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Transplantation and Cellular Therapy May 2024The present study compared lower-dose melphalan (80 mg/m, FM80) and higher-dose melphalan (140 mg/m, FM140) when administering reduced-intensity conditioning with... (Comparative Study)
Comparative Study
The present study compared lower-dose melphalan (80 mg/m, FM80) and higher-dose melphalan (140 mg/m, FM140) when administering reduced-intensity conditioning with fludarabine in adult patients with myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We retrospectively analyzed nationwide registry data (2006 to 2019) and compared transplant outcomes between the 2 groups. Ninety-two patients (median age, 61 [interquartile range, 56 to 65] years) were assigned to the FM80 and FM140 groups by propensity score matching. The 3-year overall survival (OS) rate in the FM140 group (63.9%; 95% confidence interval [CI], 52.9% to 73.0%) was significantly higher than that in the FM80 group (54.2%; 95% CI, 37.1% to 52.1%) (P = .038). The FM140 group had a nonsignificantly (P = .095) lower 3-year cumulative incidence of relapse (15.5%; 95% CI, 8.9% to 23.8% versus 26.0%; 95% CI, 17.3% to 35.5%). The 3-year cumulative incidences of nonrelapse mortality were 22.3% (95% CI, 14.1% to 31.8%) and 23.7% (95% CI, 15.4% to 33.2%) in the FM80 and FM140 groups, respectively (P = .49). The beneficial effect of FM140 was more evident in patients with a poor cytogenetic risk. Our findings suggest the superiority of FM140 in patients with MDS undergoing allo-HSCT, especially in high-risk patients.
Topics: Humans; Myelodysplastic Syndromes; Melphalan; Middle Aged; Transplantation Conditioning; Male; Female; Hematopoietic Stem Cell Transplantation; Aged; Transplantation, Homologous; Retrospective Studies; Vidarabine; Graft vs Host Disease; Adult
PubMed: 38331193
DOI: 10.1016/j.jtct.2024.01.083 -
Radiation Research Mar 2024The objective of this study is to investigate the impact of fludarabine, a signal transducer and activator of transcription-1 (STAT1) inhibitor, on the radiosensitivity...
The objective of this study is to investigate the impact of fludarabine, a signal transducer and activator of transcription-1 (STAT1) inhibitor, on the radiosensitivity of B-cell lymphoma (BCL) and to explore the underlying mechanisms. Radiotherapy is one of the primary treatments for BCL, and STAT1 plays a critical role in the transcription of cell proliferation-related genes, which are associated with radiotherapy and ferroptosis. This study aims to determine whether fludarabine can enhance the radiosensitivity of BCL and to elucidate the molecular pathways involved. Various in vitro methodologies, including CCK-8 assays, clonogenic formation assays, immunohistochemistry, immunofluorescence, flow cytometry, qRT-PCR, and Western blot analyses, were employed in B-cell lymphoma cell models to thoroughly investigate the effects of fludarabine on radiosensitivity. Subsequently, the obtained results were further validated through in vivo animal models and by examining human diffuse large B-cell lymphoma (DLBCL) cancer samples. Our findings demonstrate that the combination of fludarabine and irradiation synergistically inhibits cell viability and colony formation, while inducing apoptosis and ferroptosis in B-cell lymphoma cell lines Raji and Su-DHL-10. Moreover, fludarabine was found to enhance the ferroptosis induced by radiation, thereby synergistically impeding the growth of BCL. In vivo experiments confirmed these findings, revealing that the intraperitoneal injection of fludarabine significantly enhanced the inhibitory effects of radiation on Raji cell xenograft models, leading to an increased percentage of ferroptosis compared to models without fludarabine. Additionally, the administration of liproxstatin-1, a ferroptosis inhibitor, attenuated the inhibition of xenograft growth caused by the combination of fludarabine and irradiation. Furthermore, our analysis of clinical data revealed that increased co-expression of STAT1 and GPX4 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. These results highlight the potential of fludarabine to enhance radiosensitivity and ferroptosis induction as a promising therapeutic strategy for BCL. Our results demonstrated that fludarabine promoted radiation-induced BCL death through the ferroptosis pathway. We have identified a previously unrecognized mechanism in the fludarabine and radiation combination, indicating that it is necessary to conduct prospective clinical trials to verify this new treatment regimen in BCL.
Topics: Animals; Humans; Ferroptosis; Prospective Studies; Cell Line, Tumor; Radiation Tolerance; Apoptosis; Lymphoma, Large B-Cell, Diffuse; Vidarabine
PubMed: 38235545
DOI: 10.1667/RADE-23-00018.1 -
Blood Advances May 2024
Topics: Humans; Vidarabine; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Male; Antineoplastic Agents
PubMed: 38231085
DOI: 10.1182/bloodadvances.2023011433 -
Pediatric Blood & Cancer Apr 2024Hematopoietic stem cell transplantation can be curative for children with difficult-to-treat leukemia. The conditioning regimen utilized is known to influence outcomes....
Busulfan with 400 centigray of total body irradiation and higher dose fludarabine: An alternative regimen for hematopoietic stem cell transplantation in pediatric acute lymphoblastic leukemia.
BACKGROUND
Hematopoietic stem cell transplantation can be curative for children with difficult-to-treat leukemia. The conditioning regimen utilized is known to influence outcomes. We report outcomes of the conditioning regimen used at the Alberta Children's Hospital, consisting of busulfan (with pharmacokinetic target of 3750 μmol*min/L/day ±10%) for 4 days, higher dose (250 mg/m ) fludarabine and 400 centigray (cGy) of total body irradiation.
PROCEDURE
This retrospective study involved children receiving transplant for acute lymphoblastic leukemia (ALL). It compared children who fell within the target range for busulfan with those who were either not measured or were measured and fell outside this range. All other treatment factors were identical.
RESULTS
Twenty-nine children (17 within target) were evaluated. All subjects engrafted neutrophils with a median [interquartile range] time of 14 days [8-30 days]. The cumulative incidence of acute graft-versus-host disease was 44.8% [95% confidence interval, CI: 35.6%-54.0%], while chronic graft-versus-host disease was noted in 16.0% [95% CI: 8.7%-23.3%]. At 2 years, the overall survival was 78.1% [95% CI: 70.8%-86.4%] and event-free survival was 74.7% [95% CI: 66.4%-83.0%]. Cumulative incidence of relapse was 11.3% [95% CI: 5.1%-17.5%]. There were no statistically significant differences in between the group that received targeted busulfan compared with the untargeted group.
CONCLUSION
Our conditioning regiment for children with ALL resulted in outcomes comparable to standard treatment with acceptable toxicities and significant reduction in radiation dose. Targeting busulfan dose in this cohort did not result in improved outcomes.
Topics: Child; Humans; Busulfan; Whole-Body Irradiation; Retrospective Studies; Hematopoietic Stem Cell Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vidarabine; Graft vs Host Disease; Transplantation Conditioning; Leukemia, Myeloid, Acute
PubMed: 38217082
DOI: 10.1002/pbc.30844 -
Journal of Clinical Oncology : Official... Apr 2024To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. (Randomized Controlled Trial)
Randomized Controlled Trial
Fludarabine, Cytarabine, Granulocyte Colony-Stimulating Factor, and Idarubicin With Gemtuzumab Ozogamicin Improves Event-Free Survival in Younger Patients With Newly Diagnosed AML and Overall Survival in Patients With and Mutations.
PURPOSE
To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics.
PATIENTS AND METHODS
One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS).
RESULTS
There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% 91%) or in day 60 mortality (4.3% 4.6%). There was no difference in OS (66% 63%; = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% 41%; < .001) and 3-year event-free survival was higher (57% 45%; < .001). In patients with an mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% 64%; = .005). measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 ( = .02). Three-year OS was also higher in patients with a mutation (64% 54%; = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 278; = .02). There was no difference in outcome according to the number of GO doses, although MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO.
CONCLUSION
Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with and mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit.
Topics: Adult; Humans; Idarubicin; Gemtuzumab; Granulocyte Colony-Stimulating Factor; Leukemia, Myeloid, Acute; Progression-Free Survival; Cytarabine; Neoplasm Recurrence, Local; Vidarabine; Nuclear Proteins; Mutation; Core Binding Factors; Recurrence; Antineoplastic Combined Chemotherapy Protocols; fms-Like Tyrosine Kinase 3
PubMed: 38215358
DOI: 10.1200/JCO.23.00943 -
Blood Advances Feb 2024
Topics: Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Receptors, Antigen, T-Cell; Cell- and Tissue-Based Therapy; Vidarabine
PubMed: 38191740
DOI: 10.1182/bloodadvances.2023012068 -
Radiology Case Reports Mar 2024Coronavirus disease 2019 (COVID-19) causes a systemic inflammatory response and a temporary immunosuppression of hosts. Several reports have showed that reactivation of...
Coronavirus disease 2019 (COVID-19) causes a systemic inflammatory response and a temporary immunosuppression of hosts. Several reports have showed that reactivation of herpes simplex virus type 1 (HSV-1) is strongly associated with COVID-19. We present a case of a 66-year-old female, who developed HSV-1 encephalitis, showing impaired consciousness and typical MRI findings such as hyperintense lesions in the temporal lobe, insular cortices, bilateral medial frontal lobe on diffusion-weighted imaging, 7 days after the onset of COVID-19 symptoms. The number of cases of encephalitis in patients with COVID-19 is increasing. However, there has been limited reports of HSV-1 encephalitis following COVID-19, especially for cases with an interval of 7 days or less from the onset of COVID-19 symptoms to the onset of HSV-1 encephalitis. Our case highlights the importance of considering HSV-1 encephalitis in the differential when managing a patient with COVID-19-associated neurologic complications, even if it is in the early stages of COVID-19.
PubMed: 38188949
DOI: 10.1016/j.radcr.2023.11.044 -
American Journal of Hematology Feb 2024Fludarabine/busulfan and fludarabine/melphalan are viable options as conditioning regimens. However, the optimal fludarabine-based conditioning in cord blood...
Fludarabine/busulfan and fludarabine/melphalan are viable options as conditioning regimens. However, the optimal fludarabine-based conditioning in cord blood transplantation (CBT) remains unclear. Therefore, this retrospective, registry-based study aimed to analyze the impact of five fludarabine-containing conditioning regimens on 1395 adult patients (median age, 61 years) with acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia who underwent their first CBT. Treatment outcomes of fludarabine combined with melphalan (100-140 mg/m ) and low-dose total body irradiation (TBI; FM140T); melphalan (80-99 mg/m ) and TBI (FM80T); busulfan (12.8 mg/kg) and melphalan (FB4M); busulfan (12.8 mg/kg) and TBI (FB4T); and busulfan (6.4 mg/kg) and TBI (FB2T) were compared. The 3-year survival rate was 67%, 53%, 44%, 36%, and 39%, respectively (p < .0001). The FM140T survival rate was the most favorable after adjusting for confounders, and the hazard ratios (vs. FM140T) for overall mortality were as follows: FM80T, 1.6 (95% confidence interval [CI], 1.2-2.2); FB4M, 2.1 (95% CI, 1.6-2.8); FB4T, 2.7 (95% CI, 2.0-3.7); and FB2T, 2.2 (95% CI, 1.6-3.1). The better survival observed with FM140T, regardless of the disease, disease risk, age, or transplant year, was attributed to the lower relapse rate and lower non-relapse mortality (NRM) associated with fewer infectious deaths. Conversely, FB4T was associated with a higher relapse rate and higher NRM. The findings indicate that the outcomes of CBT in myeloid malignancies were highly dependent on both the alkylating agent and its dose in combination with fludarabine. Therefore, compared with fludarabine/busulfan-based conditioning, FM140T may be the preferred regimen.
Topics: Adult; Humans; Middle Aged; Busulfan; Melphalan; Retrospective Studies; Cord Blood Stem Cell Transplantation; Hematopoietic Stem Cell Transplantation; Vidarabine; Leukemia, Myeloid, Acute; Myeloproliferative Disorders; Recurrence; Graft vs Host Disease; Transplantation Conditioning
PubMed: 38165068
DOI: 10.1002/ajh.27172 -
Blood Advances Feb 2024We previously reported high rates of undetectable minimal residual disease <10-4 (uMRD4) with ibrutinib plus fludarabine, cyclophosphamide, and rituximab (iFCR) followed...
We previously reported high rates of undetectable minimal residual disease <10-4 (uMRD4) with ibrutinib plus fludarabine, cyclophosphamide, and rituximab (iFCR) followed by 2-year ibrutinib maintenance (I-M) in treatment-naïve chronic lymphocytic leukemia (CLL). Here, we report updated data from this phase 2 study with a median follow-up of 63 months. Of 85 patients enrolled, including 5 (6%) with deletion 17p or TP53 mutation, 91% completed iFCR and 2-year I-M. Five-year progression-free survival (PFS) and overall survival were 94% (95% confidence interval [CI], 89%-100%) and 99% (95% CI, 96%-100%), respectively. No additional deaths have occurred with this extended follow-up. No difference in PFS was observed by immunoglobulin heavy-chain variable region gene status or duration of I-M. High rates of peripheral blood (PB) uMRD4 were maintained (72% at the end of iFCR, 66% at the end of 2-year I-M, and 44% at 4.5 years from treatment initiation). Thirteen patients developed MRD conversion without clinical progression, mostly (77%) after stopping ibrutinib. None had Bruton tyrosine kinase (BTK) mutations. One patient had PLCG2 mutation. Six of these patients underwent ibrutinib retreatment per protocol. Median time on ibrutinib retreatment was 34 months. The cumulative incidence of atrial fibrillation was 8%. Second malignancy or nonmalignant hematologic disease occurred in 13%, mostly nonmelanoma skin cancer. Overall, iFCR with 2-year I-M achieved durably deep responses in patients with diverse CLL genetic markers. Re-emergent clones lacked BTK mutation and retained sensitivity to ibrutinib upon retreatment. This trial is registered at www.clinicaltrials.gov as #NCT02251548.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Follow-Up Studies; Treatment Outcome; Cyclophosphamide; Adenine; Piperidines; Vidarabine
PubMed: 38163317
DOI: 10.1182/bloodadvances.2023011574 -
Experimental and Clinical... Nov 2023Allogeneic hematopoietic stem cell transplant is the only curative treatment for patients with transfusion-dependent thalassemia major. In recent years, a number of...
Busulfan-Based and Treosulfan-Based Myeloablative Conditioning for Allogeneic Transplantation in Children with Thalassemia Major: a Single-Center Experience From Southern Turkey.
OBJECTIVES
Allogeneic hematopoietic stem cell transplant is the only curative treatment for patients with transfusion-dependent thalassemia major. In recent years, a number of novel approaches have improved patient outcomes and quality of life by minimizing the toxicity of conditioning regimens. The objective of this study was to compare the role of treosulfan- and busulfan-based conditioning in transfusion-dependent thalassemia.
MATERIALS AND METHODS
Data were collected retrospectively on 121 children with beta thalassemia major who underwent hematopoietic stem cell transplant using treosulfan-based (n = 37) or busulfan-based (n = 84) conditioning regimens between 2012 and 2022.
RESULTS
Two-year overall survival was 87.5% in the busulfan-based conditioning group and 91.1% in the treosulfan-based conditioning group.The group given the busulfan regimen compared with treosulfan regimen had significantly increased number of side effects (58.3% vs 21.6%, respectively; P < .001). When the busulfan-based regimen by level was evaluated, we observed no significant differences between the frequency of side effects according to drug serum levels. In addition, no significant differences were shown between the 2 regimen groups for cumulative incidence of acute and chronic graft-versus-host disease.
CONCLUSIONS
The safety and effectiveness of a treosulfan-based myeloablative conditioning regimen has been confirmed by ourretrospective investigation of pediatric patients with beta thalassemia.
Topics: Humans; Child; Busulfan; beta-Thalassemia; Retrospective Studies; Quality of Life; Turkey; Transplantation, Homologous; Hematopoietic Stem Cell Transplantation; Transplantation Conditioning; Graft vs Host Disease; Vidarabine
PubMed: 38140932
DOI: 10.6002/ect.2023.0143