Leukemia & Lymphoma, August 2014; 55(8): 1918–1921 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2013.854887
LETTER TO THE EDITOR
Cytomegalovirus retinitis in children and young adults with acute lymphoblastic leukemia in Lebanon Loma Samia1,2, Rola Hamam3, Ghassan Dbaibo1,4, Raya Saab1,2, Hassan El-Solh1,2, Miguel Abboud1,2 & Samar Muwakkit1,2 1Department of Pediatrics and Adolescent Medicine, 2Children’s Cancer Center of Lebanon, 3Department of Ophthalmology
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 07/21/15 For personal use only.
and 4The Center for Infectious Diseases Research, American University of Beirut Medical Center, Beirut, Lebanon
the left eye with hemorrhages and exudates (Figure 1). She also had a CMV PCR of 11 200 copies. She was treated with intravenous ganciclovir followed by oral valganciclovir. Eight months after the end of all chemotherapy and while on valganciclovir, she developed recurrence of retinitis. Her visual acuity was measured at 20/100. She was successfully treated with intravenous ganciclovir and systemic corticosteroids for 21 days then discharged on oral valganciclovir therapy. She maintained a visual acuity of 20/25 with no active retinitis for several months on valganciclovir. Her condition was complicated by reactivation of her hepatitis C. Ten months later, she presented again with a decrease in visual acuity in the left eye to 20/100, and was found to have an aggressive inflammatory reaction. Her CD4 count was 38 cells/μL (reference range ⬎ 500 cells/μL). She was started on intravenous ganciclovir then oral corticosteroids were added, yet with limited improvement, thus requiring an intravitreal injection of ganciclovir, to which she responded favorably with improvement in vision and inflammation. The injection was repeated after 1 week and the patient was discharged on oral valganciclovir. Her active retinitis recurred after 9 months and was treated by intravitreal injection of ganciclovir. We decided to taper her systemic treatment and replace it with local weekly intravitreal injections to be spread out slowly as her immune system reconstituted. The patient currently maintains a 20/300 vision with no active retinitis. The third patient presented with blurring of vision and a visual field defect affecting his right eye of 3 weeks’ duration; on ophthalmological examination his visual acuity was normal. The optic nerve head in both eyes showed infiltrates, with hemorrhages and edema. He responded well to intravenous ganciclovir treatment for 2 weeks, and was maintained on oral valganciclovir therapy which was later tapered and stopped without recurrences. His CD4 level was 41.4 cells/μL and he had positive CMV viremia.
Data on cytomegalovirus (CMV) retinitis infection in patients with acute lymphoblastic leukemia (ALL) treated with chemotherapeutic regimens are limited, especially in children. During the period between April 2002 and May 2011, we observed four (3.6%) cases of CMV retinitis in children and young adults with ALL treated at the Children’s Cancer Center of Lebanon (CCCL) (n ⫽ 111). The CCCL adopts the St. Jude TOTAL-XV protocol [1] with minor modifications; the median age of our ALL cohort was 5 years and 5 months (refer to our previous study) [2]. The four patients developed CMV retinitis while on maintenance treatment for ALL on the intermediate/high risk protocol arm; these accounted for 8.6% of the total number of patients on the intermediate/high risk arm [2]. Table I summarizes the characteristics of patients. We herein describe our experience with these patients with regard to presentation, management and prognosis. The first patient presented with blurring of vision in his right eye; ophthalmological examination revealed frosted branch angiitis, retinal edema, hemorrhages and exudates reaching the posterior pole and involving the inferior macula, and his visual acuity was 20/30 [3]. The left eye examination was normal. The findings were suggestive of CMV retinitis. His serum CMV polymerase chain reaction (PCR) was negative. He responded to treatment with intravenous ganciclovir with resolution of the retinitis, but recurred in both eyes 1 month later. Due to lack of sufficient response to intravenous ganciclovir, foscarnet was added to the treatment and the patient responded completely. He continued on oral valganciclovir until 2 years post-end of all chemotherapy. He remains 4 years later with visual impairment 20/400 right eye, 20/200 left eye, but with no evidence of retinitis. The second patient presented with vomiting, fever and blurring of vision affecting the left eye; she had retinitis of
Correspondence: Samar A. Muwakkit, MD, Children’s Cancer Center of Lebanon, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, P.O. Box: 11-0236, Riad El Solh, 1107 2020 Beirut, Lebanon. Tel: 00961-1-350000, ext. 8100. Fax: 00961-1-370814. E-mail: sm03@aub. edu.lb Received 9 June 2013; revised 28 August 2013; accepted 7 October 2013
1918
12
23
21
2
3
4
M
M
F
M
Risk category
Blurring of vision
Blurring of vision
Presenting symptoms
Intermediate/ Maintenance Blurring of high (pre-B week 142/146 vision cell) Intermediate/ Maintenance No visual high week 70/146 complaints (pre-B cell)
Intermediate/ Maintenance high (T cell) week 88/120
Intermediate/ Maintenance high (T cell) week 96/146
Phase of treatment∗
Yes
Yes
Yes
No
27.8
41.4
38.3
Normal
CD4 CMV count viremia (cells/μL)†
0.42
0.9
1.85
1.1
CD4/ CD8 ratio†
3.8
16.6
4.25
6.8
3rd line
2nd line
1st line
1st line
3rd line
2nd line
1st line
2nd line
1st line
IgG level (g/L)† Treatment Medications Ganciclovir (IV) (19 days), foscarnet Ganciclovir (IV), valganciclovir (2 years) Ganciclovir (IV) (19 days), valganciclovir (6 months) Ganciclovir (IV) plus corticosteroids (21 days), valganciclovir Ganciclovir (IV) plus corticosteroids plus ganciclovir (intravitreal), valganciclovir Ganciclovir (IV) (2 weeks), valganciclovir Ganciclovir (IV) (21 days), valganciclovir Ganciclovir (intravitreal) (2 mg biweekly), valganciclovir Ganciclovir (intravitreal), foscarnet, cidofovir 3
0
3
1
Recurrences
None
None
Visual impairment, left eye
Visual impairment, both eyes
Residual symptoms
Lungs
None
Liver
None
None
None
Hepatitis C
None
Coexistent Other organ viral involvement infections
75 mg/m2 PO h.s. daily ⫻ 7 days, days 1–7 (weeks 1 and 2, every 4 weeks) 40 mg/m2 IV or IM, day 1 (weeks 1 and 2, every 4 weeks) 12 mg/m2 (int/high risk) PO daily (tid) ⫻ 5, days 1–5 (week 3 every 4 weeks) 2 mg/m2 IV push (max. 2 mg), day 1 300 mg/m2 IV, day 1 (week 4, every 4 weeks) 300 mg/m2 IV, day 1 (week 4 every 4 weeks)
The same treatment will be repeated for a total of 12 times (until week 68). After week 68, all patients will receive daily 6MP and weekly MTX with pulses of dexamethasone and vincristine every 4 weeks until week 100, after which only 6MP and methotrexate will be given. The end result is that patients on the intermediate risk arm receive dexamethasone 12 mg/m2/day ⫻ 5 days every 4 weeks for a total of 100 weeks. Intrathecal treatment was given every 8 weeks only to patients at high risk of CNS relapse after week 48 and was discontinued after week 96. Continuation therapy was discontinued after 120 weeks in girls and after 146 weeks in boys. †Tests done during active CMV retinitis except for patient 2, tests were done 2 years after end of treatment during reactivation of CMV retinitis. CMV, cytomegalovirus; Ig, immunoglobulin; IV, intravenous; CNS, central nervous system.
6MP (6-mercaptopurine) MTX (methotrexate) DEX (dexamethasone) VCR (vincristine) cyclo (cyclophosphamide) Ara-C (cytarabine)
∗Beginning day 1 of maintenance, dexa (12 mg/m2/day ⫻ 5 days) plus VCR are given every 4 weeks. They are even intensified during reinductions I and II where patients receive during weeks 7–10 and 17–20, 2 weeks of dexa plus vincristine. Drug dosages, schedules and routes for continuation/maintenance therapy from week 21 to end of therapy include alternating pairs of methotrexate plus 6MP ⫻ 2 weeks (weeks 1 and 2) followed by 1 week of dexamethasone plus vincristine (week 3) followed by cyclo plus Ara-C on week 4. The doses are shown below:
15
1
Age Patient (years) Sex
Table I. Patients’ characteristics.
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 07/21/15 For personal use only.
Letter to the Editor 1919
1920
L. Samia et al.
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 07/21/15 For personal use only.
Figure 1. Active CMV retinitis involving the posterior pole and inferior retina.
The fourth patient presented with fever and lung infiltrates but no visual symptoms; he had a positive serum CMV PCR. Screening eye examination revealed active retinitis of the right eye with no changes in visual acuity. He received intravenous ganciclovir treatment for 21 days and was discharged on oral valganciclovir. Six months later, while on maintenance valganciclovir, he was found to have reactivation of his retinitis on regular eye examination. Vision was still maintained at 20/20, and he was asymptomatic. His CD4 level was 27.8 cells/μL. He was treated with intravitreal injection of ganciclovir in the right eye. With halted progression of the retinitis, the patient was maintained on intravitreal injections of ganciclovir to the right eye along with systemic treatment with valganciclovir, with persistently high serum CMV PCR count. Biweekly intravitreal injections of ganciclovir were necessary to control the retinitis. Three months later, the left eye was found to have active retinitis. As such, the patient was given biweekly intravitreal ganciclovir injections to both eyes. Meanwhile the serum CMV PCR was still increasing to 150 000 copies, and resistance studies were positive for ganciclovir. Subsequently, the patient was given foscarnet then cidofovir systemic treatment with a subsequent decrease in serum CMV PCR. The eyes remain with no active retinitis with a 20/20 vision on last follow-up. CMV retinitis has been frequently reported in immunocompromised patients undergoing bone marrow transplant [4,5]. However, data on patients with leukemia who did not undergo a transplant are limited [6–9]. To our knowledge, CMV retinitis in ALL has only been reported five times during maintenance chemotherapy without stem cell transplant [7–11]. Retinal involvement in acute leukemia may be due to different causes such as direct leukemic infiltrates, vitreous and retinal hemorrhage caused by anemia, thrombocytopenia or hyperviscosity [12,13]. Patients with ALL are also susceptible to opportunistic infections [13]. However, the incidence of CMV antigenemia and retinal disease in patients with hematological malignancies who are not transplant recipients or human immunodeficiency virus (HIV) infected remains unknown. In one retrospective cohort
study [14], the incidence of CMV antigenemia in more than 2000 adult patients with hematological malignancies who did not undergo stem cell transplant was 13.6% in lymphoid malignancies. This suggests that CMV reactivation occurs primarily in situations of severe lymphoid disease, as was the case in our patients. Around 3.6% of children and young adults with ALL on our protocol developed symptomatic CMV retinitis; these accounted for 8.6% of the total number of patients on the intermediate/high risk arm [2]. Our patients received the intermediate/high risk arm of the St. Jude TOTAL-XV protocol, including highly immunosuppressive drugs such as high-dose steroids, cyclophosphamide and cytarabine. Three of our patients had a documented suppressed immune system, as reflected by immune profiling and CD4 counts. Individuals with CMV retinitis typically exhibit a progressive decrease in visual acuity, which may progress to blindness if not treated promptly. All four patients had retinitis affecting zone 1, and two of them had severe loss of vision to legal blindness subsequently, probably due to a delay in symptom development and diagnosis (two patients had symptoms for weeks before presentation). Only one of our patients (patient 4) had asymptomatic retinitis discovered on a screening retinal examination for systemic CMV infection. Owing to the potential serious impact on vision, prompt diagnosis followed by treatment is thus essential. Health care providers should be on the alert for symptoms and signs of CMV retinitis, more so if the patient has any visual complaint or the CD4 count is ⬍ 50–100 cells/μL. Three of our four patients had positive serum CMV PCR, and two of them were systemically symptomatic (patients 2 and 4). Current drugs such as ganciclovir, valganciclovir, cidofovir and foscarnet have been highly active against CMV. Although prolonged therapy with these approved drugs is needed to prevent relapse, it may be associated with dose-limiting toxicities. Our experience with these patients suggests that intravitreal therapy is better tolerated and more successful in treating the disease. To the best of our knowledge, there are only five reports of CMV retinitis in the setting of maintenance treatment for childhood ALL. This makes our report the sixth of its type, and the first to report this large series of CMV retinitis in pediatric patients with ALL. We are not sure whether the high doses of dexamethasone during maintenance therapy contributed to this complication, or whether this high incidence is because of exposure of Lebanese children to CMV at an early age (almost all patients screened were positive for CMV immunoglobulin G [IgG] at diagnosis of the ALL), or a combination of both criteria in our childhood ALL patient population. In conclusion, CMV retinitis may occur in children and young adults with ALL during the maintenance phase. Physicians should be alerted to this rare occurrence. Ophthalmological screening examination should be considered in patients with ALL receiving intensive treatment and prone to immunosuppression, or those having documented low CD4 counts. Early detection and management are vital. Resistance to ganciclovir was noted
Letter to the Editor 1921 in one patient (patient 4), and therefore its implications for intravitreal injections must be addressed in the future. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 07/21/15 For personal use only.
References [1] Pui CH, Campana D, Pei D, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009;360:2730–2741. [2] Muwakkit S, Al-Aridi C, Samra A , et al. Implementation of an intensive risk-stratified treatment protocol for children and adolescents with acute lymphoblastic leukemia in Lebanon. Am J Hematol 2012; 87:678–683. [3] Holland GN, Buhles WC Jr, Mastre B, et al. A controlled retrospective study of ganciclovir treatment for cytomegalovirus retinopathy. Use of a standardized system for the assessment of disease outcome. UCLA CMV Retinopathy. Study Group. Arch Ophthalmol 1989;107:1759–1766. [4] Baumal CR, Levin AV, Read SE. Cytomegalovirus retinitis in immunosuppressed children. Am J Ophthalmol 1999;127:550–558. [5] Yoon HS, Lee JH, Choi ES, et al. Cytomegalovirus infection in children who underwent hematopoietic stem cell transplantation at a single center: a retrospective study of the risk factors. Pediatr Transplant 2009;13:898–905.
[6] Libby E, Movva S, Quintana D, et al. Cytomegalovirus retinitis during chemotherapy with rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone. J Clin Oncol 2010;28:e661–e662. [7] Taha R, Al Hijji I, El Omri H, et al. Two ocular infections during conventional chemotherapy in a patient with acute lymphoblastic leukemia: a case report. Case Rep Oncol 2010;3:234–239. [8] Singh R, Trehan A , Jain R, et al. Cytomegalovirus retinitis in an ALL child on exclusive chemotherapy treated successfully with intravitreal ganciclovir alone. J Pediatr Hematol Oncol 2013;35: e118–e119. [9] Wakai K , Sano H, Shimada A , et al. Cytomegalovirus retinitis during maintenance therapy for T-cell acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2013;35:162–163. [10] Kobayashi R, Takanashi K, Suzuki D, et al. Retinitis from cytomegalovirus during maintenance treatment for acute lymphoblastic leukemia. Pediatr Int 2012;54:288–290. [11] Moritake H, Kamimura S, Kojima H, et al. Cytomegalovirus retinitis as an adverse immunological effect of pulses of vincristine and dexamethasone in maintenance therapy for childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 2013;60:329–331. [12] Reddy SC, Jackson N, Menon BS. Ocular involvement in leukemia—a study of 288 cases. Ophthalmologica 2003;217:441–445. [13] Sharma T, Grewal J, Gupta S, et al. Ophthalmic manifestations of acute leukaemias: the ophthalmologist’s role. Eye (Lond) 2004;18: 663–672. [14] Han XY. Epidemiologic analysis of reactivated cytomegalovirus antigenemia in patients with cancer. J Clin Microbiol 2007;45: 1126–1132.
LETTER TO THE EDITOR
Cytomegalovirus retinitis in children and young adults with acute lymphoblastic leukemia in Lebanon Loma Samia1,2, Rola Hamam3, Ghassan Dbaibo1,4, Raya Saab1,2, Hassan El-Solh1,2, Miguel Abboud1,2 & Samar Muwakkit1,2 1Department of Pediatrics and Adolescent Medicine, 2Children’s Cancer Center of Lebanon, 3Department of Ophthalmology
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 07/21/15 For personal use only.
and 4The Center for Infectious Diseases Research, American University of Beirut Medical Center, Beirut, Lebanon
the left eye with hemorrhages and exudates (Figure 1). She also had a CMV PCR of 11 200 copies. She was treated with intravenous ganciclovir followed by oral valganciclovir. Eight months after the end of all chemotherapy and while on valganciclovir, she developed recurrence of retinitis. Her visual acuity was measured at 20/100. She was successfully treated with intravenous ganciclovir and systemic corticosteroids for 21 days then discharged on oral valganciclovir therapy. She maintained a visual acuity of 20/25 with no active retinitis for several months on valganciclovir. Her condition was complicated by reactivation of her hepatitis C. Ten months later, she presented again with a decrease in visual acuity in the left eye to 20/100, and was found to have an aggressive inflammatory reaction. Her CD4 count was 38 cells/μL (reference range ⬎ 500 cells/μL). She was started on intravenous ganciclovir then oral corticosteroids were added, yet with limited improvement, thus requiring an intravitreal injection of ganciclovir, to which she responded favorably with improvement in vision and inflammation. The injection was repeated after 1 week and the patient was discharged on oral valganciclovir. Her active retinitis recurred after 9 months and was treated by intravitreal injection of ganciclovir. We decided to taper her systemic treatment and replace it with local weekly intravitreal injections to be spread out slowly as her immune system reconstituted. The patient currently maintains a 20/300 vision with no active retinitis. The third patient presented with blurring of vision and a visual field defect affecting his right eye of 3 weeks’ duration; on ophthalmological examination his visual acuity was normal. The optic nerve head in both eyes showed infiltrates, with hemorrhages and edema. He responded well to intravenous ganciclovir treatment for 2 weeks, and was maintained on oral valganciclovir therapy which was later tapered and stopped without recurrences. His CD4 level was 41.4 cells/μL and he had positive CMV viremia.
Data on cytomegalovirus (CMV) retinitis infection in patients with acute lymphoblastic leukemia (ALL) treated with chemotherapeutic regimens are limited, especially in children. During the period between April 2002 and May 2011, we observed four (3.6%) cases of CMV retinitis in children and young adults with ALL treated at the Children’s Cancer Center of Lebanon (CCCL) (n ⫽ 111). The CCCL adopts the St. Jude TOTAL-XV protocol [1] with minor modifications; the median age of our ALL cohort was 5 years and 5 months (refer to our previous study) [2]. The four patients developed CMV retinitis while on maintenance treatment for ALL on the intermediate/high risk protocol arm; these accounted for 8.6% of the total number of patients on the intermediate/high risk arm [2]. Table I summarizes the characteristics of patients. We herein describe our experience with these patients with regard to presentation, management and prognosis. The first patient presented with blurring of vision in his right eye; ophthalmological examination revealed frosted branch angiitis, retinal edema, hemorrhages and exudates reaching the posterior pole and involving the inferior macula, and his visual acuity was 20/30 [3]. The left eye examination was normal. The findings were suggestive of CMV retinitis. His serum CMV polymerase chain reaction (PCR) was negative. He responded to treatment with intravenous ganciclovir with resolution of the retinitis, but recurred in both eyes 1 month later. Due to lack of sufficient response to intravenous ganciclovir, foscarnet was added to the treatment and the patient responded completely. He continued on oral valganciclovir until 2 years post-end of all chemotherapy. He remains 4 years later with visual impairment 20/400 right eye, 20/200 left eye, but with no evidence of retinitis. The second patient presented with vomiting, fever and blurring of vision affecting the left eye; she had retinitis of
Correspondence: Samar A. Muwakkit, MD, Children’s Cancer Center of Lebanon, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, P.O. Box: 11-0236, Riad El Solh, 1107 2020 Beirut, Lebanon. Tel: 00961-1-350000, ext. 8100. Fax: 00961-1-370814. E-mail: sm03@aub. edu.lb Received 9 June 2013; revised 28 August 2013; accepted 7 October 2013
1918
12
23
21
2
3
4
M
M
F
M
Risk category
Blurring of vision
Blurring of vision
Presenting symptoms
Intermediate/ Maintenance Blurring of high (pre-B week 142/146 vision cell) Intermediate/ Maintenance No visual high week 70/146 complaints (pre-B cell)
Intermediate/ Maintenance high (T cell) week 88/120
Intermediate/ Maintenance high (T cell) week 96/146
Phase of treatment∗
Yes
Yes
Yes
No
27.8
41.4
38.3
Normal
CD4 CMV count viremia (cells/μL)†
0.42
0.9
1.85
1.1
CD4/ CD8 ratio†
3.8
16.6
4.25
6.8
3rd line
2nd line
1st line
1st line
3rd line
2nd line
1st line
2nd line
1st line
IgG level (g/L)† Treatment Medications Ganciclovir (IV) (19 days), foscarnet Ganciclovir (IV), valganciclovir (2 years) Ganciclovir (IV) (19 days), valganciclovir (6 months) Ganciclovir (IV) plus corticosteroids (21 days), valganciclovir Ganciclovir (IV) plus corticosteroids plus ganciclovir (intravitreal), valganciclovir Ganciclovir (IV) (2 weeks), valganciclovir Ganciclovir (IV) (21 days), valganciclovir Ganciclovir (intravitreal) (2 mg biweekly), valganciclovir Ganciclovir (intravitreal), foscarnet, cidofovir 3
0
3
1
Recurrences
None
None
Visual impairment, left eye
Visual impairment, both eyes
Residual symptoms
Lungs
None
Liver
None
None
None
Hepatitis C
None
Coexistent Other organ viral involvement infections
75 mg/m2 PO h.s. daily ⫻ 7 days, days 1–7 (weeks 1 and 2, every 4 weeks) 40 mg/m2 IV or IM, day 1 (weeks 1 and 2, every 4 weeks) 12 mg/m2 (int/high risk) PO daily (tid) ⫻ 5, days 1–5 (week 3 every 4 weeks) 2 mg/m2 IV push (max. 2 mg), day 1 300 mg/m2 IV, day 1 (week 4, every 4 weeks) 300 mg/m2 IV, day 1 (week 4 every 4 weeks)
The same treatment will be repeated for a total of 12 times (until week 68). After week 68, all patients will receive daily 6MP and weekly MTX with pulses of dexamethasone and vincristine every 4 weeks until week 100, after which only 6MP and methotrexate will be given. The end result is that patients on the intermediate risk arm receive dexamethasone 12 mg/m2/day ⫻ 5 days every 4 weeks for a total of 100 weeks. Intrathecal treatment was given every 8 weeks only to patients at high risk of CNS relapse after week 48 and was discontinued after week 96. Continuation therapy was discontinued after 120 weeks in girls and after 146 weeks in boys. †Tests done during active CMV retinitis except for patient 2, tests were done 2 years after end of treatment during reactivation of CMV retinitis. CMV, cytomegalovirus; Ig, immunoglobulin; IV, intravenous; CNS, central nervous system.
6MP (6-mercaptopurine) MTX (methotrexate) DEX (dexamethasone) VCR (vincristine) cyclo (cyclophosphamide) Ara-C (cytarabine)
∗Beginning day 1 of maintenance, dexa (12 mg/m2/day ⫻ 5 days) plus VCR are given every 4 weeks. They are even intensified during reinductions I and II where patients receive during weeks 7–10 and 17–20, 2 weeks of dexa plus vincristine. Drug dosages, schedules and routes for continuation/maintenance therapy from week 21 to end of therapy include alternating pairs of methotrexate plus 6MP ⫻ 2 weeks (weeks 1 and 2) followed by 1 week of dexamethasone plus vincristine (week 3) followed by cyclo plus Ara-C on week 4. The doses are shown below:
15
1
Age Patient (years) Sex
Table I. Patients’ characteristics.
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 07/21/15 For personal use only.
Letter to the Editor 1919
1920
L. Samia et al.
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 07/21/15 For personal use only.
Figure 1. Active CMV retinitis involving the posterior pole and inferior retina.
The fourth patient presented with fever and lung infiltrates but no visual symptoms; he had a positive serum CMV PCR. Screening eye examination revealed active retinitis of the right eye with no changes in visual acuity. He received intravenous ganciclovir treatment for 21 days and was discharged on oral valganciclovir. Six months later, while on maintenance valganciclovir, he was found to have reactivation of his retinitis on regular eye examination. Vision was still maintained at 20/20, and he was asymptomatic. His CD4 level was 27.8 cells/μL. He was treated with intravitreal injection of ganciclovir in the right eye. With halted progression of the retinitis, the patient was maintained on intravitreal injections of ganciclovir to the right eye along with systemic treatment with valganciclovir, with persistently high serum CMV PCR count. Biweekly intravitreal injections of ganciclovir were necessary to control the retinitis. Three months later, the left eye was found to have active retinitis. As such, the patient was given biweekly intravitreal ganciclovir injections to both eyes. Meanwhile the serum CMV PCR was still increasing to 150 000 copies, and resistance studies were positive for ganciclovir. Subsequently, the patient was given foscarnet then cidofovir systemic treatment with a subsequent decrease in serum CMV PCR. The eyes remain with no active retinitis with a 20/20 vision on last follow-up. CMV retinitis has been frequently reported in immunocompromised patients undergoing bone marrow transplant [4,5]. However, data on patients with leukemia who did not undergo a transplant are limited [6–9]. To our knowledge, CMV retinitis in ALL has only been reported five times during maintenance chemotherapy without stem cell transplant [7–11]. Retinal involvement in acute leukemia may be due to different causes such as direct leukemic infiltrates, vitreous and retinal hemorrhage caused by anemia, thrombocytopenia or hyperviscosity [12,13]. Patients with ALL are also susceptible to opportunistic infections [13]. However, the incidence of CMV antigenemia and retinal disease in patients with hematological malignancies who are not transplant recipients or human immunodeficiency virus (HIV) infected remains unknown. In one retrospective cohort
study [14], the incidence of CMV antigenemia in more than 2000 adult patients with hematological malignancies who did not undergo stem cell transplant was 13.6% in lymphoid malignancies. This suggests that CMV reactivation occurs primarily in situations of severe lymphoid disease, as was the case in our patients. Around 3.6% of children and young adults with ALL on our protocol developed symptomatic CMV retinitis; these accounted for 8.6% of the total number of patients on the intermediate/high risk arm [2]. Our patients received the intermediate/high risk arm of the St. Jude TOTAL-XV protocol, including highly immunosuppressive drugs such as high-dose steroids, cyclophosphamide and cytarabine. Three of our patients had a documented suppressed immune system, as reflected by immune profiling and CD4 counts. Individuals with CMV retinitis typically exhibit a progressive decrease in visual acuity, which may progress to blindness if not treated promptly. All four patients had retinitis affecting zone 1, and two of them had severe loss of vision to legal blindness subsequently, probably due to a delay in symptom development and diagnosis (two patients had symptoms for weeks before presentation). Only one of our patients (patient 4) had asymptomatic retinitis discovered on a screening retinal examination for systemic CMV infection. Owing to the potential serious impact on vision, prompt diagnosis followed by treatment is thus essential. Health care providers should be on the alert for symptoms and signs of CMV retinitis, more so if the patient has any visual complaint or the CD4 count is ⬍ 50–100 cells/μL. Three of our four patients had positive serum CMV PCR, and two of them were systemically symptomatic (patients 2 and 4). Current drugs such as ganciclovir, valganciclovir, cidofovir and foscarnet have been highly active against CMV. Although prolonged therapy with these approved drugs is needed to prevent relapse, it may be associated with dose-limiting toxicities. Our experience with these patients suggests that intravitreal therapy is better tolerated and more successful in treating the disease. To the best of our knowledge, there are only five reports of CMV retinitis in the setting of maintenance treatment for childhood ALL. This makes our report the sixth of its type, and the first to report this large series of CMV retinitis in pediatric patients with ALL. We are not sure whether the high doses of dexamethasone during maintenance therapy contributed to this complication, or whether this high incidence is because of exposure of Lebanese children to CMV at an early age (almost all patients screened were positive for CMV immunoglobulin G [IgG] at diagnosis of the ALL), or a combination of both criteria in our childhood ALL patient population. In conclusion, CMV retinitis may occur in children and young adults with ALL during the maintenance phase. Physicians should be alerted to this rare occurrence. Ophthalmological screening examination should be considered in patients with ALL receiving intensive treatment and prone to immunosuppression, or those having documented low CD4 counts. Early detection and management are vital. Resistance to ganciclovir was noted
Letter to the Editor 1921 in one patient (patient 4), and therefore its implications for intravitreal injections must be addressed in the future. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
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References [1] Pui CH, Campana D, Pei D, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009;360:2730–2741. [2] Muwakkit S, Al-Aridi C, Samra A , et al. Implementation of an intensive risk-stratified treatment protocol for children and adolescents with acute lymphoblastic leukemia in Lebanon. Am J Hematol 2012; 87:678–683. [3] Holland GN, Buhles WC Jr, Mastre B, et al. A controlled retrospective study of ganciclovir treatment for cytomegalovirus retinopathy. Use of a standardized system for the assessment of disease outcome. UCLA CMV Retinopathy. Study Group. Arch Ophthalmol 1989;107:1759–1766. [4] Baumal CR, Levin AV, Read SE. Cytomegalovirus retinitis in immunosuppressed children. Am J Ophthalmol 1999;127:550–558. [5] Yoon HS, Lee JH, Choi ES, et al. Cytomegalovirus infection in children who underwent hematopoietic stem cell transplantation at a single center: a retrospective study of the risk factors. Pediatr Transplant 2009;13:898–905.
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