Imatinib entered clinical trials for patients with CML in chronic phase as well as those in more advanced phases in 1998. The drug caused a rapid reversal of clinical and hematologic abnormalities and major cytogenetic responses in over 50% of chronic phase patients. It was administered orally, and side effects were relatively minor, with nausea, headache, rashes, and fluid retention being the most common; significant cytopenias and hepatotoxicity were less frequent. The toxicity, in general, seems to be appreciably less than that associated with interferon-alfa. Current studies confirm the initial impressive results of imatinib.[8,30,31] Notably, over 95% of patients in chronic phase who are refractory or resistant to interferon-alfa achieved a complete hematologic response, and 55% of these patients achieved a major cytogenetic response, but thus far very few patients have achieved convincing molecular remissions.[32,33] To what extent such patients obtained survival benefit could not immediately be ascertained, though it does now appear that patients who obtained cytogenetic responses survive longer than matched controls. A prospective, randomized phase III trial designed to answer this question therefore started in 2000, and the interim results were published recently; they revealed that 74% of the patients treated with imatinib achieved a complete cytogenetic remission (CCR). Progression-free survival was significantly better in the imatinib-treated cohort compared to the interferon-alfa and cytarabine cohort (97.2% vs 90.3%, P < .001), but it is too early to expect evidence of prolonged surviv- al. It is therefore not possible to conclude that imatinib as a single agent cures substantial numbers of patients, but it may well offer the prospect of "operational cure" to a significant proportion. Moreover, whether imatinib is superior to interferon-alfa plus cytarabine in previously untreated chronic phase CML patietns remains to be determined. In the molecular analysis of the cohort achieving a CCR, 3.6% of these patients achieved a complete molecular remission (defined by a complete absence of detectable BCR-ABL transcripts in the blood; the investigators considered this to represent > 4.5 log reduction in BCR-ABL/BCR level when compared to the median pretreatment level). Although imatinib appears to be quite safe, caution must be exercised in light of several recent reports. Gratwohl and his colleagues have reported a potentially fatal side effect- cerebral edema-soon after the initiation of imatinib therapy. An interesting nonsinister effect-hair repigmentation-has been reported in a small cohort of responders. The mechanisms for these unique effects remain speculative, although the possible inhibition of the platelet-derived growth factor receptor has been suggested for the former effect. Imatinib is known to be a potent competitive inhibitor of the tyrosine kinase associated with the platelet-derived growth factor receptor, and a recent report has confirmed its usefulness in patients with chronic myeloproliferative disorders with rearrangements of this receptor.
- Imatinib in Advanced Phases of CML-CML-Studies have also confirmed impressive (although less durable) clinical activity of imatinib in advanced phases of CML.[40-42] This is remarkable because imatinib targets mainly the Abl kinase activity of the Bcr-Abl oncoprotein, and as other (additional) genetic events underlie disease progression, the drug might have been expected to have little or no activity in the advanced phases. It is now likely to be tested in combination with various chemotherapeutic agents. Notably, some in vitro evi- evidence demonstrates that the combination of imatinib and agents such as interferon-alfa and hydroxyurea may result in anatagonism.[43,44]
- Imatinib-Refractory Patients-Acquired resistance to imatinib among patients in chronic phase appears to be rare and can often be overcome by increasing the dose of the agent. In contrast, resistance has been seen in up to 70% of those in myeloid blast crisis, and all patients in lymphoid blast crisis relapse within 6 months of responding to imatinib. This reaction appears to result from a variety of diverse mechanisms, including acquired mutations in the Abl kinase domain, Bcr-Abl overexpression, Pglycoprotein overexpression reducing the cellular uptake of imatinib, selection of preexisting mutant cells, and possibly excessive degradation of the Bcr-Abl protein.[46-49] The intrinsic production of some proteins, such as alpha-1 acid glycoprotein or a P450 enzyme, may neutralize imatinib and render it ineffective. Of great interest is the recent finding of "acquired" mutations, which result in structural changes that prevent imatinib binding but do not prevent pathologic phosphorylation of the relevant substrates by the oncoprotein. Currently, at least 18 different mutations have been described and are associated with some degree of resistance to imatinib. Of particular interest is the recent report that mutations in the P loop of the Abl kinase domain predict for disease progression, whereas mutations not involving the P loop are less ominous.[ 51] Various lines of evidence suggest that these "acquired" mutations reflect selection by imatinib of mutant clones already present at low levels before inititation of treatment rather than de novo acquisition during imatinib therapy.[52-55] These observations mean that even when multiple additional genetic events predominate in the advanced stages of CML, the original molecular event still appears to play some role in maintaining the aggressively transformed phenotype, emphasizing the importance of BCR-ABL in the pathogenesis of CML.
Interferon-alfa treatment was until recently the mainstay of treatment for CML. It is associated with a wide range of side effects including flulike symptoms, lethargy, depression, and weight loss. In an attempt to reduce this toxicity, clinicians have begun using a long-acting form of the drug-pegylated interferon-alfa. The notion of adding cytarabine to interferon- alfa appeared attractive on the basis of a recent study demonstrating superior survival for the combination compared to interferon-alfa alone, but this result has more recently been called into question. It is remarkable that despite being in clinical use for 2 decades, the precise mechanism of interferon-alfa's action remains unknown. Although it was undoubtedly a valuable drug, it did not appear to produce any durable molecular responses. If one defines "cure" as complete eradication of all leukemia cells (which would require persisting failure to detect BCR-ABL transcripts by reverse transcription polymerase chain reaction), then interferon- alfa did not result in cure, but in a small percentage of patients, an "operational cure"-low numbers of cells persisted but appeared unable to reestablish clinical disease. Allogeneic Stem Cell Transplant
Cure by allo-SCT depends on the combined effects of chemotherapy or chemoradiotherapy conditioning before transfusion and the graft-vs-leukemia effect mediated by allogeneic T lymphocytes. Current results using human leukocyte antigen (HLA)-identical sibling donors suggest the probability of event-free survival at 5 years of about 60%; the probability of relapse at 5 years is 15%. In contrast, the results of allo-SCT performed in more advanced phases of the disease are generally poor. Because only about one-third of all patients considered for an allo-SCT have an HLAmatched sibling donor, many efforts have been directed toward the identification of suitable alternative donors, ie, either partially matched family members or unrelated volunteers. Clinical results with these alternative donors appear to be slightly inferior or comparable to HLA-matched sibling transplants.[60-62] The major determinants of survival, other than the phase of the disease, include the patient's age at transplant, the duration of disease from diagnosis, the cytomegalovirus status of the patient, acute and chronic GVHD, and the sex of the donor. Thus, survival appears to be best among patients who are transplanted within 1 year of diagnosis, are less than 40 years of age, and have a male donor, and in cases where both patient and donor are cytomegalovirus- seronegative. For such a cohort, 5-year disease-free survival is around 70% to 80%, and the relapse rate, 10% to 20%. The precise details of the transplant procedure and the choice of stem cells (marrow vs peripheral blood) also influence outcome. Engraftment appears to be more rapid following a peripheral blood stem cell transplant, but the incidence of chronic GVHD may be increased.[66,67] It remains unclear whether the risk of relapse differs significantly following transplantation of allogeneic blood cells rather than marrow cells.[68,69] Acute and chronic GVHD continues to be a significant cause of transplant- related mortality. The best approach to prophylaxis of GVHD, usually a combination of cyclosporine and methotrexate(Drug information on methotrexate), remains controversial. Over a decade ago, it was demonstrated that alloreactive T lymphocytes cause GVHD reactions and that T-cell depletion of the graft substantially reduces the incidence of acute and chronic GVHD but also increases the risk of relapse. Allo-SCT using T-cell depletion with the CD52 monoclonal antibody Campath-1 results in an actuarial relapse rate (after transplantation in chronic phase) of 60% to 70%. Other methods of T-cell depletion, including use of other antibodies and E-rosette formation/soybean lectin agglutination, also reduce the incidence of GVHD but increase the incidence of relapse to varying degrees. Recently, it was shown that transplantation of highly purified CD34+ peripheral blood stem cells with Tlymphocyte add-back does not appear to be associated with an increased risk of relapse; this strategy is being tested further. Prior use of interferonalfa may be associated with an inferior survival, although reports are conflicting.[73-75] Preliminary data from the European Group for Blood and Marrow Transplantation (EBMT) suggest that treatment with imatinib mesylate does not have a deleterious effect on subsequent allogeneic transplantation,[ 76,77] but this will require further observation.