|Year : 2014 | Volume
| Issue : 1 | Page : 5-9
Imatinib mesylate as first-line therapy in patients with chronic myeloid leukemia in accelerated phase and blast phase: A retrospective analysis
NK Thota1, S Gundeti1, VG Linga1, P Coca1, RP Tara2, Raghunadharao1
1 Department of Medical Oncology, Nizam's Institute of Medical Sciences, Hyderabad, Andhra pradesh, India
2 Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, Andhra pradesh, India
|Date of Web Publication||18-Jun-2014|
Department of Medical Oncology, Nizam's Institute of Medical Sciences, Hyderabad, Andhra pradesh
Source of Support: None, Conflict of Interest: None
Introduction: Imatinib is a bcr-abl tyrosine kinase inhibitor which has revolutionized the treatment for chronic myeloid leukemia (CML). Even though there is much data on CML chronic phase, there is limited data on imatinib-naοve advanced phase CML. Materials and Methods: We retrospectively analysed 90 patients with advanced phase CML (accelerated phase [AP]: 51 and blast crisis [BC]: 39), patients who received imatinib as frontline therapy. Results: The median age of presentation in CML-AP and CML-BC were 32 years (12-61) and 39 years (8-59), respectively. Imatinib at 600 mg/day was initiated within 2 weeks of diagnosis. Median time to complete hematological response in both CML-AP and CML-BC was 3 months (CML-AP: 1-9 months and CML-BC: 1-14 months). At 6 months 30 (59%) CML-AP and 15 (38%) CML-BC patients achieved major cytogenetic response (MCyR), of them 24 (47%) and 10 (25.6%) being the complete cytogenetic response, respectively. At a median follow-up of 41 months, the median overall survival in CML-AP was 61 months, but in CML-BC it was 14 months. The median progression-free survival and event-free survival were 30 months and 23 months in CML-AP and 14 and 12 months in CML-BC, respectively. On univariate analysis, performance status (PS), spleen size, and MCyR predicted survival in AP, whereas in BC, platelet count, PS, and early MCyR were predictive. Non-hematologic and hematologic adverse events were observed in 80% and 60% of patients, respectively. Dose was reduced in 10% of patients for grade IV toxicity and interrupted in 30% for grade III toxicity. Conclusion: Front-line imatinib is an option in advanced phases of CML especially in CML-AP in low-resource countries, where stem cell transplantation and alternate TKIs are not available.
Keywords: Accelerated phase and blast crisis, chronic myeloid leukemia, imatinib
|How to cite this article:|
Thota N K, Gundeti S, Linga V G, Coca P, Tara R P, Raghunadharao. Imatinib mesylate as first-line therapy in patients with chronic myeloid leukemia in accelerated phase and blast phase: A retrospective analysis. Indian J Cancer 2014;51:5-9
|How to cite this URL:|
Thota N K, Gundeti S, Linga V G, Coca P, Tara R P, Raghunadharao. Imatinib mesylate as first-line therapy in patients with chronic myeloid leukemia in accelerated phase and blast phase: A retrospective analysis. Indian J Cancer [serial online] 2014 [cited 2022 Oct 7];51:5-9. Available from: https://www.indianjcancer.com/text.asp?2014/51/1/5/134598
| » Introduction|| |
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by a reciprocal t(9; 22) (q34; q11) chromosomal translocation,  which results in the hallmark Philadelphia chromosome (Ph)  leading to the expression of the fusion protein, bcr-abl. The constitutively activated bcr-abl protein is responsible for the leukemia. , The disease may follow a biphasic  or triphasic course. Most patients present in the chronic phase (CP), later evolving into the accelerated phase (AP) and/or blast crisis (BC). ,, At presentation, around 90% of the patients are in CML-CP and the remaining in advanced phases (AP/BC).
Since its introduction in 2000, imatinib mesylate (IM), a small-molecule tyrosine kinase inhibitor against bcr-abl, has revolutionized the treatment for CML.  IM has demonstrated considerable efficacy in all phases of CML.  Recently published long-term results of phase II study of IM in CML-AP and BC suggest better survival of patients who attain early hematological and cytogenetic response. ,, We retrospectively analyzed the outcome of patients with CML-AP and BC on IM at our center. As there are no phase 3 randomized trials and these are unlikely in future, due to ethical reasons, we present our data of IM in chemo-naïve patients of CML-AP and BC.
| » Materials and Methods|| |
Consecutive patients attending the medical oncology outpatient department from January 1, 2002, to December 31, 2011, were analyzed retrospectively for hematological and cytogenetic responses, side effects profile, and survival. Patients were evaluated with complete blood counts, bone marrow aspiration/biopsy and conventional cytogenetics. CML-AP and CML-BC were defined according to WHO criteria.  The main eligibility criteria for inclusion in this analysis were patients with (Ph+) CML-AP and CML-BC. Exclusion criteria were: (i) patients who are non-compliant, (ii) on drugs other than IM, and (iii) patient who progressed on imatinib from CML-CP to CML-AC and CML-BC. Imatinib was started at 600 mg/day orally to both CML-AP and CML-BC patients. Dose escalation to 800 mg was done for progression or suboptimal response. Short-duration dose interruption was done for myelosuppression. Dose reduction to 300 mg was done for grade III and IV toxicities.
Hematological response was evaluated every month, and cytogenetic response was assessed at 0, 6, 12, 18, and 24 months. All the adverse events were recorded according to the NCI/NIH CTC AE v4.  A complete hematologic response (CHR) was defined as the normalization of platelet and white blood cell differential counts and absence of extramedullary involvement. Cytogenetic response was assessed by standard cytogenetic analysis of 20 metaphase spreads. Depending on the percentage of Ph-positive cells, the cytogenetic response was classified as complete (0%), partial (1-35%), major (0-35%), minor (36-65%), minimal (66-95%), or none (96-100%).
Survival distributions were estimated by the Kaplan and Meier  method and were compared using the log-rank test.  Overall survival (OS) was calculated from the start of IM treatment to the date of death from any cause or loss to follow-up, whichever came first. Progression-free survival (PFS) was calculated from the time IM was begun to progression, death from any cause, or loss to follow-up. Event-free survival (EFS) was calculated from the day of starting of IM to progression, loss of hematological/cytogenetic response, death from any cause, and loss to follow-up. The life-table method was used to determine the yearly event probabilities. The associations of pre-treatment factors with survival were analyzed by using univariate analysis (log-rank test) and multivariate analysis (Cox-proportional hazards regression model).  A P ≤ 0.05 was considered statistically significant.
| » Results|| |
Ninety patients with CML-AP (51) and CML-BC (39) were analyzed. These patients accounted for 5.14% (90 of 1750) of all CML cases. The baseline characteristics of patients are detailed in [Table 1].
Overall, 26 of 51 (50%) CML-AP and 17 of 39 (43.5%) CML-BC patients achieved CHR at 3 months. Median time to CHR in CML-AP and CML-BC was 3 months in both groups (CML-AP: 1-9 months and CML-BC: 1-14 months). Cytogenetic responses are shown in [Figure 1].
At a median follow-up of 41 months, 32 of 51 (62.7%) CML-AP and 17 of 39 (43%) CML-BC patients are alive and on follow-up. Of them 29 (57%) and 16 (41%) are in cytogenetic remission at the time of reporting. Of the 29 CML-AP patients, 24 attained complete cytogenetic response (CCyR) at 6 months. Of 16 CML-BC patients, 10 attained CCyR at 6 months. The median OS of CML-AP was 61 months; it was 33 months for CML-BC [Figure 2]. Estimated OS at 1, 2, 3, and 5-years in CML-AP are 84%, 74%, 63%, and 54%, whereas in CML-BC the estimated OS at 1, 2.5, and 4.5 years are 51.3%, 46%, and 36%, respectively.
|Figure 2: Overall survival in chronic myeloid leukemia‑accelerated phase and CML‑blast crisis|
Click here to view
Median PFS of CML-AP and CML-BC is 30 months (range: 2-83) and 14 months (range: 1-70), respectively. PFS at 1, 2, and 3 years is 72%, 55%, and 36% in CML-AP and 53%, 33%, and 19% in CML-BC.
Median EFS was 23 months (range: 2-83) in CML-AP and 12 months (range: 1-70) in CML-BC. EFS at 1, 2, and 3 years were 72%, 39.8%, and 23% in CML-AP and 43.6%, 25%, and 14.3% in CML-BC, respectively.
Univariate (log-rank) analysis was used to test the effects of the pre-treatment characters of CML-AP and CML-BC on survival. The results are detailed in [Table 2]. The results of log-rank analysis indicated that better performance status (PS) (0, 1), spleen size ≤8 cm, and major cytogenetic response (MCyR) at 6 months were associated with better survival in CML-AP. In patients with CML-BC, platelet count, PS (0, 1), and MCyR at 6 months were associated with better survival. As expected, the median OS was better in patients who achieved MCyR at 6 months (CML-AP - not reached versus 35 months, P = 0.004; CML-BC - 72 versus 6 months, P < 0.00).
In multivariate analysis, spleen size ≥ 8 cm, total leukocyte count >1 lakh, and less than MCyR at 6 months predicted the outcome of CML-AP [Table 3]a. Whereas in CML-BC, female gender, PS, and less than MCyR at 6 months predicted the survival [Table 3]b. Hematologic and non-hematologic adverse events are described in [Table 4].
Dose reduction was done in 9.8% of patients for grade 4 toxicity. IM dose was reduced to 400 mg/day in three patients for grade 4 skin toxicity and in two patients for grade 4 myelosuppression in CML-AP. One patient developed bilateral painless visual loss and was lost for follow-up. In patients with CML-BC, dose was reduced in two patients for grade 4 myelosuppression and in one patient for grade 4 mucositis. One patient developed anasarca. Dose interruption was done in 30% of the patients during their course of treatment. No treatment-related deaths occurred.
| » Discussion|| |
Limited data are available on IM-naïve CML-AP and CML-BC patients. Kantarjian et al. recently reported an 8-year OS of 75% in IM-naïve CML-AP and a median OS of 6.5 months for CML-BC patients.  Jiang et al.  classified CML-AP (WHO criteria) patients based on duration of disease and hemoglobin and peripheral blast count into low-, intermediate-, and high-risk groups. Their data demonstrated equal survival between imatinib and transplant in the low-risk CML-AP patients with 6-year EFS, OS, and PFS rates were 39.2%, 51.4%, and 48.3%, respectively. In our study, the better outcome was observed in both phases of CML with dosages, ranging from 400 to 800 mg in all age-groups compared to the published literature. ,, At a median follow-up of 41 months, the median OS of CML-AP was 61 months, and the median OS of CML-BC was 14 months.
Median PFS in CML-AP and CML-BC were 30 months and 14 months, respectively. Moreover, the median EFS of CML-AP and CML-BC were 23 months and 14 months, respectively. Patients who attained a MCyR at 6 months had a better OS in our study. The median OS of AP patients, who attained MCyR at 6 months, was not reached while it was 35 months in those who did not attain a MCyR at 6 months. In light of this evidence and considering the transplant-related mortality associated with allogenic transplant, it may be wise to withhold allogenic transplant until progression after use of imatinib, for patients of CML-AP.
Our results in CML-BC also illustrate the above fact, and the median OS was 72 months and 6 months, respectively, for those who attained a MCyR at 6 months and for those who did not. This supports the therapeutic principle in CML that deep and early responses result in better OS. A study by Jiang et al.,  124 CML-AP and CML-BC patients who were treated with IM at 600 and 800 mg, showed the similar results.
The effect of "stage migration" or the "Will Rogers phenomenon" was used by Savage et al. to describe the better 5-year survival probabilities of bone marrow transplant patients with CML-CP and AP after reclassifying them from Hammersmith criteria to International Bone Marrow Transplant Registry (IBMTR) criteria (5-year OS: 58% and 22% vs. 60% and 38%). Similarly, Cortes et al.  used the same phenomenon to describe better results after reclassifying patients from standard criteria (most widely used and validated criteria until date in advanced phase CML) to the WHO criteria. The rates of CCyR for patients in CP, AP, and BC according to the standard definition were 72%, 45%, and 8%, after reclassifying, were 77% (P = 0.07), 39% (P = 0.28), and 11% (P = 0.61), respectively. Similarly, the 3-year survival rates were 91%, 65%, and 10%, after reclassifying, were 95% (P = 0.05), 63% (P = 0.76), and 16% (P = 0.18), respectively. Patients who had a blast percentage of 20-29%, which is considered CML-BC according to the WHO classification, had a significantly better response rate (21% vs. 8%; P = 0.11) and 3-year survival rate (42% vs. 10%; P = 0.0001) compared with patients who had blasts ≥ 30%.
In our study, after reclassifying patients from the WHO to the standard criteria, 27 of 51 (53%) patients were downstaged from AP to CP and 19 of 49 (49%) patients from BC to AP; as a result, the total number of patients in BC was reduced from 39 to 20 patients. The median OS in CML-AP changed from 61 to 60 months and in CML-BC from 33 months to 23 months. Similarly, the estimated survival of CML-AP at 1, 2, and 5 years were decreased from 84%, 74%, and 54% to 67%, 57%, and 44%, respectively, whereas, in CML-BC survival at 1 and 2.5 years, i.e., from 51.3% and 46% to 52.4% and 43%, respectively. The better results in our study can be explained partly by this "stage migration."
A recent study by Kantarjian et al.  showed that age, gender, blast percent, and platelet count predicted the survival in advanced phase CML. In our study PS, spleen size, and MCyR at 6 months had a major impact on OS in CML-AP. On the other hand, gender, better PS, and early MCyR have had a major effect on survival in CML-BC. In multivariate analysis spleen size, total leukocyte count, and early MCyR predicted the OS in CML-AP and gender, PS, and early MCyR in CML-BC.
Short duration of symptoms, early initiation of IM therapy from diagnosis, might have affected the OS, as described by Sureda et al.  Staging according to WHO criteria, dose adjustments according to the European LeukaemiaNet response criteria, better PS, younger age, and early MCyR might have contributed to better survival in both phases CML-AP and CML-BC in our study. Study limitations are the following: (1) Retrospective analysis, (2) small sample size, (3) molecular monitoring was not done, and (4) lineage of BC not categorized.
As in CML-CP, frontline IM has a vital role in the treatment for CML-AP keeping transplant as a second-line option after progression. Even though allogeneic transplant might still the best option for CML-BC, in developing countries like India, IM still plays a role, because of poor availability of allogenic transplant due to logistic and socioeconomic reasons.
Our study confirms the early initiation of therapy; early and deep response improves survival even in advanced phase imatinib-naïve CML especially in AP.
| » Acknowledgment|| |
Glivec International Patient Assistance Program (GIPAP). Under this program all CML patients received imatinib at free of cost.
| » References|| |
|1.||Rowley JD. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973;243:290-3. |
|2.||Nowell PC, Hungerford DA. A minute chromosome in human granulocytic leukemia. Science 1960;142:1497. |
|3.||Daley GQ, van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210BCR/ABL gene of the Philadelphia chromosome. Science 1990;247:824-30. |
|4.||Kelliher MA, McLaughlin J, Witte ON, Rosenberg N. Induction of a chronic myelogenous leukemia-like syndrome in mice with v-ABL and BCR/ABL. Proc Natl Acad Sci U S A 1990;87:6649-53. |
|5.||Cortes J. Natural history and staging of chronic myelogenous leukemia. Hematol Oncol Clin North Am 2004;18:569-84. |
|6.||Goldman JM, Melo JV. Chronic myeloid leukemia-advances in biology and new approaches to treatment. N Engl J Med 2003;349:1451-64. |
|7.||Sawyers CL. Chronic myeloid leukemia. N Engl J Med 1999;340:1330-40. |
|8.||Kantarjian HM, Dixon D, Keating MJ, Talpaz M, Walters RS, McCredie KB, et al. Characteristics of accelerated disease in chronic myelogenous leukemia. Cancer 1988;61:1441-6. |
|9.||Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031-7. |
|10.||Giles FJ, Cortes JE, Kantarjian HM, O′Brien SM. Accelerated and blastic phases of chronic myelogenous leukemia. Hematol Oncol Clin North Am 2004;18:753-74. |
|11.||Palandri F, Castagnetti F, Alimena G, Testoni N, Breccia M, Luatti S, et al. The long-term durability of cytogenetic responses in patients with accelerated phase chronic myeloid leukemia treated with imatinib 600 mg: The GIMEMA CML working party experience after a 7-year follow-up. Haematologica 2009;94:205-12. |
|12.||Palandri F, Castagnetti F, Testoni N, Luatti S, Marzocchi G, Bassi S, et al. GIMEMA working party on chronic myeloid leukemia. Chronic myeloid leukemia in blast crisis treated with imatinib 600 mg: Outcome of the patients alive after a 6-year follow-up. Haematologica. 2008;93:1792-6. |
|13.||Silver RT, Cortes J, Waltzman R, Mone M, Kantarjian H. Sustained durability of responses and improved progression-free and overall survival with imatinib treatment for accelerated phase and blast crisis chronic myeloid leukemia: Long-term follow-up of the STI571 0102 and 0109 trials. Haematologica 2009;94:743-4. |
|14.||Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002;100:2292-302. |
|15.||Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events (CTCAE) v4.0. NCI, NIH, 2010. Available from: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40. |
|16.||Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81. |
|17.||Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer 1977;35:1-39. |
|18.||Cox DR. Regression models and life tables. JR Stat Soc B 1972;34:187-220. |
|19.||Kantarjian H, O′Brien S, Jabbour E, Garcia-Manero G, Quintas-Cardama A, Shan J, et al. Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: A single-institution historical experience. Blood 2012;119:1981-7. |
|20.||Jiang Q, Xu LP, Liu DH, Liu KY, Chen SS, Jiang B, et al. Imatinib mesylate versus allogeneic hematopoietic stem cell transplantation for patients with chronic myelogenous leukemia in the accelerated phase. Blood 2011;117:3032-40. |
|21.||Jiang Q, Chen SS, Jiang B, Jiang H, Qiu JY, Liu YR, et al. The efficacy of imatinib mesylate for 124 patients with chronic myeloid leukemia in accelerated and blastic phase. Zhonghua Xue Ye Xue Za Zhi 2007;28:721-6. |
|22.||Savage DG, Szydlo RM, Chase A, Apperley JF, Goldman JM. Bone marrow transplantation for chronic myeloid leukaemia: The effects of differing criteria for defining chronic phase on probabilities of survival and relapse. Br J Haematol 1997;99:30-5. |
|23.||Cortes JE, Talpaz M, O′Brien S, Faderl S, Garcia-Manero G, Ferrajoli A, et al. Staging of chronic myeloid leukemia in the imatinib era: An evaluation of the World Health Organization proposal. Cancer 2006;106:1306-15. |
|24.||Sureda A, Carrasco M, de Miguel M, Martínez JA, Conde E, Sanz MA, et al. Imatinib mesylate as treatment for blastic transformation of Philadelphia chromosome positive chronic myelogenous leukemia. Haematologica 2003;88:1213-20. |
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]
|This article has been cited by|
||CircBA9.3 supports the survival of leukaemic cells by up-regulating c-ABL1 or BCR-ABL1 protein levels
| ||Yuming Pan,Jin Lou,Heng Wang,Na An,Huan Chen,Qiaoxia Zhang,Xin Du |
| ||Blood Cells, Molecules, and Diseases. 2018; 73: 38 |
|[Pubmed] | [DOI]|
||Chronic Myeloid Leukemia in India
| ||Prasanth Ganesan,Lalit Kumar |
| ||Journal of Global Oncology. 2017; 3(1): 64 |
|[Pubmed] | [DOI]|
||Health-related quality of life during bosutinib (SKI-606) therapy in patients with advanced chronic myeloid leukemia after imatinib failure
| ||Jennifer Whiteley,Arlene Reisman,Mark Shapiro,JorgeE. Cortes,David Cella |
| ||Current Medical Research and Opinion. 2016; 32(8): 1325 |
|[Pubmed] | [DOI]|
||Pattern of chronic myeloid leukemia in the imatinib era in a Sub-Saharan African setting
| ||Blaise Felix Faye,Nata Dieng,Moussa Seck,Macoura Gadji,Youssou Bamar Gueye,Diariatou Sy,Sokhna Aissatou Toure,Abibatou Sall,Awa Oumar Toure,Tandakha Ndiaye Dieye,Saliou Diop |
| ||Annals of Hematology. 2016; 95(10): 1603 |
|[Pubmed] | [DOI]|
| || |
| ||Reactions Weekly. 2015; 1574(1): 136 |
|[Pubmed] | [DOI]|
||Durability of Kinase-Directed Therapies—A Network Perspective on Response and Resistance
| ||Brion W. Murray, Nichol Miller |
| ||Molecular Cancer Therapeutics. 2015; 14(9): 1975 |
|[Pubmed] | [DOI]|