Hepatitis B relapse after entecavir or tenofovir alafenamide cessation under anti-viral prophylaxis for cancer chemotherapy.

BACKGROUND: No study has comparing hepatitis B virus (HBV) relapse rates among patients with both cancer and hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) who completed anti-viral prophylaxis for chemotherapy and then stopped taking entecavir or tenofovir alafenamide (TAF). METHODS: A total of 227 HBeAg-negative cancer patients without cirrhosis who previously took entecavir (n = 144) or TAF (n = 83) for antiviral prophylaxis were enrolled. RESULTS: The cumulative incidence of virological and clinical relapse at 2 years was 37% and 10.4%, respectively, in the entecavir group, and 46.7% and 19.5%, respectively, in the TAF group. The multivariate analysis revealed that the use of hematologic malignancy, TAF use, and high-viremia group at baseline were independent risk factors for virological relapse, and use of rituximab, TAF use, higher FIB-4 index and high-viremia group at baseline were independent risk factors for clinical relapse. After propensity score-matching, the patients who discontinued TAF therapy still exhibited higher virological (P = 0.031) and clinical relapse rates (P = 0.012) than did those who discontinued entecavir therapy. The patients were allocated to high- (> 2000 IU/mL), moderate- (between 20 and 2000 IU/mL) and low- (< 20 IU/mL) viremia groups. In the high-viremia group, those who had taken TAF for antiviral prophylaxis had higher rates of virological and clinical relapse than did those who had taken entecavir; in the moderate- and low-viremia groups, no significant difference in virological and clinical relapse rates was detected between the entecavir and TAF groups. Three patients experienced hepatic decompensation upon clinical relapse. All three patients were lymphoma and underwent rituximab therapy. One patient developed acute on chronic liver failure and died even though timely retreatment. CONCLUSIONS: In patients with both cancer and CHB who underwent antiviral prophylaxis, TAF use was associated with a higher chance of HBV relapse than entecavir use after nucleos(t)ide analogue cessation, particularly in the high-viremia group. Patients who are hematologic malignancy and undergo a rituximab-containing cytotoxic therapy should be monitored closely after withdrawal from prophylactic NA treatment.

Survey on the Knowledge and Management of Cancer-Associated Thrombosis (CAT) in Haemato-Oncology Patients with Thrombocytopenia among Haematologists and Haematology Residents in Nigeria.

BACKGROUND: Arterial or venous thrombosis can complicate cancer, and 20% of cancer patients may develop venous thromboembolic disorders. Venous thromboembolism (VTE) is common in some haematologic malignancies and may coexist with thrombocytopenia in those haematologic malignancies. We carried out this survey to assess the knowledge and practice of haematologists and resident doctors in haematology in Nigeria regarding the management of thrombocytopenia and cancer-associated thrombosis. METHODS: This was a survey that was shared electronically with participants who were consultant haematologists and resident doctors in haematology in Nigeria.. RESULTS: There were 106 respondents, 70 (66%) of which were consultant haematologists. About a third (30.2%) of the respondents saw 6-10 patients with blood malignancies monthly. Fifty-seven (53.8%) of the respondents carried out risk assessment in their patients for cancer-associated thrombosis (CAT); 63 (59.4%) of the respondents saw 1-2 cancer patients with thrombosis in 3 months. The most common mode of treatment was pharmacological - 94 (88%) respondents used low molecular weight heparin. The most common haematologic malignancies associated with thrombocytopenia were acute leukaemias (69; 67%). The most common decision taken by respondents was to stop anticoagulants and transfuse platelets because the most frequent concern was the risk of bleeding in this group of patients. CONCLUSION: Many haematologists and haematology residents had a high level of awareness, knowledge and good practice regarding thrombocytopenia with CAT in haematooncology patients; however, there is a need for improved knowledge and unified protocols for treatment in line with newer management guidelines.

CONTEXTE: La thrombose artérielle ou veineuse peut compliquer le cancer, et 20 % des patients cancéreux peuvent présenter des troubles thromboemboliques veineux. La thromboembolie veineuse (TEV) est fréquente dans certaines hémopathies malignes et peut coexister avec une thrombocytopénie dans ces hémopathies malignes. Nous avons mené cette enquête pour évaluer les connaissances et la pratique des hématologues et des médecins résidents en hématologie au Nigeria concernant la gestion de la thrombocytopénie et de la thrombose associée au cancer. MÉTHODES: Il s'agit d'une enquête qui a été partagée électroniquement avec les participants qui sont des hématologues consultants et des médecins résidents en hématologie au Nigéria. RÉSULTATS: 106 personnes ont répondu à l'enquête, dont 70 (66%) étaient des hématologues consultants. Environ un tiers (30,2 %) des personnes interrogées voyaient chaque mois 6 à 10 patients atteints de tumeurs hématologiques malignes. Cinquante-sept (53,8 %) des personnes interrogées ont procédé à une évaluation du risque de thrombose associée au cancer chez leurs patients ; 63 (59,4 %) des personnes interrogées ont vu 1 à 2 patients cancéreux atteints de thrombose en 3 mois. Le mode de traitement le plus courant était pharmacologique - 94 (88%) des personnes interrogées utilisaient de l'héparine de faible poids moléculaire. Les hémopathies malignes les plus fréquemment associées à la thrombocytopénie étaient les leucémies aiguës (69 ; 67%). La décision la plus fréquente prise par les personnes interrogées était d'arrêter les anticoagulants et de transfuser des plaquettes parce que la préoccupation la plus fréquente était le risque de saignement dans ce groupe de patients. CONCLUSION: De nombreux hématologues et résidents en hématologie avaient un niveau élevé de sensibilisation, de connaissances et de bonnes pratiques concernant la thrombocytopénie avec CAT chez les patients hémato-oncologiques; cependant, il est nécessaire d'améliorer les connaissances et d'unifier les protocoles de traitement conformément aux nouvelles directives de prise en charge. Mots clés: Thrombose associée au cancer, Hémato-oncologie, Thrombocytopénie, Hemorragie, Thrombose.

Common Cancer Types and Risk of Stroke and Bleeding in Patients With Nonvalvular Atrial Fibrillation: A Population-Based Study in England.

BACKGROUND: The association between cancer and stroke or bleeding outcomes in atrial fibrillation is unclear. We sought to examine how certain types of cancer influence the balance between stroke and bleeding risk in patients with nonvalvular atrial fibrillation (NVAF). METHODS AND RESULTS: We estimated stroke and bleeding risk among adult patients with NVAF and certain types of cancer (breast, prostate, colorectal, lung, and hematological cancer) from 2009 to 2019 based on data from the UK Clinical Practice Research Datalink GOLD and Aurum databases. The control group included patients with NVAF only. Of 177 065 patients with NVAF, 11379 (6.4%) had cancer (1691 breast, 3955 prostate, 1666 colorectal, 2491 hematological, and 1576 lung). Compared with patients without cancer, stroke risk was higher in patients with breast cancer (adjusted hazard ratio [aHR], 1.20 [95% CI, 1.07-1.35) and with prostate cancer (aHR, 1.11 [95% CI, 1.01-1.12) if diagnosed within 6 months before NVAF. The risk of bleeding was increased in subjects with hematological cancer (aHR, 1.55 [95% CI, 1.40-1.71]), lung cancer (aHR, 1.49 [95% CI, 1.25, 1.77]), prostate cancer (aHR, 1.38 [95% CI, 1.28-1.49]), and colorectal cancer (aHR, 1.36 [95% CI, 1.21-1.53]), but not for subjects with breast cancer. The more recent the cancer diagnosis before NVAF diagnosis (within 6 months), the higher the risk of bleeding. CONCLUSIONS: Breast and prostate cancer are associated with increased stroke risk, whereas in some cancer types, the risk of bleeding seemed to exceed stroke risk. In these patients, prescribing of oral anticoagulant should be carefully evaluated to balance bleeding and stroke risk.

Bone morphogenetic protein and cancer in spinal fusion: a propensity score-matched analysis.

OBJECTIVE: Bone morphogenetic protein (BMP) has been increasingly used in spinal surgery to promote arthrodesis. Because BMP stimulates cellular proliferation, its association with tumorigenesis is a concern. Previous research has generated conflicting conclusions on the risk of cancer in patients receiving BMP. The authors aimed to compare the incidence of solid organ and hematopoietic malignancies in patients undergoing spinal arthrodesis with or without BMP. METHODS: The PearlDiver Mariner Patient Claims Database was queried for patients undergoing thoracolumbar fusion between 2015 and 2021. Patients with preexisting malignancy were excluded. Data were analyzed for incidence of solid organ malignancy and hematopoietic malignancy diagnosed after spinal surgery. Propensity score matching using age, sex, tobacco usage, and year of surgery was performed between patients who did and those who did not receive BMP. RESULTS: Among patients without prior solid organ malignancy, BMP was used in 22,139 patients and not used in 306,249. In the propensity score-matched group, 3.1% of the BMP group developed solid organ malignancy following surgery compared with 3.5% in the non-BMP group. The relative risk (RR) of developing solid organ malignancy after BMP exposure was 0.89 (95% CI 0.81-0.98, p = 0.02). Among patients without prior hematopoietic malignancy, BMP was used in 23,505 patients and not used in 328,796 patients. In the propensity score-matched group, 0.4% of the BMP group developed hematopoietic malignancy compared with 0.6% of the non-BMP group. The RR of developing hematopoietic malignancy after BMP exposure was 0.71 (95% CI 0.55-0.93, p = 0.015). CONCLUSIONS: BMP use in thoracolumbar fusion was not associated with an increased risk of new malignancy, which further supports emerging data on the lack of an association between BMP use and increased malignancy.

Amphotericin B colloidal dispersion: an effective drug for the treatment of mucormycosis in China.

Objective: Mucormycosis has emerged as an increasingly important cause of morbidity and mortality in immunocompromised patients, but the effective drugs for the treatment are limited. Hence, the study aimed to summarize the characteristics of mucormycosis in patients with hematological malignancies, and investigate the efficacy and safety of Amphotericin B Colloidal Dispersion (ABCD) in treating mucormycosis. Methods: In this study, patients with mucormycosis complicated by hematological malignancies who received ABCD at the First Affiliated Hospital of Zhengzhou University from April 2021 to May 2022 were retrospectively enrolled. The clinical data of the enrolled patients were collected, and then, the drug response at 2 weeks, 4 weeks, and the end of treatment; the survival rate at 4, 8, and 12 weeks; and the laboratory-related indicators and adverse events (AEs) associated with ABCD were evaluated. Results: In total, 9 patients with mucormycosis complicated by hematological malignancies were enrolled. The main symptoms were fever, cough, and chest pain. In addition, reversed halo signs (RHS) were found on chest CTs. The responses to ABCD at 2 weeks, 4 weeks, and the end of treatment were 100% (9/9), 77.8% (7/9), and 77.8% (7/9), respectively. The survival rates of the patients at 4, 8, and 12 weeks were 77.8% (7/9), 66.7% (6/9), and 66.7% (6/9), respectively. Among laboratory-related indicators, white blood cell (WBC) counts were significantly increased from baseline after 1 and 2 weeks of ABCD treatment (P<0.05), whereas neutrophil counts were only increased significantly from baseline at 2 weeks post-treatment (P<0.05). The most common AEs were infusion-related AEs manifesting as fever, chills, and pruritus. Moreover, none of the patients suffered from renal injury once again. Conclusion: ABCD is a promising treatment strategy for patients with mucormycosis complicated by hematologic malignancies, showing remarkable efficacy and safety.

Hematological and Other Cancers in People Using Clozapine: Analysis of Australian Spontaneous Reports Between 1995 and 2020.

BACKGROUND: Recent observational study evidence suggests that clozapine, unlike other antipsychotics, may be associated with a small increased risk of hematological malignancy. This study described characteristics of hematological and other cancers in those taking clozapine reported to the Australian Therapeutic Goods Administration. METHODS: We analyzed public case reports for "clozapine," "Clozaril," or "Clopine" from January 1995 to December 2020 classified as "neoplasm benign, malignant and unspecified" by the Australian Therapeutic Goods Administration. Data on age, sex, dose, clozapine start and cessation dates, Medical Dictionary for Regulatory Activities reaction terms, and date of cancer were extracted. RESULTS: Overall, 384 spontaneous reports of cancers in people taking clozapine were analyzed. The mean age of patients was 53.9 years (SD, 11.4 years), and 224 (58.3%) were male. The most frequent cancers were hematological (n = 104 [27.1%]), lung (n = 50 [13.0%]), breast (n = 37 [9.6%]), and colorectal (n = 28 [7.3%]). The outcome was fatal for 33.9% of cancer reports. Lymphoma comprised 72.1% of all hematological cancers (mean patient age, 52.1 years; SD, 11.6 years). The median daily dose of clozapine at the time of hematological cancer report was 400 mg (interquartile range, 300-543.8 mg), and the median duration of clozapine use before hematological cancer diagnosis was 7.0 years (interquartile range, 2.8-13.2 years). CONCLUSIONS: Lymphoma and other hematological cancers are overrepresented in spontaneous adverse event reports compared with other cancer types. Clinicians should be aware of the possible association with hematological cancers and monitor for and report any hematological cancers identified. Future studies should examine histology of lymphomas in people using clozapine and corresponding blood level of clozapine.

Mobile Source Benzene Regulations and Risk of Childhood and Young Adult Hematologic Cancers in Alaska: A Quasi-experimental Study.

BACKGROUND: We aimed to evaluate the impact of the EPA's Mobile Source Air Toxics rules (MSAT), which targeted benzene emissions, on childhood and young adult leukemia and lymphoma incidence in Alaska. METHODS: MSAT was implemented in 2011 and produced a dramatic decline in ambient benzene in Alaska. Due to previous benzene-related regulations enacted in the continental United States, MSAT had relatively modest impacts in other states. This created quasi-experimental conditions leveraged in this study. Using 2-year state-level incidence rates of childhood and young adult leukemia and lymphoma for each US state 2001-2018, we examined MSAT-attributable changes in incidence by applying a difference-in-differences approach. RESULTS: We found evidence of a substantial reduction associated with MSAT in incidence of childhood and young adult lymphoma (-1.23 [-1.84, -0.62] cases per 100,000), but not in leukemia (-0.13 [-0.77, 0.51] cases per 100,000). CONCLUSIONS: Our findings are consistent with the hypothesis that MSAT, which reduced benzene levels in Alaska, led to a decline in lymphoma incidence in children and young adults.

Role of Bcl-2 inhibition in myelodysplastic syndromes.

Myelodysplasic syndromes (MDS) are diseases occurring mainly in the elderly population. Although hematopoietic stem cell transplantation is the only hope for cure, a majority of the patients suffering from MDS are too old or frail for intensive treatment regimens such as intensive chemotherapy and transplantation. The gold standard for those patients is currently treatment with hypomethylating agents, although real-life data could not reproduce the overall survival rates reported for the pivotal azacitidine phase III study. MDS treatment is often inspired by treatment for acute myeloid leukemia (AML). The new gold standard for elderly and frail patients not able to undergo intensive treatment regimens in AML is the combination of hypomethylating agents with venetoclax, a BCL-2 inhibitor that also showed excellent treatment outcomes in other hematological malignancies. In this review, we explain the rationale for the use of venetoclax in hematological malignancies, study outcomes available so far and the current knowledge of its use in MDS.

Delayed Adverse Events after Procedural Sedation in Pediatric Patients with Hematologic Malignancies.

Background and objectives: Procedural sedation for bone marrow examination (BME) and intrathecal chemotherapy (ITC) is necessary for pediatric patients with hematological malignancies. There has been no report on adverse events after discharge from the recovery room. This retrospective study evaluated the types and incidences of delayed adverse events among pediatric patients scheduled for BME or ITC under deep sedation in a single center for 3 years. Materials and Methods: The patients were divided into two groups: inpatients (group I) and outpatients (group O). All patients were managed during the procedures and the recovery period. In total, 10 adverse events were assessed; these occurred 2 h (T1, acute), 12 h (T2, early), and 24 h (T3, delayed) after the procedure. The duration of each adverse event was also recorded and was classified as 2 h (D1), 12 h (D2), or 24 h (D3). The data of 263 patients (147 inpatients and 116 outpatients) who met the inclusion criteria were analyzed. Results: The overall incidence of adverse events was statistically significant difference: 48.3% in group I and 33.6% in group O (p = 0.011). The rates of adverse events at T1 and T2 were significantly different between groups I and O (42.8% vs. 11.2% and 7.5% vs. 20.7%, respectively) (p < 0.001). The adverse events were mostly of D1 or D2 duration in both groups. Patients with a higher proportion of ketamine in a propofol−ketamine mixture had a significantly higher proportion of adverse events at T1 (34.6%), as compared with those with a mixture with a lower proportion of ketamine (21.1%) or propofol alone (17.9%) (p = 0.012). Conclusions: The most common adverse events were dizziness or headache; typically, they did not last longer than 12 h. The propofol-ketamine combination with a higher proportion of ketamine seems to produce more adverse events within 2 h after the procedure. Nevertheless, all sedative types appear safe to use without additional management.

Patient-controlled analgesia and oral mucositis pain in hematological malignancies.

Oral mucositis (OM) pain is an anticipated complication of immunosuppressive therapies for hematological malignancies. Opioids are effective for OM-associated pain and dysfunction that is refractory to simple measures. At the study institution, parenteral opioids are preferentially prescribed for the treatment of complicated OM. This audit explores the efficacy of opioids for the management of OM pain using morphine, oxycodone, and fentanyl patient-controlled analgesia (PCA). Pain scores, opioid consumption, resumption of oral intake, and the duration of admission were retrospectively analyzed from patient records over an 18-month period. Two-thirds of included patients had ceased PCA therapy by day 6, by which time there was a meaningful 35.4 percent reduction in pain scores, with very few side effects reported. Interagent comparison demonstrated no significant differences in mean daily pain scores; however, a larger sample size would facilitate an investigation of clinically significant nuances in treatment differences, if they exist.

Acute myeloid leukaemia following direct acting antiviral drugs in HCV-infected patients: A 10 years' retrospective single-center study.

BACKGROUND: After several cases of peculiar hematological malignancies following introduction of new oral anti-hepatitis C virus (HCV) treatments in our recent practice, we aimed to systematically identify all cases of hematological malignancies (HM) in patients with chronic HCV infection and to compare them according to the prescription of oral anti-HCV Direct Acting Antivirals (DAA) treatment or not. MATERIAL/METHODS: In this single-center retrospective observational study, we included all patients with confirmed HM and chronic HCV infection managed between 2010 and 2019 in the Pitié-Salpêtrière hospital, Paris. Non-inclusion criteria were a benign hematological disorder, an HM preceding chronic HCV infection and HCV acute infection. We compared characteristics of patients who received DAA before HM diagnosis to those with no DAA before HM. RESULTS: Over the 10 years, 61 cases of HM among HCV infected patients were identified (female 29%, median age of 58.0 years [IQR 17]). Twenty-one received DAA before the onset of HM (Group DAA+) and 40 did not (Group DAA-) including 22 having received DAA after HM. In the DAA+ group, oral NS5B, NS5A and NS3A inhibitors were used in 90, 76 and 29% respectively. HM developed in the two years following DAA initiation in 76%. Eight (38%) had Non-Hodgkin Lymphoma, 5 (24%) had an Acute Myeloid Leukaemia (AML) including two with a mixed phenotype, 2 each had Hodgkin Lymphoma, Multiple Myeloma or a myeloproliferative disorder and one each had a chronic Lymphocytic Leukaemia or AL Amyloidosis. In the Group DAA-, HM were NHL in 20(50%) patients, Myeloproliferative neoplasms in 7 (17%), Multiple Myeloma in 5, Hodgkin Lymphoma in 3, Myelodysplastic syndrome and AML in 2 (5%) each and Acute Lymphoblastic Leukaemia in one. No significant difference between the groups DAA + and - was found according to age, sex, HCV genotype, viral load, co-infection or type and exposition of previous HCV treatments. AML, liver transplantation and cirrhosis were significantly more frequent in the DAA+ group (p = 0.020, 0.045 and 0.032, respectively). CONCLUSION: AML seemed more frequent after using DAA treatments, notably in severe HCV patients including cirrhotic and/or liver transplanted patients. A multicentric observational study is ongoing to confirm and explore the results.

Temozolomide duration and secondary hematological neoplasms: A literature review and implications for patients with neuroendocrine neoplasms.

Evidence-based recommendations for the optimal duration and sequencing of temozolomide-based treatments in advanced neuroendocrine neoplasms are lacking. Here, we conducted a systematic review of the literature for a descriptive analysis of temozolomide-associated myelodysplasias and leukemias to guide treatment planning. A database search of PubMed and Embase was conducted to identify case reports and/or case series reporting secondary myelodysplasias or leukemias in the setting of temozolomide therapy. Key data items extracted from the studies were the temozolomide dose and duration, latency to hematological disorder, type of secondary malignancy and cytogenetics. Reported cases were summarized graphically. A total of 16 studies with 27 patient cases of therapy-related hematologic neoplasms were identified, all of which were case reports or case series. The median treatment duration and cumulative dose were 19 months and 18,000 mg/m2 , respectively. Most patients (21/27) were diagnosed on, or after, 12 months, while only one patient was diagnosed before 6 months of treatment. Most of the patients were diagnosed, while still on treatment with temozolomide. Graphically, cases clustered around a cumulative dose of 10,000 to 30,000 mg/m2 and a latency period of 10 to 40 months which translates to an approximate treatment duration of 12.5 to 37.5 months. Taken together, most reported treatment-related hematological neoplasms appear to develop on or beyond the 12-month mark, while patients are still on treatment with temozolomide. For patients with neuroendocrine neoplasms, where sequencing of multiple therapies is important, we suggest an approach to optimizing treatment duration by establishing disease response at 6 months before continuing further treatment and restricting treatment to or establishing closer vigilance beyond 12 months.

Clinical Development and Therapeutic Applications of Bispecific Antibodies for Hematologic Malignancies.

Bispecific antibodies are composed of two monoclonal antibodies that engage T cells with tumor cell antigens and lead to tumor cell lysis. The most common types fall into the category of bispecific T cell engagers, or BiTEs, that have the canonical CD3-CD19 bispecific construct. Blinatumomab is the first bispecific antibody that received FDA approval for relapsed refractory B cell precursor acute lymphoblastic leukemia. Blinatumomab has been shown to have robust clinical outcomes and is associated with adverse events such as cytokine release syndrome and neurotoxicity. Other bispecific antibodies are under clinical investigation for multiple myeloma and acute myeloid leukemia. Along with immune checkpoint inhibitors and chimeric antigen T cell receptor therapies, bispecific antibodies are considered a mainstay as a therapeutic option for cancer immunotherapies for Hematologic malignancies.

Arsenic in Drinking Water and Incidences of Leukemia and Lymphoma: Implication for Its Dual Effects in Carcinogenicity.

Arsenic in drinking water has been recognized as carcinogenic to humans and can cause solid cancers of lung, urinary bladder, and skin. Positive associations have also been reported between arsenic ingestion and cancers of kidney, liver and prostate. Nevertheless, arsenic trioxide has been used successfully in the treatment of acute promyelocytic leukemia. Therefore, arsenic might play different roles in the carcinogenesis of solid cancers and hematologic malignancies. The relationship between arsenic in drinking water and the incidences of hematologic malignancies has not been fully investigated. We established a cohort of Taiwanese population and assorted 319 townships of Taiwan into two exposure categories using 0.05 mg/L as the cutoff. Then, we linked these data to the Taiwan Cancer Registry and computed standardized incidence ratios (SIRs) of lymphoma and leukemia by sex, exposure category and time period. The trend of changes in the SIRs over time was assessed, from 1981-1990 to 1991-2000 and then to 2001-2010. We found that in both lymphoma and leukemia, the higher exposure category was associated with lower SIRs in both men and women. In terms of time trends, the SIRs in both lymphoma and leukemia showed increasing trends in both sexes, while exposure to arsenic in drinking water decreased over time. The arsenic level in drinking water was negatively associated with the incidences of lymphoma and leukemia in both men and women. This study supports the dual effects of arsenic on carcinogenesis, with a potential protective effect against hematologic malignancies.

A review of the mutagenic potential of N-ethyl-N-nitrosourea (ENU) to induce hematological malignancies.

This review is intended to summarize the existing literature on the mutagenicity of N-ethyl-N-nitrosourea (ENU) in inducing hematological malignancies, including acute myeloid leukemia (AML) in mice. Blood or hematological malignancies are the most common malignant disorders seen in people of all age groups. Driven by a number of genetic alterations, leukemia rule out the normal proliferation and differentiation of hematopoietic stem cells (HSCs) and their progenitors in the bone marrow (BM) and severely affects blood functions. Out of all hematological malignancies, AML is the most aggressive type, with a high incidence and mortality rate. AML is found as either de novo or secondary therapeutic AML (t-AML). t-AML is a serious adverse consequence of alkylator chemotherapy to the cancer patient and alone constitutes about 10%-20% of all reported AML cases. Cancer patients who received alkylator chemotherapy are at an elevated risk of developing t-AML. ENU has a long history of use as a potent carcinogen that induces blood malignancies in mice and rats that are pathologically similar to human AML and t-AML. ENU, once entered into the body, circulates all over the body tissues and reaches BM. It creates an overall state of suppression within the BM by damaging the marrow cells, alkylating the DNA, and forming DNA adducts within the early and late hematopoietic stem and progenitor cells. The BM holds a weak DNA repair mechanism due to low alkyltransferase, and poly [ADP-ribose] polymerase (PARP) enzyme content often fails to obliterate those adducts, acting as a catalyst to bring genetic abnormalities, including point gene mutations as well as chromosomal alterations, for example, translocation and inversion. Taking advantage of ENU-induced immune-suppressed state and weak immune surveillance, these mutations remain viable and slowly give rise to transformed HSCs. This review also highlights the carcinogenic nature of ENU and the complex relation between the ENU's overall toxicity in the induction of hematological malignancies.

Long-term treatment with clozapine and other antipsychotic drugs and the risk of haematological malignancies in people with schizophrenia: a nationwide case-control and cohort study in Finland.

BACKGROUND: Clozapine is the most efficacious treatment for schizophrenia and is associated with lower overall mortality than are other antipsychotic drugs, despite the risk of agranulocytosis. Preliminary reports over the past 10 years suggest a possible risk of haematological malignancies, but the issue has remained unsettled. We aimed to study the risk of haematological malignancies associated with use of clozapine and other antipsychotics. METHODS: We did a nationwide case-control (and cohort) study of people with schizophrenia, using prospectively gathered data from Finnish national registers. A nested case-control study was constructed by individually matching cases of lymphoid and haematopoietic tissue malignancy with up to ten controls without cancer by age, sex, and time since first schizophrenia diagnosis. For the case-control study, we restricted inclusion criteria to malignancies diagnosed on a histological basis, and excluded individuals outside of the age range 18-85 years, and any patients that had a previous malignancy. Analyses were done using conditional logistic regression adjusting for comorbid conditions. FINDINGS: For the case-control study 516 patients with a first-time diagnosis of lymphoid and haematopoietic tissue malignancy during years 2000-17 and diagnosed after their first diagnosis of schizophrenia were identified. 102 patients were excluded due to diagnosis that was without a histological basis, five patients were excluded because of their age, and 34 were excluded for a previous malignancy, resulting in 375 patients being matched to controls. We selected up to ten controls without cancer (3734 in total) for each case from the base cohort of people with schizophrenia. For the cohort study, data for 55 949 people were included for analysis. Cumulative incidence of haematological malignancies during the mean follow-up of 12·3 years (SD 6·5) was 102 (0·7%) cases among 13 712 patients who had used clozapine (corresponding to event rate of 61 cases per 100 000 person-years), and during mean follow-up of 12·9 years (SD 7·2) was 235 (0·5%) malignancies among 44 171 patients having used other antipsychotic medication than clozapine (corresponding to 41 cases per 100 000 person-years). Of the 375 individuals with haematological malignancies (305 lymphomas, 42 leukaemia, 22 myelomas, 6 unspecified) observed from 2000-17, 208 (55%) were males and 167 (45%) were female. Ethnicity data were not available. Compared with non-use of clozapine (most had used other antipsychotics and a few had used no antipsychotics), clozapine use was associated with increased odds of haematological malignancies in a dose-response manner (adjusted odds ratio 3·35, [95% CI 2·22-5·05] for ≥5000 defined daily dose cumulative exposure, p<0·0001). Exposure to other antipsychotic drugs was not associated with increased odds. A complementary analysis showed that the clozapine-related risk increase was specific for haematological malignancies, because no such finding was observed for other malignancies. Over 17 years of follow-up of the base cohort, 37 deaths occurred due to haematological malignancy among patients exposed to clozapine (26 with ongoing use at time of haematological malignancy diagnosis, and 11 in patients who did not use clozapine at the exact time of their cancer diagnosis), whereas only three deaths occurred due to agranulocytosis. INTERPRETATION: Unlike other antipsychotics, long-term clozapine use is associated with increased odds of haematological malignancies. Long-term clozapine use has a higher effect on mortality due to lymphoma and leukaemia than due to agranulocytosis. However, acknowledging that the absolute risk is small compared with the previously observed absolute risk reduction in all-cause mortality is important. Our results suggest that patients and caregivers should be informed about warning signs of haematological malignancies, and mental health clinicians should be vigilant for signs and symptoms of haematological malignancy in patients treated with clozapine. FUNDING: The Finnish Ministry of Social Affairs and Health and Academy of Finland.

Ledipasvir-sofosbuvir in Adolescents With Chronic Hepatitis C and Hematological Malignancies Undergoing Chemotherapy.

OBJECTIVES: In children with hematological malignancies, chronic hepatitis C virus (HCV) infection has been associated with more rapid liver disease progression and higher risk of malignancy relapse due to chemotherapy interruption. We evaluated the safety and efficacy of ledipasvir-sofosbuvir for 12weeks in these patients. METHODS: In a phase 2, open-label study, at one site in Egypt, patients ages 12-<18years with chronic HCV genotype 1 or 4 infection undergoing maintenance chemotherapy for hematological malignancies received ledipasvir-sofosbuvir (90 mg/400 mg) once daily for 12weeks. The efficacy endpoint was sustained virologic response 12 weeks after treatment (SVR12). Safety was assessed by the incidence of adverse events and clinical and laboratory data, including HCV flares defined as alanine aminotransferase >3-fold increase from Day 1 and HCV RNA elevation >1 × log10 from Day 1. RESULTS: Of the 19 adolescents enrolled and treated, median age was 14 years (range 12-17), 84% (16/19) were male, and all had HCV genotype 4 and were HCV treatment naive. All patients completed treatment and achieved SVR12 (19/19, 100%, 95% confidence interval, 82-100). Common adverse events were pyrexia (5/19, 26%), diarrhea (4/19, 21%), and headache (4/19, 21%). Three patients experienced serious adverse events of pneumonia (two patients), and osteoarthritis and diarrhea (one patient); none were considered related to study drug. No patient experienced HCV flares. CONCLUSIONS: Ledipasvir-sofosbuvir was well-tolerated and efficacious in adolescents with chronic HCV genotype 4 and leukemia undergoing maintenance chemotherapy. These data support the use of this interferon and ribavirin-free regimen in adolescents with hematological malignancies.

High dose methotrexate in adult Egyptian patients with hematological malignancies: impact of ABCB1 3435C > T rs1045642 and MTHFR 677C > T rs1801133 polymorphisms on toxicities and delayed elimination.

High dose methotrexate (HDMTX) is an essential agent in chemotherapeutic regimens used in various hematological malignancies in Egyptian adults. The research for the impact of gene polymorphism on HDMTX induced toxicities and delayed elimination is an important ongoing objective in many studies, variable and conflicting results produced in the past years to clarify that impact. This study aimed to investigate the role of ABCB1 3435 C > T rs1045642 and MTHFR 677 C > T rs1801133 polymorphisms on HDMTX induced toxicity outcomes and delayed elimination in Egyptian adult patients with hematological malignancies. A prospective, observational cohort study was conducted on a total of 62 Egyptian adult patients with hematological malignancies age ≥ 18-years-old. All demographic, medical, and laboratory data were continuously collected from the patients' medical files in an up-to-date follow-up in selected clinics during the period from April 2018 to March 2020. Venous blood samples were collected for the purpose of genotyping, DNA extraction, and measurement of MTX levels. All the relevant data were statistically analyzed. The studied patients' median age was 25 years old with a range of (18-62) years. Forty-six patients were males with about 74%, and 16 were females with about 26%. Eighty-nine percent of the patients diagnosed with acute lymphoblastic leukemia 'ALL', 5% of the patients had B cell non-hodgkin lymphoma 'B-NHL' and 3% diagnosed with primary central nervous system lymphoma 'PCNSL' and Burkitt's lymphoma 'BL' Hematological, hepatic, renal and gastrointestinal toxicities observed post-HDMTX were recorded with the hematological toxicities toping on all the others, also patients with delayed elimination at 72 hours post the HDMTX dose were determined. Statistical analysis revealed a significant association between ABCB1 3435 C > T rs1045642 and HDMTX delayed elimination with about 10 times higher risk among the minor allele 'T' carriers (p-value = 0.006) (odds ratio [OR]: 10.470; 95% CI: 1.961-55.904). No significant association observed between the studied gene polymorphisms: MTHFR 677 C > T rs1801133, ABCB1 3435 C > T rs1045642, and different toxicity outcomes. According to our best knowledge, this study is the first to conclude a significant association between ABCB1 3435 C > T rs1045642 gene polymorphism and HDMTX delayed elimination at 72 hours post HDMTX infusion; also, it is the first study to analyze the association between ABCB1 3435 C > T rs1045642 polymorphism with HDMTX toxicity and delayed elimination in adult Egyptian patients with hematological malignancies.

Passive environmental residential exposure to agricultural pesticides and hematological malignancies in the general population: a systematic review.

Incidence rates of hematological malignancies have been constantly increasing over the past 40 years. In parallel, an expanding use of agricultural pesticides has been observed. Only a limited number of studies investigated the link between hematological malignancies risk and passive environmental residential exposure to agricultural pesticides in the general population. The purpose of our review was to summarize the current state of knowledge on that question. A systematic literature search was conducted using PubMed and Scopus databases. We built a scoring scale to appraise relevance of each selected articles. We included 23 publications: 13 ecological studies, 9 case-control studies and a cohort study. Positive associations were reported between hematological malignancies and individual pesticides, pesticide groups, all pesticides without distinction, or some crop types. Relevance score was highly various across studies regardless of their design. Children studies were the majority and had overall higher relevance scores. The effect of passive environmental residential exposure to agricultural pesticides on hematological malignancies risk is suggested by the literature. The main limitation of the literature available is the high heterogeneity across studies, especially in terms of exposure assessment approach. Further studies with high methodological relevance should be conducted.

Dietary Acrylamide Intake and the Risk of Hematological Malignancies: The Japan Public Health Center-Based Prospective Study.

Acrylamide, which is present in many daily foods, is a probable human carcinogen. In 2002, it was identified in several common foods. Subsequently, western epidemiologists began to explore the relationship between dietary acrylamide exposure and cancer risk; however, limited suggestive associations were found. This prospective study aimed to examine the association between dietary acrylamide intake and the risk of hematological malignancies, including malignant lymphoma (ML), multiple myeloma (MM), and leukemia. We enrolled 85,303 participants in the Japan Public Health Center-based Prospective study on diet and cancer as from 1995. A food frequency questionnaire that included data on acrylamide in all Japanese foods was used to assess dietary acrylamide intake. We applied multivariable adjusted Cox proportional hazards models to reckon hazard ratios (HRs) for acrylamide intake for both categorical variables (tertiles) and continuous variables. After 16.0 median years of follow-up, 326 confirmed cases of ML, 126 cases of MM, and 224 cases of leukemia were available for final multivariable-adjusted analysis. HRs were 0.87 (95% confidence interval [CI]: 0.64-1.18) for ML, 0.64 (95% CI: 0.38-1.05) for MM, and 1.01 (95% CI: 0.71-1.45) for leukemia. Our results implied that acrylamide may not be related to the risk of hematological malignancies.