Malaysia Stop Tyrosine Kinase Inhibitor Trial

Leukemia, Chronic Myeloid Clinical Trial

— MSIT  

Official title:

A Randomized Control Trial Comparing Peginterferon-α-2a Versus Observation After Stopping Tyrosine Kinase Inhibitor in Chronic Myeloid Leukemia With Deep Molecular Response for at Least Two Years

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02381379
• Other study ID #: NMRR-13-1186-15491
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: March 2015
• Est. completion date: October 2021

Study information

• Verified date: September 2020
• Source: Ministry of Health, Malaysia
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To compare administration of peginterferon-α-2a for 1 year versus observation after stopping tyrosine kinase inhibitor (TKI) in chronic myeloid leukemia (CML) patients with deep MR ≥ 2 years.

Description:

Chronic myeloid leukemia (CML) is a chronic myeloproliferative neoplasm signified by the presence of Philadephia chromosome, which is the derivative of chromosome 22 after translocation between chromosome 9 and 22. The Philadephia chromosome will produce the mutated tyrosine kinase (BCR-ABL1), which will initiate the pathogenesis of the disease.

Imatinib is the first tyrosine kinase inhibitor (TKI), which has changed the treatment paradigm of CML since its approval from U.S. Food and Drug Administration in 2001 for the treatment of CML. It signifies a new era of oncological treatment using targeted therapy. Subsequent generation TKIs have been marketed as a more potent therapy for CML. Tyrosine kinase inhibitor is conventionally thought not able to cure CML and it has to be taken for life. It is able to induce a very deep molecular response (MR) in about 10% of CML patients as evidenced by persistent undetectable or ≤0.0032% (International Scale IS) BCR-ABL1 transcript in quantitative polymerase chain reaction (PCR) test on current molecular assays, which is labelled as MR4.5 or more. However these patients have to continue taking their TKIs as per recommendations from the European Leukaemia Net and this is the current practice in our institution and in Malaysia. Long term treatment is cumbersome, there is a concern of chronic side effects with long term tyrosine kinase inhibition and it is a financial burden on most countries' health budget as these drugs are very expensive.

Current available data showed that 40% of CML patients with prior stable MR4.5 for 2 years or more will be able to stay imatinib-free for at least 2 years. About 13% of patients without confirmed molecular relapse by the study criteria have low persistent BCR-ABL1 but remain imatinib-free for median follow-up of 22 months (range 6 - 35). A few patients with confirmed molecular relapse by study criteria remained drug free on follow-up. This postulates a component of immunity suppressing the leukemic clone.

Interferon is the standard treatment of CML before the era of TKI. As a single agent, it induces complete cytogenetic response (CCR) in about 20%, and non-sustainable deep MR in about 10% of patients in early chronic phase. These are much smaller figures compared to TKI. Imatinib at the dose of 400mg daily induces CCR in about 70% and deep MR in about 10% of patient in chronic phase after one year of treatment. However, interferon-responded patients may indeed retain the response once interferon was withdrawn via interferon-induced immunity towards the leukemic clone, which leads to longer drug free period compared to TKI. Hence, it is logical to postulate the use of interferon after TKI was stopped when patients have attained deep MR for more than two years will increase the percentage of patients remain TKI-free on follow-up. Unfortunately, there are not many studies concerning this matter. Carella et al described a case series of five patients with deep MR ranging from 12 to 41 months, were put on interferon with follow-up ranging from three to 16 months. Recently, there was a study from Japan, nine out of 12 analyzable patients including 3 patients with previous treatment of interferon, who stopped TKI, was put on interferon remained in deep MR after median follow-up of 23 months (6-27 months). In regards to peginterferon, there is a small studies by Hardan I et al describing 11 CML patients with various responses after imatinib (from complete cytogenetic response N=3, major molecular response N=6, deep MR N=2) were put on peginterferon-α-2a for nine months together with imatinib, then imatinib was stopped and continued with peginterferon-α-2a for another three months. It is difficult to draw any conclusion from this paper because of the small number of subjects, only two subjects have achieved deep MR (with unknown duration) before study entry, and peginterferon-α-2a was combined with imatinib for nine months which will cloud the true effect of peginterferon-α-2a after imatinib was stopped.

So far, there is no randomized study comparing interferon administered for fix duration after TKI was stopped versus observation to see whether the percentage and duration of CML patient who remains TKI-free can be increased and prolonged with interferon, respectively. It will be of interest to see how long the group which was given interferon remains TKI-free. If they remain TKI-free for a long duration, it not only suggests the interferon-induced immunity, but also suggests the interferon-induced immunity can be induced when only a very low level of leukemic cells present. Economical wise, TKI-free certainly give a big relief on the limited health budget of the on-growing CML population.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 118
• Est. completion date: October 2021
• Est. primary completion date: October 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• The subject must be 18 years old or above

• The subject has CML in chronic phase during diagnosis

• The subject is treated with ongoing TKI at any dose for at least 3 years

• The subject has achieved stable deep molecular response (DMR) on International Scale (IS) for 2 years or more by any TKI

• Definition of deep molecular response (IS) = 2 years

• Deep molecular response = MR4 (IS 0.01%) or better

• There must be at least 2 results (including the latest) of MR4.5 with an acceptable control gene copy number for the assay over the last two years

• There must not be any result exceeding a major molecular response (MMR) (IS 0.1%) over the last two years

• The latest PCR result should be compelled with Intervention Start Date, which is within 4 weeks of Study Entry Date or 17 weeks of the latest PCR test.

Exclusion Criteria:

• The subject has previous history of any TKI failure as according to European LeukemiaNet 2009(17).

• The subject has previous history of successfully engrafted autologous or allogeneic haematopoeitic stem cell transplant and after transplant no disease relapse as defined by MSIT protocol

• The subject is planned for autologous or allogeneic stem cell transplantation

• The subject has previous history of interferon or peginterferon administration and achieved complete cytogenetic response with interferon or peginterferon

• The subject had undergone or on immune-modulatory treatments other than interferon or peginterferon

• The subject is undergoing treatment for other malignancies

• The subject has haemoglobin <9g/dL and platelet count <90x109/L for two successive readings of 1 month apart

• The subject has positive Hepatitis B surface Ag (HBsAg), Hepatitis C antibody (anti-HCV), or Human Immunodeficiency Virus 1 antibody (anti-HIV1)

• The subject has creatinine clearance of =50mL/min

• The subject has persistent alanine transaminase =2x upper normal limit for two successive readings of 1 month apart.

• Adults under law protection or without ability to consent

• The subject has previous history or on-going psychiatric illness

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Chronic Myeloid
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Intervention

Drug:
• Peginterferon-a-2a
Subcutaneous peginterferon-a-2a (PEGASYS®) starting at 180µg weekly for one year.

Locations

Country	Name	City	State
Malaysia	Sultanah Bahiyah Hospital	Alor Setar	Kedah
Malaysia	Ampang Hospital	Ampang	Selangor
Malaysia	Sultanah Aminah Hospital	Johor Bahru	Johor
Malaysia	Queen Elizabeth Hospital	Kota Kinabalu	Sabah
Malaysia	Sarawak General Hospital	Kuching	Sarawak
Malaysia	Malacca General Hospital	Melaka
Malaysia	Miri Hospital	Miri	Sarawak
Malaysia	Hospital Pulau Pinang	Pulau Pinang
Malaysia	Sibu Hospital	Sibu	Sarawak

Sponsors (1)

Lead Sponsor	Collaborator
Ministry of Health, Malaysia

Country where clinical trial is conducted

Malaysia, 

References & Publications (12)

Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, Cervantes F, Deininger M, Gratwohl A, Guilhot F, Hochhaus A, Horowitz M, Hughes T, Kantarjian H, Larson R, Radich J, Simonsson B, Silver RT, Goldman J, Hehlmann R; European LeukemiaNet. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009 Dec 10;27(35):6041-51. doi: 10.1200/JCO.2009.25.0779. Epub 2009 Nov 2. Review. — View Citation

Carella AM. Interferon-alpha is able to maintain complete molecular remission induced by imatinib after its discontinuation. Leukemia. 2008 May;22(5):1090-1. doi: 10.1038/leu.2008.94. Epub 2008 Apr 3. — View Citation

Hardan I, Stanevsky A, Volchek Y, Tohami T, Amariglio N, Trakhtenbrot L, Koren-Michowitz M, Shimoni A, Nagler A. Treatment with interferon alpha prior to discontinuation of imatinib in patients with chronic myeloid leukemia. Cytokine. 2012 Feb;57(2):290-3. doi: 10.1016/j.cyto.2011.11.018. Epub 2011 Dec 13. — View Citation

Kantarjian HM, O'Brien S, Cortes JE, Shan J, Giles FJ, Rios MB, Faderl SH, Wierda WG, Ferrajoli A, Verstovsek S, Keating MJ, Freireich EJ, Talpaz M. Complete cytogenetic and molecular responses to interferon-alpha-based therapy for chronic myelogenous leukemia are associated with excellent long-term prognosis. Cancer. 2003 Feb 15;97(4):1033-41. — View Citation

Mahon FX, Delbrel X, Cony-Makhoul P, Fabères C, Boiron JM, Barthe C, Bilhou-Nabéra C, Pigneux A, Marit G, Reiffers J. Follow-up of complete cytogenetic remission in patients with chronic myeloid leukemia after cessation of interferon alfa. J Clin Oncol. 2002 Jan 1;20(1):214-20. — View Citation

Mahon FX, Réa D, Guilhot J, Guilhot F, Huguet F, Nicolini F, Legros L, Charbonnier A, Guerci A, Varet B, Etienne G, Reiffers J, Rousselot P; Intergroupe Français des Leucémies Myéloïdes Chroniques. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010 Nov;11(11):1029-35. doi: 10.1016/S1470-2045(10)70233-3. Epub 2010 Oct 19. — View Citation

Mauro E. Long-term molecular response after discontinuation of interferon-alpha in two patients with chronic myeloid leukaemia. Blood Transfus. 2012 Oct;10(4):559; author reply 560. doi: 10.2450/2012.0144-11. Epub 2012 Feb 29. — View Citation

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 Dec 23;363(26):2511-21. doi: 10.1056/NEJMoa1004095. — View Citation

Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Bartley PA, Slader C, Field C, Dang P, Filshie RJ, Mills AK, Grigg AP, Melo JV, Hughes TP. Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR. Leukemia. 2010 Oct;24(10):1719-24. doi: 10.1038/leu.2010.185. Epub 2010 Sep 2. — View Citation

Usuki K, Kanda Y, Iijima K, Iki S, Hirai H, Urabe A. [Chronic myelogenous leukemia in cessation of therapy after sustained CCR with interferon]. Rinsho Ketsueki. 2003 Dec;44(12):1161-5. Japanese. — View Citation

Veneri D, Tecchio C, De Matteis G, Paviati E, Benati M, Franchini M, Pizzolo G. Long-term persistence of molecular response after discontinuation of interferon-alpha in two patients with chronic myeloid leukaemia. Blood Transfus. 2012 Apr;10(2):233-4. doi: 10.2450/2011.0057-11. Epub 2011 Sep 22. — View Citation

Verbeek W, König H, Boehm J, Kohl D, Lange C, Heuer T, Scheibenbogen C, Reis HE, Hochhaus A, Graeven U. Continuous complete hematological and cytogenetic remission with molecular minimal residual disease 9 years after discontinuation of interferon-alpha in a patient with Philadelphia chromosome-positive chronic myeloid leukemia. Acta Haematol. 2006;115(1-2):109-12. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Relapse rate	Relapse is defined as either i. Loss of MMR, which is a reading of > 0.1% IS, which need to be confirmed by a second analysis point if no previous increasing trend of PCR result, or ii. Positivity of BCR-ABL1 transcripts in quantitative PCR, as confirmed by a second analysis point, indicating the increase (at least 1 log) in relation to the first analysis point at two successive assessments.	3 years
Secondary	The number of patients who developed adverse side-effects of interferon	The number of patients who developed adverse side-effects of interferon vs observation arm.	1 year
Secondary	The rate of reattaining deep MR	The success rate of reattaining deep MR after restarting TKI in those patients who relapse.	3 years
Secondary	Time to regain deep MR after relapse	Defined as time of relapse to the first time point, after restarting whatever treatment, patient has deep MR confirmed by second analysis point.	3 years
Secondary	Quality of life (QoL) assessment	Assessed by questionnaire from INTERNATIONAL PROJECT ON QUALITY OF LIFE IN CHRONIC MYELOID LEUKEMIA.	3 year