Imatinib Mesylate in Chronic Myeloid Leukemia: A Prospective, Single Arm, Non-randomized Study

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1 Original Article Imatinib Mesylate in Chronic Myeloid Leukemia: A Prospective, Single Arm, Non-randomized Study C Deshmukh*, T Saikia**, A Bakshi*, P Amare - Kadam***, C Baisane+, P Parikh++ Abstract Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by the balanced reciprocal translocation t (9:22). The resulting fusion gene, the BCR-ABL, is responsible for oncogenesis. Imatinib mesylate is a novel molecule, which inhibits the protein product of this fusion gene and hence has been used in the treatment of CML. The present study evaluates 174 patients with CML treated with imatinib mesylate. Of these 174 patients, 97 were in chronic phase, 47 in accelerated phase and 30 patients had blast crisis. Patients in chronic phase received imatinib mesylate in the dose of 400-mg daily, while those in accelerated phase and blast crisis received 600 to 800 mg daily. Of the 97 patients with chronic phase, 49 patients (50.5%) achieved a major (major +complete) cytogenetic response. Of the 47 patients in accelerated phase, 10 patients (21.3%) achieved a major cytogenetic response and in 30 patients with blast crisis, 7 (23.3%) achieved a major cytogenetic response. Dermatitis, mucositis, neutropenia and thrombocytopenia were some of the major toxicities. Of interest, 121 of the 174 patients (69.5%) developed generalized hypopigmentation. We conclude that imatinib mesylate is a safe and effective first-line therapy for chronic myeloid leukemia. INTRODUCTION Chronic myeloid leukemia (CML) is a clonal disorder of hematopoietic stem cells, characterized by a shortened chromosome 22, which results from a balanced reciprocal translocation between chromosomes 9 and 22 [t (9:22)]. 1 This abnormal translocation results in a fusion gene, the BCR/ABL on chromosome 22 and the ABL/BCR gene on chromosome 9 2,3 which is both necessary and sufficient for leukemic transformation. 4 Allogeneic hematopoietic stem cell transplantation has been the only curative modality for Chronic Myeloid Leukemia (CML). However, stem cell transplantation has its own share of both acute and chronic toxicities and is possible only in a limited number of patients. Among the nontransplant-treatment modalities, only interferons produce a cytogenetic response in 15-20% of patients but not without troublesome side effects. Imatinib mesylate, a selective inhibitor of the protein tyrosine kinase has shown promising results in chronic myeloid leukemia in all phases. Its efficacy, specificity and the safety profile makes it a strong contender for the first line therapy in CML. In the present study, we have evaluated the efficacy *Registrar; **Professor; ***Scientific Officer; +Scientific Assistant; ++Professor and Head; Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India. Received : ; Revised : ; Accepted : and safety of this drug prospectively in patients with CML. MATERIAL AND METHODS Patients with Philadelphia positive CML treated with imatinib at our centre from May 2001 to September 2003 were evaluated. Aims and Objectives: To assess the hematologic and cytogenetic response to imatinib in various phases of CML and the toxicities of imatinib. Inclusion criteria: All patients with Philadelphia positive chronic myeloid leukemia. Newly diagnosed patients as well as patients pretreated with interferons, hydroxyurea or hematopoietic stem cell transplantation were also included in the study. Exclusion criteria: Pregnant women, patients with Philadelphia chromosome negative myeloproliferative disorders and Philadelphia positive acute leukemias. All patients underwent a complete physical examination and the baseline clinical findings including the spleen size were recorded. The diagnosis of CML was based on characteristic peripheral blood and bone marrow picture and was confirmed by conventional karyotyping. The standard criteria for the diagnoses of chronic phase, accelerated phase and blast crisis were used. 5 Patients received Imatinib mesylate as a single dose after the largest meal of the day. Patients in chronic phase JAPI VOL. 53 APRIL

2 received 400 mg daily and patients in accelerated phase/ blast crisis received mg daily as per the recommendation. Complete blood counts were monitored weekly for the first month, fortnightly thereafter till patient achieved hematological remission and then monthly. Every patient underwent a cytogenetic evaluation by a bone marrow examination at the end of 6 months of therapy. Response evaluation : Complete hematologic response (CHR) - Absence of splenomegaly and normalization of the peripheral blood picture. Complete cytogenetic remission (CCyR) - Absence of Philadelphia chromosome in all metaphases. Major cytogenetic response (MCyR) - Philadelphia chromosome positivity in less than 35% metaphases. Minor cytogenetic response (mcyr) - Philadelphia chromosome positivity in 35-95% metaphases. No cytogenetic response (NCyR) - Philadelphia chromosome in all analyzed metaphases. Cytogenetic response was not assessed in patients with overt hematologic progression. Toxicities encountered during therapy were graded as per the National Cancer Institute criteria and dose modifications were done as per the toxicity and hematological and cytogenetic responses. The patient characteristics are represented in Table 1. RESULTS One hundred and seventy four patients (122 males Table 1 : (n=174) M: F= 122:52 Age Median 38 yrs. Range 4-79 yrs. First line therapy Hydroxyurea % Interferons % Cytosine arabinoside* * With Interferon alpha. Phase of CML prior to starting imatinib: Chronic phase Accelerated phase Blast crisis Median time from diagnosis to receiving imatinib (months): Median Range Chronic phase Accelerated phase Blast crisis Overall Table 2 : Response to imatinib (n=174) and 52 females) were evaluated in this prospective single arm study. The median age at presentation was 38 years. Six patients were younger than 15 years. All patients received Hydroxyurea as primary treatment. In addition, 99 patients received Interferons. Majority of our patients ( %) were in chronic phase prior to receiving imatinib. Forty-seven patients (27%) were in accelerated phase and 30 patients (17.3%) were in blast crisis. The median time from diagnosis was nearly 3 years for all our patients. The response to imatinib therapy has been shown in Table 2. The major toxicities experienced by our patients are shown in Table 3. Cytopenias, mucositis and dermatitis responded to discontinuation of imatinib and/or addition of corticosteroids. Myalgias responded to analgesics. None of the patients developed life-threatening complications and none needed hospitalization for any complications. There were no deaths due to toxicity. DISCUSSION Imatinib mesylate has brought about a paradigm shift in the treatment of chronic myeloid leukemia (CML). It specifically inhibits the fusion protein of Philadelphia chromosome the BCR-ABL. The BCR-ABL is an ideal target for therapy as it is present in 95-98% of patients, it Table 3 Toxicity Chronic phase Accelerated Blast crisis (n=97) phase (n=47) (n=30) Dermatitis Grade I+II 18 (18.5) 9 (19.1) 4 (13.3) Grade III+IV 3 (3.1) 4 (8.5) Mucositis Grade I+II 14 (14.5) 10 (21.2) 5(16.7) Grade III+IV 1 (2.1) 1(3.3) Neutropenia Grade I+II 16 (16.5) 10(21.3) 8 (26.3) Grade III+IV 4 (4.1) 3(6.4) 2(6.7) Thrombocytopenia Grade I+II 14 (14.4) 11 (23.4) 6 (20) Grade III+IV 3 (3.1) 2 (4.3) 5 (16.7) Facial Puffiness 62 (63.9) 32 (68.1) 17 (56.7) Pedal edema 39 (40.2) 22 (46.8) 12 (40) Weight gain 37 (38.1) 19 (40.4) 10 (33.3) Generalized 71 (73.2) 30 (63.8) 20 (66.7) hypopigmentation Figures in parentheses indicate percentages. Phase of CML CHR Cytogenetic response Complete Major Minor NR NA* Early chronic phase (n=24) 24 (100%) 10 (41.7%) 5 (20.8%) 6 (25%) 3 (12.5%) Late chronic phase (n=73) 65 (89.04%) 20 (27.34%) 14 (19.1%) 26 (35.61%) 9 (16.43%) 4 Accel. phase (n=47) 26 (55.3%) 3 (6.4%) 7 (14.9%) 8 (17%) 16 (34%) 13 Blast crisis (n=30) 11 (36.7%) 4 (13.3%) 3 (10%) 2 (6.7%) 3 (10%) 18 * Patients who had hematological progression/no response. # Patients who received imatinib within 12 months of diagnosis JAPI VOL. 53 APRIL 2005

3 is unique to leukemic cells and its activity is essential to induce leukemogenesis. Some of the major studies of imatinib in CML are shown in Table 4. Table 4 : Imatinib mesylate in various phases of CML (Refs 6-12) Study Number of CHR MCyR CCyR patients Chronic phase S O Brien et al % 87.1% 76.2% (IRIS study) Kantarjian et al % 60% 41% Cervantes et al 97 99% 66% 44% Kantarjian et al 50 98% 90% 72% (Early CP) Accelerated phase Kantarjian et al % 45% 24% Talpaz et al % 24% 17% Blast crisis Kantarjian et al % 10.6% 6.6% Sawyer et al % 16% 7% Chronic myeloid leukemia is commoner in males; the ratio is usually 1.4:1, 13 but the ratio is higher in our study (2.3:1). This could partly be explained by the referral bias since this is a hospital-based study. The median age of presentation of CML has been reported to be 53 years, however, in India, a relatively younger population (patients in the 3 rd or 4 th decade of life) is affected commonly. 14 In our study, 97 patients in chronic phase received imatinib either as a first line therapy or following a relapse/intolerance on interferons. Eighty-nine (91.8%) chronic phase patients achieved a complete hematologic response, 5 patients remained in state of partial hematologic response, 2 patients had no response and 1 patient had a progressive disease. Progression on imatinib in chronic phase CML is rare. However, this patient received imatinib 6 years after the diagnosis of CML. Forty-nine patients (50.5%) achieved a major cytogenetic response (complete response in 30 patients). Similar encouraging results were found in the studies Cervantes and Kantarjian et al (Table 4). A large majority of our patients received imatinib rather late in the course of their disease. The median time from diagnosis to receiving imatinib was 36 months (range months). In our study, 24 patients received imatinib in an early chronic phase (within 12 months of diagnosis). All 24 patients had a complete hematologic response. Fifteen patients (62.5%) achieved a major cytogenetic response as compared to 34 (46.5%) of the 73 patients who received imatinib after 1 year of diagnosis (p=0.132). This difference did not reach statistical significance probably due to the small number of patients, but it certainly reflects a trend towards superior response in patients who receive the drug early in the course of their disease. The response to imatinib in early chronic phase has similarly been impressive in the other study from M.D. Anderson Cancer Centre. The IRIS (International Randomized study of Interferon and STI 571) study included patients who had received hydroxyurea / anagrelide for a period of less than 6 months. In this largest study of early chronic phase CML, 87.1% have achieved a major cytogenetic response 6. This study has established that imatinib started early can produce significantly better cytogenetic response as compared to the combination of interferon-cytosine arabinoside- the previous standard non-transplant treatment. This study has established imatinib as the treatment of choice for newly diagnosed CML patients. Seventeen patients (17.5%) required modification of their imatinib dose (12 - for hematologic toxicity, 4 - nonhematologic toxicity and 1 patient - both). Imatinib had to be discontinued for a median of 2 weeks (range 2-8 weeks) in 29 patients (29.9%) (hematologic toxicity- 21, non-hematologic toxicity - 6 and both - 2). The dose of imatinib was escalated in 6 patients (poor cytogenetic response - 4 patients, poor cytogenetic and hematologic response - 2 patients). Dose escalation has been attempted to overcome resistance to imatinib and has been met with some success, at least temporarily. 15 Traditionally, the treatment of accelerated phase has been a therapeutic challenge. Treatment with chemotherapy, interferons or stem cell transplantation has been unsatisfactory and progression to blast crisis has been the rule. In our study, 47 patients had an accelerated phase disease before receiving imatinib, of which 26 (55.3%) achieved a complete hematologic response. Unfortunately, 14 patients (29.8%) progressed to develop blast crisis. Among the responders, 10 patients (21.3%) had a major cytogenetic response (complete response in 3 patients). The studies from the M.D. Anderson Cancer Centre have shown that imatinib mesylate can produce complete hematologic response and at least a major cytogenetic response in a large number of patients 9,10. These cytogenetic responses are certainly encouraging and provide a hope of arresting the progression to blast crisis. Among these patients with accelerated phase, the dose of imatinib had to be reduced in 26 patients (55.3%) (20 with hematologic toxicity, 4 with non-hematologic toxicity 2 with both). Imatinib had to be discontinued in 21(44.7%) patients (13 for hematologic toxicity, 3 for nonhematologic toxicity and 5 for both). These patients stayed off imatinib for a median of 3.5 weeks (range 2-14 weeks). In contrast, in the study by Kantarjian et al 9, only 3% patients required discontinuation of therapy. In the study by Talpaz et al 10, imatinib was not discontinued in any patient. In an attempt to enhance the response, the dose was escalated to 800 mg in 14 patients (8 for poor hematologic JAPI VOL. 53 APRIL

4 response, 2 for poor cytogenetic response and 2 for both). The prognosis of blast crisis has been grave with a median survival of 3-12 months. Chemotherapy produced short-lived hematologic responses (usually partial) in few patients and cytogenetic responses were even more rare. In our study, 30 patients had blast crisis prior to starting imatinib. Of these, 11 patients (36.7%) achieved a complete hematologic response with imatinib alone. Eighteen patients (60%) patients developed a progressive disease. Of the responders, 7 patients (23.3%) had a major cytogenetic response (complete response in four patients). Patients in blast crisis usually acquire additional cytogenetic abnormalities 16. These abnormalities may induce leukemogenesis, enhance proliferation and prevent apoptosis by pathways other than the tyrosine kinase pathway. A specific targeted molecule like imatinib may not be enough to control the disease processes occurring through all of these pathways. Hence, a combination of imatinib with another active agent needs to be evaluated in blast crisis. The outlook for blast crisis has been dismal in other studies too. The results in accelerated phase and blast crisis highlight the fact that treatment of CML is best done in early chronic phase. Eleven patients (36.7%) in this group needed reduction in the dose of imatinib (7 for hematologic toxicity, 1 for non-hematologic toxicity and 3 for both). Due to toxicities, 9 patients (30%) required discontinuation of imatinib therapy for a median of 3 weeks (range 2-6 weeks). In contrast, the study by Sawyer et al had only 5% patients in whom imatinib was discontinued. 12 Imatinib therapy was associated with a considerable hematologic and non-hematologic toxicity in our patients. Patients in accelerated phase and blast crisis predictably had more hematologic toxicity. However, none of these patients suffered from grade IV toxicity or needed hospitalization for febrile neutropenia. The hematologic toxicity in our study is comparable to some other studies but the IRIS study had a higher incidence of hematologic toxicity. 6 Dermatitis was the commonest non-hematologic toxicity. This toxicity has been limited to a skin rash in other studies, 6,7,17 but some of our patients had a severe exfoliative dermatitis. Symptoms related to fluid retention (puffiness of face, pedal edema and weight gain) were not so significant in these other studies. Imatinib has produced lightening of the skin color in 121 of the 174 patients (69.5%). This side effect has been reported earlier from our institution 18,19 as well as other studies. 20,21 This effect has been well marked in the naturally brown Indian population. This side effect was also seen in patients who had never received hydroxyurea or any other chemotherapy. Imatinib inhibits the platelet derived growth factor receptor and the c-kit tyrosine kinases. These tyrosine kinases have an important role in skin pigmentation. Hypopigmentation disorders like vitiligo and piebaldism have mutations in the c-kit genes. 22 The inhibition of these genes by imatinib may result in generalized hypopigmentation. In our study, hyperpigmentation induced by the hydroxyurea was effectively reversed by imatinib. It is interesting to note that the two drugs used in the treatment of CML have radically opposite actions on skin pigmentation. This certainly warrants further studies. The response rate and toxicity profile in our patients appears to be different in our patients. It is possible that the Indian population handles imatinib differently. Imatinib is metabolized in the liver by the cytochrome enzyme system. There may exist a genetic polymorphism for this enzyme in the Indian population, which may result in the different pharmacodynamic profile. Several enzyme inducers can induce this enzyme system. Dietary factors, additional non-conventional remedies and alcohol may induce the cytochrome enzyme system and alter the metabolism of imatinib. Last but not the least important is patient compliance, which may have a bearing on the ultimate response. CONCLUSION After reviewing the available literature and our experience, we feel that: Imatinib is a safe and effective first-line therapy for CML. The recommended dose for chronic phase is 400 mg/day and for accelerated phase and blast crisis is mg/day. Any dose less than 300 mg/day is unlikely to achieve any therapeutic response. The dose of imatinib is irrespective of weight and body-surface area. The dose for children is 300 mg/ day. Imatinib mesylate is a targeted therapy and its continued administration is required for maximum benefit. It should not be withheld on normalization of counts. Only grade III-IV toxicities mandate discontinuation of imatinib. Thus, imatinib may be safely administered with a hemoglobin upto 8 gm/dl, a total leucocyte count of 3500/mm 3, an absolute neutrophil count of 1000/mm 3 and a platelet count of 50,000/mm 3. Addition of interferons/other agents may augment the response to imatinib. Patients with accelerated phase/ blast crisis may need additional therapies to combat their aggressive disease. Such studies are in progress. Based on the results from our study and other studies done in similar patients, we conclude that imatinib mesylate is the best non-transplant therapy available today. Acknowledgement We thank Mrs. S. S. Lawate for her help in preparing this manuscript. REFERENCES 1. Nowell PC, Hungerford DA. A minute chromosome in human Chronic Granulocytic Leukemia. Science 1960;132: JAPI VOL. 53 APRIL 2005

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