-
The Lancet. Haematology Jun 2024Realizing Effectiveness Across Continents with Hydroxyurea (REACH) is an open-label non-randomised trial of hydroxyurea (hydroxycarbamide) in children with sickle cell...
BACKGROUND
Realizing Effectiveness Across Continents with Hydroxyurea (REACH) is an open-label non-randomised trial of hydroxyurea (hydroxycarbamide) in children with sickle cell anaemia in sub-Saharan Africa. The short-term results of REACH on safety, feasibility, and effectiveness of hydroxyurea were published previously. In this paper we report results from extended hydroxyurea treatment in the REACH cohort up to 8 years.
METHODS
In this open-label, non-randomised, phase 1/2 trial, participants were recruited from four clinical sites in Kilifi, Kenya; Mbale, Uganda; Luanda, Angola; and Kinshasa, Democratic Republic of Congo. Eligible children were 1-10 years old with documented haemoglobin SS or haemoglobin Sβ zero thalassaemia, weighing at least 10 kg. Participants received fixed-dose hydroxyurea of 17.5 (±2.5) mg/kg per day for 6 months (fixed-dose phase), followed by 6 months of dose escalation (2·5-5·0 mg/kg increments every 8 weeks) as tolerated, up to 20-35 mg/kg per day (maximum tolerated dose; MTD), defined as mild myelosuppression. After the MTD was reached, hydroxyurea dosing was optimised for each participant on the basis of changes in bodyweight and laboratory values over time (MTD with optimisation phase). After completion of the first 12 months, children with an acceptable toxicity profile and favourable responses were given the opportunity to continue hydroxyurea until the age of 18 years. The safety and feasibility results after 3 years has been reported previously. Here, haematological responses, clinical events, and toxicity rates were compared across the dosing phases (fixed-dose hydroxyurea vs MTD with optimisation phase) as protocol-specified outcomes. REACH is registered on ClinicalTrials.gov (NCT01966731) and is ongoing.
FINDINGS
We enrolled 635 children between July 4, 2014, and Nov 11, 2016. 606 children were given hydroxyurea and 522 (86%; 266 [51%] boys and 256 [49%] girls) received treatment for a median of 93 months (IQR 84-97) with 4340 patient-years of treatment. The current (Oct 5, 2023) mean dose is 28·2 (SD 5·2) mg/kg per day with an increased mean haemoglobin concentration (7·3 [SD 1·1] g/dL at baseline to 8·5 [1·5] g/dL) and mean fetal haemoglobin level (10·9% [SD 6·8] to 23·3% [9·5]) and decreased absolute neutrophil count (6·8 [3·0] × 10 cells per L to 3·6 [2·2] × 10 cells per L). Incidence rate ratios (IRR) comparing MTD with fixed-dose hydroxyurea indicate decreased vaso-occlusive episodes (0·60; 95% CI 0·52-0·70; p<0·0001), acute chest syndrome events (0·21; 0·13-0·33; p<0·0001), recurrent stroke events (0·27; 0·07-1·06; p=0·061), malaria infections (0·58; 0·46-0·72; p<0·0001), non-malarial infections (0·52; 0·46-0·58; p<0·0001), serious adverse events (0·42; 0·27-0·67; p<0·0001), and death (0·70; 0·25-1·97; p=0·50). Dose-limiting toxicity rates were similar between the fixed-dose (24·1 per 100 patient-years) and MTD phases (23·2 per 100 patient-years; 0·97; 0·70-1·35; p=0·86). Grade 3 and 4 adverse events were infrequent (18·5 per 100 patient-years) and included malaria infection, non-malarial infections, vaso-occlusive pain, and acute chest syndrome. Serious adverse events were uncommon (3·6 per 100 patient-years) and included malaria infections, parvovirus-associated anaemia, sepsis, and stroke, with no treatment-related deaths.
INTERPRETATION
Hydroxyurea dose escalation to MTD with dose optimisation significantly improved clinical responses and treatment outcomes, without increasing toxicities in children with sickle cell anaemia in sub-Saharan Africa.
FUNDING
US National Heart, Lung, and Blood Institute and Cincinnati Children's Research Foundation.
Topics: Humans; Hydroxyurea; Anemia, Sickle Cell; Child, Preschool; Child; Male; Female; Africa South of the Sahara; Follow-Up Studies; Infant; Antisickling Agents; Treatment Outcome; Dose-Response Relationship, Drug
PubMed: 38701812
DOI: 10.1016/S2352-3026(24)00078-4 -
The American Journal of Managed Care May 2024Numerous advances in the standard of care for metastatic colorectal cancer (mCRC), including the approval of several new treatments indicated for treatment in the third...
Numerous advances in the standard of care for metastatic colorectal cancer (mCRC), including the approval of several new treatments indicated for treatment in the third line or later (3L+), have been made, yet data and appropriate guidance on the optimal sequencing and treatment strategies for these lines of therapy are lacking. Four treatments-regorafenib, trifluridine/tipiracil alone or with bevacizumab, and fruquintinib-are FDA-approved and recommended by the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for the treatment of mCRC in the 3L+. When considering sequencing of treatment options for patients in the 3L+, the goal of treatment is to improve survival, but also maintain quality of life, a goal that requires consideration of relative efficacy and cumulative toxicity such as persistent myelosuppression.
Topics: Humans; Colorectal Neoplasms; Trifluridine; Antineoplastic Combined Chemotherapy Protocols; Thymine; Bevacizumab; Pyridines; Phenylurea Compounds; Pyrrolidines; Drug Combinations; Neoplasm Metastasis; Quality of Life
PubMed: 38701364
DOI: 10.37765/ajmc.2024.89546 -
In Vivo (Athens, Greece) 2024Immune checkpoint inhibitors can induce immune-related adverse events in various organs, thus careful observation is required.
BACKGROUND/AIM
Immune checkpoint inhibitors can induce immune-related adverse events in various organs, thus careful observation is required.
CASE REPORT
A 69-year-old man was diagnosed with advanced lung adenocarcinoma and treated with combined therapy of carboplatin plus pemetrexed plus pembrolizumab. After two cycles of treatment, anemia was noted. Myelosuppression due to cytotoxic anticancer agents was suspected and the cytotoxic agents were discontinued, followed by three courses of pembrolizumab monotherapy. However, the anemia persisted, requiring red blood cell transfusions. A bone marrow biopsy revealed erythroblast hypoplasia and chromosomal abnormalities, resulting in a diagnosis of pure red cell aplasia. These adverse events were considered immune-related because of the treatment history with an immune checkpoint inhibitor, and 60 mg/day (1 mg/kg/day) of prednisolone was initiated. Anemia improved, and it did not recur during the tapering of prednisolone.
CONCLUSION
Immune-related pure red cell aplasia should be considered for patients presenting anemia during treatment with immune checkpoint inhibitors.
Topics: Humans; Red-Cell Aplasia, Pure; Male; Aged; Adenocarcinoma of Lung; Immune Checkpoint Inhibitors; Lung Neoplasms; Chromosome Aberrations; Antineoplastic Combined Chemotherapy Protocols; Antibodies, Monoclonal, Humanized
PubMed: 38688637
DOI: 10.21873/invivo.13599 -
In Vivo (Athens, Greece) 2024Multiple doses of vaccines against the coronavirus disease (COVID-19) provide patients with cancer the opportunity to continue cancer treatment. This study investigated...
BACKGROUND/AIM
Multiple doses of vaccines against the coronavirus disease (COVID-19) provide patients with cancer the opportunity to continue cancer treatment. This study investigated the safety and efficacy of COVID-19 vaccination in patients with cancer and the optimal timing of vaccination during chemotherapy.
PATIENTS AND METHODS
A total of 131 patients with gastrointestinal (GI) cancer who received two doses of the COVID-19 vaccine were included in this study. This study combined two cohorts: an evaluation cohort of 79 patients receiving chemotherapy and a control cohort of 52 patients under follow-up after radical surgery. None of the patients had any history of COVID-19. Treatment- and vaccine-related adverse events (AEs) were recorded through outpatient interviews and self-reports.
RESULTS
In the evaluation cohort, 62 patients (78.4%) experienced vaccine-related AEs after the first dose, and 62 patients (78.4%) experienced vaccine-related AEs with an increased rate of fever and fatigue after the second dose. In the control cohort, vaccine-related AEs occurred in 28 (53.8%) patients after the first dose and in 37 (71.2%) patients after the second dose, with increased fever and fatigue after the second dose. Of the 79 patients, 49 received chemotherapy before vaccination. Twelve patients (24.5%) changed their treatment schedule: four for safety reasons, four for myelosuppression, and four for convenience. Three patients discontinued the treatment because of disease progression.
CONCLUSION
Systemic chemotherapy in patients with GI cancer does not have a markedly negative effect on COVID-19 vaccination, resulting in manageable vaccine-related AEs, and minimizing the need for treatment schedule changes.
Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Antineoplastic Agents; COVID-19; COVID-19 Vaccines; Gastrointestinal Neoplasms; Vaccination
PubMed: 38688608
DOI: 10.21873/invivo.13566 -
Pharmacogenetics and Genomics Jul 2024Acute lymphoblastic leukemia (ALL) is the most frequent pediatric cancer. 6-Mercaptopurine (6-MP) is a key component of ALL treatment. Its use, however, is also...
Acute lymphoblastic leukemia (ALL) is the most frequent pediatric cancer. 6-Mercaptopurine (6-MP) is a key component of ALL treatment. Its use, however, is also associated with adverse drug reactions, particularly myelosuppression. Thiopurine S-methyltransferase (TPMT) and, more recently, Nudix hydrolase 15 (NUDT15) deficiency, due to no-function variants in their respective genes, are well known for their role in the development of this toxicity. Two novel genetic variants, rs12199316 in TPMT and rs73189762 in the NUDT15 gene, were recently identified by targeted sequencing. The latter is particularly interesting because of its potential association with 6-MP intolerance. Here, we assessed the relationship of this variant with the risk of myelosuppression and 6-MP dose intensity in 275 patients treated with Dana Farber Cancer Institute ALL protocols at the Sainte Justine University Health Center. Carriers of the NUDT15 rs73189762 variant allele were at a higher risk of myelosuppression, as shown by absolute phagocyte count reduction during consolidation II and maintenance phases of therapy. Reduction in 6-MP dose intensity was observed in patients with both rs73189762 and known no-function variants in the NUDT15 and TPMT genes. This finding supports the initial observation and suggests that 6-MP dose reduction might be beneficial for individuals with this genotype combination.
Topics: Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Child; Male; Female; Child, Preschool; Adolescent; Antimetabolites, Antineoplastic; Methyltransferases; Infant; Polymorphism, Single Nucleotide; Nudix Hydrolases
PubMed: 38682355
DOI: 10.1097/FPC.0000000000000533 -
Cureus Mar 2024Pineal parenchymal tumors (PPTs) are rare, accounting for less than 0.3% of all primary central nervous system (CNS) tumors. Pineal parenchymal tumors of intermediate...
Pineal parenchymal tumors (PPTs) are rare, accounting for less than 0.3% of all primary central nervous system (CNS) tumors. Pineal parenchymal tumors of intermediate differentiation (PPTID) (WHO grade 2 or 3) show an intermediate prognosis between pineocytoma and pineoblastoma. The clinical course is unknown, and the optimal treatment for PPTID, especially for recurrence, has not been determined. We report a case of PPTID with spinal dissemination over 10 years after treatment and survival for four years. A 56-year-old woman presented with headaches and diplopia. Computerized tomography (CT) and magnetic resonance imaging (MRI) revealed a pineal mass, but leptomeningeal dissemination was not identified on whole-spine MRI. Microsurgical gross total tumor resection (GTR) was performed, and the pathological diagnosis was PPTID (grade 3). In addition, a later study found it to harbor a mutation. She underwent whole-brain radiation therapy with a focal boost. The patient was unable to continue chemotherapy for severe myelosuppression after the first course of treatment. Eleven years after the surgery, she was unable to walk, and a whole-spine MRI revealed multiple masses at C3-4, T4, and cauda equina. Fluorodeoxyglucose-positron emission tomography (FDG-PET) revealed accumulations of the same lesions. No recurrence was observed in the brain. A biopsy of the caudal portion was performed, and the histopathological findings were the same as those of the initial surgery. Spinal dissemination was refractory to chemotherapy but responded to whole spine radiotherapy with focal boost, and she remained tumor-free for four years. We considered good local control with a combination of GTR and subsequent radiation therapy to contribute to long-term survival. The timing of spinal radiation administration is controversial because of the tendency for late cerebrospinal dissemination. The importance of long-term follow-up of the spine and head is emphasized. In PPTID cases with good local control, withholding spinal radiation until spinal dissemination occurs may become a long-term treatment plan.
PubMed: 38681294
DOI: 10.7759/cureus.57147 -
Viruses Mar 2024HHV-6B reactivation affects approximately half of all allogeneic hematopoietic cell transplant (HCT) recipients. HHV-6B is the most frequent infectious cause of... (Review)
Review
HHV-6B reactivation affects approximately half of all allogeneic hematopoietic cell transplant (HCT) recipients. HHV-6B is the most frequent infectious cause of encephalitis following HCT and is associated with pleiotropic manifestations in this setting, including graft-versus-host disease, myelosuppression, pneumonitis, and CMV reactivation, although the causal link is not always clear. When the virus inserts its genome in chromosomes of germ cells, the chromosomally integrated form (ciHHV6) is inherited by offspring. The condition of ciHHV6 is characterized by the persistent detection of HHV-6 DNA, often confounding diagnosis of reactivation and disease-this has also been associated with adverse outcomes. Recent changes in clinical practice in the field of cellular therapies, including a wider use of post-HCT cyclophosphamide, the advent of letermovir for CMV prophylaxis, and the rapid expansion of novel cellular therapies require contemporary epidemiological studies to determine the pathogenic role and spectrum of disease of HHV-6B in the current era. Research into the epidemiology and clinical significance of HHV-6B in chimeric antigen receptor T cell (CAR-T cell) therapy recipients is in its infancy. No controlled trials have determined the optimal treatment for HHV-6B. Treatment is reserved for end-organ disease, and the choice of antiviral agent is influenced by expected toxicities. Virus-specific T cells may provide a novel, less toxic therapeutic modality but is more logistically challenging. Preventive strategies are hindered by the high toxicity of current antivirals. Ongoing study is needed to keep up with the evolving epidemiology and impact of HHV-6 in diverse and expanding immunocompromised patient populations.
Topics: Herpesvirus 6, Human; Humans; Hematopoietic Stem Cell Transplantation; Virus Activation; Roseolovirus Infections; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Graft vs Host Disease
PubMed: 38675841
DOI: 10.3390/v16040498 -
Journal of Clinical Medicine Apr 2024: Linezolid is used for Gram-positive bacterial infections. Thrombocytopenia is one of its main adverse effects resulting from myelosuppression. Several studies have...
: Linezolid is used for Gram-positive bacterial infections. Thrombocytopenia is one of its main adverse effects resulting from myelosuppression. Several studies have assessed risk factors that may increase the risk of this adverse effect. However, most studies included patients with hemato-oncologic diseases, which may confound such assessments. This study aimed to investigate risk factors for linezolid-associated thrombocytopenia in patients without hemato-oncologic diseases. : This was a multicenter retrospective case-control study of adult patients treated with linezolid twice daily for ≥3 days. Patients with hemato-oncologic diseases, active dengue fever, active COVID-19, baseline platelet count <100 × 10/mm, concurrent therapy with trimethoprim/sulfamethoxazole or valproic acid, and a recent platelet transfusion within 7 days were excluded. Thrombocytopenia was defined as a drop in platelet count below 100 × 10/mm. : Out of 158 evaluated patients, 33 developed thrombocytopenia, indicating an incidence rate of 20.9%. Of all the risk factors assessed, creatinine clearance of <60 mL/min and bacteremia/infective endocarditis were significantly associated with linezolid-associated thrombocytopenia (adjusted odds ratios, 3.25 and 5.95; 95% CI 1.12-9.45 and 1.23-28.66; = 0.031 and 0.026, respectively). End of therapy platelet counts were significantly lower in the cases than in the controls (79 vs. 243 × 10/mm; < 0.001). Similarly, the percentage of platelet count change was significantly different (-55.1% vs. -10.2%; < 0.001). : In our study, the incidence rate of linezolid-associated thrombocytopenia was 20.9%, and we found that patients with renal impairment and bacteremia may need close monitoring of platelet counts. Prospective studies are warranted to evaluate the potential need for renal dose adjustment.
PubMed: 38673653
DOI: 10.3390/jcm13082380 -
Journal of the American Animal Hospital... May 2024Only one report on the successful use of filgrastim (granulocyte colony-stimulating factor) in cats for severe neutropenia following azathioprine toxicity exists. Here,...
Only one report on the successful use of filgrastim (granulocyte colony-stimulating factor) in cats for severe neutropenia following azathioprine toxicity exists. Here, we report on a case in which a cat was prescribed methimazole but the medication was filled incorrectly with azathioprine tablets and the prescription label indicated a methimazole dosing regimen that was administered for three days before recognition of the error. On presentation, the cat's physical examinations were consistent with previous examinations before ingestion of azathioprine. A complete blood cell count revealed neutropenia and leukopenia. The cat later developed hyporexia, dehydration, and vomiting. Treatment included antinausea and appetite stimulant medications, filgrastim, and antibiotics. Filgrastim given as subcutaneous injections over the course of treatment increased neutrophil cell counts after suppression. The cat made a full recovery after responding to the treatment protocol. Based on the perceived response to filgrastim in this single feline case report, its use can be considered for the treatment of azathioprine-induced neutropenia in cats.
Topics: Animals; Cats; Filgrastim; Cat Diseases; Azathioprine; Neutropenia; Medication Errors; Immunosuppressive Agents; Male; Methimazole; Female
PubMed: 38662994
DOI: 10.5326/JAAHA-MS-7409 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Apr 2024To observe the clinical efficacy and safety of venetoclax (VEN) combined with azacitidine (AZA) in the treatment of adult acute myeloid leukemia (AML) patients who are...
OBJECTIVE
To observe the clinical efficacy and safety of venetoclax (VEN) combined with azacitidine (AZA) in the treatment of adult acute myeloid leukemia (AML) patients who are unfit for intensive chemotherapy.
METHODS
The clinical data of 21 adult patients with unfit AML who were treated with VEN combined with AZA in the Second Hospital of Shanxi Medical University from January 2021 to May 2022 were collected, and the efficacy and safety were analyzed retrospectively.
RESULTS
After one course of treatment with VEN and AZA, 16 out of 21 unfit AML patients reached complete remission (CR)/CR with incomplete hematologic recovery (CRi), 2 patients reached partial remission (PR), the overall response rate (ORR) was 85.7%. Among the 16 patients with CR/CRi, 13 achieved minimal residual disease (MRD) negativity. Among the 11 patients with adverse prognosis, 8 achieved CR/CRi. By the deadline of follow-up, the median overall suivival (OS) of the entire cohort was not reached, with 1-year OS rate of 61.7%. The main adverse events of VEN combined with AZA were myelosuppression, gastrointestinal reactions and infections. There were 13 cases of leukopenia, 7 cases of neutropenia, 7 cases of anemia, 4 cases of thrombocytopenia, and these hematologic adverse events were all grade 3-4. There were 11 cases with gastrointestinal reactions and 7 cases with infections. The above adverse events were controllable and tolerable. No tumor lysis syndrome or infection related death occurred.
CONCLUSION
VEN combined with AZA can quickly achieve deep remission in adult patients with unfit AML, and it shows a good safety profile.
Topics: Humans; Leukemia, Myeloid, Acute; Sulfonamides; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Retrospective Studies; Antineoplastic Combined Chemotherapy Protocols; Remission Induction; Treatment Outcome; Male; Adult; Female; Middle Aged
PubMed: 38660834
DOI: 10.19746/j.cnki.issn.1009-2137.2024.02.003