Hematological Side Effects Research Articles

Gemtuzumab Ozogamicin in Acute Myeloid Leukemia: Efficacy, Toxicity, and Resistance Mechanisms-A Systematic Review.

Acute myeloid leukemia (AML) is a diverse group of leukemias characterized by the uncontrolled proliferation of clonal neoplastic hematopoietic precursor cells with chromosomal rearrangements and multiple gene mutations and the impairment of normal hematopoiesis. Current efforts to improve AML outcomes have focused on developing targeted therapies that may allow for improved antileukemic effects while reducing toxicity significantly. Gemtuzumab ozogamicin (GO) is one of the most thoroughly studied molecularly targeted therapies in adults. GO is a monoclonal antibody against CD33 IgG4 linked to the cytotoxic drug calicheamicin DMH. The use of GO as a chemotherapeutic agent is not generalized for all patients who suffer from AML, particularly for those whose health prevents them from using intensive conventional chemotherapy, in which case it can be used on its own, and those who have suffered a first relapse, where its combination with other chemotherapeutic agents is possible. This systematic review aimed to comprehensively evaluate GO, focusing on its molecular structure, mode of action, pharmacokinetics, recommended dosage, resistance mechanisms, and associated toxicities to provide valuable information on the potential benefits and risks associated with its clinical use. A systematic review of eight scientific articles from 2018 to 2023 was conducted using PRISMA analysis. The results showed that GO treatment activates proapoptotic pathways and induces double-strand breaks, initiating DNA repair mechanisms. Cells defective in DNA repair pathways are susceptible to GO cytotoxicity. GO has recommended doses for newly diagnosed CD33+ AML in combination or as a single agent. Depending on the treatment regimen and patient status, GO doses vary for induction, consolidation, and continuation cycles. Multidrug resistance (MDR) involving P-glycoprotein (P-gp) is associated with GO resistance. The overexpression of P-gp reduces GO cytotoxicity; inhibitors of P-gp can restore sensitivity. Mitochondrial pathway activation and survival signaling pathways are linked to GO resistance. Other resistance mechanisms include altered pharmacokinetics, reduced binding ability, and anti-apoptotic mechanisms. GO has limited extramedullary toxicity compared to other AML treatments and may cause hepatic veno-occlusive disease (HVOD). The incidence of hepatic HVOD after GO therapy is higher in patients with high tumor burden. Hematological side effects and hepatotoxicity are prominent, with thrombocytopenia and neutropenia observed. In conclusion, GO's reintroduction in 2017 followed a thorough FDA review considering its altered dose, dosing schedule, and target population. The drug's mechanism involves CD33 targeting and calicheamicin-induced DNA damage, leading to apoptosis and resistance mechanisms, including MDR and survival signaling, which impact treatment outcomes. Despite limited extramedullary toxicity, GO is associated with hematological side effects and hepatotoxicity.

Efficacy evaluation of carboplatin -etoposide Co-loaded PLGA microparticles for subconjunctival chemotherapy in retinoblastoma

Systemic chemotherapy for retinoblastoma comes with various haematological side effects, hence, require newer treatment approaches. This study developed carboplatin (CPT) and etoposide (ETP) loaded biodegradable PLGA microparticles as a combination therapy for extended action decreasing frequency of administration. CPT and ETP loaded PLGA microparticles (CE-MIP) were prepared by emulsification-spray drying technique. The optimized drug loaded PLGA microparticles were characterized for particle size (3–14 μm), zeta potential (−23.0 to −34.2 mV), entrapment efficiency (ETP - >80 % & CPT - >60 %) and in vitro release (CPT – 4 h & ETP – 72 h). In vitro cytotoxicity studies of CE-MIP showed greater anti-cancer effect (25.33 % cell viability) compared to plain drug mixture (38.56 % cell viability) in Y-79 cells. In WERI-Rb cell lines, the CE-MIP and plain drug mixture at 100 μM showed percent cell viability as 37.82 % and 66.08 % respectively. In the soft agar assay, the CE-MIP treatment demonstrated a significant reduction in the number of colonies (∼50 % reduction) formed compared to control. In orthotropic mouse model of retinoblastoma, the apoptotic effect of subconjunctival CE-MIP (15.7 %) was greater compared to control (7.9 %). Mean tumor burden of CE-MIP treated eyes was significantly smaller compared to the untreated control eyes showing the anti-tumor efficacy of developed CE-MIP.

Incidence of valganciclovir-related leukopenia and neutropenia in solid organ transplant recipients at high risk of cytomegalovirus disease.

Valganciclovir (VGCV) prophylaxis is associated with an increased risk of hematologic side effects. We analyzed the impact of VGCV prophylaxis on leukopenia and neutropenia rates and explored risk factors for its occurrence. Retrospective cohort study of adult cytomegalovirus (CMV)-seronegative solid organ transplantation (SOT) recipients of either CMV-seropositive (CMV D+/R-) or CMV-seronegative (CMV D-/R-) donors between July 2005 and March 2019. CMV D+/R- SOT recipients received 3-12 months of VGCV prophylaxis whereas CMV D-/R- SOT recipients received no VGCV prophylaxis. Competing risk regression was used to calculate risk factors for significant neutropenia (neutrophil count < 1000/μL). A total of 430 CMV-seronegative SOT recipients (median age of 52.1 years, 76.5% males) were included, of which 203 (47.2%) were CMV D+/R- and 227 (52.8%) CMV D-/R-. The unadjusted incidence rate ratio of significant neutropenia attributable to VGCV exposure in the first year post-transplant was 13.50 (95% confidence interval 7.36-27.11). Acute rejection occurred more frequently in neutropenic patients at 32.5% compared to 19.1% in those without neutropenia (p = .033). On multivariate analysis, VGCV prophylaxis for 1-90 days and 91-180 days versus no VGCV were the strongest risk factors for significant neutropenia with a sub-distribution hazard ratio of 39.6 (95% CI, 8.57-182.6) and 13.2 (95% CI, 5.46-32.0), respectively. VGCV prophylaxis is limited by high rates of neutropenia. Future prospective studies are needed to assess alternative CMV prophylactic strategies in SOT recipients.

Segurança clínica à administração intravenosa de células mesenquimais alógenas em cães saudáveis

ABSTRACT Despite the significance of adipose-derived stem cells in complementary and regenerative medicine, studies regarding clinical safety for allogeneic intravenous administration in healthy dogs remain insufficiently conducted. This study aimed to assess cellular viability through laboratory and microbiological evidence, along with genetic markers, in addition to evaluating clinic-laboratory safety for allogeneic intravenous administration of adipose-derived stem cells in healthy dogs. To achieve this, two cell batches and eight dogs were included in the study. The results revealed positive genetic markers for CD29, CD44, CD105, SOX2, and OCT3.4. Both batches exhibited positive cell differentiation into adipocytes, chondrocytes, and osteoblasts. Microbiological evidence showed negative results, and cell viability after thawing indicated 92% and 88.5% viable cells after 30 minutes, and 86% and 83.5% after 24 hours, respectively, for both batches. Hematological cell counts and serum biochemical enzyme levels, before and after intravenous treatment, did not exhibit statistical differences between the time points (p&gt;0.05). Median values remained within the reference range for the species during and after 30 days of treatment. Based on the cellular viability results, observed patterns, and the absence of hematological side effects, it can be concluded that intravenous therapy with allogeneic adipose-derived stem cells is clinically safe.

Use of venetoclax in t(11;14) positive relapsed/refractory multiple myeloma: A systematic review.

The plasma cell malignancy, multiple myeloma (MM), remains incurable despite advanced treatment protocols. Overexpression of Bcl-2 (an anti-apoptotic protein), in MM harboring the translocation (11;14), contributes to resistance to prior therapy. Venetoclax, a selective oral inhibitor of BCL-2 is a novel agent that shows promise as a therapeutic agent. The objective of this systematic review is to address how the use of venetoclax, alone or as a combination regimen, contributed to the treatment of patients with t(11:14) positive relapsed/refractory multiple myeloma (RRMM). This systematic review was conducted in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was done on 5th June 2022. A literature search was conducted on PubMed and Scopus, 145 articles were screened and 10 studies were included. Risk of bias assessment was performed using the Methodological Index for Non-Randomized Studies (MINORS) criteria. Across the studies reviewed, a total of 311 patients were identified with t(11;14) positive RRMM. The overall response rate achieved ranged between 33% and 95.5%. Furthermore, the use of venetoclax has exhibited a favorable adverse effect profile. Side effects included hematological side effects, nausea, vomiting, and diarrhea. Venetoclax demonstrates promising results. When given with drugs like dexamethasone, daratumumab and carfilzomib, a synergistic effect is seen in treating translocation (11:14) positive relapsed/refractory MM. The use of venetoclax in clinical practice can potentially improve outcomes and quality of life in RRMM patients, and future research should continue to explore this promising treatment option.

Preclinical and Clinical Use of AB1, a DNMT1 Protein Depleter, to Upregulate Fetal Hemoglobin in Townes Sickle Cell Disease (SCD) Mice and Patients with SCD

Background: Sickle Cell Disease (SCD) is an inherited hematologic disorder characterized by lifelong hemolysis, vaso-occlusion and severe complications including pain, acute chest syndrome and stroke among others. Its complex pathophysiology is driven by polymerization of mutated sickle hemoglobin (HbS) in red blood cells. Fetal hemoglobin (HbF) has been well documented to interfere with HbS polymerization, however, γ-globin gene transcription is silenced after birth through the action of a repressor complex including DNA methyltransferase 1 (DNMT1) during hemoglobin switching. We previously demonstrated the ability of AB1, a potent non-cytotoxic agent which depletes DNMT1 protein, to induce HbF in sickle erythroid progenitors. To expand these findings, we aimed to 1) perform preclinical studies in the Townes SCD mouse model to determine the ability of AB1 to induce HbF and deplete DNMT1 protein; and 2) evaluate the safety of oral AB1 in patients with SCD through an open-label, dose escalating phase 1/2 study (NCT05261711). Methods: Preclinical. Townes SCD mice, 4 months old (6 mice per group) were treated by intraperitoneal injections of escalating AB1 doses of 0.5, 1.5 and 3.0 mg/dose, hydroxyurea (HU; 100 mg/kg/dose) alone or HU combined with AB1 (0.5mg/dose) and water control, 5 days/week for 6 weeks. Every 2 weeks, complete blood counts with differentials were performed along with flow cytometry for HbF positive cells (F-cells) and reticulocytes; RT-qPCR for γ- and β-globin mRNA levels was completed and the spleen was harvested for weights and DNMT1 protein levels by Western blot. Clinical Trial. After informed consent, patients with confirmed HbSS or HbSb 0 thalassemia, on stable HU doses (if on treatment), and no recent/chronic transfusions or pain crisis were approached for the study. Patients were enrolled at Duke and Augusta University, starting on 2 mg of AB1 with 4 additional cohorts (4mg, 8mg, 16mg, and 32mg) to be recruited. Doses were taken daily by mouth for 8 weeks. Safety and tolerability (primary outcomes), as well as pharmacokinetics, pharmacodynamics and HbF response (secondary outcomes) were assessed. The F-cells and mean fluorescence intensity were measured by flow cytometry and HbF% by HPLC. Results: Preclinical. In general, SCD mice treated with AB1 showed good weight gain without toxicity. Three deaths occurred in the HU and combination treatment groups along with a significant decrease in platelets, granulocytes, and monocytes; by contrast, one death occurred in the 3mg/kg AB1 group, but the blood or reticulocyte counts were not affected. By week 6, HU increased F-cells by 2.1-fold (p=0.02) compared to a 2.2-fold (p=0.006) and 1.5-fold (p=0.03) increase by AB1 1.5mg/kg and 3.0 mg/kg respectively. Likewise, γ-globin mRNA increased, and β-globin mRNA decreased at the highest dose. Spleen analysis showed decreased weights and an 80% decrease in reactive oxygen species by AB1. Finally, DNMT1 protein levels were depleted by AB1 in spleen tissue. Clinical Trial. The clinical trial opened for enrollment in the winter of 2022. Two patients completed cohort 1 and two patients have enrolled and started cohort 2. Both cohort 1 patients had HbSS with a median age of 29.5 years (range 28-31). No change in total hemoglobin or reticulocyte counts was observed in either subject treated with 2mg AB1 daily. During the treatment period two adverse events occurred (rash-drug related and elevated liver enzymes-unrelated), however there were no serious adverse events. AB1 increased F-cell levels in subject 1 by 5.7-fold (2.9% to 16.4%). Expanded analysis of subject 2 showed an increase in F-cells 3-fold (4.8% to 14.4%) and 3-fold increase in F-reticulocytes. At the lowest 2mg dose, by HPLC analysis both patients had an increase in HbF% from a mean of 6.3% to 7% supporting protein induction by AB1. Discussion: The goal of this project is to develop an oral-active HbF inducer for the treatment of individuals with SCD. Data generated in the SCD mouse showed a significant increase in F-cells and γ-globin gene transcription, along with DNMT1 protein depletion. Subsequent oral AB1 treatment of patients with HbSS confirmed increased F-cells and HbF protein levels without clinical toxicities. These findings support continuing the ongoing phase 1/2 study, which will provide further insights into the ability of AB1 to increase HbF without hematologic side effects in patients with SCD.

CAR-T Cell Therapy Vs. Standard of Care for B-Cell Lymphoma: A Systematic Review and Meta- Analysis of Updated Results of Clinical Trials

Background: For many years, platinum based immunochemotherapy followed by high dose chemotherapy and stem cell transplantation remained standard of care for relapsed/refractory large B-cell lymphoma. About half of the patients do not undergo transplantation due to disease insensitivity to 2 nd line therapy and cured in &amp;lt;30%. In recent years, feasibility of chimeric antigen receptor (CAR) t-cell therapies is tested as 2 nd line of treatment. In this meta-analysis, we will assess the efficacy and safety of CAR-T cell therapy as 2 nd line therapy as compared to standard therapy in large B cell lymphoma based on updated clinical trial results. Methods: A literature search was performed on PubMed and Embase with keywords for “CAR-T cell therapy” and “B-cell lymphoma” from the inception of data till 07/01/2023. PRISMA guidelines were followed while conducting this meta-analysis. A total of 3091 articles were screened and 3 randomized clinical trials (RCTs, N=865) were included based on inclusion criteria. “R” software was used to conduct this meta-analysis. Results: In 3 RCTs (N=865), 180 patients were treated with axicabtagene ciloleucel, 92 patients with lisocabtagene maraleucel, 162 patients with tisagenlecleucel, and 431 patients with standard therapy. Based on updated results of 2 trials (N=543), pooled hazard ratios (HRs) of progression free survival (PFS) was 0.47 (95% CI= 0.37-0.60, I 2=0), overall survival (OS) was 0.73 (95% CI=0.56-0.94, I 2=0), and event free survival (EFS) was 0.4 (95% CI=0.32-0.49, I 2=0) in favor of CAR-T cell therapy as compared to standard therapy. Pooled relative risk (RR) of complete response (CR) and overall response (ORR) were 1.88 (95% CI=1.57-2.25, I 2=2%), and 1.69 (95% CI=1.48-1.92, I 2=0%), respectively, in favor of CAR-T cell therapy. The Belinda RCT on tisagenlecleucel by Bishop et al. was the outlier. HR of EFS, RR of CR, and RR of ORR were 1.07 (95% CI= 0.82-1.4), 1.03 (0.73-1.47), and 1.09 (95% CI= 0.85-1.39), respectively, similar in the two groups. In 3 RCTs, RR of ≥ grade 3 any adverse effects were 1.02 (95% CI=0.92-1.12, I 2=72%), neurotoxicity was 7.35 (95% CI=0.97-55, I 2=64%), and neutropenia was 1.41 (95% CI=1.04-1.91, I 2=78%). Pooled incidence of ≥ grade cytokine release syndrome (CRS) was 5% (CI=0.03-0.08) and was 0 with standard therapy. Fig 1. Conclusion: Based on updated results, CAR-T cell therapies, axicabtagene ciloleucel and lisocabtagene maraleucel, were significantly more effective in terms of response and survival rates. ≥Grade 3 side effects were similar with CAR-T cell and standard therapy. CRS, neurotoxicity, and hematological side effects were higher with CAR-T cells. Tisagenlecleucel was found as an outlier and the efficacy was similar to standard care. More randomized double-blind large-scale phase III clinical trials are needed to confirm these results.

Efficacy and Safety of Polatuzumab Vedotin in Follicular Lymphoma: A Systematic Review of Clinical Trials

Introduction: Polatuzumab vedotin (Pola) is a humanized anti-CD79b monoclonal antibody linked with antimitotic agent monomethyl auristatin E. On internalization, the linker is cleaved, and antimitotic activity inhibits the cell division and growth of cancer cells. Pola is tested in multiple combinations in relapsed/refractory (RR) follicular lymphoma (FL) in recent years. In this systematic study, we will assess the efficacy and safety of Pola based combinations in RR FL. Methods: A literature search was performed on PubMed with keywords, “Polatuzumab vendotin” and “lymphoma” from the inception of data till 07/01/2023. PRISMA guidelines were followed while conducting this systematic review. We reviewed 160 articles and included 1 randomized clinical trial (RCT, N=41), and 4 non-randomized clinical trials (nRCT, N=163) based on inclusion criteria. Data was extracted for complete response (CR), partial response (PR), overall response (ORR), progression free survival (PFS), overall survival (OS) and ≥grade 3 side effects. Results: In 5 trials (N=204), 13 patients with Pola + atezolizumab (Ate) + obinutuzumab (Obi), 49 patients with Pola + Obi + venetoclax (Ven), 39 patients with Pola + Obi, 62 with Pola + Obi + lenalidomide (Len), and 20 patients with Pola + rituximab (Rit). In an RCT by Morschhauser et al. (N=41), Pola + Rit was compared with pinatuzumab vedotin (Pina) + Rit. ORR, CR, PR, and mPFS was 70%, 45%, 25%, and 15.3 months, respectively with Pola + Rit, as compared to 62%, 5%, 57%, and 12.7 months, respectively, with Pina + Rit. In a trial by Philips et al. (N=39), ORR, CR, PR, and mPFS were 67%, 36%, 31%, and 11.5 months, respectively. In 3 nRCTs (N=124), three drug regimens were used with Pola and Obi as backbone. ORR, CR, PR were 50%-83%, 20%-61%, and 20%-39%. Table 1. ≥ Grade 3 hematological and non-hematological side effects are given in table 1. Conclusion: Pola was well tolerated by most of the patients with FL alone or in combination with Obi, Rit, Len, Ven. Pola had relatively better response and survival rates as compared to Pina in combination with Rit. In early phase clinical trials, three drug regimens of Pola and Obi with Ven, and Len were effective in the treatment of heavily pretreated follicular lymphoma. In an early phase trial, Pola + Obi + Ate had limited efficacy in FL with safety concerns. More randomized double blind multicenter phase III clinical trials are needed to confirm these results.

Efficacy and Safety of FLT-3 Inhibitors in Newly Diagnosed FLT-3 Mutated AML Patients: A Systematic Review of Clinical Trials

Introduction: FMS-like tyrosine kinase 3 (FLT-3) is the most commonly reported gene alteration in acute myeloid leukemia (AML) patients and is associated with relatively poor survival outcomes and response rates. Multiple FLT-3 inhibitors were tested in combination with standard first line therapy in recent years in both medically fit and unfit patients for intensive chemotherapy. In this systematic study, we will assess the efficacy and safety of FLT-3 inhibitors in newly diagnosed patients with AML. Methods: A literature search was performed on PubMed and Embase with keywords for, “FLT-3 mutations” AND “AML” from the inception of data till 6/31/23. PRISMA guidelines were followed while conducting this systematic review. We screened 5,983 articles and included 5 randomized clinical trials (RCTs, N=1,906) and 6 non-randomized clinical trials (nRCTs, N=891) based on inclusion criteria. Results: In 11 clinical trials (N=2,797), 233 patients were unfit for intensive chemotherapy while 2,464 were fit for intensive chemotherapy. 1,906 patients were treated with FLT-3 inhibitor-based regimens while 891 patients were treated with standard therapy. In an RCT by Wang et al. (N=123) on unfit patients, CR/ORR were 58%/63.5% with giltritinib (Gil)+ azacytadine (Aza) vs. 26.5%/34.7% with Aza. Hazard ratio (HR) for overall survival (OS) was 0.9, similar in two groups. In subgroup of an RCT by Dennis et al. (N=27), HR of OS was 0.36 (0.16-0.85) significantly in favor of quizartinib (Qui) + low dose cytarabine (LDAC) vs. LDAC alone. In two nRCTs (N=63) on unfit patients, Qui + venetoclax (Ven) +Aza/LDAC showed complete response (CR)/overall response (ORR) of 42%/72% and Qui+Aza/LDAC showed CR/ORR of 44%/56%. In an RCT by Stone et al. (N=617) on fit patients up to 59 years old, CR/CRi was 58.9% and 53.5% with midostaurin (Mid)+ chemotherapy and chemotherapy, respectively. HRs of event free survival (EFS) and OS were 0.78 (0.66- 0.93) and 0.78 (0.63-0.96), respectively, significantly in favor of Mid+chemotherapy as compared to chemotherapy alone. In two nRCTs (740) including older fit patients up to 85 years of age, CR/CRi was 77% with no new safety signal. In an RCT by Erb et al. (N=539), CR/CRi was 71.6% and 64.9% with Qui + chemotherapy and chemotherapy, respectively. HRs of EFS and OS were 0.92 (0.75-1.11)* and 0.78 (0.62-0.98), respectively, in favor of Qui + chemotherapy (*not statistically significant). In an RCT by Knapper et al. (N=500) on fit patients, HRs of relapse free survival (RFS) and overall survival (OS) were 0.88 (0.69-1.12) and 0.9 (0.7-1.15), respectively, with no significant difference among lustaurtinib (Lus) + chemotherapy vs. chemotherapy alone. In two RCTs (N=88), CR/CRi was 90.9% and 73% with Gil+chemotherapy and crenolanib (Cren) + chemotherapy, respectively. Table 1. ≥3 grade 3 hematological and non-hematological side effects are given in table 1. Conclusion: Addition of Gil, Qui, Lus, Mid, or Cren to standard therapy was well tolerated by most of the patients with FLT-3 mutation. Addition of Mid or Qui to chemotherapy significantly improved survival and response rates as compared to chemotherapy alone in fit patients with FLT-3 mutation and the results were consistent in both young and old fit patients. In early phase trials, Gil and Cren were effective in combination with chemotherapy in fit patients. In subgroup analysis of an RCT, Qui significantly improved survival and response rates in FLT-3 mutated unfit patients in combination with LDAC. Gil and Lus failed to improve survival in FLT-3 mutated unfit and fit patients, respectively. More randomized double-blind multicenter phase III clinical trials are needed to confirm these results.

CYP Inhibition and Low-Dose Dasatinib for Chronic Myeloid Leukemia: Preliminary Results of a Promising, Cost-Effective Treatment Option

Introduction The standard treatment for newly diagnosed (ND)-CML is tyrosine kinase inhibitors (TKIs) such as dasatinib. However, the cost of treatment with these drugs can be prohibitively high. The CYP inhibition strategy involves intentionally inhibiting a specific enzyme, in this case CYP3A4, to increase plasma concentration of dasatinib and reduce the required dose from 100mg to 25mg daily. Patients and methods Five consecutive patients older than 18 years, with ND-CML in chronic phase and Eastern Cooperative Oncology Group (ECOG) of 0-2.The diagnosis and classification of CML followed the ESMO guidelines. After diagnostic confirmation, patients continuously received half pill of dasatinib (25mg orally daily) and a strong CYP3A4 inhibitor (ketoconazole, 200mg orally twice daily). Patients were monitored weekly during the first month and then monthly after that. The response to treatment was established according to the ESMO guidelines. Statistical analysis We examined the distribution of variables using the Shapiro-Wilk test, and descriptive analyses were conducted for demographic and clinical characteristics. The proportion of hematological and non-hematological side effects and the proportion of hematological response were obtained. To demonstrate the effect of dasatinib on hematological cells, we constructed a line plot showing the values of hemoglobin, leukocytes, and platelets in each visit. We compared basal hemoglobin, leukocytes, and platelets vs. follow-up counts at each visit with the Kruskal-Wallis test Results The median age of the patients was 42 years. All patients had a median ECOG score of 0. Three patients (60%) presented with thrombocytosis, three (60%) with splenomegaly, and two patients (40%) had B symptoms. Basal median (range) hemoglobin, leukocytes, and platelets counts were 9.9 g/dL , 272×10 9/L and 451×10 9/L, respectively. Three patients (60%) had low-risk CML, and two patients (40%) had high-risk disease, with a median EUTOS score of 71 points. Dasatinib treatment was initiated within a median of 9 days from diagnosis. In the first 28 days of treatment, median leukocytes and platelets were significantly reduced compared to baseline, with a reduction in leukocytes of 93.7% (125×10 9/L vs. 7.9×10 9/L, p=0.005) and in platelets of 64.6% (407×10 9/L, vs. 144×10 9/L, p=0.027). Hemoglobin levels significantly increased by the second month of treatment, with an increase of 26.4% from baseline (10.2 g/dL vs. 12.9 g/dL, p=0.023). All patients (100%) achieved major hematological response within a median of 22 days. Patient number 1 achieved the 3-month and 6-month treatment goals with 6.4% and &amp;lt;1% reduction in BCR-ABL transcript levels, respectively. After 3 months of treatment, 60% of patients achieved the BCR/ABL1 transcript level on the IS &amp;lt;10%, which is the optimal response according to guidelines, in the rest of the patients the time of evaluation has not been reached. Mild and self-limited adverse events were reported in 40% of patients at some point in their treatment. Non-hematological toxicity occurred in one patient (20%) with nausea and galactorrhea due to ketoconazole. Hematological toxicity occurred in (20%) of patients; the platelet count returned to normal after suspending ketoconazole for one week. No serious adverse events were reported. Conclusion Apart from this preliminary study, there is currently no evidence supporting the intentional use of CYP inhibition to reduce the dosage and cost of dasatinib for patients with ND-CML. Dasatinib is primarily metabolized using the CYP3A4 isoenzyme, and studies have shown that ketoconazole, an accessible antifungal, can strongly inhibit CYP3A4, increase dasatinib's plasma concentration and AUC by 5-fold and 385%, respectively, and allow for a reduction in dosage while maintaining therapeutic efficacy. The CYP inhibition strategy can decrease the cost of dasatinib to a point where it is cheaper than full-dose imatinib -the cheapest TKI- and represent a treatment option for patients who cannot afford full-dose dasatinib in low income countries. The CYP inhibition strategy can be of added value to the lower effective dose concept and give rise to ultra-low-dose schemes. This strategy could significantly increase dasatinib accessibility in many countries by reducing costs from $1,343.7 to $40.3-$100.8 monthly

Detailed review on Bevacizumab and its target therapies

The review in this article focuses on bevacizumab, an agent widely used in a variety of treatment strategies. It provides an overview of the pharmacokinetics and pharmacodynamics of bevacizumab, with a focus on intravenous administration and available specific dose strengths. This article discusses treatment strategies with bevacizumab and emphasizes the importance of understanding its pharmacokinetic properties to optimize its efficacy. In addition, this review covers a wide range of side effects associated with bevacizumab, including cardiovascular, gastrointestinal, hematological, immune, musculoskeletal, nervous, renal, respiratory, and other side effects. The importance of close monitoring and prompt management of adverse events is emphasized to ensure patient safety and optimize patient outcomes. Overall, this literature review provides valuable insight into the use of bevacizumab and helps health professionals make informed decisions regarding dosing, monitoring, and management of side effects.

Clozapine monitoring at a specialised psychiatric hospital: A retrospective chart review

Background: Clozapine is the only Food and Drug Administration (FDA) and National Institute for Care and Excellence (NICE) approved drug for treatment-resistant schizophrenia (TRS). Its potentially life-threatening haematological side effects of neutropaenia and agranulocytosis mandate rigorous monitoring of neutrophil counts, presenting unique, Third-World population challenges.Aim: To describe the Clozapine white blood cell monitoring practice and outcomes in a local psychiatric hospital.Setting: At a specialist Psychiatry unit in Durban, KwaZulu-Natal, which follows a modified algorithm of the South African Standard Treatment Guidelines for Clozapine monitoring.Methods: A retrospective chart review composed of 120 patients on Clozapine treatment from 01 July 2018–31 December 2020. Demographic and clinical information was captured in a Redcap database. Descriptive statistics using categorical variables were used.Results: The study population was from a low socioeconomic background, with low levels of education and employment. A baseline neutrophil count was recorded in 58 files (48.3%). Clozapine was stopped in 6 out of the 120 patients due to ‘neutropaenia’ (absolute neutrophil counts ranging from 1.18 to 1.6); none developed agranulocytosis. Their duration of Clozapine treatment ranged from 2 weeks–15 years.Conclusion: Haematological monitoring frequency and documentation of patients receiving Clozapine were not in compliance with the hospital’s adapted guidelines and may have resulted in the termination of treatment before true neutropaenia developed. Patients developed neutropaenia at low doses of Clozapine and after many years of treatment.Contribution: These results suggest local Clozapine monitoring guidelines should be more strictly adhered to.

DNA repair biomarkers to guide usage of combined PARP inhibitors and chemotherapy: A meta-analysis and systematic review

PurposeThe addition of PARP inhibitors to chemotherapy has been assessed in > 80 clinical trials across multiple malignancies, on the premise that PARP inhibitors will increase chemotherapy effectiveness regardless of whether cancers have underlying disruption of DNA repair pathways. Consequently, the majority of combination therapy trials have been performed on patients without biomarker selection, despite the use of homologous recombination deficiency to dictate use of PARP inhibitors in the maintenance setting. An unresolved question is whether biomarkers are needed to identify patients who respond to combination PARP inhibitors and chemotherapy. MethodsA systematic literature review identified studies using PARP inhibitors in combination with chemotherapy versus chemotherapy alone, where the study included a biomarker of DNA repair function (BRCA1, BRCA2, homologous recombination deficiency test, ATM, ERCC1, SLFN11). Hazard ratios (HR) were pooled in a meta-analysis using generic inverse-variance, and fixed or random effects modelling. Subgroup analyses were conducted on biomarker selection and type of malignancy. ResultsNine studies comprising 2547 patients met the inclusion criteria. Progression-free survival (PFS) was significantly better in patients with a DNA repair biomarker (HR: 0.57, 95% CI: 0.48–0.68, p < 0.00001), but there was no benefit in patients who lacked a biomarker (HR: 0.94, 95% CI: 0.82–1.08, p = 0.38). Subgroup analysis showed that BRCA status and SLFN11 biomarkers could predict benefit, and biomarker-driven benefit occurred in ovarian, breast and small cell lung cancers. The addition of PARP inhibitors to chemotherapy was associated with increased grade 3/4 side effects, and particularly neutropenia. ConclusionsCombination therapy only improves PFS in patients with identifiable DNA repair biomarkers. This indicates that PARP inhibitors do not sensitise patients to chemotherapy treatment, except where their cancer has a homologous recombination defect, or an alternative biomarker of altered DNA repair. While effective in patients with DNA repair biomarkers, there is a risk of high-grade haematological side-effects with the use of combination therapy. Thus, the benefit in PFS from combination therapy must be weighed against potential adverse effects, as individual arms of treatment can also confer benefit.

Effect of Aloe vera extract on some parameter liver functions changes and complete blood count induced by Azathioprine in male rats

The present study aimed to reveal the biological vitality of the immune suppressant medicine azathioprine (AZA), which has been used to treat immunological illnesses like acute lymphoblastic leukemia (ALL), inflammatory bowel disease, and organ transplants, successfully lowers immune reactivity for liver and bone marrow. The goal of the current study was to evaluate the preventive effects of Aloe Vera extract in treating hematological and biochemical side effects brought on by azathioprine. Have been selected There were four groups of adult male rats. A mixture of azathioprine (50 mg/kg) and Aloe Vera (500 mg/kg) was given to group 4 in addition saline that group 1 received. Group 2 received azathioprine (50 mg/kg) orally for during a 30 days period. The findings show that azathioprine significantly reduced blood test results (RBC , WBC , PCV). While AST and ALT levels significantly increased in the biochemical test in contrast to the control group , Conclusions the Hepatotoxicity, or liver damage from immunosuppressive medications like azathioprine, is a possible side effect and Due to the damage that has happened to the hepatic tissue, the enzymes that assess the activities of the liver are raised.

P11.80.A DOUBLE BLIND RANDOMISED TRIAL WITH ADD-ON OF VALGANCICLOVIR OR PLACEBO TO STANDARD THERAPY OF NEWLY DIAGNOSED GLIOBLASTOMA

Abstract BACKGROUND The origin of glioblastoma is not known. Our earlier and other groups research have shown the presence of cytomegalovirus in glioblastoma, but not in adjacent tumor-free tissue. Furthermore there is a significant correlation between the amount of virus proteins in the tumor and prognosis, patients with low tumoral load have longer survival compared to patient with hogh tumoral viral load. In a retrospective study with 100 newly diagnosed patients with glioblastoma we showed tha the addition of valganciclovir yielded a median survival of 25 months as compared to 13 months for contemporary controls from the same institution. In the case of maximal surgical resection, the median survival reached 29 months. We therefore aimed to run a randomised doule blind study in newly diagnosed glioblastoma. MATERIAL AND METHODS The study started in September 2019, and has the goal to recruit 220 patients, 110 in the valganciclovir group and 110 in the placebo. A macroscopic surgery (at least 90% resection of contrast enhancing tumor on post op MRI), followed by radiation and chemotherapy with temozolomide. Patients receive the study drug, 900mg twice daily during the first 6 weeks, followed by maintenance 450mg twice daily for 2 years. There is no cross-over. The use of Optune is allowed. There is a stratification for MGMT methylation status. Only IDH1 wt tumors can be included, and the randomization has to take place within 10 weeks from surgery. The primary outcome is overall survival, secondary endpoints are the proportion surviving at 2 years and quality of life. 20 patients who fullfilled inclusions criteria have not been randomised. RESULTS since September 2019, 120 patients have been included at Karolinska Hospital in Stockholm. The oncology clinics in Oslo and Stavanger started including patients in September 2022, and have so far included 20 patients. At Karolinska there are 47 MGMT methylated and 73 unmethylated. Nineteen deceased patients and 45 deceased respectively. The median survival is 22 and 14 months respectively. Forteen patients with MGMT methyl completed the study (24 months and 6 months follow-up) versus 8 in the unmethylated. The survival of 20 patients not randomised was 18 months. Five patients showed reversibel hematological side effects grade 3-4, always with the initial high dose and concomittant to radiochemotherapy. No patient stopped the study due to side effects. CONCLUSION the is an ongoing trial, that has recruited about 35 patients per year at the main center, even during the 2 years of pandemics. about half of newly diagnosed patients are eligible for this study, and more than 80% of eligible patients are randomized which is remarkable for this category of patients. There may be a trend as a group for positive survival results, but we need to wait the final results, which may be available in 2-3 years. The study wil recruit until December 2024.

PROPSEA, safety evaluation of palbociclib and ribociclib in older patients with breast cancer: A prospective real-world TOG study

IntroductionIn this study, the toxicities and management of palbociclib and ribociclib in older patients (≥65 years) with metastatic breast cancer patients were investigated. Materials and MethodsAmong older patients receiving palbociclib and ribociclib, Geriatric 8 (G8) and Groningen Frailty Index were used to evaluate frailty status. Dose modifications, drug withdrawal and other serious adverse events (SAEs) were recorded and analyzed according to baseline patient characteristics. ResultsA total of 160 patients from 28 centers in Turkey were included (palbociclib = 76, ribociclib = 84). Forty-three patients were ≥ 75 years of age. The most common cause of first dose modification was neutropenia for both drugs (97% palbociclib, 69% ribociclib). Liver function tests elevation (10%) and renal function impairment (6%) were also causes for ribociclib dose modification. Drug withdrawal rate was 3.9% for palbociclib and 6% for ribociclib. SAEs were seen in 11.8% of those taking palbociclib and 15.5% of those on riboclib. An ECOG performance status of ≥2 and being older than 75 years were associated with dose reductions. Severe neutropenia was more common in patients with non-bone-only metastatic disease, those receiving treatment third-line therapy or higher, coexistance of non-neutropenic hematological side effects (for ribociclib). Neutropenia was less common among patients with obesity. DiscussionOur results show that it can be reasonable to start palbociclib and ribociclib at reduced dose in patients aged ≥75 years and/or with an ECOG performance status ≥2.

Nitrous oxide-induced polyneuropathy, pancytopenia and pulmonary embolism: a case report

BackgroundNitrous oxide is a medical and household gas that has seen its use drift to recreational purpose among the young population in recent years. Significant neurological, hematological and psychiatric side effects, generally related to an induced functional vitamin B12 deficiency, have been described separately in the literature.Case reportA 22-year-old woman of North African origin experienced an exceptional combination of polyneuropathy, bilateral pulmonary embolism and severe pancytopenia related to vitamin B12 deficiency and hyperhomocysteinemia induced by recreational nitrous oxide use. After treatment with vitamin B12 supplementation and intensive rehabilitative management, the patient progressively regained the ability to walk and her biological parameters gradually returned to normal. The pathophysiological mechanisms related to a decrease in vitamin B12 activity are the reduction of products needed for synthesis of deoxyribonucleic acid, carbohydrate or fatty acids, and the increase of hyperhomocysteinemia. Other mechanisms involving a direct action of N2O are also suspected.ConclusionThis case report brings elements to support our knowledge about pathological pathway, recovery and prognosis of recreational N2O abuse complications. The general and medical population should be aware to the serious consequences of this type of consumption.

The prevalence and risk factors of coagulopathy in pediatric patients undergoing surgery for epilepsy.

Hematological consequences of novel antiseizure medications (ASMs) or combined therapies are rarely reported, especially in pediatric patients undergoing surgery for epilepsy. This study aimed to assess the prevalence and risk factors of coagulation dysfunction in this population and evaluate their relationship with intra- and postoperative bleeding. Three hundred ninety children who underwent surgery for epilepsy and 104 children without epilepsy who underwent nonepilepsy surgery at the authors' center were included in the study. The authors retrospectively collected and analyzed the following clinical data: sex, age, weight, course of epilepsy, antiseizure therapy, first laboratory data after admission, and transfusion-related data. ASMs were responsible for the higher incidence of coagulation dysfunction in pediatric epilepsy surgery patients. Low body weight (OR 0.95, 95% CI 0.92-0.98) and valproic acid (VPA) therapy (OR 5.13, 95% CI 3.25-8.22) were the most relevant factors leading to coagulation dysfunction. The most common hematological side effects of VPA were thrombocytopenia and hypofibrinogenemia, whereas low body weight was only associated with hypofibrinogenemia. Both VPA and low body weight increased the need for intra- or postoperative transfusion (p < 0.001). Pediatric epilepsy surgery patients often take multiple ASMs, resulting in an increased incidence of coagulopathy. VPA levels and low body weight were found to be the main influential factors associated with an increased risk of coagulation dysfunction. Platelet and fibrinogen levels were the main indices that were affected. Both VPA and low body weight were relevant to additional surgery-related transfusion, necessitating the need for increased awareness of preoperative coagulopathy before pediatric epilepsy surgery. Clinical trial registration no.: NCT05675254 (ClinicalTrials.gov).

Hematological Side Effects Management of Paclitaxel - Carboplatin Chemotherapy in Lung Cancer

Background: Paclitaxel-carboplatin chemotherapy can cause hema-tological disorders. This regiment's hematological side effects include anemia, neutropenia, and thrombocytopenia. Data showed this regiment side effect occurs with grade iii/iv toxicity anemia, grade III/IV anemia by 41%, neutropenia (78%), and thrombocytopenia (41%). This hema-tological disorder occurs in bone marrow-producing areas due to chemotherapy. Each hematological disorder requires separate interven-tion.Case Presentation: A 54-year-old woman was diagnosed with a progressive disease of left lung adenocarcinoma (Exon 21 mutation) with TKI and received paclitaxel-carboplatin chemotherapy. The patient experienced side effects of anemia, neutropenia, and thrombocytopenia. Anemia was treated with PRC transfusion, neutropenia corrected with Filgrastim, and thrombocytopenia with platelet transfusion. Chemo-therapy was discontinued after five cycles because the Thrombo-cytopenia condition did not improve.Conclusion: Hematological parameters are essential in preparing for lung cancer chemotherapy. Uncorrectable hematological disorders lead to discontinuation of chemotherapy

Relaps/refrakter T hücreli akut lenfoblastik lösemili erişkin hastalarda klofarabin, siklofosfamid, etoposid (CLOVE): tek merkez deneyimi

Purpose: Clofarabine is a second-generation purine analog that inhibits DNA synthesis. It is used as an effective new agent in relapsed refractory acute leukemia. We aimed to report our single center experience about CLOVE protocol as a clofarabine-based regimen in patients with relapsed or refractory T-cell acute lymphoblastic leukemia. &#x0D; Materials and Methods: Thirteen patients with relapsed or resistant T-cell acute lymphoblastic leukemia were included in this study. Patients were administered clofarabine (40 mg/m2/day), etoposide (100 mg/m2/day), and cyclophosphamide (440 mg/m2/day) (5 days chemotherapy). The patients' data were reviewed retrospectively, the demographic and clinical characteristics of patients were recorded.&#x0D; Results: The patients' median age was 47, and 77% (n:10) of them were male. The median number of chemotherapy regimens they received before clofarabine was 3. Of the patients, 54% (n=7) presented with relapse, and 46% (n=6) with refractory disease. Hematological side effects were observed in all patients during treatment, and 4 (31%) patients were complicated by febrile neutropenia. Other side effects were hepatotoxicity 39%, skin reaction 2%, nausea 54%, and mucositis 31%. Three (23%) patients were unresponsive to treatment. A response was obtained in 10 (77%) patients. Allogeneic stem cell transplantation was performed in 4 of 5 patients with complete response. The median follow-up time after CLOVE was 2.3 (0.69-26.02) months. The median estimated survival time was 21.04 ± 3.88 (95%CI: 13.43 -28.64) months. Overall survival was 85.7% at three months and 57.1% at one year. Three patients were alive at the end of our study.&#x0D; Conclusion: The combination of clofarabine, etoposide, and cyclophosphamide (CLOVE) appears to be successful in achieving a response in relapsing or resistant acute leukemia. However, more effective regimens are still needed.