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Problema de salud AUGE N° 45

Leucemia en personas de 15 años y más

Leucemia Aguda – Recomendación T2 – Juicio del Panel y Evidencia

T.2 En personas con leucemia linfoblástica aguda Philadelphia positivo Ph (+), el Ministerio de Salud SUGIERE utilizar inhibidores de tirosina quinasa más quimioterapia por sobre quimioterapia sola.
Comentarios del Panel de Expertos:
►El uso de inhibidores de tirosina quinasa aumenta la sobrevida global y sobrevida libre de enfermedad a largo plazo en personas con leucemia linfoblástica aguda Ph (+).

El Panel de Expertos analizó y debatió cada uno de las preguntas de la “Tabla de la evidencia a la decisión”, considerando tanto la evidencia de investigación, experiencia clínica, conocimiento de gestión o experiencia de los pacientes. Una vez consensuada la postura del panel respecto a las preguntas, emitieron un juicio seleccionando la opción de respuesta que mejor representaba la opinión del conjunto (destacada con color). Finalmente cuando el panel emitió su juicio sobre todas las preguntas, se emitió la recomendación.

A continuación se presenta la “Tabla de la evidencia a la decisión” con el resumen de los juicios, la evidencia de investigación evaluada, consideraciones adicionales y comentarios planteados por el panel.

 1.- ¿El problema es una prioridad?
No Probablemente no Probablemente sí Varía No lo sé

El problemade salud ha sido definido como prioritario de abordar a través de una Guía de Práctica Clínica por la División de Prevención y Control de Enfermedades del Ministerio de Salud. La pregunta ha sido priorizada por el equipo de esta Guía, ya sea porque existía variabilidad o incertidumbre.

 2.- ¿Qué tan significativos son los efectos deseables anticipados?
Trivial Pequeño Moderado Grande Varía No lo sé

Grandes: El equipo elaborador de la Guía estimó que los efectos deseables de «utilizar inhibidores de tirosina quinasa más quimioterapia» en comparación a «solo quimioterapia» son grandes, considerando la evidencia, experiencia clínica, conocimiento de gestión o experiencia de las personas con la condición o problema de salud.

Consideraciones Adicionales

El panel señala que el uso de inhibidores de tirosina kinasa aumenta la sobrevida global y sobrevida libre de enfermedad a largo plazo en pacientes con leucemia linfoblástica aguda Ph(+).

Evidencia de investigación

Tabla de Resumen de Resultados (Summary of Findings)

Inhibidores de tirosina kinasa para leucemia linfoblástica aguda Philadelphia positivo

 

Población

Personas con leucemia linfoblástica aguda Philadelphia positivo Ph (+).

 

Intervención

Inhibidores de tirosina kinasa más quimioterapia

 

Comparación

Quimioterapia.

 

Desenlaces

Efecto

Certeza de la evidencia

(GRADE)

Mensajes clave en términos sencillos

 
 

Impacto clínico

Se decidió no construir la tabla de resumen de resultados. Ver detalles en estimador del efecto.

 

GRADE: Grados de evidencia Grading of Recommendations Assessment, Development and Evaluation.
*Impacto clínico se refiere a cualquier desenlace que tenga impacto directo o indirecto en el manejo de los pacientes. Esto incluye a los desenlaces priorizados por el panel de expertos.
Fecha de elaboración de la tabla: Diciembre, 2018.

Referencias

1. Couban S, Savoie L, Mourad YA, Leber B, Minden M, Turner R, Palada V, Shehata N, Christofides A, Lachance S. Evidence-based guidelines for the use of tyrosine kinase inhibitors in adults with Philadelphia chromosome-positive or BCR-ABL-positive acute lymphoblastic leukemia: a Canadian consensus. Current oncology (Toronto, Ont.). 2014;21(2):e265-309.
2. Hoelzer D, Bassan R, Dombret H, Fielding A, Ribera JM, Buske C, ESMO Guidelines Committee. Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology : official journal of the European Society for Medical Oncology. 2016;27(suppl 5):v69-v82.
3. Brown PA, Shah B, Fathi A, Wieduwilt M, Advani A, Aoun P, Barta SK, Boyer MW, Bryan T, Burke PW, Cassaday R, Coccia PF, Coutre SE, Damon LE, DeAngelo DJ, Frankfurt O, Greer JP, Kantarjian HM, Klisovic RB, Kupfer G, Litzow M, Liu A, Mattison R, Park J, Rubnitz J, Saad A, Uy GL, Wang ES, Gregory KM, Ogba N. NCCN Guidelines Insights: Acute Lymphoblastic Leukemia, Version 1.2017. Journal of the National Comprehensive Cancer Network : JNCCN. 2017;15(9):1091-1102
4. Chalandon Y, Thomas X, Hayette S, Cayuela JM, Abbal C, Huguet F, Raffoux E, Leguay T, Rousselot P, Lepretre S, Escoffre-Barbe M, Maury S, Berthon C, Tavernier E, Lambert JF, Lafage-Pochitaloff M, Lhéritier V, Chevret S, Ifrah N, Dombret H; Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL). Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood. 2015 Jun 11;125(24):3711-9
5. Chiaretti S, Foà R. Management of adult Ph-positive acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2015;2015:406-13
6. Daver N, Thomas D, Ravandi F, Cortes J, Garris R, Jabbour E, Garcia-Manero G, Borthakur G, Kadia T, Rytting M, Konopleva M, Kantarjian H, O’Brien S. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the front-line treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Haematologica. 2015 May;100(5):653-61
7. Fielding AK. How I treat Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2010 Nov 4;116(18):3409-17
8. Gökbuget N. How I treat older patients with ALL. Blood. 2013 Aug 22;122(8):1366-75
9. Lee KH, Lee JH, Choi SJ, Lee JH, Seol M, Lee YS, Kim WK, Lee JS, Seo EJ, Jang S, Park CJ, Chi HS. Clinical effect of imatinib added to intensive combination chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia. 2005 Sep;19(9):1509-16
10. Leoni V, Biondi A. Tyrosine kinase inhibitors in BCR-ABL positive acute lymphoblastic leukemia. Haematologica. 2015 Mar;100(3):295-9
11. Ottmann OG, Larson RA, Kantarjian HM, le Coutre PD, Baccarani M, Hochhaus A, Kim DW, Fan X, Novick S, Giles FJ. Phase II study of nilotinib in patients with relapsed or refractory Philadelphia chromosome–positive acute lymphoblastic leukemia. Leukemia. 2013 Jun;27(6):1411-3
12. Ottmann OG, Pfeifer H. Management of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Hematology Am Soc Hematol Educ Program. 2009:371-81
13. Ottmann OG, Wassmann B, Pfeifer H, Giagounidis A, Stelljes M, Dührsen U, Schmalzing M, Wunderle L, Binckebanck A, Hoelzer D; GMALL Study Group. Imatinib compared with chemotherapy as front-line treatment of elderly patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Cancer. 2007 May 15;109(10):2068-76
14. Rousselot P, Cayuela JM, Hayette S, Récher C, Leguay T, Salanoubat C, Agape P.Dasatinib (Sprycel®) and low intensity chemotherapy for first-line treatment in elderly patients with de novo Philadelphia positive ALL (EWALL-PH-01): kinetic of response, resistance and prognostic significance. American Society of Hematology. 2010
15. Thomas DA, Faderl S, Cortes J, O’Brien S, Giles FJ, Kornblau SM, Garcia-Manero G, Keating MJ, Andreeff M, Jeha S, Beran M, Verstovsek S, Pierce S, Letvak L, Salvado A, Champlin R, Talpaz M, Kantarjian H. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004 Jun 15;103(12):4396-407
16. Vignetti M, Fazi P, Cimino G, Martinelli G, Di Raimondo F, Ferrara F, Meloni G, Ambrosetti A, Quarta G, Pagano L, Rege-Cambrin G, Elia L, Bertieri R, Annino L, Foà R, Baccarani M, Mandelli F. Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) LAL0201-B protocol. Blood. 2007 May 1;109(9):3676-8
17. Yanada M. Time to tune the treatment of Ph+ ALL. Blood. 2015 Jun 11;125(24):3674-5
18. AK F, SM R, HM L, al. et. Does imatinib change the outcome in Philadelphia chromosome positive acute lymphoblastic leukaemia in adults? Data from the ukallxii/ecog2993 Study. Blood [Internet]. 2007;110
19. AM C, Catania G, Pica G, al. et. Adult Philadelphia-positive acute lymphoblastic leukemia (Ph + all) treated at diagnosis with imatinib followed by 2nd line tki (imatinib or dasatinib) and stem cell transplantation. Blood [Internet]. 2009;114
20. Anderlini P, Sheth S, Hicks K, Ippoliti C, Giralt S, Champlin RE. Re: Imatinib mesylate administration in the first 100 days after stem cell transplantation. Biol Blood Marrow Transplant [Internet]. 2004 Dec 18;10(12):883–4
21. Arellano M, Muringampurath–John D, PJ S, al. et. Imatinib mesylate and hyper-cvad (im-hcvad) for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ all). Blood [Internet]. 2009;114
22. Aricò M, Valsecchi MG, Camitta B, Schrappe M, Chessells J, Baruchel A, et al. Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. N Engl J Med [Internet]. 2000;342(14):998–1006
23. Aricò M, Schrappe M, Hunger SP, Carroll WL, Conter V, Galimberti S, et al. Clinical outcome of children with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia treated between 1995 and 2005. J Clin Oncol Off J Am Soc Clin Oncol [Internet]. 2010;28(31):4755–61
24. Bachanova V, Marks DI, Zhang M-J, Wang H, de Lima M, Aljurf MD, et al. Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: impact of tyrosine kinase inhibitor and minimal residual disease. Leukemia [Internet]. 2014;28(3):658–65
25. Bassan R, Rossi G, EM P, al. et. Short chemotherapyphased imatinib (im) pulses improve long-term outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ all). Blood [Internet]. 2009;114
26. Bassan R, Rossi G, Pogliani EM, Di Bona E, Angelucci E, Cavattoni I, et al. Chemotherapy-phased imatinib pulses improve long-term outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: Northern Italy Leukemia Group protocol 09/00. J Clin Oncol Off J Am Soc Clin Oncol [Internet]. 2010;28(22):3644–52
27. Biondi A, Schrappe M, De Lorenzo P, Castor A, Lucchini G, Gandemer V, et al. Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study. Lancet Oncol [Internet]. 2012;13(9):936–45
28. Brave M, Goodman V, Kaminskas E, Farrell A, Timmer W, Pope S, et al. Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. Clin Cancer Res [Internet]. 2008;14(2):352–9
29. Burke MJ, Trotz B, Luo X, Baker KS, Weisdorf DJ, Wagner JE, et al. Allo-hematopoietic cell transplantation for Ph chromosome-positive ALL: impact of imatinib on relapse and survival. Bone Marrow Transplant [Internet]. 2009;43(2):107–13
30. Carpenter PA, Snyder DS, Flowers MED, Sanders JE, Gooley TA, Martin PJ, et al. Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome–positive leukemia. Blood [Internet]. 2007 Dec 18;109(7):2791–3
31. Chalandon Y, Thomas X, Hayette S, JM C, Abbal C, Huguet F, et al. Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood [Internet]. 2015 Dec 18;125(24):3711–9
32. Chang H, LY S. Imatinib-induced tumor lysis syndrome: report of a case and review of the literature. Chang Gung Med J [Internet]. 2008;31(5):510–4
33. Chiaretti S, Foà R. Management of adult Ph-positive acute lymphoblastic leukemia. ASH Educ Progr B [Internet]. 2015 Dec 18;2015(1):406–13
34. Cortes J, DW K, Raffoux E, Martinelli G, Ritchie E, Roy L, et al. Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase. Leuk Off J Leuk Soc Am Leuk Res Fund, UK [Internet]. 2008;22(12):2176–83
35. Cortes J, Rousselot P, DW K, Ritchie E, Hamerschlak N, Coutre S, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood [Internet]. 2007;109(8):3207–13
36. DA T, Faderl S, Cortes J, al et. Update of the hypercvad and imatinib mesylate regimen in Philadelphia (Ph) positive acute lymphocytic leukemia (all). Blood [Internet]. 2004;104
37. DA T, HM K, Cortes J, al. et. Outcome after frontline therapy with the hyper-cvad and imatinib mesylate regimen for adults with de novo or minimally treated Philadelphia chromosome (Ph) positive acute lymphoblastic leukemia (all). Blood [Internet]. 2008;112
38. DA T, SM O, Faderl S, al. et. Long-term outcome after hyper-cvad and imatinib (im) for de novo or minimally treated Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph-all). J Clin Oncol [Internet]. 2010;28
39. Daver N, Thomas D, Ravandi F, Cortes J, Garris R, Jabbour E, et al. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the front-line treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Haematologica [Internet]. 2015 Dec 18;100(5):653–61
40. de Labarthe A, Rousselot P, Huguet-Rigal F, Delabesse E, Witz F, Maury S, et al. Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood [Internet]. 2007;109(4):1408–13
41. Delannoy A, Delabesse E, Lhéritier V, Castaigne S, Rigal-Huguet F, Raffoux E, et al. Imatinib and methylprednisolone alternated with chemotherapy improve the outcome of elderly patients with Philadelphia-positive acute lymphoblastic leukemia: results of the GRAALL AFR09 study. Leukemia [Internet]. 2006;20(9):1526–32
42. Dombret H, Witz F, S DB, al. et. Imatinib combined with intensive ham chemotherapy as consolidation of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1-all). Preliminary results of the AFR03 phase i/ii study. Blood [Internet]. 2004;104
43. Fielding AK. How I treat Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood [Internet]. 2010;116(18):3409–17
44. Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, et al. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood [Internet]. 2014;123(6):843–50
45. Fielding AK, Rowe JM, Richards SM, Buck G, Moorman A V, Durrant IJ, et al. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood [Internet]. 2009;113(19):4489–96
46. Foà R, Vitale A, Vignetti M, Meloni G, Guarini A, De Propris MS, et al. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood [Internet]. 2011;118(25):6521–8
47. Gleissner B, Gökbuget N, Bartram CR, Janssen B, Rieder H, Janssen JWG, et al. Leading prognostic relevance of the BCR-ABL translocation in adult acute B-lineage lymphoblastic leukemia: a prospective study of the German Multicenter Trial Group and confirmed polymerase chain reaction analysis. Blood [Internet]. 2002;99(5):1536–43
48. Hematology AS of. Chalandon Y, Thomas X, Hayette S, et al; Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL). Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood. 2015;125(24):3711-3719. Blood [Internet]. 2015 Dec 18;126(10):1261
49. Jabbour E, Kantarjian HM, Thomas DA, Sasaki K, Ravandi F, Cortes JE, et al. Phase II Study of Combination of Hypercvad with Ponatinib in Front Line Therapy of Patients (pts) with Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL). Blood [Internet]. 2014 Dec 18;124(21):2289
50. JM R, Oriol A, Gonzalez M, al. et. Treatment of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (all) with concurrent chemotherapy and imatinib mesylate. Blood [Internet]. 2004;104
51. Kantarjian H, Giles F, Wunderle L, Bhalla K, O’Brien S, Wassmann B, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med [Internet]. 2006;354(24):2542–51
52. Kantarjian HM, O’Brien S, Smith TL, Cortes J, Giles FJ, Beran M, et al. Results of Treatment With Hyper-CVAD, a Dose-Intensive Regimen, in Adult Acute Lymphocytic Leukemia. J Clin Oncol [Internet]. 2016 Dec 18
53. Koskenvesa P, Kreutzman A, Rohon P, Pihlman M, Vakkila E, Räsänen A, et al. Imatinib and pegylated IFN-α2b discontinuation in first-line chronic myeloid leukemia patients following a major molecular response. Eur J Haematol [Internet]. 2014;92(5):413–20
54. KR S, WP B, Aledo A, WB S, Sather H, Devidas M, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children’s oncology group study. J Clin Oncol [Internet]. 2009;27(31):5175–81
55. Lee K-H, Lee J-SJ-H, Choi S-J, Seol M, Lee Y-S, Kim W-K, et al. Clinical effect of imatinib added to intensive combination chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia | Leukemia. Leukemia [Internet]. 2018 Dec 18;19(9):1509–16
56. Lee S, DW K, YJ K, al. et. Minimal residual disease-based role of imatinib as a first-line interim therapy prior to allogeneic stem cell transplantation in Philadelphia chromosome–positive acute lymphoblastic leukemia. Blood [Internet]. 2003;102:3068–70
57. Lee S, Kim D-W, Cho B, Kim Y-J, Kim Y-L, Hwang J-Y, et al. Risk factors for adults with Philadelphia-chromosome-positive acute lymphoblastic leukaemia in remission treated with allogeneic bone marrow transplantation: the potential of real-time quantitative reverse-transcription polymerase chain reaction. Br J Haematol [Internet]. 2003;120(1):145–53
58. Lee S, Kim Y-J, Min C-K, Kim H-J, Eom K-S, Kim D-W, et al. The effect of first-line imatinib interim therapy on the outcome of allogeneic stem cell transplantation in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood [Internet]. 2005;105(9):3449–57
59. Leoni V, Biondi A. Tyrosine kinase inhibitors in BCR-ABL positive acute lymphoblastic leukemia. Haematologica [Internet]. 2015 Dec 18;100(3):295–9
60. Lesokhin AM, Ansell SM, Armand P, Scott EC, Halwani A, Gutierrez M, et al. Preliminary Results of a Phase I Study of Nivolumab (BMS-936558) in Patients with Relapsed or Refractory Lymphoid Malignancies. Blood [Internet]. 2014;124(21):291
61. Marks DI, Wang T, Pérez WS, Antin JH, Copelan E, Gale RP, et al. The outcome of full-intensity and reduced-intensity conditioning matched sibling or unrelated donor transplantation in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first and second complete remission. Blood [Internet]. 2010;116(3):366–74
62. MB L, OG O, NP S, RA L, JJ R, Ehninger G, et al. Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: Results from a phase 3 study. Am J Hematol [Internet]. 2010;85(3):164–70
63. OG O, RA L, HM K, al. et. Nilotinib in patients (pts) with relapsed/refractory Philadelphia chromosome– positive acute lymphoblastic leukemia (Ph+ all) who are resistant or intolerant to imatinib. Blood [Internet]. 2007;110
64. OG O, Wassmann B, Pfeifer H, Giagounidis A, Stelljes M, Dührsen U, et al. Imatinib compared with chemotherapy as front-line treatment of elderly patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Cancer [Internet]. 2007 Dec 18;109(10):2068–76
65. Olivieri A, Locatelli F, Zecca M, Sanna A, Cimminiello M, Raimondi R, et al. Imatinib for refractory chronic graft-versus-host disease with fibrotic features. Blood [Internet]. 2009;114(3):709–18
66. Ottmann OG, Larson RA, Kantarjian HM, le Coutre PD, Baccarani M, Hochhaus A, et al. Phase II study of nilotinib in patients with relapsed or refractory Philadelphia chromosome—positive acute lymphoblastic leukemia. Leukemia [Internet]. 2013 Dec 18;27(6):1411–3
67. Ottmann O, Dombret H, Martinelli G, al. et, Simonsson B, Guilhot F, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood [Internet]. 2007;110(7):2309–15
68. Ottmann OG, Druker BJ, Sawyers CL, Goldman JM, Reiffers J, Silver RT, et al. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood [Internet]. 2002;100(6):1965–71
69. Ottmann OG, Pfeifer H. Management of Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL). ASH Educ Progr B [Internet]. 2009 Dec 18;2009(1):371–81
70. Ottmann OG, Pfeifer H, Cayuela J-M, Spiekermann K, Beck J, Jung WE, et al. Nilotinib (Tasigna®) and Chemotherapy for First-Line Treatment in Elderly Patients with De Novo Philadelphia Chromosome/BCR-ABL1 Positive Acute Lymphoblastic Leukemia (ALL): A Trial of the European Working Group for Adult ALL (EWALL-PH-02). Blood [Internet]. 2014 Dec 18;124(21):798
71. Pfeifer H, Goekbuget N, Volp C, al. et. Long-term outcome of 335 adult patients receiving different schedules of imatinib and chemotherapy as front-line treatment for Philadelphia-positive acute lymphoblastic leukemia (Ph+ all). Blood [Internet]. 2010;116
72. Pfeifer H, Wassmann B, Bethge W, Dengler J, Bornhäuser M, Stadler M, et al. Randomized comparison of prophylactic and minimal residual disease-triggered imatinib after allogeneic stem cell transplantation for BCR-ABL1-positive acute lymphoblastic leukemia. Leukemia [Internet]. 2013;27(6):1254–62
73. Pfeifer H, Wassmann B, Kabisch A, al. et. Imatinib and interferon- alpha maintenance therapy for patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+ all) ineligible for allogeneic stem cell transplantation (sct). Blood [Internet]. 2009;114:2042
74. Pfeifer H, Wassmann B, WA B, al. et. Updated long-term results of a randomized comparison of prophylactic and pre-emptive imatinib following allogeneic stem cell transplantation for Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ all). ASH Annu Meet Abstr [Internet]. 2011;118
75. Pui C-H, Evans WE. Treatment of Acute Lymphoblastic Leukemia. N Engl J Med [Internet]. 2006 Dec 18;354(2):166–78
76. Ravandi F, O’Brien S, Thomas D, Faderl S, Jones D, Garris R, et al. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood [Internet]. 2010 Dec 18;116(12):2070–7
77. Ribera J-M, Oriol A, González M, Vidriales B, Brunet S, Esteve J, et al. Concurrent intensive chemotherapy and imatinib before and after stem cell transplantation in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Final results of the CSTIBES02 trial. Haematologica [Internet]. 2010;95(1):87–95
78. Rousselot P, Cayuela JM, Hayette S, Récher C, Leguay T, Salanoubat C, et al. Dasatinib (Sprycel®) and Low Intensity Chemotherapy for First-Line Treatment In Elderly Patients with De Novo Philadelphia Positive ALL (EWALL-PH-01): Kinetic of Response, Resistance and Prognostic Significance. Blood [Internet]. 2010 Dec 18;116(21):172
79. Rousselot P, Coudé MM, Huguet F, Lafage M, Leguay T, Salanoubat C, et al. Dasatinib (Sprycel®) and Low Intensity Chemotherapy for First-Line Treatment in Patients with De Novo Philadelphia Positive ALL Aged 55 and Over: Final Results of the EWALL-Ph-01 Study. Blood [Internet]. 2012 Dec 18;120(21):666
80. Saglio G, Hochhaus A, YT G, Masszi T, Pasquini R, Maloisel F, et al. Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer [Internet]. 2010;116(16):3852–61
81. Sakamaki H, Ishizawa K, Taniwaki M, Fujisawa S, Morishima Y, Tobinai K, et al. Phase 1/2 clinical study of dasatinib in Japanese patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. Int J Hematol [Internet]. 2009;89(3):332–41
82. Schlegel P, Lang P, Zugmaier G, Ebinger M, Kreyenberg H, Witte K-E, et al. Pediatric posttransplant relapsed/refractory B-precursor acute lymphoblastic leukemia shows durable remission by therapy with the T-cell engaging bispecific antibody blinatumomab. Haematologica [Internet]. 2014;99(7):1212–9
83. Schultz KR, Carroll A, Heerema NA, Bowman WP, Aledo A, Slayton WB, et al. Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children’s Oncology Group study AALL0031. Leukemia [Internet]. 2014;28(7):1467–71
84. Squibb B-M. Advanced Chronic Myelogenous Leukemia (CML) – Follow On: Study of BMS-354825 in Subjects With CML. clinicaltrials.gov [Internet]. 2005
85. Stirewalt DL, Guthrie KA, Beppu L, Bryant EM, Doney K, Gooley T, et al. Predictors of relapse and overall survival in Philadelphia chromosome-positive acute lymphoblastic leukemia after transplantation. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant [Internet]. 2003;9(3):206–12
86. Talpaz M, NP S, Kantarjian H, Donato N, Nicoll J, Paquette R, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med [Internet]. 2006;354(24):2531–41
87. Thomas DA, Faderl S, Cortes J, O’Brien S, Giles FJ, Kornblau SM, et al. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood [Internet]. 2004 Dec 18;103(12):4396–407
88. Tojo A, Usuki K, Urabe A, Maeda Y, Kobayashi Y, Jinnai I, et al. A Phase I/II study of nilotinib in Japanese patients with imatinib-resistant or -intolerant Ph+ CML or relapsed/refractory Ph+ ALL. Int J Hematol [Internet]. 2009;89(5):679–88
89. Topp MS, Kufer P, Gökbuget N, Goebeler M, Klinger M, Neumann S, et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol Off J Am Soc Clin Oncol [Internet]. 2011;29(18):2493–8
90. Vignetti M, Fazi P, Cimino G, Martinelli G, Raimondo F Di, Ferrara F, et al. Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) LAL0201-B protocol. Blood [Internet]. 2007 Dec 18;109(9):3676–8
91. Wassmann B, Gökbuget N, UJ S, Binckebanck A, Reutzel R, Gschaidmeier H, et al. A randomized multicenter open label phase II study to determine the safety and efficacy of induction therapy with imatinib (Glivec, formerly STI571) in comparison with standard induction chemotherapy in elderly (>55 years) patients with Philadelphia chromosome-positive (Ph+/BCR-ABL+) acute lymphoblastic leukemia (ALL) (CSTI571ADE 10). Ann Hematol [Internet]. 2003;82(11):716–20
92. Wassmann B, Pfeifer H, Goekbuget N, Beelen DW, Beck J, Stelljes M, et al. Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood [Internet]. 2006;108(5):1469–77
93. Wassmann B, Pfeifer H, Stadler M, Bornhaüser M, Bug G, Scheuring UJ, et al. Early molecular response to posttransplantation imatinib determines outcome in MRD+ Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood [Internet]. 2005;106(2):458–63
94. Wetzler M, Stock W, Owzar K, al. et. Sequential imatinib and chemotherapy yield reverse-transcriptase polymerase chain reaction (rt-pcr)–negative peripheral stem cell collections in Philadelphia (Ph) chromosome positive acute lymphoblastic leukemia (all)—preliminary results of calgb 10001. J Clin Oncol [Internet]. 2006;24
95. Yanada M. Time to tune the treatment of Ph+ ALL. Blood [Internet]. 2015 Dec 18;125(24):3674–5
96. Yanada M, Sugiura I, Takeuchi J, Akiyama H, Maruta A, Ueda Y, et al. Prospective monitoring of BCR-ABL1 transcript levels in patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia undergoing imatinib-combined chemotherapy. Br J Haematol [Internet]. 2008;143(4):503–10
97. Yanada M, Takeuchi J, Sugiura I, Akiyama H, Usui N, Yagasaki F, et al. High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol [Internet]. 2006;24(3):460–6

Búsqueda y Síntesis de Evidencia

 3.- ¿Qué tan significativos son los efectos indeseables anticipados?
Grande Moderado Pequeño Trivial Varía No lo sé

Pequeños: El equipo elaborador de la Guía estimó que los efectos indeseables de «utilizar inhibidores de tirosina quinasa más quimioterapia» en comparación a «solo quimioterapia» son pequeños, considerando la evidencia, experiencia clínica, conocimiento de gestión o experiencia de las personas con la condición o problema de salud.

Consideraciones Adicionales

Los efectos adversos varían dependiendo de cada inhibidor de tirosina kinasa. Sin embargo, la mayoría de estos efectos son leves y tratables.

Evidencia de investigación

Tabla de Resumen de Resultados (Summary of Findings)

Inhibidores de tirosina kinasa para leucemia linfoblástica aguda Philadelphia positivo

 

Población

Personas con leucemia linfoblástica aguda Philadelphia positivo Ph (+).

 

Intervención

Inhibidores de tirosina kinasa más quimioterapia

 

Comparación

Quimioterapia.

 

Desenlaces

Efecto

Certeza de la evidencia

(GRADE)

Mensajes clave en términos sencillos

 
 

Impacto clínico

Se decidió no construir la tabla de resumen de resultados. Ver detalles en estimador del efecto.

 

GRADE: Grados de evidencia Grading of Recommendations Assessment, Development and Evaluation.
*Impacto clínico se refiere a cualquier desenlace que tenga impacto directo o indirecto en el manejo de los pacientes. Esto incluye a los desenlaces priorizados por el panel de expertos.
Fecha de elaboración de la tabla: Diciembre, 2018.

Referencias

1. Couban S, Savoie L, Mourad YA, Leber B, Minden M, Turner R, Palada V, Shehata N, Christofides A, Lachance S. Evidence-based guidelines for the use of tyrosine kinase inhibitors in adults with Philadelphia chromosome-positive or BCR-ABL-positive acute lymphoblastic leukemia: a Canadian consensus. Current oncology (Toronto, Ont.). 2014;21(2):e265-309.
2. Hoelzer D, Bassan R, Dombret H, Fielding A, Ribera JM, Buske C, ESMO Guidelines Committee. Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology : official journal of the European Society for Medical Oncology. 2016;27(suppl 5):v69-v82.
3. Brown PA, Shah B, Fathi A, Wieduwilt M, Advani A, Aoun P, Barta SK, Boyer MW, Bryan T, Burke PW, Cassaday R, Coccia PF, Coutre SE, Damon LE, DeAngelo DJ, Frankfurt O, Greer JP, Kantarjian HM, Klisovic RB, Kupfer G, Litzow M, Liu A, Mattison R, Park J, Rubnitz J, Saad A, Uy GL, Wang ES, Gregory KM, Ogba N. NCCN Guidelines Insights: Acute Lymphoblastic Leukemia, Version 1.2017. Journal of the National Comprehensive Cancer Network : JNCCN. 2017;15(9):1091-1102
4. Chalandon Y, Thomas X, Hayette S, Cayuela JM, Abbal C, Huguet F, Raffoux E, Leguay T, Rousselot P, Lepretre S, Escoffre-Barbe M, Maury S, Berthon C, Tavernier E, Lambert JF, Lafage-Pochitaloff M, Lhéritier V, Chevret S, Ifrah N, Dombret H; Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL). Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood. 2015 Jun 11;125(24):3711-9
5. Chiaretti S, Foà R. Management of adult Ph-positive acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2015;2015:406-13
6. Daver N, Thomas D, Ravandi F, Cortes J, Garris R, Jabbour E, Garcia-Manero G, Borthakur G, Kadia T, Rytting M, Konopleva M, Kantarjian H, O’Brien S. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the front-line treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Haematologica. 2015 May;100(5):653-61
7. Fielding AK. How I treat Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2010 Nov 4;116(18):3409-17
8. Gökbuget N. How I treat older patients with ALL. Blood. 2013 Aug 22;122(8):1366-75
9. Lee KH, Lee JH, Choi SJ, Lee JH, Seol M, Lee YS, Kim WK, Lee JS, Seo EJ, Jang S, Park CJ, Chi HS. Clinical effect of imatinib added to intensive combination chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia. 2005 Sep;19(9):1509-16
10. Leoni V, Biondi A. Tyrosine kinase inhibitors in BCR-ABL positive acute lymphoblastic leukemia. Haematologica. 2015 Mar;100(3):295-9
11. Ottmann OG, Larson RA, Kantarjian HM, le Coutre PD, Baccarani M, Hochhaus A, Kim DW, Fan X, Novick S, Giles FJ. Phase II study of nilotinib in patients with relapsed or refractory Philadelphia chromosome–positive acute lymphoblastic leukemia. Leukemia. 2013 Jun;27(6):1411-3
12. Ottmann OG, Pfeifer H. Management of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Hematology Am Soc Hematol Educ Program. 2009:371-81
13. Ottmann OG, Wassmann B, Pfeifer H, Giagounidis A, Stelljes M, Dührsen U, Schmalzing M, Wunderle L, Binckebanck A, Hoelzer D; GMALL Study Group. Imatinib compared with chemotherapy as front-line treatment of elderly patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Cancer. 2007 May 15;109(10):2068-76
14. Rousselot P, Cayuela JM, Hayette S, Récher C, Leguay T, Salanoubat C, Agape P.Dasatinib (Sprycel®) and low intensity chemotherapy for first-line treatment in elderly patients with de novo Philadelphia positive ALL (EWALL-PH-01): kinetic of response, resistance and prognostic significance. American Society of Hematology. 2010
15. Thomas DA, Faderl S, Cortes J, O’Brien S, Giles FJ, Kornblau SM, Garcia-Manero G, Keating MJ, Andreeff M, Jeha S, Beran M, Verstovsek S, Pierce S, Letvak L, Salvado A, Champlin R, Talpaz M, Kantarjian H. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004 Jun 15;103(12):4396-407
16. Vignetti M, Fazi P, Cimino G, Martinelli G, Di Raimondo F, Ferrara F, Meloni G, Ambrosetti A, Quarta G, Pagano L, Rege-Cambrin G, Elia L, Bertieri R, Annino L, Foà R, Baccarani M, Mandelli F. Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) LAL0201-B protocol. Blood. 2007 May 1;109(9):3676-8
17. Yanada M. Time to tune the treatment of Ph+ ALL. Blood. 2015 Jun 11;125(24):3674-5
18. AK F, SM R, HM L, al. et. Does imatinib change the outcome in Philadelphia chromosome positive acute lymphoblastic leukaemia in adults? Data from the ukallxii/ecog2993 Study. Blood [Internet]. 2007;110
19. AM C, Catania G, Pica G, al. et. Adult Philadelphia-positive acute lymphoblastic leukemia (Ph + all) treated at diagnosis with imatinib followed by 2nd line tki (imatinib or dasatinib) and stem cell transplantation. Blood [Internet]. 2009;114
20. Anderlini P, Sheth S, Hicks K, Ippoliti C, Giralt S, Champlin RE. Re: Imatinib mesylate administration in the first 100 days after stem cell transplantation. Biol Blood Marrow Transplant [Internet]. 2004 Dec 18;10(12):883–4
21. Arellano M, Muringampurath–John D, PJ S, al. et. Imatinib mesylate and hyper-cvad (im-hcvad) for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ all). Blood [Internet]. 2009;114
22. Aricò M, Valsecchi MG, Camitta B, Schrappe M, Chessells J, Baruchel A, et al. Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. N Engl J Med [Internet]. 2000;342(14):998–1006
23. Aricò M, Schrappe M, Hunger SP, Carroll WL, Conter V, Galimberti S, et al. Clinical outcome of children with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia treated between 1995 and 2005. J Clin Oncol Off J Am Soc Clin Oncol [Internet]. 2010;28(31):4755–61
24. Bachanova V, Marks DI, Zhang M-J, Wang H, de Lima M, Aljurf MD, et al. Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: impact of tyrosine kinase inhibitor and minimal residual disease. Leukemia [Internet]. 2014;28(3):658–65
25. Bassan R, Rossi G, EM P, al. et. Short chemotherapyphased imatinib (im) pulses improve long-term outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ all). Blood [Internet]. 2009;114
26. Bassan R, Rossi G, Pogliani EM, Di Bona E, Angelucci E, Cavattoni I, et al. Chemotherapy-phased imatinib pulses improve long-term outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: Northern Italy Leukemia Group protocol 09/00. J Clin Oncol Off J Am Soc Clin Oncol [Internet]. 2010;28(22):3644–52
27. Biondi A, Schrappe M, De Lorenzo P, Castor A, Lucchini G, Gandemer V, et al. Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study. Lancet Oncol [Internet]. 2012;13(9):936–45
28. Brave M, Goodman V, Kaminskas E, Farrell A, Timmer W, Pope S, et al. Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. Clin Cancer Res [Internet]. 2008;14(2):352–9
29. Burke MJ, Trotz B, Luo X, Baker KS, Weisdorf DJ, Wagner JE, et al. Allo-hematopoietic cell transplantation for Ph chromosome-positive ALL: impact of imatinib on relapse and survival. Bone Marrow Transplant [Internet]. 2009;43(2):107–13
30. Carpenter PA, Snyder DS, Flowers MED, Sanders JE, Gooley TA, Martin PJ, et al. Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome–positive leukemia. Blood [Internet]. 2007 Dec 18;109(7):2791–3
31. Chalandon Y, Thomas X, Hayette S, JM C, Abbal C, Huguet F, et al. Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood [Internet]. 2015 Dec 18;125(24):3711–9
32. Chang H, LY S. Imatinib-induced tumor lysis syndrome: report of a case and review of the literature. Chang Gung Med J [Internet]. 2008;31(5):510–4
33. Chiaretti S, Foà R. Management of adult Ph-positive acute lymphoblastic leukemia. ASH Educ Progr B [Internet]. 2015 Dec 18;2015(1):406–13
34. Cortes J, DW K, Raffoux E, Martinelli G, Ritchie E, Roy L, et al. Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase. Leuk Off J Leuk Soc Am Leuk Res Fund, UK [Internet]. 2008;22(12):2176–83
35. Cortes J, Rousselot P, DW K, Ritchie E, Hamerschlak N, Coutre S, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood [Internet]. 2007;109(8):3207–13
36. DA T, Faderl S, Cortes J, al et. Update of the hypercvad and imatinib mesylate regimen in Philadelphia (Ph) positive acute lymphocytic leukemia (all). Blood [Internet]. 2004;104
37. DA T, HM K, Cortes J, al. et. Outcome after frontline therapy with the hyper-cvad and imatinib mesylate regimen for adults with de novo or minimally treated Philadelphia chromosome (Ph) positive acute lymphoblastic leukemia (all). Blood [Internet]. 2008;112
38. DA T, SM O, Faderl S, al. et. Long-term outcome after hyper-cvad and imatinib (im) for de novo or minimally treated Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph-all). J Clin Oncol [Internet]. 2010;28
39. Daver N, Thomas D, Ravandi F, Cortes J, Garris R, Jabbour E, et al. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the front-line treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Haematologica [Internet]. 2015 Dec 18;100(5):653–61
40. de Labarthe A, Rousselot P, Huguet-Rigal F, Delabesse E, Witz F, Maury S, et al. Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood [Internet]. 2007;109(4):1408–13
41. Delannoy A, Delabesse E, Lhéritier V, Castaigne S, Rigal-Huguet F, Raffoux E, et al. Imatinib and methylprednisolone alternated with chemotherapy improve the outcome of elderly patients with Philadelphia-positive acute lymphoblastic leukemia: results of the GRAALL AFR09 study. Leukemia [Internet]. 2006;20(9):1526–32
42. Dombret H, Witz F, S DB, al. et. Imatinib combined with intensive ham chemotherapy as consolidation of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1-all). Preliminary results of the AFR03 phase i/ii study. Blood [Internet]. 2004;104
43. Fielding AK. How I treat Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood [Internet]. 2010;116(18):3409–17
44. Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, et al. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood [Internet]. 2014;123(6):843–50
45. Fielding AK, Rowe JM, Richards SM, Buck G, Moorman A V, Durrant IJ, et al. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood [Internet]. 2009;113(19):4489–96
46. Foà R, Vitale A, Vignetti M, Meloni G, Guarini A, De Propris MS, et al. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood [Internet]. 2011;118(25):6521–8
47. Gleissner B, Gökbuget N, Bartram CR, Janssen B, Rieder H, Janssen JWG, et al. Leading prognostic relevance of the BCR-ABL translocation in adult acute B-lineage lymphoblastic leukemia: a prospective study of the German Multicenter Trial Group and confirmed polymerase chain reaction analysis. Blood [Internet]. 2002;99(5):1536–43
48. Hematology AS of. Chalandon Y, Thomas X, Hayette S, et al; Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL). Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood. 2015;125(24):3711-3719. Blood [Internet]. 2015 Dec 18;126(10):1261
49. Jabbour E, Kantarjian HM, Thomas DA, Sasaki K, Ravandi F, Cortes JE, et al. Phase II Study of Combination of Hypercvad with Ponatinib in Front Line Therapy of Patients (pts) with Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL). Blood [Internet]. 2014 Dec 18;124(21):2289
50. JM R, Oriol A, Gonzalez M, al. et. Treatment of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (all) with concurrent chemotherapy and imatinib mesylate. Blood [Internet]. 2004;104
51. Kantarjian H, Giles F, Wunderle L, Bhalla K, O’Brien S, Wassmann B, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med [Internet]. 2006;354(24):2542–51
52. Kantarjian HM, O’Brien S, Smith TL, Cortes J, Giles FJ, Beran M, et al. Results of Treatment With Hyper-CVAD, a Dose-Intensive Regimen, in Adult Acute Lymphocytic Leukemia. J Clin Oncol [Internet]. 2016 Dec 18
53. Koskenvesa P, Kreutzman A, Rohon P, Pihlman M, Vakkila E, Räsänen A, et al. Imatinib and pegylated IFN-α2b discontinuation in first-line chronic myeloid leukemia patients following a major molecular response. Eur J Haematol [Internet]. 2014;92(5):413–20
54. KR S, WP B, Aledo A, WB S, Sather H, Devidas M, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children’s oncology group study. J Clin Oncol [Internet]. 2009;27(31):5175–81
55. Lee K-H, Lee J-SJ-H, Choi S-J, Seol M, Lee Y-S, Kim W-K, et al. Clinical effect of imatinib added to intensive combination chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia | Leukemia. Leukemia [Internet]. 2018 Dec 18;19(9):1509–16
56. Lee S, DW K, YJ K, al. et. Minimal residual disease-based role of imatinib as a first-line interim therapy prior to allogeneic stem cell transplantation in Philadelphia chromosome–positive acute lymphoblastic leukemia. Blood [Internet]. 2003;102:3068–70
57. Lee S, Kim D-W, Cho B, Kim Y-J, Kim Y-L, Hwang J-Y, et al. Risk factors for adults with Philadelphia-chromosome-positive acute lymphoblastic leukaemia in remission treated with allogeneic bone marrow transplantation: the potential of real-time quantitative reverse-transcription polymerase chain reaction. Br J Haematol [Internet]. 2003;120(1):145–53
58. Lee S, Kim Y-J, Min C-K, Kim H-J, Eom K-S, Kim D-W, et al. The effect of first-line imatinib interim therapy on the outcome of allogeneic stem cell transplantation in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood [Internet]. 2005;105(9):3449–57
59. Leoni V, Biondi A. Tyrosine kinase inhibitors in BCR-ABL positive acute lymphoblastic leukemia. Haematologica [Internet]. 2015 Dec 18;100(3):295–9
60. Lesokhin AM, Ansell SM, Armand P, Scott EC, Halwani A, Gutierrez M, et al. Preliminary Results of a Phase I Study of Nivolumab (BMS-936558) in Patients with Relapsed or Refractory Lymphoid Malignancies. Blood [Internet]. 2014;124(21):291
61. Marks DI, Wang T, Pérez WS, Antin JH, Copelan E, Gale RP, et al. The outcome of full-intensity and reduced-intensity conditioning matched sibling or unrelated donor transplantation in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first and second complete remission. Blood [Internet]. 2010;116(3):366–74
62. MB L, OG O, NP S, RA L, JJ R, Ehninger G, et al. Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: Results from a phase 3 study. Am J Hematol [Internet]. 2010;85(3):164–70
63. OG O, RA L, HM K, al. et. Nilotinib in patients (pts) with relapsed/refractory Philadelphia chromosome– positive acute lymphoblastic leukemia (Ph+ all) who are resistant or intolerant to imatinib. Blood [Internet]. 2007;110
64. OG O, Wassmann B, Pfeifer H, Giagounidis A, Stelljes M, Dührsen U, et al. Imatinib compared with chemotherapy as front-line treatment of elderly patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Cancer [Internet]. 2007 Dec 18;109(10):2068–76
65. Olivieri A, Locatelli F, Zecca M, Sanna A, Cimminiello M, Raimondi R, et al. Imatinib for refractory chronic graft-versus-host disease with fibrotic features. Blood [Internet]. 2009;114(3):709–18
66. Ottmann OG, Larson RA, Kantarjian HM, le Coutre PD, Baccarani M, Hochhaus A, et al. Phase II study of nilotinib in patients with relapsed or refractory Philadelphia chromosome—positive acute lymphoblastic leukemia. Leukemia [Internet]. 2013 Dec 18;27(6):1411–3
67. Ottmann O, Dombret H, Martinelli G, al. et, Simonsson B, Guilhot F, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood [Internet]. 2007;110(7):2309–15
68. Ottmann OG, Druker BJ, Sawyers CL, Goldman JM, Reiffers J, Silver RT, et al. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood [Internet]. 2002;100(6):1965–71
69. Ottmann OG, Pfeifer H. Management of Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL). ASH Educ Progr B [Internet]. 2009 Dec 18;2009(1):371–81
70. Ottmann OG, Pfeifer H, Cayuela J-M, Spiekermann K, Beck J, Jung WE, et al. Nilotinib (Tasigna®) and Chemotherapy for First-Line Treatment in Elderly Patients with De Novo Philadelphia Chromosome/BCR-ABL1 Positive Acute Lymphoblastic Leukemia (ALL): A Trial of the European Working Group for Adult ALL (EWALL-PH-02). Blood [Internet]. 2014 Dec 18;124(21):798
71. Pfeifer H, Goekbuget N, Volp C, al. et. Long-term outcome of 335 adult patients receiving different schedules of imatinib and chemotherapy as front-line treatment for Philadelphia-positive acute lymphoblastic leukemia (Ph+ all). Blood [Internet]. 2010;116
72. Pfeifer H, Wassmann B, Bethge W, Dengler J, Bornhäuser M, Stadler M, et al. Randomized comparison of prophylactic and minimal residual disease-triggered imatinib after allogeneic stem cell transplantation for BCR-ABL1-positive acute lymphoblastic leukemia. Leukemia [Internet]. 2013;27(6):1254–62
73. Pfeifer H, Wassmann B, Kabisch A, al. et. Imatinib and interferon- alpha maintenance therapy for patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+ all) ineligible for allogeneic stem cell transplantation (sct). Blood [Internet]. 2009;114:2042
74. Pfeifer H, Wassmann B, WA B, al. et. Updated long-term results of a randomized comparison of prophylactic and pre-emptive imatinib following allogeneic stem cell transplantation for Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ all). ASH Annu Meet Abstr [Internet]. 2011;118
75. Pui C-H, Evans WE. Treatment of Acute Lymphoblastic Leukemia. N Engl J Med [Internet]. 2006 Dec 18;354(2):166–78
76. Ravandi F, O’Brien S, Thomas D, Faderl S, Jones D, Garris R, et al. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood [Internet]. 2010 Dec 18;116(12):2070–7
77. Ribera J-M, Oriol A, González M, Vidriales B, Brunet S, Esteve J, et al. Concurrent intensive chemotherapy and imatinib before and after stem cell transplantation in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Final results of the CSTIBES02 trial. Haematologica [Internet]. 2010;95(1):87–95
78. Rousselot P, Cayuela JM, Hayette S, Récher C, Leguay T, Salanoubat C, et al. Dasatinib (Sprycel®) and Low Intensity Chemotherapy for First-Line Treatment In Elderly Patients with De Novo Philadelphia Positive ALL (EWALL-PH-01): Kinetic of Response, Resistance and Prognostic Significance. Blood [Internet]. 2010 Dec 18;116(21):172
79. Rousselot P, Coudé MM, Huguet F, Lafage M, Leguay T, Salanoubat C, et al. Dasatinib (Sprycel®) and Low Intensity Chemotherapy for First-Line Treatment in Patients with De Novo Philadelphia Positive ALL Aged 55 and Over: Final Results of the EWALL-Ph-01 Study. Blood [Internet]. 2012 Dec 18;120(21):666
80. Saglio G, Hochhaus A, YT G, Masszi T, Pasquini R, Maloisel F, et al. Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer [Internet]. 2010;116(16):3852–61
81. Sakamaki H, Ishizawa K, Taniwaki M, Fujisawa S, Morishima Y, Tobinai K, et al. Phase 1/2 clinical study of dasatinib in Japanese patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. Int J Hematol [Internet]. 2009;89(3):332–41
82. Schlegel P, Lang P, Zugmaier G, Ebinger M, Kreyenberg H, Witte K-E, et al. Pediatric posttransplant relapsed/refractory B-precursor acute lymphoblastic leukemia shows durable remission by therapy with the T-cell engaging bispecific antibody blinatumomab. Haematologica [Internet]. 2014;99(7):1212–9
83. Schultz KR, Carroll A, Heerema NA, Bowman WP, Aledo A, Slayton WB, et al. Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children’s Oncology Group study AALL0031. Leukemia [Internet]. 2014;28(7):1467–71
84. Squibb B-M. Advanced Chronic Myelogenous Leukemia (CML) – Follow On: Study of BMS-354825 in Subjects With CML. clinicaltrials.gov [Internet]. 2005
85. Stirewalt DL, Guthrie KA, Beppu L, Bryant EM, Doney K, Gooley T, et al. Predictors of relapse and overall survival in Philadelphia chromosome-positive acute lymphoblastic leukemia after transplantation. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant [Internet]. 2003;9(3):206–12
86. Talpaz M, NP S, Kantarjian H, Donato N, Nicoll J, Paquette R, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med [Internet]. 2006;354(24):2531–41
87. Thomas DA, Faderl S, Cortes J, O’Brien S, Giles FJ, Kornblau SM, et al. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood [Internet]. 2004 Dec 18;103(12):4396–407
88. Tojo A, Usuki K, Urabe A, Maeda Y, Kobayashi Y, Jinnai I, et al. A Phase I/II study of nilotinib in Japanese patients with imatinib-resistant or -intolerant Ph+ CML or relapsed/refractory Ph+ ALL. Int J Hematol [Internet]. 2009;89(5):679–88
89. Topp MS, Kufer P, Gökbuget N, Goebeler M, Klinger M, Neumann S, et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol Off J Am Soc Clin Oncol [Internet]. 2011;29(18):2493–8
90. Vignetti M, Fazi P, Cimino G, Martinelli G, Raimondo F Di, Ferrara F, et al. Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) LAL0201-B protocol. Blood [Internet]. 2007 Dec 18;109(9):3676–8
91. Wassmann B, Gökbuget N, UJ S, Binckebanck A, Reutzel R, Gschaidmeier H, et al. A randomized multicenter open label phase II study to determine the safety and efficacy of induction therapy with imatinib (Glivec, formerly STI571) in comparison with standard induction chemotherapy in elderly (>55 years) patients with Philadelphia chromosome-positive (Ph+/BCR-ABL+) acute lymphoblastic leukemia (ALL) (CSTI571ADE 10). Ann Hematol [Internet]. 2003;82(11):716–20
92. Wassmann B, Pfeifer H, Goekbuget N, Beelen DW, Beck J, Stelljes M, et al. Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood [Internet]. 2006;108(5):1469–77
93. Wassmann B, Pfeifer H, Stadler M, Bornhaüser M, Bug G, Scheuring UJ, et al. Early molecular response to posttransplantation imatinib determines outcome in MRD+ Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood [Internet]. 2005;106(2):458–63
94. Wetzler M, Stock W, Owzar K, al. et. Sequential imatinib and chemotherapy yield reverse-transcriptase polymerase chain reaction (rt-pcr)–negative peripheral stem cell collections in Philadelphia (Ph) chromosome positive acute lymphoblastic leukemia (all)—preliminary results of calgb 10001. J Clin Oncol [Internet]. 2006;24
95. Yanada M. Time to tune the treatment of Ph+ ALL. Blood [Internet]. 2015 Dec 18;125(24):3674–5
96. Yanada M, Sugiura I, Takeuchi J, Akiyama H, Maruta A, Ueda Y, et al. Prospective monitoring of BCR-ABL1 transcript levels in patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia undergoing imatinib-combined chemotherapy. Br J Haematol [Internet]. 2008;143(4):503–10
97. Yanada M, Takeuchi J, Sugiura I, Akiyama H, Usui N, Yagasaki F, et al. High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol [Internet]. 2006;24(3):460–6

Búsqueda y Síntesis de Evidencia

 4.- ¿Cuál es la certeza general de la evidencia sobre efectos?
Muy baja Baja Moderada Alta Ningún estudio incluido

Ningún estudio incluido: No se encontraron estudios que respondieran la preguntan de interés, por lo tanto existe considerable incertidumbre respecto del efecto de «utilizar inhibidores de tirosina quinasa más quimioterapia» en comparación a «solo quimioterapia».

 5.- ¿Hay incertidumbre importante o variabilidad sobre qué tanto valora la gente los desenlaces principales?
Incertidumbre o variabilidad importantes Posiblemente hay incertidumbre o variabilidad importantes Probablemente no hay incertidumbre ni variabilidad importantes No hay variabilidad o incertidumbre importante

No hay variabilidad o incertidumbre importante: En función de la evidencia de investigación, experiencia clínica, conocimiento de gestión o experiencia de las personas con la condición o problema de salud, el equipo elaborador de la Guía consideró que no existe incertidumbre o variabilidad importante respecto a lo que escogería una persona informada de los efectos deseables e indeseables de «utilizar inhibidores de tirosina quinasa más quimioterapia» y «solo quimioterapia». Todas o casi todas las personas escogerían utilizar inhibidores de tirosina quinasa más quimioterapia.

Evidencia de investigación

No se encontraron estudios que desarrollen los valores y preferencia de pacientes con Leucemia Aguda linfoblástica Ph (+) y los medicamentos indicados.

Búsqueda y Síntesis de Evidencia

 6.- El balance entre efectos deseables e indeseables favorece la intervención o la comparación?
Favorece la comparación Probablemente favorece la comparación No favorece la intervención ni la comparación Probablemente favorece la intervención Favorece la intervención Varía No lo sé

Favorece la intervención: Considerando que la intervención es «utilizar inhibidores de tirosina quinasa más quimioterapia» y la comparación es «solo quimioterapia», el equipo elaborador de la Guía opinó que el balance entre efectos deseables e indeseables claramente favorece «utilizar inhibidores de tirosina quinasa más quimioterapia».

 7.- ¿Qué tan grandes son los recursos necesarios (costos)?
Costos extensos Costos moderados Costos y ahorros despreciables Ahorros moderados Ahorros extensos Varía No lo sé

Costos extensos: El equipo elaborador de la Guía consideró que los costos de «utilizar inhibidores de tirosina quinasa más quimioterapia» son grandes si se compara con los costos de «solo quimioterapia», en función de los antecedentes, experiencia clínica, conocimiento de gestión o experiencia de los pacientes.

Consideraciones Adicionales

El panel destaca que hay que considerar que se estima 50 a 60 casos nuevos al año en personas mayores de 15 años.

Evidencia de investigación

Tabla. Precios referenciales *

        

       Personas mayores de 15 años y menores de 60 años con leucemia linfoblástica aguda Philadelphia positivo Ph (+)

       Realizar quimioterapia más Inhibidores de la Tirosina Quinasa (TKI) de 1era y 2ª generación**

       Realizar quimioterapia sin TKI

QMT: Protocolo Mayores de 15 y menores de 60 años LLA Ph +

 

QMT Con Imatinib (De marca)

 

QMT Con  Imatinib (Genérico)

 

QMT Sin imatinib

 

 

Inducción

Hyper-CVAD, CICLO A

 

 

$362.237

 

 

$90.559

 

 

$ 137.313

 

Hyper CVAD, Ciclo B (cálculo a 1 año)

 

$6.491.082

$ 1.622.771

 

$ 626.992

 

Mantención

Hyper-CVAD

 

 $15.176.160

 

$ 3.794.040

 

$3.608.640

 

 

$ 22.029.479

 

$ 5.507.370

 

$ 4.372.945

Total

$ 22.029.479

$ 5.507.370

$ 4.372.945

*El porcentaje de cobertura del seguro de salud sobre el precio de la(s) prestación(es) sanitaria(s), dependerá del tipo de seguro de cada paciente.
**Otro TKI: Dasatinib (70 mg) 70 mg c/12 hrs VO x día x30 días x 24 meses $ 69.003 por comprimido= $ 66.364.320

Referencias

1. Precios obtenidos de la base de datos del Estudio de Verificación de Costos 2015 MINSAL. El precio fue actualizado utilizando la UF al 1 de julio 2018.
2. Precio de Imatinib fue obtenido de Mercado Público, últimas adjudicaciones 2018.

Búsqueda y Síntesis de Evidencia

 8.- ¿La costo-efectividad de la intervención beneficia la intervención o la comparación?
Favorece la comparación Probablemente favorece la comparación No favorece la intervención ni la comparación Probablemente favorece la intervención Favorece la intervención Varía Ningún estudio incluido

Probablemente favorece la intervención: Considerando que la intervención es «utilizar inhibidores de tirosina quinasa más quimioterapia» y la comparación es «solo quimioterapia», el equipo elaborador de la Guía opinó que probablemente la alternativa más costo-efectiva es «utilizar inhibidores de tirosina quinasa más quimioterapia».

Evidencia de investigación

No hay estudios costo-efectividad.

Búsqueda y Síntesis de Evidencia

 9.- ¿Cuál sería el impacto en equidad en salud?
Reducido Probablemente reducido Probablemente ningún impacto Probablemente aumentado Aumentado Varía No lo sé

Reducida: El equipo elaborador de la Guía consideró que la equidad en salud se reduciría si se recomendase «utilizar inhibidores de tirosina quinasa más quimioterapia», dado que identificó grupos o contextos que actualmente tiene barreras de acceso importantes, ya sea en términos económicos, geográficos u otros.

 10.- ¿La intervención es aceptable para las partes interesadas?
No Probablemente no Probablemente sí Varía No lo sé

Probablemente no: El equipo elaborador de la Guía consideró que «utilizar inhibidores de tirosina quinasa más quimioterapia» probablemente NO es aceptable para las partes interesadas (profesionales de la salud, gestores de centros de salud, directivos de centros de salud, pacientes, cuidadores, seguros de salud, otros).

 11.- ¿Es factible implementar la intervención?
No Probablemente no Probablemente sí Varía No lo sé

Sí: El equipo elaborador de la Guía consideró que «utilizar inhibidores de tirosina quinasa más quimioterapia» SÍ es factible implementar, contemplando la capacidad de la red asistencial, los recursos humanos disponibles a nivel país, recursos financieros, etc.