- Email: [email protected]
Safe treatment of a patient with CML using dasatinib after prior retinal oedema due to imatinib
Letters to the editor / Leukemia Research 32 (2008) 1776–1790
[6]
[7]
[8]
[9]
[10]
[11]
[12]
classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 1999;17(12):3835–49. Saif MW, Hopkins JL, Gore SD. Autoimmune phenomena in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia. Leuk Lymphoma 2002;43(11):2083–92. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89(6):2079–88. Kumar PV, Vasei M, Sadeghipour A, Sadeghi E, Soleimanpour H, Mousavi A, Tabatabaei AH, Rizvi MM. Visceral leishmaniasis: bone marrow biopsy findings. J Pediatr Hematol Oncol 2007;29(2):77–80. Magalhães SM, Filho FD, Vassallo J, Pinheiro MP, Metze K, LorandMetze K. Bone marrow lymphoid aggregates in myelodysplastic syndrome: incidence, immunomorphological characteristics and correlation with clinical features and survival. Leuk Res 2002;26(6):525–30. Novaretti MC, Sopelete CD, Velloso ER, Dorlhiac PEL, Chamone DA. Immunohematological findings in myelodysplastic syndrome. Acta Haematol 2001;105(1):1–6. Vilela RB, Bordin JO, Chiba AK, Castelo A, Barbosa MC. RBCassociated IgG in patients with visceral leishmaniasis (kala-azar): a prospective analysis. Transfusion 2002;42(11):1442–7. Pedras MJ, de Gouvêa Viana L, de Oliveira EJ, Rabello A. Comparative evaluation of direct agglutination test, rK39 and soluble antigen ELISA and IFAT for the diagnosis of visceral leishmaniasis. Trans R Soc Trop Med Hyg 2008;102(2):172–8.
Ronald Feitosa Pinheiro ∗ Viviane Chaves Pereira Fernando Barroso Carlos da Costa Ribeiro Neto Sílvia M.M. Magalhães Federal University of Ceará, Walter Cantídio Hospital, Division of Hematology, Brazil ∗ Corresponding
author: Pereira Valente, 738, Meireles, 60160250, Fortaleza-Ceará-Brazil. Tel.: +55 85 32640898. E-mail address: [email protected] (R.F. Pinheiro) 29 January 2008
1789
effects reported. The most common adverse effects include superficial oedema, nausea, muscle cramps, musculoskeletal pain, rash, fatigue, diarrhoea and myelosuppression [2]. Ocular toxicities including periorbital oedema, epiphora and rarely retinal oedema have also been reported [3,4]. Dasatinib (BMS-354825), a novel multi-targeted kinase inhibitor of BCR-ABL and SRC kinases, exhibits high haematologic and cytogenetic response rates in imatinib resistant/intolerant CML patients with an acceptable toxicity profile.
2. Case report A previously well 38-year-old man with history of left eye amblyopia and acuity of 6/12 (right eye 6/5) was diagnosed with chronic-phase CML in July04 (WCC 172 × 109 /L) and started on imatinib 400 mg/day after brief course of hydroxyurea. He noted mild visual detoriation on commencement of imatinib. Ophthalmic review in September 2004 due to persisting visual disturbance revealed deterioration in visual acuity to 6/9 (left) and 6/18 (right) with bilateral widespread moderate-sized retinal haemorrhages and macular oedema more pronounced in the left. There was localised swelling of the superior border of the right optic nerve head. A fluorescein angiogram confirmed bilateral macular oedema and right disc leakage with no associated retinal ischemia (Fig. 1). A normal MRI brain and CSF cytology excluded CNS leukaemia. By October 2004 he was in complete haematological remission but decreased visual acuity persisted. In view of the rare occurrence of retinal complications with imatinib and the risk of further deterioration, imatinib was ceased [3,4]. The patient’s vision and his ophthalmic findings showed improvement 2 weeks after cessation. The macular and disc oedema had totally resolved and retinal haemorrhages started to fade with vision improving to 6/5 (right) and 6/12 (left) by 6 weeks. Resolution of the ophthalmic changes on cessation of imatinib established a causal relationship.
3 April 2008 5 April 2008 Available online 3 June 2008 doi: 10.1016/j.leukres.2008.04.015
Safe treatment of a patient with CML using dasatinib after prior retinal oedema due to imatinib
1. Introduction Imatinib, a Bcr-Abl kinase inhibitor is the standard therapy for all phases of CML [1]. Imatinib also inhibits other kinases, including ABL, c-kit, PDGFR-␣ and -, ARG and cfms. While the activity against these targets is being exploited therapeutically, it may also underlie some of the adverse
Fig. 1. Mid phase fluorescein angiogram of the left eye showing severe patelloid angiographic macular oedema.
1790
Letters to the editor / Leukemia Research 32 (2008) 1776–1790
His disease was well controlled in chronic phase with hydroxyurea for 5 months. He then consented to participate in a phase-II trial of Dasatinib (Protocol CA180-034) [5], commencing 70 mg twice daily in June 2005. At commencement there were 100% Ph+ bone marrow metaphases and quantitative PCR revealed both b2a2 and b3a2 transcripts, but the later predominated, and was quantitated as 99% relative to the normal ABL transcript. He tolerated the drug well except for transient headache and a minor scalp rash. Repeated ophthalmic evaluation (till September05) revealed preserved visual acuity and no evidence of recurrent retinal changes. He is continuing on dasatinib at 24+ months and has attained complete cytogenetic response and a major molecular response (BCR-ABL: ABL transcripts 0.004%) with no visual symptoms or ophthalmic complications.
3. Discussion Fluid retention and oedema due to imatinib occur in 60% patients [2]. The exact mechanism of fluid retention remains unclear; however, experimental evidence indicates a role of PDGFR inhibition. Studies in mouse yolk-sac have demonstrated that PDGFR- is expressed on early hemangioprecursor cells, regulating vascular/hematopoietic development. PDGF are potent mitogens and play an important role in interstitial fluid homeostasis. Animal studies have shown that treatment with imatinib decreased interstitial hypertension and increased capillary-to-interstitium transport of 51 Cr-EDTA in subcutaneous tumor grafts in mice [6]. PDGFR-␣ and - have been detected in the vessels of the normal choroid and retina [7] and inhibition of these may contribute to retinal oedema. PDGFR gene polymorphisms do not predispose to imatinib related oedema. The clinical course and response of our patient to dasatinib demonstrates a toxicity profile different from imatinib. While phase II studies with dasatinib have reported fluid retention (18%) and pleural effusion (19%), these are anatomically distinct from the typical pattern of peripheral and peri-orbital oedema seen with imatinib [5]. Grade 3–4 pleural effusions noted in a subset of patients (3%) on dasatinib resolved with simple measures [5]. While it is tempting to suggest the different toxicity profile may relate to differences in PDGFR inhibition between the two drugs, available data has shown that both agents are effective inhibitors of PDGFR-, with dasatinib being more potent [8]. The spectrum of tyrosine kinase inhibition of dasatinib needs further exploration considering the potential use in patients with PDGFR-related toxicities with imatinib.
with patient management and provided the photographs. John F. Seymour was involved with patient management and preparation of the manuscript. All authors reviewed and approved the final manuscript.
References [1] Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F, et al., Recommendations from an expert panel on behalf of the European LeukemiaNet et al. Evolving concepts in the management of chronic myeloid leukemia. Blood 2006;108:1809–20. [2] Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. IRIS investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukaemia. N Engl J Med 2006;355(23):2408–17. [3] Kusumi E, Arakawa A, Kami M, Kato D, Yuji K, Kishi Y, et al. Visual disturbance due to retinal edema as a complication of imatinib. Leukemia 2004;18:1138–9. [4] Masood I, Negi A, Dua HS. Imatinib as a cause of cystoid macular edema following uneventful phacoemulsification surgery. J Cataract Refract Surg 2005;31:2427–8. [5] Hochhaus A, Kantarjian HM, Baccarani M, Lipton JH, Apperley JF, Druker BJ, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 2007;109(6):2303–9. [6] Pietras K, Ostman A, Sjoquist M, Buchdunger E, Reed RK, Heldin CH, et al. Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res 2001;61(7):2929–34. [7] Robbins SG, Mixon RN, Wilson DJ, Hart CE, Robertson JE, Westra I, et al. Platelet-derived growth factor ligands and receptors immunolocalized in proliferative retinal diseases. Invest Ophthalmol Vis Sci 1994;35(10):3649–63. [8] Chen Z, Lee FY, Bhalla KN, Wu J. Potent inhibition of plateletderived growth factor-induced responses in vascular smooth muscle cells by BMS-354825 (dasatinib). Mol Pharmacol 2006;69:1527– 33.
Ashish Bajel a Saf Bassili b John F. Seymour a,c,∗ a Peter MacCallum Cancer Institute, Department of Haematology and Medical Oncology, Locked Bag 1, A’Beckett Street, Melbourne, VIC 8006, Australia b Austin Hospital, Melbourne, Victoria, Australia c University of Melbourne, Melbourne, Australia ∗ Corresponding author. Tel.: +61 3 96561111; fax: +61 3 96561408. E-mail address: [email protected] (J.F. Seymour) 4 February 2008 26 March 2008 27 March 2008
Acknowledgements The authors disclose no conflict of interest. Contributions. Ashish Bajel was involved with writing up the manuscript and literature review. Saf Bassili was involved
Available online 6 May 2008 doi: 10.1016/j.leukres.2008.03.027
[6]
[7]
[8]
[9]
[10]
[11]
[12]
classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 1999;17(12):3835–49. Saif MW, Hopkins JL, Gore SD. Autoimmune phenomena in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia. Leuk Lymphoma 2002;43(11):2083–92. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89(6):2079–88. Kumar PV, Vasei M, Sadeghipour A, Sadeghi E, Soleimanpour H, Mousavi A, Tabatabaei AH, Rizvi MM. Visceral leishmaniasis: bone marrow biopsy findings. J Pediatr Hematol Oncol 2007;29(2):77–80. Magalhães SM, Filho FD, Vassallo J, Pinheiro MP, Metze K, LorandMetze K. Bone marrow lymphoid aggregates in myelodysplastic syndrome: incidence, immunomorphological characteristics and correlation with clinical features and survival. Leuk Res 2002;26(6):525–30. Novaretti MC, Sopelete CD, Velloso ER, Dorlhiac PEL, Chamone DA. Immunohematological findings in myelodysplastic syndrome. Acta Haematol 2001;105(1):1–6. Vilela RB, Bordin JO, Chiba AK, Castelo A, Barbosa MC. RBCassociated IgG in patients with visceral leishmaniasis (kala-azar): a prospective analysis. Transfusion 2002;42(11):1442–7. Pedras MJ, de Gouvêa Viana L, de Oliveira EJ, Rabello A. Comparative evaluation of direct agglutination test, rK39 and soluble antigen ELISA and IFAT for the diagnosis of visceral leishmaniasis. Trans R Soc Trop Med Hyg 2008;102(2):172–8.
Ronald Feitosa Pinheiro ∗ Viviane Chaves Pereira Fernando Barroso Carlos da Costa Ribeiro Neto Sílvia M.M. Magalhães Federal University of Ceará, Walter Cantídio Hospital, Division of Hematology, Brazil ∗ Corresponding
author: Pereira Valente, 738, Meireles, 60160250, Fortaleza-Ceará-Brazil. Tel.: +55 85 32640898. E-mail address: [email protected] (R.F. Pinheiro) 29 January 2008
1789
effects reported. The most common adverse effects include superficial oedema, nausea, muscle cramps, musculoskeletal pain, rash, fatigue, diarrhoea and myelosuppression [2]. Ocular toxicities including periorbital oedema, epiphora and rarely retinal oedema have also been reported [3,4]. Dasatinib (BMS-354825), a novel multi-targeted kinase inhibitor of BCR-ABL and SRC kinases, exhibits high haematologic and cytogenetic response rates in imatinib resistant/intolerant CML patients with an acceptable toxicity profile.
2. Case report A previously well 38-year-old man with history of left eye amblyopia and acuity of 6/12 (right eye 6/5) was diagnosed with chronic-phase CML in July04 (WCC 172 × 109 /L) and started on imatinib 400 mg/day after brief course of hydroxyurea. He noted mild visual detoriation on commencement of imatinib. Ophthalmic review in September 2004 due to persisting visual disturbance revealed deterioration in visual acuity to 6/9 (left) and 6/18 (right) with bilateral widespread moderate-sized retinal haemorrhages and macular oedema more pronounced in the left. There was localised swelling of the superior border of the right optic nerve head. A fluorescein angiogram confirmed bilateral macular oedema and right disc leakage with no associated retinal ischemia (Fig. 1). A normal MRI brain and CSF cytology excluded CNS leukaemia. By October 2004 he was in complete haematological remission but decreased visual acuity persisted. In view of the rare occurrence of retinal complications with imatinib and the risk of further deterioration, imatinib was ceased [3,4]. The patient’s vision and his ophthalmic findings showed improvement 2 weeks after cessation. The macular and disc oedema had totally resolved and retinal haemorrhages started to fade with vision improving to 6/5 (right) and 6/12 (left) by 6 weeks. Resolution of the ophthalmic changes on cessation of imatinib established a causal relationship.
3 April 2008 5 April 2008 Available online 3 June 2008 doi: 10.1016/j.leukres.2008.04.015
Safe treatment of a patient with CML using dasatinib after prior retinal oedema due to imatinib
1. Introduction Imatinib, a Bcr-Abl kinase inhibitor is the standard therapy for all phases of CML [1]. Imatinib also inhibits other kinases, including ABL, c-kit, PDGFR-␣ and -, ARG and cfms. While the activity against these targets is being exploited therapeutically, it may also underlie some of the adverse
Fig. 1. Mid phase fluorescein angiogram of the left eye showing severe patelloid angiographic macular oedema.
1790
Letters to the editor / Leukemia Research 32 (2008) 1776–1790
His disease was well controlled in chronic phase with hydroxyurea for 5 months. He then consented to participate in a phase-II trial of Dasatinib (Protocol CA180-034) [5], commencing 70 mg twice daily in June 2005. At commencement there were 100% Ph+ bone marrow metaphases and quantitative PCR revealed both b2a2 and b3a2 transcripts, but the later predominated, and was quantitated as 99% relative to the normal ABL transcript. He tolerated the drug well except for transient headache and a minor scalp rash. Repeated ophthalmic evaluation (till September05) revealed preserved visual acuity and no evidence of recurrent retinal changes. He is continuing on dasatinib at 24+ months and has attained complete cytogenetic response and a major molecular response (BCR-ABL: ABL transcripts 0.004%) with no visual symptoms or ophthalmic complications.
3. Discussion Fluid retention and oedema due to imatinib occur in 60% patients [2]. The exact mechanism of fluid retention remains unclear; however, experimental evidence indicates a role of PDGFR inhibition. Studies in mouse yolk-sac have demonstrated that PDGFR- is expressed on early hemangioprecursor cells, regulating vascular/hematopoietic development. PDGF are potent mitogens and play an important role in interstitial fluid homeostasis. Animal studies have shown that treatment with imatinib decreased interstitial hypertension and increased capillary-to-interstitium transport of 51 Cr-EDTA in subcutaneous tumor grafts in mice [6]. PDGFR-␣ and - have been detected in the vessels of the normal choroid and retina [7] and inhibition of these may contribute to retinal oedema. PDGFR gene polymorphisms do not predispose to imatinib related oedema. The clinical course and response of our patient to dasatinib demonstrates a toxicity profile different from imatinib. While phase II studies with dasatinib have reported fluid retention (18%) and pleural effusion (19%), these are anatomically distinct from the typical pattern of peripheral and peri-orbital oedema seen with imatinib [5]. Grade 3–4 pleural effusions noted in a subset of patients (3%) on dasatinib resolved with simple measures [5]. While it is tempting to suggest the different toxicity profile may relate to differences in PDGFR inhibition between the two drugs, available data has shown that both agents are effective inhibitors of PDGFR-, with dasatinib being more potent [8]. The spectrum of tyrosine kinase inhibition of dasatinib needs further exploration considering the potential use in patients with PDGFR-related toxicities with imatinib.
with patient management and provided the photographs. John F. Seymour was involved with patient management and preparation of the manuscript. All authors reviewed and approved the final manuscript.
References [1] Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F, et al., Recommendations from an expert panel on behalf of the European LeukemiaNet et al. Evolving concepts in the management of chronic myeloid leukemia. Blood 2006;108:1809–20. [2] Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. IRIS investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukaemia. N Engl J Med 2006;355(23):2408–17. [3] Kusumi E, Arakawa A, Kami M, Kato D, Yuji K, Kishi Y, et al. Visual disturbance due to retinal edema as a complication of imatinib. Leukemia 2004;18:1138–9. [4] Masood I, Negi A, Dua HS. Imatinib as a cause of cystoid macular edema following uneventful phacoemulsification surgery. J Cataract Refract Surg 2005;31:2427–8. [5] Hochhaus A, Kantarjian HM, Baccarani M, Lipton JH, Apperley JF, Druker BJ, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 2007;109(6):2303–9. [6] Pietras K, Ostman A, Sjoquist M, Buchdunger E, Reed RK, Heldin CH, et al. Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res 2001;61(7):2929–34. [7] Robbins SG, Mixon RN, Wilson DJ, Hart CE, Robertson JE, Westra I, et al. Platelet-derived growth factor ligands and receptors immunolocalized in proliferative retinal diseases. Invest Ophthalmol Vis Sci 1994;35(10):3649–63. [8] Chen Z, Lee FY, Bhalla KN, Wu J. Potent inhibition of plateletderived growth factor-induced responses in vascular smooth muscle cells by BMS-354825 (dasatinib). Mol Pharmacol 2006;69:1527– 33.
Ashish Bajel a Saf Bassili b John F. Seymour a,c,∗ a Peter MacCallum Cancer Institute, Department of Haematology and Medical Oncology, Locked Bag 1, A’Beckett Street, Melbourne, VIC 8006, Australia b Austin Hospital, Melbourne, Victoria, Australia c University of Melbourne, Melbourne, Australia ∗ Corresponding author. Tel.: +61 3 96561111; fax: +61 3 96561408. E-mail address: [email protected] (J.F. Seymour) 4 February 2008 26 March 2008 27 March 2008
Acknowledgements The authors disclose no conflict of interest. Contributions. Ashish Bajel was involved with writing up the manuscript and literature review. Saf Bassili was involved
Available online 6 May 2008 doi: 10.1016/j.leukres.2008.03.027