Regimen For Stem Cell Transplantation Research Articles

Fludarabine, busulfan, and melphalan conditioning regimen in allogeneic hematopoietic stem cell transplantation for adult patients with myeloid malignancies: A multicenter retrospective study

AbstractRelapse remains the main cause of treatment failure in patients with myeloid malignancies even after allogeneic hematopoietic stem cell transplantation (allo‐HSCT). We observed a particularly low incidence of relapse in patients prepared with fludarabine, busulfan and melphalan in our previous study and this multicenter retrospective analysis aimed to confirm the feasibility of the regimen and to identify the potential prognostic factors. This study was performed using registry data from adults patients with myeloid malignancies who underwent their first allo‐HSCT following fludarabine(≥100 mg/m2), busulfan (≥3.2 mg/kg) and melphalan (≥100 mg/m2) based conditioning at nine transplantation centers in China between Jan. 2020 and Mar. 2022. A total of 221 consecutive patients (AML n = 171, MDS‐IB‐1 or 2 n = 44, CMML n = 6) with median age of 46 were enrolled in this study. The median follow‐up was 507 days for survivors. The 2‐year NRM, CIR, OS and DFS were 10.6% ± 2.2%, 14.8% ± 3.3%, 79.4% ± 3.7% and 74.6% ± 3.7%, respectively. In multivariate analyses, high HCT‐CI (≥3) was the only independent factor for higher NRM [hazard ratio (HR), 2.96; 95% confidence interval (CI), 1.11 to 7.90; p = 0.030] and ECOG score ≥2 was the only independent factor for inferior OS (HR, 2.43; 95%CI, 1.15 to 5.16; p = 0.020) and DFS (HR, 2.12; 95%CI, 1.13 to 4.02; p = 0.020). AML diagnosis and positive measurable residual disease (MRD) at transplantation were predictors for higher CIR (HR = 7.92, 95%CI 1.05‐60.03, p = 0.045; HR = 3.64, 95%CI 1.40‐9.44, p = 0.008; respectively), while post‐transplantation cyclophosphamide based graft‐versus‐host disease prophylaxis was associated with lower CIR (HR = 0.24 95%CI 0.11‐0.54, p = 0.001). The intensity of conditioning regimen did not impact CIR, NRM, DFS and OS. These results supported that double alkylating agents of busulfan and melphalan based conditioning regimens were associated with low relapse rate and acceptable NRM in adult patients with myeloid malignancies. The optimal dose remained to be confirmed by further prospective studies.

Fludarabine-induced bradycardia in allogeneic hematopoietic stem cell transplantation: A retrospective study.

Fludarabine, a purine analog, is getting more attention with the increasing use of reduced intensive conditioning regimens in allogeneic hematopoietic stem cell transplantation (allo-HSCT). The side effect of bradycardia was observed in only a few cases reported in the literature. In clinical practice, bradycardia can be asymptomatic or cause syncope and cardiac arrest. This study aimed to evaluate the bradycardia side effect of fludarabine used in the conditioning regimen in allo-HSCT recipients and to increase awareness of this issue. This retrospective study included 73 patients who received fludarabine in the allo-HSCT conditioning regimen between January 2015 and January 2021. Patients with and without bradycardia were compared regarding demographic data, allo-HSCT characteristics, electrolyte values, fludarabine administration dose and duration, and survival. Univariate and multivariate analyzes were performed to evaluate independent predictors for fludarabine-induced bradycardia. Fludarabine administration doses and days were higher in the bradycardia group, but no statistically significant difference was observed. In the multivariate analysis, age was the only independent predictor of fludarabine-induced bradycardia (odds ratio (OR) 0.93, 95% confidence interval (CI): 0.89-0.98, p = 0.007). The median age in the group with bradycardia was 19 years younger than those without bradycardia (34 (19-49) vs 53 (19-69), p = 0.005). In 11 (84.6%) of the patients who had bradycardia, bradycardia improved with the discontinuation of fludarabine alone, but atropine was administered in 2 (15.4%) patients. Age was the only independent predictor of fludarabine-induced bradycardia; therefore, close heart rate monitoring is recommended during fludarabine administration, especially in younger patients.

BeEAM vs. BEAM: evaluating conditioning regimens for autologous stem cell transplantation in patients with relapsed or refractory DLBCL.

To evaluate whether BeEAM is an alternative to BEAM for autologous stem cell transplantation (ASCT) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Data of 60 patients with relapsed or refractory DLBCL who underwent ASCT from January 2018 to June 2023 in our center, including 30 patients in the BeEAM group and 30 patients in the BEAM group, were retrospectively analyzed. The time to hematopoietic reconstitution, treatment-related adverse events, number of hospitalization days, hospitalization cost, and survival benefit were compared between the two groups. The clinical characteristics of the patients did not significantly differ between the two groups. The median number of reinfused CD34 + cells was 5.06 × 106/kg and 5.17 × 106/kg in the BeEAM and BEAM groups, respectively, which did not significantly different (p = 0.8829). In the BeEAM and BEAM groups, the median time to neutrophil implantation was 10.2 and 10.27 days, respectively (p = 0.8253), and the median time to platelet implantation was 13.23 and 12.87 days, respectively (p = 0.7671). In the BeEAM and BEAM groups, the median hospitalization duration was 30.37 and 30.57 days, respectively (p = 0.9060), and the median hospitalization cost was RMB 83,425 and RMB 96,235, respectively (p = 0.0560). The hospitalization cost was lower in the BeEAM group. The most common hematologic adverse events were grade ≥ 3 neutropenia and thrombocytopenia, whose incidences were similar in the two groups. The most common non-hematologic adverse events were ≤ grade 2 and the incidences of these events did not significantly differ between the two groups. Median overall survival was not reached in either group, with predicted 5-year overall survival of 72.5% and 60% in the BeEAM and BEAM groups, respectively (p = 0.5872). Five-year progression-free survival was 25% and 20% in the BeEAM and BEAM groups, respectively (p = 0.6804). As a conditioning regimen for relapsed or refractory DLBCL, BeEAM has a desirable safety profile and is well tolerated, and its hematopoietic reconstitution time, number of hospitalization days, and survival benefit are not inferior to those of BEAM. BeEAM has a lower hospitalization cost and is an alternative to BEAM.

Total body irradiation versus thiotepa/busulfan-based conditioning regimens for myeloablative allogeneic stem cell transplantation in adults with acute lymphoblastic leukemia.

Total body irradiation (TBI)-based conditioning regimens are generally recommended for allogeneic HSCT (allo-HSCT) in patients with acute lymphoblastic leukemia (ALL). Recent evidence suggests that modern chemotherapy-based regimens may be as effective. This multicenter retrospective study compared the clinical outcomes of myeloablative allo-HSCT with thiotepa, busulfan, and cyclophosphamide/fludarabine (TTB) to TBI-based conditioning. Between 2002 to 2018, 63 and 114 patients received TTB- and TBI-based conditioning regimens, respectively. The 5-year cumulative incidence of relapse was lower in the TBI cohort compared to the TTB cohort (30% [95% CI, 22-38] versus 47% [95% CI, 36-59]; P = 0.03). Multivariate analysis identified T-ALL, Ph-negative B-ALL, and measurable residual disease associated with a higher relapse risk. The 5-year cumulative incidence of non-relapsed mortality (NRM) was significantly lower with TTB (12% [95% CI, 5-20]) compared to TBI (25% [95% CI, 18-33]) (P = 0.001). Multivariate analysis found TBI conditioning, older age, and advanced stages of ALL at transplantation associated with a higher NRM. No statistical difference was seen in overall survival (49% [95% CI, 40-58] and 46% [95% CI, 35-60]) in the TBI and TTB groups, respectively; P = 0.9). The study suggests that TTB-based conditioning may be a promising option for ALL patients undergoing allo-HSCT, as it resulted in similar OS and lower NRM than TBI-based conditioning.

Deep learning-based optimization of field geometry for total marrow irradiation delivered with volumetric modulated arc therapy.

Total marrow (lymphoid) irradiation (TMI/TMLI) is a radiotherapy treatment used to selectively target the bone marrow and lymph nodes in conditioning regimens for allogeneic hematopoietic stem cell transplantation. A complex field geometry is needed to cover the large planning target volume (PTV) of TMI/TMLI with volumetric modulated arc therapy (VMAT). Five isocenters and ten overlapping fields are needed for the upper body, while, for patients with large anatomical conformation, two specific isocenters are placed on the arms. The creation of a field geometry is clinically challenging and is performed by a medical physicist (MP) specialized in TMI/TMLI. To develop convolutional neural networks (CNNs) for automatically generating the field geometry of TMI/TMLI. The dataset comprised 117 patients treated with TMI/TMLI between 2011 and 2023 at our Institute. The CNN input image consisted of three channels, obtained by projecting along the sagittal plane: (1) average CT pixel intensity within the PTV; (2) PTV mask; (3) brain, lungs, liver, bowel, and bladder masks. This "averaged" frontal view combined the information analyzed by the MP when setting the field geometry in the treatment planning system (TPS). Two CNNs were trained to predict the isocenters coordinates and jaws apertures for patients with (CNN-1) and without (CNN-2) isocenters on the arms. Local optimization methods were used to refine the models output based on the anatomy of the patient. Model evaluation was performed on a test set of 15 patients in two ways: (1) by computing the root mean squared error (RMSE) between the CNN output and ground truth; (2) with a qualitative assessment of manual and generated field geometries-scale: 1=not adequate, 4=adequate-carried out in blind mode by three MPs with different expertise in TMI/TMLI. The Wilcoxon signed-rank test was used to evaluate the independence of the given scores between manual and generated configurations (p<0.05 significant). The average and standard deviation values of RMSE for CNN-1 and CNN-2 before/after local optimization were 15±2/13±3mm and 16±2/18±4mm, respectively. The CNNs were integrated into a planning automation software for TMI/TMLI such that the MPs could analyze in detail the proposed field geometries directly in the TPS. The selection of the CNN model to create the field geometry was based on the PTV width to approximate the decision process of an experienced MP and provide a single option of field configuration. We found no significant differences between the manual and generated field geometries for any MP, with median values of 4versus 4 (p=0.92), 3versus 3 (p=0.78), 4versus 3 (p=0.48), respectively. Starting from October 2023, the generated field geometry has been introduced in our clinical practice for prospective patients. The generated field geometries were clinically acceptable and adequate, even for an MP with high level of expertise in TMI/TMLI. Incorporating the knowledge of the MPs into the development cycle was crucial for optimizing the models, especially in this scenario with limited data.

Impact of prophylactic echinocandin on the development of neurological complications in patients receiving busulfan-containing conditioning regimens for stem cell transplantation: A single-center retrospective study.

Although neurotoxicity is a major adverse event associated with busulfan, little information is available regarding the association between drug interactions and neurological symptoms during busulfan-based regimens. This study evaluated the association between prophylactic echinocandins and neurological complications in patients receiving busulfan-containing conditioning regimens for stem cell transplantation. We retrospectively included consecutive patients who administered intravenous busulfan as a conditioning regimen at our facility between 2007 and 2022. Prophylactic echinocandin use was defined as the use of an echinocandin antifungal drug to prevent invasive fungal disease in SCT recipients. The primary outcome was the incidence of neurological complications within 7 days of busulfan initiation and was compared between the echinocandin group (patients received prophylactic echinocandin) and nonechinocandin group (patients received prophylactic antifungal drugs other than echinocandin and those without antifungal prophylaxis). Among the 59 patients included in this study, the incidence of neurological complications in the echinocandin (n = 26) and nonechinocandin groups (n = 33) was 30.8% and 63.6%, respectively. We observed a negative association between prophylactic echinocandin use and the development of neurological complications after adjusting for the propensity score for receiving prophylactic echinocandins (adjusted odds ratio 0.294, 95% confidence interval 0.090 to 0.959). We observed a lower incidence of neurological complications in the echinocandin group than in the nonechinocandin group. Our results suggested that the choice of antifungal prophylaxis is associated with busulfan neurotoxicity.

High dose total marrow irradiation (TMI) does not increase long-term toxicity of myeloablative fludarabine/busulfan (FluBu4) conditioning regimen in allogeneic hematopoietic stem cell transplantation (HSCT).

Based on a previous phase 1 study, total marrow irradiation (TMI) at 9Gy was added to a myeloablative FluBu4 conditioning regimen in allogeneic hematopoietic stem cell transplantation (HSCT) for myeloid malignancies. Here, we report on the long-term toxicity of TMI combined with FluBu4 and compare it to patients who received only FluBu4. We retrospectively analyzed 38 consecutive patients conditioned with FluBu4/TMI (n = 15) or FluBu4 (n = 23, control group) who had at least 1 year follow-up post-transplant. The rate of long-term adverse events that have been previously associated with total body irradiation (TBI) was analyzed in the two groups. The baseline characteristics did not differ between the two groups. The control group had a longer median follow-up (71.2 mo) than the TMI group (38.5 mo) (p = .004). The most common adverse events were xerostomia, dental complications, cataracts, or osteopenia and did not differ between the two groups. Cognitive dysfunction or noninfectious pneumonitis, often detected after high dose TBI, were also not different in the two groups (p = .12 and p = .7, respectively). There was no grade 4 adverse event. Our results suggest that a conditioning regimen with TMI 9Gy and FluBu4 does not increase long-term adverse events after allogeneic HSCT.

Maintain Efficacy and Spare Toxicity: Traditional and New Radiation-Based Conditioning Regimens in Hematopoietic Stem Cell Transplantation.

Novelty in total body irradiation (TBI) as part of pre-transplant conditioning regimens lacked until recently, despite the developments in the field of allogeneic stem cell transplants. Long-term toxicities have been one of the major concerns associated with TBI in this setting, although the impact of TBI is not so easy to discriminate from that of chemotherapy, especially in the adult population. More recently, lower-intensity TBI and different approaches to irradiation (namely, total marrow irradiation, TMI, and total marrow and lymphoid irradiation, TMLI) were implemented to keep the benefits of irradiation and limit potential harm. TMI/TMLI is an alternative to TBI that delivers more selective irradiation, with healthy tissues being better spared and the control of the radiation dose delivery. In this review, we discussed the potential radiation-associated long-term toxicities and their management, summarized the evidence regarding the current indications of traditional TBI, and focused on the technological advances in radiotherapy that have resulted in the development of TMLI. Finally, considering the most recent published trials, we postulate how the role of radiotherapy in the setting of allografting might change in the future.

Clofarabine and High-Dose Melphalan Reduced Intensity Conditioning Regimen for Allogeneic Stem Cell Transplantation

Clofarabine and High-Dose Melphalan Reduced Intensity Conditioning Regimen for Allogeneic Stem Cell Transplantation

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.

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 3750μmol*min/L/day ±10%) for 4days, higher dose (250mg/m2 ) fludarabine and 400centigray (cGy) of total body irradiation. 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. Twenty-nine children (17 within target) were evaluated. All subjects engrafted neutrophils with a median [interquartile range] time of 14days [8-30days]. 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 2years, 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. 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.

Evolution of dosimetric treatment planning for pediatric total lymphoid irradiation (TLI): a single-institution experience.

Total lymphoid irradiation (TLI) is a conditioning regimen in allogeneic hematopoietic stem cell transplantation (allo-HSCT) which may reduce long-term toxicities attributed to other techniques, such as total body irradiation (TBI). At our institution, TLI treatments were first planned with the three-dimensional conformal radiation therapy (3D-CRT) technique and later with volumetric modulated arc therapy (VMAT). With the recent availability of a basic helical tomotherapy (HT), the possible dosimetric gain of the latter for TLI is studied. 22 pediatric patients were planned for VMAT and HT, prescribed to 8 Gy in 4 fractions. VMAT was planned with template based on a single cost function, using the Monaco treatment planning system (TPS). HT plans were planned using Accuray Precision TPS for a basic HT without the dynamic jaws feature or VOLO-Ultra algorithm. Plan quality was analyzed based on four quality indices, mean and maximum doses to planning target volume (PTV) and organs at risk (OARs), dose gradient and integral doses. Differences were analyzed with Wilcoxon signed-rank test. HT plans resulted in improved conformity (CI) and homogeneity indices (HI) (p < 0.05) but less steep dose gradient (p = 0.181). VMAT plans created larger areas with high doses within the PTV, while comparable doses to OARs, except mainly for the spinal marrow, for which a reduction of 37.7% in D2% was obtained (p < 0.05). Integral dose for non-tumor tissue was 11.3% lower with the VMAT template (p < 0.05). HT achieves better conformity and homogeneity even without its more advanced features. Nevertheless, the VMAT template achieves dosimetric results close to those of HT, both with similar clinical outcome.

Evaluation of busulfan, cyclophosphamide, and etoposide as a preparation regimen for autologous stem cell transplantation in Hodgkin’s lymphoma patients

Abstract: BACKGROUND: Hodgkin’s lymphoma (HL) exhibits a cure rate of 90% in patients diagnosed at an early stage and a cure rate ranging from 70% to 90% in patients diagnosed at an advanced stage. In the case of patients with relapsed/refractory HL (r/rHL), it is recommended to provide salvage chemotherapy initially, followed by autologous stem cell transplantation (ASCT). The ideal conditioning regimen for the transplantation process is still being investigated. OBJECTIVES: For individuals with r/rHL, high-dose chemotherapy combined with ASCT (HD-ASCT) is thought to be the most effective method of treatment. The purpose of this research was to evaluate the effectiveness and safety of the busulfan, cyclophosphamide, and etoposide (BuCyE) preparation regimen in r/rHL patients. MATERIALS AND METHODS: Retrospective analysis was conducted on the data of 67 lymphoma patients older than 18 years who had HD-ASCT with the BuCyE conditioning regimen between September 2014 and November 2021 (86 months). The research consisted of 34 r/r HL patients among them. A parenteral regimen of 0.8 mg/kg of busulfan every 6 h from day −7 to day −5, 50 mg/kg of cyclophosphamide on days −3 and −2, and 400 mg/m2 of etoposide on days −5 and −4 comprised the patient preparation regimen before ASCT. All data were collected from inpatient files and the Inonu University Turgut Ozal Medical Center Hospital Information System. RESULTS: The median age of the patients was 43 years, and 67.6% were males. The most common type of HL was nodular sclerosis, which was followed by mixed cellularity. The median time for platelet and neutrophil engraftment was 14 and 11 days, respectively. 5.0 × 106/kg was the median transplanted dose of CD34+ cells (2.1–13.55). Liver toxicity was observed in 6 (17.6%) patients. Eight patients suffered from pulmonary side effects. The median number of previous chemotherapies was 2 (2–4). In all lymphoma patients, the complete response rate was 61.8% (n = 21), whereas the disease progression rate was 32.3% (n = 11). Transplantation-related mortality on the 100th day was 8.8% (n = 3). Three-year overall survival was 57.17%. CONCLUSION: When the literature was reviewed, the studies with the BuCyE preparation regimen in patients with r/rHL were limited. This conditioning regimen was found to have fewer side effects and a lower cost. It can be preferable when compared to carmustine (BCNU), etoposide, cytarabine (ARA-C), and melphalan (known as BEAM) in r/rHL.

The Impact of 131I-Metaiodobenzylguanidine as a Conditioning Regimen of Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation for High-Risk Neuroblastoma.

The optimal conditioning regimen of tandem high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) for high-risk neuroblastoma (HR-NBL) has not been established. The efficacy of 131I-MIBG therapy is under exploration in newly diagnosed HR-NBL patients. Here, we compared the outcomes of tandem HDC/ASCT between the 131I-MIBG combination and non-MIBG groups. We retrospectively analyzed the clinical data of 33 HR-NBL patients who underwent tandem HDC/ASCT between 2007 and 2021 at the Seoul National University Children's Hospital. The median age at diagnosis was 3.6 years. 131I-MIBG was administered to 13 (39.4%) of the patients. Thirty patients (90.9%) received maintenance therapy after tandem HDC/ASCT, twenty-two were treated with isotretinoin ± interleukin-2, and eight received salvage chemotherapy. The five-year overall survival (OS) and event-free survival (EFS) rates of all patients were 80.4% and 69.4%, respectively. Comparing the 131I-MIBG combined group and other groups, the five-year OS rates were 82.1% and 79.7% (p = 0.655), and the five-year EFS rates were 69.2% and 69.6% (p = 0.922), respectively. Among the adverse effects of grade 3 or 4, the incidence of liver enzyme elevation was significantly higher in the non-131I-MIBG group. Although tandem HDC/ASCT showed promising outcomes, the 131I-MIBG combination did not improve survival rates.

Helical Tomotherapy and Melphalan As the Conditioning Regimen in Autologous Stem Cell Transplantation for Multiple Myeloma with Extramedullary Plasmacytoma: A Single Center Clinical Research

Background Multiple myeloma(MM) is the second hematologic malignancy. Extramedullary myeloma indicates a poorer prognosis and survival. High dose Melphalan is the most widely used conditioning regimen. Helical tomotherapy(TOMO) is one of the most advanced intensity-modulated conformal radiotherapy technologies. We applied the combination of TOMO and Melphalan as the conditioning regimen in MM patients, and analyzed its efficacy and safety. Methods Clinical data were collected and compared between TOMO combined with melphalan group and non-TOMO group. SPSS V.25.0 was used for statistical analysis. Results Two methods were not significant difference by statistics analysis. The complete response rate of 100d in non-TOMO group significantly decreased compared to 1 month after transplantation (P=0.001). The 1-year PFS rate in the TOMO group was 86%, while non-TOMO group was 91%. There was no myeloma related death in the two groups within one year. TOMO group showed earlier enter platelet count below 20x109/L (P=0.003) and granulocyte deficiency (P=0.000). In terms of platelet implantation time,TOMO group was superior in platelet implantation time (P=0.041). No atrial fibrillation, heart failure, hepatic small vein occlusion, or transplant related death occurred during the transplantation period. Conclusion: The combination of TOMO and reduced dose Melphalan conditioning regimen is clinically feasible in terms of safety and efficacy evaluation. This scheme could improve the long-term survival of MM patients with extramedullary plasmacytoma.

Efficacy of Venetoclax Combined with Decitabine Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in High-Risk and Elderly Patients with Myeloid Neoplasms

Background High-risk and elderly patients with myeloid neoplasms are a special group because it's challenging to find the right balance between safety and efficacy during the peri-transplant period. Traditional transplant protocols have unsatisfactory treatment outcomes for patients with a high risk of recurrence, while the elderly couldn't tolerate the toxicity of high-dose chemotherapy drugs. Thus, new regimens are needed to improve treatment outcomes for high-risk and elderly patients. Through BCL-2 binding, venetoclax could induce leukemia cell apoptosis, increase chemosensitivity, and perform a synergistic role with HMAs. And its combination with HMAs or other cytotoxic drugs showed a promising effect on R/R AML. This prospective clinical study reported the efficacy and safety of adding venetoclax and decitabine to myeloablative conditioning regimens in high-risk and elderly patients receiving allogeneic hematopoietic stem cell transplantation. Methods We performed an investigator-initiated, prospective, one-arm, single-center, open-label trial. In total, 19 patients were enrolled in the trial between December 2021 and February 2023. Eligible patients met the following inclusion criteria: (1) undergoing allo-HSCT over the age of 50 years (i.e., ≥50 years), (2) having an Eastern Cooperative Oncology Group performance status of 0-2, and (3) having AML, MDS, and CMML with a high risk of recurrence: (a) For patients with MDS, (i) a diagnosis of MDS with excess blasts 2 (EB-2), (ii) a poor karyotype, (iii) a very high-risk disease according to the International Prognostic Scoring System-Revised, and (iv) a TP53 mutation; (b) For patients with AML, (i) relapsed/refractory AML, (ii) detected MRD test before transplantation, (iii) with adverse risk according to the European Leukemia Net (ELN) Guidelines 2017, and (iv) AML transformed from MDS or CMML. Venetoclax was administered at 400 mg per day orally from day -14 to day -1 in the initial regimen and from day -14 to day -5 in the modified regimen. Decitabine was administered at 20mg/m 2/d orally from day -7 to day -3. Detailed dosage of the Bu/Flu/Cy comprised of fludarabine 30 mg/m 2/d IV Qd, day -4 to -2, busulfan 3.2 mg/kg/d IV Q6h, day -7 to -5, and cyclophosphamide 40mg/kg/d IV Qd, day -3 to day -2. Either rabbit ATG or porcine ATG was administered at 2.5mg/kg/d IV Qd, day -4 to -1, or 20mg/kg/d IV Qd, day -3 to -1 for GVHD prophylaxis. Results 19 patients were enrolled in the trial with a median follow-up time of 258 (range, 35-544) days. Grade 3/4 adverse events included hematological events, hypertension, infections, allergy, and increased amylase. The 30-day cumulative incidence of neutrophil and platelet engraftment was 100% and 68% (Figure 1A). Acute GVHD occurred in 9 of 19 patients (grade I, n=2; grade II, n=1; grade III, n =4; grade IV, n =2). The cumulative incidence of grade II to IV acute GVHD events at 100 days was 31% (95% confidence interval (CI], 12-53) among all patients, and 45% (95% CI, 15-72), and 13% (95% CI, 0-45) for the initial regimen group and the modified regimen group, respectively (p=0.28, Figure 1B, C). While 1 patient in the modified regimen group occurred diarrhea and was clinically diagnosed with grade III acute GVHD (late-onset) at 132 days post-HSCT. The cumulative incidence of chronic GVHD at 1 year was 37% (95% CI, 16-58). For the entire cohort, OS and RFS at 6 months was 63% (95% CI, 45-89) and 63% (95% CI, 45-89), and the NRM and CIR at 6 months was 37% (95% CI, 16-58) and 0, respectively (Figure 1D, E). All 8 deaths were attributed to transplant-related complications, including 4 patients from aGVHD, 2 patients from infection, 1 from transplant-associated thrombotic microangiopathy (TA-TMA) and 1 from bloody pleural effusion. Here it should be pointed out that the patient with bloody pleural effusion couldn't exclude the probability of tumor invasion because he had previous esophageal carcinoma. Conclusion In conclusion, although the hematological and molecular recurrence rate of the venetoclax combined with the decitabine conditioning regimen is significantly decreased, the high incidence of severe aGVHD and NRM limits its clinical application. It still needs further exploration to optimize the conditioning regimen for high-risk and elderly patients with myeloid neoplasms.

Addition of Inotuzumab Ozogamicin to the Conditioning Regimen of Allogeneic Stem Cell Transplantation (allo-SCT) for Relapsed CD22 (+) Lymphoid Malignancies: Long-Term Survival Results

Background: Inotuzumab ozogamicin (InO) is a humanized antibody-drug conjugate that targets CD22+ B-cells. InO demonstrated antitumor activity and manageable toxicity in phase 1/2 trials for the treatment of B-cell non-Hodgkin lymphoma (NHL) as a single agent and in combination with rituximab. In order to improve outcomes in patients with relapsed CD22 (+) NHL, or chronic lymphocytic leukemia (CLL) who failed targeted therapies and were candidates for allo-SCT, we prospectively studied the addition of InO to our standard chemo-conditioning of BFR (bendamustine, fludarabine and rituximab-Khouri Blood 2014). Herein we report long-term survival outcomes. Methods: InO was infused intravenously (iv) on day -13 outpatient, with a dose cohort of 0.6, 1.2 or 1.8 mg/m2. Bendamustine 130 mg/m 2 iv daily on days -5 to -3 together with 30 mg/m 2 iv of fludarabine on days -5 to -3 were given prior to transplantation. Rituximab was given at a dose of 375 mg/m 2 iv on days -6, +1, and +8. Tacrolimus and mini-methotrexate were used for graft versus host disease (GVHD) prophylaxis. Results: The study included 26 patients. Median age was 59 (range, 26-70) years. Disease types: CLL [n=11 (27%) ; 64% with TP53 mutations (either alone, or with other mutations such as BTK, CDH2, ZMYM3); 22% with complex cytogenetics; 75% with unmutated IGHV; mantle cell lymphoma ( MCL) [n=8 (31%); 83% had Ki 67 &amp;gt;30%; 25% TP53 mutation; and 25% blastoid histology]; Follicularlymphoma (n=5, 19%), and diffuse large b cell ( DLBCL[n= 2; (8%)]. Median # prior treatments was 2.5 (range, 1-6). Patients with CLL/MCL were previously treated with ibritunib (n=10), venetoclax (n=5), idelalisib (n=2), nivolumab (n=1) and CAR T (n=1). At study entry, 18 (69%) patients were in CR, 7 (27%) in PR, and 1 (4%) had SD. Eleven (42%) received their transplants from matched sibling donors (MSDs) and 15 (58%) from matched unrelated donors (MUDs). The number of patients who received the 0.6, 1.2 or 1.8 mg/m2 of InO were 4, 2 and 20 patients, respectively. No DLT was observed. Forty-two percent of patients never experienced severe neutropenia and 77% never experienced platelet counts &amp;lt; 20K x 10 9/L. Only 1 patient developed veno-occlusive disease, confounded by the simultaneous manisfestation of hyper-acute GVHD related to prior nivolumab pre-alloSCT. Treatment-related mortality (TRM) at 2-years was 12%. With a median follow-up of 48.7 months (range, 3.6-82.8), the 5-year overall survival (OS) and progression-free survival rates (PFS) were 84% and 80%, respectively. Seven of 8 (87.5%) patients with PR/SD at study entry converted to CR after allo-SCT. There was no significant difference in OS or PFS by histology subtype. Patients who received a transplant from MSDs had OS and PFS rates of 100% v 79% ( P = .060) and 64% ( P = .032) for those who received MUDs, respectively (Figure 1). We compared results of this trial to a group of patients (n=56) with relapsed lymphoid malignancies who received allo-SCT at our center in a preceding prospective trial using BFR conditioning without InO and the same GVHD prophylaxis (clinicaltrials.gov #NCT00880815) which was previously published. There was no statistically significant difference in patients, disease (including histology, disease status pre-transplant) or transplant characteristics between the 2 groups. We found no statistically significant differences in engraftment times, incidence and grades of liver toxicity, TRM, risk of acute grade II-IV or III-IV GVHD. However, the study group containing InO had a higher incidence of extensive chronic GVHD (mainly de novo) than the control group (50% vs 25%, P = .019), respectively. There was a trend in patients with NHL to have a better 5-year OS (93% vs 68%) and 5-year PFS (93% vs 58%, Figure 2) in the study group vs the control groups. We did not observe such a trend in patients with CLL (5-year PFS 62% vs 59%): this could be related to small #patients, level of expression of CD22, more adverse mutations in the study group. Conclusions: Our results show that InO is safe when combined with an allo-SCT conditioning regimen and may improve survival outcomes in patients with CD22 (+) NHL. This needs to be validated in a larger number of patients. An ongoing trial at our center involves fractionating InO dose pre-and post-allo-SCT in patients with lymphoma or acute lymphoblastic leukemia receiving a reduced-intensity conditioning, and adding post-transplant cyclophosphamide to decrease the risk of GVHD.

ACS10- Cytarabine Pharmacogenomics Score Impacts Survival in Pediatric AML Patients Treated on AAML1031 Trial and Associates with Outcome Differences in Black AML Patients

Cytarabine (ara-C) has been used to treat acute myeloid leukemia (AML) for decades. While ara-C based regimens successfully induce remission in the majority of patients, significant number of patients experience relapse. Although advances in hematopoietic stem cell transplantation (HSCT) and supportive care regimens have improved over the years, it is imperative that personalized methods to optimize pharmacological intervention and improve outcomes are needed. To identify genetic predictors of ara-C response, we recently reported an ara-C pharmacogenomics score (ACS10) consisting of 10 SNPs in nine ara-C pathway genes (PMID: 34990262). In pediatric patients treated on AML02 and AAML0531 trials, low ACS10 score (&amp;lt;0) was associated with poor survival as compared to patients with high score (&amp;gt;0). Given these promising results, we sought to investigate the ACS10 score in a large cohort of children treated on Children's Oncology Group clinical trial AAML1031 (NCT01371981). AAML1031 trial enrolled 1,097 newly diagnosed patients from 0 to 29.5 years of age that received either conventional AML treatment (ara-C, daunorubicin and etoposide (ADE): arm A) or conventional treatment with the addition of bortezomib (ADE+bortezomib: arm B). Overall, no benefit for adding bortezomib was observed (PMID: 32029509). The current study included 717 patients with both DNA specimens and clinical outcome data available. ACS10 SNPs were genotyped using Taqman assays and ACS10 score was calculated for each patient as per previous report (PMID: 34990262). Overall, for the 717 patients included in this study, 249 patients had low ACS10score (&amp;lt; 0) and 468 patients had a high ACS10 score (&amp;gt;0). When combining patients treated on arm A and arm B, ACS10 score was not associated with overall survival (OS). However, patients with low ACS10 scores had poorer event-free survival (EFS) than those with high ACS10 scores, although this difference was not statistically significant (HR: 0.827, 95% CI (0.669-1.022), P=0.078). Patients with high ACS10 scores in arm A had improved EFS (HR: 0.689, 95% CI (0.50-0.94), P=0.023, Fig1), while OS did not show significant differences (P=0.378). Excluding the patients who received HSCT, showed increased EFS for patients with high ACS10 scores as compared to low ACS10 scores when treated with standard chemotherapy (HR: 0.628, 95% CI (0.445-0.887), P=0.008 Fig 1). In contrast, a significant difference was not observed within the standard ADE+bortezomib arm (arm B). At the whole cohort level, black patients (N=84) had reduced OS (HR: 1.47, 95% CI (1.02-2.13), P=0.041) as compared to white patients, while there was no significant decrease in EFS (HR: 1.22, 95% CI (0.89-1.66), P=0.206) (N=522). Within arm A, black patients had significantly poorer outcome as compared to white patients (EFS, HR: 1.718, 95% CI (1.099-2.686), P=0.018 Fig1; OS HR: 1.80, 95% CI (1.05-3.10), P=0.032). Difference in outcome by race in arm B was not significant implying addition of bortezomib might have some benefit to black patients. Subsequent comparison by treatment arm showed a non-significant but better outcome in black patients when treated on arm B (Black patients: EFS, arm A vs. arm B: HR:0.66, 95% CI (0.37-1.17), P=0.154). Consistent with our previous investigation, low ACS10 score group was more abundant in black patients as compared to white patients (69% of black patients vs. 28% of white patients had low ACS10 score, P&amp;lt;0.001). These results are particularly salient given trends showing poor outcome in black as compared to white AML patients. Despite AAML1031 being one of the largest pediatric AML cohorts, the small number of black patients limited our ability to do further subset analyses by scores and arms (only 10 of 39 black patients treated on arm A had high ACS10 score). In conclusion, we demonstrate the utility of the PGx-based ACS10 score in a large cohort of newly diagnosed pediatric AML patients when treated with standard ADE induction regimen. Consistent with previous observation, black patients with low ACS10 score had inferior outcome in standard arm, however such an association was not observed for the bortezomib arm. Higher abundance of the low ACS10 SNP scores in black patients warrants further in-depth evaluation. Our future and ongoing studies include compiling data from multiple clinical trials to increase the sample size as well as expanding investigations within Hispanic/Latino AML patients

Long Non-Coding RNA LINC00XPRR Is Upregulated in Newly Diagnosed Multiple Myeloma Promoting Poor Response to High-Dose Melphalan with Autologous Stem Cell Transplantation and Three-Drug Regimen

Abstract Multiple myeloma is an incurable malignant hematopoietic blood cancer. It develops from genetic disposition and abnormal plasma cells with over 30,000 new cases diagnosed in the United States every year. The 5-year relative survival rate for myeloma patients if diagnosed at early stage is 79.5%, however majority of patients are diagnosed once the cancer has already metastasized which decreases the 5-year relative survival rate to only 59%. The standard care for treating newly diagnosed multiple myeloma (NDMM) is three-drug induction therapy followed by high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT). While there is no cure for multiple myeloma, diagnosis and standard therapy leads to prolonged remission and improved quality of life. Identifying genetic predictors for positive treatment responses and survival represents an unmet medical need. Long non-coding RNAs (lncRNAs) play important regulatory roles in promoting cancer growth and metastasis and due to their tissue-specificity they are becoming important players for development of personalized therapies. In addition, lncRNA-protein interactions have shown to be vital for biological processes associated with cancer, but currently there is a lack in our understanding of their role in initiation or progression of myeloma. Further, the roles of lncRNAs as biomarkers or targets for myeloma therapies have not yet been defined. In order to address these issues, we performed transcriptome sequencing from NDMM patients which identified 244 differentially expressed lncRNAs in poor responders (indicated as &amp;lt;24 months progression free survival (PFS)) to three-drug regimen, HDM and ASCT (n=38) compared to standard responders (indicated as &amp;gt;24 months PFS) to three-drug regimen, HDM and ASCT (n=78). Our analysis revealed LINC00XPRR (lncRNA00Xpoor responder-related) as one of the top-most upregulated novel lncRNA associated with poor responders to standard myeloma care. We next validated LINC00XPRR high expression in single cell RNA-sequencing data in NDMM patient samples. Multiplexed fluorescent RNA in situ hybridization (mFISH) analysisshowed that LINC00XPRR expression increased in melphalan treated myeloma cell lines and is highly expressed in bone marrow aspirates from patient samples. We further determined higher levels of LINC00XPRR in the cytoplasmic compartment of the cells compared to nuclear localization through QuPath analysis. LINC00XPRR mechanistically and epigenetically modulates cytotoxic and apoptotic phenotypes in myeloma cell lines when overexpressed in U266B1 and MM1.S cells or using RPMI8226 CRISPR/Cas9 knockdown system and in appropriate multiple myeloma-associated mouse models. Additionally, we used RNA immunoprecipitation (RIP) combined with qPCR to determined that LINC00XPRR directly interacts with CELF2, RNA-binding protein. Lastly, using target specific LINC00XPRR designed locked-nucleic acid antisense oligonucleotides (LNA ASOs) to knockdown LINC00XPRR, we saw an increase in apoptotic phenotypes indicating clinical potential of LNA ASOs-mediated LINC00XPRR knockdown. Overall, we are the first to identify lncRNAs associated with poor response in NDMM patients to standard three-drug induction chemotherapy followed by HDM and ASCT and show that LINC00XPRR enhanced expression may be both an important biomarker and target for future therapeutic interventions. Our current studies focus on the biology of lncRNAs in myeloma and the mechanism by which increased expression of LINC00XPRR is associated with poor outcomes in patients with NDMM receiving standard induction therapy, HDM and ASCT. Topics: multiple myeloma, long non-coding RNAs, LNA ASOs, RNA therapeutics, treatment response, RNA sequencing, apoptosis

Effect of exercise interventions on hospital length of stay and admissions during cancer treatment: a systematic review and meta-analysis

ObjectiveTo assess the effect of participating in an exercise intervention compared with no exercise during cancer treatment on the duration and frequency of hospital admissions.DesignSystematic review and meta-analysis.Data sourcesMEDLINE, EMBASE,...

Fludarabine melphalan versus fludarabine treosulfan for reduced intensity conditioning regimen in allogeneic hematopoietic stem cell transplantation: a retrospective analysis.

Various reduced-intensity conditioning (RIC) regimens are used to decrease toxicity while providing comparable outcomes to myeloablative regimens. We compared toxicity and outcomes between two RIC regimens, fludarabine with melphalan (Flu-Mel) and fludarabine with treosulfan (Flu-Treo), retrospectively over a 10-year period in two donor groups, matched related donor (MRD)/matched unrelated donor (MUD) and haploidentical (Haplo) transplants. The study included 138 patients, of which 105 received MRD/MUD (Flu-Mel: 94, Flu-Treo: 11) and 33 Haplo (Flu-Mel: 17, Flu-Treo: 16) transplants. In the MRD/MUD group, 44 (47%) of patients who received Flu-Mel had grade 3/4 oral mucositis compared to 1 (9%) who received Flu-Treo (P = 0.02). Corresponding numbers in the Haplo group were 7 (41%) and 1 (6%). Grade 3/4 diarrhoea was more frequent with Flu-Mel than Flu-Treo in the Haplo group (41% vs 6%; P = 0.039), but not the MRD/MUD group. Median follow-up time for all patients was 4.8years. Five-year OS in the MRD/MUD group was 62% with Flu-Mel versus 53% with Flu-Treo (P = 0.0694). Similarly, 5-year OS was 41% with Flu-Mel and 28% with Flu-Treo (P = 0.770) in the Haplo group. Severe mucositis and diarrhoea were significantly less frequent with Flu-Treo than Flu-Mel. Flu-Treo provided comparable outcomes to Flu-Mel in all donor transplants.