Conditioning Chemotherapy Regimen Research Articles

Role of Endoscopic Techniques in the Diagnosis of Complications of Allogeneic Hematopoietic Stem Cell Transplantation: A Review of the Literature.

Allogeneic stem cell transplantation (Allo-SCT) implies that a donor and a recipient are not genetically identical. Allo-SCT is used to cure a variety of conditions, including hematologic malignancies using the graft versus tumor effect, nonmalignant hematologic, immune deficiencies, and, more recently, genetic disorders and inborn errors of metabolism. Given the immunosuppressive and myeloablative nature of some of the conditioning chemotherapy regimens used during the Allo-SCT, patients are often at high risk of infection, including viral infections affecting the gastrointestinal tract, following the transplant. Furthermore, other complications such as hepatic sinusoidal obstruction syndrome (SOS) or graft-versus-host disease may occur post-transplant and may require endoscopy to assist in the diagnosis. This review will provide newer insights into the importance of endoscopic techniques in the diagnosis of post-Allo-SCT complications with a focus on safety and timing.

Assessment of Inpatient Mortality in the Peri-Transplant Period in Elderly Allogeneic Stem Cell Transplant Recipients with Co-Existing Mental Health Illnesses

Background Allogeneic hematopoietic stem cell transplant (alloHCT) is a potentially curative treatment for patients with hematological malignancies and nonmalignant conditions. AlloHCT involves invasive procedures, conditioning chemotherapy regimens, and prolonged isolation during hospitalization, which is physically and emotionally challenging. Transplant related mortality is higher in older individuals. Careful assessment of mortality risk before transplant is essential for optimal patient selection and informed decision-making, especially in elderly patients. Hematopoietic cell transplantation-specific comorbidity index (HCT-CI), an important prognostic scoring tool used in patients before alloHCT, includes psychiatric comorbidity as one of the scoring criteria. Patients with depression or anxiety disorders receive one point on the scoring scale, with the assumption that the two groups of patients are at an equivalent risk. However, there is literature showing decreased overall survival and worse inpatient outcomes in patients receiving alloHCT with co-morbid depression. Our primary objective was to evaluate the inpatient outcomes of elderly patients undergoing allogeneic stem cell transplant with a concurrent diagnosis of depression and patients with anxiety and adjustment disorders. Methods: Patients of ages ≥ 60 years, admitted with a principal procedure code of allogeneic stem cell transplant, were recruited from the 2016-2020 National Inpatient Sample. Three cohorts were created based on ICD-10 diagnostic codes for Depression and Anxiety and adjustment disorders: patients without depression and anxiety disorders, patients with depression only, and patients with anxiety and adjustment disorders only. Patients with diagnoses of other mental illnesses were excluded. The patient characteristics between the three cohorts were evaluated. Multiple Logistic Regression models were used to determine the impact of depression and anxiety disorders on inpatient mortality. Results: We evaluated 11655 hospital admissions with the primary procedure code for Allogeneic Stem Cell Transplant in patients aged 60 years and above. 8375 patients did not have any mental illness. 800 patients (9.5%) had a diagnosis of Depression, and 1640 patients (19.5%) had a diagnosis of Anxiety and adjustment disorders. Comparing the primary outcomes in patients with and without Depression, the length of stay was 31.3 days vs 28.2 days (p<0.01), the mean hospital charge was 558398.01 USD vs 498971.9 USD (p <0.01), and in-patient mortality was 8.1% vs 5.9% (aOR = 1.359, 95% CI 1.010-1.829, p=0.04). Utilization of mechanical ventilation was more prevalent in patients with depression (8.8 %vs 5.8 %, p <0.01). Out of different infectious complications, pneumonia was more common in patients with depression (14.4 % vs 9.8 %, p <0.01) (Table 1a). Baseline socio-demographic characteristics that were associated with having depression included: Female gender, White race, and Medicare insurance. Patients with depression had an increased prevalence of congestive heart failure, prior stroke, Obesity with BMI >= 35, chronic kidney disease, and COPD compared to patients without depression (p<0.01). For the primary outcomes in patients with and without anxiety and adjustment disorders, the length of stay was 29.15 days vs 28.2 days (p <0.01), the mean hospital charge was 474274.71 USD vs 498971.94 USD (p 0.612), and the in-patient mortality was 4% vs 5.9 % (aOR=0.61, 95% CI 0.45-0.83, p<0.01). Baseline socio-demographic characteristics that were prevalent in patients with anxiety and adjustment disorders were: female gender, white race, and Medicare as the most common insurance (P<0.01) (Table 1b). Conclusion We found that in elderly patients admitted for alloHCT, depression was independently associated with worse inpatient outcomes, while anxiety was not. Patients with depression were noted to have an increased incidence of infectious complications as compared to those without depression, possibly accounting for their increased mortality. Prognostic scoring systems like HCT-CI may need to be modified to assign more weight to depression as a psychiatric co-morbidity. Elderly transplant recipients with depressive disorders are a vulnerable group and multidisciplinary teams such as psychiatry and palliative care should be involved in their care.

Utilization of a Population Pharmacokinetic Model to Improve a Busulfan Test-Dose Strategy in Allogeneic Hematopoietic Cell Transplant Recipients.

Busulfan is an alkylating agent used as part of conditioning chemotherapy regimens prior to allogeneic hematopoietic cell transplant (allo-HCT). Pharmacokinetic (PK)-guided test-dose strategies have been shown to improve the number of patients achieving busulfan exposure goals and improve clinical outcomes. However, current practices require extensive PK sampling. In this study, PK data were retrospectively collected from busulfan drug monitoring records from adult allo-HCT recipients who received once-daily intravenous busulfan at the University of North Carolina Medical Center (UNCMC). A population pharmacokinetic (popPK) model was developed to identify sources of interindividual variability and evaluate alternative PK sampling strategies. A 2-compartment model, with covariate effects of actual body weight and sex, best described the data. The typical value of clearance for an 83kg male was estimated to be 11.21L/h. Fifty-nine percent of allo-HCT recipients were estimated to have met the UNCMC institutional myeloablative conditioning (MAC) exposure goal based on model post hoc estimates of clearance using all PK samples obtained following MAC dosing. Fifty-seven percent of patients were estimated to have met this goal based on post hoc estimates using a single PK sample. Our results indicate once-daily, intravenous busulfan PK in adult allo-HCT recipients receiving MAC dosing can be reasonably described by a popPK model, and the use of a sparse PK sampling strategy may be feasible for determining target exposure attainment following MAC dosing. Use of a popPK model and sparse PK sampling strategy to carry out busulfan test-dose procedures could reduce health care costs and inconvenience to patients.

ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN ELDERLY PATIENTS IN BRAZIL

The allogeneic hematopoietic stem cell transplant (allo-HCT) represents an important therapeutic strategy for acute leukemias, lymphomas and solid neoplasms, also used in benign diseases, such as aplastic anemia and inborn errors of immunity. This treatment requires myeloablative chemotherapy (conditioning regimen) followed by the infusion of donor-derived hematopoietic stem cells. However, this procedure carries some risks, such as infections, graft versus host disease (GVHD) and conditioning toxicity, which may result in transplant-related mortality. Over the decades, due to the increasing life expectancy and new advances in medicine, the cases of patients > 50 years with hematologic diseases that need allogeneic transplant have grown, requiring a comprehensive geriatric assessment as a mechanism for the best treatment option choice.
 Objective: To apply a clinical frailty score and Karnofsky score in allogeneic hematopoietic stem cell older than 50 years old for three years in Walter Cantídio University Hospital (Fortaleza/Ceará) and in Amaral Carvalho Hospital (Jaú/São Paulo), expecting to recognize the profile of this patients and to demonstrate the relation between the clinical frailty score and overall survived, besides to estimate the contribution of GVHD prophylaxis and relapse in overall survival. Methods: Multicentric, retrospective, descriptive, analytical and quantitative study, acquiring dates by means of exams and medical record from Walter Cantídio University Hospital in Fortaleza/Ceará and Amaral Carvalho Hospital in Jaú/São Paulo. Results: The study selected 252 patients, 147 males and 105 females, sort in gender, disease, HCTCI score, CFS and KPS. In three years, the overall survival in FIT score is 2,46 years, while in FRAILTY score is 1,82 years. About the prophylaxis, the combination of cyclosporine, mycophenolate mofetil, cyclophosphamide had worse results than others prophylaxis. As expected, in case of relapse, there is shorter survival. Conclusion: The elderly population require a geriatric score in order to evaluate the profile of this patients once the allogeneic transplant must happen, then FIT patients has longer survival than FRAILTY patients.

The Gonadotoxic Effects of Conditioning Chemotherapy Regimens Prior to Hematopoietic Stem Cell Transplantation [ID: 1376168

INTRODUCTION: Primary ovarian insufficiency secondary to high-dose chemotherapy in females undergoing the conditioning regimen before hematopoietic stem cell transplantation is a challenging late complication. Limited studies have investigated the ovarian toxicity of various conditioning regimens. This study aimed to explore the gonadotoxic effects of cyclophosphamide (CY) and busulfan (BU) in CD-1 mice strain. METHODS: Sixteen 1-month-old female CD-1 mice (n=4/group) were subcutaneously injected with solvent, BU, CY, or BU+CY, respectively. The doses (144 mg/kg BU and 300 mg/kg CY) and injection plan were adjusted to human doses. The ovaries and female reproductive tracts were harvested 1 week after the last administration. Follicle counting was performed. The levels of serum antimüllerian hormone (AMH) and 17-beta-estradiol were measured. Animal use approval was obtained from the Institutional Animal Care and Use Committee at the University of Nebraska Medical Center. RESULTS: All mice survived the injections and grossly appeared normal. The average ovary weight was significantly lower in BU (P=.0007) and BU+CY (P<.0001) groups than in the control and CY groups. The primordial (P<.0001) and primary follicles (P=.01) in treatment groups were decreased compared to the control group. The serum AMH level in the BU group was also significantly lower than the control and CY group (P=.003). CONCLUSION: We show that conditioning chemotherapy with CY and BU can reduce the ovarian reserve in CD-1 mice strain and may have a synergic effect. Future studies to investigate the mechanism of chemotherapy-related ovarian follicle death are needed to improve fertility outcomes in patients receiving conditioning chemotherapy.

Total marrow irradiation in hematopoietic stem cell transplantation for hematologic malignancies.

Total body irradiation (TBI) has been an essential component of the conditioning regimen in hematopoietic cell transplantation for many years. However, higher doses of TBI reduce disease relapse at the expense of more significant toxicities. Therefore, total marrow irradiation and total marrow and lymphoid irradiation have been developed to deliver organ-sparing targeted radiotherapy. Data from different studies show that TMI and TMLI can be safely administered in escalating doses in association with different chemotherapy conditioning regimen protocols, in situations with unmet needs, such as multiple myeloma, high-risk hematologic malignancies, relapsed or refractory leukemias, and elderly or frail patients, with low rates of transplant-related mortality. We reviewed the literature on applying TMI and TMLI techniques in autologous and allogeneic hematopoietic stem cell transplantation in different clinical situations.

Respiratory Viral Infections in Recipients of Cellular Therapies: A Review of Incidence, Outcomes, Treatment, and Prevention.

Respiratory viral infections (RVIs) are of major clinical importance in immunocompromised patients and represent a substantial cause of morbidity and mortality in patients with hematologic malignancies and those who have undergone hematopoietic cell transplantation. Similarly, patients receiving immunotherapy with CD19-targeted chimeric antigen receptor-modified T cells, natural killer cells, and genetically modified T-cell receptors are susceptible to RVIs and progression to lower respiratory tract infections. In adoptive cellular therapy recipients, this enhanced susceptibility to RVIs results from previous chemotherapy regimens such as lymphocyte-depleting chemotherapy conditioning regimens, underlying B-cell malignancies, immune-related toxicities, and secondary prolonged, profound hypogammaglobulinemia. The aggregated risk factors for RVIs have both immediate and long-term consequences. This review summarizes the current literature on the pathogenesis, epidemiology, and clinical aspects of RVIs that are unique to recipients of adoptive cellular therapy, the preventive and therapeutic options for common RVIs, and appropriate infection control and preventive strategies.

A phase I study of GPC3 targeted CAR-T cell therapy in advanced GPC3-expressing hepatocellular carcinoma (HCC).

TPS624 Background: The mortality of hepatocellular carcinoma (HCC) is increasing worldwide, but outcome of systemic treatments in advanced HCC is suboptimal. Adoptive T-cell transfer therapy represents a promising field that exploits the ability of T-cells to recognize and eliminate their target. Targeting the tumor-associated antigen glypican- 3 (GPC3) through chimeric antigen receptors (CAR) engineered T cells is a mechanistically rational novel treatment for advanced HCC. This study aims to determine the dose and early signals of GPC3 targeted (CAR)-T cells in advanced GPC3 expressing HCC (NCT05003895). Methods: This phase I first in human dose escalation trial will study the safety and feasibility of CAR (hYP7)- T cells in advanced HCC patients expressing GPC3. Eligibility criteria includes advanced HCC, not candidates for curative interventions, progressed on first line systemic treatment, tumor GPC3 positivity of ³ 25% by IHC, Child-Pugh Class A, ³1 measurable lesion, ECOG 0 or 1, adequate organ and marrow function. ParticipantsÕ T cells collected through leukapheresis will be transduced with a lentivirus encoding the CAR construct to generate CAR expressing T cells. Patients receive a conditioning chemotherapy regimen of cyclophosphamide and fludarabine prior to the infusion of the GPC3 directed CAR-T cells (Table). The trial has a 4-level modified Fibonacci dose escalation with a minimum of 3 patients at each level and a 28-day interval between the first three patients. Response will be assessed by imaging every two months during the first year. Patients undergo close monitoring with safety assessments during the first year and are followed for life. The primary objective is to determine the MTD, DLT, safety and feasibility of anti-GPC3 CAR expressing T- cells in patients with GPC3-expressing advanced HCC. Secondary objectives include best overall response and overall survival. Exploratory objectives are multiple and include studies to evaluate the persistence and peak levels of anti-GPC3 CAR-T cells after infusion. Recruitment began in December 2021 and the two patients at dose level -1 has been treated; the planned sample size is 38 patients. Table 1 Dose Level Anti-GPC3 CAR-T Cyclophosphamide (mg/m2) Fludarabine (mg/m2) Level -1 0.3x106 CAR-T per kg bw 200 30 Level 1 0.3x106 CAR-T per kg bw 300 30 Level 2 1x106 CAR-T per kg bw 300 30 Level 3 3x106 CAR-T per kg bw 300 30. Clinical trial information: NCT05003895 .

Improved Lentiviral In Vivo Gene Therapy for Chronic Granulomatous Disease

Background: Chronic granulomatous disease (CGD) is a congenital immunodeficiency characterized by severe life-threatening infections. CGD patients lack reactive oxygen species (ROS) in phagocytic leukocytes and often develop widespread tissue granulomas. The current treatment for CGD is lifelong antibiotic prophylaxis or hematopoietic stem cell transplantation (HSCT). However, most patients cannot find matched donors, and HSCT is known to have increased risk in CGD patients. Gene therapy has become a promising treatment for CGD. At present, "ex vivo" HSC gene therapy is the widely applied strategy. "In vivo" gene therapy is based on direct delivery of gene therapy vectors into patients, which could overcome the difficulties in HSCT. Methods: We have developed an in vivo CGD gene therapy strategy by intravenous (iv) injection of lentiviral vectors (LVs) carrying an universal EF1a promoter or a myeloid-specific miR223 promoter driving the expression of CYBB (cytochrome B-245 beta chain, or p91-phox) in X-CGD mice (X-CGD; B6.129S-Cybbtm1Din/J). Each mouse received 1x109 transduction units (TU) of LV-CYBB via iv injection after non-myeloablative conditioning. A second injection of 1x109 TU of LV-CYBB after re-conditioning was given 12 weeks later. Results: We developed a chemotherapy conditioning regimen to improve gene delivery efficiency by using busulfan, cyclophosphamide and dexamethasone. The X-CGD mice received two iv injections of LVs, and the expression and function of the LV-CYBB gene were analyzed by intracellular gp91-phox staining and DHR123 assay 4 weeks after each injection. Based on flow cytometry, we detected gp91-phox positive cells in the blood as the following, EF1a: 1.14-5.18% and 5.27-14.36%, and miR223: 1.65-5.17% and 4.59-17.89% after the first and the second injections, respectively, as compared with the WT mice: 79.9-87.6%. Functional analyses of ROS showed the following, EF1a: 1.93-5.2% and 2.39-18.51%, miR223: 2.65-6.67% and 3.75-19.8%, after the first and the second injections respectively, as compared with WT: 72.6-85.31% (Figure A). The LV vector copy number (VCN) in the peripheral blood mononuclear cells was detected by qPCR as the following, EF1a: 1.11-2.32% and 1.35-9.32%, and miR223: 1.01-2.39% and 2.71-8.51% after the first and the second injections, respectively. These results indicated that iv LV injection effectively delivered and expressed the LV-CYBB gene in vivo, and repeated injection of the LVs could increase the gene transfer efficiency in the CGD mice. Importantly, after the second injection, we found no antibody response to the LV particle-associated protein p24. However, after 3-12 months, markedly reduced VCN was found in the blood of the treated mice, suggesting exhaustion of the transgenes in the somatic cells. To improve the gene delivery into HSCs, we treated the mice with AMD3100 to mobilize HSCs into peripheral blood. The mice were treated with chemo-conditioning and AMD3100 prior to LV ivinjection. After four weeks, the gp91-phox positive HSCs of total Sca1+ HSCs in blood with or without (+/-) AMD3100 treatment were examined by flow cytometry, and the results showed the following, EF1a: (-) 9.52-15.43%, (+) 16.1-29.4%, and miR223: (-) 4.49-10.35% and (+) 7.06-16.84%. To confirm stem cell gene transfer, we transplanted the bone marrow cells from the LV-CYBB-treated CGD mice into untreated CGD mice. The VCN in blood was examined before (donor mice) and 4 weeks after (recipient mice) the HSCT, and the results showed the following, EF1a: before 4.49% (in the donor) and after 1.05-2.57% (in the recipients), and miR223: before 4.91% (in the donor) and after 1.04-2.69% (in the recipients) (Figure B). This transplantation study confirmed that the AMD3100 treatment effectively increased iv LV gene delivery into HSCs. Conclusion: We have developed an improved LV iv gene delivery strategy by applying chemo-conditioning and AMD3100 mobilization prior to the injection of the LVs into CGD mice. This in vivo LV gene therapy strategy could potentially be translated into future CGD gene therapy applications. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Thay đổi chức năng thất trái trên siêu âm tim sau 6 tháng ở bệnh nhân có bệnh máu ác tính được ghép tế bào gốc tạo máu điều trị

Objective: Evaluation of the impact of treatment with hematopoietic stem cells transplantation (HSCT) after six months on echocardiographic parameters of left ventricular fuction in patients with hematological malignancies.Methods: Cardiac function was prospectively assessed in 31 patients by echocardiography after bone marrow transplantation for Hodgkin or non- Hodgkin lymphoma; acute leukemia and multiple myeloma. Studies were performed before (baseline) and six months after chemotherapy conditioning followed by hematopoietic stem cells transplantation.Results: Mean ages at hematopoietic stem cell transplantation was 44.61 (range, 21 to 65 years). Baseline means left ventricular end diastolic dimension was 46.35 ± 5.25 mm and decreased considerably to 44.58 ± 4.68 mm after 6 months post-HSCT. End diasystolic volume followed a similar pattern with significantly decline (96.00±18.08 ml vs 88.61 ± 20.52 ml). In addition, the subgroup of the patients who had previously been treated with Anthracycline had lower global longitudinal speckle strain than those without anthracycline exposure in 6 months post-HSCT (-17.76 ± 2.70 % vs -19.81 ± 1.90 %).Conclusion: There was a significant decline in dimension and volume of left ventricular after six months post- HSCT. Chemotherapy conditioning regimen for bone marrow transplant and anthracyclines exposure are associated to cardiotoxicity.

Single Institute Experience – Linear Accelerator Based Total Body Irradiation Using Volumetric Modulated Arc Therapy Planning in Standard Size Linear Accelerator Room

<h3>Purpose/Objective(s)</h3> To share experience of linear accelerator based total body irradiation (TBI) with volumetric modulated arc therapy (VMAT) in a standard size linear accelerator room <h3>Materials/Methods</h3> 30 patients aged 2-18 years (between 2018-2021) were treated with TBI as conditioning for bone marrow transplant (BMT)using VMAT based plan on our linear accelerator in a standard sized linear accelerator room. Indication of BMT was – acute lymphoblastic leukemia, acute myelogenous leukemia, chronic myeloid leukemia, myelodysplasia, aplastic anemia etc. Patient selection involved assessment regarding need of anesthesia, details of previous radiation, details of conditioning regimen for scheduling, organs dysfunction, adequate counselling and written consent from parents. With or without anesthesia, patients were immobilized using full body vacloc, head rest, brain orfit cast and knee rest. Position was supine, hands by side. Both head first (HF) and feet first (FF) scans were acquired if body length was more than 120 cm (for 120 cm, HF scan alone was acquired). A wire was placed on thigh to aid fusion of HF and FF scans for plan evaluation. Fiducials at three levels and optically stimulated luminescent dosimeter for dose monitoring were placed. Dose was 2-4 Gy single fraction and 12-13.2Gy/6 fractions (twice daily over 3 days, with 6 hours gap) based on chemotherapy conditioning regimen- delivered to 14 and 16 patients respectively. The planning objective was 90-100% coverage and dose max less than 120%. For multifraction plans, target was mean dose to lungs and kidney less than 10 Gy and 8Gy respectively. VMAT plans were generated with 3-5 iso-centers with fixed couch vertical and lateral values and changing longitudinal value, ensuring only longitudinal couch movement. Plan was made using 6MV energy and 5-9 arcs and 3 cm overlap between fields (avoid over joints to prevent effusion and over lungs to reduce lung dose) <h3>Results</h3> Mean PTV V95 – 93% (92-96%), Dmax – 115% mean (109%-120%). Mean lung dose (for 12-13.2Gy plans) was 9.4Gy/ (9-10 Gy), kidney mean dose was 7.8Gy (7.5-8 Gy). Mean monitor units in the plans were 1120 for complete arc and 690 for partial arcs. Treatment was delivered in strict aseptic precautions, under cover of steroids and antiemetics - in presence of radiation oncologist and physicist. Cone beam CT scan was used for position verification before and after treatment. The mean duration of treatment was 75 mins (range 60-90 minutes). 18 patients had grade 2 nausea and vomiting, one had knee joint effusion. No other side effects were reported. All transplants were successful except one reported graft versus host disease. <h3>Conclusion</h3> The procedure needs careful planning and delivery. It is feasible and possible to deliver TBI using VMAT in a standard sized linear accelerator room and should be offered to patients requiring the same.

Addition of romiplostim to conditioning prior to HSCT allows chemotherapy reduction while maintaining engraftment levels

AbstractAllogeneic hematopoietic stem cell transplantation (HSCT) offers a curative treatment approach for certain benign and malignant hematologic diseases. The actual HSCT is preceded by a conditioning therapy that reduces host-vs-HSCT graft rejection and creates niche space for transplanted hematopoietic stem and progenitor cells (HSPCs). Conditioning consists of chemotherapy with or without irradiation and is a major cause of side effects in HSCT. However, reduction of the intensity of cytotoxic conditioning leads to higher rates of engraftment failure and increased rates of relapse. We here tested if the addition of an HSC cycling inducing agent during conditioning allows to diminish the dose of conditioning drugs without reducing subsequent transplanted HSC engraftment in a mouse HSCT model. The thrombopoietin receptor agonist romiplostim was shown to induce cell cycling activity in hematopoietic stem cells (HSCs). We thus tested if the addition of romiplostim to the clinically applied conditioning chemotherapy regimen cyclophosphamide and busulfan leads to increased efficacy of the chemotherapeutic regimen. We found that romiplostim not only sensitizes HSCs to chemotherapy but also enables a reduction of the main chemotherapeutic component busulfan by half while HSC engraftment levels are maintained in long-term, serial transplantation assays.

Relma-cel (JWCAR029) in relapsed and refractory B-cell non-Hodgkin lymphoma: A two-year survival update of a phase I study.

e19555 Background: B-cell non-Hodgkin lymphoma (B-NHL) has a very poor prognosis. Relma-cel (JWCAR029) is a CD19-targeted chimeric antigen receptor T (CAR-T) cell suspension. In a phase I trial performed in November 2017 in Beijing Cancer Hospital, China, JWCAR029 was used to treat relapsed/refractory B-NHL (R/R B-NHL) in adult patients, showing a high response rate and persistent response. This report aimed to update 2-year survival data generated in the above trial. Methods: This was an open-label, dose-escalating phase I study (JWCAR029-001, NCT03344367) involving patients with R/R B-NHL. The patients received a 3-day treatment with the conditioning chemotherapy regimen, consisting of fludarabine (25 mg/m2/day) and cyclophosphamide (250 mg/m2/day). Then, they received a single dose of intravenous JWCAR029 (25×106, 50×106, 100×106, or 150×106 CAR T cells). Two-year PFS and OS after JWCAR029 treatment were evaluated. The data were updated till the cut-off date of January 18, 2021. Results: A total of 23 patients with R/R B-NHL were enrolled, of whom 22 completed single-dose JWCAR029 cell infusion. All patients completed the 2-year follow-up, with a median time of 24.2 (95%CI 24.0-24.3) months. Based on the efficacy analysis set comprising 20 patients, the best ORR and CRR were 85.00% and 70.00%, respectively. In subgroup analysis, 1-year ORR and CRR in patients administered 100×106 cells were both 3/5 (60%); they were both 5/8 (62.5%) in those administered 150×106 cells. The 1-year and 2-year PFS rates (11 patients censored) were both 55.0%. Median PFS was not reached (95%CI 3.0 months-NA). The 1-year and 2-year PFS rates in patients administered 100×106 cells were both 60.0%; these values were both 62.5% in individuals treated with 150×106 cells. The 1-year and 2-year OS rates (3 patients censored) were both 68.6%. Median OS was not reached (95%CI 10.4 months-NA). The 1-year and 2-year OS rates in patients administered 100×106 cells were both 60.0%; these values were both 75.0% in those treated with 150×106 cells. A total of 6 patients (30%) died. No grade 3 and above CRS or NT were found. Conclusions: JWCAR029 was approved in China in September 2021 after the RELIANCE study (NCT04089215) reported its excellent efficacy and tolerable toxicity in the treatment of relapsed/refractory B-cell lymphoma. This report indicated that R/R B-NHL cases could benefit from JWCAR029. R/R B-NHL cases administered JWCAR029 at 100×106 or 150×106 cells had a promising response rate, with durable PFS and sustained OS benefits after 12 months. The effectiveness and safety of JWCAR029 need to be confirmed in the real-world setting. Clinical trial information: NCT03344367.

Hematopoietic Cell Transplantation for Adenosine Deaminase Severe Combined Immunodeficiency—Improved Outcomes in the Modern Era

Current treatment for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) includes enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplant (HSCT), or ex vivo corrected autologous hematopoietic stem cell gene therapy. Historic data show HSCT survival is superior using unconditioned matched sibling and family compared to matched unrelated and haploidentical donors. Recent improvement in HSCT outcomes prompted us to retrospectively examine HSCT survival and long-term graft function in ADA-SCID transplanted at our center. Thirty-three ADA-deficient patients received HSCT between 1989 and 2020, with follow-up data to January 2021. Chemotherapy conditioning regimens were defined as myeloablative (MAC—busulfan/cyclophosphamide), reduced-toxicity myeloablative (RT-MAC—treosulfan-based, since 2007), or no conditioning. Serotherapy used included alemtuzumab (with or without other conditioning agents) or antithymocyte globulin (ATG). ERT was introduced routinely in 2010 until commencement of conditioning. Median age at HSCT was 3.2 (0.8–99.8) months. Twenty-one (63.6%) received stem cells from unrelated or haploidentical donors. Seventeen (51.5%) received chemotherapy conditioning and 16 (48.5%) received alemtuzumab. Median follow-up was 7.5 (0.8–25.0) years. Overall survival (OS) and event-free survival (EFS) at 8 years were 90.9% (95% CI: 79.7–100.0%) and 79% (55–91%), respectively. OS after 2007 (n = 21) was 100% vs 75% before 2007 (n = 12) (p = 0.02). Three (9.1%) died after HSCT: two from multiorgan failure and one from unexplained encephalopathy. There were no deaths after 2007, among those who received ERT and treosulfan-based conditioning pre-HSCT. Ten (30.3%) developed acute GvDH (3 grade II, 2 grade III); no chronic GvHD was observed. In the modern era, conditioned HSCT with MUD has a favorable outcome for ADA-deficient patients.

Lenalidomide enhances the efficacy of anti-BCMA CAR-T treatment in relapsed/refractory multiple myeloma: a case report and revies of the literature

We report successful clinical experience using anti-BCMA CAR-T combined with lenalidomide in a patient who was refractory to a previous CAR-T treatment. The patient was a 51-year-old man, and was diagnosed with IgD-λ multiple myeloma(MM) in October 2015. 10 courses of chemotherapy including immunomodulators and proteasome inhibitors were used for remission and autologous hematopoietic stem cell transplantation was performed. MM relapsed after 12 months of remission. His disease continued to progress after multiple chemotherapy regimens, mouse anti-BCMA CAR-T and human-derived anti-BCMA CAR-T therapy. After a conditioning chemotherapy regimen of fludarabine and cyclophosphamide, patient took lenalidomide on day -1 and human-derived anti-BCMA CAR-T cells were infused on the next day. He suffered grade 2 cytokine-releasing syndrome(CRS) and grade 3 myelosuppression after infusion, and were resolved after symptomatic treatment. Very good partial response (VGPR) was achieved 14 days after CAR-T treatment, and had been maintained for more than 8 months. We demonstrated for the first time in patients that anti-BCMA CAR-T cell therapy combined with lenalidomide is feasible and effective in the treatment of RRMM. It provides a new strategy for RRMM patients who do not respond to anti-BCMA CAR-T cell therapy alone, and the adverse event is reversible.

The Monocytes That Repopulate in Mice After Cyclophosphamide Treatment Acquire a Neutrophil Precursor Gene Signature and Immunosuppressive Activity.

Cyclophosphamide (CTX) is a major component of the chemotherapy conditioning regimens used in the clinic to prepare cancer patients for hematopoietic stem cell transplantation or adoptive T cell therapy. Previous studies have shown that CTX given at nonmyeloablative doses in mice and patients leads to expansion of myeloid cells within which the monocytic subset exhibits immunosuppressive activity. However, the ontogeny and gene expression signature of these CTX-induced monocytes are not well-defined. Here, we report that the expansion of myeloid cells is a default process intrinsic to hematopoietic recovery after chemotherapy. During this process, the monocytes repopulated in mice acquire immunosuppressive activity, which can persist long after cessation of chemotherapy. Moreover, monocytes acquire a gene signature characteristic of neutrophil precursors, marked by increased proliferative capability and elevated expressions of multiple primary and secondary granules. We provide evidence that CTX-induced myeloid cell expansion is regulated by DNA methyltransferase 1 (Dnmt1) and dependent on chemotherapy-induced microbial translocation. These findings help advance our understanding of the differentiation, heterogeneity, and function of myeloid cells repopulating after chemotherapy.

Electrophilic reactivity of the Busulfan metabolite, EdAG, towards cellular thiols and inhibition of human thioredoxin-1

Busulfan is an alkylating agent used in chemotherapy conditioning regimens prior to hematopoietic stem cell transplantation (HSCT). However, its administration is associated with a great risk of adverse toxicities, which have been historically attributed to busulfan’s mechanism of non-specific DNA alkylation. A phase II generated metabolite of busulfan, EdAG (γ-glutamyldehydroalanylglycine), is a dehydroalanine analog of glutathione (GSH) with an electrophilic moiety, suggesting it may bind to proteins and disrupt biological function. However, EdAG’s reactions with common cellular thiols such as glutathione (GSH) and l-cysteine are understudied, along with possible inhibition of glutathionylation-dependent enzymes (with active site cysteine residues). We established a physiologically-relevant in vitro model to readily measure thiol loss over time. Using this model, we compared the apparent rates of thiol depletion in the presence of EdAG or arecoline, a toxic constituent of the areca (betel) nut and known GSH depletor. Simulated kinetic modeling revealed that the mean (±SE) alpha (α) second order rate constants describing GSH and l-cysteine depletion in the presence of EdAG were 0.00522 (0.00845) μM−1∙min−1 and 0.0207 (0.00721) μM−1∙min−1, respectively; in the presence of arecoline, the apparent rates of depletion were 0.0619 (0.009) μM−1∙min−1 and 0.2834 (0.0637) μM−1∙min−1 for GSH and l-cysteine, respectively. Under these experimental conditions, we conclude that EdAG was a weaker electrophile than arecoline. Arecoline and EdAG both depleted apparent l-cysteine concentrations to a much greater extent than GSH, approximately 4.58-fold and 3.97-fold change greater, respectively. EdAG modestly inhibited (∼20%) the human thioredoxin-1 (hTrx-1) catalyzed reduction of insulin with a mean IC50 of 93 μM [95% CI: 78.6–110 μM). In summary, EdAG’s ability to spontaneously react with endogenous thiols and inhibit hTrx-1 are potentially biochemically relevant in humans. These findings continue to support the growing concept that EdAG, an underrecognized phase II metabolite of busulfan, plays a role in untoward cellular toxicities during busulfan pharmacotherapy.

Oral nutritional support to adult patients with acute intestinal Graft Versus Host Disease (GVHD): A proposal for dietary intervention as a model to clinical trials

Acute Graft Versus Host Disease (GVHD) affects about 20%-80% of the patients after the hematopoietic stem cell transplant (HSCT) and it is amongst the main causes of morbidity and mortality both in children and adults. The intestine is one of the most affected organs by GVHD causing important alterations in the nutritional status and quality of life, considering that the dysfunctional intestine could decrease food intake as well as an inappropriate dietary plan could worsen the clinical condition. In addition to GVHD, chemotherapy conditioning regimen suppresses the immune system, promotes mucositis and increases the risk of infectious complications. Taking the above into consideration, when per oral diet is possible; the food choices should be carefully planned and monitored to promote nutritional support and avoid worsening the intestinal function and clinical condition. This work was aimed to present a practice guideline proposal, to be validated, based on literature review, regarding to oral dietary recommendations for acute intestinal GVHD after HTSC. Two research phases were defined: Phase one: evidence-based literature review; Phase 2: Practice Guideline Proposal. 1: Evidence based literature review SEARCH METHODS: A literature review (1997-2019) was performed including PubMed, in English, and Lilacs, in Portuguese electronic database to address the subject of dietary intervention for intestinal GVHD related to the HSCT, with children and adults, whose receiving oral or tube feeding nutrition therapy. The study selection was based on the PRISMA method. Controlled clinical trials were searched. Randomization was not possible considering the rare condition. Two independent authors assessed the abstracts of the selected studies to determine the articles feasible to compose the review as the base to elaborate the practice guideline proposal protocol, object of the present study. To determine the level of evidence of the selected article, GRADE criteria were used. One controlled clinical trial study was included. The study was developed in Japan with a total of 35 patients. The dietary plan was characterized by gradual increasing food consistency/density. They found better nutritional parameters in the treated group, however, following GRADE criteria, we rated the quality of evidence as very low. We could not demonstrate confidence in the effect estimate based on the selected study. However, considering the lack of literature information and the relevance of the topic, we decided to proceed and propose a practice guideline for an oral diet protocol for acute intestinal GVHD as a reference to be a starting point to validate protocols in future clinical trials. 2: Practice Guideline Proposal The criteria to elaborate the protocol were based on the RIGHT Statement. In addition to the literate information about diet and intestinal health, recommendations already adopted in the Service of Bone Marrow Transplant in the Complex Hospital of Clinics of Curitiba, in the state of Paraná, Brazil, were also considered.

Preclinical Development of an Actinium-225-Labeled Antibody Radio-Conjugate Directed Against CD45 for Targeted Conditioning and Radioimmunotherapy

Introduction Radiolabeled CD45 antibodies have demonstrated clinical promise as targeted conditioning agents prior to bone marrow transplant (BMT) as a better tolerated and potentially more effective alternative to chemotherapy and/or total body irradiation myeloablative conditioning regimens. CD45 is expressed on all immune cells, including hematopoietic stem cells and both precursor and mature lymphoid and myeloid cells, making it an ideal antigen for directing targeted radiation for conditioning. It is also highly expressed on most hematological cancers, offering the potential for a substantial anti-tumor effect. We describe the preclinical development of a novel anti-CD45 antibody radio-conjugate that consists of the pan-CD45 antibody BC8 labeled with the potent alpha emitter Actinium-225 (225Ac). Methods and Results The monoclonal antibody BC8 (apamistamab) was first conjugated with the DOTA chelator and then labeled with 225Ac, achieving a labeling efficiency typically greater than 80%. Furthermore, 225Ac-BC8 was shown to be stable and retain selective immunoreactivity to CD45+ cells following conjugation and labeling. To evaluate the anti-tumor potency of 225Ac-BC8, two CD45+ human multiple myeloma (MM) cell lines with high or low relative CD45 antigen density, U266 and H929, respectively, (Collette, et al. 2007 Eur. Cytokine Netw. 18:120-126) were tested by cell cytotoxicity assay and achieved greater than 90% cell killing of both lines. To assess the therapeutic potential of 225Ac-BC8, its anti-tumor activity was tested in xenograft models of H929 and U266. NOD-SCID mice bearing established tumors received a single dose of 300 nCi of 225Ac-BC8, 300 nCi of an irrelevant radio-conjugate 225Ac-18B7, naked BC8 antibody, or no treatment. In both models, 225Ac-BC8 exerted complete and durable tumor control for the duration of study. None of the control groups exhibited any anti-tumor effect. Favorable biodistribution results were obtained with SPECT/CT imaging using an 111In-labeled mouse pan CD45 surrogate antibody 30F11 (111Ac-30F11), since BC8 does not cross react with mouse CD45. 225Ac-30F11 is a useful surrogate molecule to study the tolerability and myeloablative properties of 225Ac-anti-CD45 antibodies for targeted conditioning prior to donor BMT, using B6-Ly5b donor cells in B6-Ly5a mice. Results of ongoing conditioning studies will be presented. Conclusions The pan-CD45 antibody BC8 was shown to be efficiently conjugated and labeled with the potent alpha emitter 225Ac to mediate robust and selective killing of CD45+ MM cells and xenografts. Biodistribution analysis confirmed selective uptake into organs of the immune system including homing to BM. These preclinical data and ongoing myeloablative/BM reconstitution studies support the development of 225Ac-BC8 as a novel potent and safe targeted conditioning approach for BMT.

Hyperbaric oxygen for refractory hemorrhagic cystitis after stem cell transplantation: case report

Hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (AHSCT) in both children and adults has been associated with significant morbidity and mortality. Early HC can occur within 48 hours of completing the chemotherapy conditioning regimen, is usually associated with agents such as cyclophosphamide, and generally resolves promptly. Late HC is commonly associated with BK and other viruses and can prove refractory to antiviral and supportive therapy. There are limited reports of hyperbaric oxygen (HBO2) therapy showing benefit for refractory HC cases. We describe our experience with salvage HBO2 for a 15-yearold male with refractory HC beginning one month post AHSCT and associated with BK virus. Despite supportive therapies including hyperhydration, forced diuresis, transfusions, intravenous and intravesical cidofovir, macroscopic hematuria persisted and resulted in post-obstructive acute renal failure, need for a suprapubic catheter, then bilateral percutaneous nephrostomy tubes. HBO2 was started two months after the AHSCT and one month after detection of BK viremia. In the week prior to starting HBO2 therapy the patient required transfusion with 25 units of red blood cells and seven units of platelets. After HBO2 was started his transfusion requirements progressively decreased, and he had return of renal function. He had no adverse effect from the HBO2. HBO2 therapy could thus be useful in controlling refractory HC after AHSCT.