OncohematologyOncohematologyОнкогематология1818-83462413-4023Publishing House ABV Press14010.17650/1818-8346-2015-10-2-8-13HEMATOLOGIC MALIGNANCIES: DIAGNOSIS, TREATMENT, SUPPORTIVE CAREГЕМОБЛАСТОЗЫ: ДИАГНОСТИКА, ЛЕЧЕНИЕ, СОПРОВОДИТЕЛЬНАЯ ТЕРАПИЯCombination of arsenicum trioxide and all trans retinoic acid in the treatment of relapsed acute promyelocytic leukemiaСочетание триоксида мышьяка с полностью трансретиноевой кислотой в лечении рецидивов острого промиелоцит арного лейкозаSokolovA. N.СоколовА. Н.
Russian Federation
cat@blood.ruParovichnikovaE. N.ПаровичниковаЕ. Н.
Russian Federation
TroitskayaV. V.ТроицкаяВ. В.
Russian Federation
KuzminaL. A.КузьминаЛ. А.
Russian Federation
SavchenkoV. G.СавченкоВ. Г.
Russian Federation
Hematological Research Center, Ministry of Health of RussiaФГБУ «Гематологический научный центр» Минздрава России4a Novyy Zykovskiy Pr-d, Moscow, 125167, RussiaРоссия, 125167, Москва, Новый Зыковский проезд, 4а040620151028130406201504062015https://oncohematology.abvpress.ru/ongm/article/view/140

From 2001 to 2013 eleven patients with relapsed acute promyelocytic leukemia (APL) (median age – 30 years) received arsenicum trioxide (ATO). ATO was administered as a 2nd line relapse therapy in 9 patients, as 1st line relapse therapy in 2 patients. ATO was administered in a dose of 0.1 mg/kg in 7 patients, 0.15 mg/kg – in 4 patients. The induction duration was 14 days in 3 patients, 24–35 days in 2 patients, 60 days in 6 patients. From the 1st day of ATO patients received 45 mg/m2 all trans retinoic acid (ATRA) (1 patient – from day 29 of ATO therapy). Maintenance therapy ATO + ATRA (10–14 days courses, every four weeks) patients were receiving during 10–15 months. 2 from 3 patients with molecular relapses achieved remission lasting 57 and 89 months after the 14-day ATO courses. 1 from 2 patients with bone marrow relapse achieved remission lasting 27 months after the 24–35-day ATO courses. 60-day courses were effective in 5 of 6 patients: in 4 of which remission are retained during 16, 19, 27, 57 months; 1 patient was relapsed after 12 months; 1 patient did not achieve molecular remission. 3 patients received allogeneic hematopoietic stem cell transplantation (alloHSCT), 2 of which alive in remission. 1 patient received autologous hematopoietic stem cell transplantation in the 2nd molecular remission (alive in remission). 4 patients died: 1 – in the 3rd relapse (duration of 2nd remission – 9 months), 1 – in remission from complications after alloHSCT, 1 – from APL progression, 1 – sudden death in 2nd remission lasting 72 months. ATO + ATRA for 60 days with supportive therapy are more effective than chemotherapy in the treatment of APL relapse. Interferon α + ATRA are inappropriate treatment of APL molecular and cytogenetic relapse. Using autologous HSCT in 2nd molecular remission will improve the results of APL relapse treatment.

acute promyelocytic leukemiarelapsearsenicum trioxideall trans retinoid acidострый промиелоцитарный лейкозрецидивтриоксид мышьякаполностью трансретиноевая кислота1. Sun H. D., Ma L., Hu X. C., Zhang T. D. Ai-Lin I treated 32 cases of acute promyelocytic leukemia. Chin J Integr Chin West Med 1992(Chinese);12:170.Sun H. D., Ma L., Hu X. C., Zhang T. D. Ai-Lin I treated 32 cases of acute promyelocytic leukemia. Chin J Integr Chin West Med 1992(Chinese);12:170.2. Zhang P., Wang S. Y., Hu L. H. et al. Arsenic trioxide treated 72 cases of acute promyelocytic leukemia. Chin J Hematol 1996;2:58.Zhang P., Wang S. Y., Hu L. H. et al. Arsenic trioxide treated 72 cases of acute promyelocytic leukemia. Chin J Hematol 1996;2:58.3. Zhou J. Arsenic trioxide: an ancient drug revived. Chin Med J (Engl) 2012;125(19):3556–60.Zhou J. Arsenic trioxide: an ancient drug revived. Chin Med J (Engl) 2012;125(19):3556–60.4. Alimoghaddam K. A review of arsenic trioxide and acute promyelocytic leukemia. Int J Hematol-Oncol & Stem Cell Res 2014;8(3):44–54.Alimoghaddam K. A review of arsenic trioxide and acute promyelocytic leukemia. Int J Hematol-Oncol & Stem Cell Res 2014;8(3):44–54.5. Mathews V., Chendamarai E., George B. et al. Treatment of acute promyelocytic leukemia with single-agent arsenic trioxide. Mediterr J Hematol Infect Dis 2011;3(1):e2011056.Mathews V., Chendamarai E., George B. et al. Treatment of acute promyelocytic leukemia with single-agent arsenic trioxide. Mediterr J Hematol Infect Dis 2011;3(1):e2011056.6. Савченко В. Г., Паровичникова Е. Н., Исаев В. Г. Программное лечение острых лейкозов. М., 2002. С. 88–101.Савченко В. Г., Паровичникова Е. Н., Исаев В. Г. Программное лечение острых лейкозов. М., 2002. С. 88–101.[Savchenko V. G., Parovichnikova E. N., Isaev V. G. Program treatment of acute leukemia. M., 2002. Pp. 88–101. (In Russ.)].7. Савченко В. Г., Паровичникова Е. Н., Исаев В. Г. Программное лечение острых лейкозов. М., 2002. С. 102–115. [Savchenko V. G., Parovichnikova E. N., Isaev V. G. Program treatment of acute leukemia. M., 2002. Pp. 102–15. (In Russ.)].Савченко В. Г., Паровичникова Е. Н., Исаев В. Г. Программное лечение острых лейкозов. М., 2002. С. 102–115. [Savchenko V. G., Parovichnikova E. N., Isaev V. G. Program treatment of acute leukemia. M., 2002. Pp. 102–15. (In Russ.)].8. Shen Z. X., Chen G. Q., Ni J. H. et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 1997;89(9):3354–60.Shen Z. X., Chen G. Q., Ni J. H. et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 1997;89(9):3354–60.9. Hu J., Shen Z. X., Sun G. L. et al. Long- term survival and prognostic study in acute promyelocytic leukemia treated with all- trans-retinoic acid, chemotherapy, and As2O3: an experience of 120 patients at a single institution. Int J Hematol 1999;70(4):248–60.Hu J., Shen Z. X., Sun G. L. et al. Long- term survival and prognostic study in acute promyelocytic leukemia treated with all- trans-retinoic acid, chemotherapy, and As2O3: an experience of 120 patients at a single institution. Int J Hematol 1999;70(4):248–60.10. Shigeno K., Naito K., Sahara N. et al. Arsenic trioxide therapy in relapsed or refractory Japanese patients with acute promyelocytic leukemia: updated outcomes of the phase II study and postremission therapies. Int J Hematol 2005;82(3):224–9.Shigeno K., Naito K., Sahara N. et al. Arsenic trioxide therapy in relapsed or refractory Japanese patients with acute promyelocytic leukemia: updated outcomes of the phase II study and postremission therapies. Int J Hematol 2005;82(3):224–9.11. Raffoux E., Rousselot P., Poupon J. et al. Combined treatment with arsenic trioxide and all-trans-retinoic acid in patients with relapsed acute promyelocytic leukemia. J Clin Oncol 2003;21(12):2326–34.Raffoux E., Rousselot P., Poupon J. et al. Combined treatment with arsenic trioxide and all-trans-retinoic acid in patients with relapsed acute promyelocytic leukemia. J Clin Oncol 2003;21(12):2326–34.12. Lengfelder E., Lo-Coco F., Ades L. et al. Arsenic trioxide-based therapy of relapsed acute promyelocytic leukemia: updated results of the European registry of relapsed APL (PROMYSE). Blood 2013;122(21):1406.Lengfelder E., Lo-Coco F., Ades L. et al. Arsenic trioxide-based therapy of relapsed acute promyelocytic leukemia: updated results of the European registry of relapsed APL (PROMYSE). Blood 2013;122(21):1406.13. Thirugnanam R., George B., Chendamarai E. et al. Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen. Biol Blood Marrow Transplant 2009;15(11):1479–84.Thirugnanam R., George B., Chendamarai E. et al. Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen. Biol Blood Marrow Transplant 2009;15(11):1479–84.14. Yanada M., Tsuzuki M., Fujita H. et al. Japan Adult Leukemia Study Group. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood 2013;121(16):3095–102.Yanada M., Tsuzuki M., Fujita H. et al. Japan Adult Leukemia Study Group. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood 2013;121(16):3095–102.15. Fujita H., Asou N., Iwanaga M. et al. Role of hematopoietic stem cell transplantation for relapsed acute promyelocytic leukemia: a retrospective analysis of JALSG-APL97. Cancer Sci 2013;104(10):1339–45.Fujita H., Asou N., Iwanaga M. et al. Role of hematopoietic stem cell transplantation for relapsed acute promyelocytic leukemia: a retrospective analysis of JALSG-APL97. Cancer Sci 2013;104(10):1339–45.16. Pemmaraju N., Tanaka M. F., Ravandi F. et al. Outcomes in patients with relapsed or refractory acute promyelocytic leukemia treated with or without autologous or allogeneic hematopoietic stem cell transplantation. Clin Lymphoma Myeloma Leuk 2013;13(4):485–92.Pemmaraju N., Tanaka M. F., Ravandi F. et al. Outcomes in patients with relapsed or refractory acute promyelocytic leukemia treated with or without autologous or allogeneic hematopoietic stem cell transplantation. Clin Lymphoma Myeloma Leuk 2013;13(4):485–92.17. Байдильдина Д. Д., Масчан М. А., Скоробогатова Е. В. и др. Рецидивы острого промиелоцитарного лейкоза у детей: опыт терапии с применением триоксида мышьяка и трансплантации аутологичных гемопоэтических клеток. Терапевтический архив 2010;7:20–5. [Baydildina D. D., Maschan M. A., Skorobogatova E. V. et al. Recurrences of acute promyelocytic leukemia in children: experience with arsenic trioxide therapy and autologous hematopoietic cell transplantation. Terapevticheskiy arkhiv = Therapeutic Archive 2010;7:20–5. (In Russ.)].Байдильдина Д. Д., Масчан М. А., Скоробогатова Е. В. и др. Рецидивы острого промиелоцитарного лейкоза у детей: опыт терапии с применением триоксида мышьяка и трансплантации аутологичных гемопоэтических клеток. Терапевтический архив 2010;7:20–5. [Baydildina D. D., Maschan M. A., Skorobogatova E. V. et al. Recurrences of acute promyelocytic leukemia in children: experience with arsenic trioxide therapy and autologous hematopoietic cell transplantation. Terapevticheskiy arkhiv = Therapeutic Archive 2010;7:20–5. (In Russ.)].18. Goto E., Tomita A., Hayakawa F. et al. Missense mutations in PML-RARA are critical for the lack of responsiveness to arsenic trioxide treatment. Blood 2011;118(6):1600–9.Goto E., Tomita A., Hayakawa F. et al. Missense mutations in PML-RARA are critical for the lack of responsiveness to arsenic trioxide treatment. Blood 2011;118(6):1600–9.19. Ganesan S., Alex A. A., Chendamarai E. et al. Proteasome Activity is Dispensable for the Degradation of PML-RARα: Efficacy of Bortezomib Along with Arsenic Trioxide in the Treatment of Arsenic Sensitive and Resistant Acute Promyelocytic Leukemia. Blood 2014;124(21):3741.Ganesan S., Alex A. A., Chendamarai E. et al. Proteasome Activity is Dispensable for the Degradation of PML-RARα: Efficacy of Bortezomib Along with Arsenic Trioxide in the Treatment of Arsenic Sensitive and Resistant Acute Promyelocytic Leukemia. Blood 2014;124(21):3741.20. Sokolov A., Parovichnikova E., Savchenko V. et al. Long Remissions after Late Relapse of Acute Myeloid Leukemia (AML) with Idarubicin + Cytarabine Conventional Doses Treatment. In: Acute Leukemias IX. Basic Research, Experimental Approaches and Novel Therapies. . Hiddemann, T. Buchner, J. Ritter et al. (eds.). Springer-Verlag, Berlin Heidelberg, 2003. Pp. 404–407.Sokolov A., Parovichnikova E., Savchenko V. et al. Long Remissions after Late Relapse of Acute Myeloid Leukemia (AML) with Idarubicin + Cytarabine Conventional Doses Treatment. In: Acute Leukemias IX. Basic Research, Experimental Approaches and Novel Therapies. . Hiddemann, T. Buchner, J. Ritter et al. (eds.). Springer-Verlag, Berlin Heidelberg, 2003. Pp. 404–407.