Imatinib mesylate (STI 571)--a new oral target therapy for chronic myelogenous leukemia (CML).

The publication provides an up-to-date review of the significance of cytogenetic abnormalities in chronic myelogenous leukemia (CML) and the development of a promising agent with specific molecular target against tyrosine kinase, product of the BCR-ABL fusion gene, namely imatinib mesylate (STI 571, Glivec). The publication summarizes the achieved results with this compound in the chronic phase CML (in patients resistant to interferon and in newly diagnosed patients) further in patients in the accelerated phase and in blast crisis and in patients in relapse after allogeneic stem cells transplantations for CML. The results in Ph+ acute lymphoblastic leukemia are also presented. The mechanisms of resistance to imatinib mesylate and the possibilities how to overcome or circumvent it are mentioned (escalation of the dosage, combination of imatinib with some other treatment modalities as immunotherapy, interferon or convention chemotherapy and development of new drugs).

encompasses three distinct phases becoming more resistant to treatment in each successive phase. The chronic phase is characterized by expansion of terminally differentiated neutrophils. Within 3 to 5 years the disease progresses to an accelerated phase manifested by increasing constitutional symptoms, progressive splenomegaly, refractorness to standard therapy, rising percentage of blasts without meeting the criteria for acute leukemia. The duration of the accelerated phase may last as long as one year. The terminal acute phase termed blast crisis is characterized by cells that fail to mature and represent undifferentiated myeloid or lymphoid progenitor cells. The BCR-ABL oncogen is present in all stages. The blast crisis is characterized by additional genetic abnormalities (18).

Therapy of CML
CML can be cured only by hematopoietic stem cell transplantation. Allogeneic bone marrow transplantation is largely limited to younger patients with an HLA-identical sibling in an acceptable health status to tolerate the procedure. Stem cell transplantation should preferably be offered to patients within 1 year of diagnosis. For all other patients chemotherapy was the only therapeutic option. For many years the principal options for treating CML included busulphan and hydroxyurea. Busulphan demonstrated a 90% hematologic response, but did not alter the progression of the disease. The survival outcome was 3 to 4 years. Hydroxy-urea induced to the therapy several years later had a longer duration in chronic phase, but the progression to blast crises was not deterred. The median survival was 4 to 5 years (53). After introduction of interferonα (IFNα) in the mid 1980 (50) in the therapy of CML the survival compared with hydroxyurea was prolonged. IFNα induced in 80 % of patients in chronic phase CML a complete hematologic remission and in 26 % patients complete cytogenetic remission (25). The addition of ARA-C to IFN further improved survival but increased toxicity (9).
Novel therapies for CML were pursued and various signal transduction inhibitor were developed, among them STI-571 (imatinib mesylate, Glivec, Gleevec) a 2-phenylaminopyrimidine. Imatinib is a highly selective inhibitor of the protein tyrosine kinase family, which includes BCR-ABL protein, the platelet-derived growth factor (PDGF) receptor and the c-kit receptor (12,45). Imatinib competitively binds to the ATP-binding site of BCR-ABL and inhibits protein tyrosine phosphorylation (47). In vivo studies STI-571 prevented growth of hematopoietic cells that expressed BCR-ABL but did not affect normal cells and their function (11).

Imatinib in the late chronic phase CML
On the basis of the promising preclinical data, in June 1998 Drucker at al (13) initiated a phase I trial designed to determine the safety and efficiency. The efficiency was found to be with the dose over 300 mg/day. 54 patients in the late chronic phase CML who were unable to tolerate IFNα or who had no response to the drug were enrolled in the study.
The criteria for response to IFNα were as follows (49): CHR (complete hematologic response): normalization of peripheral counts and differential count, disappearance of all signs and symptoms of disease PHR (partial hematologic response): similar to CHR except for persistence of peripheral immature cells (blasts, promyelocytes, myelocytes), persistence but improvement more than 50 % in splenomegaly. CR (cytogenetic responses) complete: no evidence of Ph-chromosome positive cells major: Ph 1-35 % minor: Ph 36-65 % minimal: Ph 66-95 % Out of 54 patients 53 (98 %) achieved CHR and 17 (31 %) major cytogenetic responses. Normal leukocyte and platelet counts were reached usually within four weeks after the initiation of treatment.
Good effect of imatinib therapy was also confirmed in further studies in patients with late chronic phase CML in whom previous therapy with IFNα failed. In phase II trial a total of 454 patients were treated with 400 mg of oral imatinib daily. Imatinib induced CHR in 95 % of patients, major cytogenetic response in 60 % and 41 % of the total number of patients experienced complete cytogenetic remission. Progression-free survival was 89 % at 18 months (24).

Imatinib as the frontline therapy in CML
The positive results with imatinib in the late chronic phase CML were followed with the phase III trial in which 1106 patients were randomized to the two arms. Imatinib was used as frontline therapy in 553 patients and the results compared with the same number of patients treated with IFNα plus ARA-C. Complete cytogenetic remission was achieved in 68 % of patients (vs 7 % in IFNα plus ARA-C arm). Imatinib was found to have longer time to progression. The results of this study suggest that imatinib should be utilized as frontline therapy in CML (9).
Hematologic responses with imatinib typically occur within 3 months, major cytogenetic responses after 9-12 months of therapy.
The trials with imatinib in late chronic phase or as frontline therapy in CML have shown remarkable results. Imatinib is superior to IFNα and ARA-C in terms of cytogenetic response, progression rates, tolerability and quality of life. The durability of response, the possible longterm effect and the survival data are unknown. Imatinib is used since June 1998, that means 5 years, the median survival with combination of IFNα plus hydroxyurea was 89 months (25).It can be only supposed that the survival will be better because of high complete cytogenetic responses as compared with IFNα.

Imatinib in accelerated phase CML
In accelerated phase CML, phase II trial showed that patients taking 600 mg/d imatinib had longer time to progression and superior survival when compared to 400 mg/d. With the two different dosage regimens cytogenetic response with 600 mg/d was 28 % vs 16 % and survival at 12 months 78 % vs 65 %. In 181 evaluated patients the overall hematologic response was 82 % with 34 % CHR. Major cytogenetic response was 24 %, complete cytogenetic response 17 %. There was no higher toxicity with the 600 mg oral dose (51).

Imatinib in blastic phase CML
In CML blast crises, two recently published studies showed benefit in using imatinib over standard cytotoxic therapies. Seventy-five patients were treated with imatinib in a dose escalation (300 mg to 1000 mg) trial. Fifty-two percent (39 of 75) had a hematologic response and 16 % cytogenetic response. The estimated median overall survival was 6,5 months and the estimated 1-year survival was 22 %. For patients given imatinib mesylate as the frontline therapy for nonlymphoid blast phase disease, the response rate was higher with imatinib mesylate as compared with cytarabine-based chemotherapy (7 vs 4 months). Side effects were less severe than those associated with standard chemotherapy (21). In a separate multicenter phase II trial 229 patients in CML blast crises were enrolled, of which 148 (65 %) were newly diagnosed CML and 81 (35 %) had received prior therapy. In 36 % of previously untreated patients a sustained hematological response was noted and 9 % achieved a sustained CHR. Sixteen percent established a major cytogenetic response and 7 % achieved complete cytogenetic response (46).

Imatinib in acute lymphoblastic leukemia Ph+ ALL
Patients who relapse after intensive combination chemotherapy or allogenic transplantation, or who are refractory to treatment, have few therapeutic options. Ottmann et al. treated with imatinib 56 patients, 48 patients with relapsed or refractory ALL and 8 patients with CML in lymphoid blast crisis (41). Imatinib was given once daily at 400 mg or 600 mg. CHR was induced in 29 % of ALL patients and sustained for at least 4 weeks in 6 % of patients. Grade 4 neutropenia (< 0,5 x 10 9 /l) and thrombocytopenia ((< 10 x 10 9 /l) occurred in 54 % of patients with ALL. Imatinib therapy resulted in a clinically relevant hematologic response rate in relapsed or refractory Ph+ ALL patients, but development of resistance and subsequent disease progression were rapid, but the clinically relevant response offers the possibility of SCT.

Imatinib for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia
Relapse after allogenic SCT has been treated with donor lymphocyte infusion (DLI), IFNα therapy, or additional transplantation. Although DLI can produce complete molecular-level response (ie abolishment of the BCR-ABL oncoprotein), it can also cause recurrence of GVHD, myelosuppression-associated complications, and death (30), IFNα based therapy is only moderately successful, second transplantation is usually reserved for patients whose disease does not responded to DLI.
Thirteen patients had undergone salvage donor lymphocyte infusion. CHR rate was 74 % (17 of 23 patients) and the cytogenetic response rate was 58 % (15 of 28 patients). The 1-year estimated survival rate was 74 %, complete response in 9 (35 %) patients CHR rates were 100 % for chronic phase, 83 % for accelerated phase and 43 % for blastic phase. Recurrence of GVHD occurred in 5 patients (in 3 grade 3), severe granulocytopenia in 43 % and thrombocytopenia in 27 %. Imatinib effectively controlled CML that recurred after allogenic SCT but was associated with considerable side effects. Imatinib therapy alone may be reasonable especially in patients who still have persistent GVHD at the time of CML recurrence to avoid potential worsening of GVHD (22).

Imatinib mesylate dosage
Imatinib is used in standard doses of 400 mg/day for patients in chronic phase, 600 mg/day for patients in accelerated phase and up to 1000 mg in blastic transformation. Kantarjian et al. (26) on the basis of positive current clinical experience and the experience with higher doses of imatinib (600 mg) in accelerated phase recommended the investigation of higher dose as frontline therapy in patients with newly diagnosed or in late chronic phase CML to obtain better and more durable complete cytogenetic and possibly molecular remission. Dose adjustment is often necessary due to side effects. When serious hematologic toxicity or non-hematologic adverse effects develop it is usually necessary to stop imatinib and to restart at a lower dose after the toxicity resolved.

Monitoring the response to therapy
For patients in chronic phase cytogenetic response can occur within 3 months of starting therapy. Marrow assessment with metaphase cytogenetics (flurescence in situ hybridization) can be used after six months for this purpose. Patients in major cytogenetic remission should be optimally monitored by quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) for the presence of BCR-ABL transcripts. It is important to continue to perform conventional cytogenetics at regular internal to detect additional chromosomal abnormalities.

Myelosupression
In the chronic phase the current policy is to interrupt imatinib at the first episode of grade III-IV neutropenia/or thrombocytopenia. Treatment can be resumed once the absolute neutrophil count has risen above 1 x 10 9 /l and/or the platelet count above 100 x 10 9 /. If the blood counts fails to recover within two weeks, it is recommended to reintroduce imatinib at the lower dosage of 300 mg (36).
In patients in blastic phase the support with red cells, platelet transfusions and G-CSF is usually necessary.

The non-hematologic side effects (36, 54)
Increase of weight and peripheral edema occur in about 60 % of patients. Common are muscle craps, bone pain and arthralgias. Normally the patients respond well to non steroidal anti-inflammatory drugs. Relatively common are skin rashes. They usually appear soon after commencing imatinib therapy, but may developed several weeks or even months later. Hsiao et al. reported a patient in blast crisis who developed a lifethreatening cutaneous reaction, Stevens-Johnson syndrome, following 1 week of mesylate therapy (20). Hepatotoxicity grade II -IV has been reported in 2-15 % (36, 54). It typically presents as mild hepatitis, but a cholestatic pattern has been also seen. Other less frequent non-hematologic side effects include fatigue, weakness, dyspepsia, pyrexia, anorexia, hypokaliemia. Increase of intraocular pressure was also noticed in one patient (54).

Resistance of CML to imatinib mesylate
Imatinib demonstrated remarkable activity in CML but a critical clinical problem is the resistance to this compound. The estimated 2 year incidence of imatinib resistance was 10 % in the chronic phase and 40 % to 50 % in accelerated phase post interferonα failure (26).
The relative resistance of blast phase to imatinib was considered to be consistent with the hypothesis that secondary mutations (and not BCR-ABL itself) are responsible for the resistance. Nevertheless Deininger et al. (6) made the observation that some cells do escape to the pro-apoptotic effect of mesylate and are able to establish a subline of cells that can grow continuously in the presence of pharmacologic concentrations of imatinib that inhibit growth of most other CML lines. It has been also observed that some quiescent CD 34+Ph+ cells were highly insensitive to imatinib (19). A variety of mechanisms involved in imatinib resistance to CML have been described (17,32). They include BCR-ABL amplifications (an extra Ph chromosome or high level of BCR-ABL mRNA for other reasons) (55), or mutations within the protein kinase domain (3). Up till now at least 9 different point mutations have been identified (33). There is currently little insight into the underlying mechanism that leads to BCR-ABL gene amplification or mutation. It has been suggested that BCR-ABL itself may confer a mutator phenotype leading to greater genetic instability during disease progression. Some data lead one to believe, that clinical resistance to imatinib, just like antibiotic resistance to bacteria, arises through a process by which pre-existing mutant cells outgrow drug sensitive cells (34). It has been recently confirmed that BCR-ABL mutations preexist in patients who had never received imatinib (16). Further mechanisms of resistance are increased levels of plasma α -1 acid glycoprotein (16), that binds to imatinib in the serum and blocks its activity against BCR-ABL, overexpression of Pgp multidrug resistant protein, that may impair the uptake of imatinib by resistant subline (35), some other tyrosine kinases (7), enhanced expression of the interleukin 3 which protects BCR-ABL transformed hematopoietic progenitor cells from apoptosis induced by BCR-ABL tyrosine kinase inhibitors (10).
A critical clinical question is how to overcome or circumvent the resistance. The escalation of the dosage is successful in some cases but not in other (4,26). It has been observed, that patients who have become resistant to the drug responded again if imatinib has been temporarily interrupted (52). Most promising approach is the combination of imatinib with other treatment modalities such as immunotherapy with specific vaccines (42), interferon, convention chemotherapy (ARA-C) (37) which are now being examined. Other possibilities are to combine various signal transduction pathway inhibitors (8,48). One might exploit drugs that trigger BCR-ABL protein degradation such as geldamycin or 17-AGG (2). A number of novel agent are still under investigation for treatment of CML. Homoharringtonine, a plant alkaloid (27,40), decitabine, a potent hypomethylating agent (23), fernesyltransferase inhibitor (28) and other have shown activity in CML.