Introduction

Chronic myeloid leukemia (CML) is diagnosed in about 6,000 people annually in the USA. 20% to 30% of them die within 2 years, and about 25% die each year after that. There are three progressive phases - an initial chronic phase, an accelerated phase, and the blast crisis, when myeloblasts (or lymphoblasts in 1/3 of the cases) flood the peripheral blood. The average survival time after a blast crisis is only 2 months, but chemotherapy can sometimes extend survival to 8 to 12 months. Allogeneic bone marrow transplantation is potentially curative, but the procedure and the after-regime carries a considerable morbidity and mortality, and lack of suitable donors limits its application. Interferon alfa prolongs survival, but produces substantial side effects.

Characteristically, the leukemic cells contain the Philadelphia (Ph) chromosome (a chromosome that has a specific piece of another chromosome attached to it), which is associated with generation of the oncogenic protein BCR-ABL, a tyrosine kinase. BCR-ABL is present in virtually all cases of CML as well as in 20% of cases of acute lymphoblastic leukemia (ALL). The drug substance STI571 (STI stands for signal-transduction inhibitor) is a fairly specific blocker of BCR-ABL tyrosine kinase activity, was therefore considered ideal for trial in CML patients and in Ph-positive ALL patients. The first clinical results, summarized here, have just been published.

Methods

Two clinical studies have been reported, both of them essentially safety and tolerability trials (so-called Phase 1 studies). In the first, 83 patients in the chronic (initial) phase, whose disease had failed to be controlled with interferon alfa, were given escalating doses of STI571 in cohorts of 3-6 patients. Criteria were set for 'chronic phase' and 'failed on interferon alfa'; the latter included patients with intolerable side effects with the drug.

Patients were successively assigned to one of 14 dose cohorts, with STI571 doses ranging from 25 to 1,000 mg daily; higher dose levels were given in twice-daily divided doses. Treatment was continued until unacceptable side effects or disease progression occurred. Starting a new cohort at a higher dose could only occur if, after 28 days of treatment, there were no severe adverse non-hematologic effects in 3 subjects, or such an event in only 1 of 6 subjects.

A hematologic response was defined as a 50% reduction in the white blood cell count (WBC) from baseline, maintained for at least 2 weeks. A complete hematologic response was defined as a WBC falling to less than 10,000/mm³ and a platelet count to less than 450/mm³, maintained for 4 weeks. Cytogenic responses were determined by the percentage of bone marrow cells with the Ph chromosome. Criteria were established for such responses being complete, partial, minor, or absent.

The second study enrolled CML and ALL patients who tested positive for the Ph chromosome and were in blast crisis (>30% blast cells in the peripheral blood or bone marrow0, and, in the case of ALL, if they had failed on standard remission-induction or consolidation chemotherapy. There were 58 patients in all - 38 with myeloid blast crisis and 20 with lymphoid blast crisis. The study design was the same as in the first study, except that the first of seven dose cohorts received 300 mg daily, with decisions to start a higher-dose cohort was based on data from the first study rather than on the condition of subjects in blast crisis. Neutropenia (neutrophil count <500/mm³) with a marrow cellularity of <10% led to interruption of STI571 treatment until the neutrophils rose to 1,000/mm³.

A complete hematologic response was defined as a decrease in marrow blast cells to 5% or less, absence of blasts in the peripheral blood, neutrophils >1,000/mm³, and platelets >100,000/mm³. A marrow response was a decrease in marrow blast cells to <5%, or between 5% and 15%, irrespective of peripheral blood findings.

Results of treating chronic CML

Of the 83 patients enrolled (median age 55, range 19-76), 37 had hematologic resistance or relapse, 33 had cytogenic resistance or relapse, and 13 could not tolerate interferon alfa. The median duration of disease was 3.8 years. Nineteen of them had evidence of accelerated disease (5-15% blast cells or basophils in the bone marrow). The median duration of treatment with STI571 was 310 days.

Hematologic responses were seen in all patients treated with 140 mg or more of STI571 daily. At daily doses of 300 mg or more, 53 of 54 patients had complete hematologic responses. Typically, responses were seen within 2 weeks after starting the drug. Complete hematologic responses were maintained in 51 of the 53 patients with a median follow-up of 265 days (range 17 to 468 days).

Of the 54 patients given 3000 mg daily or more, 17 (31%) had a major cytogenic response, and a further 12 (22%) had a minor cytogenic response. These responses occurred as early as 2 months and as late as 10 months after starting treatment with STI571.

Pharmacokinetic studies showed that STI571 was rapidly absorbed, and had a half-life of 13-16 hours. Tolerability was good, and a maximal tolerated dose was not found. The most common adverse effects, which were mostly graded as mild or moderate, were nausea (43%), myalgia (41%), edema (39%), and diarrhea (25%). Anemia, thrombocytopenia and neutropenia were seen in several patients given higher doses. Liver enzymes were raised in 7 of the 83 patients - in some the elevation was reversed during continued STI571 administration, while in others the drug was discontinued temporarily, or the dose reduced. One patient had a persistent progressive rash.

Results of treating blast crises in CML and ALL

Overall, there was a 55% response rate in the 38 myeloid blast crisis patients, and 70% in the 20 lymphoid blast crisis patients. Complete hematologic remissions were obtained in 4/38 (11%) myeloid, and 4/20 lymphoid (20%) blast crises, respectively. Marrow responses were seen in 17/38 (45%) myeloid, and 10/20 (50%) lymphoid cases, respectively.

Seven of the 38 myeloid subjects (18%) were still receiving STI571 at the time of publication, having remained in remission for between 101 and 349 days after starting treatment. All but one of the 20 ALL patients had relapsed by the time of publication. All the patients who relapsed were still Ph-chromosome-positive.

Tolerability was generally good. The commonest side effects, which were dose-dependent and mostly mild or moderate in severity, were nausea (55%), vomiting (41%), and edema (41%). Neutropenia and thrombocytopenia were over a third of the patients. Liver enzyme increases occurred in 8 (14%) of the patients, usually about 16 days after starting treatment, but STI571 was only discontinued in one of these.

Sixteen patients died due to disease progression. No deaths were considered to be related to STI571 treatment. At the higher doses (800 and 1,000 mg daily), in addition to severe nausea, vomiting, and neutropenia, there were single reports of exfoliative dermatitis, gastric hemorrhage, renal failure, pancytopenia and congestive heart failure.

Comment

The investigators point out that these results were obtained in late-stage disease - thus the first study in initial chronic phase patients was, in fact, done in subjects who had failed on alfa interferon and had been diagnosed for a median of 3.8 years. The responses obtained were rapid (within a few weeks) and dose-dependant. Side effects were minimal, when compared with those usually encountered with chemotherapeutic agents. Based on the findings, and the pharmacokinetic data, the authors suggest an STI571 dose of at least 400 mg daily for future studies.

In the second study, where the leukemias were in their pre-terminal phase, STI571 was marginally more successful in inducing remission in myeloid, rather than lymphoid, blast crises. Previous work has shown that stem-cell transplants have more successful outcomes in CML patients in blast crisis who are returned to the chronic phase first. STI571 may, therefore, be a useful bridge to transplantation. Based on the results of this study, the appropriate dose of STI571 probably between 400 and 700 mg daily.

Taken together, these two studies show that STI571 has the ability 'to reverse very rapidly the clinical and hematologic abnormalities of CML in the chronic phase, and, in many cases, to reduce to zero or to low levels the proportion of Ph-chromosome-positive cells in the bone marrow. The toxicity profile seems very mild for a drug with this degree of potency' (Editorial in the Journal¹ ). Further studies are indicated using the drug in combination with alfa interferon and/or cytarabine. There is reason to believe that STI571 represents that often trumpeted, but rarely substantiated sobriquet, "a breakthrough". Clinical trials have begun in patients with lung, prostate, and cerebral tumors, and their results are awaited with great interest.

STI571 is marketed by Novartis Pharmaceuticals in the USA under the name Gleevec (and by Novartis as Glivec in other countries). To learn more, click here to go to the Novartis Oncology website for Gleevec.