ALBERT

Description: Key Points This analysis demonstrates the universality of the early response in CML, regardless of the treatment modality used. Factors correlating with poor cytogenetic responses at 3-mo assessment in a multivariate analysis across all 4 TKIs.

Description: Introduction Ponatinib is a multi-targeted tyrosine kinase inhibitor (TKI) efficacious in pts with refractory CML. Ponatinib inhibits other tyrosine kinases (e.g. RET, FGFR, FLT3) that may lead to off target adverse effects (AE). We report a single-institution experience of frequencies of non-hematological AE among pts on therapy with ponatinib. Methods A total of 90 pts with CML-CP[49 relapsed refractory (RR), 41 frontline] treated at our institution on clinical trials with ponatinib were analyzed. AE were recorded on each pt visit and charts were reviewed for AE and risk factors. Results For RR pts (n=49)the starting dose of ponatinib was 45 mg in 42 (86%) pts. 39 (80%) had dose interruptions, due in 17 (44%) to grade 3 thrombocytopenia and in 22 (56%) to non-hematological AE (elevated pancreatic enzymes 7 pts of whom 5 had pancreatitis; body aches and headache 7; hypertension 7; skin toxicity 5; fatigue 5). 35 pts (71%) had dose reduction to 30 or 15 mg. Hypertension (H.T.) stage 2 (≥160/100 mm Hg) occurred in 15 (31%) pts; only 2 of new onset. Blood pressure was controlled in all with antihypertensives. Other cardiovascular AE included QTc prolongation in 1 pt, atrial fibrillation in 1 pt, acute myocardial infarction in 3, venous thrombosis in 3, arterial thrombosis in 4, transient ischemic attack (TIA) in 1 and Raynaud’s in 1. No pt discontinued ponatinib due to cardiovascular AE’s. Symptomatic pancreatitis developed in 8 pts (16%). Grade 3/4 elevations in serum lipase and amylase occurred in 12 (24%) pts and 2 (4%) pts respectively. Median days to onset of pancreatitis was 24 (range 7-456). 27 pts (55%) developed cutaneous toxicity including xerosis/dry skin in 10 (37%) and grade 3 erythroderma and exfoliation of the skin in 5. Four pts died, none related to ponatinib. 13 pts went off the study: 5 went to SCT, 3 progressed, 1 pt died in CCyR of multiple co-morbidities, 1 pt had progressive melanoma, 1 pt was transferred to another hospital, and 2 for ponatinib-related AE (headache in 1 and headache, fatigue, depression, and abdominal pain in 1). For pts in frontline setting (n=41) the starting dose was 45 mg in all. 29 pts (71%) had dose interruptions due to one or more of the following: grade 3/4 pancreatic enzyme elevation in 16, myelosuppression in 4, and various non-hematological AE in 15 (skin toxicity in 4, fatigue in 2, headache in 1, chest pain in 2, elevated liver enzymes in 2, suspected seizure vs. TIA in 1, grade 3 diarrhea in 1, memory disturbances in 1, and grade 3 hypertension in 1, erectile dysfunction in 1). 24 pts (59%) had dose reduction, from 45 mg to 30 mg in 20 pts and then to 15 mg in 4 pts. H.T. stage 2 occurred in 3 (7%) pts usually among patients with pre-existing H.T. Other cardiovascular AE included grade 2 QTc prolongation in 1 pt, possible TIA vs. possible seizure in 1, and Raynaud’s in 2. Pancreatitis was seen in 12 pts (29%) with grade 1-2 and 6 pts (15%) with grade 3/4. Grade 3/4 lipase/amylase elevations occurred in 16 (39%) and 3 (7%) pts. Median days to the onset of pancreatitis were 6 (4-22). 34 pts (83%) developed skin toxicity with rash (any grade) in 25 pts (61%), xerosis/dry skin in 18 pts (44%) and grade 3 erythroderma and skin exfoliation in 2 (pts may have had ≥1 type of skin AE). 2 pts discontinued therapy, due to severe xerosis in 1 and recurrent gra 4 neutropenia in another. 1 pt developed grade 2 pericarditis possibly related to ponatinib. For all the 90 pts, risk factors for cardiovascular and pancreatic toxicities included 20 (22%) smokers, 2 heavy alcohol consumers, 27 (30%) obese (BMI ≥30 Kg/m2), 30 (33%) with hypertriglyceridemia, 17 (19%) had hypercholesterolemia and 10 pts were receiving lipid lowering therapies. Conclusions Ponatinib is generally well tolerated and AEs can usually be properly managed. AE are more common in RR pts with greater frequency of hypertension, cardiovascular complications, headache, dry mouth and dose interruptions. Most pts are able to continue therapy after dose adjustments. Disclosures: Kantarjian: ARIAD: Research Funding. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding.

Description: Key Points Patients with e13a2 transcripts have inferior outcomes with imatinib 400; e14a2 has favorable outcomes regardless of treatment modality. Multivariate analysis showed that the expression of e14a2 or both e14a2 and e13a2 predicts optimal ELN responses and longer EFS and TFS.

Description: Introduction The presence of the BCR-ABL fusion gene, resulting from the Philadelphia chromosome is the hallmark of CML. The most commonly observed transcripts in CML are b3a2 (e14a2) and b2a2 (e13a2). It is not known whether the transcript type may impact response to newer TKI. We report our experience of ponatinib in patients with CML-CP with different BCR-ABL transcripts. Methods A total of 85 pts with CML-CP [47 relapsed refractory (RR) and 38 frontline] who were treated at our institution between 2008 and 2013 on clinical trials with ponatinib were included in this analysis. Conventional cytogenetic analysis was done in bone marrow (BM) cells using a G-banding technique, and the BCR-ABL fusion transcripts were identified by the use of quantitative real-time polymerase chain reaction assay. Results Among the 47 RR patients, 14 (30%) had the b2a2 transcript (median age 47 years; range 21–82), 23 (49%) had a b3a2 transcript (median age 61; range 24–94 years), and 10 (21%) co-expressed both transcripts (median age 45; range 49–79). Two pts with e1a2 transcripts were not included in the analysis. RR patients received a median of 3 prior therapies including interferon, imatinib, nilotinib, dasatinib, bosutinib, omacetaxine and SCT. Ten (71 %) of those with b2a2 were previously treated with ≥3 different TKI (imatinib, dasatinib, nilotinib and bosutinib); of the pts with b3a2, 12 (52%) were treated with ≥3 different TKI (imatinib, dasatinib, nilotinib and bosutinib) and in the group of pts with both transcripts 5 (50%) received 3 different TKI (imatinib, dasatinib, nilotinib). T315I mutation was present in 9 (19%) pts of which 2 were b2a2, 5 were b3a2 and 2 were both. After a median follow-up of 22.4 months, the rates of overall complete cytogenetic (CCyR) and major molecular responses (MMR) were 55% and 40%. Among these RR patients, the response with b2a2, b3a2 and both transcripts, were CCyR: 50% vs. 61% vs. 50% and MMR 29% vs. 52% vs. 30%, respectively. The 3-year probability of failure free survival (FFS) was 54%, 87% and 68% for pts with b2a2, b3a2 and both groups (P=0.08). The 3-year probability of overall survival (OS) was 62%, 100% and 100% for pts with b2a2, b3a2 and both groups (P=0.03). Among the 38 pts in the frontline setting, 17 (44%) had the b2a2 transcript (median age 50.7 years; range 21–74), 14 (36%) had b3a2 transcript (median age 49.7; range 29–72 years), and 7 (18%) presented with both transcripts (median age 56; range 38–63). The Sokal risk group for those with the b2a2 transcript was high in 2/17 (12%), intermediate in 4/17 (23%), and low in 11/17 (65%). For pts with b3a2 all 14/14 (100%) were low risk, and the group with both transcripts had 0%, 1/7(14%) and 6/7 (85%), respectively. There were two pts who went off study due to toxicity. For the evaluable pts with b2a2, b3a2 and both transcripts, the median levels of transcripts at 3 months were 0.098, 0.091 and 0.042 respectively. Similarly the median levels of transcripts at 6 months were 0.00525, 0.0035 and 0.0035 respectively. The magnitude of early CCyR was very high in all groups thus not allowing to discriminate among the transcripts. The median OS was 6.6 months and none of the pts have died. Conclusions Although all pts have a good overall survival those receiving ponatinib after prior TKI failure with b3a2 transcripts have a higher rate of CCyR and MMR vs. patients with b2a2 transcripts. This mirrors what we have reported with other TKI. With early results, no difference is seen in the frontline setting perhaps because of the overall excellent results. The mechanism of differential responsiveness of pts with b2a2 transcripts and b3a2 transcripts warrants further investigation. Disclosures: Kantarjian: ARIAD, Novartis, BMS, Phizer: Research Funding. Jabbour:Ariad, BMS, Novartis, and Pfizer: Consultancy. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding.

Description: Introduction Since 2000, different TKI modalities have been used as initial therapy for CML-CP. We analyzed the responses and long-term clinical impact among pts treated with 4 TKI modalities as frontline CML-CP therapy in a single institution. Methods Outcomes of 476 consecutive pts (median age 49 yrs, range 15-86) receiving initial therapy with TKI from 2000 to 2013 were analysed. Patients received imatinib 400 mg/d (IM400; n=71), imatinib 800 mg/d (IM800; n=202), dasatinib (n=98) or nilotinib (n=105) in consecutive or parallel trials. Median follow-up was 85 months (mo) (3-154). Pts were followed uniformly with cytogenetics and PCR every 3 mo for the first 12 mo, then every 6 mo. Results Median follow-up was 144 mo for IM400, 112 mo for IM800, 52 mo for dasatinib and 48 mo for nilotinib. Overall CCyR rates were 85%, 92%, 96% and 96%, respectively. Corresponding rates of MMR were 83%, 88%, 91%, and 93%, respectively. The median time to achieve MMR was 11 mo for patients treated with IM400 and 6 mo with IM800, 5.8 mo with dasatinib, and 5.8 mo with nilotinib. Rates of MR4.5 were 61%, 76%, 75% and 68%. Rates of the CMR (5-log) were 48%, 54%, 55% and 46%. Because of the difference in follow-up between cohorts, we analyzed response at specific time points. Higher proportions of pts receiving IM800 and 2nd generation TKI achieved CCyR, MMR and MR4.5 at all time-points analyzed (3-60 months). Disease transformation occurred in 34 pts (7%), events occurred in 72 (15%) and 53 pts (11%) died. Overall, 195 (41%) pts have discontinued therapy, including 54% of pts treated with IM400, 46% with IM800, 28% with dasatinib and 27% with nilotinib. For pts taking IM400, 25% had lost CCyR by 60 mo, compared to 13% with IM800, 12% with dasatinib, and 5% with nilotinib. Estimated 60 mo outcomes for the total population were event-free survival (EFS) 85%, failure-free survival (FFS) 68%, transformation-free survival (TFS) 93%, and overall survival (OS) 93%. The 60 mo EFS was 69% with IM400, 87% with IM800, 91% with dasatinib, and 86% with nilotinib (P≤0.001). Pts who achieved a CCyR at 6 months (i.e., optimal response by ELN) had a better EFS rate at 60 mo (92%) compared to those not achieving this response (60%) (P≤0.001). Similarly, achievement of MMR at 12 mo (optimal response) resulted in 60 mo EFS probability of 92% vs. 74% for those without MMR (P≤0.001). Table -1depicts the time to event outcomes based on responses achieved by each TKI modality. The differences were similar regardless of the TKI modality used. Conclusions Excellent results are obtained with all TKI modalities with a suggestion for better long-term outcomes with IM800, dasatinib or nilotinib as compared to IM400. Higher proportions of pts who received imatinib discontinued treatment as compared to 2ndgeneration TKI. Achievement of CCyR and MMR at different time points has similar correlations with long-term outcome, regardless of the TKI used. Most patients with CML-CP can have an excellent outcome with TKI frontline therapy. Disclosures: Kantarjian: ARIAD: Research Funding. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding.