updates in the management of anemia in cancer · impaired production/hypoproliferative anemia ......

Updates in the Management of Anemia in Cancer

Taylor M. Ortiz, MD

May 19, 2017

Objectives

Recall common causes of anemia in patients with cancer

Understand risks/benefits of blood transfusion in patients with cancer

Understand the risks/benefits of erythropoiesis stimulating agents (ESAs) for anemia in patients with cancer

Anemia in Cancer

Today’s focus is on anemia in patients with solid tumors or lymphoid malignancies

Presenter

Presentation Notes

Anemia in myeloid & lymphoblastic leukemias, bone marrow transplant recipients, and myelodysplasia is beyond today’s scope, and should be managed primarily by the treating oncologist.

Prevalence of Anemia

40%-63% of patients with cancer are anemic prior to treatment 32% of patients with Non-Hodgkin’s lymphoma

49% of patients with gynecologic malignancies

Degree of anemia correlates with Cancer stage

Inflammatory markers

Albumin, cholesterol, leptin

90% of patients treated with chemotherapy are anemic

Knight W, et al. Am J Med, 2004 Maccio A, et al. Haematologica, 2015

Stasi R, et al. Cancer, 2003 NCCN Guidelines, Cancer and Chemotherapy induced Anemia, v 2.2017

Presenter

Presentation Notes

Defines as hgb <14 in men and < 12 in women Markers of inflammation include ESR/CRP and other markers, like ferritin, hepcidin are inversely proportional to the hemoglobin in many patients. WHO Grading: Mild <10, moderate 8-10, severe 6.5-8, life threatening, <6.5 or unstable patient

Etiology of Anemia in Cancer Impaired production/hypoproliferative

anemia Low reticulocyte count

Nutritional deficiency

Malignancy-induced

Myelosuppressive chemotherapy or radiation-induced

Decreased erythropoietin production

Red cell destruction/decreased RBC survival High reticulocyte count

Intra/extra-vascular hemolysis

Blood loss Hemorrhage via intraluminal bleeding or RP/hepatic

internal bleeding

Presenter

Presentation Notes

Typically, in cancer patients, anemia is multifactorial. Decreased RBC survival is defined as RBC lifetime < 100d. There are some cancer-specific causes of anemia, including direct effects of the neoplasm, anti-neoplastic therapy, and paraneoplastic phenomena.

Hypoproliferative anemia in cancer: Nutritional deficiencies

Cancer/chemotherapy-induced nausea and anorexia

Neoplastic-induced malabsorption Secondary to involvement of

duodenum/jejunum

Surgical resection Gastric tissue/terminal ileum -> B12 def

Gastrectomy->achlorhydria -> iron malabsorption

Hypoproliferative anemia in cancer: Bone-marrow infiltration

Common in leukemia, lymphoma, plasma cell dyscrasia

Uncommon in solid tumor malignancies Can be seen in gastric and prostate

Ca.

Bone marrow infiltration by

gastric carcinoma

Guner SI, J Ca Clin Trials, 2015

Myelopthisis with

dacrocytes/ teardrop cells

Presenter

Presentation Notes

Can also see a leukoerythroblastic anemia, with early RBCs/nucleated RBCs, immature granulocytes in the peripheral blood

Hypoproliferative anemia in cancer: Anemia of inflammation

Cancers frequently produce IFN-α/β/γ, TGF-β, IL-1/6

Causes a block in iron utilization or erythropoietin production

Increased hepcidin

Iron sequestration within macrophage

Decreased duodenal absorption

Decreased mobilization of stored iron

Presenter

Presentation Notes

Although common, anemia of inflammation is a diagnosis of exclusion, and other reversible causes should be considered first.

Girelli D, et al. Blood, 2016

Presenter

Presentation Notes

Hepcidin, discovered in 2001, causes degradation of the iron transporter, ferroportin. Hepcidin is produced in hepatocytes in response to a variety of stimuli as seen here.

Hypoproliferative anemia in cancer: Myelosuppressive Chemotherapy Frequently accompanied by

thrombocytopenia and neutropenia

Expected timing of anemia varies by chemotherapy regimen, schedule Hgb trend is less dynamic than WBC/ANC

during chemotherapy; is more “cumulative”

Recent labs are critically important to determine expected change in hgb over subsequent days

Example during one cycle of myelosuppressive chemotherapy

Adapted from www.neupogenhcp.com

Hemoglobin

Hypoproliferative anemia in cancer: Myelosuppressive Chemotherapy Two common mechanisms for anemia

Direct suppression of RBC precursor synthesis in bone marrow

Usually through impaired DNA synthesis/mitosis


Nephrotoxicic effects

Ex: Cisplatin Platinum-containing DNA cross-linker

Interferes with RBC precursor synthesis

Also has direct nephrotoxic effects

Etiology of Anemia in Cancer Impaired production/hypoproliferative anemia

Low reticulocyte count Nutritional deficiency

Malignancy-induced




Autoimmune

Microangiopathic hemolysis

Blood loss Hemorrhage via intraluminal bleeding or RP/hepatic internal

bleeding

Presenter

Presentation Notes


Increased RBC destruction: Autoimmune Hemolytic Anemia

Can be seen in Chronic lymphocytic leukemia

Less frequently in Carcinoma Non-Hodgkin lymphoma Myelodysplastic syndrome Others

Presenter

Presentation Notes

I’m focusing here on the Warm-autoreacting antibodies.

Increased RBC destruction: Autoimmune Hemolytic Anemia

IgG or complement mediated Labs notable for

Elevated

Reticulocyte count

LDH

Indirect bili

Decreased Haptoglobin

Positive Coombs/DAT

Spherocytes

Cold-reacting autommune hemolysis is less common

Presenter

Presentation Notes

I’m focusing here on the Warm-autoreacting antibodies.

Direct Coombs Test/DAT

Increased RBC destruction: Microangiopathic hemolysis

TTP, HUS, DIC Can be seen in liquid or

solid tumors Adenocarcinomas

Presenter

Presentation Notes

Mucinous adenocarcinomas like breast, lung, prostate, gastric, and pancreatic are

Schistocytes in microangiopathic hemolytic anemia

Presenter

Presentation Notes

Schistocytes (helmet cells) are seen in MAHA,. >5/hpf is concerning for MAHA

Etiology of Anemia in Cancer Impaired production/hypoproliferative anemia

Low reticulocyte count Nutritional deficiency

Malignancy-induced




Autoimmune

Microangiopathic hemolysis

Blood loss Hemorrhage via intraluminal bleeding or RP/hepatic internal

bleeding

Presenter

Presentation Notes


Acute and chronic hemorrhage

Intraluminal tumors (GI/GU tract)

Coagulopathies are common in cancer patients Many cancer patients are also treated with

anticoagulants

DIC in leukemias, mucinous adenocarcinomas

Stress and corticosteroids may contribute to gastric-mucosal erosive disease

Presenter

Presentation Notes

Hemorrhage doesn’t typically begin to cause iron deficiency until: 600mL blood loss in females, 1200 mL blood loss in males. Also, retroperitoneal, gluteal, and hepatic capsular bleeds can be substantial

Initial Assessment of Cancer Patient with Anemia History

Symptoms, nutritional status, EtOH

Recent transfusions

Bleeding, menses

Medications (including anticoagulants/antiplatelet agents)

Timing/duration of chemo/radiotherapy treatment

Recent labs

Physical Examination Stool guaiac*

* Digital rectal exams are relatively contraindicated in patients with absolute neutrophil count less than 500/uL

Laboratory evaluation

CBC MCV, platelets, other cytopenias

Reticulocyte count

Ferritin

B12, folate, TSH, iron/TIBC

Blood smear

PT/INR, PTT

Type and cross

Additional studies Haptoglobin

LDH

Fibrinogen, d-dimer

Coombs/DAT

Tbili/Dbili

Objectives




What is the goal hemoglobin?

There isn’t one Depends on

Timing of chemo/radiotherapy

Comorbidities

Symptoms

Recent labs are critical to predict the trend

In asymptomatic patients, short-term follow-up with repeat labs is reasonable

PRBC transfusion in cancer: Clinical pearls Understanding trend of Hgb versus chemotherapy

administration guides transfusion Avoid transfusion in the setting of autoimmune

hemolysis Ferritin prior to transfusion Leukoreduced (and irradiated) RBCs reduce

Febrile non-hemolytic reaction

Alloimmunization/platelet refractoriness

Viral infection

1 unit should increase Hgb by ~1g/dL In a patient with previous stem cell transplant, consult

transplanter first

Sirchia G, et al. Transfusion, 1987

Presenter

Presentation Notes

Leukoreduction reduces the risk of febrile non-hemolytic reaction, alloimmunization and platelet refractoriness, viral infection. In patients with previous stem cell transplant, one has to be cautious regarding the patients degree of immunosuppression, CMV status, and risk of transfusion-associated GVHD.

Risks of RBC transfusion

Transfusion associated circulatory overload (TACO)

Transfusion reactions

Bacterial contamination/viral infection

Alloimmunization

Cancer and chemotherapy induced anemia, NCCN Guidelines, 2.2017

Objectives




Erythropoiesis-stimulating agents

ESAs (darbepoetin, epoetin alfa) may be suitable in patients with non-acute needs or who refuse PRBCs

Risks Increased thromboembolic events

Potential hastened progression of malignancy*

Breast, lung, lymphoid, head & neck, cervical cancers

Untch M, et al. JCO 2015 Hedenus M, et al. BJH, 2003 Henke M, et al, Lancet 2003

Leyland-Jones B, et al. JCO 2005 Overgaard J, et al. JCO, 2009

Smith RE, et al. JCO 2008 Wright JR, et al. JCO 2007

* FDA REMS in effect thru April 2017

Epoetin alfa vs placebo in metastatic breast cancer

Leyland-Jones B, et al. JCO, 2005

Presenter

Presentation Notes

In this study, 939women with metastatic breast cancer receiving 1st line chemotherapy were randomized to epoetin alfa vs placebo with a goal hgb of 12-14 g/dL. Primary outcome was OS at 12-months. At 12 months, OS of placebo was 76%, vs 70% getting epoetin alfa (p=.01)

Epoetin-β vs placebo in head and neck cancer

Henke M, Lancet, 2003

Prog

ress

ion

free

sur

viva

l

Presenter

Presentation Notes

Placebo or epoetin (300 IU/kg) were administered subcutaneously three times per week. Additional 200 mg iron was administered intravenously once weekly if transferrin saturation was lower than 25%. Alternatively, oral iron could be given. Placebo or epoetin were started 10–14 days before and continued throughout radiotherapy. Treatment was discontinued when target haemoglobin concentrations were achieved (140 g/L in women or 150 g/L in men) or when haemoglobin increased by more than 20 g/L within 1 week; it was resumed if the haemoglobin concentrations fell to lower than the target concentration.

Anemia in cancer: Take-aways Start with a broad differential

Consider the categories of anemia

Important to understand the patient’s point in their treatment course

In patients on myelosuppressive chemotherapy, follow-up labs/visits and communication of lab results improves care

Transfuse leukoreduced PRBC when necessary

Avoid ESAs in patients with curable tumors

References Prevalence of Anemia; Knight W, et al. Am J Med, 2004

Prevalence of Anemia; Maccio A, et al. Haematologica, 2015

Prevalence of Anemia; Stasi R, et al. Cancer, 2003

NCCN Guidelines, Cancer and Chemotherapy induced Anemia, v 2.2017

Bone marrow infiltration by gastric carcinoma; Guner SI, J Ca Clin Trials, 2015

Girelli D, et al. Blood, 2016

PRBC transfusion in cancer: Clinical pearls; Sirchia G, et al. Transfusion, 1987

Cancer and chemotherapy induced anemia, NCCN Guidelines, 2.2017

Erythropoiesis-stimulating agents; Untch M, et al. JCO 2015; Hedenus M, et al. BJH, 2003; Henke M, et al, Lancet 2003; Leyland-Jones B, et al. JCO 2005; Overgaard J, et al. JCO, 2009; Smith RE, et al. JCO 2008; Wright JR, et al. JCO 2007

Epoetin alfa vs placebo in metastatic breast cancer; Leyland-Jones B, et al. JCO, 2005

Epoetin-β vs placebo in head and neck cancer; Henke M, Lancet, 2003

Cancer- and chemotherapy-induced anemia, National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, Version 2.2017, accessed February 21, 2017, https://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site

https://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site

Thank you [email protected]

updates in the management of anemia in cancer · impaired production/hypoproliferative anemia ......

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