Acute lymphoblastic leukemia is an uncontrolled proliferation and accumulation of immature lymphoid cells in the bone marrow. It is the most common childhood cancer, representing approximately one-third of pediatric cancers.1 In developed countries, the disease cure rate reaches almost 90%.2,3 However, infiltration of other organs and disease relapse worsen the prognosis.4
Ophthalmic involvement by acute lymphoblastic leukemia may occur by direct leukemic infiltration or secondary to hematological abnormalities. Ocular leukemic infiltration indicates a poor prognosis, especially when associated with central nervous system or bone marrow relapse.5 The retina is the most affected tissue, whereas the iris is one of the rarest. Changes in iris color and shape, anterior chamber reaction, and increased intraocular pressure are important signs of anterior chamber involvement.3
Treatment stratification based on relapse risk ensures fewer toxic side effects for patients with acute lymphoblastic leukemia who have favorable features and more aggressive therapies for those with a high risk of disease relapse.6 Systemic chemotherapy is administered in three phases: a short remission induction, an intensification, and a long maintenance. Relapsed acute lymphoblastic leukemia also demands individualized therapies.7 Radiotherapy is the main local treatment for ocular leukemia.8 However, early and late side effects, such as dryness of the eye, scleral necrosis, cataract, glaucoma, retinopathy, and optic neuropathy, may lead to significant visual acuity impairment.9 Therefore, alternative treatments should be considered to preserve patients' vision.
Infiltration of the anterior segment by leukemic cells rarely occurs in patients with acute lymphoblastic leukemia.3 We describe, for the first time, a child with acute lymphoblastic leukemia relapse in the iris and ciliary body treated with intravitreal methotrexate.
An 11-year-old girl was at the 43rd week of chemotherapy for B-cell progenitor acute lymphoblastic leukemia, according to the AIEOP-BFM 2009 protocol. She complained of 1-month duration of blurred vision and leukocoria in the left eye. On ocular examination, the best corrected visual acuity (BCVA) was 20/20 in the right eye and counting fingers at 2 meters in the left eye. Right eye pupillary reaction, slit-lamp biomicroscopy of the anterior segment, and funduscopy were unremarkable. The left eye presented small and diffuse keratic precipitates, a grade 4+ anterior chamber reaction with pseudohypopyon, and iris thickening predominantly from the 1- to 9-o'clock positions (Figures 1A–1C). Left eye funduscopy was unremarkable. Intraocular pressures were 12 and 25 mm Hg in the right and left eyes, respectively. Left eye B-scan ultrasound was unremarkable, but ultrasound biomicroscopy showed thickness of the iris and ciliary body associated with a cyst of the iris pigment epithelium at the 6-o'clock position (Figure 1D), suggesting iris and ciliary body infiltration by neoplastic cells.
First ophthalmological evaluation at the 43rd week of the chemotherapy regimen. (A–C) Slit-lamp photographs showing iris thickening and folds predominantly from the 1- to 9-o'clock positions, iris retraction from the 12- to 1-o'clock positions, small and diffuse keratic precipitates, and 4+/4 anterior chamber reaction with pseudohypopyon at the 3- and 6-o'clock positions. (D) Axial ultrasound biomicroscopy showing thickness of the iris and ciliary body associated with a cyst of the iris pigment epithelium at the 6-o'clock position.
Bone marrow aspirate immunophenotyping tested negative for minimal residual disease. However, cerebrospinal fluid immunophenotyping revealed 71% of B-lymphoid blasts and confirmed the hypothesis of early relapse (< 18 months). Remission induction chemotherapy was initiated, according to the ALL-REZ BFM 2002 protocol.
During the 27th week of remission induction therapy, intraocular pressures remained high (30 mm Hg), BCVA in the left eye improved to 20/50, pseudohypopyon reduced, and anterior chamber reaction improved to grade 2+. Ultrasound biomicroscopy showed a slight reduction of the iris and ciliary body thickness, suggesting persistent neoplastic cells infiltration. Vitreous biopsy was normal, but cytology of the aqueous humor showed high concentrations of lymphoblastic cells (Figure 2). Eight weekly intravitreal methotrexate injections (400 µg/0.1 mL) were performed in combination with systemic chemotherapy in the ALL-REZ BFM 2002 protocol.
Cytology of the aqueous humor showing multiple lymphoblastic cells, with nuclear-cytoplasmic disproportion, large hyperchromatic nuclei, scanty cytoplasm, and cytoplasmic vacuoles (Wright-Giemsa stain, original magnification ×100).
One week after the last intravitreal methotrexate injection, there was no anterior chamber reaction, iris and ciliary body morphology normalized, and the left eye BCVA improved to 20/50. The patient developed a mild methotrexate-associated keratopathy, treated with lubricant eye drops. Keratitis resolved within 2 months, BCVA improved to 20/30, and the left eye appeared normal without any signs of neoplasm relapse (Figure 3). Complementary examinations did not detect signs of bone marrow disease or central nervous system leukemia. Despite all therapies, the disease aggressively relapsed in the bone marrow and central nervous system 3 months after the last intravitreal methotrexate injection and the patient died without current clinical signs of ocular relapse.
Left eye ophthalmological examination 2 months after the eighth intravitreal methotrexate injection. (A–B) Slit-lamp photographs showing improvement of iris color and morphology, without anterior chamber reaction. (C) Axial vertical, (D) 6-o'clock longitudinal, and (E) 6-o'clock transverse ultrasound biomicroscopy scans showing normal iris and ciliary body morphology.
Iris and ciliary body infiltration by acute lymphoblastic leukemia is rare.3 Nevertheless, clinicians must be alert to ocular abnormalities during patient follow-up.5 Blurred vision, eye redness, anterior chamber reaction, and focal or diffuse change in iris shape or color are common clinical signs and symptoms of anterior segment neoplasm infiltration. Therefore, ophthalmologists should exclude other causes of anterior uveitis, especially rheumathologic and opportunistic infections.3 In this case report, anterior chamber leukemic infiltration was the first sign of systemic relapse in acute lymphoblastic leukemia. Cytology of intraocular fluids and serial ultrasound biomicroscopy were essential tools in patient diagnosis and follow-up. We are aware of only one other report of ultrasound biomicroscopy findings in ocular relapse in acute lymphoblastic leukemia.10
Patients with leukemic infiltration of the eye must also be screened for relapse in other tissues and organs, especially the central nervous system. Regardless of the involvement of non-ocular tissues, a combination of local ocular treatments with systemic chemotherapy is indicated to eliminate the underlying disease.3 Methotrexate is a well-established drug in systemic chemotherapy for acute lymphoblastic leukemia and intrathecally for central nervous system relapse.11 Additionally, intravitreal methotrexate for intraocular lymphomas has also showed good outcomes.12 Currently, there is no optimal treatment for ocular infiltration by lymphoblastic cells in acute lymphoblastic leukemia.8 Radiotherapy of the eye is the most commonly used modality,3 but adverse effects such as dry eye, cataract, retinopathy, and optic neuropathy may worsen the visual prognosis.13 We report, for the first time, the use of intravitreal methotrexate for ocular acute lymphoblastic leukemia relapse, administered by weekly injections (400 µg/0.1 mL) until complete resolution of lesions.
According to Akiyama et al.,12 weekly intravitreal methotrexate (400 µg/0.1 mL) administration for ocular lymphoma yields fewer adverse effects with good outcomes. Palakurthi et al.14 also noted that tumoricidal levels of methotrexate might be achieved with weekly intravitreal injections of 400 µg.14 In our case report, after eight weekly injections, there was a complete reorganization of the anterior segment morphology, absence of anterior chamber cells, and patient visual acuity dramatically improved. Methotrexate-associated keratopathy was the only observed adverse effect.
We report a unique case of iris and ciliary body infiltration by acute lymphoblastic leukemia treated with intravitreal methotrexate. Further studies and more complex research designs are necessary to investigate the long-term benefits of intravitreal methotrexate against ocular infiltration by acute lymphoblastic leukemia, the optimal chemotherapy treatment, and to compare different treatments.
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- Pui CH, Evans WE. A 50-year journey to cure childhood acute lymphoblastic leukemia. Semin Hematol. 2013;50:185–196. doi:10.1053/j.seminhematol.2013.06.007 [CrossRef]
- Sharma T, Grewal J, Gupta S, Murray PI. Ophthalmic manifestations of acute leukaemias: the ophthalmologist's role. Eye (Lond). 2004;18:663–672. doi:10.1038/sj.eye.6701308 [CrossRef]
- Nguyen K, Devidas M, Cheng SC, et al. Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children's Oncology Group study. Leukemia. 2008;22:2142–2150. doi:10.1038/leu.2008.251 [CrossRef]
- Ohkoshi K, Tsiaras WG. Prognostic importance of ophthalmic manifestations in childhood leukaemia. Br J Ophthalmol. 1992;76:651–655. doi:10.1136/bjo.76.11.651 [CrossRef]
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- Bunin N, Rivera G, Goode F, Hustu HO. Ocular relapse in the anterior chamber in childhood acute lymphoblastic leukemia. J Clin Oncol. 1987;5:299–303. doi:10.1200/JCO.1918.104.22.1689 [CrossRef]
- Janjan NA. Radiation effects on the eye. Clin Plast Surg. 1993;20:535–549.
- Eide NA, Baerland TP, Sauesund E, Lomo J, Lund-Iversen M, Liestol S. Relapse of acute lymphoblastic leukaemia (ALL). Acta Ophthalmol. 2015;93:e395–e396. doi:10.1111/aos.12619 [CrossRef]
- Moricke A, Zimmermann M, Reiter A, et al. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia. 2010;24:265–284. doi:10.1038/leu.2009.257 [CrossRef]
- Akiyama H, Takase H, Kubo F, et al. High-dose methotrexate following intravitreal methotrexate administration in preventing central nervous system involvement of primary intraocular lymphoma. Cancer Sci. 2016;107:1458–1464. doi:10.1111/cas.13012 [CrossRef]
- Novakovic P, Kellie SJ, Taylor D. Childhood leukaemia: relapse in the anterior segment of the eye. Br J Ophthalmol. 1989;73:354–359. doi:10.1136/bjo.73.5.354 [CrossRef]
- Palakurthi NK, Krishnamoorthy M, Augsburger JJ, Correa ZM, Banerjee RK. Investigation of kinetics of methotrexate for therapeutic treatment of intraocular lymphoma. Curr Eye Res. 2010;35:1105–1115. doi:10.3109/02713683.2010.513089 [CrossRef]