Abstract
Abstract 4555
HGFs have vastly improved the management of anemia, neutropenia, and thrombocytopenia, but are associated with unexpected toxicities.
Toxicities associated with granulocyte, erythroid, and thrombopoietic growth factors were reviewed. Data sources included systematic reviews, clinical trials, guidelines, and materials disseminated by the Food and Drug Administration (FDA), the European Medicines Agency (EMEA), and Canada Health and their advisory committees; product labels and safety notifications disseminated by manufacturers; and utilization data. Data abstracted were thromboembolic complications, immune-mediated cytopenias, bone marrow toxicities, systematic and synergistic toxicities, and regulatory responses.
Pulmonary infiltrates were associated with administration of HGFs with bleomycin or chest radiation. Increased myelodysplasia (MDS) or acute myeloid leukemia (AML) risks among chemotherapy (chemo)-treated breast cancer patients were reported.
Increased mortality and tumor progression were seen when cancer patients received ESAs versus placebo; increased mortality and cardiovascular events were reported when chronic kidney disease (CKD) patients received ESAs targeted to complete anemia correction. Between 1998 and 2003, 191 CKD patients developed neutralizing antibodies and pure red cell aplasia (PRCA) following recombinant erythropoietin administration.
TPO receptor agonist administration is associated with bone marrow reticulin and collagen deposition. 3% of healthy volunteers who received repeated rHuMGDF developed neutralizing autoantibodies and severe thrombocytopenia.
While ESAs, granulopoietic factors, and thrombopoietins have important clinical benefits, they also retain the potential to exhibit serious and unanticipated toxicities.
| . | ESAs . | Granulopoiesis agents . | Thrombopoietins . |
|---|---|---|---|
| Mortality risks | Increased risks among CKD patients targeted to complete anemia correction and ESA treated cancer patients | * | * |
| Increased counts | Possibly related to mortality in cancer and CKD patients | Splenic rupture in peripheral stem cell donors | Seen with 2nd generation agents, no toxicity |
| Thrombosis | 1.6x increased risks among cancer patients, 1.3x increased risks among CKD patients randomized to complete anemia correction | Rarely reported. Case reports of heart attack or stroke among healthy peripheral blood stem cell donors who received GCSF | * |
| Tumor cell stimulation | Downstream and stimulatory effects identified with erythropoietin receptor activation | Increased risks of MDS/AML among breast cancer, chemo and chronic neutropenia patients who received GCSF | * (TPO receptor not seen in tumors) |
| Autoantibody formation | PRCA with ESAs | * | Seen among 3% of 324 healthy volunteers who received rHuMGDF |
| Stem cell depletion | * | Severe cytopenias with granulopoiesis agents and 5-fluorouracil or radiation therapy | * |
| Bone marrow reticulin/ fibrosis | * | * | Seen with 2nd generation TPOs |
| Increased bone marrow collagen | * | * | Rarely seen with 2nd generation TPOs |
| Worsening of cytopenia following treatment cessation | * | * | Seen with romiplostim and eltrombopag |
| Systemic toxicities | * | Bone pain with GCSF and peg GCSF; pleural and cardiac effusions with GMCSF | ïz½Hepatic toxicity following eltrombopag |
| Synergistic toxicities | ESAs and lenalidomide increase the risk of thrombosis ESAs are suspected to aid NSF pathogenesis | GSCF combined with topoisomerase II inhibitors shown to increase myeloid leukemias Incidences of pulmonary toxicity when bleomycin is combined with GCSF | * |
| Toxicity among healthy individuals | Deaths reported with ESA use among high performance athletes | 2 healthy donors developed AML after GCSF and peripheral blood donation 15 healthy peripheral blood stem cell donors had splenic ruptures with GCSF, GMCSF, or peg GCSF | 3% of 324 healthy volunteers developed neutralizing antibodies and severe thrombocytopenia following repeated rHuMGDF administration. 3 of the 324 volunteers developed lymphoid malignancies |
| Toxicity with off-label administration | ESA manufacturers report safety concerns with off-label ESA use | High rates of neutropenia and thrombocytopenia when GCSF or GMCSF are administered in certain off-label settings | High rates of accelerated MDS or AML when TPOR activators administered off-label to MDS patients |
| . | ESAs . | Granulopoiesis agents . | Thrombopoietins . |
|---|---|---|---|
| Mortality risks | Increased risks among CKD patients targeted to complete anemia correction and ESA treated cancer patients | * | * |
| Increased counts | Possibly related to mortality in cancer and CKD patients | Splenic rupture in peripheral stem cell donors | Seen with 2nd generation agents, no toxicity |
| Thrombosis | 1.6x increased risks among cancer patients, 1.3x increased risks among CKD patients randomized to complete anemia correction | Rarely reported. Case reports of heart attack or stroke among healthy peripheral blood stem cell donors who received GCSF | * |
| Tumor cell stimulation | Downstream and stimulatory effects identified with erythropoietin receptor activation | Increased risks of MDS/AML among breast cancer, chemo and chronic neutropenia patients who received GCSF | * (TPO receptor not seen in tumors) |
| Autoantibody formation | PRCA with ESAs | * | Seen among 3% of 324 healthy volunteers who received rHuMGDF |
| Stem cell depletion | * | Severe cytopenias with granulopoiesis agents and 5-fluorouracil or radiation therapy | * |
| Bone marrow reticulin/ fibrosis | * | * | Seen with 2nd generation TPOs |
| Increased bone marrow collagen | * | * | Rarely seen with 2nd generation TPOs |
| Worsening of cytopenia following treatment cessation | * | * | Seen with romiplostim and eltrombopag |
| Systemic toxicities | * | Bone pain with GCSF and peg GCSF; pleural and cardiac effusions with GMCSF | ïz½Hepatic toxicity following eltrombopag |
| Synergistic toxicities | ESAs and lenalidomide increase the risk of thrombosis ESAs are suspected to aid NSF pathogenesis | GSCF combined with topoisomerase II inhibitors shown to increase myeloid leukemias Incidences of pulmonary toxicity when bleomycin is combined with GCSF | * |
| Toxicity among healthy individuals | Deaths reported with ESA use among high performance athletes | 2 healthy donors developed AML after GCSF and peripheral blood donation 15 healthy peripheral blood stem cell donors had splenic ruptures with GCSF, GMCSF, or peg GCSF | 3% of 324 healthy volunteers developed neutralizing antibodies and severe thrombocytopenia following repeated rHuMGDF administration. 3 of the 324 volunteers developed lymphoid malignancies |
| Toxicity with off-label administration | ESA manufacturers report safety concerns with off-label ESA use | High rates of neutropenia and thrombocytopenia when GCSF or GMCSF are administered in certain off-label settings | High rates of accelerated MDS or AML when TPOR activators administered off-label to MDS patients |
=Not reported
No relevant conflicts of interest to declare.
Author notes
Asterisk with author names denotes non-ASH members.
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