Despite the remarkable progress made in some leukemias such as CML and CLL, cytotoxic treatment for AML remains essentially unchanged over the last 4 decades. Several lines of evidence, including the graft versus leukemia effect associated with allogeneic hematopoietic stem cell transplantation (HSCT), suggest that immunotherapy is an active modality in AML. Given the lack of progress for chemotherapy in this disease, many novel immunologic treatment approaches have been explored. The goals of non-transplantbased immune approaches have largely consisted of the stimulation or restoration of endogenous immune responses or the targeting of specific tumor antigens by immune cells. These strategies have been associated with less toxicity than allogeneic HSCT but typically have inferior efficacy. Allogeneic HSCT exploits major and minor histocompatibility differences between the donor and recipient in order to recognize and eradicate malignancy. With the recognition that the immune system itself provides a basis for treating AML, immunotherapy continues to be an attractive modality to exploit in the treatment of this disease. Cancer 2015;121:2689-704.
Acute lymphoblastic leukemia (ALL) is a heterogeneous group of hematologic malignancies that arise from clonal proliferation of immature lymphoid cells in the bone marrow, peripheral blood and other organs. There are approximately 3000 new adult cases diagnosed every year in the United States with a 5-year overall survival ranging from 22% to 50%. Most adult patients with ALL who achieve a complete response will ultimately relapse and for this subset of patients the only hope of curative therapy is successful re-induction to achieve a complete response followed by allogeneic transplant. Conventional vincristine has been used in all phases of ALL therapy but its efficacy is limited by cumulative toxicity, typically neuropathic in nature. Historically, the dose of conventional vincristine has been capped at 2 mg to avoid severe neurotoxicity. Liposomal vincristine [as vincristine sulfate liposomal injection (VSLI)] constitutes encapsulating vincristine in a sphingomyelin/cholesterol envelope. This process is thought to enhance drug delivery to the target tissues, decrease neurotoxicity by reducing the percentage of free drug in the plasma and therefore results in increased efficacy with acceptable toxicity. Results from recent trials using VSLI in the setting of relapsed/refractory Ph-negative ALL have been encouraging. VSLI as salvage monotherapy has been successful in inducing complete responses in a minority of adults with relapsed/refractory ALL so that they can be bridged to stem-cell transplantation. Rigorous post-approval testing needs to be conducted to clarify its utility in the clinic.
143 Background: Mammalian target of rapamycin (mTOR) inhibitors enhance cytotoxic chemotherapy effects in primary acute leukemia cells in preclinical assays. This prompted a multi-center evaluation of a combination of mTOR inhibitor plus induction chemotherapy in AML. As mTOR is frequently but not uniformly activated in primary AML samples, it is unclear which patients benefit from this targeted approach. Thus, we sought to monitor mTOR kinase activity during therapy to determine whether target activation and/or inhibition predicted clinical response. We previously reported our preliminary experience monitoring pS6 in AML blasts by flow during clinical trials combining sirolimus and AML induction chemotherapy (Kasner et al, ASH 2011, #230). Here we provide the final clinical and pharmacodynamic results from this cohort of subjects. Methods: Subjects had relapsed/refractory AML or untreated AML with unfavorable risk factors (e.g. therapy-related, prior MDS or MPN, or age >60 without favorable karyotype) with a median age of 60.5 years (range 32–77). Subjects received oral sirolimus (12 mg on day 1, then 4 mg daily on days 2–9) plus MEC (mitoxantrone 8 mg/m2/day, etoposide 100 mg/m2/day, cytarabine 1 gm/m2/d on days 4–8) on one of two successive clinical trials. Clinical response was assessed at hematologic recovery or day 42 using IWG criteria (CR, CRp, PR vs. non-response). Pharmacodynamic samples were collected from blood or marrow at baseline, 2 hours post-sirolimus dose on days 1 and 4, and at trough on day 4 (prior to chemotherapy administration). Concurrent blood rapamycin concentration was measured by immunoassay or HPLC. Whole blood/marrow fixation was performed using published methods (Perl, et al. Clin. Cancer Res. 2012). Positive gates for pS6 were created by comparing blasts in ex vivo stimulated (phorbol ester/PMA) and inhibited (rapamycin) conditions and/or autofluorescence (FMO) controls. Results: We enrolled 52 subjects in 2 consecutive trials; 51 were evaluable for clinical response. Toxicity was similar to published MEC data. 3 infectious deaths occurred (6%). Prolonged aplasia was not observed. 24/51 (47%) subjects responded, with 18 CR (35%), 1 CRp, and 5 PR's observed. Mean peak and trough rapamycin concentrations on day 4 were 22.0 and 8.9 ng/ml, respectively, and did not differ among clinically responding or non-responding subjects. Median survival time for the whole group was 243 days (longest follow up 1584 days). Among the 24 subjects achieving CR or PR, median duration of time to the first event (relapse or death) was 261 days. 20 subjects were able to proceed to a stem cell transplant following therapy. Serial flow cytometric analysis was performed in 46 subjects, of which 37 provided paired day 1 and day 4 flow samples and were evaluable for clinical response at count recovery. The overall response rate (ORR) among subjects with baseline constitutive pS6 was 14/27 (52%, 9 CR, 1 CRp, 4 PR). The ORR for subjects without constitutive pS6 was 4/10 (40%, 3 CR, 1 PR). Subjects with >50% reduction in pS6 positive blasts on day 4 were considered to be biochemically sensitive to rapamycin, while subjects with <50% reduction or increased pS6 were considered rapamycin-resistant. Categorizing subjects based upon the achievement of CR/CRp/PR vs. NR, the reduction in blasts' pS6 percent on day 4 was 72% among clinically responding subjects and 43% among those without clinical response. The ORR in rapamycin sensitive patients was 10/15 (67%, 6 CR, 4 PR, 5 NR), while in resistant subjects was 4/12 (33%, 3 CR, 1 CRp, 8 NR). Combining rapamycin resistant subjects and those with no basal pS6, the ORR was 8/22 (36%, 6 CR, 1 CRp, 1 PR, 14 NR). Conclusions: Sirolimus plus MEC is a tolerable and active regimen for patients with high risk AML. The addition of an mTOR inhibitor augmented chemotherapy response particularly among those with demonstrable baseline mTOR activation and target inhibition during therapy. These results demonstrate the diversity of AML with reference to the activation of ribosomal S6 and suggest that phospho-flow monitoring may be an effective tool for patient selection for use of signaling inhibitors in AML. Future trials of this regimen may benefit from enrichment for subjects with mTOR activation and/or rapamycin sensitivity assessment. Disclosures: Off Label Use: Rapamycin. FDA approved for solid organ transplant. Investigational use for treatment of leukemia. Weiss:Celgene: Consultancy.
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