Sabin Kshattry, Terri L. Parker, Scott F. Huntington<\/h3>\n\n\n\nJAMA. <\/em>2023;330(16):1581-1582. doi:10.1001\/jama.2023.17117<\/h3>\n\n\n\nCase<\/a><\/p>\n\n\n\nAn 80-year-old man with stage II bladder carcinoma (T2NXM0) and atrial fibrillation treated with apixaban presented to the emergency department with 1 week of fatigue and 2 days of dyspnea on exertion. One week prior to presentation, he received a fourth cycle of carboplatin\/gemcitabine for bladder carcinoma with 6 mg of pegylated granulocyte colony-stimulating factor (G-CSF). The patient reported no anorexia, fever, melena, hematemesis, hematuria, cough, orthopnea, or peripheral edema.<\/a><\/p>\n\n\n\nHis vital signs were normal except for a heart rate of 103\/min. His white blood cell count was 22\u2009\u00d7\u2009103<\/sup>\/\u03bcL (reference, 4-11\u2009\u00d7\u2009103<\/sup>\/\u03bcL), increased from 4.8\u2009\u00d7\u2009103<\/sup>\/\u03bcL 8 days prior. His manual differential, which was previously normal, showed 18% bands (0%-10%), 2% metamyelocytes, 7% myelocytes, 7% promyelocytes, and 6% blasts. His hemoglobin level was 5.2 g\/dL (reference, 13-17 g\/dL), decreased from 7.4 g\/dL, and platelets were 25\u2009\u00d7\u2009103<\/sup>\/\u03bcL (reference, 150-420\u2009\u00d7\u2009103<\/sup>\/\u03bcL), decreased from 268\u2009\u00d7\u2009103<\/sup>\/\u03bcL 8 days prior. Ferritin was 1423 ng\/mL (reference, 300-400 ng\/mL). Mean corpuscular volume, prothrombin time, international normalized ratio, partial thromboplastin time, fibrinogen, haptoglobin, vitamin B12<\/sub>, and methylmalonic acid values were normal, and results of a direct antiglobulin test were negative. A computed tomography (CT) scan of his abdomen and pelvis was normal. He received 2 units of packed red blood cells and was admitted to the hospital. Flow cytometry identified a small population of CD34+\/CD117+ cells (Figure<\/a>).<\/p>\n\n\n\n![\"\"\/](\"https:\/\/cdn.jamanetwork.com\/ama\/content_public\/journal\/jama\/939252\/jcg230013f1_1697473293.40749.png?Expires=1709960483&Signature=AOQUfR7UnGpNsoaQf70Lq2j4rQFWYBIdO4PwxnNWA6it7giaXUrkC9hOtFl~aAIusjQL54~FGJ2GJekSwhRx~sSmOLC5J3C4Wk4JZ8GhHzGangoxsr14QSFcGz7w-VdxA2k8hCo-qt9YO57QQ6ZDyA8mijCSqzsv3KKwlEXyhPVmm~pn8abdMXkdvuOLrvkJwe-erNQvpHbm74F6SX26ViiTLAea0XL~-Aud-i6VGvcFllcjw4co-mPHHWosL-SQ04vIVMoqvHwIRhIgmA-1n~~QroTnLPGZB6SEeHPlA4MgsUsmW~4CvSZ2M98cfF3QiSmDQoObvBXIhvXTgSTGEg__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA\")
<\/figure>\n\n\n\nLeft, Peripheral blood smear showing normocytic anemia with anisopoikilocytosis and leukocytosis with 6% to 8% blast forms. Right, Flow cytometry of peripheral blood demonstrating a small population of white blood cells that stained positive for CD34 and CD117, which are markers of immature myeloblasts.<\/p>\n\n\n\n
Esophagogastroduodenoscopy revealed 2 nonbleeding angioectasias in the stomach that were treated with argon plasma coagulation. Three days after admission, his white blood cell count was 27.7\u2009\u00d7\u2009103<\/sup>\/\u03bcL with 4% peripheral blasts, hemoglobin was 7.3 g\/dL, and platelet count had increased to 92\u2009\u00d7\u2009103<\/sup>\/\u03bcL without a platelet transfusion.<\/a><\/a><\/p>\n\n\n\nWhat Would You Do Next?<\/h4>\n\n\n\n\n- Perform a bone marrow biopsy<\/li>\n\n\n\n
- Prescribe all-trans<\/em> retinoic acid<\/li>\n\n\n\n
- Repeat complete blood cell count with differential in 1 to 2 weeks<\/li>\n\n\n\n
- Start cytoreductive therapy with hydroxyurea<\/li>\n<\/ul>\n\n\n\n
Discussion<\/a><\/p>\n\n\n\nDiagnosis<\/a><\/p>\n\n\n\nGranulocyte colony-stimulating factor (G-CSF)\u2013induced increase in peripheral blasts<\/a><\/p>\n\n\n\nWhat to Do Next<\/a><\/p>\n\n\n\nC. Repeat complete blood cell count with differential in 1 to 2 weeks<\/a><\/p>\n\n\n\nThe key to the correct diagnosis is recognizing that leukocytosis with immature granulocytes and mildly elevated blasts in the peripheral blood can occur after G-CSF administration. Bone marrow biopsy (choice A) is incorrect because his platelet count increased spontaneously 3 days after presentation, making malignant infiltration of his bone marrow unlikely, and recent G-CSF administration can alter bone marrow biopsy results. All-trans<\/em> retinoic acid and cytoreductive therapy (options B and D) should not be prescribed because the patient did not have biopsy-proven acute promyelocytic leukemia or acute leukemia.<\/a><\/p>\n\n\n\nDiscussion<\/a><\/p>\n\n\n\nMyeloblasts are immature leukocytes that arise from progenitor stem cells in the bone marrow, and their presence in peripheral blood suggests a perturbation of normal hematopoietic differentiation. Myeloblasts are characterized by the presence of CD34 and CD1171<\/a><\/sup> antigens, identified with flow cytometry. A peripheral blood myeloblast count of greater than 20% is diagnostic of acute myeloid leukemia (AML), although AML can occur with a lower myeloblast count.2<\/a><\/sup> Increased peripheral blood myeloblasts with leukopenia may be due to AML, myelodysplastic syndrome (MDS), chemotherapy, or occasionally severe infection. Causes of elevated peripheral blood myeloblasts with leukocytosis include AML, myelodysplastic syndrome, myeloproliferative neoplasms, severe infection, bone marrow damage or infiltration by fibrosis, malignancy or infection,3<\/a><\/sup>,4<\/a><\/sup> and administration of G-CSF.<\/a><\/p>\n\n\n\nG-CSF, which is produced by macrophages, T cells, endothelial cells, and fibroblasts,5<\/a><\/sup> causes proliferation and differentiation of hematopoietic stem cells and progenitor cells, generating polymorphonuclear neutrophils via the precursor stages of myeloblast, promyelocyte, myelocyte, metamyelocyte, and bands. G-CSF therapy stimulates neutrophil production in the bone marrow, causing a rapid increase in peripheral blood neutrophils (emergency granulopoiesis) during severe infections. G-CSF also acts to maintain a neutrophil reserve in the bone marrow and regulates the slow release of neutrophils into the peripheral circulation.3<\/a><\/sup><\/a><\/p>\n\n\n\nRecombinant human G-CSF (filgrastim) received US Food and Drug Administration (FDA) approval in 1991 for prevention of chemotherapy-induced neutropenia.3<\/a><\/sup>,5<\/a><\/sup> In 2002, the FDA approved pegfilgrastim, which is administered once per chemotherapy cycle, with at least 12 days between doses.6<\/a><\/sup>,7<\/a><\/sup> G-CSF use is typically recommended during all chemotherapy cycles in which there is greater than 20% risk of febrile neutropenia.7<\/a><\/sup> G-CSF can also be given to prevent infection in patients who experienced neutropenic complications during a prior round of chemotherapy.<\/a><\/p>\n\n\n\nPatients treated with G-CSF may have peripheral blasts as high as 40% of circulating leukocytes.8<\/a><\/sup> Although the mechanism of action is uncertain, induction of peripheral blasts by G-CSF may be related to differential expression of isoforms or gene variants in the G-CSF receptor. G-CSF\u2013induced transient increase in peripheral blasts, which is most commonly reported in patients with MDS, AML, and other hematologic malignancies, is treated by withholding G-CSF therapy.3<\/a><\/sup>,8<\/a><\/sup>-10<\/a><\/sup> Peripheral blasts typically resolve 1 to 2 weeks after peak blast count,8<\/a><\/sup>,9<\/a><\/sup> at which point G-CSF therapy can be reinitiated with close monitoring of blood counts.<\/a><\/p>\n\n\n\n
Case<\/a><\/p>\n\n\n\n An 80-year-old man with stage II bladder carcinoma (T2NXM0) and atrial fibrillation treated with apixaban presented to the emergency department with 1 week of fatigue and 2 days of dyspnea on exertion. One week prior to presentation, he received a fourth cycle of carboplatin\/gemcitabine for bladder carcinoma with 6 mg of pegylated granulocyte colony-stimulating factor (G-CSF). The patient reported no anorexia, fever, melena, hematemesis, hematuria, cough, orthopnea, or peripheral edema.<\/a><\/p>\n\n\n\n His vital signs were normal except for a heart rate of 103\/min. His white blood cell count was 22\u2009\u00d7\u2009103<\/sup>\/\u03bcL (reference, 4-11\u2009\u00d7\u2009103<\/sup>\/\u03bcL), increased from 4.8\u2009\u00d7\u2009103<\/sup>\/\u03bcL 8 days prior. His manual differential, which was previously normal, showed 18% bands (0%-10%), 2% metamyelocytes, 7% myelocytes, 7% promyelocytes, and 6% blasts. His hemoglobin level was 5.2 g\/dL (reference, 13-17 g\/dL), decreased from 7.4 g\/dL, and platelets were 25\u2009\u00d7\u2009103<\/sup>\/\u03bcL (reference, 150-420\u2009\u00d7\u2009103<\/sup>\/\u03bcL), decreased from 268\u2009\u00d7\u2009103<\/sup>\/\u03bcL 8 days prior. Ferritin was 1423 ng\/mL (reference, 300-400 ng\/mL). Mean corpuscular volume, prothrombin time, international normalized ratio, partial thromboplastin time, fibrinogen, haptoglobin, vitamin B12<\/sub>, and methylmalonic acid values were normal, and results of a direct antiglobulin test were negative. A computed tomography (CT) scan of his abdomen and pelvis was normal. He received 2 units of packed red blood cells and was admitted to the hospital. Flow cytometry identified a small population of CD34+\/CD117+ cells (Figure<\/a>).<\/p>\n\n\n\n Left, Peripheral blood smear showing normocytic anemia with anisopoikilocytosis and leukocytosis with 6% to 8% blast forms. Right, Flow cytometry of peripheral blood demonstrating a small population of white blood cells that stained positive for CD34 and CD117, which are markers of immature myeloblasts.<\/p>\n\n\n\n Esophagogastroduodenoscopy revealed 2 nonbleeding angioectasias in the stomach that were treated with argon plasma coagulation. Three days after admission, his white blood cell count was 27.7\u2009\u00d7\u2009103<\/sup>\/\u03bcL with 4% peripheral blasts, hemoglobin was 7.3 g\/dL, and platelet count had increased to 92\u2009\u00d7\u2009103<\/sup>\/\u03bcL without a platelet transfusion.<\/a><\/a><\/p>\n\n\n\n Discussion<\/a><\/p>\n\n\n\n Diagnosis<\/a><\/p>\n\n\n\n Granulocyte colony-stimulating factor (G-CSF)\u2013induced increase in peripheral blasts<\/a><\/p>\n\n\n\n What to Do Next<\/a><\/p>\n\n\n\n C. Repeat complete blood cell count with differential in 1 to 2 weeks<\/a><\/p>\n\n\n\n The key to the correct diagnosis is recognizing that leukocytosis with immature granulocytes and mildly elevated blasts in the peripheral blood can occur after G-CSF administration. Bone marrow biopsy (choice A) is incorrect because his platelet count increased spontaneously 3 days after presentation, making malignant infiltration of his bone marrow unlikely, and recent G-CSF administration can alter bone marrow biopsy results. All-trans<\/em> retinoic acid and cytoreductive therapy (options B and D) should not be prescribed because the patient did not have biopsy-proven acute promyelocytic leukemia or acute leukemia.<\/a><\/p>\n\n\n\n Discussion<\/a><\/p>\n\n\n\n Myeloblasts are immature leukocytes that arise from progenitor stem cells in the bone marrow, and their presence in peripheral blood suggests a perturbation of normal hematopoietic differentiation. Myeloblasts are characterized by the presence of CD34 and CD1171<\/a><\/sup> antigens, identified with flow cytometry. A peripheral blood myeloblast count of greater than 20% is diagnostic of acute myeloid leukemia (AML), although AML can occur with a lower myeloblast count.2<\/a><\/sup> Increased peripheral blood myeloblasts with leukopenia may be due to AML, myelodysplastic syndrome (MDS), chemotherapy, or occasionally severe infection. Causes of elevated peripheral blood myeloblasts with leukocytosis include AML, myelodysplastic syndrome, myeloproliferative neoplasms, severe infection, bone marrow damage or infiltration by fibrosis, malignancy or infection,3<\/a><\/sup>,4<\/a><\/sup> and administration of G-CSF.<\/a><\/p>\n\n\n\n G-CSF, which is produced by macrophages, T cells, endothelial cells, and fibroblasts,5<\/a><\/sup> causes proliferation and differentiation of hematopoietic stem cells and progenitor cells, generating polymorphonuclear neutrophils via the precursor stages of myeloblast, promyelocyte, myelocyte, metamyelocyte, and bands. G-CSF therapy stimulates neutrophil production in the bone marrow, causing a rapid increase in peripheral blood neutrophils (emergency granulopoiesis) during severe infections. G-CSF also acts to maintain a neutrophil reserve in the bone marrow and regulates the slow release of neutrophils into the peripheral circulation.3<\/a><\/sup><\/a><\/p>\n\n\n\n Recombinant human G-CSF (filgrastim) received US Food and Drug Administration (FDA) approval in 1991 for prevention of chemotherapy-induced neutropenia.3<\/a><\/sup>,5<\/a><\/sup> In 2002, the FDA approved pegfilgrastim, which is administered once per chemotherapy cycle, with at least 12 days between doses.6<\/a><\/sup>,7<\/a><\/sup> G-CSF use is typically recommended during all chemotherapy cycles in which there is greater than 20% risk of febrile neutropenia.7<\/a><\/sup> G-CSF can also be given to prevent infection in patients who experienced neutropenic complications during a prior round of chemotherapy.<\/a><\/p>\n\n\n\n Patients treated with G-CSF may have peripheral blasts as high as 40% of circulating leukocytes.8<\/a><\/sup> Although the mechanism of action is uncertain, induction of peripheral blasts by G-CSF may be related to differential expression of isoforms or gene variants in the G-CSF receptor. G-CSF\u2013induced transient increase in peripheral blasts, which is most commonly reported in patients with MDS, AML, and other hematologic malignancies, is treated by withholding G-CSF therapy.3<\/a><\/sup>,8<\/a><\/sup>-10<\/a><\/sup> Peripheral blasts typically resolve 1 to 2 weeks after peak blast count,8<\/a><\/sup>,9<\/a><\/sup> at which point G-CSF therapy can be reinitiated with close monitoring of blood counts.<\/a><\/p>\n\n\n\n<\/figure>\n\n\n\nWhat Would You Do Next?<\/h4>\n\n\n\n
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