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Gleevec Gains Simultaneous FDA Approval for Five Rare, Life-Threatening Disorders

Gleevec Gains Simultaneous FDA Approval for Five Rare, Life-Threatening Disorders

ROCKVILLE, Maryland--Gleevec (imatinib mesylate) tablets has received FDA approval to treat patients with five rare, potentially life-threatening disorders, representing the first time that a regulatory authority has ever simultaneously approved one targeted medicine for so many disorders, according to Novartis, maker of Gleevec. The agent previously was approved for the treatment of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GISTs).

Gleevec targets the activity of the tyrosine kinase Bcr-Abl and the receptor tyrosine kinase Kit. Researchers have found that Gleevec also inhibits other tyrosine kinases, including platelet-derived growth factor receptor (PDGFR), which have been shown to be activated in disease pathways that underlie a number of rare hematologic diseases, as well as some solid tumors.

The new approvals are for one solid tumor and four diseases of the blood:

  • Dermatofibrosarcoma protuberans (DFSP), a type of tumor that begins as a hard lump found in the skin of the chest, abdomen, or leg, which grows slowly and usually does not metastasize. Usually, surgery successfully removes the tumor, but about half the time, the tumor returns. In one uncontrolled study and five published case reports, the overall response rate to Gleevec was 83% with a complete response rate of 39%. The responses were durable and led to surgical resection of the residual tumor in a number of cases. The overall complete response rate to Gleevec and surgical resection was 67%. Relevant target: PDGFR.

Gleevec is indicated for adult patients with unresectable, recurrent, and/or metastatic DFSP at a dose of 800 mg/d.

  • Relapsed or refractory Ph+ acute lymphoblastic leukemia (ALL), a rapidly progressive leukemia. Among 43 relapsed/ refractory Ph+ ALL patients in a phase II study of Gleevec, 8 (19%) had a complete hematological response (CHR) and 15 (35%) had a major cytogenetic response (MCR).

Gleevec is indicated as a single agent for the treatment of adult ALL patients at a recommended dose of 600 mg/d.

  • Myelodysplastic/myeloproliferative diseases (MDS/MPD). These are diseases in which too many of certain types of blood cells--monocytes, platelets, fibroblasts, red blood cells--are made in the bone marrow. They include chronic myelomonocytic leukemia (CMML), atypical Ph-negative CML (aCML), Bcr- PDGFR-positive CML, and MPD associated with eosinophilia.

Of a total population of 31 patients treated for MDS/MPD with Gleevec, 14 (45%) achieved a CHR and 12 (39%) an MCR. Of the 16 patients with a translocation associated with PDGFR gene rearrangement, all had a hematologic response (13 CHR), and 12 had an MCR. Relevant target: PDGFR. Gleevec is indicated for adults with MDS/MPD associated with PDGFR gene rearrangements at a dose of 400 mg/d.

  • Hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL), which is characterized by the persistent overproduction of eosinophils, often leading to organ damage. Historically, patients with HES/CEL have shown no detectable chromosomal abnormality. Among 61 patients positive for FIP1L1-PDGFRa fusion kinase, all (100%) had a CHR to Gleevec vs 21% of those who were negative for this fusion kinase. Overall, 107 of 176 patients (61%) had a CHR.

Gleevec is indicated for HES/CEL at a dose of 400 mg/d. For HES/CEL patients with demonstrated FIP1L1-PDGFRa fusion kinase, a starting dose of 100 mg/d is recommended.

  • Aggressive systemic mastocytosis (ASM), which is marked by the presence of too many mast cells. Of a total population of 28 patients treated for ASM with Gleevec, 8 (29%) achieved a CHR and 9 (32%) a partial hematologic response (61% overall response rate). Relevant targets: PDGFR, Kit. Gleevec is indicated for adults with ASM without the D816V c-Kit mutation or with unknown c-Kit mutational status at a recommended dose of 400 mg. For patients with ASM associated with eosinophilia, a starting dose of 100 mg/d is recommended.
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