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Chronic Myeloid Leukemia

Chronic Myeloid Leukemia

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Chronic Myeloid Leukemia
N Singhal*, PP Bapsy**, KG Babu***, J George*

Abstract
Chronic myeloid leukemia is one of the commonest hematological malignancies seen in clinical practice. It is the result of abnormal and excess cell proliferation due to de-regulated bcr-abl tyrosine kinase activity as a result of Philadelphia chromosome. The present article discusses the various options available to treat the disorder. Allogeneic stem cell transplant remains the gold standard and the only curative option. Hydroxyurea and Busulfan helps in controlling the total leukocyte count but fail to impact on survival. Interferon especially when combined with cytarabine is curative in minority of patients though a substantial number of patients achieve functional cure. Imatinib, a molecular targeted oral therapy, against bcr-abl tyrosine kinase is the latest addition to various treatment options. Early results appear very promising and can be considered as non- transplant standard of care. ©

C

hronic myeloid/myelogenous leukemia (CML) is a clonal myeloproliferative disorder of pluripotent stem cell affecting myeloid, erythroid, megakaryocyte, B and some time T lymphoid cells. It accounts for 50-70% of leukemias in India1 with an annual incidence of 1-2/ lack population. The median age of presentation is 50 years. The patient generally presents with progressive granulocytosis, marrow hypercellularity and splenomegaly. In recent times, asymptomatic presentation is seen quite often. Untreated the disease typically passes through three phases - chronic phase (approximate duration: 3-5 years), accelerated and blast phase (approximate duration: 3-6 months) ultimately terminating fatally. The diagnostic hallmark of CML is Philadelphia chromosome (Ph) which results from a balanced translocation between the long arms of chromosomes 9 and 22 [t 9; 22(q34; q11)], resulting in bcr/abl chimeric gene that expresses an abnormal fusion protein with deregulated tyrosine kinase activity. Ph chromosome can be detected in 95% cases of CML by conventional cytogenetics and the remaining 5% patients have gene product of Ph chromosome i.e. bcr-abl that can be detected by PCR. The deregulated bcr-abl tyrosine kinase phosphorylates a host of intracellular substrates, which results in activation of downstream signal transduction pathways resulting in unregulated and excessive proliferation of cells. (Table 1) The present article aims at delineating the various treatment options available to a patient with CML and

Table 1 : Pathogenesis of CML

BCR-ABL increases CRK-L which decreases stromal-clonal cell adhesion. Activation of RAS leads to increase proliferation. Decreased levels of BAD (apoptotic protein), increased levels of BCL (anti apoptotic protein) and IAP (inhibition of apoptosis protein) leads to decreased levels of cytochrome-c, caspase 3,9 (apoptotic protein) which leads to decreased apoptosis (reference 2).

*Resident; **President and HOD; ***Associate Professor, Departmnt of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore 560029. Received : 3.10.2003; Revised : 6.2.2004; Accepted : 1.4.2004

highlights the shifting paradigm which the malignancy has seen with the introduction of targeted molecular therapy. We will also try to find out how best to integrate the various treatment options into the treatment decision-making process for a patient newly diagnosed with CML. The treatment of CML can be divided into transplant and non-transplant modalities. Since the transplant still remains the gold standard, it will be discussed first followed by an overview of non-transplant modalities (Table 2).
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Table 2 : Criteria for hematologic, cytogenetic and molecular remissions in CML
* Complete hematologic response(CHR) 1. WBC<10,000/µl 2. Platelets <450,000/µl 3. No immature cells-blasts, promyelocytes or metamyelocytes * Partial hematologic response(PHR) As per CHR except 1. Persistence of immature cells 2. Platelets <50% pretreatment level but >450,000/µl 3. Persistent splenomegaly but <50% of pretreatment level * Cytogenetic response(CYGR) (requires evaluation of minimum of 20 metaphases) Complete : no Ph+ cell in bone marrow metaphases Partial : 1-34% Ph+ cell in bone marrow metaphases Minor : 35-90% Ph+ cell in bone marrow metaphases Major : complete plus partial CYGR * Minimal residual disease(MRD) + Persistence of bcr-abl as detected by RT-PCR

ALLOGENEIC STEM CELL TRANSPLANT
Introduced in 1970s, allogeneic stem cell transplant (ASCT) has established itself as the only curative option as far as the treatment of CML is concerned. The procedure entails eradicating the host marrow and suppressing the host immunity with supra doses of chemotherapy (preparatory regimen) followed by infusion of donor stem cells which will take over the function of myelopoiesis and immune reconstitution. Eradication of leukemia depends to a large degree on donor lymphocyte mediated graft versus leukemia (GVL) effect. The efforts are on to decrease the intensity of preparatory regimen and to rely more on GVL effect for curing CML (reduced intensity or mini transplant or nonmyeloablative transplant). This hopefully will decrease the treatment-related mortality (TRM) and thereby increasing the survival. With conventional transplant, in chronic phase, projected 5 years survival ranges between 50-60%. Relapses occur in approximately 15-30% cases and are commonly seen with in the first 5 years. Procedure-related mortality is around 10-40%.3 Transplant performed in blast phase is unsatisfactory with survival less than 10%. Intermediate survival of 25-35% is reported for ASCT in accelerated phase. Increased relapse rate and increased TRM accompany ASCT in transformed phases. Outcome following ASCT not only depends on the phase of disease but a host of other factors are also important. 1. Age : Patients have a continuous and inverse relationship between age and survival. Older patients do worse mainly because of an increased TRM; relapse rates are almost similar. In IBMTR (international bone marrow transplant registry) data, patients above 50 years had survival of 30% as compared to younger patients in whom survival of 60-70% is expected. 2. Timing of transplant : As the disease progresses the outcome of transplant worsens. Hence ASCT is performed within 1-2 years of diagnosis of CML. 3. Pretransplant treatment : Patients treated with Busulfan
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before ASCT have worse outcome. Prior therapy with hydroxyurea or interferon does not appear to affect outcome.4 4. Preparatory regimen : Conventional ASCT uses cyclophosphamide with busulfan or total body irradiation as conditioning regimen. With the recognition of importance of GVL effect, a number of centres have attempted to use reduced intensity regimen. However there is disagreement to what constitutes reduced intensity regimen. Various combinations that have been tried are cyclophosphamide and fludarabine with or without antithymocyte globulin and fludarabine with melphalan. 5. GVHD (graft versus host disease) prophylaxis : Donor T-lymphocytes mediated reaction in host general manifests as diarrhea, elevated liver enzymes, fever and cutaneous changes. Acute GVHD5 seen in first 100 days occurs in 8-63% and causes death in around 13% cases. Chronic GVHD (after 100 days) is seen in upto 75% cases with a mortality of upto 10%. 6 Methotrexate and cyclosporine is commonly used for GVHD prophylaxis. With reduced intensity conditioning regimens choice of GVHD prophylaxis has been cyclosporine alone. Attempts to decrease intensity of GVHD have been fraught with increased treatment failure. Another approach to abrogate GVHD is to use T lymphocyte depleted allogeneic marrow, but it increases risk of nonengraftment, risk of relapse and delays immune reconstitution.7 6. Relatedness of donor: With scarcity of HLA matched sibling donor attempts have been made to use HLA matched transplant from unrelated donors (MURD). But these grafts are associated with increased TRM and morbidity. Graft failure, severe and extreme acute and chronic GVHD contributes to it. Matching at HLA DR81 locus is most important. Ideal patients for MURD are patients with age less than 30 years, early chronic phase, CMV negative and having received non-T cell depleted marrow infusions.8 Such patients can be expected to have a 2 years survival of 51%, a TRM of 47% and relapse rate of 2%. Gratwohl9 analysed the data from EBMTR (European Bone Marrow Transplant Registry) and came up with 5 factor risk score for individual transplant procedure. For each factor a patient can have a score from 0 to 2 and the aggregate score correlates well with survival. This approach is extremely useful for helping clinicians to make recommendations and the patients to decide whether or not to undergo ASCT (Table 3). Recognition and management of relapse Incidence of relapse within first 5 years in chronic phase ranges between 0-30%. The majority of relapses occur with in the first 4 years post ASCT. Relapses normally proceed in an orderly manner with molecular relapse progressing to cytogenetic and eventually hematologic relapse. The best option for these patients is original donor lymphocyte
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Table 3 : Risk score for individual transplant procedure
Feature A. Donor type HLA identical sibling Unrelated/non-identical Stage of disease Chronic Accelerated Blast Age < 20 years 20 - 40 years > 40 years Donor/recipient sex combination Other Female donor for male recipient Interval from diagnosis to treatment < 12 months > 12 months Score 0 1 0 1 2 0 1 2 0 1 0 1

Table 4 : Rough guide to Hydroxyurea dosage
WBC count (/µl) < 10,000 10-20,000 20-30,000 30-50,000 50-80,000 80-100,000 > 1 Lac Dose 500mg 1gm 1.5gm 2 gm 3 gm 4 gm 5 gm

B.

C.

Table 5 : Prognostic index for patients treated with Hydroxyurea and Interferon
Sokal12 Age (years) 0.0116 (age - 43.4) Spleen (below costal margin) (cm) 0.0345 (spleen - 7.51) 0.188 [(platelet)2 / Platelet x 109/L* 700 - 0.563] Myeloblast %* 0.0887 (myeloblast - 2.10) Eosinophils %* — Basophils %* — Relative risk exponential of total Euro13 0.6666 when aged ≥ 50 0.042 x spleen 1.0956, when ≥ 1500 0.0584 x myeloblast 0.0413 x eosinophils 0.2039 when basophils ≥ 3% Total x 1000

D.

E.

infusion in an escalating dose manner.10 The other options include 2nd transplant using same donor, STI 571 or IFN α. Overall contribution of allografting to cure of CML Data from Goldman shows that out of total cohort of CML patients, 55% are ineligible for ASCT because of age more than 55 years. Of the remaining 45%, 15% patients do not have any donor. Remaining 30% have either HLA identical sibling or unrelated donor and undergo transplant with cure rate of approximately 10% and 8% respectively. So transplant can be offered to 30% patients with CML and 18% of total cohort is cured by transplant.11 This leaves roughly more than 70% patients who will be candidate for various forms of non-transplant treatment modalities. Non-transplant treatment Historically CML was treated with splenic irradiation, P32, splenectomy and arsenicals. Busulfan Busulfan was the first cytotoxic agent introduced for the treatment of CML is 1950s. Busulfan is given in the dose of 0.1mg/kg/day per-orally with 50% dose reduction with reduction of WBC count by 50%. Drug is discontinued when counts reach less than 20000/µl. Over the years, the use of busulfan has fallen out of favour due to adverse events as pulmonary fibrosis, rash, hypoadrenalism, severe and prolonged marrow aplasia and poor ASCT outcome. Currently busulfan use is limited to the patients who are intolerant to hydroxyurea. Hydroxyurea Hydroxyurea (OH-urea), a ribonucleotide reductase inhibitor was introduced in 1970s. It has the advantage of modest side effect profile, rapid onset of action and rapid recovery if excessive lowering of WBC occurs. Dose of OHurea varies as per WBC counts and it is recommended to maintain WBC between 20-30000/µl (Table 4).
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*% in peripheral blood, Sokal Low Intermediate High <0.8 0.8 - 1.2 > 1.2 Euro ≤ 780 781 - 1479 ≥ 1480

OH-urea does not affect transplant outcome and can be given in pregnant females. Major problem with OH-urea usage is difficulty in sustaining normal WBC counts. A prognostic score was developed by Sokal et al12 for patients treated with OH-urea, and the patients can be divided into low, intermediate and high risk (Table 5). Both hydroxyurea and busulfan can be used for controlling counts and splenomegaly but the cytogenetic response is exceptional and thus no meaningful survival advantage can be achieved. These drugs do not alter the natural history of CML.

INTERFERON (IFN)
Introduction of IFN-α in mid 1980 was the first nontransplant modality that was shown to prolong survival over OH-urea and busulfan by 1-2 years. Exact mechanism of action though unknown is considered apoptosis, differentiation and antiangiogenesis. It eliminates the deficient inhibitory stroma - cell progenitor interaction in CML. Drug is more effective in the early chronic phase rather than late chronic phase and ineffective in accelerated or blast phase. In chronic phase major CYGR can be achieved in around 18% of the patients and complete CYGR in less than 5%. Interferon has shown survival benefit when compared to hydroxyurea or busulfan (57% vs. 46%/34%).14 Addition of low dose cytarabine to IFN
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increases the major cytogenetic response from 21 to 35% and survival from 52 to 70%.15 Survival with IFN-α is influenced by achieving a CHR at 3 months and a cytogenetic response at 12 months. The high hematologic and cytogenetic responses observed with interferon are dose-dependent and recommended dose varies from 3-5 mu/m2/day. But the molecular cure with IFN remains elusive with only a minority of patients achieving bcr-abl negative status. Majority of patients who have cytogenetic remission though achieve a functional cure, and are longterm survivors. Side effects with IFN are bothersome and include flu-like symptoms, anorexia, nausea, vomiting, diarrhea, fatigue, depression, alopecia, dysguesia, nephrotoxicity, hypothyroidism, autoimmune hemolytic anemia, paresthesias and hypertriglyceridemia. Hydroxyurea is added prior to and during treatment with IFN to maintain WBC<10000/µl. IFN is generally started at the dose of 3mu/m2 alternate day and gradually escalated to 5 mu/m2/day. Pegylation of IFN allows for weekly injection, decreased toxicity and equal efficacy.17 In a randomized study, in patients with early chronic phase CML, PEG-IFN achieved higher CHR (69% v/s 41%), major CYGR (35% v/s 18%) and lower incidence of withdrawal for side effects (8.5% v/s 22%) when compared to conventional IFN.18 Selecting a patient for IFN-α treatment. α 13 1. Hasford et al developed scoring system for the patients treated on interferon and stratified them into low, intermediate and high risk. Patients with lower score are candidates for IFN treatment (Table 5). 2. Treatment response - A CHR at 6 months, partial CYGR at 12 months and complete CYGR at 2 years identifies the patients who can obtain maximum benefit from IFN and can become long-term survivors.

Table 6 : Mechanism of action : Imatinib mesylate

Imatinib acts as ATP mimic occupying the binding site for ATP with in bcr-abl which leads to inhibition of the phosphorylation of tyrosine residues on substrate proteins and bcr-abl itself.

Table 7 : Phase II trials of Imatinib
Chronic 21 No of patients CHR Major CYGR Complete CYGR 18 months survival Disease progression at 2 years 532 97 60 41 95 13% Accelerated22 293 34 25 17 74 50% Blast23 260 8 15 7 35 90%

Table 8 : Phase III trial comparing Imatinib with IFN and Cytarabine24
Imatinib IFN-α+ low dose Ara-C No of patients CHR Major CYGR Complete CYGR Progression-free survival(PFS) Crossed to imatinib Crossed to IFN PCR negativity 553 97% 87% 76% 97% — 2% 10.6% 553 69% 35% 14% 92% 58% — 5%

IMATINIB MESYLATE
Imatinib or signal transduction inhibitor-571 was developed in the lab of Ciba-Geigy as a specific inhibitor of platelet-derived growth factor receptor (PDGFR) tyrosine kinase inhibitor. It was subsequently shown to be powerful and selective inhibitor of all abl tyrosine kinases including 210 kd bcr-abl and 190 kd bcr-abl. The other tyrosine kinases inhibited by imatinib were C-KIT, the receptor for stem cell factor and PDGFR (platelet-derived growth factor receptor). Bcr-abl is ideal target for the treatment of CML as it is expressed in high concentration, only in leukemic cells and clonal expansion of stem cells is dependent on bcr-abl tyrosine kinase activity19 (Table 6). In June 2001, the results of phase I trial were reported.20 Fifty four patients of CML chronic phase refractory or intolerant to IFN were treated with escalating dose of imatinib. A CHR of 98%, major CYGR of 31% and complete CYGR of 13% was achieved. Side effects were mild to moderate. A dose of 400mg/day was recommended for Phase II studies. Enthused by these exciting results, three phase II trials of imatinib in chronic, accelerated and blast phase have been
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conducted and reported in 2002.21-23 (Table 7). In the blast phase, duration of response was 10 months and median survival was 6.9 months. Among Ph + ALL, 60% of 48 patients responded but median time to progression was only 2.2 months. .In chronic phase, cytogenetic responses have been durable and correlates with increased PFS and OS. Achievement of major CYGR within 12 months was associated with statistically significant improvement in OS. The percentage of patients that have relapsed per year has remained constant at 6-7% per year. Subsequently, imatinib was compared with previous standard IFN + low dose cytarabine24 (Table 8). This randomized trial provided a level I evidence of superiority of imatinib over IFN + low dose Ara-C. Survival
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data from the above trial is immature at present and will be known after 3-4 years. Side effects of imatinib Common side effects seen with imatinib are listed in the Table 9. Dosage and dose adjustment25 In the dose finding study, imatinib was used in doses ranging from 300-1000mg. None of the patient derived any benefit from the dose below 300 mg. So the minimum effective dose is 300mg. Half-life of the drug is 16 hours permitting once daily dosage. Moreover size of the patient had no effect on the plasma levels of imatinib hence flat dosing for all the patients is feasible. Recommended dose for chronic phase is 400mg once daily with meals while patient in transformed phase do better on 600 mg/day given in divided dosages. Myelosuppression begins in 2-4 weeks of starting treatment. Imatinib does not affect normal hematopoiesis in conventional doses and lacks any mucosal toxicity. Hence infections are rare with imatinib. Dose adjustment for chronic phase Interruption of treatment is preferred when Grade III or higher myelosuppression develops till recovery of counts more than Grade II occurs. Imatinib is restarted at full dose then. Dose adjustment for transformed phases Thrombocytopenia It is recommended to continue imatinib till clinically significant bleeding occurs unresponsive to platelet support.
Table 9 : Side Effects of Imatinib25
Nausea Edema (superficial, periorbital) Muscle cramps Diarrhea Vomiting Musculoskeletal pain Hemorrhage Chronic phase Blast phase Neutropenia Chronic phase Gr. III IV Accelerated phase Gr. III IV Blast phase Gr. III IV .Anemia Chronic phase Gr. III IV Accelerated Gr. III IV Blast Gr. III IV Thrombocytopenia Chronic phase Gr. III IV Accelerated phase Gr. III IV Blast phase Gr. III IV 68% 60% 30% 40% 50% 35% 13% 48% 25% 8% 24% 34% 16% 46% 4% <1% 31% 5% 40% 10% 16% <1% 30% 12% 27% 31%

Then therapy is interrupted and restarted when platelets are Grade II or higher. Neutropenia For neutrophils less than 500/mm3, it is recommended to do bone marrow examination. If the marrow is hypercellular or blasts are greater than 30%, then imatinib is continued. Else reduction of doses up till 300mg or interrupting the dose till counts recover is recommended. Another approach is to use growth factors G-CSF to maintain neutrophil count without reducing the dose of imatinib. For non-hematological toxicity, treatment remains supportive as salt restriction/diuretics for clinically significant edema, analgesic for muscular cramps and musculoskeletal pain and antimotility drugs for diarrhea. Drug interactions Imatinib is metabolized by CYP 3A 4/5 cytochrome P450 enzyme system. Hence the enzyme inducers as anticonvulsants and steroids reduce the plasma level of imatinib while drugs such as cimetidine, erythromycin, ketoconazole and verapamil which inhibit CYP enzyme, increase the plasma level of imatinib. Imatinib resistance and relapse Unfortunately if cure is the question, then imatinib is not the answer. We know that imatinib is very effective in inducing complete hematological and cytogenetic response, but molecular remission is not achieved in majority of patients. And the problem of resistance and relapse though small is real. Two-year incidence of resistance and or relapse in previously cited phase II trials was 10% in chronic phase, 40% in accelerated phase and 80% in blast phase. Mechanism of imatinib resistance26,27 a. Leukemic cell based a. bcr-abl kinase dependent * Mutation of bcr-abl * bcr-abl amplification b. bcr-abl kinase independent * Other mutations * Increased survival signaling : LYN kinase, MRP kinase * Drug efflux - increased P-GP levels Host cell based * Increased α 1 acid glycoprotein binding

b.

* Increased drug metabolism. Methods to circumvent resistant and relapse 1. Increasing dose of imatinib: Trials are underway to test the effectiveness of increased dose imatinib. In one study, 800 mg of imatinib induced major CYGR in 83% as compared to 63% cases with 400 mg of imatinib. 2. Combination with IFN: In vitro studies have demonstrated additive or synergistic antiproliferative effect of the combination of imatinib with IFN. In phase I/II study, imatinib was combined with PEG-IFN. Major
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Table 10 : Decision tree for a CML patient 2.

granulocytic leukemia. A study of 160 cases. JAPI 1990;38:199202. Mauro MJ, O’Dwyer M, Heinrich MC, Druker BJ. STI 571: A paradigm of new agents for cancer therapeutics. J Clin Oncol 2002;20:325-334. Horowitz MM, Rowling PA, Passweg JR. Allogeneic BMT for chronic myeloid leukemia - a report from IBMTR. Bone Marrow Transplant 1996;17(Suppl 3): S5-6. Tomas JF, Lopez-Lorenzo JL, Requena MJ, Aguilar R, Steegman JL, Camara R, et al. Absence of influence of prior treatment with interferon on the outcome of allogeneic bone marrow transplantation for chronic myeloid leukemia. Bone marrow transplant 1998;22:47-52. Goldman JM, Szydlo R, Horowitz MM, Gale RP, Ash RC, Atkinson K, et al. Choice of a pretransplant treatment and timing of transplant for chronic myeloid leukemia in chronic phase. Blood 1993;82:2235-38. Chao NJ, Schimdt GM, Niland JC, Amylon MD, Dagis AC, Long GD, et al. Cyclosporine, methotrexate and prednisone for prophylaxis of acute GVHD. NEJM 1993;329:1225-30. Goldman JM, Gale RP, Horowitz MM. Bone Marrow Transplant for chronic myeloid leukemia in chronic phase: increased risk of relapse associated with T cell depletion. Annals of Internal Medicine 1988;108:806-14. Hansen JA, Gooley TA, Martin PJ, Appelbaum F, Chaincey TR, Cliff RA et al. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. NEJM 1998;338:962-8. Gratwohl A, Hermans J, Goldman JM, Arcese W, Carrera Se, Devergie A et al. Risk assessment for patients with chronic myeloid leukemia before allogeneic blood or marrow transplantation. Lancet 1998;35:1087-92.

3.

4.

5.

cytogenetic remission was achieved in 73% of cases. But the increased side effects forced the reduction of dose of PEG-IFN to 0.5µg/kg/week.28 3. Combination with low dose cytarabine: In a study, when imatinib was combined with low dose Ara-C, major CYGR achieved at 6 months was 74%, with moderate side effects. Further trials are underway to test this combination. Combination with other targeted molecules as farnesyl transferase inhibitors.

6.

7.

8.

4.

Other experiment approaches that are underway include use of arsenic, multiple tyrosine kinase inhibitor, farnesyl transferase inhibitor, MEK 1/2 inhibitor, homoharringtonine and decitabine.

9.

CONCLUSION
The prognosis for patients with CML has significantly improved over the last 20 years. Falling transplant related mortality, introduction of IFN and now imatinib has made it possible. We have seen that imatinib is very effective in the treatment of CML. But that is not the end of story but beginning of a problem. Many questions are still unanswered - as how best to integrate imatinib in the decision making for a newly diagnosed case of CML? Should imatinib be given upfront and transplant be offered to relapsing cases? Or imatinib should be reserved for patients who have failed on transplant? And how best to treat patients relapsing on imatinib especially who are not candidates for transplant? And how long to give imatinib once patient has achieved remission? And what is the role of combination treatment in CML? Data from ongoing and future trials will be able to solve many of these problems. For present times, a decision tree is presented in Table 10, which can help us to select best treatment option for our chronic phase patients. For patients in accelerated and blast phase, ASCT remains the best approach followed by imatinib.

10. Dazzi F, Szydlo RM, Craddock C, Cross NCP, Kaeda J, Chase A, et al. Comparison of single dose and escalating dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood 2000;95:6771. 11. Goldman JM. Stem cell transplant for chronic myeloid leukemia: Its place in treatment algorithm - 2001. ASH educational book 2001;103-112. 12. Sokal JE, Cox EB, Baccarni M, Tura S, Gomez GA, Robertson JE, et al. Prognostic discrimination in “Good Risk” chronic granulocytic leukemia. Blood 1984;63:789-99. 13. 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 alpha. J Nat Cancer Inst 1998;90:850-8. 14. CML trialists’ collaborative Group. Interferon alpha versus chemotherapy for chronic myeloid leukemia: a meta analysis of seven randomized trials. J Nat Cancer Inst 1997; 89:161620. 15. Guilhot F, Chatang C, Michallet M, Guerci A, Horousseau JL, Maloisel F, et al. Interferon (-2b combined with cytarabine versus interferon alone in chronic myeloid leukemia. NEJM 1997;337:223-29. 16. Silver RT, Woolf SH, Hehlmann R, Appelbaum FR, Anderson J, Bennett C, et al. An evidence based analysis of the effect of Busulfan, Hydroxyurea, Interferon and Allogeneic bone marrow transplantation in treating the chronic phase of 415

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chronic myeloid leukemia: results of a phase II study. Blood 2002;99:1928 -37. 23. Sawyers CL, Hochhaus A, Feldman E, Goldman JM, Miller CB, Ottmann OG, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 2002;99:3530 -39. 24. 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. NEJM 2003;348:994-1004. 25. Deininger MWN, O’Brien SG, Ford JM, Druker JB. Practical management of patients with chronic myeloid leukemia receiving imatinib. J Clin Oncol 2003;21:1637-47. 26. Hochhaus A, Kriel S, Corbin AS, La Rosce P, Muller MC, Lahaye T, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI 571) therapy. Leukemia 2002;16:2190-96. 27. Nimmanapalli R, Bhalla K. Mechanisms of resistance of imatinib mesylate in bcr-abl positive leukemia. Curr Opin Oncol 2002;14:616-20. 28. Rosti G, Trabacchi E, Bassi S, Bonifazi F, de Vivo A, Martinelli G, et al. Risk and early cytogenetic response to imatinib and interferon in chronic myeloid leukemia. Hematologica 2003;88:256-59.

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