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• AML and metastatic risk after ophthalmic artery chemosurgery for retinoblastoma
  GUILLERMO L CHANTADA, PAULA S. SCHAIQUEVICH
  Published on: 7 March 2018
• Response to AML after OAC
  David H. Abramson, Larissa A. Habib, Jasmine H. Francis, Armida WM Fabius, Ira J. Dunkel and Y. Pierre Gobin
  Published on: 15 February 2018
• Acute Myeloid Leukemia following OAC
  Ann Leahey, MD, Anna Meadows, MD
  Published on: 5 February 2018

• Published on: 7 March 2018

  AML and metastatic risk after ophthalmic artery chemosurgery for retinoblastoma

  • GUILLERMO L CHANTADA, Pediatric Oncologist Hospital JP Garrahan, Buenos Aires, Argentina and Hospital Sant Joan de Deu, Barcelona, Spain
  • Other Contributors:
    • PAULA S. SCHAIQUEVICH, PhD, Pharmacist

  We would like to add some data to this interesting discussion about the impact of ophthalmic artery chemosurgery or intra-arterial chemotherapy (OAC) in the occurrence of secondary malignancies in children with retinoblastoma with germline mutations of the Rb1 gene.
  The discussion about the incidence of secondary leukemia is an important one. Secondary leukemias usually present early in the patient follow-up, usually around 2-3 years. Systemic chemotherapy has been implicated in their occurrence since, they were not identified as a common secondary malignancy in patients with retinoblastoma not receiving chemotherapy1. Their occurrence is low1, but as the case Dr Meadows and Lahey report are usually refractory to treatment and usually fatal. In our series of patients treated with systemic chemoreduction for conservative therapy from Argentina, secondary AML was the most common fatal secondary malignancy with a total of 2 out of 129 cases. We had a third case in a child receiving chemotherapy for extraocular disease, similarly to Dr Meadows and Lahey’s case2. In our current, yet unpublished results with ophthalmic artery chemosurgery, we had no case of secondary AML , in 71 consecutive cases with bilateral retinoblastoma treated with OAC with a median follow-up of 42 months. Secondary AML has been widely reported as a complication of systemic chemotherapy in pediatric oncology patients 3 including those receiving epipodophillotoxins 4and also alkylating agents5. Cum...

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  We would like to add some data to this interesting discussion about the impact of ophthalmic artery chemosurgery or intra-arterial chemotherapy (OAC) in the occurrence of secondary malignancies in children with retinoblastoma with germline mutations of the Rb1 gene.
  The discussion about the incidence of secondary leukemia is an important one. Secondary leukemias usually present early in the patient follow-up, usually around 2-3 years. Systemic chemotherapy has been implicated in their occurrence since, they were not identified as a common secondary malignancy in patients with retinoblastoma not receiving chemotherapy1. Their occurrence is low1, but as the case Dr Meadows and Lahey report are usually refractory to treatment and usually fatal. In our series of patients treated with systemic chemoreduction for conservative therapy from Argentina, secondary AML was the most common fatal secondary malignancy with a total of 2 out of 129 cases. We had a third case in a child receiving chemotherapy for extraocular disease, similarly to Dr Meadows and Lahey’s case2. In our current, yet unpublished results with ophthalmic artery chemosurgery, we had no case of secondary AML , in 71 consecutive cases with bilateral retinoblastoma treated with OAC with a median follow-up of 42 months. Secondary AML has been widely reported as a complication of systemic chemotherapy in pediatric oncology patients 3 including those receiving epipodophillotoxins 4and also alkylating agents5. Cumulative systemic exposure to chemotherapy , along with genetic predisposition, seem to play a major role in its occurrence4, 5. In the case, Dr Meadows and Lahey report, the doses of alkylating agents received for the treatment with high dose chemotherapy should have been significantly higher than those from intra-arterial melphalan. We have estimated from our pharmacokinetic study of melphalan in patients receiving OAC for the treatment of retinoblastoma that systemic exposure is at least 10 times lower compared to systemic doses which are regularly used for preparation for high dose therapy and stem cell rescue as Dr Meadows and Lahey’s case6. Additionally, since OAC regimens do not include epipodophillotoxins, secondary leukemias caused by exposure to these drugs are eliminated. So, while it is likely that the significantly lower systemic exposure to chemotherapy obtained by OAC6 might add some risk of secondary leukemia to these predisposed patients, date presented up to the present time suggest that, compared to systemic chemotherapy a lower incidence of secondary leukemia or in fact no cases in children only treated with OAC are seen.
  The discussion about the potential prevention of metastatic dissemination and the role of systemic versus OAC in it is also an open one. While it is likely that lower systemic chemotherapy levels achieved with OAC might provide a lower protection against systemic dissemination, on the other hand OAC provides a significantly higher exposure to chemotherapy in the optic nerve, which is a major source of dissemination for retinoblastoma to the CNS. Dissemination to this critical compartment is usually fatal7. If we apply the rationale proposed by Dr Lahey and Meadows of thinking that a higher exposure to chemotherapy would be more effective in preventing metastasis in minimally disseminated disease, OAC would be more effective in preventing dissemination through the optic nerve compared to systemic chemotherapy.

  References

  1. Gombos DS, Hungerford J, Abramson DH, et al. Secondary acute myelogenous leukemia in patients with retinoblastoma: is chemotherapy a factor? Ophthalmology. 2007;114: 1378-1383.
  2. Chantada GL, Fandino AC, Raslawski EC, et al. Experience with chemoreduction and focal therapy for intraocular retinoblastoma in a developing country. Pediatr Blood Cancer. 2005;44: 455-460.
  3. Hijiya N, Ness KK, Ribeiro RC, Hudson MM. Acute leukemia as a secondary malignancy in children and adolescents: current findings and issues. Cancer. 2009;115: 23-35.
  4. Pui CH, Ribeiro RC, Hancock ML, et al. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med. 1991;325: 1682-1687.
  5. Davies SM. Therapy-related leukemia associated with alkylating agents. Med Pediatr Oncol. 2001;36: 536-540.
  6. Schaiquevich P, Buitrago E, Taich P, et al. Pharmacokinetic analysis of melphalan after superselective ophthalmic artery infusion in preclinical models and retinoblastoma patients. Invest Ophthalmol Vis Sci. 2012;53: 4205-4212.
  7. Taich P, Requejo F, Asprea M, et al. Topotecan Delivery to the Optic Nerve after Ophthalmic Artery Chemosurgery. PLoS One. 2016;11: e0151343.

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  Conflict of Interest:
  None declared.

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• Published on: 15 February 2018

  Response to AML after OAC

  • David H. Abramson, Ocular Oncologist Memorial Sloan Kettering Cancer Center, New York, NY USA
  • Other Contributors:
    • Larissa A. Habib, Ophthalmologist
    • Jasmine H. Francis, Ocular Oncologist
    • Armida WM Fabius, PhD
    • Ira J. Dunkel, Oncologist
    • Y. Pierre Gobin, Interventional Radiologist

  Dear Sir,

  We are writing this letter in response to a “letter to the editor” from Drs. Leahey and Meadows about our recently published paper “Second primary malignancies in retinoblastoma patients treated with intra-arterial chemotherapy: the first 10 years”.1 There are a number of incorrect statements in their letter and we hope this letter will clarify those errors made by them.

  1) Drs. Leahey and Meadows state that…”the author’s report is profoundly misleading with regard to the risk of SPMs following OAC”. To prove that they then state that the median follow-up range is 2.5 years with a maximum follow-up of 12 years. How is that “profoundly misleading”? In the same paragraph they then state that patients failing OAC required radiation therapy and suggest that all of these second neoplasms are a consequence of radiation. That is not true. In our paper (page 273, Table 3) we documented that not one of the children who developed a second tumor had received radiation. How could radiation be the cause of a second tumor if the patients never received radiation? Dr. Leahey and Meadows also wrote that…”patients failing OAC require radiation”. That’s not true. On page 272 we stated that…”patients who received external beam radiation prior to presentation at our clinic were excluded from analysis”. None of the patients in this series received radiation after OAC and no patient in our center has received radiation in the past 10 years. We do not dispute that radia...

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  Dear Sir,

  We are writing this letter in response to a “letter to the editor” from Drs. Leahey and Meadows about our recently published paper “Second primary malignancies in retinoblastoma patients treated with intra-arterial chemotherapy: the first 10 years”.1 There are a number of incorrect statements in their letter and we hope this letter will clarify those errors made by them.

  1) Drs. Leahey and Meadows state that…”the author’s report is profoundly misleading with regard to the risk of SPMs following OAC”. To prove that they then state that the median follow-up range is 2.5 years with a maximum follow-up of 12 years. How is that “profoundly misleading”? In the same paragraph they then state that patients failing OAC required radiation therapy and suggest that all of these second neoplasms are a consequence of radiation. That is not true. In our paper (page 273, Table 3) we documented that not one of the children who developed a second tumor had received radiation. How could radiation be the cause of a second tumor if the patients never received radiation? Dr. Leahey and Meadows also wrote that…”patients failing OAC require radiation”. That’s not true. On page 272 we stated that…”patients who received external beam radiation prior to presentation at our clinic were excluded from analysis”. None of the patients in this series received radiation after OAC and no patient in our center has received radiation in the past 10 years. We do not dispute that radiation affects the development of second cancers in germline affected retinoblastomas-but that is not the explanation for these cancers in our report.

  2) In the many large series published worldwide on second cancers in retinoblastoma patients secondary AML does not appear to be a cancer that develops2,3 unless systemic chemotherapy is used4. In fact there are published series of secondary AML in retinoblastoma patients published prior to the introduction of OAC and in each case systemic chemotherapy was implicated as the cause. There has not been an increase in sAML in our patients treated with OAC and no other center has suggested or reported an increase in sAML after adopting OAC.

  3) Drs. Leahey and Meadows imply that the Melphalan given for OAC is responsible for the secondary AML but that seems unlikely and is not consistent with the published, peer review literature. The Japanese used similar doses of Melphalan in their series of patients treated with intra-arterial chemotherapy (published in 2011) between 1988 and 2007.5 In their 343 patients they meticulously pointed out that long-term follow-up of these patients did not reveal an increase in second cancers and in fact all of the second cancers but one they attributed to the use of external beam radiation combined with chemotherapy. The one patient they had who developed secondary AML they attributed to the four courses of systemic chemotherapy utilizing Vincristine, Carboplatin and Etoposide. We don’t understand why Dr. Leahey and Meadows implicate the Melphalan but not the seven cycles of multiagent systemic chemotherapy they delivered. This child did not have AML while under our care. Finally, FLT3 mutations (present in this child) have usually been associated with topoisomerase induced sAML and de novo (no prior chemotherapy) sAML and not sAML from alkylating agents (e.g. Melphalan). 6 Their child’s sAML may be unrelated to any chemotherapy but more likely the systemic chemotherapy (with doses a hundred times the small amount of Melphalan delivered by OAC) is the culprit.

  4) Secondary AML from chemotherapy is well known in pediatric oncology and well known by Drs. Leahey and Meadows. It is a devastating and often lethal complication of systemic chemotherapy and was the subject of a paper by Drs. Leahey and Meadows in 1999.7 They described this complication as a…”late effect of chemotherapy” in their cohort of 228 patients. We agree that secondary AML can be a late and devastating effect of systemic chemotherapy and that is why we have abandoned it for intraocular retinoblastoma and one of the reasons we developed OAC.

  5) Drs. Leahey and Meadows correctly state that the goal of retinoblastoma is to cure the child of cancer (and suggest that OAC does not do that). A large, collaborative manuscript (which included their patients) was published a December 2017 on the worldwide experience with OAC8 since we introduced it in 20069. In 1139 patients who received 4396 infusions only three patients died of metastatic disease (all from Argentina and all had prior systemic chemotherapy). The conclusion is clear: using OAC to save children’s eyes and vision does not compromise patient survival.

  6) Drs. Leahey and Meadows and the Philadelphia retinoblastoma team have considerable experience with OAC over the past 10 years and have published more than 20 papers on the subject. They have not published on their second tumor experience in the OAC era. We challenge them to collect and publish their data on second cancers in germline patients treated with OAC alone. If they have additional sAML cases we suggest their use of multi-agent systemic chemotherapy for retinoblastoma is the cause (as we abandoned that 12 years ago because of that well documented adverse effect).

  7) We are saddened by this patient’s course but have no way of evaluating the risk/benefit discussion that Drs. Leahey and Meadows had with the family when they decided to use adjuvant multiagent chemotherapy which may have induced resistance and then a total of seven cycles of multiagent chemotherapy which are proven to cause secondary AML. The conclusion from this case is that we should all avoid systemic chemotherapy in retinoblastoma if there is a better option…and for intraocular disease fortunately there is: OAC.

  References

  1. Habib LA, Francis JH, Fabius AW, Gobin PY, Dunkel IJ, Abramson DH. Second primary malignancies in retinoblastoma patients treated with intra-arterial chemotherapy: the first 10 years. Br J Ophthalmol. 2018;102(2):272–275. doi:10.1136/bjophthalmol-2017-310328.

  2. Kleinerman RA, Yu C-L, Little MP, et al. Variation of second cancer risk by family history of retinoblastoma among long-term survivors. J Clin Oncol. 2012;30(9):950–957. doi:10.1200/JCO.2011.37.0239.

  3. Abramson DH, Frank CM. Second nonocular tumors in survivors of bilateral retinoblastoma: a possible age effect on radiation-related risk. Ophthalmology. 1998;105(4):573–9–discussion579–80. doi:10.1016/S0161-6420(98)94006-4.

  4. Gombos DS, Hungerford J, Abramson DH, et al. Secondary acute myelogenous leukemia in patients with retinoblastoma: is chemotherapy a factor? Ophthalmology. 2007;114(7):1378–1383. doi:10.1016/j.ophtha.2007.03.074.

  5. Suzuki S, Yamane T, Mohri M, Kaneko A. Selective ophthalmic arterial injection therapy for intraocular retinoblastoma: the long-term prognosis. Ophthalmology. 2011;118(10):2081–2087. doi:10.1016/j.ophtha.2011.03.013.

  6. Godley LA, Larson RA. Therapy-related myeloid leukemia. Semin Oncol. 2008;35(4):418–429. doi:10.1053/j.seminoncol.2008.04.012.

  7. Leahey AM, Teunissen H, Friedman DL, Moshang T, Lange BJ, Meadows AT. Late effects of chemotherapy compared to bone marrow transplantation in the treatment of pediatric acute myeloid leukemia and myelodysplasia. Med Pediatr Oncol. 1999;32(3):163–169.

  8. Abramson DH, Shields CL, Jabbour P, et al. Metastatic deaths in retinoblastoma patients treated with intraarterial chemotherapy (ophthalmic artery chemosurgery) worldwide. Int J Retina Vitreous. 2017;3:40. doi:10.1186/s40942-017-0093-8.

  9. Abramson DH, Dunkel IJ, Brodie SE, Kim JW, Gobin YP. A phase I/II study of direct intraarterial (ophthalmic artery) chemotherapy with melphalan for intraocular retinoblastoma initial results. Ophthalmology. 2008;115(8):1398–404–1404.e1. doi:10.1016/j.ophtha.2007.12.014.

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  Conflict of Interest:
  None declared.

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• Published on: 5 February 2018

  Acute Myeloid Leukemia following OAC

  • Ann Leahey, MD, Pediatric Oncologist Children's Hospital of Philadelphia
  • Other Contributors:
    • Anna Meadows, MD, Pediatric Oncologist

  Having read the article of secondary primary malignancies (SPM) in patients treated with ophthalmic artery chemosurgery (OAC) (1), we wish to update Dr. Habib’s report. A patient with unilateral Group D heritable retinoblastoma (RB) treated by their team with 5 OAC treatments in 2012 through 2013 developed acute myeloid leukemia (AML) on 4/26/2017 and died 3 months later.
  Following an intraocular recurrence after OAC and subsequent enucleation the patient’s care was transferred to our institution. Despite adjuvant chemotherapy he developed widespread bone and marrow metastases 8 months after enucleation. He then underwent intensive chemotherapy and an autologous stem cell transplant. Twenty eight months later he developed AML with a fms-like tyrosine kinase 3 (FLT3) mutation. Melphalan administered during all OAC treatments and the drugs administered following that failure must be implicated in this outcome (2). By failing to eradicate retinoblastoma, metastatic disease ensued requiring further treatment and subsequently, AML.
  The author’s report is profoundly misleading with regard to the risk of SPMs following OAC. Although the maximum period of follow-up is 12 years, the median is 2.5 years. Patients failing OAC required radiation therapy and are known to be 3 times more likely to develop additional cancers (3). We await that follow-up.
  The goal of RB care is cure. This patient’s course illustrates the danger of failing to prevent metastatic disease wi...

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  Having read the article of secondary primary malignancies (SPM) in patients treated with ophthalmic artery chemosurgery (OAC) (1), we wish to update Dr. Habib’s report. A patient with unilateral Group D heritable retinoblastoma (RB) treated by their team with 5 OAC treatments in 2012 through 2013 developed acute myeloid leukemia (AML) on 4/26/2017 and died 3 months later.
  Following an intraocular recurrence after OAC and subsequent enucleation the patient’s care was transferred to our institution. Despite adjuvant chemotherapy he developed widespread bone and marrow metastases 8 months after enucleation. He then underwent intensive chemotherapy and an autologous stem cell transplant. Twenty eight months later he developed AML with a fms-like tyrosine kinase 3 (FLT3) mutation. Melphalan administered during all OAC treatments and the drugs administered following that failure must be implicated in this outcome (2). By failing to eradicate retinoblastoma, metastatic disease ensued requiring further treatment and subsequently, AML.
  The author’s report is profoundly misleading with regard to the risk of SPMs following OAC. Although the maximum period of follow-up is 12 years, the median is 2.5 years. Patients failing OAC required radiation therapy and are known to be 3 times more likely to develop additional cancers (3). We await that follow-up.
  The goal of RB care is cure. This patient’s course illustrates the danger of failing to prevent metastatic disease with initial therapy. As Dr. Desjardins wrote in her recent review “ local administration [via OAC] cannot be used to treat micrometastases in advanced forms of the disease “ (4). Although metastatic RB can be treated if it develops (5), not all patients survive.

  References:
  1. Habib LA, Francis JH, Fabius A et al. Second primary malignancies in retinoblastoma patients treated with intra-arterial chemotherapy: the first 10 years. Br J Ophthalmol 2018; 102: 272-5.
  2. Levine EG and Bloomfield CO. Leukemias and myelodysplastic syndromes secondary to drugs, radiation and environmental exposures. Semin Oncol 1982; 19: 471-84.
  3. Kleinerman RA, Tucker MA, Tarone RE, et al. Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol 2005; 23: 2272-9.
  4. Kassoux N, Lumbroso L, Levy-Gabriel C et al. Retinoblastoma: updates on current management. Asia-Pac J Ophthalmol 2017; 6: 290-5.
  5. Dunkel IJ, Khakoo Y, Kernan NA et al. Intensive multi-modal therapy for patients with stage 4A metastatic retinoblastoma. Pediatr Blood Cancer 201; 55: 55-9.

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  Conflict of Interest:
  None declared.

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