ALBERT

Description: The 2nd generation tyrosine kinase inhibitors (TKI), nilotinib and dasatinib, are effective after imatinib failure. These agents are now also being used as 3rd line therapy after failure to 2 prior TKI. Preliminary data suggests responses can be achieved with this strategy, but the long-term benefit is unknown. To investigate the long-term benefit of using a 2nd generation TKI after having failed imatinib and another TKI. Patients with CML who were sequentially treated with 3 different TKI’s at M.D. Anderson Cancer Center were reviewed. Response to the 3rd TKI were scored according to standard definitions. Event-free survival (EFS) was considered from the time the 3rd TKI was started to loss of major hematologic response, loss of cytogenetic response, transformation to accelerated (AP) or blast (BP) phase, or death. Failure-free survival (FFS) was considered from start of 3rd TKI to event as defined for EFS, or loss of complete cytogenetic response (CCyR) or discontinuation because of toxicity. 37 patients were treated: 29 with dasatinib after imatinib and nilotinib failure, and 8 with nilotinib after imatinib and dasatinib failure. The median age was 61 years (yrs) (range, 19 to 70). The median time on imatinib was 33 months (mo) and 15 (41%) had transformation before starting 2nd TKI. Median time on 2nd TKI was 7.7 mo. At the start of 3rd TKI, 16 pts (43%) were in chronic phase (CP), 9 (24%) in AP, and 12 (32%) in BP. Best response to 3rd TKI in CP was 1 major molecular response (MMR), 2 CCyR, 1 partial cytogenetic response (PCyR), 5 minor cytogenetic response (mCyR), 2 complete hematologic response (CHR), and 5 no responses (NR); in AP, there was 1 CCyR, 2 PCyR, 1 mCyR, 4 CHR, and 1 NR; in BP, 2 CCyR, 1 PCyR, 1 mCyR, 2 return to CP (RCP), and 6 NR. Four patients discontinued treatment because of toxicity despite an acceptable response. The median CCyR duration was 28 mo; only 2 pts in CP who achieved CCyR (1 had MMR) had a sustained response lasting 20 and 24 mo, respectively. Both received dasatinib after imatinib and nilotinib failure, and had G250E and H396R at start of dasatinib, respectively. The table shows median (in months) OS, EFS and FFS by disease stage. CP AP BP OVERALL No. 16 9 12 37 OS NR 19.6 4.8 18 EFS NR 4.7 4 8 FFS 20 4.7 2 4 7 pts continue on therapy (all CP): 2 sustained CCyR (1 MMR), 1 PCyR (lost CCyR), 2 mCyR, 2 no cytogenetic response (1 lost mCyR). Use of 2nd generation TKI after failure to 2 TKI may induce responses in some pts but these are usually not durable except in some pts in CP. New treatment options are needed for these pts.

Description: Aplastic anemia (AA) is treated with equine anti-thymocyte globulin (hATG) and cyclosporine with response rates up to 65%. Rabbit anti-thymocyte globulin (rATG, Thymoglobulin®) has been used successfully in relapsed and refractory patients with AA, reducing the risk associated with readministration of equine preparations. Immunosuppressive therapy is also effective in some subsets of patients with Myelodysplastic syndrome (MDS). To evaluate if the combination of rATG, cyclosporine and G-CSF is safe and effective as first-line treatment of AA and low-risk MDS. In this single-arm, phase II study, we investigated the efficacy (primary endpoint) and safety (secondary endpoint) of combined rATG, cyclosporine and G-CSF as first-line therapy for patients with AA and Hypoplastic MDS. After 8 patients were enrolled, the study was modified to also include patients with low/intermediate-1 per the International Prognostic Scoring System. Thymoglobulin 3.5 mg/kg (or 2.5 mg/kg/day for patients ≥55 years) was given for 4 days in the first 10 patients and for 5 days in the remaining patients. Methylprednisolone (1 mg/kg/day) was given for 5 days followed by a tapering dose of oral prednisone. G-CSF (5 μg/kg) was given subcutaneously daily for up to 3 months starting after thymoglobulin. Cyclosporine (5 mg/kg) was given daily and continued for 6 months or longer at the discretion of the treating physician. All patients received prophylactic broad-spectrum antimicrobials. Responses were assessed about 3 months after initiating therapy. Thirty-six patients have been enrolled on study with 3 patients choosing alternate therapies and 1 patient dying before initiation of therapy. Among the thirty-two patients treated, 4 have been on study for less than 2 months; therefore 14 patients with AA and 14 with MDS were evaluable for a response. The median age was 62 years (20–83) for patients with AA and 63 (42–80) for patients with MDS. Thirteen of the fourteen (93%) patients with AA responded (5 CR, 7 PR, 1 HI-N), while four of 14 (29%) patients with MDS responded (1 CR, 3 PR). For patients with AA, the median time to response (TTR) was 93 days (79–623). For patients with MDS, the median TTR was 111 days (77–139). The median response duration for both groups has not been reached. Side effects were listed for 30 of 36 patients on treatment. The main grade 3/4 toxicities included thrombocytopenia in 20 patients (67%), anemia in 8 (27%), leukopenia in 17 (57%), and neutropenic fever in 4 (13%). Other grade 3/4 toxicities included renal failure, hypertension, pneumonia, urinary tract infection, fever, leukocytosis, increased liver function tests, hyperglycemia, and syncope (in 1 patient each). The combination of rabbit thymoglobulin (rATG), cyclosporine and G-CSF is safe and effective in first-line treatment of AA and has significant activity in low-risk MDS.