Monoclonal antibodies as COVID-19 prophylaxis therapy in immunocompromised patient populations.

OBJECTIVES: The objective of this review was to examine the latest literature regarding the effectiveness of monoclonal antibodies as COVID-19 prophylaxis therapy for immunocompromised patient populations. METHODS: Literature review of published real-world and randomized control trials (RCTs) from 2020 to May 2023. RESULTS: COVID-19 is highly transmissible with potentially serious health outcomes, underscoring the need for effective prevention and treatment strategies. Vaccines are highly effective at preventing COVID-19 for the general population; however, efficacy is often impaired in immunocompromised patients given insufficient response to initial exposure and/or memory for secondary exposures. Some individuals may also have contraindications to vaccination. As such, additional protective measures are needed to bolster the immune response in these populations. Monoclonal antibodies have been effective at bolstering immune system responses to COVID-19 among immunocompromised patients; however, they are proving ineffective against the most recent Omicron strains (BA.4 and BA.5). CONCLUSION: Several studies have investigated the efficacy of monoclonal antibodies as pre- and post-prophylaxis for COVID-19. Historical evidence is promising; however, new variants of concern are proving challenging for currently available regimens.

A Canadian Perspective: Monoclonal Antibodies for Pre- and Post-Exposure Protection from COVID-19 in Vulnerable Patients with Hematological Malignancies.

Patients with hematological malignancies have an increased risk of serious outcomes following COVID-19 infection, suggesting broader protection is needed beyond vaccination. Monoclonal antibodies such as sotrovimab, casirivimab-imdevimab, and bamlanivimab have provided valuable options for the treatment of COVID-19 disease. More recently, monoclonal antibodies have been examined for the prevention of COVID-19 infection. The monoclonal antibody combination, tixagevimab-cilgavimab, was recently approved by Health Canada as pre-exposure prophylaxis against COVID-19 in individuals who are immunocompromised or where vaccination is not recommended. Prophylactic approaches such as the use of tixagevimab-cilgavimab, in addition to COVID-19 vaccination, may provide additional protection for patients with hematological malignancies who are at greater risk of serious outcomes from COVID-19 infection.

Novel Therapies for the Treatment of HER2-Positive Advanced Breast Cancer: A Canadian Perspective.

The advent of anti-HER2 targeted therapies has dramatically improved the outcome of HER2-positive breast cancer; however, resistance to treatment in the metastatic setting remains a challenge, highlighting the need for novel therapies. The arrival of new treatment options and clinical trials examining the efficacy of novel agents may improve outcomes in the metastatic setting, including in patients with brain metastases. In the first-line setting, we can potentially cure a selected number of patients treated with pertuzumab + trastuzumab + taxane. In the second-line setting, clinical trials show that trastuzumab deruxtecan (T-DXd) is a highly effective option, resulting in a shift from trastuzumab emtansine (T-DM1) as the previous standard of care. Moreover, we now have data for patients with brain metastases to show that tucatinib + trastuzumab + capecitabine can improve survival in this higher-risk group and be an effective regimen for all patients in the third-line setting. Finally, we have a number of effective anti-HER2 therapies that can be used in subsequent lines of therapy to improve patient outcomes. This review paper discusses the current treatment options and presents a practical treatment sequencing algorithm in the context of the Canadian landscape.

A Canadian Perspective on the Challenges for Delivery of Curative-Intent Therapy in Stage III Unresectable Non-Small Cell Lung Cancer.

Stage III non-small cell lung cancer (NSCLC) comprises a highly heterogenous group of patients with regards to patient fitness and tumour size and distribution, resulting in a wide range of treatment goals and therapy options. Curative-intent multimodality treatment should be considered in all patients with stage III NSCLC. For patients with unresectable disease who are fit, have adequate lung function, and have a disease that can be encompassed within a radical radiation volume, concurrent chemoradiation therapy (cCRT) is the standard of care and can produce cure rates of 20-30%. Recently, consolidation immunotherapy with durvalumab has been recognized as the standard of care following cCRT based on significant improvement rates in overall survival at 4 years. The large heterogeneity of the stage III NSCLC population, along with the need for extensive staging procedures, multidisciplinary care, intensive cCRT, and now consolidation therapy makes the delivery of timely and optimal treatment for these patients complex. Several logistical, communication, and education factors hinder the delivery of guideline-recommended care to patients with stage III unresectable NSCLC. This commentary discusses the potential challenges patients may encounter at different points along their care pathway that can interfere with delivery of curative-intent therapy and suggests strategies for improving care delivery.

Use of minimal residual disease assessment in the treatment of chronic lymphocytic leukemia.

Progress in chronic lymphocytic leukemia (CLL) therapies has extended greatly the length and depth of remission, with the goal of treatment advancing towards a cure for some patients. Accordingly, clinical endpoints must evolve to capture these outcomes, and to provide faster access to novel therapies. Minimal residual disease (MRD) is an important endpoint representing more accurately the depth of remission than complete response (CR), and is highly prognostic of progression-free survival (PFS) and overall survival (OS). MRD could be considered a key outcome of clinical trials and, as a surrogate for PFS, could identify the most cost-effective and durable treatment sequencing. MRD testing could also determine which patients would benefit from additional therapy and, accordingly, ascertain when therapy should be stopped earlier, to reduce toxicity and increase treatment-free intervals. Our article discusses possible uses of MRD in the modern era of CLL, including its definition, measurement, and value as a surrogate endpoint in clinical trials, and its potential roles in clinical practice.

Novel regimens prior to autologous stem cell transplantation for the management of adults with relapsed/refractory non-Hodgkin lymphoma and Hodgkin lymphoma: alternatives to BEAM conditioning.

High-dose therapy (HDT) followed by autologous stem cell transplant (ASCT) is the standard treatment for relapsed or refractory non-Hodgkin and Hodgkin lymphoma. Until recently, carmustine, etoposide, cytarabine and melphalan (BEAM) was the most commonly used conditioning regimen in this setting, given its acceptable efficacy and tolerability. Despite reasonable success with BEAM, carmustine is associated with a number of acute and late toxicities. Moreover, recent supply and cost issues for this agent have created an urgent need for alternative conditioning regimens. As such, etoposide and melphalan (VP16/MEL) or busulfan, cyclophosphamide, and etoposide (BuCyE) are currently being used with limited success. A number of novel conditioning regimens that replace carmustine with other agents are under investigation, which may provide effective alternatives to BEAM. In considering novel agents to replace carmustine, bendamustine may provide the best alternative, as demonstrated by the results of a number of phase II, multicenter, controlled studies.

A canadian perspective on the first-line treatment of chronic lymphocytic leukemia.

Despite important advances in the treatment of first-line chronic lymphocytic leukemia (CLL) over the past decade, CLL remains an incurable disease with significant unmet needs. The combination of rituximab with fludarabine and cyclophosphamide (FCR) significantly improved overall survival and progression-free survival compared with fludarabine and cyclophosphamide alone in first-line treatment of CLL. However, because of its high toxicity, FCR is only recommended for younger, fit patients who can tolerate the treatment. This excludes a large fraction of CLL patients who are elderly and/or who have comorbidities. Thus, determining the appropriate treatment choices for this group of patients who are unfit for FCR treatment is a significant challenge in CLL. Current treatment choices in Canadian practice include bendamustine with rituximab, fludarabine with rituximab, and chlorambucil with rituximab. Two novel monoclonal antibodies, ofatumumab and obinutuzumab, have also recently received Health Canada approval for the first-line treatment of CLL patients in combination with chlorambucil. In addition, the Bruton tyrosine kinase inhibitor, ibrutinib, has recently been approved by Health Canada for the first-line treatment of CLL patients with deletion 17p. In the coming years, several other novel agents that are being developed are likely to change the CLL treatment landscape dramatically, however, because these novel agents are currently unavailable, the purpose of this review is to recommend the best treatment approaches in Canada using currently available therapies.

A Canadian evidence-based guideline for the first-line treatment of follicular lymphoma: joint consensus of the Lymphoma Canada Scientific Advisory Board.

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma (NHL) in North America. Because of the heterogeneity of the disease, treatment options vary from observation to aggressive therapies or stem cell transplantation, or both. Although advances in treatment have improved outcomes, the disease remains largely incurable. In Canada, no unified national guideline exists for the front-line treatment of FL; provincial guidelines vary and are largely based on funding. There is therefore a need for evidence-based national treatment guidelines that are supported by Canadian hematologists to ensure that patients with FL have equitable access to the best available care. A group of experts from across Canada developed a national evidence-based treatment guideline to provide health care professionals with clear guidance on the first-line management of FL. Results of a systematic review of the literature are presented with consensus recommendations based on available evidence.

Relative bioavailability of iron and folic acid from a new powdered supplement compared to a traditional tablet in pregnant women.

BACKGROUND: Deficiencies of iron and folic acid during pregnancy can lead to adverse outcomes for the fetus, thus supplements are recommended. Adherence to current tablet-based supplements is documented to be poor. Recently a powdered form of micronutrients has been developed which may decrease side-effects and thus improve adherence. However, before testing the efficacy of the supplement as an alternate choice for supplementation during pregnancy, the bioavailability of the iron needs to be determined. Our objective was to measure the relative bioavailability of iron and folic acid from a powdered supplement that can be sprinkled on semi-solid foods or beverages versus a traditional tablet supplement in pregnant women. METHODS: Eighteen healthy pregnant women (24 - 32 weeks gestation) were randomized to receive the supplements in a crossover design. Following ingestion of each supplement, the changes (over baseline) in serum iron and folate over 8 hours were determined. The powdered supplement contained 30 mg of iron as micronized dispersible ferric pyrophosphate with an emulsifier coating and 600 mug folic acid; the tablet contained 27 mg iron from ferrous fumarate and 1000 mug folic acid. RESULTS: Overall absorption of iron from the powdered supplement was significantly lower than the tablet (p = 0.003). There was no difference in the overall absorption of folic acid between supplements. Based on the differences in the area under the curve and doses, the relative bioavailability of iron from powdered supplement was lower than from the tablet (0.22). CONCLUSION: The unexpected lower bioavailability of iron from the powdered supplement is contrary to previously published reports. However, since pills and capsules are known to be poorly accepted by some women during pregnancy, it is reasonable to continue to explore alternative micronutrient delivery systems and forms of iron for this purpose. TRIAL REGISTRATION: ClinicalTrials.gov NCT00789490.

Low dose 'Sprinkles'-- an innovative approach to treat iron deficiency anemia in infants and young children.

UNLABELLED: Iron supplementation programs using pediatric tablets or drops have not been successful in the control of anemia amongst infants and children in India. Sprinkles is an innovative multi-micronutrient home fortification strategy to control iron deficiency and anemia. OBJECTIVE: We aimed to determine the hematologic response to different doses and forms of iron in Sprinkles and iron drops. SETTING: Twenty two villages of Vadu Rural Health Program, KEM Hospital, Pune. DESIGN: Double blind clustered randomized community-based trial. SUBJECTS: Children (n=432) aged 6 to 18 mo age with Hb between 70 to 100 g/L were enrolled. METHODS: Selected villages were randomized into 5 groups: Sprinkles 12.5, 20 or 30 mg ferrous fumarate, Sprinkles 20 mg micronized ferric pyrophosphate or drops 20 mg ferrous glycine sulphate (DROPS) for 8 weeks. Household socio-demographic information was collected at baseline. Side effects and compliance were monitored through weekly visits. Hemoglobin was estimated at baseline, 3 and 8 weeks. Ferritin was assessed at baseline and 8 weeks. RESULTS: Baseline characteristics were similar across all groups. Hemoglobin increased significantly (P<0.0001) in all groups at 8 weeks with no difference between groups. Ferritin increased (P<0.0001) significantly in all groups with no difference across the groups. Compliance (overall range: 42 to 62 %) was lowest for DROPS. Side effects were significantly higher among DROPS compared to Sprinkles (p>0.05). CONCLUSIONS: Sprinkles 12.5 mg FF dose is as efficacious as higher doses of iron in Sprinkles or DROPS in increasing hemoglobin. Sprinkles FF 12.5 mg is recommended as it has fewer reported side effects and better compliance compared to DROPS.

Multi-micronutrient Sprinkles including a low dose of iron provided as microencapsulated ferrous fumarate improves haematologic indices in anaemic children: a randomized clinical trial.

Home-fortification of complementary foods with micronutrients (including iron) as Sprinkles is a new strategy to control iron deficiency and anaemia in developing countries. However, the most effective dose and form of iron is not known. The purpose of this study was to compare the efficacy of various doses (12.5, 20 or 30 mg) and treatment methods (multi-micronutrient Sprinkles vs. ferrous sulphate drops) on haemoglobin (Hb) concentration after 8 weeks of treatment in anaemic children. In total, 133 anaemic Ghanaian children (Hb 70-99 g L(-1)) aged 6-18 months were randomly assigned to one of five daily interventions for 8 weeks. Out of the five interventions, four used Sprinkles, and one used iron drops. Of the four Sprinkles groups, three included 12.5, 20 or 30 mg of iron as ferrous fumarate, and one included 20 mg of iron as ferric pyrophosphate. The iron drops group included 12.5 mg of iron as liquid ferrous sulphate. Hb concentrations were measured at baseline, week 3 and week 8. The primary outcome measure was Hb concentration at 8 weeks after treatment. We compared differences in Hb and ferritin concentrations and prevalence of iron deficiency anaemia (Hb < 100 g L(-1) and soluble transferrin receptor concentrations >8.5 mg L(-1)) from baseline to 8 weeks within and between groups. Adherence and reporting of side effects (staining of the teeth, ease of use, diarrhoea and darkening of stools) were compared between groups. Mean change in Hb was 1.4 g L(-1) (SD = 1.8) (P = 0.0001). Change in Hb concentrations from baseline to 8 weeks was significant in all groups (P = 0.0001-0.0007), with no differences across groups. Geometric means of serum ferritin varied from 18.6 to 44.0 microg L(-1) at baseline. At week 8, these means were in the interval of 48.0-78.3 microg L(-1), with no group differences. Prevalence of iron deficiency anaemia decreased significantly from baseline to 8 weeks in all groups with the exception of the iron drops group, with no group differences. Adherence was lower in the drops group (64%) as compared with Sprinkles groups (84%). Greater staining of the teeth and less ease of use were reported in the drops group as compared with Sprinkles groups. A dose as low as 12.5 mg of iron as ferrous fumarate when provided as Sprinkles may be effective in anaemic children.

Iron deficiency and anemia prevalence and associated etiologic risk factors in First Nations and Inuit communities in Northern Ontario and Nunavut.

BACKGROUND: Anemia is common among children in Aboriginal communities in Canada. The objectives of this study were to determine the prevalence of anemia and to identify its associated risk factors among young children in Aboriginal communities in northern Ontario and Nunavut. METHODS: 115 children from one Inuit and two Cree First Nations communities participated. We collected information on demographic and dietary factors and measured hemoglobin (Hb), ferritin (SF), serum transferrin receptor (sTfR) and Helicobacter pylori IgG antibodies. Odds ratios and 95% confidence intervals were determined to examine risk factors associated with anemia and iron deficiency (ID) and further analyzed using stepwise regression procedures. RESULTS: Prevalence of anemia (Hb<110 g/L) was 36.0%. Iron deficiency (sTfR>8.5 mg/L) was present in 27.6% of the study population. Approximately 53.3% had depleted iron stores (SF<12 microg/L). Consumption of cow/evaporated milk was the only independent risk factor associated with anemia. Infection with H. pylori and prolonged consumption of breastmilk were also associated, although not independently, with anemia. Formula intake was negatively associated with ID. INTERPRETATION: The prevalence of anemia in Aboriginal children was eight times higher than among similar populations in urban Canada and was especially high among Inuit children. ID was the major cause of anemia, but not the only one, since 10% of anemic children were not iron deficient. Given that the consumption of cow/evaporated milk was found to be a significant independent risk factor associated with anemia, public health strategies should include promotion of breastfeeding, combined with iron-rich complementary foods, while addressing socio-economic conditions that may be preventing these practices from being adopted. H. pylori may be a major contributing factor to anemia, thus improvements in water quality and sanitation also need to be considered.

Iron deficiency anemia among children: Addressing a global public health problem within a Canadian context.

Despite current Canadian pre- and perinatal nutrition programs, the prevalence of both iron deficiency and iron deficiency anemia (IDA) is very high among young Aboriginal children from Canada's remote north. The major risk factors for IDA include prolonged consumption of evaporated cow's milk, chronic infection and prolonged exclusive breastfeeding. In the present article, the authors discuss IDA as a significant public health problem in Canadian Aboriginal communities. Whereas the prevalence of IDA in Canadian children is between 3.5% and 10.5% in the general population, in two Northern Ontario First Nations communities and one Inuit community, the anemia rate was 36%, with 56% having depleted iron stores. Traditional methods of preventing IDA, including targeted fortification, dietary diversification and supplementation, have not solved the problem. The authors' research group at The Hospital for Sick Children in Toronto, Ontario, conceived of the strategy of 'home fortification' with 'Sprinkles' - single-dose sachets containing micronutrients in a powder form, which are easily sprinkled onto any foods prepared in the household. In Sprinkles, the iron (ferrous fumarate) is encapsulated within a thin lipid layer to prevent the iron from interacting with food. Sprinkles have been shown to be efficacious in the treatment of anemia in many developing countries. Their use in Aboriginal communities to treat and prevent anemia is described in the present paper. The authors believe that children in Aboriginal communities across Canada would potentially benefit if Sprinkles were incorporated into Health Canada's current distribution system, in combination with a social marketing strategy to encourage their use.

Acceptability of micronutrient sprinkles: a new food-based approach for delivering iron to First Nations and Inuit children in Northern Canada.

Iron deficiency anemia (IDA) is a significant public health problem among Canadian Aboriginal children. The objectives of this study were to determine the acceptability and safety of microencapsulated-iron sprinkles, a new powdered form of iron packaged in a single-serving sachet for prevention of IDA. A total of 102 non-anemic children aged 4 to 18 months from three communities were randomized to receive sprinkles containing 30 mg Fe/day (NR = 49) or placebo (NR = 53) for six months. To assess acceptability, adherence and side effects were monitored bi-weekly. To assess safety, serum ferritin (SF) concentration and anthropometry were measured at baseline and end. Mean adherence was 59.6 +/- 27.7 percent. There were no differences in adherence, SF, anthropometric status or side effects between groups. Although there were no differences in hemoglobin (Hb) concentration and anemia prevalence from baseline to end and between groups, the Hb curve shifted to the right (increased) for the sprinkles group and to the left (decreased) for the placebo group. Sprinkles may provide a safe and acceptable option to the current standard of care (i.e. ferrous sulphate drops) for the provision of iron in Canadian Aboriginal populations.

Controlling iron deficiency anemia through the use of home-fortified complementary foods.

Iron deficiency anemia (IDA) is more common in South Asian countries including India, Bangladesh and Pakistan than anywhere else in the world. During infancy and early childhood, IDA is associated with impaired psycho-motor development and cognitive function that may be irreversible. As a consequence, there is a growing awareness that IDA is one of many factors impeding socio-economic prosperity of developing nations. The combination of unacceptably high prevalence rates and inadequate preventative programs highlights the need for new effective sustainable strategies to control IDA. The burden of iron deficiency can be reduced by taking a more holistic approach that would include promotion of healthy weaning practices and use of appropriate complementary foods, together with improving the nutritional value of such foods. There is an increasing body of peer-reviewed literature to support the contention that "micronutrient Sprinkles" is an effective strategy to improve the nutritional value of home-prepared complementary foods and thus to reduce the burden of iron deficiency among children. By combining data from recently conducted randomised control trials, Sprinkles were shown to be as efficacious as iron drops for treating childhood anemia. The iron in Sprinkles is well absorbed, and Sprinkles are easy to use and well accepted by young children and their caregivers. Integrated into existing public health programs, Sprinkles has the potential to improve the effectiveness of such programs.

Determination of iron absorption from intrinsically labeled microencapsulated ferrous fumarate (sprinkles) in infants with different iron and hematologic status by using a dual-stable-isotope method.

BACKGROUND: The use of microencapsulated ferrous fumarate sprinkles is a new approach for home fortification. Iron and hematologic status may affect the absorption of iron from sprinkles. OBJECTIVE: The objective was to measure the absorption (corrected erythrocyte incorporation of (57)Fe) of 2 different doses of iron from sprinkles added to a maize-based complementary food provided to infants with different iron and hematologic status. DESIGN: Infants aged 6-18 mo were randomly assigned to receive either 30 (n = 45) or 45 (n = 45) mg elemental Fe as (57)Fe-labeled sprinkles added to a maize-based porridge on 3 consecutive days. A (58)Fe tracer (0.2 mg as ferrous citrate) was also infused intravenously (n = 46). Blood was drawn at baseline and 14 d later to determine erythrocyte incorporation of (57)Fe and (58)Fe by using inductively coupled plasma mass spectrometry. On the basis of hemoglobin and soluble transferrin receptor concentrations, subjects were classified as having iron deficiency anemia (IDA), iron deficiency (ID), or sufficient iron status. RESULTS: There was no significant effect of dose on iron absorption (P > 0.05). Geometric mean iron absorption was 8.25% (range: 2.9-17.8%) in infants with IDA (n = 32), 4.48% (range: 1.1-10.6%) in infants with ID (n = 20), and 4.65% (range: 1.5-12.3%) in iron-sufficient infants (n = 20). Geometric mean iron absorption was significantly higher in infants with IDA than in infants with ID or iron-sufficient infants (P = 0.0004); however, there were no significant differences between infants with ID and iron-sufficient infants. CONCLUSION: During infancy, iron absorption from sprinkles in a maize-based porridge meets and surpasses requirements for absorbed iron and is up-regulated in infants with IDA.