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U.S. Food and Drug Administration Drug Approval Summary: Conversion of Imatinib Mesylate (STI571; Gleevec) Tablets from Accelerated Approval to Full Approval

Division of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland

Requests for reprints: Martin H. Cohen, U.S. Food and Drug Administration, HFD-150, 5600 Fishers Lane, Rockville, MD 20857. Phone: 301-594-5740; Fax: 301-594-0499; E-mail: cohenma{at}cder.fda.gov.

	ABSTRACT

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Imatinib mesylate (Gleevec, Novartis Pharmaceuticals East Manruer, NJ) received accelerated approval on May 10, 2001 for the treatment of patients with chronic myeloid leukemia (CML) in (a) chronic phase after failure of IFN- therapy, (b) accelerated phase, and (c) blast crisis. The accelerated approval was accompanied by a postmarketing commitment by Novartis Pharmaceuticals to continue patient follow-up to determine duration of treatment response and survival. The present review, based on a safety and efficacy report submitted on December 20, 2002, summarizes data applicable to the conversion of these three CML indications to full approval status.

Results: Chronic phase CML: Five hundred thirty-two chronic phase CML patients who had not benefited from prior IFN therapy were treated at a starting imatinib mesylate dose of 400 mg p.o. qd; dose escalation to 800 mg p.o. qd was allowed. Patients had received a median of 14 months of IFN therapy at doses 25 million IU/wk and were all in late chronic phase, with a median time from diagnosis of 32 months. Median duration of imatinib mesylate treatment was 29 months, with 81% of patients treated for 24 months (maximum 31.5 months). Initial favorable treatment responses were sustained. An estimated 87.8% of patients who had a major cytogenetic response maintained their response 2 years after their initial response. After 2 years of treatment, an estimated 85.4% of patients were free of progression to accelerated phase or blast crisis, and the estimated overall survival was 90.8% (95% confidence interval, 88.3-93.2). Accelerated phase CML: Patients enrolled totaled 293: 235 with CML accelerated phase, 48 with relapsed/refractory acute lymphocytic leukemia, 2 with relapsed/refractory acute myelocytic leukemia, and 8 with relapsed/refractory CML in lymphoid blast crisis. Patients received imatinib mesylate 400 or 600 mg p.o. qd. Dose escalation was permitted, to a maximum of 800 mg/d, taken as 400 mg bid. Efficacy results were improved in patients receiving imatinib mesylate 600 mg qd versus patients receiving 400 mg qd. The median duration of hematologic response was 29 versus 17 months and the estimated 24-month maintained hematologic response rate was 61% versus 42%. The median survival of patients treated with imatinib mesylate 600 mg qd was not reached versus 20.9 months for patients receiving 400 mg qd. Estimated 24-month survival rate was 66% versus 46%. The median survival in the advanced leukemia population (acute lymphocytic leukemia, acute myelocytic leukemia, and lymphoid blast crisis) was only 5 months, and only two patients are still on treatment. Blast crisis CML: A total of 260 patients were recruited. The imatinib mesylate dose was initially 400 mg qd (37 patients) but was subsequently increased to 600 mg qd (223 patients). Patients receiving imatinib mesylate 600 mg qd had a higher hematologic response rate than did patients receiving 400 mg (33% versus 16%). Major cytogenetic responses occurred in 15% of the 260 study patients. The overall median survival was 6.9 months: 7.1 months for patients treated with imatinib mesylate 600 mg and 4.7 months for patients receiving imatinib mesylate 400 mg. Estimated 12-month survival rate for all study patients was 32.1% and estimated 24-month survival rate was 18.3%. Safety: Imatinib mesylate was generally well tolerated, but relatively frequent reports of common toxicity criteria grade 3/4 neutropenia and thrombocytopenia were encountered. The most frequently reported adverse events included gastrointestinal disturbances, edema, rash, and musculoskeletal complaints. These rarely led to discontinuation of therapy.

Conclusions: The results confirm those of the interim analysis and suggest that imatinib mesylate represents an effective therapeutic agent for the treatment of patients with CML in chronic phase after failure of IFN- therapy, in blast crisis, and in accelerated phase.

Key Words: Imatinib mesylate • Gleevec • STI571 • Gleevec tablets • chronic myeloid leukemia chronic phase • chronic myeloid leukemia accelerated phase • chronic myeloid leukemia blast crisis

	INTRODUCTION

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On December 5, 2003, the U.S. Food and Drug Administration converted the approval of imatinib mesylate tablets (Gleevec, Novartis Pharmaceuticals) for the treatment of adult patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in (a) chronic phase after failure of IFN- therapy, (b) accelerated phase, and (c) blast crisis from accelerated to regular approval. Accelerated approval, allowed on May 10, 2001 (1), permits approval of a drug for a serious or life-threatening disease for which treatment is inadequate based on an effect on a surrogate end point (in this case, cytogenetic and hematologic responses) that is reasonably likely to predict clinical benefit. Patient follow-up was relatively short at the time of accelerated approval (3-7 months after recruitment of the last chronic phase, accelerated phase, or blast crisis patient), too short to establish clinical benefit. Therefore, Novartis Pharmaceuticals was required to continue patient follow-up to determine response duration and to obtain additional safety data.

Imatinib mesylate subsequently received accelerated approval for treatment of newly diagnosed CML on December 20, 2002; this indication has not yet been converted to regular approval.

	EXPERIMENTAL DESIGN

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Study Populations. Definitions of CML chronic phase, accelerated phase, and blast crisis are summarized in Table 1. Definitions or hematologic and cytogenetic response criteria for each of the three CML phases are summarized in Table 2.

Study eligibility included Ph+ CML, ages 18 years, and with IFN failure or intolerance defined as any of the following: (a) failure to achieve a CHR, lasting for at least 1 month despite 6 months of IFN or an IFN-containing regimen, in which IFN was administered at a dose of at least 25 million IU (MIU)/wk. During this treatment period, the cumulative duration of hydroxyurea therapy may not have exceeded 50% of the treatment period with the IFN-containing regimen (hematologic resistance); (b) bone marrow cytogenetics showing >65% Ph+ after 1 year of IFN-based therapy (cytogenetic resistance); (c) an increase in the Ph+ chromosome in bone marrow cells by at least 30 percentage points (e.g., from 20% to 50% or from 30% to 60%), confirmed by two samples at least 1 month apart, or an absolute increase to >65% (cytogenetic refractoriness); and (d) a rising WBC count (to a level >20 x 10⁹/L confirmed by two samples taken at least 2 weeks apart) for patients achieving a CHR while receiving IFN or an IFN-containing regimen at a dose of at least 25 MIU/wk. During this treatment period, the cumulative duration of hydroxyurea therapy may not have exceeded 50% of the treatment period with the IFN-containing regimen (hematologic refractoriness), or (e) intolerance to IFN therapy defined as a grade >3 nonhematologic toxicity persisting for at least 1 month, for patients receiving IFN alone or in combination when IFN was administered at a dose of at least 25MIU/wk. Patients who were intolerant of IFN were to have been diagnosed 6 months before the time of entry into the study.

Patients received imatinib mesylate 400 mg p.o. qd. Dose escalation was permitted to 600 mg p.o. qd or to a maximum of 800 mg daily taken as 400 mg bid.

Accelerated Phase CML Study. The primary objective was to determine the rate of hematologic response lasting >4 weeks. Secondary objectives included determination of the duration of hematologic response, overall survival, cytogenetic response, time to blast crisis, and tolerability and safety of ST1571 treatment. The first patient was recruited on August 9, 1999, whereas the last patient was recruited on May 12, 2000. Data cutoff for this analysis was December 16, 2002.

To be eligible for the study, patients had to be ages >18 years, with performance status <2, and with a histologically confirmed diagnosis of Ph+ leukemia of one of the following types: accelerated phase CML (Table 1), relapsed/refractory acute lymphocytic leukemia, relapsed/refractory acute myelocyticleukemia, and relapsed/refractory CML in lymphoid blast crisis.

Patients received imatinib mesylate 400 or 600 mg p.o. qd. Dose escalation was permitted, to a maximum of 800 mg daily, taken as 400 mg bid.

Blast Crisis Phase CML Study. The primary objective was to determine the rate of hematologic response lasting 4 weeks. Secondary objectives included determination of the duration of hematologic response, overall survival, cytogenetic response, and tolerability and safety of imatinib mesylate treatment. The first patient was recruited on June 30, 1999, whereas the last patient was recruited on May 12, 2000. Data cutoff for this analysis was July 31, 2002.

To be eligible for the study, patients had to be ages 18 years, with performance status 2, and with a histologically confirmed diagnosis of Ph+ CML in myeloid blast crisis (Table 1). Both newly diagnosed patients and patients who had received prior therapies for CML accelerated phase or blast crisis were eligible. Newly diagnosed patients were not to have received prior accelerated phase or blast crisis therapies, with the exception of IFN or hydroxyurea.

Patients received imatinib mesylate 400 or 600 mg p.o. qd. Dose escalation was permitted, to a maximum of 800 mg daily, taken as 400 mg bid.

	RESULTS

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Chronic Phase CML Study. Table 3 summarizes patient demographics characteristics and Table 4 summarizes pertinent data concerning disease history at baseline. Patients studied were in late chronic phase CML, with a median time since diagnosis of 32 months. As expected, patients with cytogenetic failure had the longest IFN exposure, and IFN-intolerant patients the shortest. Even for IFN intolerant patients, however, 26% received IFN for 6 to 12 months and 30% received it for 1 year.

Confirmed Cytogenetic Response Rate. Confirmed cytogenetic responses are shown in Table 5; 38% of study patients attained a CCyR and 59% had a MCyR. More than 50% of the MCyRs were noted at the time of the first on-study bone marrow (3 months). The percentage of patients with a MCyR steadily increased with increasing time on treatment. Approximately 9% of MCyRs occurred after 1 year of treatment and 7% occurred after 2 years of treatment. The MCyR rate was highest in patients with a recent diagnosis of CML (within 1 year of study enrollment) and was lower in patients with laboratory evidence of more advanced disease (i.e., high WBC count, high platelet count, low hemoglobin, and 3% blasts in the peripheral blood).

Complete Hematologic Response. A CHR was achieved in 503 of 532 study patients (95% CI, 92.3-96.3) CHR was lost during treatment in 117 (23.2%) patients. Sixty-six (13.1%) of these patients progressed to accelerated phase or blast crisis.

Time to Accelerated Phase or Blast Crisis. Of the 532 patients, 85 (16.0%) patients had values indicating progression to accelerated phase or blast crisis. The estimated probabilities (95% CI) of being free of progression to accelerated or blast crisis are 88.4% (85.7-91.2) at 18 months and 85.4% (82.4-88.5) at 24 months.

Survival. At time of analysis, 65 (12.2%) of the 532 patients had died. Of the 64 deaths (1 death was reported after bone marrow transplant), 8 occurred on study treatment and 56 occurred during follow-up after discontinuation of treatment (mostly due to progression; n = 45). The estimated probabilities (95% CI) of being alive are 94.2% (92.2-96.2) at 18 months and 90.8% (88.3-93.2) at 24 months.

Accelerated Phase CML Study. Demographics and performance status of the study population are summarized in Table 6. As indicated, patients receiving imatinib mesylate 400 or 600 mg/d were comparable.

Blast Crisis CML. Baseline demographics and performance status of the study population are summarized in Table 9. Table 10 summarizes prior disease history. As indicated, 37 patients received imatinib mesylate 400 mg/d and 223 received imatinib mesylate 600 mg/d. One hundred sixty-five (63.5%) patients were considered previously untreated for blast crisis, as either no accelerated phase or blast crisis treatment was recorded or they had received only IFN, hydroxyurea, or low-dose cytosine arabinoside, which was considered palliative treatment in this setting. The remaining 95 (36.5%) patients had received cytotoxic chemotherapy and/or bone marrow transplantation for advanced disease.

Unconfirmed MCyR (single bone marrow cytogenetic examination) was noted in 40 (16.4%) patients. Confirmed MCyRs are shown in Table 12. It should also be noted that 50% of patients had other chromosomal abnormalities in addition to being Ph+. The median duration of cytogenetic response was 4.6 months.

Safety. Table 13 lists systemic adverse events and Table 14 lists laboratory adverse events. The most frequent systemic adverse events were fluid retention nausea and muscle cramps. There was a trend suggesting increased grade 3/4 adverse events with advancing phase of disease.

View this table: [in this window] [in a new window]   Table 13 Imatinib mesylate adverse experiences (10% of all patients in any trial)

Cytopenias, particularly neutropenia and thrombocytopenia, were a consistent finding and occurred with increasing frequency with advancing disease phase (i.e., blast crisis > accelerated phase < chronic phase CML). The median duration of the neutropenic and thrombocytopenic episodes varied from 2 to 4 weeks. Neutropenia and thrombocytopenia were usually managed with either dose reduction or an interruption of treatment. In rare cases, permanent discontinuation of treatment was required.

Grade 3 elevation of transaminases or bilirubin occurred in3% to 6% (Table 14) and were usually managed with dose reduction or interruption. The median duration of these episodes was 1 week. Treatment was discontinued permanently because of liver laboratory abnormalities in <1% of patients. However, one patient, who was taking acetaminophen regularly for fever, died of acute liver failure.

Systemic toxicity did not increase with increased duration of treatment. Cytopenias were not consistently reported as adverse events so that treatment duration effects cannot be precisely determined.

	DISCUSSION

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Imatinib mesylate has proven to be a very effective drug for the treatment of CML.

The drug initially received accelerated approval for treatment of CML in blast crisis, accelerated phase, and chronic phase after failure of IFN treatment on May 10, 2001. Because the data were consistent and showed a sizable effect, a very rapid review (2.5 months) was possible.

Under the accelerated procedure, the U.S. Food and Drug Administration may approve a new drug or biologic if adequate and well-controlled trials establish that the product has an effect on a surrogate end point that is reasonably likely to predict clinical benefit. Approvals for imatinib mesylate were based on the results of three nonrandomized, single-arm trials including a total of 1,027 CML patients. The surrogate end points supporting imatinib mesylate efficacy were high hematologic and cytogenetic response rates and these were considered likely to lead to a real benefit (generally improved symptoms or survival). The accelerated approval regulations require the applicant to verify and describe the clinical benefit of the drug in additional adequate and well-controlled studies or by continued follow-up of the original study population. Such studies must be conducted with due diligence.

At the time of original approval, patient follow-up was short (3-7 months from the time of accrual of the last study patient). The current submission is based on a median drug exposure of 29 months. The maximum duration of study treatment is 32 (chronic phase) to 35 (blast crisis and accelerated phase) months, with 21% of patients treated >1 year and 10% treated >2 years (blast crisis), 61% patients treated >1 year and 45% treated >2 years (accelerated phase), and 91% patients treated >1 year and 81% treated >2 years (chronic phase).

The U.S. Food and Drug Administration converted accelerated approval to regular approval because favorable treatment responses were sustained and clearly represented clinical benefit. In the chronic phase CML study, an estimated 87.8% of patients who achieved MCyR maintained their response 2 years after achieving their initial response. After 2 years of treatment, an estimated 85.4% of patients were free of progression to accelerated phase or blast crisis, and estimated overall survival was 90.8% (95% CI, 88.3-93.2). These results are superior to historical IFN- or chemotherapy treatment results (2–4). Median survival from randomized trials comparing IFN- with hydroxyurea or busulfan treatment reports median survival of 61 to 72 months for IFN treatment and 41 to 56 months for hydroxyurea or busulfan.

In accelerated phase CML treatment, results were also favorable. Hematologic response occurred in 72% and MCyR occurred in 27% of treated patients (either imatinib mesylate 400 or 600 mg/d, nonrandomized). These results are superior to historical IFN- or chemotherapy treatment results (5–7). Overall median survival for patients receiving imatinib mesylate 600 mg/d has not yet been reached and the estimated 24-month survival is 65.8%.

In blast crisis CML, the terminal phase of CML, imatinib mesylate treatment produced a hematologic response rate of 31% and a MCyR rate of 15%. These responses are considerably higher than those described in other blast crisis studies (8). Whereas blast crisis CML is usually fatal in 3 to 6 months (9), imatinib mesylate treatment produced a median survival of 6.9months, with estimated 12- and 24-month survival rates of 32% and 18%, respectively.

In conclusion, imatinib mesylate produced sustained responses in all three phases of CML. Toxicity is acceptable. Imatinib mesylate represents an important addition to the armamentarium of drugs active in the treatment of chronic myelocytic leukemia.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: The views expressed are the result of independent work and do not necessarily represent the views and findings of the U.S. Food and Drug Administration.

Received 4/13/04; revised 9/24/04; accepted 10/11/04.

	REFERENCES

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