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Blood Advances Dec 2021Adding the selective BCL-2 inhibitor venetoclax to reduced-intensity conditioning chemotherapy (fludarabine and busulfan [FluBu2]) may enhance antileukemic cytotoxicity... (Clinical Trial)
Clinical Trial
Adding the selective BCL-2 inhibitor venetoclax to reduced-intensity conditioning chemotherapy (fludarabine and busulfan [FluBu2]) may enhance antileukemic cytotoxicity and thereby reduce the risk of posttransplant relapse. This phase 1 study investigated the recommended phase 2 dose (RP2D) of venetoclax, a BCL-2 selective inhibitor, when added to FluBu2 in adult patients with high-risk acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and MDS/myeloproliferative neoplasms (MPN) undergoing transplant. Patients received dose-escalated venetoclax (200-400 mg daily starting day -8 for 6-7 doses) in combination with fludarabine 30 mg/m2 per day for 4 doses and busulfan 0.8 mg/kg twice daily for 8 doses on day -5 to day -2 (FluBu2). Transplant related-toxicity was evaluated from the first venetoclax dose on day -8 to day 28. Twenty-two patients were treated. At study entry, 5 patients with MDS and MDS/MPN had 5% to 10% marrow blasts, and 18 (82%) of 22 had a persistent detectable mutation. Grade 3 adverse events included mucositis, diarrhea, and liver transaminitis (n = 3 each). Neutrophil/platelet recovery and acute/chronic graft-versus-host-disease rates were similar to those of standard FluBu2. No dose-limiting toxicities were observed. The RP2D of venetoclax was 400 mg daily for 7 doses. With a median follow-up of 14.7 months (range, 8.6-24.8 months), median overall survival was not reached, and progression-free survival was 12.2 months (95% confidence interval, 6.0-not estimable). In patients with high-risk AML, MDS, and MDS/MPN, adding venetoclax to FluBu2 was feasible and safe. To further address relapse risk, assessment of maintenance therapy after venetoclax plus FluBu2 transplant is ongoing. This study was registered at clinicaltrials.gov as #NCT03613532.
Topics: Adult; Bridged Bicyclo Compounds, Heterocyclic; Busulfan; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Sulfonamides; Transplantation, Homologous; Vidarabine
PubMed: 34614506
DOI: 10.1182/bloodadvances.2021005566 -
Transplantation and Cellular Therapy Aug 2021Fludarabine 30 mg/m/d × 5 and melphalan 140 mg/m × 1 (Flu-Mel140) is a commonly used reduced-intensity conditioning regimen. We hypothesized that addition of...
Outcomes of Fludarabine, Melphalan and Total Body Irradiation as a Reduced Intensity Conditioning Regimen in Matched Donor Allogeneic Peripheral Blood Stem Cell Transplantation.
Fludarabine 30 mg/m/d × 5 and melphalan 140 mg/m × 1 (Flu-Mel140) is a commonly used reduced-intensity conditioning regimen. We hypothesized that addition of 200cGy total body irradiation (TBI) to Flu-Mel140 may improve antitumor activity and transplant outcomes. Primary objectives was overall survival (OS) at 3 years. Secondary objectives were to assess the cumulative incidences of acute and chronic GVHD, relapse-free survival (RFS), relapse rate, and nonrelapse mortality (NRM). We retrospectively evaluated outcomes of patients receiving Flu-Mel140-TBI followed by HLA-matched donor allogeneic hematopoietic stem cell transplantation (alloSCT) using peripheral blood stem cells. Eighty-one patients (median age, 58 years) underwent alloSCT between January 2008 and December 2018. Thirty-one percent of patients had a prior transplant, 32% had high or very-high disease risk index, and the donor was unrelated in 70% of patients. Grade 3 to 4 regimen-related toxicities were mucositis (37%), cardiac toxicity (17%), and renal toxicity (10%). The cumulative incidence of grade III to IV acute GVHD at day +100 was 24.7% and chronic GVHD at 1 year was 51.3%. Median follow-up for survival was 6.1 years. At 3 years, OS was 39.81%, RFS was 31.47%, and relapse rate was 30.5%. One-year NRM was 29.9%. Patients undergoing first transplantation experienced improved OS compared with second or beyond (63.08% versus 42.31%, P = .02). After adjusting for disease subtypes, age (≤55 versus 55), comorbidity index (CI), number of transplant and GVHD prophylaxis, multivariable analysis did not demonstrate any survival difference among disease subtypes. High CI (≥3) was predictive of adverse OS and NRM, whereas older age (>55 years) was associated with high NRM. Our study shows that Flu-Mel140-TBI seems feasible and provides durable disease control. Addition of TBI did not appear to improve outcomes compared to previously published reports of Flu-Mel140. Considerable NRM could result from the inclusion of patients with older age and prior transplants.
Topics: Aged; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Peripheral Blood Stem Cell Transplantation; Retrospective Studies; Vidarabine; Whole-Body Irradiation
PubMed: 33991722
DOI: 10.1016/j.jtct.2021.04.029 -
Molecular Medicine Reports Oct 2020The present study aimed to investigate the role of janus kinase (JAK)1/STAT1 in interferon (IFN)‑γ‑induced apoptosis in human melanocytes. Following IFN‑γ...
The present study aimed to investigate the role of janus kinase (JAK)1/STAT1 in interferon (IFN)‑γ‑induced apoptosis in human melanocytes. Following IFN‑γ treatment, the viability of human melanocytes were analyzed using a Cell Counting Kit‑8 assay and the apoptotic rate was determined using flow cytometry. Western blotting was also performed to analyze the phosphorylation levels of JAK1, JAK2 and the transcriptional factor STAT1, as well as the expression levels of Bcl‑2, Bax, Bcl‑2 homologous antagonist killer (Bak) and cleaved caspase‑3. Finally, following the pretreatment with the STAT1 inhibitor fludarabine, human melanocytes were treated with IFN‑γ and flow cytometry was used to detect the apoptotic rate. The results revealed that IFN‑γ reduced the proliferation and induced the apoptosis of human melanocytes. In addition, IFN‑γ treatment led to decreased expression levels of Bcl‑2 and increased expression levels of Bax, Bak and cleaved caspase‑3, alongside the activation of the JAK1/STAT1 signaling pathway. Conversely, the pretreatment with the STAT1 inhibitor fludarabine decreased the apoptotic rate of human melanocytes following IFN‑γ induction. In conclusion, the findings of the present study suggested that IFN‑γ may induce the apoptosis of human melanocytes by activating the JAK1/STAT1 signaling pathway, alongside increasing the expression levels of Bax, Bak and cleaved caspase‑3, and decreasing the expression levels of Bcl‑2.
Topics: Cell Line; Cell Survival; Gene Expression Regulation; Humans; Interferon-gamma; Janus Kinase 1; MAP Kinase Signaling System; Melanocytes; Phosphorylation; STAT1 Transcription Factor; Vidarabine
PubMed: 32945463
DOI: 10.3892/mmr.2020.11403 -
Biology of Blood and Marrow... Apr 2017Alemtuzumab is frequently used as part of reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic cell transplantation (HCT) in pediatric patients...
Alemtuzumab is frequently used as part of reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic cell transplantation (HCT) in pediatric patients with nonmalignant diseases. We previously suggested an optimal day 0 targeted range of alemtuzumab, but there are no pediatric data regarding the pharmacokinetics (PK) of subcutaneous alemtuzumab to guide precision dosing trials. The goal of this study was to prospectively characterize alemtuzumab PK and to explore absolute lymphocyte count (ALC) as a predictor of interindividual variability. We prospectively enrolled 23 patients who received an alemtuzumab, fludarabine, and melphalan RIC regimen. Seventeen patients completed study and received 1 mg/kg alemtuzumab divided over 5 days subcutaneously, starting on day -14. The median age was 7 years (range, .5 to 18). Blood sampling for PK measurements and descriptive PK analyses were performed. The median maximum alemtuzumab concentration was 2.39 µg/mL (interquartile range, 1.98 to 2.92). The median terminal half-life was 5.2 days (interquartile range, 2.7 to 7.8). The median concentration at day 0 was 1.27 µg/mL (interquartile range, .35 to 1.51). Importantly, day 0 alemtuzumab levels and area under the curve negatively correlated with predose ALC and ALC area-time, respectively. In conclusion, we reported the PK of subcutaneous alemtuzumab given to pediatric allogeneic HCT patients and observed that almost all patients have persistence of lytic levels of alemtuzumab beyond day 0, at levels in excess of that needed to reduce the risk of acute graft-versus-host disease. Additionally, levels correlate with pretransplant ALC. These results will allow the development of population PK models for precision dosing trials.
Topics: Adolescent; Alemtuzumab; Antineoplastic Agents, Immunological; Child; Child, Preschool; Graft vs Host Disease; Half-Life; Hematopoietic Stem Cell Transplantation; Humans; Infant; Lymphocyte Count; Melphalan; Prospective Studies; Transplantation Conditioning; Vidarabine
PubMed: 28089878
DOI: 10.1016/j.bbmt.2017.01.071 -
Leukemia Research May 2018We evaluated outcomes of 100 patients with high risk AML treated with Ida-FLAG induction as first-line therapy. 72 achieved remission with one cycle; 19 did not. High...
We evaluated outcomes of 100 patients with high risk AML treated with Ida-FLAG induction as first-line therapy. 72 achieved remission with one cycle; 19 did not. High risk cytogenetics and TP53 mutations were associated with failure to achieve remission. In those reaching remission, allogeneic bone marrow transplantation was associated with better relapse-free and overall survival. Those not achieving remission with induction therapy were extremely unlikely to reach remission with further therapy and had a dismal prognosis. Exploratory molecular analysis confirmed persistence of the dominant genetic mutations identified at diagnosis. Ex vivo chemosensitivity did not demonstrate significant differences between responders and non-responders. Thus, Ida-FLAG induction has a high chance of inducing remission in patients with high risk AML. Those achieving remission require allogeneic transplantation to achieve cure; those not achieving remission rarely respond to salvage chemotherapy and have a dismal outcome. Alternatives to conventional chemotherapy must be considered in this group.
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; Genes, p53; Granulocyte Colony-Stimulating Factor; Humans; Idarubicin; Induction Chemotherapy; Leukemia, Myeloid, Acute; Male; Middle Aged; Mutation; Prognosis; Remission Induction; Retrospective Studies; Treatment Outcome; Vidarabine; Young Adult
PubMed: 29518628
DOI: 10.1016/j.leukres.2018.02.012 -
Pediatric Transplantation Feb 2020TBC regimens are considered as "reduced toxicity" and are increasingly employed in pediatric HSCT. In our center, we commonly use the combination of... (Observational Study)
Observational Study
TBC regimens are considered as "reduced toxicity" and are increasingly employed in pediatric HSCT. In our center, we commonly use the combination of treosulfan-thiotepa-fludarabine and ATG for pediatric non-malignant diseases. As we often observe acute skin toxicities following this conditioning regimen, we conducted a prospective observational study to describe and characterize these toxicities. Fifteen pediatric patients undergoing HSCT for non-malignant diseases who were treated at Hadassah-Hebrew University Medical Center during 2015 were enrolled. A thorough dermatological assessment was done on days 0, 1, 7, and 14 from treatment initiation and included description of cutaneous reactions, measurement of BSA of affected skin, and response to local treatment. All the fifteen enrolled patients developed some degree of acute skin reaction. Cutaneous manifestations were variable and included erythematous patches in inguinal area and genitalia (80%), in neck and axillae (40%), diffuse hyperpigmentation (73%), erosions in inguinal area and buttock (47%), and xerosis and desquamation (40%). Average affected BSA reached 71.8%. Erosions were more prevalent in children younger than 2 years of age. The eruptions resolved without sequela in all patients and did not necessitate treatment other than topical agents. Observed extracutaneous toxicities included oral mucositis (40%), diarrhea (47%), and elevated liver enzymes (47%). TBC combined with thiotepa is highly toxic to the skin with various cutaneous manifestations. The toxicity resolves with no long-term sequela.
Topics: Busulfan; Child; Child, Preschool; Drug Eruptions; Drug Therapy, Combination; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infant; Male; Prognosis; Prospective Studies; Thiotepa; Transplantation Conditioning; Vidarabine
PubMed: 31840362
DOI: 10.1111/petr.13626 -
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.... Dec 2017Objective To evaluate the efficacy of rituximab in treating chronic lymphocytic leukemia (CLL). Methods The clinical data of CLL patients receiving...
Objective To evaluate the efficacy of rituximab in treating chronic lymphocytic leukemia (CLL). Methods The clinical data of CLL patients receiving fludarabine,cyclophosphamide±rituximab (with or without rituximab) regimen or cyclophosphamide,vincristine,and prednisone±doxorubicin±rituximab regimen in our hospital from March 2000 to February 2015 were analyzed retrospectively. Therapeutic efficacies and survivals of patients treated with different regimens were evaluated and compared. Results The complete response (CR) rate and the overall response rate (ORR) in 72 patients (43.6%) treated with rituximab were significantly higher than those treated without rituximab (38.9% vs. 21.5%,P=0.015;83.3% vs. 60.2%,P=0.001). The median PFS and OS for patients treated with rituximab were 53.0 (27.0-79.0) months and 112.0 (81.1-142.9) months,and the median PFS and OS for patients treated without rituximab were 28.0 (18.3-37.7) months and 89.0(72.0-106.0),but the results were not statistically significant (P=0.094,P=0.109). According to the cytogenetic features,patients were further divided into high-risk subgroup (with chromosome 17p deletion or 11q deletion) and non-high-risk subgroup. And in the high-risk subgroup,the ORR of patients treated with rituximab was 86.4%,which was significantly higher than that in patients treated without rituximab (53.3%)(P=0.012);in the non-high-risk subgroup,the PFS was marginally prolonged in patients treated with rituximab,but the difference was not statistically significant(P=0.050). Conclusions Compared with traditional chemotherapy,the chemoimmunotherapies with rituximab result in higher CR rate and ORR in CLL patients. In patients without 17p deletion or 11q deletion,the use of rituximab can marginally prolong PFS.
Topics: Antineoplastic Combined Chemotherapy Protocols; Chromosome Aberrations; Cyclophosphamide; Doxorubicin; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Retrospective Studies; Rituximab; Treatment Outcome; Vidarabine; Vincristine
PubMed: 29338825
DOI: 10.3881/j.issn.1000-503X.2017.06.011 -
Blood Advances Jul 2019Fludarabine is the most frequently used agent in conditioning regimens for allogeneic hematopoietic cell transplantation (HCT). Body surface area-based dosing leads to...
Fludarabine is the most frequently used agent in conditioning regimens for allogeneic hematopoietic cell transplantation (HCT). Body surface area-based dosing leads to highly variable fludarabine exposure. We studied the relation between fludarabine exposure and clinical outcomes. A retrospective, pharmacokinetic-pharmacodynamic analysis was conducted with data from patients undergoing HCT with fludarabine (160 mg/m) as part of a myeloablative conditioning (busulfan targeted to an area under the plasma-concentration-time curve [AUC] of 90 mg*h/L) and rabbit antithymocyte globulin (6-10 mg/kg; from day -9/-12) between 2010 and 2016. Fludarabine exposure as AUC was calculated for each patient using a previously published population pharmacokinetic model and related to 2-year event-free survival (EFS) by means of (parametric) time-to-event models. Relapse, nonrelapse mortality (NRM), and graft failure were considered events. One hundred ninety-two patients were included (68 benign and 124 malignant disorders). The optimal fludarabine exposure was determined as an AUC of 20 mg*h/L. In the overexposed group, EFS was lower (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.1-3.5; = .02), due to higher NRM (HR, 3.4; 95% CI, 1.6-6.9; 001) associated with impaired immune reconstitution (HR, 0.43; 95% CI, 0.26-0.70; 001). The risks of NRM and graft failure were increased in the underexposed group (HR, 3.3; 95% CI, 1.2-9.4; = .02; HR, 4.8; 95% CI, 1.2-19; = .02, respectively). No relationship with relapse was found. Fludarabine exposure is a strong predictor of survival after HCT, stressing the importance of optimum fludarabine dosing. Individualized dosing, based on weight and "renal function" or "therapeutic drug monitoring," to achieve optimal fludarabine exposure might improve survival.
Topics: Adolescent; Adult; Cause of Death; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Mortality; Myeloablative Agonists; Prognosis; Retrospective Studies; Risk Factors; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Young Adult
PubMed: 31324638
DOI: 10.1182/bloodadvances.2018029421 -
Bone Marrow Transplantation Jul 2021Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative option in MF. There is no consensus on the optimal conditioning regimen. We report...
Thiotepa-busulfan-fludarabine (TBF) conditioning regimen in patients undergoing allogeneic hematopoietic cell transplantation for myelofibrosis: an outcome analysis from the Chronic Malignancies Working Party of the EBMT.
Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative option in MF. There is no consensus on the optimal conditioning regimen. We report outcomes of 187 patients with MF transplanted between 2010 and 2017 conditioned with TBF. Median age was 58 years. Median interval from diagnosis to allo-HCT was 44 months. Donors were haploidentical (41%), unrelated (36%) or HLA-identical siblings (23%). Stem cell source was PB in 60%. Conditioning was myeloablative in 48% of cases. Antithymocyte globulin (ATG) was used in 41% of patients. At 100 days, neutrophil and platelet engraftment were 91% and 63% after a median of 21 and 34 days, respectively. Grade II-IV and III-IV acute GVHD occurred in 24% and 12%, while at 3 years, all grade chronic GVHD and chronic extensive GVHD had been diagnosed in 38% and 11%. At 3 years, OS, RFS and GRFS were 55%, 49% and 43%, respectively. RI and NRM were 17% and 33%. On multivariate analysis, poor KPS and the use of unrelated donors were associated with worse GRFS and a higher grade II-IV acute GVHD, respectively. Neither donor type nor intensity of the conditioning regimen influenced survival outcomes. TBF is a feasible conditioning regimen in allo-HCT for MF in all donor settings although longer term outcomes are required.
Topics: Busulfan; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Middle Aged; Neoplasms; Primary Myelofibrosis; Retrospective Studies; Thiotepa; Transplantation Conditioning; Vidarabine
PubMed: 33526919
DOI: 10.1038/s41409-021-01222-z -
Blood Jul 2017Primary chronic cold agglutinin disease (CAD) is a well-defined clinicopathologic entity in which a bone marrow clonal B-cell lymphoproliferation results in autoimmune... (Clinical Trial)
Clinical Trial
Primary chronic cold agglutinin disease (CAD) is a well-defined clinicopathologic entity in which a bone marrow clonal B-cell lymphoproliferation results in autoimmune hemolytic anemia and cold-induced circulatory symptoms. Rituximab monotherapy and fludarabine-rituximab in combination are documented treatment options. In a prospective, nonrandomized multicenter trial, 45 eligible patients received rituximab 375 mg/m day 1 and bendamustine 90 mg/m days 1 and 2 for 4 cycles at a 28-day interval. Thirty-two patients (71%) responded; 18 (40%) achieved complete response (CR) and 14 (31%) partial response (PR). Among 14 patients previously treated with rituximab or fludarabine-rituximab, 7 (50%) responded to bendamustine-rituximab (3 CR and 4 PR). Hemoglobin levels increased by a median of 4.4 g/dL in the complete responders, 3.9 g/dL in those achieving PR, and 3.7 g/dL in the whole cohort. The 10th percentile of response duration was not reached after 32 months. Grade 3-4 neutropenia occurred in 15 patients (33%), but only 5 (11%) experienced infection with or without neutropenia. Thirteen patients (29%) had their dose of bendamustine reduced. In conclusion, bendamustine-rituximab combination therapy is highly efficient, sufficiently safe, and may be considered in first line for patients with CAD requiring therapy. The trial was registered at www.clinicaltrials.gov as #NCT02689986.
Topics: Aged; Aged, 80 and over; Anemia, Hemolytic, Autoimmune; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Chronic Disease; Europe; Female; Hemoglobins; Humans; Male; Middle Aged; Prospective Studies; Rituximab; Vidarabine
PubMed: 28533306
DOI: 10.1182/blood-2017-04-778175