|Year : 2015 | Volume
| Issue : 4 | Page : 157-161
Outcome of young adults with chronic myeloid leukemia treated with upfront imatinib: A single institutional experience
Govind K Babu, Aditi Thanky, Linu Abraham Jacob, MC Suresh Babu, Loknatha Dasappa, Sandip Ganguly
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
|Date of Web Publication||16-Dec-2015|
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None
Background: Young adult patients with malignancy are a distinct group of the population. In addition to their ailment, psychosocial issues including fertility issues should be addressed. Chronic myeloid leukemia (CML) is a disease of the elderly population. The outcome with imatinib in young population is not known. Aim: To study the clinical profile and outcome of young patients newly diagnosed with CML on imatinib and to compare with those of elderly population in a tertiary cancer center. Materials and Methods: 369 patients with newly diagnosed CML were included in the study. Patients belonging to the age group of 20–39 years were used as the study group and those who were more than 40 years were used as controls. Both the groups were treated with imatinib. They were followed up for a period of 3 years. Milestones in terms of achieving hematological, cytogenetic and molecular responses were noted. Toxicity profile of the imatinib and the compliance of the patients were also recorded. Results: A total of 173 patients were in the study group and 196 patients were in the control group. Rates of achieving a hematological response at 3 months (94.2% vs. 93%), the complete cytogenetic response at 12 months (68% vs. 61%) and major molecular response at 18 months (72.2% vs. 67.6%) were among the study group and control group, respectively. None of them were statistically significant. Three years event free survival among the study group and the control group was (85.2% vs. 83.4%) respectively; however, the difference did not reach statistical significant value. Conclusion: This study shows that the outcome of young adults with CML is comparable to those of the elderly people with imatinib both in terms of response rates and survival.
Keywords: Chronic myeloid leukemia, imatinib, pregnancy, young adults
|How to cite this article:|
Babu GK, Thanky A, Jacob LA, Suresh Babu M C, Dasappa L, Ganguly S. Outcome of young adults with chronic myeloid leukemia treated with upfront imatinib: A single institutional experience. J Appl Hematol 2015;6:157-61
|How to cite this URL:|
Babu GK, Thanky A, Jacob LA, Suresh Babu M C, Dasappa L, Ganguly S. Outcome of young adults with chronic myeloid leukemia treated with upfront imatinib: A single institutional experience. J Appl Hematol [serial online] 2015 [cited 2019 May 26];6:157-61. Available from: http://www.jahjournal.org/text.asp?2015/6/4/157/171987
| Introduction|| |
Chronic myeloid leukemia (CML) is a myeloproliferative disease with a characteristic cytogenetic abnormality. The cytogenetic characteristic is the reciprocal translocation between the long arms of chromosome 9 and 22 leading to the formation of the fusion protein BCR-ABL with a constitutive tyrosine kinase activity. This leads to the transformation of CML cells which are a clonal expansion of hematopoietic cells carrying this unique cytogenetic abnormality. Age group for adolescents and young adults has been defined by National Comprehensive Cancer Guidelines to be 15–39 years. CML is a disease of elderly with a median age of being around 67 years. However in India, the median age at diagnosis of CML is 38–40 years. Reports of imatinib on children and adolescents have been reported. However, clinical profile and treatment outcome of the disease in young adults are sparse in the literature. As far as our knowledge goes, this type of study has not been done in India. Hence, this study has been planned to see the outcome of the young population of CML with imatinib.
| Materials and Methods|| |
Newly diagnosed patients with CML who were registered in our institution between 2010 and 2011 were enrolled in the study. Patients were followed up for a total duration of 3 years. Young adults were defined to be in the age group of 20–39 years. Patients aged more than 40 years were used as controls. Both the groups were included in the study after obtaining written informed consent. Spleen size, total count, basophil and eosinophil counts, platelet count, cytogenetic abnormalities, and reverse transcription-polymerase chain reaction (RT-PCR) for BCR-ABL were documented at baseline. Cytogenetic analysis was performed by karyotyping at baseline in all patients using the International System for Human Cytogenetic Nomenclature (ISCN 2009). CML-chronic phase (CP) and CML-accelerated phase (AP) were defined according to WHO criteria. All patients were started on imatinib and were monitored for tolerability and adverse effects during treatment. Patients were followed up at regular intervals for response assessment. Response assessment was done according to ELN 2009 recommendations on the management of patients with CML. Hemograms were done every month to look for hematological response. None of the patients received second generation tyrosine kinase inhibitors (TKIs) or underwent allogeneic stem cell transplant due to financial constraints. A complete hematologic response was defined as a white blood cell count of <10 ×109/L, a platelet count of <450 ×109/L, no immature cells (blasts, promyelocytes, or myelocytes) in the peripheral blood, and the disappearance of all signs and symptoms related to leukemia (including palpable splenomegaly). Cytogenetic response was assessed by doing bone marrow karyotyping study every 6 months until patients achieved a CCyR and thereafter annually. Cytogenetic response was defined as: Complete (CCyR), 0% Ph-positive metaphases; partial (PCyR), 1–35% Ph-positive metaphases; major (MCyR), 0–35% Ph-positive metaphases; minor, 36–65% Ph-positive metaphases; minimal, 66–95% Ph-positive metaphases; or no response, >95% Ph-positive metaphases. Molecular response was observed by doing RT-PCR study for BCR-ABL fusion protein every 6 months till achievement of major molecular response (MMR) and then yearly. MMR was defined if the BCR-ABL/ABL ratio of ≤0.10% or less. Patients were explained about the potential risk of imatinib to the fetus if they would have conceived on imatinib. Options of alternative therapy like interferon alfa were also given. It was up to the patient to decide about the continuation of imatinib, and they were allowed to do that after obtaining written informed consent. Drug was withheld if the patients developed neutropenia (<1000/cumm) or thrombocytopenia (<50,000/cumm) till recovery of counts.
Events were defined as progression of disease and any loss of previously achieved hematological response, cytogenetic response or molecular response. Progression was defined as progression to accelerated and blast crisis of CML including death. AP was defined by the presence of at least 10% blasts in the blood or bone marrow, clonal cytogenetic evolution, at least 20% peripheral basophils, or thrombocytopenia or thrombocytosis unrelated to treatment. Progression to blast-phase CML was defined by the presence of at least 20% blasts in the blood or bone marrow or extramedullary involvement.
Statistical analysis was performed by SPSS version 21 IBM. Kaplan–Meir graph was used to depict the 3 years event free survival (EFS) among the study and the control group.
| Results|| |
A total of 369 patients with CML who were treated in our institute during the study period was included in the study. 173 patients belonged to the age group of 20–39 years and were included in the study group. 196 patients aged ≥40 years were used as controls. Baseline characteristics of the patients are shown in [Table 1]. In the study group, 160 patients (92.4%) presented in CP of the disease and 13 patients (7.6%) presented in the AP. Patients were followed up for a median period of 3 years. Imatinib was started at a dose of 400 mg/day for patients in CP, and it was 600 mg/day for those in the AP.
Comparison of achievement of milestones in the study group and the control group has been depicted in [Table 2]. Toxicity of the drug was assessed in the study as shown in [Table 3]. Nonhematological toxicity was common than hematological ones. Nonhematological toxicity was more common during the initial phases of treatment. The most common nonhematological toxicities were musculoskeletal including myalgia and arthralgia and hypopigmentation of skin. Among the hematological toxicity, most common were transient myelosuppression and thrombocytopenia. They were easily reversible with temporary cessation of drugs. Compliance of the patients was noted. The rates of noncompliance were higher among the study population which was 6% compared to 4% in the control group. Eight patients from the study group gained parenthood during the study period. Three male patients and five female patients were on imatinib at the time of confirmation of pregnancy. All female patients continued on imatinib except one who was willing to take interferon alfa during the gestational period. All eight pregnancies were uneventful and there were no congenital abnormalities in the children. None of the patients in our study died during the study period. Hence, the overall survival was 100%. The estimated 3 years EFS rate was 85.2% in the study group compared to 83.4% in control group as shown in [Figure 1] (P = 0.1).
|Table 2: Comparison of response rate between study and control population|
Click here to view
|Figure 1: Kaplan–Meir graph showing the event free survival among the two study groups|
Click here to view
| Discussion|| |
Advent of TKIs has led to a dramatic improvement outcome in CML. CML is a disease of the elderly most commonly presenting in sixth decade. However, recent studies have demonstrated the median age to be 45–55 years. In India, the median age of CML falls in the fourth decade. Reasons for this early incidence of CML are not fully known. Because of the perception that CML is a disease of the elderly, prognostic scoring systems considered age as an important risk factor. Reasons for considering age were due to the poor tolerance of elderly individuals to interferons and limited facility for allogeneic stem cell transplant. Both Sokal and EURO score have determined age >40 years as a risk factor.,, Hence, applying this score to individuals <40 years may erroneously lead them into the low risk group. Recently, EUTOS score has been proposed as a new scoring system in CML which does not include age as a risk factor.
There are very few reports in literature about the natural history of CML in young population. Pemmaraju et al. have described outcome of CML in adolescents and young adults treated with upfront TKIs. The age of the study population was defined as 15–29 years. In their study, 13% of the patient population belonged to the study group. In that study, the percentage of patients achieving CCyR among the study group and control group was 84% and 93%, while that for MMR was 75% and 86% and both the difference being statistically significant. In contrast, in our study, the rates of achieving CCyR among the study and control group was 68% and 61%, while that of MMR was 72.2% and 67.6%, respectively and the difference was not significant. The lower rates of achieving milestones can be explained by the fact that only imatinib was used in our study compared to usage of all three TKIs in the other one. The increased rates in the study group compared to control group was also a different from that of the one done by Pemmaraju et al. This can be attributed either due to lesser number of patients in the study group or due to adherence or availability of the drugs.
Adolescents and young adults constitute a distinct patient population to the treating oncologist as they have unique clinical characteristics and psychosocial issues. Young adults have a unique drug distribution and body metabolism of drugs. Though studies regarding pharmaceutical effect of imatinib with age have not shown any significant correlation, analyses have revealed that bodyweight and sex can influence the steady state of drugs,, which in turn may influence drug metabolism. However, their effect on clinical outcome is not clear because of the heterogeneity of the population.
CML is a chronic disease which requires long (indefinite) period of drug intake. Proper adherence is required for the successful treatment of CML. Adherence to treatment is a difficult proposition for young adults. In this population, nonadherence to treatment has been reported to be more than their younger or older counterparts having the same disease and taking the same treatment protocol. In our study, reports of nonadherence were higher in the study population. It was assessed by noting the interval of visit to the hospital to get the medicines. Hence, in clinical practice measures should be taken to check the compliance for drug intake.
Another important issue in CML among young adults is the issue of fertility. Reports have suggested that there may be poor gonadal functions while they are on imatinib. Effects of imatinib on teratogenicity are not convincingly clear. The outcomes of pregnancy on patients taking imatinib are diverse. Though there are reports of normal pregnancy on imatinib, reports of spontaneous abortion, and congenital malformation of neonates have been reported., The common congenital malformations are meningocele, hypospadiasis, and hypoplasia of frontal and parietal bones. Discontinuation of drugs during pregnancy can be an option. Studies are there to evaluate discontinuation of imatinib after a patient achieved complete molecular response. Around 40% patients remained in molecular remission in spite of not taking the drug., Low risk sokal score is considered as an independent prognostic factor for molecular relapse. However, this clinical practice has not been validated outside clinical trials. Hence, the patients were continued on imatinib during pregnancy.
Thus, management of young adults with CML can be extrapolated on the basis of its experience in elderly population. Validation of a proper prognostic system in CML is still not clear because different studies have shown variable results in terms of superiority over one another. Tailoring of therapy according to prognostic score is still not clear. In addition to treatment, compliance should be monitored and family and societal support should be ensured. Proper counseling and guidance regarding psychosocial issues is a must for optimal outcome in this patient population.
Financial Support and Sponsorship
Conflicts of Interest
There are no conflicts of interest
| References|| |
Rowley JD. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973;243:290-3.
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300.
Subramanian PG. Cytogenetic study in CML. Indian J Med Res 2012;135:12-3.
Lakshmaiah KC, Bhise R, Purohit S, Abraham LJ, Lokanatha D, Suresh TM, et al.
Chronic myeloid leukemia in children and adolescents: Results of treatment with imatinib mesylate. Leuk Lymphoma 2012;53:2430-3.
Adolescent and Young Adult Oncology Progress Review Group. Closing the Gap: Research and Care Imperatives for Adolescents and Young Adults with Cancer. Department of Health and Human Services, National Institutes of Health, National Cancer Institute, and the Live Strong Young Adult Alliance, NIH Publication No. 06-6067, Bethesda, MD; 2006. Available from: http://www.planning.cancer.gov/library/AYAO_PRG_Report_2006_FINAL.pdf
O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, et al.
Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994-1004.
Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J, et al.
Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: Review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006;108:28-37.
Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al.
European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013;122:872-84.
Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al.
Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355:2408-17.
Sawyers CL. Chronic myeloid leukemia. N Engl J Med 1999;340:1330-40.
Sokal JE, Baccarani M, Russo D, Tura S. Staging and prognosis in chronic myelogenous leukemia. Semin Hematol 1988;25:49-61.
Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC, et al.
A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst 1998;90:850-8.
Hasford J, Baccarani M, Hoffmann V, Guilhot J, Saussele S, Rosti G, et al.
Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: The EUTOS score. Blood 2011;118:686-92.
Pemmaraju N, Kantarjian H, Shan J, Jabbour E, Quintas-Cardama A, Verstovsek S, et al.
Analysis of outcomes in adolescents and young adults with chronic myelogenous leukemia treated with upfront tyrosine kinase inhibitor therapy. Haematologica 2012;97:1029-35.
Peeters M, Koren G, Jakubovicz D, Zipursky A. Physician compliance and relapse rates of acute lymphoblastic leukemia in children. Clin Pharmacol Ther 1988;43:228-32.
Larson RA, Druker BJ, Guilhot F, O'Brien SG, Riviere GJ, Krahnke T, et al.
Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: A subanalysis of the IRIS study. Blood 2008;111:4022-8.
Menon-Andersen D, Mondick JT, Jayaraman B, Thompson PA, Blaney SM, Bernstein M, et al.
Population pharmacokinetics of imatinib mesylate and its metabolite in children and young adults. Cancer Chemother Pharmacol 2009;63:229-38.
Marin D, Bazeos A, Mahon FX, Eliasson L, Milojkovic D, Bua M, et al.
Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 2010;28:2381-8.
Lansky SB, Smith SD, Cairns NU, Cairns GF Jr. Psychological correlates of compliance. Am J Pediatr Hematol Oncol 1983;5:87-92.
Zamah AM, Mauro MJ, Druker BJ, Oktay K, Egorin MJ, Cedars MI, et al.
Will imatinib compromise reproductive capacity? Oncologist 2011;16:1422-7.
Ault P, Kantarjian H, O'Brien S, Faderl S, Beran M, Rios MB, et al.
Pregnancy among patients with chronic myeloid leukemia treated with imatinib. J Clin Oncol 2006;24:1204-8.
Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Yeung DT, et al.
Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: Results from the TWISTER study. Blood 2013;122:515-22.
Mahon FX, Réa D, Guilhot J, Guilhot F, Huguet F, Nicolini F, et al.
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;11:1029-35.
[Table 1], [Table 2], [Table 3]