Adjuvant Treatment with PROLIA® Improves Disease Free Survival in Early Stage Breast Cancer

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. About 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. Approximately 75% of patients with breast cancer are hormone receptor positive (Estrogen Receptor/Progesterone Receptor positive) and this is a predictor of response to endocrine therapy. These patients are often treated with anti-estrogen therapy as first line treatment. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol in extragonadal/peripheral tissues. In postmenopausal women with hormone receptor-positive, early-stage breast cancer, treatment with adjuvant Aromatase Inhibitors is the standard of care.

ARIMIDEX® (Anastrozole), FEMARA® (Letrozole) and AROMASIN® (Exemestane) are Aromatase Inhibitors that bind reversibly to the Aromatase enzyme and inhibit the conversion of androgens to estrogens in the extra-gonadal tissues. Aromatase Inhibitors however are associated with accelerated bone loss, leading to a decrease in Bone Mineral Density (BMD) and can thus cause osteopenia and osteoporosis, thereby increasing fracture risk.Interplay-of-Bone-Formation-and-Bone-Resorption

PROLIA® (Denosumab) is a monoclonal antibody that inhibits osteoclast formation, function and survival, by selectively targeting the RANK ligand. The RANK-RANK ligand system is an important mediator of signaling in the genesis of osteoclasts and bone resorption. Additionally, the RANK-RANK ligand system has been implicated in antitumor immunity and may have a role in suppressing tumor agenesis. It has been hypothesized that targeting RANK with anti-RANK inhibitor might reverse the immunosuppressive effect of the RANK-RANK ligand signaling pathway.

ABCSG-18 is a randomized, double-blind, placebo controlled, Phase III trial in which the authors evaluated the benefits of the anti-RANK ligand antibody PROLIA® on bone health, in postmenopausal patients, with early stage hormone receptor-positive breast cancer, treated with Aromatase Inhibitors. Of the 3425 patients enrolled in this study, 3420 patients were randomly assigned 1:1 to receive PROLIA® 60 mg (N=1711) or matching placebo (N=1709), subcutaneously every 6 months, during Aromatase Inhibitor therapy. Majority of the patients participating in this study had breast cancer with good prognosis and only 25% of the patients required adjuvant chemotherapy. Patient received a median of 7 doses of PROLIA®. The Primary endpoint was the time to first clinical fracture after randomization. The Secondary endpoint was Disease Free Survival (defined as time from randomization to first evidence of local or distant metastasis, contralateral breast cancer, secondary carcinoma, or death from any cause) in the intention-to-treat population. The Primary endpoint of the ABCSG-18 trial was met (The Lancet 2015;386:433-443) and the use of PROLIA® as an adjuvant to Aromatase Inhibitor therapy significantly delayed time to first clinical fracture, compared to Placebo (HR=0.50; P<0.0001). The authors in publication reported the Secondary endpoint of Disease Free Survival (DFS) outcomes from this study.

After a median follow-up of 73 months, there was a significant improvement in the Disease Free Survival among patients in the PROLIA® group compared to the placebo group (HR=0•82; P=0.026). In the PROLIA® group, the DFS was 89.2% at 5 years and 80.6% at 8 years of follow-up, compared with 87.3% at 5 years and 77.5% at 8 years in the placebo group. The total number of adverse events was similar in the PROLIA® and placebo groups and there were no reported cases of osteonecrosis of the jaw bone or atypical femoral fractures.

It was concluded that PROLIA® constitutes an effective and safe adjuvant treatment for patients with postmenopausal hormone receptor-positive early breast cancer receiving Aromatase Inhibitor therapy, with a Disease Free Survival benefit similar to bisphophonates, but with a better toxicity profile and convenient subcutaneous injections twice yearly. Adjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): disease-free survival results from a randomised, double-blind, placebo-controlled, phase 3 trial. Gnant M, Pfeiler G, Steger GG, et al. Lancet Oncol 2019;20:339-351

Telomerase Inhibitor Imetelstat Provides Durable Transfusion Independence in Myelodysplastic Syndrome

SUMMARY: It is estimated that in the United States approximately 13,000 people are diagnosed with MyeloDysplastic Syndromes (MDS) each year. MyeloDysplastic Syndromes are a heterogenous group of stem cell disorders characterized by marrow failure resulting in cytopenias with associated cytogenetic abnormalities, and abnormal cellular maturation with morphologic changes in clonal cells. Majority of the individuals diagnosed with MDS are aged 65 years and older and die as a result of infection and/or bleeding, consequent to bone marrow failure. About a third of patients with MDS develop Acute Myeloid Leukemia (AML). Patients with low-risk MDS have an indolent disease course with a median survival of about 6 years with no therapeutic intervention. Patients with intermediate and higher-risk disease however have a shorter median survival even with treatment, with approximately a third of the patients progressing to AML within 3 years. The International Prognostic Scoring System (IPSS) for MDS has 4 risk groups based on Total Risk Score (Low, Intermediate-1, Intermediate-2 and High). The three prognostic factors scored to predict the course of the patient's disease include, percentage of blast cells in the bone marrow, type of chromosomal changes in the marrow cells and number of cytopenias (anemia, neutropenia or thrombocytopenia).

Management of patients with MDS includes supportive care with Erythropoiesis Stimulating Agents (ESAs), hypomethylating agents such as VIDAZA® (Azacitidine) and DACOGEN® (Decitabine), Immunomodulatory agents such as REVLIMID® (Lenalidomide), and Immunosuppressive agents such as AntiThymocyte Globulin (ATG) and Cyclosporine. Symptomatic patients with MDS are often treated with either VIDAZA® or DACOGEN® as these agents have been shown to improve survival in higher-risk MDS patients. It has remained unclear however, if one is better than the other.

Erythropoiesis Stimulating Agents (ESAs) are first-line therapy for anemia associated with lower-risk non-del(5q) MDS. ESAs such as Darbepoetin alfa and Epoetin alfa are re-engineered and recombinant DNA technology products of Erythropoietin (EPO), and they stimulate erythropoiesis by binding and activating the EPO receptor. There are however limited treatment options for RBC Transfusion Dependent (TD), Low Risk (IPSS Low/Int-1) MDS patients, who are Relapsed/Refractory to ESAs. There is therefore an unmet clinical need for safe and effective treatment options, to reduce the RBC transfusion burden in these patients. Imetelstat is a first-in-class Telomerase inhibitor that targets cells with short telomere length and active Telomerase, a feature often observed in some MDS patients across all stages of their disease. Higher Telomerase activity and shorter Telomeres in the blood cells of some patients with lower-risk MDS are known to predict for shorter overall survival.

IMerge is an ongoing global Phase II/III study of Imetelstat in RBC Transfusion Dependent patients with Low Risk-MDS (IPSS Low or Int-1). Previously reported data have demonstrated clinical benefit with Imetelstat in Low Risk-MDS patients inducing durable Transfusion Independence (Steensma et al ASH 2018 Abstr463). The authors now reported updated efficacy data in Low Risk, non-del(5q) MDS patients, Relapsed/Refractory to ESAs and Lenalidomide/HypoMethylating Agents naïve, from the open-label, single-arm Part 1 of IMerge study.

Part 1 of the IMerge study included patients with Low Risk MDS, who were heavily transfused (4 or more units /8wks), were Refractory or Relapsed on ESA or had serum EPO level of more than 500 mU/mL. This part of the study included 38 patients who were non-del(5q) and had not received either Lenalidomide/HypoMethylating Agents. Imetelstat was administered at 7.5 mg/kg IV every 4 weeks. The median patient age was 72 years, median baseline RBC transfusion burden was 8U/8weeks (range 4-14), 37% of the patients had IPSS Intermediate-1 risk score, 71% had WHO 2001 classification RARS (Refractory Anemia with Ringed Sideroblasts) or RCMD-RS (Refractory Cytopenia with Multilineage Dysplasia and Ringed Sideroblast) subtype and 32% with evaluable serum EPO levels had baseline level of more than 500 mU/mL. The Primary endpoint was 8-week Transfusion Independence rate. Secondary endpoints included 24-week Transfusion Independence rate, Safety, Duration of Transfusion Independence, and Hematologic Improvement rate. The median follow up was 12.1 months. The authors in this publication reported long-term efficacy, safety and biomarker data from these 38 patients.

Treatment with single-agent Imetelstat resulted in 8-week Transfusion Independence rate of 45% and the median Transfusion Independence duration was 8.5 months. Among those responding to Imetelstat, 59% remained transfusion free for over 24 weeks. The presence of Ring Sideroblasts or baseline serum EPO levels did not have an impact on 8-week Transfusion Independence rate. The 24-week Transfusion Independence rate was 26%. Erythroid Hematologic Improvement, defined as transfusion reduction by at least 4 units/8 weeks (IWG2006), was achieved in 68% of the patients. All patients (N=6) who had IPSS- Intermediate/poor cytogenetic risk achieved 8-week Transfusion Independence and 2 patients achieved partial cytogenetic response. Post treatment decrease in Telomerase (human Telomerase Reverse Transcriptase-hTERT) RNA level was observed in 73.5% of patients. Further, among patients with pre and post-treatment mutation analyses, six patients had SF3B1 mutations at baseline, and 2 patients who had a decrease in the mutation burden had longest Transfusion Independence duration on study. The most frequently reported adverse events were manageable and reversible grade 3 cytopenias.

It was concluded that treatment with single agent Imetelstat resulted in meaningful and durable Transfusion Independence, in Transfusion Dependent patients with non-del(5q) Lower-Risk MDS, who had relapsed or were refractory to ESA. Transfusion Independence was observed across different clinical subgroups, including patients with Intermediate and Poor cytogenetic risk, with a positive effect on malignant mutant clones. TREATMENT WITH IMETELSTAT PROVIDES DURABLE TRANSFUSION INDEPENDENCE (TI) IN HEAVILY TRANSFUSED NON-DEL(5Q) LOWER RISK MDS (LR-MDS) RELAPSED/REFRACTORY (R/R) TO ERYTHROPOIESIS STIMULATING AGENTS (ESAS). Fenaux P, Steensma DP, Eygen KV, et al. Presentation during European Hematology Association, Jun 15, 2019; 267420; S837

Anticonvulsant Prophylaxis and Steroid Use in Adults with Metastatic Brain Tumors ASCO and SNO Endorsement of the Congress of Neurological Surgeons Guidelines

SUMMARY: Brain metastases are the most common intracranial tumors in adults in the United States. In patients with systemic malignancies, brain metastases occur in 10-30% of adults, with Lung, Breast, and Melanoma continuing to be the leading cause of brain metastases. The incidence of brain metastases may be on the rise due to both improved imaging techniques, as well as better control of extracerebral disease from advances in systemic therapy.

The Congress of Neurological Surgeons (CNS) developed a series of guidelines for the treatment of adult patients with metastatic brain tumors, including systemic therapy and supportive care topics. The ASCO/SNO (Society of NeuroOncology) Expert Panel determined that the recommendations from the CNS anticonvulsants and steroids guidelines, published January 9, 2019, are clear, thorough, and based on the most relevant scientific evidence. ASCO/SNO endorsed these two CNS guidelines with minor alterations. This guideline was developed by a multidisciplinary Expert Panel that included a patient representative and an ASCO guidelines staff member with health research methodology expertise.

Guideline Questions

CNS Anticonvulsant Guideline

1) Do prophylactic antiepileptic drugs decrease the risk of seizures in nonsurgical patients with brain metastases who are otherwise seizure free?

2) Do prophylactic antiepileptic drugs decrease the risk of seizures in patients with brain metastases and no prior history of seizures in the postoperative setting?

CNS Steroids Guideline

1) Do steroids improve neurologic symptoms and/or quality of life in patients with metastatic brain tumors compared with supportive care only or other treatment options?

2) If steroids are administered, what dose should be given?

Target Population

Adults with metastatic brain tumors.

Target Audience

Medical oncologists, Neurologists, and others who provide care for adults with metastatic brain tumors.

Recommendations

CNS Anticonvulsants Guideline: 

1) Prophylactic antiepileptic drugs are not recommended for routine use in patients with brain metastases who did not undergo surgical resection and who are otherwise seizure free.

2) Routine postcraniotomy antiepileptic drug use for seizure-free patients with brain metastases is not recommended.

CNS Steroids Guideline: Steroid Therapy Versus No Steroid Therapy

Patients with asymptomatic brain metastases without mass effect:

Insufficient evidence exists to make a treatment recommendation for this clinical scenario.

Patients with brain metastases with mild symptoms related to mass effect:

1) Corticosteroids are recommended to provide temporary symptomatic relief of symptoms related to increased intracranial pressure and edema secondary to brain metastases. It is recommended for patients who are symptomatic from metastatic disease to the brain that a starting dose of Dexamethasone 4 to 8 mg/day be considered. Patients with brain metastases with moderate to severe symptoms related to mass effect

2) Corticosteroids are recommended to provide temporary symptomatic relief of symptoms related to increased intracranial pressure and edema secondary to brain metastases. If patients exhibit severe symptoms that are consistent with increased intracranial pressure, it is recommended that higher doses, such as Dexamethasone 16 mg/day or more, be considered.

Choice of steroid:

If corticosteroids are administered, Dexamethasone is the best drug choice, given the available evidence.

Duration of corticosteroid administration:

Corticosteroids, if administered, should be tapered as rapidly as possible, but no faster than clinically tolerated, on the basis of an individualized treatment regimen and a full understanding of the long-term sequelae of corticosteroid therapy.

ASCO/SNO Expert Panel comment: The Panel’s expert opinion is that, given the important adverse effects of steroids, the minimum effective dose (often no more than 4 mg) should be used where possible and night-time doses of steroids should be avoided to minimize toxicity.

Note regarding CNS Level 3 recommendation classification: CNS defines a Level 3 recommendation as, one based on “Evidence from case series, comparative studies with historical controls, case reports, and expert opinion, as well as significantly flawed randomized controlled trials”

Anticonvulsant Prophylaxis and Steroid Use in Adults With Metastatic Brain Tumors: ASCO and SNO Endorsement of the Congress of Neurological Surgeons Guidelines. Chang SM, Messersmith H, Ahluwalia M, et al. J Clin Oncol 2019;37:1130-1135

Association between Androgen Deprivation Therapy and Diagnosis of Alzheimer Disease or Dementia in Patients with Prostate Cancer

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 174,650 new cases of Prostate cancer will be diagnosed in 2019 and 31,620 men will die of the disease. The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide). The first-generation Androgen Receptor (AR) inhibitors act by binding to the Androgen Receptor (AR) and prevent the activation of the AR and subsequent up-regulation of androgen responsive genes. They may also accelerate the degradation of the AR. These agents have a range of pharmacologic activity from being pure anti-androgens to androgen agonists. The second-generation, anti-androgen agents include, ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide) and ERLEADA® (Apalutamide). ZYTIGA® inhibits CYP17A1 enzyme and depletes adrenal and intratumoral androgens, thereby impairing AR signaling. XTANDI® and ERLEADA® compete with Testosterone and Dihydrotestosterone and avidly binds to the Androgen Receptor, thereby inhibiting AR signaling, and in addition inhibits translocation of the AR into the nucleus and thus inhibits the transcriptional activities of the AR.

Androgen Deprivation Therapy (ADT) is often recommended alone or as a part of multimodality therapy, as ADT reduces the likelihood of cancer progression and/or mortality, in high-risk localized, locally advanced, recurrent, or metastatic Prostate cancer. ADT however can be associated with side effects such as fatigue, loss of muscle mass, impotence, anemia, osteoporosis, depression, etc., which in turn can have a significant negative impact on an individual’s quality of life. ADT has also been associated with cognitive dysfunction and there has been conflicting evidence establishing an association between ADT use and diagnosis of Alzheimer disease or Dementia. It has been postulated that lower testosterone levels impair neuron growth and axonal regeneration, in addition to accumulation of abnormally folded β-amyloid protein. With the earlier introduction of ADT in the course of disease progression for patients with Prostate cancer, it is important to discuss the association between ADT and Dementia with patients, which in turn can improve shared decision making around the risks and benefits of ADT in Prostate cancer.

The present study was conducted to analyze the association between ADT exposure and diagnosis of Alzheimer disease or Dementia, among elderly men with Prostate cancer. The authors in this retrospective cohort study used data from the NCI’s Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, and the participants included 154,089 elderly men with newly diagnosed Prostate cancer, between 1996 and 2003. The analyses were conducted in 2018 and patients receiving ADT within 2 years of Prostate cancer diagnosis were identified. In this study, 62,330 men received ADT within 2 years of Prostate cancer diagnosis, and 91,759 men did not receive ADT. Mean follow up was 8.3 years, and survival analysis was used to determine association between ADT exposure and diagnosis of Alzheimer disease or Dementia.

The researchers noted that exposure to ADT, compared with no ADT exposure, was associated with a diagnosis of Alzheimer disease (13.1% vs 9.4%; HR=1.14; P<0.001) and Dementia (21.6% vs 15.8%; HR=1.20; P<0.001). There was a dose-response relationship and patients who received more than 8 doses of ADT were at a significantly higher hazard of diagnosis of both Alzheimer disease and Dementia, than those receiving fewer doses ADT.

The authors concluded that over a follow-up period of at least 10 years, ADT exposure among elderly patients with Prostate cancer was associated with subsequent diagnosis of Alzheimer disease or Dementia. They added that clinicians should carefully weigh the long-term risks and benefits of ADT, in patients with a prolonged life expectancy, and stratify patients based on Dementia risk, prior to ADT initiation. Association Between Androgen Deprivation Therapy Use and Diagnosis of Dementia in Men With Prostate Cancer. Jayadevappa R, Chhatre S, Malkowicz SB, et al. JAMA Netw Open. 2019;2(7):e196562. doi:10.1001/jamanetworkopen.2019.6562

Survival Benefit with KEYTRUDA® After Locally Ablative Therapy (LAT) for Oligometastatic NSCLC

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2019, about 228,150 new cases of lung cancer will be diagnosed and 142,670 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas.

It is estimated that approximately 7% of patients with NSCLC present with a limited number of metastatic foci (oligometastatic). Several retrospective studies have shown that the use of Locally Ablative Therapy (LAT) to all sites of disease in oligometastatic NSCLC is associated with a significant improvement in Progression Free Survival (PFS) and Overall Survival (OS), when compared with historical data. Preclinical evidence had suggested that chemotherapy and radiotherapy may upregulate PD-L1 expression in tumor cells. Therefore, incorporating immunotherapy along with LAT has been an area of active research. In the PACIFIC trial, consolidation therapy with PD-L1 inhibitor IMFINZI® (Durvalumab), following chemoradiation, significantly improved PFS and OS among patients with locally advanced NSCLC suggesting that there is a strong biological rationale for the use of immunotherapy in patients with minimal residual disease state.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. The primary objective of this study was to evaluate whether the addition of KEYTRUDA® after Locally Ablative Therapy (LAT) improves outcomes among patients with oligometastatic NSCLC, compared with historical data.

The authors conducted a single arm Phase II trial at an academic referral cancer center, and 51 eligible patients with oligometastatic NSCLC (no more than 4 metastatic sites) were enrolled. Enrolled patients had oligometastatic disease at diagnosis (synchronous disease) or who developed oligometastatic disease after initial definitive therapy (metachronous disease). There was no limit on the number of prior therapies, although patients could not have received prior therapy with a Programmed Death 1 (PD-L1) inhibitor. Any form of Locally Ablative Therapy (LAT) was acceptable and LATs included Surgery, Chemoradiotherapy, Stereotactic radiotherapy, and/or Interventional ablation. Forty five of the 51 patients enrolled received KEYTRUDA® within 4 to 12 weeks of completing LAT. Patients received KEYTRUDA® 200 mg IV every 21 days, for 8 cycles and were allowed to continue therapy for a total of 16 cycles in the absence of progressive disease or untoward toxicities. The median age was 64 years and patients were eligible regardless of their PD-L1 or molecular target status. Thirty-two patients had adequate tissue for assessment of PD-L1 status, and 29 patients had adequate tissue for assessment of CD8 T-cell infiltration. In patients undergoing testing, 34% had results positive for PD-L1 (1% or more) and 52% had CD8 T-cell infiltration of greater than 2.5%. Patients received a median of 11 cycles of KEYTRUDA®.

The two Primary efficacy end points were Progression Free Survival (PFS) from the start of Locally Ablative Therapy (PFS-L) and PFS from the start of KEYTRUDA® therapy (PFS-P). This study was powered for comparison with historical data on the first efficacy end point. Secondary outcomes included Overall Survival, Safety, and Quality of Life, as measured by the Functional Assessment of Cancer Therapy–Lung (FACT-L) instrument.

After a median follow-up of 23.2 months for surviving patients, the median PFS from the start of Locally Ablative Therapy (PFS-L) was 19.1 months, which was a statistically significant improvement from the historical median of 6.6 months (P=0.005). The median PFS from the start of KEYTRUDA® therapy (PFS-P) was 18.7 months. The mean Overall Survival rate at 12 months was 90.9% and at 24 months was 77.5%. The Progression Free Survival from the start of Locally Ablative Therapy (PFS-L) was not influenced by PD-L1 expression or CD8 T-cell tumor infiltration. Quality of Life as measured by the FACT-L scores at cycles 8 and 16 were not significantly different from FACT-L scores at baseline.

The authors concluded that KEYTRUDA® after Locally Ablative Therapy for oligometastatic NSCLC was associated with a clinically and statistically significant improvement in Progression Free Survival, compared with historical data, without a decrement in Quality of Life. They added that the Overall Survival data is encouraging but will require further follow up. Pembrolizumab After Completion of Locally Ablative Therapy for Oligometastatic Non–Small Cell Lung Cancer: A Phase 2 Trial. Bauml JM, Mick R, Ciunci C, et al. JAMA Oncol. Published online July 11, 2019. doi:10.1001/jamaoncol.2019.1449

ASCO/ASH Update on Erythropoiesis Stimulating Agents for Cancer-Associated Anemia

SUMMARY: The American Society of Clinical Oncology (ASCO) along with American Society of Hematology (ASH) updated recommendations for use of Erythropoiesis Stimulating Agents (ESAs) in patients with cancer. The primary literature review included 15 meta-analyses of Randomized Clinical Trials and two Randomized Clinical Trials. These recommendations were developed using a systematic review of the literature from January, 2010, through May, 2018, and clinical experience.

Guideline question: When and how should Erythropoiesis Stimulating Agents (ESAs) be used to manage anemia in adults with cancer?

Target population: Adults with Cancer and Anemia.

Target audience: Oncologists, Hematologists, Oncology Nurses, Oncology Pharmacists, and other health care professionals who care for patients with cancer, and patients with cancer.

RECOMMENDATIONS

Clinical question 1: To reduce the need for RBC transfusions, should ESAs be offered to patients who have chemotherapy-associated anemia?

Recommendation 1.1. Depending on clinical circumstances, ESAs may be offered to patients with chemotherapy-associated anemia whose cancer treatment is not curative in intent and whose hemoglobin has declined to less than 10 g/dL. RBC transfusion is also an option, depending on the severity of the anemia or clinical circumstances

Recommendation 1.2. ESAs should not be offered to patients with chemotherapy-associated anemia whose cancer treatment is curative in intent

Clinical question 2: To reduce the need for RBC transfusions, should ESAs be offered to anemic patients with cancer who are not receiving concurrent myelosuppressive chemotherapy?

Recommendation 2.1. ESAs should not be offered to most patients with nonchemotherapy-associated anemia

Recommendation 2.2. ESAs may be offered to patients with lower risk MyeloDysplastic Syndromes and a serum Erythropoietin level 500 IU/L or less.

Clinical question 3: What special considerations apply to adult patients with nonmyeloid hematologic malignancies who are receiving concurrent myelosuppressive chemotherapy?

Recommendation 3. In patients with Myeloma, Non-Hodgkin Lymphoma, or Chronic Lymphocytic Leukemia, clinicians should observe the hematologic response to cancer treatment before considering an ESA. Particular caution should be exercised in the use of ESAs concomitant with treatment strategies and diseases where risk of thromboembolic complications is increased (see Recommendations 4 and 6). In all cases, blood transfusion is a treatment option that should be considered

Clinical question 4: What examinations and diagnostic tests should be performed before making a decision about using an ESA to identify patients who are likely to benefit from an ESA?

Recommendation 4. Before offering an ESA, clinicians should conduct an appropriate history, physical examination, and diagnostic tests to identify alternative causes of anemia aside from chemotherapy or an underlying hematopoietic malignancy. Such causes should be appropriately addressed before considering the use of ESAs. Suggested baseline investigations include thorough drug exposure history, peripheral blood smear review, analyses where indicated, for Iron, TIBC, Ferritin, Transferrin saturation, Folate, Vitamin B12, or Hemoglobinopathy screening, assessment of Reticulocyte count, occult blood loss and renal Insufficiency and baseline Erythropoietin level and TSH. Investigations may also include Direct Antiglobulin Testing (eg, Coombs test) for patients with Chronic Lymphocytic Leukemia, Non-Hodgkin Lymphoma, or a history of autoimmune disease.

Clinical question 5: Among adult patients who receive an ESA for chemotherapy-associated anemia, do Darbepoetin, Epoetin beta and alfa originator, and currently available biosimilars of Epoetin alfa differ with respect to safety or efficacy?

Recommendation 5. The Expert Panel considers Epoetin beta and alfa, Darbepoetin, and biosimilar Epoetin alfa to be equivalent with respect to effectiveness and safety

Clinical question 6: Do ESAs increase the risk of thromboembolism?

Recommendation 6. ESAs increase the risk of thromboembolism, and clinicians should carefully weigh the risks of thromboembolism and use caution and clinical judgment when considering use of these agents

Clinical question 7: Among adult patients who will receive an ESA for chemotherapy-associated anemia, what are recommendations for ESA dosing and dose modifications?

Recommendation 7. It is recommended that starting and modifying doses of ESAs follow FDA guidelines

Clinical question 8: Among adult patients who will receive an ESA for chemotherapy-associated anemia, what is the recommended target HgB level?

Recommendation 8. HgB may be increased to the lowest concentration needed to avoid or reduce the need for RBC transfusions, which may vary by patient and condition

Clinical question 9: Among adult patients with chemotherapy-associated anemia who do not respond to ESA therapy (less than 1 to 2 g/dL increase in HgB or no decrease in transfusion requirements), does continuation of ESA therapy beyond 6-8 weeks provide a benefit?

Recommendation 9. ESAs should be discontinued in patients who do not respond within 6-8 weeks. Patients who do not respond to ESA treatment should be reevaluated for underlying tumor progression, Iron deficiency, or other etiologies for anemia

Clinical question 10: Among adult patients with chemotherapy-associated anemia, does Iron supplementation concurrent with an ESA reduce transfusion requirements?

Recommendation 10. Iron replacement may be used to improve HgB response and reduce RBC transfusions for patients receiving ESA with or without iron deficiency. Baseline and periodic monitoring of Iron, total Iron-Binding Capacity, Transferrin saturation, or Frritin levels is recommended

Management of cancer-associated anemia with erythropoiesis-stimulating agents: ASCO/ASH clinical practice guideline update. Bohlius J, Bohlke K, Castelli R, et al. Blood Advances 2019;3:1197-1210