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Todaro J, Ferreira E, Hamerschlak N, Simon SD, Kutner JM, Pietrocola M, Borovik CL
ORIGINAL ARTICLE
Imatinib improves survival of CML patients in accelerated phase: A 48-month follow-up Imatinib melhora a taxa de sobrevida de pacientes com LMC na fase acelerada: Acompanhamento de 48 meses Juliana Todaro1, Euripides Ferreira2, Nelson Hamerschlak3, Sergio Daniel Simon4, Jose Mauro Kutner5, Marci Pietrocola6, Cleide Largman Borovik7
ABSTRACT
RESUMO
Objective: To analyze the clinical evolution of chronic myeloid leukemia patients who had received Imatinib, 48 months after the beginning of a study carried out at Hospital Israelita Albert Einstein. Methods: The progress of the disease of 66 patients that enrolled in an expanded access program was evaluated and the treatment responses were monitored by the hematological and cytogenetic responses. Of these patients, 28 (42.42%) were in chronic phase, 23 (38.85%) in accelerated phase, and 15 (22.75%) in blast crisis. They were contacted 24 months after the end of the study and inquired about the use of the medication, as well as about symptoms related to toxicity and results of the last hemogram and cytogenetic tests. Results: After 36 months of the beginning of the treatment, 41 patients (62.12%) were alive (25 in chronic phase, 15 in accelerated phase, and 1 in blasr crisis. Thirty seven patients could be contacted 37 to 48 months after the beginning of the treatment. One of them dropped out. Of the remaining, 21 belonged to the chronic phase group, 14 to the accelerated phase group, and one to the blast crisis group. Conclusion: The follow-up of patients using Imatinib shows a improve on the survival rates of patients with chronic myeloid leukemia, particularly during the acute phase, in which a good hematological and cytogenetic response was observed in over 65% of the patients, after 4 years of acceleration of the disease. This study shows that an additional 3-years’ survival with good quality of life was achieved by those patients.
Objetivo: Avaliar a evolução clínica de pacientes com leucemia mielóide crônica submetidos a tratamento com imatinib após 48 meses do início do tratamento em um estudo realizado no Hospital Israelita Albert Einstein. Métodos: A evolução da doença e a resposta ao tratamento dos 66 pacientes que ingressaram no estudo expandido com imatinib foram avaliadas pela monitoração das respostas hematológicas e citogenéticas. Destes pacientes, 28 (42,42%) estavam em fase crônica, 23 (38,85%) em fase acelerada e 15 (22,75%) em crise blástica. Os pacientes foram contatados 24 meses após o término do estudo e questionados quanto ao uso da medicação, sintomas relacionados à toxicidade e resultados dos últimos exames hematológicos e citogenéticos. Resultados: Trinta e seis meses após o início do tratamento, 41 (62,12%) pacientes estavam vivos (25 do grupo de fase crônica, 15 do grupo fase acelerada e 1 do grupo crise blástica). Trinta e sete destes puderam ser contatados 37 a 48 meses após o início do tratamento. Um deles desistiu da medicação, 21 pertenciam ao grupo fase crônica, 14 ao grupo fase acelerada e um ao grupo da crise blástica. Conclusão: O seguimento dos pacientes submetidos ao tratamento com imatinib mostrou melhora na taxa de sobrevida dos pacientes com leucemia mielóide crônica, particularmente no grupo fase acelerada, em que se observou boa resposta hematológica e citogenética em mais de 65% dos casos, após 4 anos da aceleração da doença.
Keywords: Leukemia, myeloid, chronic/drug therapy; Proteintyrosine kinase/therapeutic use; Piperazines; Survival
Descritores: Leucemia mielóide crônica/quimioterapia; Proteínatirosina quinase/uso terapêutico; Piperazinas; Sobrevida
Study carried out at Hospital Israelita Albert Einstein – HIAE, São Paulo (SP), Brazil. 1
Graduate course (lato sensu) in Clinical Pathology - Hematology, Instituto Israelita de Ensino e Pesquisa Albert Einstein - IIEP and Department of Clinical Pathology, Hospital Israelita Albert Einstein - HIAE, São Paulo (SP), Brazil.
2
Hematologist, Hospital Israelita Albert Einstein - HIAE, São Paulo (SP), Brazil.
3
Ph.D. in Immunology, Hematologist, Hospital Israelita Albert Einstein - HIAE, São Paulo (SP), Brazil.
4
Ph.D. in Immunology, Oncologist, Hospital Israelita Albert Einstein - HIAE, São Paulo (SP), Brazil.
5
Ph.D. in Hematology. Hematologist, Service of Hematology and Blood Transfusion, Hospital Israelita Albert Einstein - HIAE, São Paulo (SP), Brazil.
6
Nurse, Instituto Israelita de Ensino e Pesquisa Albert Einstein - IIEP, São Paulo (SP), Brazil.
7
Ph.D. in Human Genetics, Department of Clinical Pathology, Hospital Israelita Albert Einstein - HIAE, São Paulo (SP), Brazil. Corresponding author: Cleide Largman Borovik – Av. Albert Einstein, 627/701 – 1° andar - Morumbi - CEP 05651-901 - São Paulo (SP), Brazil - Tel.: 11 37472042 - e-mail:
[email protected] Received on November 21, 2005 - Accepted on February 10, 2006
einstein. 2006; 4(1):16-21
Imatinib improves survival of CML patients in accelerated phase: A 48-month follow-up
INTRODUCTION Chronic Myeloid Leukemia (CML) is a myeloproliferative disease originated from the clonal expansion of a stem cell. It is characterized by a translocation between chromosomes 9 and 22 generating the Philadelphia (Ph) chromosome, detected in 95% of the patients with CML(1). Described in 1960 by Nowell and Hungerford as the first cytogenetic alteration associated with neoplasia and identified as the result of a translocation by Rowley in 1973, the Ph chromosome or its gene product is nowadays pathognomonic for CML. At the molecular level, a translocation of the c-ABL gene located on chromosome 9 to chromosome 22 occurs, next to the BCR gene (breakpoint cluster region), thus forming the fusion gene BCR-ABL. During this process, two messenger RNAs, b3a2 and b2a2, might be formed; a2 (formed by ABL exon 2), and b2 and b3 (formed by BCR exons 2 and 3). The translation of these RNAs produces 210 kd, 190 kd or 230 kd proteins(2-3). The BCR/ABL tyrosine kinase inhibitor Imatinib mesylate (Gleevec, STI571; Novartis, Basel, Switzerland) operates by competitive inhibition at the ATP-binding site of the enzyme. Thus, even though it does not act directly in the pathogenesis of chronic myeloid leukemia (CML), impairing the codification of BCRABL, it causes growth arrest or apoptosis in hematopoietic cells that express the gene BCR-ABL. After determining the safety of the treatment with this drug during the chronic phase of the disease, it was used in patients in the acute phase and in patients in which treatment with interferon alpha (IFN-α) had failed(4-5). Initially, the studies focused on the discussion of a better response in terms of cytogenetics and residual disease obtained using this drug, as compared to IFN-α and the combination of IFN-α and arabinoside cytokine (AraC)(6). In addition to the better response shown, Imatinib is an orally administered drug of low toxicity. OBJECTIVE The objective of this work was to analyze the clinical evolution of CML patients who had received Imatinib, 48 months after the beginning of the study carried out at Hospital Israelita Albert Einstein in October, 2000. METHODS Sixty-six patients with CML enrolled in an expanded access program conducted at our institution (Hospital Israelita Albert Einstein - HIAE). Of these patients, 28 (42.42%) were in chronic phase (CP), 23 (38.85%) in accelerated phase (AP), and 15 (22.75%) in blast crisis
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(BC)(4-5). An initial dose of 400 mg of Imatinib was given to CP patients and of 600 mg to AP and BC patients. The progress of the disease was evaluated with the support of the following laboratory tests: hemogram (CBC), myelogram, cytogenetics – karyotype, FISH (fluorescence in situ hybridization), and PCR (polymerase chain reaction). The treatment responses were monitored by comparing them with the hematological and cytogenetic response standards. The hematological response was considered as complete whenever the normal standards established for peripheral blood cell count were regained, along with the disappearence of signals and symptoms, including splenomegaly. The response was considered partial whenever there was a 50% reduction of the leukocyte count (lower than 20 x 109/L) or the persistence of symptoms and signals of the disease, even with a normal leukocyte count(7). The cytogenetic response was classified as higher or lower; according to the percentage of Ph-positive metaphases: higher if 60 mean range with imatinib Previous
2 1 3 0 0 49.67 46-56 0 45 31-60 1 1
2 6 5 2 1 43.13 24-62 1 58 20-117 3 0
7 7 14 0 0 50.64 15-73 5 34 3-109 2 1
Ethnicity
Age (years)
Time since diagnosis (months) Clonal evolution
11 (44%) 14 (66%) 22 (88%) 2 (8%) 1 (4%) 47.81 16-73 6 45.66 3-117 6 2
Figure 1. Survival of patients in use of imatinib
einstein. 2006; 4(1):16-21
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Todaro J, Ferreira E, Hamerschlak N, Simon SD, Kutner JM, Pietrocola M, Borovik CL
In the AP group, 5 patients had used Imatinib for 36 to 42 months, 6 for 43 to 48 months, and 3 for 49 to 54 months. Access to their test results was granted by 9 patients, 6 of which showed complete CHR, and 2 PHR. Eight of these patients had hemoglobin levels below 13.5 g/dl (lowest value recorded: 9.2 g/dl); 5 had a platelet level below 150x103/µl, and 2 above 400x103/ µl. The cytogenetic follow-up data available for these patients are: 4 with major CR (only one followed-up for 42 months, when he showed 0% of Ph-positive cells). The only patient of the BC group, diagnosed with CML six years earlier, had used Imatinib for 38 months. He was in complete hematological remission, and his BCR-ABL quantification by quantitative PCR was 80%. As for the toxicity presented during the use of Imatinib, in the beginnings of the trial, only 4 of the 66 patients had no complaints. The most frequent adverse effects were diarrhea, nausea, vomiting, epigastralgia, myalgias, fatigue, cramps, insomnia, head ache, rash and itching. At the time of contact (December, 2004), 18/36 patients did not report any of those symptoms. The symptomatic patients reported: nausea (5), edema (4), cramps (3), itching (2), rash (2), pain in a lower limb (2), vomiting (1), fatigue (1), and epigastralgia (1). Seven patients reported temporary discontinuation of the medication, 2 of them due to systemic toxicity (upper digestive hemorrhage and elevations of liver enzyme levels), and 2 due to hematological toxicity. During the progress of the treatment, the medication doses did not remain static; most of the CP patients continued with a 400 mg dose (18 patients used 400 mg, one used 500 mg, one used 600 mg, and one used 100 mg), yet, in the AP and BC patients, the doses had to be changed more frequently. Among the 14 AP patients alive, the doses did not follow a standard regimen: six patients received 400 mg, three 600 mg, three 300 mg, one received 500 mg, and another one 200 mg. In the AP group as a whole (23 patients), the dosage was increased to 700 mg, in an attempt to improve the response to the treatment. The BC patient followed the trend observed along the trial for this phase, i. e., a dose increase from 600 mg to 800 mg.
beginning of the trial, 89.29% of the CP patients and 65.22% of the AP patients were alive, and no death occurred during the following 12 months either. Despite the high survival rate found in both these phases, the accelerated phase is more important, since with other treatments it lasts from 4 to 6 months, progressing toward the blast crisis(8). As for the CP patients, the data obtained do not yet allow making any statement about an increase in the survival rate with the use of Imatinib, because – regardless of medication – the patient usually stays in this phase for 3 to 8 years(8). As the patients of our sample had been diagnosed, on average, 8 years earlier, they had not yet exceeded the natural period of progress of the disease. In the BC group, there were 3 patients (20%) alive after 1 year of treatment, one of them still alive in December, 2004. A similar survival rate (22%) had been considered as a benefit of the treatment with Imatinib by Kantarjian et al. (2002)(9), taking into account that the mean duration of this phase is 4.5 months. In the patients who died, the main factor interfering with their outcome was the type of response to the treatment. Most of these patients showed no cytogenetic response, and 8 of them had additional chromosome alterations; 6 of these patients showed alterations during the treatment, with immediate progress of the disease as a consequence. These findings are similar to those of O’Dweyer et al. (2004) (10). Recently published studies show that primary refractoriness or relapse after an initial response are observed in a significant proportion of patients, due to the presence of point mutations within the ABL kinase domain of the BCR-ABL gene that interfere with drug binding(11).
DISCUSSION It is important to note that in our sample, besides the hematological and cytogenetic responses achieved during the first 12 months, there is clear evidence that the drug actually prolongs survival. After 36 months from the
ACKNOWLEDGEMENTS We thank Nicole S.L. Grosso for critical reading of the English manuscript; Michele Rorato Sagrillo, Silvia Helena F Cardoso and Luciana Rodrigues Jacy da Silva for technical assistance.
einstein. 2006; 4(1):16-21
CONCLUSION It always takes years to assess the advantages and disadvantages of a new drug. The follow-up of patients using Imatinib has brought great hope regarding the survival rates achieved, particularly during the acute phase, in which a good hematological and cytogenetic response was observed in over 65% of the patients, after 4 years of acceleration of the disease. It is worth pointing out that this study shows that an additional 3-years’ survival with good quality of life was achieved by treatment with Imatinib, a low-toxicity oral administration drug.
Imatinib improves survival of CML patients in accelerated phase: A 48-month follow-up
REFERENCES 1. Peng B, Hayes M, Resta D, Racine-Poon A, Druker BJ, Talpaz M, et al. Pharmacokinets and pharmacodynamics of Imatinib in a phase I trial with chronic myeloid leukemia patients. J Clin Oncol. 2004;22(5):935-42. 2. Kantarjian HM, Deisseroth A, Kurzrock R, Estrov Z, Talpaz M. Chronic myelogenous leukemia: a concise update. Blood. 1993;82(3):691-703. 3. Sattler M, Griffin JD. Molecular mechanisms of transformation by the BCRABL oncogenes. Semin Hematol. 2003;40(2 Suppl 2):4-10. Review. 4. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of BcrAbl positive cells. Nat Med. 1996;2(5):561-6. 5. Druker BJ, Lydon NB. Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest. 2000;105(1):3-7. 6. Rosti G, Martinelli G, Bassi B, Amabile M, Trabacchi E, Giannini B, et al. Molecular response to Imatinib in late chronic-phase chronic myeloid leukemia. Blood. 2004;103(6):2284-90.
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7. Talpaz M, Kantarjian H, Kurzroch R, Trujillo JM, Gutterman JU. Interferonalpha produces sustained cytogenetic responses in chronic myelogenous leukemia. Ann Intern Med. 1991;114(7):532-8. 8. Lee SJ. Chronic myelogenous leukaemia. Br J Haematol. 2000;111(4):9931009. 9. Kantarjian HM, Cortes J, O’Brien S, Giles FJ, Albitar M, Rios MB, et al. Imatinib mesylate (STI571) therapy for Philadelphia chromossome-positive chronic leukemia myelogenous in blast phase. Blood. 2002;99(10):3547-53. 10. ODwyer ME, Mauro MJ, Blasdel C, Farnsworth M, Kurilik G, Hsieh YC, et al .Clonal evolution and lack of cytogenetic response are adverse prognostic factors for hematologic relapse of chronic phase CML patients treated with Imatinib mesylate. Blood. 2004;103(2):451-5. 11. Soverini S, Martinelli G, Rosti G, Bassi S, Amabile M, Poerio A, et al. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J Clin Oncol. 2005;23(18):4100-9.
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