Current Status of Therapy for Chronic Myeloid Leukemia: A Review of Drug Development
Swami Padmanabhan; Saritha Ravella; Tyler Curiel; Francis Giles
Future Oncol. 2008;4(3):359-377. ©2008 Future Medicine Ltd.
Abstract and Introduction
Chronic myeloid leukemia (CML) has led the way for developing rational drug development in cancer. Most cases of CML diagnosed and treated in chronic phase are extremely well controlled with imatinib monotherapy, and primary resistance is very uncommon. Even though the treatment failure rate is low, the emergence of drug resistance and the lack of eradication of the hematopoietic stem cell clone has prompted a wave of drugs to address one or both these problems. Several clinical trials (Phase I and II) of dasatinib or nilotinib in the treatment of imatinib-resistant or -intolerant Ph chromosome-positive leukemia have already reported a remarkable rate of hematologic response greater than 90% for chronic-phase patients. These drugs minimize the risk of acquired drug resistance that is particularly seen within the first 24-36 months of therapy, and can prevent early failure in these patients, Furthermore, rational, noncross-resistant combinations that include a T315I inhibitor and drugs that can eradicate the hematopoietic stem cell clone may extend the coverage to virtually all patients with bcr-abl. Here we review the 6-year impact of the 'magic pill', Gleevec®, (Glivec®), including the emerging problems with its treatment, the efficacy data of dasatinib and nilotinib and the very promising data of the newer generation of drugs for CML.
Chronic myeloid leukemia (CML) is a myeloproliferative disorder that can occur in a bi- or tri-phasic course. CML occurs with an incidence of approximately 1-1.5 cases per 100,000 population, and accounts for approximately 7-15% of newly diagnosed cases of leukemia in adults. As per the NCI's Surveillance, Epidemiology, and End Results (SEER) Cancer Statistics Review, it is estimated that 4830 men and women (2800 men and 2030 women) will be diagnosed with CML, and 450 men and women will die from the disease in 2008. The median age at presentation is around 66 years. In the preimatinib era, the median survival was 4-6 years (range <1 year to >10 years). Survival after the development of an accelerated phase is usually less than 1 year and only a few months after blastic transformation.
The typical course of disease is characterized by an initial chronic phase lasting for 3-6 years, followed by an accelerated, then blastic phase usually of short duration. A total of 75-80% of patients go through an accelerated phase before the blastic phase. The definition for accelerated phase is not uniform, which needs to be verified when evaluating treatments. Specific criteria associated with a survival shorter than 18 months by multivariate analysis have been proposed, including the presence of ≥15% blasts, or ≥30% blasts and promyelocytes, or ≥20% basophils in blood or platelet count <100. A cytogenetic clonal evolution is also considered criteria for acceleration. Recent analysis suggests its prognostic effect depends on the specific abnormality, its predominance in marrow metaphases and the time of appearance.
The cytogenetic hallmark of CML is a reciprocal t(9,22)(q34;q11) chromosomal translocation that creates a derivative 9q+ and a small 22q-, known as the Ph chromosome. The latter harbors the bcr-abl fusion gene encoding the chimeric bcr-abl protein with a deregulated tyrosine kinase activity, the expression of which has been shown to be necessary and sufficient for the transformed phenotype of CML cells. The activation of multiple signal transduction pathways in bcr-abl transformed cells leads to increased proliferation, reduced growth-factor dependence and apoptosis, and perturbed interaction with the extracellular matrix and stroma. CML is a quintessential example in human neoplasia, wherein a single oncogenic fusion abnormality plays a central role in its pathology.
Bcr-abl as the Target for Drug Development: Paradigm Shift With Imatinib
This understanding of the cytogenetic and molecular pathophysiology underlying CML has paved a way for the development of effective targeted molecular therapies. This ultimately led to the development of imatinib mesylate (STI-571, Gleevec®, Glivec®), an oral inhibitor of bcr-abl kinase activity. The clinical success of imatinib mesylate in the treatment of CML, especially the high durable response rates in patients with chronic phase CML, has validated the therapeutic strategy of rationally targeting the causative molecular abnormality of CML. In the international randomized study of IFN-α versus STI571 (IRIS) study, of 343 patients in whom at least 20 cells in metaphase had been cytogenetically analyzed in 3 months, 152 had a major cytogenetic response (no more than 35% Ph+ cells in metaphase). Whereas CML progressed in only five of the patients with major cytogenetic response (3.3%), disease progression was documented in 22 of the 191 patients without such a response (11.5%; p = 0.005 by the log rank test). This is evident from the higher rates of complete hematologic response (95 vs 56% of patients; p < 0.001) and major cytogenetic response (85 vs 22% of patients; p < 0.001). A median follow-up of 19 months demonstrated that imatinib mesylate was associated with predominantly better responses than IFN-α and Ara-C combination therapy. On the basis of these results, imatinib mesylate was approved in 2001 by the US FDA for treatment of patients with Ph+ CML in blastic-phase, accelerated-phase and chronic-phase patients who failed IFN-α therapy. Subsequently, in 2002, imatinib mesylate also received accelerated approval for the treatment of newly diagnosed Ph+ CML in chronic phase. Imatinib has changed the management of CML and has become the current standard of treatment for CML.
Dose & Duration of Imatinib Therapy & the Race for the Cure
Imatinib Dose Schedules
The optimal dose of imatinib is yet to be clearly defined. Although the maximum tolerated dose was not identified in the Phase I study, 400 mg per day is the dose selected for subsequent studies, as imatinib at 400 mg daily could achieve a blood concentration higher than IC50 in vitro.[3,4] Moreover, reliable clinical responses were seen at doses of 300-400 mg daily, especially in chronic-phase patients.
In Phase II trials of accelerated- and blastic-phase CML patients, imatinib at 600 mg/800 mg daily demonstrated greater efficacy over 400 mg.[5,6]
There is also a correlation of clinical responses with the steady-state trough plasma concentrations (Cmin) of imatinib mesylate and its major active metabolite, CGP74588. A total of 551 patients in the IRIS study had trough pharmacokinetic samples (24 h post dose) obtained at day 1 and steady state (day 29). The overall mean coefficient of variation (CV) for the steady-state trough levels (Cmin) is a reflection of imatinib mesylate clearance and metabolism in CML patients. Pharmacokinetic trough levels obtained for imatinib could be divided into three groups - the lower and upper quartile ranges (below Q1 = 25th percentile, above Q3 = 75th percentile) and the interquartile range. Times to complete cytogenetic response (no Ph+ metaphases) and the major molecular response within these complete cytogenetic response patients were different in these three groups. Mean (±SD) trough plasma imatinib concentrations were significantly higher in the group with major molecular response (34 patients) than in the group without (1452.1 ± 649.1 ng/ml versus 869.3 ± 427.5 ng/ml, p < 0.001), whereas there was no difference in the imatinib daily dose. For trough plasma imatinib concentrations and their discrimination potential for major molecular response, the area under receiver-operating characteristic curve was 0.775, with best sensitivity (76.5%) and specificity (70.6%) at a plasma threshold of 1002 ng/ml. By 4 years, an estimated 53% achieved major molecular response despite low steady-state Cmin levels compared with 80% for patients with high Cmin (and 72% for patients within the interquartile range). These results suggest that achieving and maintaining an adequate plasma concentration (by therapeutic drug monitoring) of imatinib mesylate is important for a good clinical response.
High-dose imatinib mesylate (800 mg daily), as front-line treatment has been studied in newly diagnosed chronic-phase CML patients. Responses in 175 patients (with a median follow-up of 30 months) have been evaluated in comparison with historical controls (n = 50) receiving standard-dose imatinib (median follow-up of 53 months). A complete cytogenetic response with imatinib was achieved in 90% of high-dose-treated patients, in contrast to only 78% of standard-dose-treated patients (p = 0.03). At 12 months, the major molecular response rates were 54% with high dose, versus 24% with standard dose (p = 0.001), and complete molecular response rates at 24 months were 27 and 10%, respectively. Based on the pharmacokinetic data from the IRIS studies it is very likely that due to higher Cmin patients receiving high-dose imatinib mesylate (800 mg daily) upfront (in newly diagnosed patients) they achieve complete cytogenetic response at a rapid rate, but not necessarily at a significantly higher rate.
The results of these studies are somewhat difficult to compare, owing to differences in follow-up. In addition, the reverse transcriptase (RT)-PCR technology was not standardized. Nonetheless, the emerging picture is that the rates of major molecular remission and complete cytogenetic response in the combination studies are comparable with the IRIS trial, but higher in patients treated with 800 mg imatinib daily, while the rates of major molecular response and complete molecular response are generally higher compared to standard-dose imatinib. This increased efficacy comes at the cost of increased toxicity. For example, the incidence of grade 3/4 neutropenia was 63% in patients treated with imatinib and pegylated IFN, and 41% experienced grade 3/4 nonhematologic toxicity. As a result, only a fraction of the planned IFN dose was actually administered. Taken together, these results clearly suggest that early intensification of therapy may increase the frequency of profound remissions, although at the price of more toxicity. Standard-dose and high-dose imatinib are currently compared in a Phase III intergroup study taking place in the USA, and are part of several multi-armed studies in Europe. Initial results suggest higher rates of major molecular response and complete molecular response, although it is being observed that the standard-dose arm is catching up with time.
Duration of Imatinib Therapy
The optimal duration of imatinib therapy is yet to be determined. In 2006, 5-year follow-up data for imatinib mesylate from the Phase III, multicentered, randomized, open-label, international IRIS trial of 1106 patients showed long-term survival and safety in newly diagnosed Ph+ CML in chronic phase. An estimated 89% (95% CI: 86-92%) of patients were alive at 5 years, while the overall survival (OS) in the IFN arm was 86%. In addition, an estimated total of 93% of patients had not progressed to advanced phases of Ph+ CML, while only approximately 2.4% of patients discontinued imatinib mesylate owing to drug-related adverse events. Furthermore, the annual rates of progression events decreased with the passing years, with 1.5% in the first year, 2.8% in the second year and tapering down to less than 1% in the fourth and fifth years. Approximately 382 out of 553 (69%) patients randomized to imatinib mesylate were still receiving first-line therapy, while only 16 out of 553 in the group given IFN plus Ara-C continued their treatments. From the latter group, 359/553 (65%) had crossed over to imatinib mesylate. The progression-free survival (PFS) in the intent-to-treat group was 83.2% (95% CI: 79-87) for imatinib mesylate and 64.1% (95% CI: 59-69) in the IFN arm. In terms of confirmed responses, the complete hematologic response rate was 96.6%, the major cytogenetic response rate was 85.2%, and the complete cytogenetic response rate was 73.1%. The evolving imatinib mesylate data from the IRIS trial are summarized in Table 1 .
Given this outstanding response with imatinib mesylate, it is prudent to continue this treatment indefinitely. Furthermore, there is currently no evidence to indicate that imatinib mesylate can be discontinued safely even after attaining undetectable bcr-abl transcript levels. Most patients who have stopped imatinib mesylate therapy have experienced molecular or cytogenetic relapse even after achieving a sustained complete molecular response for a considerable duration of time.[10-12] Thus, the current recommendation suggests continuation of imatinib mesylate therapy indefinitely unless the patient experiences unacceptable toxicity or treatment failure.
It is also not clear if imatinib mesylate can be stopped when patients achieved major molecular response or complete molecular response. To date, information is mostly limited to anecdotal observations of patients who stopped therapy in complete cytogenetic response or complete molecular response for various reasons, such as side-effects or pregnancy.[10,11,13] Most of them had disease recurrence, which should not be confused with relapse, since rechallenge with imatinib mesylate usually restored response. The only patients who maintained response were individuals who had received imatinib mesylate for relapse after allogeneic transplantation or who had been treated with IFN-α before they commenced imatinib. Thus, it can be surmised from all these clinical data that imatinib alone is not capable of eradicating the leukemic stem cell clone.
Adverse Events to Imatinib
The majority of CML patients treated with imatinib mesylate experienced adverse events at some time. Most events were of mild-to-moderate grade, but the drug was discontinued for adverse events in 1% of patients in the chronic phase, 2% in the accelerated phase and 5% in blast crisis. The most frequently reported drug related (>25%) adverse events were nausea, vomiting, edema and muscle cramps. Edema was most frequently periorbital or in lower limbs, and the frequency of severe edema was 1-5%. These events appear to be dose-related, were more common in the blast crisis and accelerated phase studies (where the dose was 600 mg/day), and are more common in the elderly. The fluid retention events were usually managed by interrupting imatinib mesylate treatments and with diuretics, or other appropriate supportive care measures. In a recent 2006 report, imatinib was associated with cardiotoxicity and congestive heart failure, although this toxicity is a rare event in clinical practice. One such reported serious and life-threatening event was seen in a patient with blast crisis who subsequently died after pleural effusion, congestive heart failure and renal failure. Grade 3-4 hematologic adverse events were infrequent, except for neutropenia (14%) and thrombocytopenia (8%).
Monitoring the Disease Responses & Measuring Minimal Residual Disease
Even though routine cytogenetic analysis is still considered the gold standard for evaluating response in CML, the studies are often somewhat cumbersome in practice and require analysis in metaphase. As most patients are able to achieve complete cytogenetic responses with tyrosine kinase inhibitors (TKIs), sensitive and accurate monitoring of bcr-abl is required to measure residual disease. In CML patients who achieved a complete cytogenetic response, fluorescence in situ hybridization (FISH) is more sensitive than conventional cytogenetics to monitor Ph negativity, and thus a biologic response to treatment. Since FISH studies typically involve looking for the bcr-abl fusion fluorescence in at least 200 interphase cells, this precludes the sensitivity of FISH in making judgments on the extent of residual disease. Furthermore, since most CML studies have assessed long-term outcomes by monitoring cytogenetics and not FISH, quantitative RT-PCR (qRT-PCR) is currently used for assessing the depth of the molecular response and measurement of residual disease with a sensitivity of up to 10-8. Molecular remission can thus be defined in this fashion as a reduction in the quantification of bcr-abl transcripts to an undetectable level, and can be considered as a surrogate marker for cure and/or long-term disease control. It has been shown that such precision might help to predict disease outcome in a better way. Major molecular response is defined as a reduction of bcr-abl transcript levels by 3 or more logs, compared with a standardized baseline, obtained from newly diagnosed and untreated CML patients. So for the standardized baseline in the IRIS trial, which was the average ratio from 30 patients and was 36%, the major molecular response was defined as achieving levels of 0.036% or less. A complete molecular response is defined as undetectability of bcr-abl transcripts if confirmed on a second occasion. Given the variations in the technical aspects of the assay, there is a need for standardization. Therefore, to maximize the consistency and reliability of the qRT-PCR or real-time quantitative PCR (RQ-PCR) techniques, a recent consensus proposal suggested optimization of several procedural aspects of the complex RQ-PCR technique used for measuring bcr-abl transcripts (measuring the molecular response of imatinib mesylate therapy).[18-20] An International Scale (IS) was proposed to generate comparable values when tested in any laboratory, and the scale is fixed to a major molecular response at a value of 0.1%. It allows for differences generated by various RQ-PCR methods and controls. The ongoing validity of conversion is reliant on maintaining performance of analysis within a laboratory. The speed and amount of response are both believed to play an important role in the determination of prognosis. In the IRIS trial, patients who achieved a major molecular response at 18 months had 100% progression-free survival (without progression to accelerated phase/blastic phase at 5 years), whereas patients who failed to achieve complete cytogenetic response had a PFS of 83% (p < 0.001). Major molecular remission rates and PFS (at 12 months, 40 and 2%, respectively) were also found to be better with imatinib mesylate therapy. The patients who achieved a complete cytogenetic response by 12 months had only a 3% probability of progression to acute phase or loss of complete hematologic remission of major molecular remission over the subsequent 12 months, compared with a 15% probability of progression for those patients who did not achieve a major molecular remission. This study demonstrates that achievement of major molecular remission, complete cytogenetic response and complete molecular response are valid efficacy end points in CML, as they correlate with clinical benefit.
The unsolved challenges with imatinib mesylate include:
- Residual disease, even in those who have undetectable bcr-abl transcripts, relapses with discontinuation of imatinib mesylate;
- Development of resistance, especially in the advanced stages: CML patients in phases other than chronic-phase CML do not show a better treatment response and survival, as is seen in chronic-phase CML patients, despite dose increases to 800 mg daily. In addition, since the introduction of imatinib, median survival in blast crisis has increased from 2-3 months to only 7.5 months, with few long-term survivors;
- Long-term effects of imatinib mesylate therapy on chromosomal aberrations in the bone marrow[21,22] (the chromosomal changes most commonly reported with imatinib are trisomy 8 and monosomy 7), on bone and mineral metabolism or cardiac function are unknown.
We will now illustrate the first two of these issues and how further drug development can address these.