Panayiotidis

Tyrosine Kinase Inhibitors and Interferon

Maria Dimou and Panagiotis Panayiotidis

1st Department of Propaedeutic Medicine, Division of Hematology, University of Athens, Greece.

Corresponding author: anagiotis Panayiotidis, Assoc. Professor in Hematology, 1st Department of Propaedeutic Medicine, Division of Hematology, 3rd floor, Laikon General Hospital of Athens, Agiou Thoma 17, Athens - 11526, Greece. Tel: +3 (0)210-7456181,+30(0)210-7462183. E-mail: ppanayi@med.uoa.gr

Published: January 2, 2014
Received: November 20, 2013
Accepted: November 24, 2013
Meditter J Hematol Infect Dis 2014, 6(1): e2014006, DOI 10.4084/MJHID.2014.006
This article is available on PDF format at:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The use of interferon-α (INF) in chronic myeloid leukemia, when it started in the 80s, was considered as a breakthrough in the therapy of this disease; INF administered alone or in combination with aracytin was the standard choice for treatment for Chronic Myeloid Leukemia (CML) patients unfit for bone marrow transplantation. With the appearance of the first Tyrosine Kinase Inhibitor (TKI) (imatinib) and based on the results of the pivotal IRIS trial, imatinib monotherapy was the new treatment of choice for CML, according to the ELN recommendations. The possibility of combining INF with imatinib, for obtaining better therapeutic responses in CML patients has been already tested and reported. The current challenge is the combined use of second generation TKIs with pegylated –IFN, in order to minimize failures to therapy and increase the number of CML patients with deep molecular responses, who may be able to discontinue lifelong treatment.

Introduction

The beginning of the use of INF as treatment for CML started at 1983 after a report by Talpaz et al that leukocyte IFN induced cytoreduction in CML.[1] Other studies confirmed the effect of IFN in CML.[2,3,5] Complete hematologic responses were observed in 80% of CML patients treated with IFN and in 7-10% of them complete cytogenetic responses (CCyR) were obtained. CML patients in CCyR under IFN-a treatment have an 80% chance of 10 years survival.[6,7] Since there was a clear benefit in the survival of CML patients treated with IFN compared to bulsufan or hydroxyurea, IFN became the standard of CML therapy in the 90s and early response after 3 months of therapy was associated with good outcome.[8] The major issues raised during that time were the  right dose of IFN-α used and the issue of  combining IFN  with other drugs, e.g. busulfan, hydroxyurea, aracytin.[2-5] Most studies were performed with high dose of IFN-α, at 5MU/m2/day and side effects, mainly flu-like symptoms, fatigue, hematologic toxicity, weight loss, neurotoxicity and depression and cardiotoxicity. Dose reductions in IFN-α were frequent both in clinical trials and the everyday clinical practice. In a study comparing high dose IFN versus low dose (3MU/day/5 das/week) no difference is responses was observed. Overall survival after 5 years was 50% in the low dose arm versus 49% in the high dose IFN arm. Complete cytogenetic response was 9% in the low dose arm and 7% in the high dose IFN arm.[9]

Mechanism of Action of IFN–α in CML

CML progenitor stem cells are deficient in adhering to bone marrow stromal cells, when compared to normal hematopoietic stem cells.[10] This was considered to contribute to the pathogenesis of CML, since it was suggested that circulating CML stem cells, due to their failure to adhere to bone marrow, could contribute to leukocytosis and extra-medullary hemopoiesis e.g. splenomegaly. 
A minority of CML patients treated with a-IFN obtained CCyR, and some have discontinued treatment. In a study by Mahon et al. IFNα treated CML patients who were in CCyR or bcr-abl negativity, discontinued IFN and 8 patients lost CCyR after 3-33 months.[11] Seven patients that were in CCyR>24 months and were bcr-abl negative before discontinuation did not relapse (median time of observation 36 months).
The results of the pivotal IRIS trial documented the superiority of imatinib compared to the combination of IFN +Aracytine in the treatment of newly diagnosed patients with CML in chronic phase.[12] In 2013 the TKI inhibitors imatinib, nilotinib and dasatinib are approved as first line therapy in CML,[13,14] while bosutinib and ponatinib are approved for use as second/third line therapy in CML.[15,16]
The mode of action of TKIs is obviously, totally different from that of IFN and the issue of combining these drugs for the treatment of CML was soon raised by different groups. The basis for these trials was to have better response rates and to obtain deeper, sustained molecular responses. Although deep molecular responses (MR4, MR4.5) may not have an impact on patient survival, they may offer a higher probability of successful treatment discontinuation of TKIs.
However, all TKIs examined so far, have failed to eliminate the CD34+ CD38- CML stem cells.[17,18] In contrast to mature CML sells, survival of CML stem cells is not dependent on bcr-abl activity and various other pathways participate in CML cells survival; cellular interactions between CML stem cells and bone marrow stroma, activation of several pathways (Wnt, Hedgehog signaling, autophagy, etc).[19-22]

Published Trials of TKIs plus IFN in CML

Published Trials of TKIs plus IFN in CML
In a study by the CML Italian group, 76 early phase CML patients were treated with 400 mg imatinib in combination with 50 or 100 or 150 μg/week of pegylated –IFN. The median administered dose of peg-IFN was 32-36 μg/week and 45 of 76 patients (59%) discontinued peg-IFN during the first year of treatment.[23]
In the French SPIRIT trial,[24] 636 patients with untreated chronic phase CML were randomized to imatinib 400mg, imatinib 600mg, imatinib 400mg plus peg IFN 90μg/week, and imatinib 400mg plus cytarabine. The dose of cytarabine was 20mg/m2 on days 15-28 of a 28 days cycle. During the trial, the arm of imatinib 600 mg/day and the imatinib plus aracytin arm was omitted due to toxicity and the superior results of imatinib plus peg-IFN. The dose of peg-IFN after the first year of the study was reduced to 45μg/week which was better tolerated by the patients. In the first year of the trial, 45% of patients randomized to the peg-IFN arm discontinue treatment. The major side effects in this group of patients were an increase in hematological toxicity, skin rash and asthenia, compared to the group that received imatinib alone. The median dose of peg-IFN delivered in the first year of the study was 54μg/week. No difference in the rate of cytogenetic response after 12 months of therapy was noted between the four arms of the study. In patients who managed to receive peg-IFN more than 12 months, 82% had MMR and 49% had MR4 after two years compared to 43% and 21% respectively in the imatinib 400 arm. Patients who manage to receive IFN for less than 4 months had significantly inferior results. The results of this study demonstrated that the most tolerated dose of pegylated IFN is around 45μg/m2 and the combination with imatinib results in faster and deeper molecular responses.
The rate of responses in the Imatinib-peg-IFN arm was comparable to the responses obtained with the second generation inhibitors nilotinib and dasatinib.[15,16]
In the German CML IV randomized study,[25] 1104 newly diagnosed CML patients in chronic phase were randomized to receive imatinib 800mg/d (n=338), imatinib 400mg/d (n=325), or imatinib 400mg/d plus interferon alfa (IFN- α; n=351). Primary endpoint of the study was MMR at 12 months.
MMR rates were similar between the imatinib 400 mg and the arm of imatinib 400+IFN-α  (44% vs 46%). The IFN-α used in the study was the classical recombinant IFN –a at a schedule of 3 million units x 3 times weekly s.c. It is possible that the IFN-α formulation and e.g. pegylated versus classical recombinant may and dosage of IFN used may be responsible for the different therapeutic results between the CML IV and the  SPIRIT trial.
In another phase II study,[26] the Nordic group randomized 112 chronic phase CML patients with low or intermediate risk who were in complete hematologic remission after therapy with 400mg imatinib to a) continuation with imatinib alone b) receive imatinib plus 50μg pegylated IFNa/week; 34 of the 56 patients in the combination arm discontinued peg-IFNα and the dose of peg-IFN was reduced to 30μg/week. In accordance with the results obtained in the SPIRIT trial, the MMR rate at 12 months was significantly higher in the imatinib plus Peg–IFN-α  arm (82%) compared with the imatinib monotherapy arm (54%).
In a trial by the MD Anderson group, 94 early phase CML patients were randomized in two arms a) 800mg of imatinib and b) imatinib 800mg plus 0,5μg/kg peg-IFN/week and GM-CSF 125mcg/m2 three times per week subcutaneously. No difference in MMR at 12 months or at any other time point during the study was observed. It should be noted, however, that peg-IFN-α was discontinued in all patients due to side effects or other reasons.[27]   
IFN-α has been recently reported to induce proliferation of hematopoietic stem cells in mice.[28] Induction of CML stem cells to exit G0 and entry into cell cycle may render them susceptible to TKIs and produce the superior results when the two agents are combined for the treatment of CML patients. CML stem cells have been shown to be resistant to the administration of the second generation inhibitors dasatinib and nilotinib.[18,19] Concomitant administration of IFN-α may increase the proportion of CML patients achieving deep molecular responses that may lead to treatment discontinuation.
A number of clinical trials are currently exploring the combination of IFN-α with TKIS in the treatment of CML (Table 1).


Table 1
Table 1. 

In trial No 1 (NICOLI), the maximum tolerated dose of peg-IFN-α in CML patients receiving nilotinib will be determined.
In trial No 2, the aim is to investigate whether patients with chronic-phase chronic myeloid leukemia who have achieved a CCyR) on imatinib or nilotinib can then be treated with a combination of the tyrosine kinase inhibitor and peg-IFN-α for 2 years. Subsequently these patients will have their therapy discontinued. Relapse-free survival (RFS) rate 1 year after discontinuation of the TKI and IFN will be the main objective of the study.
Forty CML patients will participate in this study. The planned dose for peg-IFN-α, is 150μg s.c./week, and many side effects and drug discontinuations are expected.
In the trial No 3, (NILOPEG), 60 chronic phase CML patients will receive nilotinib 300mg twice a day + Pegylated interferon 2a, 45μg weekly. Peg-IFN will start after 2-12 months according to investigator choice. Primary end point is the “CMR” rate at 12 months.
In the trial No 4, by the Nordic group, the purpose will be to assess the effect of switching CML patients, who have been treated with imatinib ≥ 2 years and who have stable detectable molecular residual disease between 0.01-1.0 percent (IS), to a combination of Nilotinib and PegIFN-α, in terms of the proportion of patients who achieve confirmed MR4.0. Patients will start therapy with 300mg nilotinib BID for 3 months, and then Peg IFN will be added at 25μg/week s.c. In the absence of toxicities, the dose will increase to 40μg/week s.c. The estimated enrollment is 60 patients.
In the study No 5, by the Nordic group, 35 newly diagnosed CML patients will receive dasatinib 100mg/day for 3 months, and then 15 μg/week Peg-IFN. If no significant toxicities emerge, peg-IFN-α dose will escalate up to 25μg/week for the next 9 months. Primary end point is the rate of MMR after 1 year.
The study No 6, (TIGER) by the German group, 652 chronic phase CML patients will be randomized to:

a) nilotinib 300mg bid plus Peg-IFN-α 30μg/week s.c. After confirmed MMR and at least 24 months therapy, nilotinib will be discontinued. When MR4 for more than a year, discontinuation of peg-IFN-α.
b) nilotinib 300mg bid for more than 3 years. If MR4 more than a year, discontinuation

The aim of the trial is to improve treatment strategies in CML by improving induction therapy and deescalating maintenance therapy, using low-dose IFN as inducer of immune surveillance.
Primary end point will be the rate of MMR after 18 months and feasibility to discontinue therapy when patients have in stable MR4 response for more than a year.
From the current trials incorporating IFN in the therapy of CML, it is obvious that the pegylated form of IFN is universally used, at doses much lower than the ones used in previous studies. The question is if these lower peg-IFN doses with acceptable toxicities will retain their activity against CML. The possibility of effective targeting the CML stem cells via the combination of TKIs and peg-IFN remains an open question. If this combination will succeed in inducing higher rates of treatment discontinuations then IFN-α (the pegylated form) will reappear officially in the treatment of CML patients.

References

  1. Talpaz M, McCredie KB, Mavligit GM, Gutterman JU. Leuko- cyte interferon-induced myeloid cytoreduction in chronic myelogenous leukemia. Blood.1983;62:689-92. PMid:6192858  
  2. Italian Cooperative Study Group on Chronic Myeloid Leukemia. Interferon alpha-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. N Engl J Med. 1994;330:820-25. http://dx.doi.org/10.1056/NEJM199403243301204 PMid:8114834  
  3. Hehlman R, Heimpel H, Hasford J, Kolb HJ, Pralle H, Hossfeld DK. Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. Blood. 1994;84:4064-77.
  4. Guilhot F, Chastang C, Michallet M, Guerci A, Harousseau JL, Maloisel F, Bouabdallah R, Guyotat R, Cheron N, Nicolini F, Abgrall JF, Tanzer J, Navarro M, Bordessoule D, Morice P, Ifrah N, Rochant H, Vilque JP, Delain M, Bauters F, and Guilhot J for the French Chronic Myeloid Leukemia Study Group. Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. N Engl J Med. 1997;337:223-29. http://dx.doi.org/10.1056/NEJM199707243370402 PMid:9227927
  5. Baccarani M, Rosti G, de Vivo A, Bonifazi F, Russo D, Martinelli G, Testoni N, Amabile M, Fiacchini M, Montefusco E, Saglio G, Tura S; Italian Cooperative Study Group on Myeloid Leukemia. A randomized study of interferon-alpha versus interferon-alpha and low-dose arabinosyl cytosine in chronic myeloid leukemia. Blood. 2002;1;99:1527-35. http://dx.doi.org/10.1182/blood.V99.5.1527  
  6. Kantarjian HM, Smith TL, O'Brien S, Beran M, Pierce S, Talpaz M. Prolonged survival following achievement of cytogenetic response with alpha-interferon therapy in chronic myelogenous leukemia. The Leukemia service Ann Intern ed.1995;122:254-61.
  7. Bonifazi F, de Vivo A, Rosti G, Guilhot F, Guilhot J, Trabacchi E, Hehlmann R, Hochhaus A, Shepherd PC, Steegmann JL, Kluin-Nelemans HC, Thaler J, Simonsson B, Louwagie A, Reiffers J, Mahon FX, Montefusco E, Alimena G, Hasford J, Richards S, Saglio G, Testoni N, Martinelli G, Tura S, Baccarani M. European Study Group on Interferon in Chronic Myeloid Leukemia; Italian Cooperative Study Group on CML; France Intergroup of CML; German CML Study Group; UK Medical Research Council Working Party on CML; Spanish CML Study Group; Australian CML Study Group; Swedish CML Study Group. Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic responders. Blood. 2001; 15;98:3074-81. http://dx.doi.org/10.1182/blood.V98.10.3074  
  8. Mahon FX, Faberes C, Pueyo S, Cony-Makhoul P, Salmi R, Boiron JM, Marit G, Bilhou-Nabera C, Carrère A, Montastruc M, Pigneux A, Bernard P, Reiffers J. Response at three months is a good predictive factor for newly diagnosed chronic myeloid leukemia patients treated by recombinant interferon-alpha. Blood. 1998;92:4059-65. PMid:9834210   
  9. Kluin-Nelemans HC, Buck G, le Cessie S, Richards S, Beverloo HB, Falkenburg JH, Littlewood T, Muus P, Bareford D, van der Lelie H, Green AR, Roozendaal KJ, Milne AE, Chapman CS, Shepherd P; MRC and HOVON groups. Randomized comparison of low-dose versus high-dose interferon-alfa in chronic myeloid leukemia: prospective collaboration of 3 joint trials by the MRC and HOVON groups. Blood. 2004;103:4408-15. http://dx.doi.org/10.1182/blood-2003-10-3605 PMid:15010373  
  10. Gordon MY, Dowding C, Riley G, Goldman JM, Greaves M. Altered adhesive interactions with marrow stroma of haematopoie- tic progenitor cells in chronic myeloid leukaemia. Nature. 1987;23-29;328:342-4.
  11. Mahon FX, Fabères C, Pueyo S, Cony-Makhoul P, Salmi R, Boiron JM, Marit G, Bilhou-Nabera C, Carrère A, Montastruc M, Pigneux A, Bernard P, Reiffers J. Response at three months is a good predictive factor for newly diagnosed chronic myeloid leukemia patients treated by recombinant interferon-alpha. Blood. 1998;1;92:4059-65.
  12. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;5;344:1031-7. http://dx.doi.org/10.1056/NEJM200104053441401  PMid:11287972  
  13. Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, Moiraghi B, Shen Z, Mayer J, Pasquini R, Nakamae H, Huguet F, Boqué C, Chuah C, Bleickardt E, Bradley-Garelik MB, Zhu C, Szatrowski T, Shapiro D, Baccarani M. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;17;362:2260-70. http://dx.doi.org/10.1056/NEJMoa1002315 PMid:20525995  
  14. Saglio G, Kim DW, Issaragrisil S, Le Coutre P, Etienne G, Lobo C, Pasquini R, Clark RE, Hochhaus A, Hughes, Gallagher N, Hoenekopp A, Dong M, Haque A, Larson RA, Kantarjian HM, for the ENESTnd Investigators. Nilotinib versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia.N Engl J Med. 2010; 362:2251-59. http://dx.doi.org/10.1056/NEJMoa0912614 PMid:20525993  
  15. Cortes JE, Kantarjian HM, Brümmendorf TH, Kim DW, Turkina AG, Shen ZX, Pasquini R, Khoury HJ, Arkin S, Volkert A, Besson N, Abbas R, Wang J, Leip E, Gambacorti-Passerini C.Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011; 27;118:4567-76.  http://dx.doi.org/10.1182/blood-2011-05-355594 PMid:21865346  
  16. Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DiPersio J, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Müller M, Gambacorti-Passerini C, Wong S, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes TP, Goldman JM, Shah NP, Kantarjian H for the PACE Investigators. A Phase 2 Trial of Ponatinib in Philadelphia Chromosome–Positive Leukemias. N Engl J Med. 2013; 369:1783-96. http://dx.doi.org/10.1056/NEJMoa1306494 PMid:24180494
  17. Jørgensen HG, Allan EK, Jordanides NE, Mountford JC, Holyoake TL. Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. Blood.2007;109:4016-19. http://dx.doi.org/10.1182/blood-2006-11-057521 PMid:17213283  
  18. Copland M, Hamilton A, Elrick LJ, Baird JW, Allan EK, Jordanides N, Barow M, Mountford JC, Holyoake TL. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood. 2006;107:4532-39. http://dx.doi.org/10.1182/blood-2005-07-2947  PMid:16469872  
  19. Vianello F, Villanova F, Tisato V, Lymperi S, Ho KK, Gomes AR, Marin D, Bonnet D, Apperley J, Lam EW, Dazzi F. Bone marrow mesenchymal stromal cells non-selectively protect chronic myeloid leukemia cells from imatinib-induced apoptosis via the CXCR4/CXCL12 axis. Haematologica. 2010; 95: 1081–89. http://dx.doi.org/10.3324/haematol.2009.017178 PMid:20179085 PMCid:PMC2895031
  20. Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J, Kwon HY, Kim J, Chute JP, Rizzieri D, Munchhof M, VanArsdale T, Beachy PA, Reya T. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature. 2009:9;458:776–79. http://dx.doi.org/10.1038/nature07737 PMid:19169242 PMCid:PMC2946231
  21. Zhang B, Li M, McDonald T, Holyoake TL, Moon RT, Campana D, Shultz L, Bhatia R. Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt-β-catenin signaling. Blood. 2013;7;121:1824-38. http://dx.doi.org/10.1182/blood-2012-02-412890 PMid:23299311  
  22. Bellodi C, Lidonnici MR, Hamilton A, Helgason GV, Soliera AR, Ronchetti M, Galavotti S, Young KW, Selmi T, Yacobi R, Van Etten RA, Donato N, Hunter A, Dinsdale D, Tirrò E, Vigneri P, Nicotera P, Dyer MJ, Holyoake T, Salomoni P, Calabretta B. Targeting autophagy potentiates tyrosine kinase inhibitor–induced cell death in Philadelphia chromosome–positive cells, including primary CML stem cells. J Clin Invest. 2013;123:3634.
  23. Baccarani M, Martinelli G, Rosti G Trabacchi E, Testoni N,Bassi S, Amabile M, Soverini S, Castagnetti F, Cilloni D, Izzo B, de Vivo A, Messa E, Bonifazi F, Poerio A, Luatti S, Giugliano E, Alberti D, Fincato G, Russo D, Pane F and Saglio G. Imatinib and pegylated human recombinant interferon-α2b in early chronic-phase chronic myeloid leukemia. Blood; 2004;104:4245-51. http://dx.doi.org/10.1182/blood-2004-03-0826 PMid:15319292  
  24. Preudhomme C, Guilhot J, Nicolini FE, Guerci-Bresler A, Rigal-Huguet F, Maloisel F, Coiteux V, Gardembas M, Berthou C, Vekhoff A, Rea D, Jourdan E, Allard C, Delmer A, Rousselot P, Legros L, Berger M, Corm S, Etienne G, Roche-Lestienne C, Eclache V, Mahon FX, Guilhot F; SPIRIT Investigators; France Intergroupe des Leucémies Myéloïdes Chroniques (Fi-LMC). Imatinib plus Peginterferon Alfa-2a in Chronic Myeloid Leukemia. N Engl J Med. 2010;363:2511–21. http://dx.doi.org/10.1056/NEJMoa1004095 PMid:21175313  
  25. Hehlmann R, Lauseker M, Jung-Munkwitz S, Leitner A, Müller MC, Pletsch N, Proetel U, Haferlach C, Schlegelberger B, Balleisen L, Hänel M, Pfirrmann M, Krause SW, Nerl C, Pralle H, Gratwohl A, Hossfeld DK, Hasford J, Hochhaus A, Saussele S. Tolerability-Adapted Imatinib 800 mg/d Versus 400 mg/d Versus 400 mg/d Plus Interferon-α in Newly Diagnosed. Chronic Myeloid Leukemia. J Clin Oncol. 2011;29: 1634-42. http://dx.doi.org/10.1200/JCO.2010.32.0598 PMid:21422420
  26. Simonsson B, Gedde-Dahl T, Markevärn B, Remes K, Stentoft J, Almqvist A, Björeman M, Flogegård M, Koskenvesa P, Lindblom A, Malm C, Mustjoki S, Myhr-Eriksson K, Ohm L, Räsänen A, Sinisalo M, Själander A, Strömberg U, Bjerrum OW, Ehrencrona H, Gruber F, Kairisto V, Olsson K, Sandin F, Nagler A, Nielsen JL, Hjorth-Hansen H, Porkka K; Nordic CML Study Group. Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia. Blood. 2011;118:3228–35. http://dx.doi.org/10.1182/blood-2011-02-336685 PMid:21685374  
  27. Cortes J, Quintás-Cardama A, Jones D, Ravandi F, Garcia-Manero G, Verstovsek S, Koller C, Hiteshew J, Shan J, O'Brien S, Kantarjian H. Immune modulation of minimal residual disease in early chronic phase chronic myelogenous leukemia A randomized trial of frontline high-dose imatinib mesylate with or without pegylated interferon alpha-2b and granulocyte-macrophage colony-stimulating factor. Cancer. 2011;117:572–80. http://dx.doi.org/10.1002/cncr.25438 PMid:20886606  
  28. Essers MA, Offner S, Blanco-Bose WE, Waibler Z, Kalinke U, Duchosal MA, Trumpp A. IFNalpha activates dormant haematopoietic stem cells in vivo. Nature. 2009;16;458:904-8. http://dx.doi.org/10.1038/nature07815 PMid:19212321   

[TOP]

Abstract views:
600

Views:
PDF
261
HTML
1279

Article Metrics

Metrics Loading ...

Metrics powered by PLOS ALM

Comments on this article

View all comments


Copyright (c) 2016 Mediterranean Journal of Hematology and Infectious Diseases

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

 

The Mediterranean Journal of Hematology and Infectious Diseases [eISSN 2035-3006] is owned by the U.C.S.C. and it is published by PAGEPress®, Pavia, Italy. All credits and honors to PKP for their OJS.
 
 
© PAGEPress 2008-2017     -     PAGEPress is a registered trademark property of PAGEPress srl, Italy.     -     VAT: IT02125780185