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Blood Jan 2003Enthusiasm for the use of monoclonal antibodies, such as rituximab, has markedly changed the approach to patients with non-Hodgkin lymphomas (NHLs). Nevertheless, more... (Review)
Review
Enthusiasm for the use of monoclonal antibodies, such as rituximab, has markedly changed the approach to patients with non-Hodgkin lymphomas (NHLs). Nevertheless, more effective therapies are needed. Radioimmunotherapy as a form of targeted radiation therapy may add significantly to our therapeutic options. Yttrium Y 90 ibritumomab tiuxetan, recently approved by the Food and Drug Administration, and iodine I 131 tositumomab have demonstrated a high level of activity in patients whose NHL has failed to respond to chemotherapy and rituximab. Toxicities have primarily included prolonged myelosuppression, with a potential risk of treatment-associated myelodysplastic syndrome and acute myelogenous leukemia. Ongoing clinical trials are attempting to better characterize the role of these promising agents.
Topics: Antibodies, Monoclonal; Clinical Trials as Topic; Humans; Lymphoma, Non-Hodgkin; Radioimmunotherapy; Salvage Therapy
PubMed: 12393555
DOI: 10.1182/blood-2002-06-1793 -
Transplantation Reviews (Orlando, Fla.) Dec 2023Despite its use to prevent acute rejection, lifelong immunosuppression can adversely impact long-term patient and graft outcomes. In theory, immunosuppression withdrawal... (Review)
Review
INTRODUCTION
Despite its use to prevent acute rejection, lifelong immunosuppression can adversely impact long-term patient and graft outcomes. In theory, immunosuppression withdrawal is the ultimate goal of kidney transplantation, and is made possible by the induction of immunological tolerance. The purpose of this paper is to review the safety and efficacy of immune tolerance induction strategies in living-donor kidney transplantation, both chimerism-based and non-chimerism-based. The impact of these strategies on transplant outcomes, including acute rejection, allograft function and survival, cost, and immune monitoring, will also be discussed.
MATERIALS AND METHODS
Databases such as PubMed, Scopus, and Web of Science, as well as additional online resources such as EBSCO, were exhaustively searched. Adult living-donor kidney transplant recipients who developed chimerism-based tolerance after concurrent bone marrow or hematopoietic stem cell transplantation or those who received non-chimerism-based, non-hematopoietic cell therapy using mesenchymal stromal cells, dendritic cells, or regulatory T cells were studied between 2000 and 2021. Individual sources of evidence were evaluated critically, and the strength of evidence and risk of bias for each outcome of the transplant tolerance study were assessed.
RESULTS
From 28,173 citations, 245 studies were retrieved after suitable exclusion and duplicate removal. Of these, 22 studies (2 RCTs, 11 cohort studies, 6 case-control studies, and 3 case reports) explicitly related to both interventions (chimerism- and non-chimerism-based immune tolerance) were used in the final review process and were critically appraised. According to the findings, chimerism-based strategies fostered immunotolerance, allowing for the safe withdrawal of immunosuppressive medications. Cell-based therapy, on the other hand, frequently did not induce tolerance except for minimising immunosuppression. As a result, the rejection rates, renal allograft function, and survival rates could not be directly compared between these two groups. While chimerism-based tolerance protocols posed safety concerns due to myelosuppression, including infections and graft-versus-host disease, cell-based strategies lacked these adverse effects and were largely safe. There was a lack of direct comparisons between HLA-identical and HLA-disparate recipients, and the cost implications were not examined in several of the retrieved studies. Most studies reported successful immunosuppressive weaning lasting at least 3 years (ranging up to 11.4 years in some studies), particularly with chimerism-based therapy, while only a few investigators used immune surveillance techniques. The studies reviewed were often limited by selection, classification, ascertainment, performance, and attrition bias.
CONCLUSIONS
This review demonstrates that chimerism-based hematopoietic strategies induce immune tolerance, and a substantial number of patients are successfully weaned off immunosuppression. Despite the risk of complications associated with myelosuppression. Non-chimerism-based, non-hematopoietic cell protocols, on the other hand, have been proven to facilitate immunosuppression minimization but seldom elicit immunological tolerance. However, the results of this review must be interpreted with caution because of the non-randomised study design, potential confounding, and small sample size of the included studies. Further validation and refinement of tolerogenic protocols in accordance with local practice preferences is also warranted, with an emphasis on patient selection, cost ramifications, and immunological surveillance based on reliable tolerance assays.
Topics: Adult; Humans; Kidney Transplantation; Living Donors; Immune Tolerance; Hematopoietic Stem Cell Transplantation; Transplantation, Homologous; Transplantation Tolerance
PubMed: 37709652
DOI: 10.1016/j.trre.2023.100792 -
The Oncologist 2004Topotecan dosing considerations and alternative dosing schedules to reduce and manage myelosuppression during the treatment of relapsed ovarian cancer were reviewed. The... (Review)
Review
Topotecan dosing considerations and alternative dosing schedules to reduce and manage myelosuppression during the treatment of relapsed ovarian cancer were reviewed. The myelosuppression patterns from phase I, II, and III clinical trials were analyzed to evaluate the degree of hematologic toxicity and to determine risk factors predictive of myelosuppression. Additionally, recent publications of alternative topotecan doses and schedules were examined. Extent of prior therapy, prior platinum therapy (particularly carboplatin), advanced age, impaired renal function, and prior radiation therapy were identified as potential risk factors for greater hematologic toxicity after topotecan therapy. Reducing the starting topotecan dose to 1.0 or 1.25 mg/m2/day is recommended to reduce the incidence of severe myelosuppression in high-risk individuals receiving topotecan for 5 consecutive days. Hematopoietic growth factors, transfusion therapy, and schedule adjustments may also help manage myelosuppression. Alternative schedules of 3-day or weekly dosing appear to have less myelotoxicity and are currently under evaluation. The clinical aspects of topotecan-related myelosuppression and results from clinical trials indicate that the dose, and possibly the dosing schedule, of topotecan can be modified to reduce hematologic toxicity and improve tolerance without compromising efficacy. Prospective individualization of topotecan dosing may prevent or minimize dose-limiting myelosuppression and allow patients to achieve the maximum topotecan benefit by improving their ability to complete therapy with fewer treatment delays. Ongoing clinical trials evaluating alternative dosing schedules with superior hematologic tolerability may facilitate the inclusion of topotecan in combination regimens for patients with ovarian cancer. Proposed topotecan dosing guidelines to reduce and manage myelosuppression are outlined.
Topics: Antineoplastic Agents; Drug Administration Schedule; Female; Hematologic Diseases; Humans; Incidence; Ovarian Neoplasms; Practice Guidelines as Topic; Receptors, Colony-Stimulating Factor; Recurrence; Risk Factors; Topotecan
PubMed: 14755013
DOI: 10.1634/theoncologist.9-1-33 -
Oncoimmunology 2023Chemotherapy is the standard of care for most malignancies. Its tumor debulking effect in adjuvant or neoadjuvant settings is unquestionable, although secondary effects...
Chemotherapy is the standard of care for most malignancies. Its tumor debulking effect in adjuvant or neoadjuvant settings is unquestionable, although secondary effects have been reported that paradoxically promote metastasis. Chemotherapy affects the hematopoietic precursors leading to myelosuppression, with neutropenia being the main hematological toxicity induced by cytotoxic therapy. We used renal and lung murine tumor models metastatic to the lung to study chemotherapy-induced neutropenia (CIN) in the metastatic process. Cyclophosphamide and doxorubicin, two myelosuppressive drugs, but not cisplatin, increased the burden of artificial metastases to the lung, by reducing neutrophils. This effect was recapitulated by treatment with anti-Ly6G, the selective antibody-mediated neutrophil depletion that unleashed the formation of lung metastases in both artificial and spontaneous metastasis settings. The increased cancer dissemination was reversed by granulocyte-colony stimulating factor-mediated boosting of neutrophils in combination with chemotherapy. CIN affected the early metastatic colonization of the lung, quite likely promoting the proliferation of tumor cells extravasated into the lung at 24-72 hours. CIN did not affect the late events of the metastatic process, with established metastasis to the lung, nor was there any effect on the release of cancer cells from the primary, whose growth was, in fact, somewhat inhibited. This work suggests a role of neutrophils associated to a common cancer treatment side effect and claims a deep dive into the relationship between chemotherapy-induced neutropenia and metastasis.
Topics: Mice; Animals; Neutropenia; Granulocyte Colony-Stimulating Factor; Lung Neoplasms; Antineoplastic Agents; Cell Proliferation
PubMed: 37538353
DOI: 10.1080/2162402X.2023.2239035 -
BMC Cancer Jan 2023Currently, the standard treatment for locally advanced cervical cancer is concurrent chemoradiation (CCRT). Forty percent of patients present with disease recurrence....
BACKGROUND
Currently, the standard treatment for locally advanced cervical cancer is concurrent chemoradiation (CCRT). Forty percent of patients present with disease recurrence. This study aims to investigate the feasibility, safety and efficacy of neoadjuvant chemotherapy (NACT) with weekly cisplatin and paclitaxel (TP) followed by CCRT.
METHODS
We are conducting a phase III trial comparing the efficacy and side effects of patients with cervical cancer (FIGO 2018 stage IIB to IVA) who were assigned to four cycles of NACT with cisplatin (40 mg/m) and paclitaxel (60 mg/m) weekly followed by CCRT or CCRT alone. In this report, we studied the medium-term effect of 50 patients enrolled in the NACT + CCRT arm. The primary endpoints were the response rate post-NACT and 12 weeks post-CCRT evaluated by MR/CT based on RECIST v 1.1. The secondary endpoints were 3-year OS (overall survival) and PFS (progression-free survival) measured by the Kaplan-Meier method.
RESULTS
Among 50 patients enrolled in the NACT + CCRT arm, the complete and partial response rates were 10.4% and 68.8%, post-NACT. Twelve weeks after treatment completion, the complete response rate was 72.0%, whereas the total response rate (complete and partial response) was 90.0%. After a median follow-up of 28 months, the 3-year OS rate was 83.9%, and the 3-year PFS rate was 73.6%. NACT response was related to superior PFS and OS compared with NACT nonresponse (P < 0.01). Late AEs were exiguous, while early AEs mainly included myelosuppression and gastrointestinal AEs.
CONCLUSIONS
This study showed a good response rate achieved by dose-dense weekly cisplatin and paclitaxel followed by standard CCRT. The treatment regimen is feasible, as evidenced by the acceptable toxicity of NACT and by the high compliance with radiotherapy.
TRIAL REGISTRATION
Protocol version number and date. Chinese clinical trial registry, ChiCTR1900025327; http://www.chictr.org.cn . Registered 24 August 2019. Retrospectively registered, medresman.org.cn/ChiCTR1900025326. The date recruitment began 01-01-2019.
Topics: Female; Humans; Cisplatin; Paclitaxel; Neoadjuvant Therapy; Uterine Cervical Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Recurrence, Local; Chemoradiotherapy; Neoplasm Staging
PubMed: 36641433
DOI: 10.1186/s12885-023-10517-x -
Basic & Clinical Pharmacology &... Mar 2005For many oncological agents, myelosuppression is the dose-limiting toxicity and the quantitative characterisation of the relationship between drug dose, plasma... (Review)
Review
For many oncological agents, myelosuppression is the dose-limiting toxicity and the quantitative characterisation of the relationship between drug dose, plasma concentration and haematological toxicity is of importance in the drug development. Mechanism-based population pharmacokinetic-pharmacodynamic models have been developed for this purpose and the applications of these in candidate selection, first-in-man studies, prodrug and formulation development, dose finding, schedule optimisation, assessing influence of modifying agents, drug combination studies, subgroup identification and feedback individualisation are reviewed.
Topics: Animals; Antineoplastic Agents; Chemistry, Pharmaceutical; Drug Administration Schedule; Drug Design; Drug Therapy, Combination; Humans; Models, Biological; Prodrugs
PubMed: 15733216
DOI: 10.1111/j.1742-7843.2005.pto960310.x -
International Journal of Radiation... Mar 1995The bone marrow is an important dose-limiting cell renewal tissue for chemotherapy, wide-field irradiation, and autologous bone marrow transplantation. Over the past... (Review)
Review
The bone marrow is an important dose-limiting cell renewal tissue for chemotherapy, wide-field irradiation, and autologous bone marrow transplantation. Over the past 5-10 years a great deal has been discovered about the hematopoietic stem cell compartment. Although the toxicity associated with prolonged myelosuppression continues to limit the wider use of chemotherapy and irradiation, ways are being discovered to circumvent this toxicity such as with the increasing use of cytokines. This review describes what is known of how chemotherapy and irradiation damage stem cells and the microenvironment, how cytokines protect hematopoietic cells from radiation damage and speed marrow recovery after chemotherapy or marrow transplantation, and how various types of blood marrow cells contribute to engraftment and long-term hematopoiesis after high doses of cytotoxic agents and/or total body irradiation.
Topics: Animals; Bone Marrow Diseases; Bone Marrow Transplantation; Dogs; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Humans; Mice; Radiation Dosage; Radiation Tolerance; Radiotherapy; Whole-Body Irradiation
PubMed: 7713791
DOI: 10.1016/0360-3016(94)00430-S -
Science Translational Medicine Apr 2023Hematopoietic stem cell transplantation (HSCT) has many potential applications beyond current standard indications, including treatment of autoimmune disease, gene...
Hematopoietic stem cell transplantation (HSCT) has many potential applications beyond current standard indications, including treatment of autoimmune disease, gene therapy, and transplant tolerance induction. However, severe myelosuppression and other toxicities after myeloablative conditioning regimens have hampered wider clinical use. To achieve donor hematopoietic stem cell (HSC) engraftment, it appears essential to establish niches for the donor HSCs by depleting the host HSCs. To date, this has been achievable only by nonselective treatments such as irradiation or chemotherapeutic drugs. An approach that is capable of more selectively depleting host HSCs is needed to widen the clinical application of HSCT. Here, we show in a clinically relevant nonhuman primate model that selective inhibition of B cell lymphoma 2 (Bcl-2) promoted hematopoietic chimerism and renal allograft tolerance after partial deletion of HSCs and effective peripheral lymphocyte deletion while preserving myeloid cells and regulatory T cells. Although Bcl-2 inhibition alone was insufficient to induce hematopoietic chimerism, the addition of a Bcl-2 inhibitor resulted in promotion of hematopoietic chimerism and renal allograft tolerance despite using only half of the dose of total body irradiation previously required. Selective inhibition of Bcl-2 is therefore a promising approach to induce hematopoietic chimerism without myelosuppression and has the potential to render HSCT more feasible for a variety of clinical indications.
Topics: Animals; Chimerism; Hematopoietic Stem Cell Transplantation; Kidney Transplantation; Primates; Transplantation Tolerance; Genes, bcl-2
PubMed: 37018417
DOI: 10.1126/scitranslmed.add5318 -
Basic & Clinical Pharmacology &... Sep 2018The standard chemotherapy for ovarian cancer is paclitaxel/carboplatin. Patients often exhibit myelosuppressive toxicity, and the treatment response varies considerably.... (Randomized Controlled Trial)
Randomized Controlled Trial
The standard chemotherapy for ovarian cancer is paclitaxel/carboplatin. Patients often exhibit myelosuppressive toxicity, and the treatment response varies considerably. In this study, we investigated the previously reported SNPs 1199G>A (rs2229109), 1236C>T (rs1128503), 2677G>T/A (rs2032582), 3435C>T (rs1045642) in ABCB1, and 1196A>G (rs10509681) in CYP2C8 and their association with treatment-induced myelosuppression, progression-free survival (PFS) and overall survival (OS). From the phase III study, OAS-07OVA, 525 patients (All) treated with carboplatin and paclitaxel administered as Paclical (Arm A, n = 260) or Taxol (Arm B, n = 265) were included and genotyped using pyrosequencing. Genotype associations with myelosuppression, PFS and OS were investigated using anova, Kaplan-Meier analysis and Cox proportional hazard models. The most prominent finding was for the ABCB1 variant 3435TT, which was significantly associated with increased PFS in All (hazard ratio (HR) = 0.623), in Arm A (HR = 0.590) and in Arm B (HR = 0.627), as well as increased OS in All (HR = 0.443) and in Arm A (HR = 0.372) compared to the wild-type, 3435CC. For toxicity, the most interesting finding concerned the haplotype, including 1236TT, 2677TT and 3435TT, which was associated with higher neutrophil values in Arm B (p = 0.039) and less neutrophil decrease in All (p = 0.048) and in Arm B (p = 0.021). It is noteworthy that the results varied depending on the treatment arm which indicates that the effects of ABCB1 variants vary with the treatment regimen. Our results reflect the contradictory results of previous studies, confirming that small variations in the composition of treatment regimens and patient populations may influence the interpretation of SNPs effects on treatment outcome.
Topics: ATP Binding Cassette Transporter, Subfamily B; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Disease-Free Survival; Female; Genotype; Humans; Kaplan-Meier Estimate; Middle Aged; Neutrophils; Ovarian Neoplasms; Paclitaxel; Polymorphism, Single Nucleotide; Proportional Hazards Models; Survival Rate; Treatment Outcome
PubMed: 29504705
DOI: 10.1111/bcpt.12997 -
Frontiers in Oncology 2021Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HPSCs) often results in myelosuppression that adversely affects patient health and quality of... (Review)
Review
Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HPSCs) often results in myelosuppression that adversely affects patient health and quality of life. Currently, chemotherapy-induced myelosuppression is managed with chemotherapy dose delays/reductions and lineage-specific supportive care interventions, such as hematopoietic growth factors and blood transfusions. However, the COVID-19 pandemic has created additional challenges for the optimal management of myelosuppression. In this review, we discuss the impact of this side effect on patients treated with myelosuppressive chemotherapy, with a focus on the prevention of myelosuppression in the COVID-19 era. During the COVID-19 pandemic, short-term recommendations on the use of supportive care interventions have been issued with the aim of minimizing the risk of infection, reducing the need for hospitalization, and preserving limited blood supplies. Recently, trilaciclib, an intravenous cyclin-dependent kinase 4 and 6 inhibitor, was approved to decrease the incidence of myelosuppression in adult patients when administered prior to platinum/etoposide-containing or topotecan-containing chemotherapy for extensive-stage small cell lung cancer (ES-SCLC). Approval was based on data from three phase 2 placebo-controlled clinical studies in patients with ES-SCLC, showing that administering trilaciclib prior to chemotherapy significantly reduced multilineage myelosuppression, with patients receiving trilaciclib having fewer chemotherapy dose delays/reductions and myelosuppression/sepsis-related hospitalizations, and less need for supportive care interventions, compared with patients receiving placebo. Several other novel agents are currently in clinical development for the prevention or treatment of multilineage or single-lineage myelosuppression in patients with various tumor types. The availability of treatments that could enable patients to maintain standard-of-care chemotherapy regimens without the need for additional interventions would be valuable to physicians, patients, and health systems.
PubMed: 34307165
DOI: 10.3389/fonc.2021.697908