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Journal of Clinical Oncology : Official... Feb 2021Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients.
PATIENTS AND METHODS
FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129).
RESULTS
Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; < .0001) and 0.02 (95% CI, < 0.01 to 0.05; = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively.
CONCLUSION
Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.
Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Chemoradiotherapy; Child; Child, Preschool; Equivalence Trials as Topic; Etoposide; Female; Follow-Up Studies; Humans; International Agencies; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Survival Rate; Thiotepa; Vidarabine; Whole-Body Irradiation
PubMed: 33332189
DOI: 10.1200/JCO.20.02529 -
Blood Jul 2020We retrospectively studied 232 patients with cold agglutinin disease (CAD) at 24 centers in 5 countries. In Norway and a northern region of Italy, the study was close to... (Clinical Trial)
Clinical Trial Observational Study
We retrospectively studied 232 patients with cold agglutinin disease (CAD) at 24 centers in 5 countries. In Norway and a northern region of Italy, the study was close to being population-based. For the first time, we demonstrate fourfold differences between cold and warmer climates regarding prevalence (20 vs 5 cases/million) and incidence (1.9 vs 0.48 cases/million per year). Mean baseline hemoglobin level was 9.3 g/dL, but 27% had hemoglobin <8 g/dL. Identification of typical features of CAD-associated lymphoproliferative disorder in the bone marrow was greatly increased by centralized biopsy assessment. CAD seems to be associated with a slightly increased risk of venous thrombosis. This work includes a follow-up study of therapies, focusing on the long-term outcomes of the rituximab plus bendamustine and rituximab plus fludarabine regimens. Rituximab plus bendamustine therapy resulted in responses in 35 (78%) of 45 patients; 24 (53%) achieved complete response. Interestingly, these rates were still higher than observed in the original (2017) prospective trial, and we also found a shift toward deeper responses with time. This is explained by the prolonged time to response seen in many patients, probably related to long-lived plasma cells. In patients responding to rituximab-bendamustine, median response duration was not reached after 88 months, and estimated 5-year sustained remission was 77%. The regimen appeared safe regarding late-occurring malignancies. Rituximab plus fludarabine therapy seems to carry a higher risk of long-term adverse effects.
Topics: Adult; Aged; Anemia, Hemolytic, Autoimmune; Bendamustine Hydrochloride; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prospective Studies; Retrospective Studies; Rituximab; Vidarabine
PubMed: 32374875
DOI: 10.1182/blood.2020005674 -
American Journal of Hematology Aug 2022The phase III study was designed to compare event-free survival (EFS) after treosulfan-based conditioning with a widely applied reduced-intensity conditioning (RIC)... (Randomized Controlled Trial)
Randomized Controlled Trial
Treosulfan compared with reduced-intensity busulfan improves allogeneic hematopoietic cell transplantation outcomes of older acute myeloid leukemia and myelodysplastic syndrome patients: Final analysis of a prospective randomized trial.
The phase III study was designed to compare event-free survival (EFS) after treosulfan-based conditioning with a widely applied reduced-intensity conditioning (RIC) busulfan regimen in older or comorbid patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT). A previously reported confirmatory interim analysis of the randomized clinical study including 476 patients demonstrated statistically significant noninferiority for treosulfan with clinically meaningful improvement in EFS. Here, the final study results and pre-specified subgroup analyses of all 570 randomized patients with completed longer-term follow-up are presented. Patients presenting HCT-specific comorbidity index >2 or aged ≥50 years were randomly assigned (1:1) to intravenous (IV) fludarabine with either treosulfan (30 g/m IV) or busulfan (6.4 mg/kg IV) after stratification by disease risk group, donor type, and participating institution. The primary endpoint was EFS with disease recurrence, graft failure, or death from any cause as events. EFS of patients (median age 60 years) was superior after treosulfan compared to RIC busulfan: 36-months-EFS rate 59.5% (95% CI, 52.2-66.1) vs. 49.7% (95% CI, 43.3-55.7) with a hazard ratio (HR) of 0.64 (95% CI, 0.49-0.84), p = 0.0006. Likewise, overall survival (OS) with treosulfan was superior compared to busulfan: 36-month-OS rate 66.8% vs. 56.3%; HR 0.64 (95% CI, 0.48-0.87), p = 0.0037. Post hoc analyses revealed that these differences were consistent with the confirmatory interim analysis, and thereby the treosulfan regimen appears particularly suitable for older AML and MDS patients.
Topics: Aged; Busulfan; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Middle Aged; Myelodysplastic Syndromes; Prospective Studies; Transplantation Conditioning; Vidarabine
PubMed: 35617104
DOI: 10.1002/ajh.26620 -
Annals of Hematology Sep 2019Outcomes for patients with non-Hodgkin's lymphoma (NHL) that proves refractory to treatment remain poor. Treatment of such patients is individualized and can include... (Review)
Review
Outcomes for patients with non-Hodgkin's lymphoma (NHL) that proves refractory to treatment remain poor. Treatment of such patients is individualized and can include enrolment in a clinical trial of novel agents or use of one of a wide array of drug regimens. Initial treatment with anthracyclines such as doxorubicin limits options at later stages of treatment because of anthracycline-related cumulative cardiotoxicity. The aza-anthracenedione pixantrone was developed to reduce the likelihood of cardiotoxicity without compromising efficacy and is currently conditionally approved for use as monotherapy in patients with multiply-relapsed or refractory aggressive B cell NHL. The use of pixantrone in combination therapy, often to replace doxorubicin or mitoxantrone, has or is currently being investigated in numerous studies in patients with aggressive or indolent NHL and is the focus of this review. These include the R-CPOP regimen (rituximab, cyclophosphamide, pixantrone, vincristine, prednisone) for aggressive NHL in the first-line setting, including a study in elderly patients with limited cardiac function, and for patients with relapsed NHL with prior anthracycline exposure; the PSHAP regimen (pixantrone, cytarabine, prednisone, cisplatin), also in the latter setting; the PREBen/PEBen regimen (pixantrone, bendamustine and etoposide with or without rituximab) as salvage therapy; and pixantrone in combination with fludarabine, dexamethasone, and rituximab (FPD-R) for relapsed indolent NHL.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Humans; Isoquinolines; Lymphoma, B-Cell; Mitoxantrone; Prednisone; Rituximab; Salvage Therapy; Vidarabine; Vincristine
PubMed: 31312929
DOI: 10.1007/s00277-019-03749-0 -
Antiviral Research Feb 2022Coronavirus disease 2019 (COVID-19) is a newly emerged infectious disease caused by a novel coronavirus, the severe acute respiratory syndrome coronavirus 2...
Coronavirus disease 2019 (COVID-19) is a newly emerged infectious disease caused by a novel coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The rapid global emergence of SARS-CoV-2 highlights the importance and urgency for potential drugs to control the pandemic. The functional importance of RNA-dependent RNA polymerase (RdRp) in the viral life cycle, combined with structural conservation and absence of closely related homologs in humans, makes it an attractive target for designing antiviral drugs. Nucleos(t)ide analogs (NAs) are still the most promising broad-spectrum class of viral RdRp inhibitors. In this study, using our previously developed cell-based SARS-CoV-2 RdRp report system, we screened 134 compounds in the Selleckchemicals NAs library. Four candidate compounds, Fludarabine Phosphate, Fludarabine, 6-Thio-20-Deoxyguanosine (6-Thio-dG), and 5-Iodotubercidin, exhibit remarkable potency in inhibiting SARS-CoV-2 RdRp. Among these four compounds, 5-Iodotubercidin exhibited the strongest inhibition upon SARS-CoV-2 RdRp, and was resistant to viral exoribonuclease activity, thus presenting the best antiviral activity against coronavirus from a different genus. Further study showed that the RdRp inhibitory activity of 5-Iodotubercidin is closely related to its capacity to inhibit adenosine kinase (ADK).
Topics: Antiviral Agents; Cell Line; Deoxyguanosine; Drug Evaluation, Preclinical; HEK293 Cells; Humans; Microbial Sensitivity Tests; Nucleic Acid Synthesis Inhibitors; RNA, Viral; RNA-Dependent RNA Polymerase; SARS-CoV-2; Thionucleosides; Tubercidin; Vidarabine; Vidarabine Phosphate; COVID-19 Drug Treatment
PubMed: 35101534
DOI: 10.1016/j.antiviral.2022.105254 -
Haematologica Jan 2024Treatment options for relapsed and refractory acute myeloid leukemia patients (R/R AML) are limited. This retrospective cohort study compares safety and efficacy of...
Treatment options for relapsed and refractory acute myeloid leukemia patients (R/R AML) are limited. This retrospective cohort study compares safety and efficacy of fludarabine, cytarabine, and idarubicin (FLA-IDA) without or with venetoclax (FLAVIDA) in patients with R/R AML. Thirty-seven and 81 patients received one course FLA-IDA with or without a 7-day course of venetoclax, respectively. The overall response rate (ORR) was significantly higher in FLAVIDA compared to FLAIDA- treated patients (78% vs. 47%; P=0.001), while measurable residual disease was negative at a similar proportion in responding patients (50% vs. 57%), respectively. Eighty-one percent and 79% of patients proceeded to allogeneic hematopoietic cell transplantation or donor lymphocyte infusion after FLAVIDA and FLA-IDA, respectively. Event-free and overall survival were similar in FLAVIDA- and FLA-IDA-treated patients. Refractory patients could be salvaged more successfully after FLA-IDA compared to FLAVIDA pretreatment. Neutrophil and platelet recovery times were similar in the venetoclax and the control group. In conclusion, short-term venetoclax in combination with FLA-IDA represents an effective treatment regimen in R/R AML identifying chemosensitive patients rapidly and inducing measurable residual disease-negative remission in a high proportion of R/R AML patients.
Topics: Humans; Idarubicin; Cytarabine; Retrospective Studies; Granulocyte Colony-Stimulating Factor; Leukemia, Myeloid, Acute; Vidarabine; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37470150
DOI: 10.3324/haematol.2023.282912 -
Frontiers in Pharmacology 2021The current pandemic caused by SARS-CoV2 and named COVID-19 urgent the need for novel lead antiviral drugs. Recently, United States Food and Drug Administration (FDA)... (Review)
Review
The current pandemic caused by SARS-CoV2 and named COVID-19 urgent the need for novel lead antiviral drugs. Recently, United States Food and Drug Administration (FDA) approved the use of remdesivir as anti-SARS-CoV-2. Remdesivir is a natural product-inspired nucleoside analogue with significant broad-spectrum antiviral activity. Nucleosides analogues from marine sponge including spongouridine and spongothymidine have been used as lead for the evolutionary synthesis of various antiviral drugs such as vidarabine and cytarabine. Furthermore, the marine sponge is a rich source of compounds with unique activities. Marine sponge produces classes of compounds that can inhibit the viral cysteine protease (M) such as esculetin and ilimaquinone and human serine protease (TMPRSS2) such as pseudotheonamide C and D and aeruginosin 98B. Additionally, sponge-derived compounds such as dihydrogracilin A and avarol showed immunomodulatory activity that can target the cytokines storm. Here, we reviewed the potential use of sponge-derived compounds as promising therapeutics against SARS-CoV-2. Despite the reported antiviral activity of isolated marine metabolites, structural modifications showed the importance in targeting and efficacy. On that basis, we are proposing a novel structure with bifunctional scaffolds and dual pharmacophores that can be superiorly employed in SARS-CoV-2 infection.
PubMed: 34079462
DOI: 10.3389/fphar.2021.666664 -
American Journal of Hematology Dec 2022We analyzed a Japanese registry database to elucidate the incidence, risk factors, and outcomes of adenovirus (AdV) disease after autologous and allogeneic hematopoietic...
We analyzed a Japanese registry database to elucidate the incidence, risk factors, and outcomes of adenovirus (AdV) disease after autologous and allogeneic hematopoietic cell transplantation (HCT) in contemporary real-world patients. We evaluated the cumulative incidence of AdV disease, as well as risk factors, survival, and treatment details, among 25 233 patients who underwent autologous HCT and 48 380 patients who underwent allogeneic HCT between 2005 and 2019. The 1-year cumulative incidences of AdV disease after autologous and allogeneic HCT were 0.18% and 1.52%, respectively, in children, and 0.49% and 2.99%, respectively, in adults. Among patients with AdV disease, renourinary infection was the most common manifestation, and viremia or disseminated disease occurred in 6% of those after autologous HCT and 19% of those after allogeneic HCT. In multivariate analysis, age ≥50 years and lymphoma were associated with AdV disease after autologous HCT, while patients age ≥50 years, male patients, lymphoma, HCT-specific comorbidity index ≥3, human leukocyte antigen-mismatched or haploidentical donors, cord blood, in vivo T-cell depletion, HCT from 2005 to 2009, acute graft-versus-host disease (GVHD), and chronic GVHD were associated with AdV disease after allogeneic HCT. The 1-year probabilities of survival after disease diagnosis were 65% in autologous HCT and 44% in allogeneic HCT. Regardless of the AdV disease burden, there was an increased risk of mortality after both autologous and allogeneic HCT. The most commonly used antiviral agents were cidofovir and vidarabine. The probabilities of improvement and survival with currently available agents were suboptimal. AdV disease after HCT remains a challenge. Better antiviral modalities are necessary.
Topics: Adult; Child; Humans; Male; Middle Aged; Graft vs Host Disease; Japan; Hematopoietic Stem Cell Transplantation; Transplantation Conditioning; Lymphoma; Registries; Adenoviridae
PubMed: 36087061
DOI: 10.1002/ajh.26723 -
Haematologica Jul 2023Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with...
Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with reduced-intensity conditioning (RIC) or myeloablative conditioning (MAC) is not well known. Using the Center for International Blood and Marrow Transplant Research database, we identified adults aged ≥18 years with myelofibrosis undergoing allo-HCT between 2008-2019 and analyzed the outcomes separately in the RIC and MAC cohorts based on the conditioning regimens used. Among 872 eligible patients, 493 underwent allo-HCT using RIC (fludarabine/ busulfan n=166, fludarabine/melphalan n=327) and 379 using MAC (fludarabine/busulfan n=247, busulfan/cyclophosphamide n=132). In multivariable analysis with RIC, fludarabine/melphalan was associated with inferior overall survival (hazard ratio [HR]=1.80; 95% confidenec interval [CI]: 1.15-2.81; P=0.009), higher early non-relapse mortality (HR=1.81; 95% CI: 1.12-2.91; P=0.01) and higher acute graft-versus-host disease (GvHD) (grade 2-4 HR=1.45; 95% CI: 1.03-2.03; P=0.03; grade 3-4 HR=2.21; 95%CI: 1.28-3.83; P=0.004) compared to fludarabine/busulfan. In the MAC setting, busulfan/cyclophosphamide was associated with a higher acute GvHD (grade 2-4 HR=2.33; 95% CI: 1.67-3.25; P<0.001; grade 3-4 HR=2.31; 95% CI: 1.52-3.52; P<0.001) and inferior GvHD-free relapse-free survival (GRFS) (HR=1.94; 95% CI: 1.49-2.53; P<0.001) as compared to fludarabine/busulfan. Hence, our study suggests that fludarabine/busulfan is associated with better outcomes in RIC (better overall survival, lower early non-relapse mortality, lower acute GvHD) and MAC (lower acute GvHD and better GRFS) in myelofibrosis.
Topics: Adult; Humans; Adolescent; Primary Myelofibrosis; Busulfan; Melphalan; Retrospective Studies; Hematopoietic Stem Cell Transplantation; Cyclophosphamide; Graft vs Host Disease; Transplantation Conditioning; Vidarabine
PubMed: 36779595
DOI: 10.3324/haematol.2022.281958 -
The Journal of Allergy and Clinical... Mar 2022Allogeneic hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis (HLH) disorders is associated with substantial morbidity and mortality.
BACKGROUND
Allogeneic hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis (HLH) disorders is associated with substantial morbidity and mortality.
OBJECTIVE
The effect of conditioning regimen groups of varying intensity on outcomes after transplantation was examined to identify an optimal regimen or regimens for HLH disorders.
METHODS
We studied 261 patients with HLH disorders transplanted between 2005 and 2018. Risk factors for transplantation outcomes by conditioning regimen groups were studied by Cox regression models.
RESULTS
Four regimen groups were studied: (1) fludarabine (Flu) and melphalan (Mel) in 123 subjects; (2) Flu, Mel, and thiotepa (TT) in 28 subjects; (3) Flu and busulfan (Bu) in 14 subjects; and (4) Bu and cyclophosphamide (Cy) in 96 subjects. The day 100 incidence of veno-occlusive disease was lower with Flu/Mel (4%) and Flu/Mel/TT (0%) compared to Flu/Bu (14%) and Bu/Cy (22%) (P < .001). The 6-month incidence of viral infections was highest after Flu/Mel (72%) and Flu/Mel/TT (64%) compared to Flu/Bu (39%) and Bu/Cy (38%) (P < .001). Five-year event-free survival (alive and engrafted without additional cell product administration) was lower with Flu/Mel (44%) compared to Flu/Mel/TT (70%), Flu/Bu (79%), and Bu/Cy (61%) (P = .002). The corresponding 5-year overall survival values were 68%, 75%, 86%, and 64%, and did not differ by conditioning regimen (P = .19). Low event-free survival with Flu/Mel is attributed to high graft failure (42%) compared to Flu/Mel/TT (15%), Flu/Bu (7%), and Bu/Cy (18%) (P < .001).
CONCLUSIONS
Given the high rate of graft failure with Flu/Mel and the high rate of veno-occlusive disease with Bu/Cy and Flu/Bu, Flu/Mel/TT may be preferred for HLH disorders. Prospective studies are warranted.
Topics: Busulfan; Cyclophosphamide; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Lymphohistiocytosis, Hemophagocytic; Melphalan; Thiotepa; Transplantation Conditioning; Vidarabine
PubMed: 34375618
DOI: 10.1016/j.jaci.2021.07.031