Key Points Clinical characteristics, causes of discontinuation, and outcome of patients who progress or fail ibrutinib are described. Patients with CLL who progress early on ibrutinib therapy have poor outcomes.

BackgroundTreatment with tyrosine kinase inhibitors (TKIs) for patients with chronic myeloid leukemia (CML) is effective but needs to continue for several years, possibly indefinitely. Although generally safe, TKI may have hitherto poorly recognized effects in the quality of life (QoL) of such patients.MethodsWe prospectively measured the symptom burden of patients with chronic phase CML enrolled on frontline TKI trials with dasatinib, nilotinib, or ponatinib. A total of 219 patients were enrolled and filled out the MD Anderson Symptom Inventory (MDASI)‐CML questionnaire before the start of therapy and during follow‐up at defined time points of 3, 6, 9, 12, 18, and 24 months.ResultsThe median age was 50 years. Longitudinal analysis showed relatively stable symptom severity scores over time. Fatigue was the most common symptom in all three cohorts, both prior to the start of therapy and during therapy, including after achievement of deep molecular remission. Work was the most affected component of daily living. Overall patients tolerated therapy well with improvement of their symptoms from baseline, with few dose reductions related to toxicity or symptomatology. Although 31% of the patients who completed MDASI‐CML achieved complete molecular remission by 24 months of treatment, nearly 90% experienced persistent mild symptoms.ConclusionSide effects related to TKIs may impact the quality of life in patients with CML‐CP. Further studies should investigate factors (comorbidities, concomitant medications, dose and schedule, etc) associated with these symptoms and interventions that may improve the patients’ QoL, including treatment discontinuation when safely feasible.

Inotuzumab ozogamicin is a humanized anti-CD22 monoclonal antibody bound to a toxic natural calicheamicin, which is under investigation for the treatment of relapsed/refractory acute lymphoblastic leukemia. CD22 is commonly expressed in 90-100% of malignant mature B-lymphocyte lineage. The first Phase II study with inotuzumab ozogamicin conducted by Kantarjian et al. gave the opportunity for heavily pretreated patients with acute lymphoblastic leukemia to go for allogeneic stem cell transplant. Inotuzumab is well-tolerated with the exception of veno-occlusive disease. Overall inotuzumab ozogamicin is potentially an encouraging and promising therapy for patients.

Background: Ibrutinib (Ib) is active in relapsed/refractory (R/R) Chronic Lymphocytic Leukemia (CLL). Patients receive indefinite therapy until progression. Published reports describe the occurrence of hypertension (HTN) and Atrial Fibrillation (AF) to be 8% and 6-9% respectively in patients treated with Ib. Methods: We evaluated 176 CLL patients treated on investigational protocols with Ib-based regimens from 2010-14 to determine the incidence of AF and HTN while receiving Ib. All pts gave informed consent and studies were conducted according to the Declaration of Helsinki. Blood pressure (BP) was evaluated at baseline and 6 months (mo). New onset HTN was defined as systolic BP (SBP) >140mmHg or diastolic BP (DBP) >90mmHg at 6mo in a pt with normal baseline BP. An increase in baseline SBP by ≥20mmHg and/or increase in DBP by ≥10mmHg was considered separately to be significant regardless of the absolute BP. AF was defined by an R-R interval following no repetitive pattern with no distinct P wave and an atrial rate of more than 300 beats/min. Electrocardiography (EKG) was reviewed to confirm AF. Baseline EKGs were required, but subsequent EKGs were performed only for symptom evaluation. Echocardiography (echo) was not performed at baseline, but was available in 6 of 9 pts at onset of AF. Results: Baseline characteristics are given below: TableCharacteristicAge (median, range)65 (35-87)Male129 (73)Treatment group:Ib monotherapy, n(%)83 (47)Ib + Rituximab, n(%)78 (44)Ib + Bendamustine + Rituximab, n(%)15 (8)Unmutated IGHV gene, n(%)112 (64)FISH hierarchydel(17p), n(%)59 (34)del(11q), n(%)32 (18)Other, n(%)25 (14) The median follow up of the entire patient cohort is 13 months (mo), range, 1-47mo. 9 patients (5%) developed new onset AF after starting Ibrutinib therapy, 7/9 were not on prior Beta blocker. 5 on Ib monotherapy, 3 patients on Ib + R, 1 on Ib+BR. The median time to AF after starting Ibrutinib was 20 weeks (range, 2-101). Six pts had a Hx of paroxysmal AF pre-dating Ib therapy (3.4%) and were already on treatment with Beta blocker of which none had recurrence of AF after or during Ib therapy, after a median follow up of 24 months (range=2-46). Six of 9 pts with new AF had an echo. Echo was normal in 2 pts, while 4 showed mild-severe left atrial (LA) dilatation; severe LA dilatation had developed during Ib treatment in the 1 pt who had had a normal baseline echo. One pt also had moderate left ventricular (LV) failure in addition to LA dilatation, but LV function was normal in the remaining pts. No pt had thyrotoxicosis as a contributing factor. Serial BP results were available in 111 pts. Median BP was 129/73 at baseline and 137/73 after 6mo of Ib therapy (p<0.001). New onset HTN occurred in 26 pts (23%); this was isolated systolic HTN in 23 pts and both systolic and diastolic in 3. Median change in SBP in pts with new-onset HTN was 27mmHg, range 4-55mmHg. Increase in SBP of >20mmHg occurred in 26 pts (23%); 21 of these pts had new onset HTN, while 5 had exacerbation of pre-existing HTN. Of the 9 pts with new AF, 5 had serial BP measurements. One developed new-onset HTN and 2 had a >20mmHg rise in SBP. Conclusions: In our experience, 5% of pts undergoing treatment with Ib develop new-onset AF. This incidence is comparable to prior reported data. Given that AF may be paroxysmal and asymptomatic, routine surveillance was not performed, the true incidence may be higher. The causative mechanism is unclear. 2/3 of pts with new AF, echo results showed significant structural LA abnormalities which have been associated with AF in the general cardiology literature. Twenty-three % of the pts developed new onset HTN, which was usually isolated systolic HTN. Most of these pts had increases in SBP >20mmHg. New onset HTN is likely therapy-related, although the mechanism is unclear. Development of AF did not appear to be dependent on the development of HT, as only 1 of 5 pts with new AF had new-onset HT. AF and HTN were generally manageable with medical intervention and did not require permanent cessation of Ib. Close monitoring of heart rhythm and blood pressure is recommended during treatment with Ib. Disclosures Jan: pharmacyclics: Research Funding. Wierda:Pharmacyclics: Consultancy. O'Brien:Pharmacyclics: Research Funding.

Introduction: Nilotinib is a second generation Tyrosine kinase inhibitor, approved for the treatment of CP-CML after imatinib failure and as frontline therapy. Nilotinib was first used as initial therapy in 2005 and the early results showed deep and fast response rates (JCO 2010 Jan 20; 28(3):392-7). The ENESTnd later showed response rates to be superior to those obtained with imatinib. Here we report the long-term follow-up results of the first trial of nilotinib frontline therapy for CML-CP. Objective: To assess the long term outcome of patients with CML treated with nilotinib as initial therapy. Methods: We analyzed a total of 148 patients (≥17 years old) with newly diagnosed CML who were enrolled between July 2005 and November of 2014 at MDACC on a clinical trial (NCT00129740) of nilotinib 400mg twice daily. Patients were assessed for cytogenetic and molecular response rate (measured every 3 months for the first year, every 6 month thereafter), overall survival (OS), event-free survival (EFS), transformation-free survival (TFS), and failure-free survival (FFS) using Kaplan-Meier method. Results: The baseline patient characteristics are shown on table 1. The median age was 51 years, with 20 patients aged ≥65. High sokal risk score was seen in 17% patients, and 17% of patients were in accelerated phase (AP) at diagnosis. Rates of complete cytogenetic response (CCyR) were: 78% at 3 months, 89% at 1 year, 94% at 5 years, and 97% at 7 years. Rates of MMR were 76% at 1 year, 87% at 5 years, and 93% at 7 years. Corresponding rates of MR4.5 were 39%, 76% and 83%, respectively. With a median follow-up of 59 months, 51 (34%) patients have discontinued therapy. Reasons for treatment discontinuation includes: 9 (6%) with non- cardiac toxicity including 3 with grade ≥3 increase in liver function tests, 2 with acute pancreatitis, 1 with renal failure, 1 with grade ≥2 increase in creatinine, 1 with grade ≥3 elevated lipase, 1 with headache; 6 (4%) with cardiovascular events including 2 myocardial infarction, 1 positive stress test, 1 stroke, 1 pericarditis, and 1 atrial fibrillation; 8 (5%) transformed to blast phase; 5 (3%) for resistance in CP; and 16 (10%) for other reasons including; patient request (n=8), patient noncompliance (n=6), insurance reasons (n=2); and 5 because of death due to unrelated reasons. After nilotinib discontinuation, patients received dasatinib (n=13), imatinib (n=8), bosutinib (n=3), ponatinib (n=2), rebastinib (n=1), chemotherapy plus dasatinib (n=3), AML-like chemotherapy (n=1), hydroxyurea (n=1), stem cell transplant (n=1), and unknown or none (because of lost to follow up, insurance or noncompliance (n=11). At 1, 5 and 7 year projected OS was 98%, 88% and 88%, respectively; EFS was 91%, 83% and 77%, respectively; TFS was 95%, 89% and 87%, respectively; and FFS was 82%, 70% and 57%, respectively, shown in figure (1,2,3) Conclusion: The long-term results from this study of nilotinib as frontline treatment of newly diagnosed CP-CML confirm the excellent results achieved with rapid and deep cytogenetic and molecular response, translating into very favorable long-term survival endpoints. Use of nilotinib in this setting has a favorable toxicity profile confirming its value as frontline therapy for CML-CP. Table 1. Patient Characteristics Median [range] or No. (%) Patients, n 148 Age, years, median [range] 51 [17-86] Age ≥65 years 20 (13) Follow up in months 59 [0-113] Patients ≥ 65 20 Male 91 (61) CP-CML 121 (82) AP- CML 27 (17) Risk score, n (%) - Low - Intermediate - High 101 (68) 21 (14) 26 (17) WBC (x109/L) 57 [0.8-342] PB Blast, % 0 [0-20] BM Blast, % 2 [0-25] PB Basophil, % 3 [0-13] BM Basophil, % 2 [0-13] Splenomegaly,cm 0 (0-30) Clonal evolution at diagnosis 3 (0.2) Patient Characteristics: Table (1) Figure 1. Overall survival Figure 1. Overall survival Figure 2. Event-Free Survival Figure 2. Event-Free Survival Figure 3. Transformation-free survival Figure 3. Transformation-free survival Disclosures Cortes: Novartis: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding.