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1.
Leukemia ; 27(7): 1479-86, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23321953

ABSTRACT

The mTORC1 signaling pathway is constitutively activated in almost all acute myelogenous leukemia (AML) patients. We conducted a phase Ib trial combining RAD001 (everolimus), an allosteric inhibitor of mTORC1, and conventional chemotherapy, in AML patients under 65 years of age at first relapse (clinical trial NCT 01074086). Increasing doses of RAD001 from 10-70 mg were administrated orally on days 1 and 7 (d1 and d7) of a 3+7 daunorubicin+cytarabine conventional induction chemotherapy regimen. Twenty-eight patients were enrolled in this trial. The treatment was well tolerated with <10% toxicity, mainly involving the gastrointestinal tract and lungs. In this phase Ib trial, the RAD001 maximum tolerated dose was not reached at 70 mg. Sixty-eight percent of patients achieved CR, of which 14 received a double induction. Eight subsequently were intensified with allogeneic-stem cell transplant. Strong plasma inhibition of P-p70S6K was observed after RAD001 administration, still detectable at d7 (d7)at the 70 mg dosage. CR rates in patients with RAD001 areas under or above the curve median were 53% versus 85%. A 70 mg dose of RAD001 at d1 and d7 of an induction chemotherapy regimen for AML has acceptable toxicity and may improve treatment.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Cytarabine/administration & dosage , Daunorubicin/administration & dosage , Leukemia, Myeloid, Acute/drug therapy , Sirolimus/analogs & derivatives , TOR Serine-Threonine Kinases/antagonists & inhibitors , Adult , Aged , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/adverse effects , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cytarabine/adverse effects , Daunorubicin/adverse effects , Everolimus , Female , Humans , Male , Middle Aged , Recurrence , Signal Transduction/drug effects , Sirolimus/administration & dosage , Sirolimus/adverse effects , Treatment Outcome , Young Adult
2.
Bone Marrow Transplant ; 38(6): 417-20, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16951691

ABSTRACT

The optimum treatment of primary CNS lymphoma (PCNSL) is not yet determined. The objective of this study was to assess the safety and efficacy of initial methotrexate-based chemotherapy followed by high-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) in patients with newly diagnosed PCNSL. Twenty-five patients received two courses of initial chemotherapy combining methotrexate, etoposide, carmustine and methylprednisolone, and one course of ifosfamide-cytarabine followed by peripheral stem cell collection. Seventeen responsive patients then received HDT using carmustine, etoposide, cytarabine and melphalan with autologous stem cell rescue. After ASCT for responding patients or after salvage therapy for non-responders, whole brain radiation therapy at a dose of 30 Gy was delivered. The objective response rate to the induction chemotherapy was 84%. Four of the 21 responding patients did not have ASCT because of toxicity or refusal. With a median follow-up time of 34 months, the projected event free survival rate is 46% at 4 years. Projected overall survival is 64% at 4 years. Sixteen patients are actually in continuous complete response. No evidence of late treatment-related toxicity was observed. This treatment approach appears feasible in newly diagnosed PCNSL with encouraging results.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Central Nervous System Neoplasms/therapy , Lymphoma/therapy , Stem Cell Transplantation , Adult , Carmustine/administration & dosage , Central Nervous System Neoplasms/mortality , Combined Modality Therapy , Cytarabine/administration & dosage , Disease-Free Survival , Etoposide/administration & dosage , Female , Follow-Up Studies , Humans , Ifosfamide/administration & dosage , Lymphoma/mortality , Male , Methotrexate/administration & dosage , Methylprednisolone/administration & dosage , Middle Aged , Remission Induction , Stem Cell Transplantation/mortality , Transplantation, Autologous
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