CHRONIC MYELOGENOUS LEUKEMIA AND RETINOPATHY TREATED WITH IMATINIB Lili Grunwald, MD,* Sonia Mehta, MD,* Michael D. Hogarty, MD,† Grant T. Liu, MD*‡
Purpose: To describe a case of a rapid clinical response to treatment of leukemic retinopathy and optic nerve infiltration with cytoreductive therapy, including imatinib mesylate (Gleevec), without radiation therapy. Methods: Observational case report. Results: A 13-year-old boy presented with blurry vision and a visual acuity of 20/20 in each eye. On examination, he had infiltrative retinopathy and optic nerve elevation bilaterally. Further testing revealed chronic myelogenous leukemia with severe leukocytosis. The results of the bone marrow biopsy showed the Philadelphia chromosome, t(9;22), which indicated he might respond to imatinib. He was treated with leukopheresis, followed by systemic imatinib and hydroxyurea, and his leukemic retinopathy and optic neuropathy quickly improved. Conclusion: This case demonstrates an excellent clinical response to systemic therapy, including imatinib, without urgent radiation. It is possible, in select cases, to consider treatment with systemic cytoreductive therapy in patients with infiltrative optic neuropathy and retinopathy with the Philadelphia chromosome. RETINAL CASES & BRIEF REPORTS 5:366–368, 2011
(hemoglobin, 5.6 gm/dL) and normal platelets of 483,000/mm3. Bone marrow evaluation was consistent with chronic myelogenous leukemia (CML) in chronic phase with ,5% bone marrow myeloblasts, confirmed by the presence of the Philadelphia chromosome, t(9;22). He underwent immediate leukopheresis, followed immediately by hydroxyurea and imatinib mesylate (Gleevec, Novartis, East Hanover, NJ) therapy. Three weeks later, the visual acuity remained normal, the optic nerve elevation improved, and the retinopathy almost completely resolved.
From the *Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; †Division of Oncology; and ‡Neuro-Ophthalmology Service, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.
Case Report Discussion
A
13-year-old boy presented with blurry vision in the left eye for 3 days with fatigue, dizziness, and abdominal fullness. Visual acuity was 20/20 in each eye. The optic nerves were elevated, and the retinal vasculature was dilated and tortuous bilaterally (Figure 1). There were multiple, focal, round, white, elevated retinal lesions with retinal hemorrhages. The results of the neurologic examination were normal, and the remainder of his physical examination was notable for pallor and massive splenomegaly. Complete blood count revealed a leukocyte count of 650,000/ mm3, with a relative paucity of blasts (1%) along with anemia
Chronic myelogenous leukemia is characterized by a balanced translocation between Chromosomes 9 and 22 (called the ‘‘Philadelphia chromosome’’), creating the novel BCR-ABL fusion gene.1 Imatinib, an oral inhibitor of the BCR-ABL tyrosine kinase, has revolutionized the treatment of CML and can induce protracted remission, particularly when the disease is treated in its early phase.2 Children are more likely to have hyperleukocytosis and ocular involvement in CML.3 Leukemia can involve the fundus mainly in one of the following ways: hematologic abnormalities without direct leukemic infiltration, or, less commonly, direct infiltration by
The authors have no proprietary or conflict of interest to disclose. Reprint requests: Grant T. Liu, MD, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104; e-mail: [email protected]
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LEUKEMIC RETINOPATHY AND OPTIC NEUROPATHY
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Fig. 1. Montage fundus photograph of the right eye (A) and the left eye (B). Bilateral multifocal elevated retinal infiltrates and hemorrhages throughout the retina with dilated and tortuous vasculature. There was bilateral optic nerve elevation.
leukemic cells.4,5 Ocular findings from hematologic abnormalities may include retinal hemorrhages (preretinal, subretinal, or intraretinal), retinal nerve fiber
layer infarctions, vascular dilation and tortuosity, venous occlusion, and retinal neovascularization.6 Findings of leukemic infiltration of the retina include
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RETINAL CASES & BRIEF REPORTS´ 2011 VOLUME 5 NUMBER 4
Fig. 2. Fundus photograph of the right eye (left image) and the left eye (right image) 3 weeks after treatment. The optic nerve elevation has improved, and the retinopathy has almost completely resolved bilaterally.
multifocal yellowish white masses.4,5,7 Optic nerve elevation may be the result of direct infiltration of the optic nerve or elevated intracranial pressure. Our case demonstrates an impressive presentation of bilateral ophthalmic findings from CML. The authors believe that most likely the white patches in the retina and the optic nerve elevation represent leukemic infiltration of the retina and optic nerve. It is important to differentiate these etiologies because infiltration of the optic nerve in leukemia often requires emergent radiation to the eyes, particularly in cases of progressive vision loss.5,8 In our patient’s case, radiation was avoided because he maintained excellent vision and the retinopathy rapidly responded to systemic therapy that included leukopheresis, hydroxyurea, and imatinib. In addition to maintaining normal vision, the patient has achieved a complete molecular remission of his CML and may receive an allogeneic stem cell transplant to achieve cure because long-standing disease control is not always achieved with biologic agents, such as Gleevec. Acknowledgment Thank-you to William Nyberg for assembling the photograph montage.
Key words: chronic myelogenous leukemia, hyperleukocytosis, hyperviscosity, imatinib mesylate, Gleevec, leukemic retinopathy, retinopathy, CML, infiltrative optic neuropathy.
References 1. Goldman JM, Melo JV. Chronic myeloid leukemia—advances in biology and new approaches to treatment. N Engl J Med 2003; 349:1451–1464. 2. Schiffer CA. BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia. N Engl J Med 2007;357:258–265. 3. Rowe JM, Lichtman MA. Hyperleukocytosis and leukostasis: common features of childhood chronic myelogenous leukemia. Blood 1984;63:1230–1234. 4. Gordon KB, Rugo HS, Duncan JL, et al. Ocular manifestations of leukemia: leukemic infiltration versus infectious process. Ophthalmology 2001;108:2293–2300. 5. Dhwali RS, Schachat AP. Leukemias and lymphomas. In: Ryan SJ, ed. Retina. 4th ed. Philadelphia, PA: Elsevier; 2006: 851–858. 6. Kincaid MC, Green WR. Ocular and orbital involvement in leukemia. Surv Ophthalmol 1983;27:211–232. 7. Allen RA, Straatsma BR. Ocular involvement in leukemia and allied disorders. Arch Ophthalmol 1961;66:490–508. 8. Shields JA, Shields CL. Intraocular leukemia. In: Jonathan W, Pine Jr JW, Jacobs A, eds. Intraocular Tumors: An Atlas and Textbook. 2nd ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2008:530–533.
Purpose: To describe a case of a rapid clinical response to treatment of leukemic retinopathy and optic nerve infiltration with cytoreductive therapy, including imatinib mesylate (Gleevec), without radiation therapy. Methods: Observational case report. Results: A 13-year-old boy presented with blurry vision and a visual acuity of 20/20 in each eye. On examination, he had infiltrative retinopathy and optic nerve elevation bilaterally. Further testing revealed chronic myelogenous leukemia with severe leukocytosis. The results of the bone marrow biopsy showed the Philadelphia chromosome, t(9;22), which indicated he might respond to imatinib. He was treated with leukopheresis, followed by systemic imatinib and hydroxyurea, and his leukemic retinopathy and optic neuropathy quickly improved. Conclusion: This case demonstrates an excellent clinical response to systemic therapy, including imatinib, without urgent radiation. It is possible, in select cases, to consider treatment with systemic cytoreductive therapy in patients with infiltrative optic neuropathy and retinopathy with the Philadelphia chromosome. RETINAL CASES & BRIEF REPORTS 5:366–368, 2011
(hemoglobin, 5.6 gm/dL) and normal platelets of 483,000/mm3. Bone marrow evaluation was consistent with chronic myelogenous leukemia (CML) in chronic phase with ,5% bone marrow myeloblasts, confirmed by the presence of the Philadelphia chromosome, t(9;22). He underwent immediate leukopheresis, followed immediately by hydroxyurea and imatinib mesylate (Gleevec, Novartis, East Hanover, NJ) therapy. Three weeks later, the visual acuity remained normal, the optic nerve elevation improved, and the retinopathy almost completely resolved.
From the *Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; †Division of Oncology; and ‡Neuro-Ophthalmology Service, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.
Case Report Discussion
A
13-year-old boy presented with blurry vision in the left eye for 3 days with fatigue, dizziness, and abdominal fullness. Visual acuity was 20/20 in each eye. The optic nerves were elevated, and the retinal vasculature was dilated and tortuous bilaterally (Figure 1). There were multiple, focal, round, white, elevated retinal lesions with retinal hemorrhages. The results of the neurologic examination were normal, and the remainder of his physical examination was notable for pallor and massive splenomegaly. Complete blood count revealed a leukocyte count of 650,000/ mm3, with a relative paucity of blasts (1%) along with anemia
Chronic myelogenous leukemia is characterized by a balanced translocation between Chromosomes 9 and 22 (called the ‘‘Philadelphia chromosome’’), creating the novel BCR-ABL fusion gene.1 Imatinib, an oral inhibitor of the BCR-ABL tyrosine kinase, has revolutionized the treatment of CML and can induce protracted remission, particularly when the disease is treated in its early phase.2 Children are more likely to have hyperleukocytosis and ocular involvement in CML.3 Leukemia can involve the fundus mainly in one of the following ways: hematologic abnormalities without direct leukemic infiltration, or, less commonly, direct infiltration by
The authors have no proprietary or conflict of interest to disclose. Reprint requests: Grant T. Liu, MD, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104; e-mail: [email protected]
366
LEUKEMIC RETINOPATHY AND OPTIC NEUROPATHY
367
Fig. 1. Montage fundus photograph of the right eye (A) and the left eye (B). Bilateral multifocal elevated retinal infiltrates and hemorrhages throughout the retina with dilated and tortuous vasculature. There was bilateral optic nerve elevation.
leukemic cells.4,5 Ocular findings from hematologic abnormalities may include retinal hemorrhages (preretinal, subretinal, or intraretinal), retinal nerve fiber
layer infarctions, vascular dilation and tortuosity, venous occlusion, and retinal neovascularization.6 Findings of leukemic infiltration of the retina include
368
RETINAL CASES & BRIEF REPORTS´ 2011 VOLUME 5 NUMBER 4
Fig. 2. Fundus photograph of the right eye (left image) and the left eye (right image) 3 weeks after treatment. The optic nerve elevation has improved, and the retinopathy has almost completely resolved bilaterally.
multifocal yellowish white masses.4,5,7 Optic nerve elevation may be the result of direct infiltration of the optic nerve or elevated intracranial pressure. Our case demonstrates an impressive presentation of bilateral ophthalmic findings from CML. The authors believe that most likely the white patches in the retina and the optic nerve elevation represent leukemic infiltration of the retina and optic nerve. It is important to differentiate these etiologies because infiltration of the optic nerve in leukemia often requires emergent radiation to the eyes, particularly in cases of progressive vision loss.5,8 In our patient’s case, radiation was avoided because he maintained excellent vision and the retinopathy rapidly responded to systemic therapy that included leukopheresis, hydroxyurea, and imatinib. In addition to maintaining normal vision, the patient has achieved a complete molecular remission of his CML and may receive an allogeneic stem cell transplant to achieve cure because long-standing disease control is not always achieved with biologic agents, such as Gleevec. Acknowledgment Thank-you to William Nyberg for assembling the photograph montage.
Key words: chronic myelogenous leukemia, hyperleukocytosis, hyperviscosity, imatinib mesylate, Gleevec, leukemic retinopathy, retinopathy, CML, infiltrative optic neuropathy.
References 1. Goldman JM, Melo JV. Chronic myeloid leukemia—advances in biology and new approaches to treatment. N Engl J Med 2003; 349:1451–1464. 2. Schiffer CA. BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia. N Engl J Med 2007;357:258–265. 3. Rowe JM, Lichtman MA. Hyperleukocytosis and leukostasis: common features of childhood chronic myelogenous leukemia. Blood 1984;63:1230–1234. 4. Gordon KB, Rugo HS, Duncan JL, et al. Ocular manifestations of leukemia: leukemic infiltration versus infectious process. Ophthalmology 2001;108:2293–2300. 5. Dhwali RS, Schachat AP. Leukemias and lymphomas. In: Ryan SJ, ed. Retina. 4th ed. Philadelphia, PA: Elsevier; 2006: 851–858. 6. Kincaid MC, Green WR. Ocular and orbital involvement in leukemia. Surv Ophthalmol 1983;27:211–232. 7. Allen RA, Straatsma BR. Ocular involvement in leukemia and allied disorders. Arch Ophthalmol 1961;66:490–508. 8. Shields JA, Shields CL. Intraocular leukemia. In: Jonathan W, Pine Jr JW, Jacobs A, eds. Intraocular Tumors: An Atlas and Textbook. 2nd ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2008:530–533.
