for prevention of OM were investigated in patients undergoing hematopoietic stem cell transplantation (HSCT). METHODS Thirty patients scheduled to receive allogeneic grafts were enrolled from July 2020 to December 2021. They were randomly assigned to two groups and instructed to wash their mouth using HST dissolved in saline solution or using only saline solution three times a day. The observation period was from the initiation date of the conditioning regimen to the date of engraftment, and the end point was the incidence of OM. RESULTS Eighteen patients developed OM, the most severe of which was Grade (G)3. There was no significant difference in the incidence of OM between the HST group and the control group. However, a negative correlation tended to be observed between the duration using HST use and the duration of OM (G2-3: P = 0.027, G3: P = 0.047). CONCLUSIONS The present study demonstrated that HST use did not clearly inhibit onset of OM but showed a tendency to inhibit OM exacerbation. However, further studies are necessary to fully understand the effects of HST on OM in patients undergoing HSCT. TRIAL REGISTRATION This study was registered in the Japan Registry of Clinical Trials on 7 May 2020 (jRCTs071200012).
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N-acetylcysteine as prophylactic therapy for transplant-associated thrombotic microangiopathy: a randomized, placebo-controlled trial
Pan, T., Qi, J., Tang, Y., Yao, Y., Chen, J., Wang, H., Yang, J., Xu, X., Shi, Q., Liu, Y., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication for patients undergoing hematopoietic stem cell transplantation (HSCT). N-acetylcysteine (NAC) has recently been considered as a potential treatment for patients with thrombotic thrombocytopenic purpura. OBJECTIVES To assess the value of NAC for the prevention of TA-TMA, we conducted a prospective study at the First Affiliated Hospital of Soochow University. STUDY DESIGN This open-label, randomized placebo-controlled trial included 160 patients who were scheduled to receive allogeneic HSCT. Participants were randomly assigned 1:1 to either oral NAC (50 mg/kg daily from 9 days before HSCT to 30 days after HSCT) or placebo treatment. The primary outcome was the incidence of TA-TMA. Overall survival (OS) and event-free survival (EFS) were assessed between NAC and placebo cohorts. RESULTS The incidence of TA-TMA in the NAC cohort was 9.1% (95% confidence interval (CI), 0.02-0.162), compared with 23% (95% CI, 0.132-0.328) in placebo cohort, with a rate ratio of 0.34 (95% CI, 0.123-0.911; p=0.039). The median time to onset of TA-TMA was 60 (interquartile range [IQR] 42-129) and 36 (IQR 30.5-51) days in the NAC and control groups, respectively (p=0.063). The 2-year rates of OS in the NAC and placebo groups were 75.4% (95% CI, 2.865-7.353) and 63.0% (95% CI, 0.508-0.735), respectively, with a hazard ratio (HR) of 0.622 (95% CI, 0.334-1.155; p=0.132). The EFS rate was 25.8% in NAC patients and 8.1% in placebo patients, with an HR of 0.254 (95% CI, 0.094-0.692; p=0.024). The median time of EFS was 60 and 38 days in NAC and placebo cohorts. CONCLUSION Our findings suggest that NAC may be a potential treatment to reduce TA-TMA incidence.
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The effects of a combination oral spray (Mucosamin®) for the prevention of oral mucositis in pediatric patients undergoing hematopoietic stem cell transplantation: a double blind randomized clinical trial
Shahrabi, M., Solduzian, M., Babaie, M. H., Mousavi, S. A., Goodarzi, N., Ravari, N. S., Sadeghi, K.
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2022
Abstract
PURPOSE Oral mucositis (OM) is a frequent complication of conditioning regimens for hematopoietic stem cell transplantation (HSCT). Damage to the nuclear and non-nuclear materials of the mucosal cells by the production of Reactive Oxygen Species (ROS) and proinflammatory cytokines could result to development and progression of OM. Previous studies have shown the effectiveness of !!!Mucosamin® oral spray in the management of pain and acceleration of OM healing. The aims of the current study were to evaluate prophylactic effects of Mucosamin® oral spray in reducing the incidence and severity of OM in pediatric patients undergoing allogeneic HSCT. METHOD The current study was designed as a double-blind, placebo-controlled randomized clinical trial. Sixty patients were enrolled in the study and received placebo or Mucosamin® spray. Patients in both groups used sprays 4 times daily. Product application was begun at the time of initiation of conditioning regimen and was continued for 14 days. RESULTS Mucosamin® significantly reduced incidence and severity of OM compared to the placebo (P values: 0.027 and 0.035, respectively). This product could also decrease OM duration and delay OM onset (P values: 0.007 and 0.006, respectively). CONCLUSION Mucosamin® could effectively reduce incidence, severity, and duration of OM and delay OM onset in pediatric patients undergoing allogeneic HSCT. TRIAL REGISTRATION The study protocol was registered in the Iranian Registry of Clinical Trials under the registry number IRCT20190917044805N1.
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A randomized controlled trial of manual versus powered tooth brushing during haematopoietic stem cell transplantation
Potting, C. M. J., van Leeuwen, S. J. M., Kurstjens, M. H., Bronkhorst, E. M., Thomas, R. Z., Blijlevens, N. M. A., Huysmans, Mcdnjm
Oral diseases. 2021
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Abstract
AIM: To compare manual and powered tooth brushing (MT and PT) with respect to patient compliance to brushing frequency advice, plaque removal and severity of oral mucositis (OM) in patients undergoing hematopoietic stem cell transplantation (HSCT) after high dose chemotherapy. MATERIALS & METHODS A randomized controlled trial was conducted. Forty six patients scheduled to receive myelo-ablative conditioning regimen before autologous HSCT were included and randomly assigned to control (MT, n=23) or test (PT, n=23) groups. Starting at day 1 (day of hospital admission for HSCT), brushing frequency (patient recorded diary), plaque scores (Plaque Control Index) and oral mucositis (Oral Mucositis Nursing Index) were recorded daily. Data for days 1 to 17 were analysed using regression analysis and general linear models. RESULTS Few patients maintained 4 times per day brushing, but most brushed at least 2 times per day throughout the study. In PT overall plaque scores were lower by 6.98% (p=0.006) as compared to MT. No differences were seen in OM scores between the groups (p=0.968). A small but significant positive correlation was found between plaque scores and OM severity: R(2) =0.15 (p<0.01). CONCLUSIONS Powered tooth brushing resulted in lower plaque scores, but was not associated with reduced OM severity. Individual plaque scores were positively related to OM severity.
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Intraoral versus extraoral photobiomodulation therapy in the prevention of oral mucositis in HSCT patients: a randomized, single-blind, controlled clinical trial
Ramos-Pinto, M. B., de Lima Gusmão, T. P., Schmidt-Filho, J., Jaguar, G. C., Martins, M. D., Alves, F. A.
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2021
Abstract
To compare the efficacy of intraoral and extraoral photobiomodulation (PBM) protocols for the prevention of oral mucositis (OM) in hematopoietic stem cell transplantation (HSCT) patients. A total of 60 patients was randomized into intraoral PBM (IOPBM) and extraoral PBM (EOPBM) groups. Both PBM protocols were well tolerated and no side effects were observed. EOPBM session times were one fourth of IOPBM durations. Of 60 patients, 35 (58.3%) developed ulcerated OM between day +3 and day +12. No intergroup difference was observed in OM healing times (p?=?0.424). The lateral border of the tongue was the most common site affected in both groups. However, the incidence of mucositis on buccal mucosa was significantly reduced in the EOPBM group (p?=?0.021). Young patients (OR.5.35, 95%CI 0.94-30.4, p?=?0.058) and those who had received myeloablative conditioning (OR.55.1, 95%CI 2.69-1129.3, p?=?0.009) were more likely to develop ulcerated OM, whereas autologous HSCT recipients (OR 0.079, 95% CI 0.009-0.67, p?=?0.021) had a lower probability of developing ulcerated OM independent of PBM protocol. EOPBM protocol was as effective as IOPBM in the management of OM in HSCT patients, with the advantage of shorter treatment sessions. Trial registration number: RBR-7nww56. Date of trial registration submission: 30th September 2019.
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Low-dose decitabine for refractory prolonged isolated thrombocytopenia after HCT: a randomized multicenter trial
Tang, Y., Chen, J., Liu, Q., Chu, T., Pan, T., Liang, J., He, X. F., Chen, F., Yang, T., Ma, X., et al
Blood advances. 2021;5(5):1250-1258
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Abstract
Refractory prolonged isolated thrombocytopenia (RPIT) is an intractable complication after allogeneic hematopoietic cell transplantation (HCT), which often leads to poor prognosis. A clinical study was designed to validate the efficacy and safety of low-dose decitabine for RPIT after HCT and explore the related underlying mechanisms. Eligible patients were randomly allocated to receive 1 of 3 interventions: arm A, low-dose decitabine (15 mg/m2 daily IV for 3 consecutive days [days 1-3]) plus recombinant human thrombopoietin (300 U/kg daily); arm B, decitabine alone; or arm C, conventional treatment. The primary end point was the response rate of platelet recovery at day 28 after treatment. Secondary end points included megakaryocyte count 28 days after treatment and survival during additional follow-up of 24 weeks. Among the 91 evaluable patients, response rates were 66.7%, 73.3%, and 19.4% for the 3 arms, respectively (P < .001). One-year survival rates in arms A (64.4% ± 9.1%) and B (73.4% ± 8.8%) were similar (P = .662), and both were superior to that in arm C (41.0% ± 9.8%; P = .025). Megakaryocytes, endothelial cells (ECs), and cytokines relating to megakaryocyte migration and EC damage were improved in patients responding to decitabine. This study showed low-dose decitabine improved platelet recovery as well as overall survival in RPIT patients after transplantation. This trial was registered at www.clinicaltrials.gov as #NCT02487563.
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Efficacy of a novel device for cryoprevention of oral mucositis: a randomized, blinded, multicenter, parallel group, phase 3 trial
Walladbegi, J., Henriksson, R., Tavelin, B., Svanberg, A., Larfors, G., Jädersten, M., Schjesvold, F., Mahdi, A., Garming Legert, K., Peterson, D. E., et al
Bone marrow transplantation. 2021
Abstract
Cryoprevention (CP) using ice (IC) is an effective strategy to prevent chemotherapy-induced oral mucositis (OM). However, the use of IC may cause adverse reactions and requires water of safe quality to minimize risk of serious infections. This randomized, blinded, parallel group, phase 3 trial was conducted in five Scandinavian centers. Eligible patients were diagnosed with multiple myeloma or lymphoma, scheduled to receive conditioning with high-dose chemotherapy prior to autologous hematopoietic stem cell transplantation (ASCT). Patients were assigned to cooling with IC or a novel intraoral cooling device (ICD). The primary outcome was the highest OM score during the study period, expressed as peak value on the Oral Mucositis Assessment Scale (OMAS-total). When the entire study population (n?=?172) was analyzed for peak OMAS-total, the two cooling methods were equally effective. However, when the lymphoma group was analyzed separately, the ICD significantly reduced the peak OMAS-total score to a greater extent compared to IC (x¯?±?SD; 1.77?±?1.59 vs. 3.08?±?1.50; p?=?0.047). Combined with existing evidence, the results of the present trial confirm that CP is an effective method to prevent OM. ClinicalTrials.gov. NCT03203733.
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Azithromycin oral suspension in prevention and management of oral mucositis in patients undergoing hematopoietic stem cell transplantation: a randomized controlled trial
Parkhideh, S., Zeraatkar, M., Moradi, O., Hajifathali, A., Mehdizadeh, M., Tavakoli-Ardakani, M.
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2021
Abstract
OBJECTIVES This study aimed to investigate the effects of azithromycin suspension on oral mucositis in patients undergoing hematopoietic stem cell transplantation (HSCT). METHODS AND MATERIAL The study was designed as a single-blind randomized controlled trial in Taleghani medical center affiliated to Shahid Beheshti University of Medical Sciences Tehran Iran. Patients undergoing HSCT were randomly assigned to intervention or control groups. Azithromycin suspension was administered twice daily by gargling for 30 s and swallowing, on the first day of chemotherapy for patients in the intervention group. Graded oral mucositis (OM) occurrence based on National Cancer Institute Common Toxicity Criteria (NCI-CTC) scale (grade 0 to 5) was considered the main outcome, and the Numerical Rating Scale (NRS:0-10) measured the severity of OM symptoms. RESULTS In a duration of 15 months, 88 patients were randomly assigned and finally 70 patients were evaluable for study outcomes (randomized 1:1 to azithromycin versus no-azithromycin). The incidence and duration of the mucositis significantly improved in the intervention group compared to the control. Azithromycin use was consistent with a lower rate of dryness (P?0.001), dysphagia (P?0.001), and loss of sense of taste (P?0.001). Also, in the intervention group, lower intensity of pain due to mucositis (P?=?0.01) and lower duration of mucositis were observed (p?=?0.045). No significant adverse drug reaction was observed in patients receiving azithromycin. CONCLUSION Based on the result from this study, azithromycin suspension is an effective option in the prevention and treatment of chemotherapy-induced OM. Further study is needed to assess the effect of azithromycin and comparison with other therapeutic options. TRIAL REGISTRATION Iranian Registry of Clinical Trials: IRCT201603093210N13.