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Vascular and cardiac safety during tyrosine kinase inhibitor (TKI) therapy is an emerging issue. We evaluated vascular/cardiac toxicities associated with long-term bosutinib treatment for Philadelphia chromosome-positive (Ph+) leukemia based on treatment-emergent adverse events (TEAEs) and changes in QTc intervals and ejection fraction in two studies: a phase 1/2 study of second-/third-/fourth-line bosutinib for Ph+ leukemia resistant/intolerant to prior TKIs (N = 570) and a phase 3 study of first-line bosutinib (n = 248) versus imatinib (n = 251) in chronic phase chronic myeloid leukemia. Follow-up time was ≥48 months (both studies). Incidences of vascular/cardiac TEAEs in bosutinib-treated patients were 7%/10% overall with similar incidences observed with first-line bosutinib (5%/8%) and imatinib (4%/6%). Few patients had grade ≥3 vascular/cardiac events (4%/4%) and no individual TEAE occurred in2% of bosutinib patients. Exposure-adjusted vascular/cardiac TEAE rates (patients with events/patient-year) were low for second-line or later bosutinib (0.037/0.050) and not significantly different between first-line bosutinib (0.015/0.024) and imatinib (0.011/0.017; P ≥ 0.267). Vascular/cardiac events were managed mainly with concomitant medications (39%/44%), bosutinib treatment interruptions (18%/21%), or dose reductions (4%/8%); discontinuations due to these events were rare (0.7%/1.0%). Based on logistic regression modelling, performance status0 and history of vascular or cardiac disorders were prognostic of vascular/cardiac events in relapsed/refractory patients; hyperlipidemia/hypercholesterolemia and older age were prognostic of cardiac events. In newly diagnosed patients, older age was prognostic of vascular/cardiac events; history of diabetes was prognostic of vascular events. Incidences of vascular and cardiac events were low with bosutinib in the first-line and relapsed/refractory settings following long-term treatment in patients with Ph+ leukemia. Am. J. Hematol. 91:606-616, 2016. © 2016 Wiley Periodicals, Inc.

BACKGROUND The use of haploidentical stem cell transplantation (haploSCT) in patients without suitable matched sibling/unrelated donors has greatly improved access to potentially curative treatment for myeloid malignancies [Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), Myelofibrosis (MF)]. We aim to investigate the efficacy of haploidentical unmanipulated peripheral blood stem cell (PBSC) transplantation in 44 patients with myeloid malignancies using a reduced toxicity conditioning regimen with post-transplant cyclophosphamide (PTCy), anti-thymocyte globulin (ATG), and cyclosporine (CsA) to prevent rejection and graft versus host disease (GVHD). METHODS Forty-four adults with myeloid malignancies (AML=31, MDS=8, MF=5) underwent haplo-transplants between August 2016 and February 2018 at our centre. Conditioning included fludarabine (30mg/m2/day on day -5 to -2), busulfan (3.2mg/m2/day on day -3 and -2), and total body irradiation (200 cGy) on day -1. Unmanipulated PBSCs were infused on day 0. GVHD prophylaxis included ATG (4.5 mg/kg over day -3 to -1), PTCy (50mg/kg/day on day +3,+4), and CsA from day+5. Baseline clinical information was collected through retrospective chart review. Last follow up was June 2018. Median follow up for patients known to be alive was 5 months (range 0-15). The main variables of interest were overall survival (OS), progression-free survival (PFS) and non-relapse mortality (NRM) at 6 months and 1 year. The cumulative incidences (CI) of acute and chronic GVHD were calculated accounting for death and relapse as competing risks. RESULTS Baseline characteristics are shown in Table 1. Median time to neutrophil and platelet engraftment was 17 days (range 10-43) and 23 days (range 7-98) respectively. Post-transplant complications are described in Table 2. Two (5%) patients had primary graft failure and four (9%) had secondary graft failure. The cumulative incidence (CI) of grade II-IV and III-IV acute GVHD at day +100 was 35.7% (95% CI 23-48) and 5.7% (95% CI 1.5-14) respectively. The CI of moderate chronic GVHD at 6 months was 5.9% (95% CI 1.5-14.8) and the CI for severe chronic GVHD was 0%. Thirty-two (73%) patients had CMV reactivation, four (9%) patients had CMV disease. EBV reactivation was documented in 30 (68%) recipients. Five (11%) required Rituximab treatment for EBV titres >1x10E6 or biopsy proven Post-Transplantation Lymphoproliferative Disorder (PTLD) with 100% response. Ten (23%) patients had BK virus related hemorrhagic cystitis and 14 (42%) patients were diagnosed with other viral infections during follow up. Finally, 6 (14%) patients had probable lung fungal infection. Six (14%) relapses occurred during follow up. Main cause of death was infection in 10 (23%) patients, followed by graft failure in 4 (9%) cases, relapse in 3 (7%) and organ failure in 3 (7%). Six months OS, PFS and NRM are exposed in Table 2 and Figure 1. Significant differences in OS were found according to Disease Risk Index (DRI) (p=0.02) (Figure 1). CONCLUSION HaploSCT with unmanipulated PBSCs provides a route to potentially curative therapy for patients without access to conventional donor sources. In vivo T-cell depletion leads to low incidence of acute and chronic GvHD but high rates of infectious complications, particularly viral infections. Disclosures Lipton: Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

BACKGROUND The use of immunosuppressive agents such as antithymocyte globulin (ATG) as graft-versus host disease (GVHD) prophylaxis may increase the risk of Epstein Barr Virus (EBV) related post-transplant lymphoproliferative disorder (PTLD). The aim of the present study is to report the incidence, risk factors, and outcome of PTLD in the setting of haploidentical stem cell transplant (haploSCT) combining PTCy and ATG as GVHD prophylaxis. METHODS From August 2016 to May 2018, 55 adult patients diagnosed with hematological malignancies underwent T-cell replete haploSCT. All patients received a reduced intensity conditioning regimen (RIC) with fludarabine, busulfan, and 200cGy of total body irradiation (TBI), combined with rabbit ATG, PTCy and cyclosporine (Cy). EBV titre was monitored by quantitative PCR in plasma samples. The cut-off value for test positivity was >600 copies of EBV DNA per milliliter of plasma. Testing was performed weekly from engraftment to day 100 and beyond in case the patients were on immunosuppression. Data was collected through retrospective chart review. Last follow up was updated in June 31, 2018. Median follow-up was 9.5 months (range 1-21). RESULTS Patient and donor characteristics are summarized in Table 1. Median age was 57 (22-73) years, with 23 (43%) patients ≥60 years. Overall survival of the 55 patients at 6 months was 70% (95% CI 57-83), and 51% (95% CI 46-66) at 1 year. EBV reactivation was documented in 31 (57%) patients. Median time to EBV reactivation was 54 (20-326) days. Three (5.5%) patients developed presumed PTLD with EBV-viremia higher than 1x10E6 copies and corroborative imaging. Three (5.5%) had biopsy-proven PTLD (Table 2). Median time since EBV reactivation to presumed/proven (P/P)-PTLD was 25 (3-36) days. All cases occurred early post-transplant within the first 100 days. Four patients were on therapeutic doses of cyclosporine. All 6 (11%) patients received treatment with weekly Rituximab 375 mg/m+. Five (83%) patients achieved complete clinical responses with PCR negativity with reduction of immunosuppression and single agent rituximab. One patient died of complications of viral encephalitis and bacterial pneumonia. CONCLUSION ATG based conditioning can be associated with increased viral reactivations. Frequent EBV monitoring and pre-emptive treatment may lead to rapid disease control. While no guidelines exist currently, further investigation is needed to define optimal monitoring strategies. Disclosures Lipton: BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.

Background Frontline nilotinib 300 mg twice daily (BID) provides superior efficacy vs imatinib in pts with CML-CP, with good tolerability. Evaluating Nilotinib Efficacy and Safety in Clinical Trials—Extending Molecular Reponses (ENESTxtnd) is evaluating the kinetics of molecular response to frontline nilotinib 300 mg BID in pts with newly diagnosed CML-CP, as assessed in national and local laboratories, and is also the first study to evaluate the safety and efficacy of nilotinib dose optimization (including dose re-escalation in pts who require dose reductions due to adverse events [AEs] and dose increase in pts with less than optimal response). Here, we present results of a preplanned, interim analysis (IA) based on the first 20% of pts who completed 12 mo of treatment or discontinued early. Methods ENESTxtnd (NCT01254188) is an open-label, multicenter, phase 3b clinical trial of nilotinib 300 mg BID in adults with CML-CP newly diagnosed within 6 mo of study entry. The primary endpoint is rate of MMR by 12 mo. Molecular responses were monitored by real-time quantitative polymerase chain reaction (RQ-PCR) at local laboratories at baseline, at 1, 2, and 3 mo, and every 3 mo thereafter. Bone marrow cytogenetic analyses were performed locally at baseline, 6 mo, and end of study. Dose reductions were allowed for grade ≥ 2 nonhematologic AEs and grade 3/4 hematologic AEs. Pts with dose reductions could attempt to re-escalate (successful re-escalation defined as ≥ 4 wk on nilotinib 300 mg BID with no dose adjustments for any AE) and remain on study. Dose increase to nilotinib 400 mg BID was allowed in cases of BCR-ABL > 10% on the International Scale (BCR-ABLIS) at 3 mo or later, no major molecular response (MMR; BCR-ABLIS ≤ 0.1%) at 12 mo, loss of MMR, or treatment failure. Results This IA includes 85 pts treated in 12 countries (Argentina, Australia, Brazil, Canada, Israel, Lebanon, Mexico, Malaysia, Saudi Arabia, Thailand, Taiwan, and South Africa). Median age was 49 y (range, 19-85 y), and 58% of pts were male. Median time since diagnosis was 35 days (range, 2-157 days). Prior to study entry, 64 pts (75%) received hydroxyurea, and 3 pts (4%) received imatinib (all for ≤ 2 wk). At the data cutoff, 68 pts (80%) had treatment ongoing, and the remaining 17 had discontinued due to AEs/laboratory abnormalities (n = 8; nonhematologic AEs [n = 5], biochemical abnormalities [n = 2], and hematologic abnormalities [n = 1]), loss to follow-up (n = 2), administrative problems (n = 2), intolerance to the protocol-proposed dose (n = 2), suboptimal response (n = 1), withdrawal of consent (n = 1), or protocol deviation (n = 1). Median time on treatment was 13.8 mo (range, 1 day-18 mo). Median actual dose intensity of nilotinib was 597 mg/day (range, 165-756 mg/day), and 85% of pts had an actual dose intensity of > 400 mg/day to ≤ 600 mg/day. Of 30 pts with dose reductions due to AEs, 19 (63%) successfully re-escalated to nilotinib 300 mg BID. Nine pts (11%) dose escalated to nilotinib 400 mg BID due to lack of efficacy. The primary endpoint of MMR by 12 mo was achieved by 57 pts (67%; 99.89% CI, 49%-82%). Complete cytogenetic response by 6 mo was achieved by 48 pts (56%). Median BCR-ABLIS decreased over time, with a median value of 0.05% (range, 0.00%-41.36%) at 12 mo (Figure). Most pts (91%) achieved early molecular response (BCR-ABLIS ≤ 10% at 3 mo). Of the 8 pts (9%) with BCR-ABLIS > 10% at 3 mo (4 of whom were then dose escalated), 3 achieved MMR by 12 mo (1 of whom had been dose escalated). By the data cutoff, no pt had progressed to accelerated phase/blast crisis (AP/BC), and there had been no deaths on study. Nilotinib was well tolerated, with a safety profile similar to that seen in other frontline studies. Drug-related nonhematologic AEs (≥ 10% of pts) were rash (31%), constipation (13%), and headache (13%). Newly occurring or worsening grade 3/4 hematologic or biochemical abnormalities (≥ 10% of pts) were neutropenia (17%), thrombocytopenia (17%), increased lipase (13%), and increased bilirubin (12%). Conclusions These results demonstrate that dose-optimized nilotinib affords high rates of molecular response in pts with newly diagnosed CML-CP. Further, they support the feasibility of nilotinib dose re-escalation in pts who require temporary dose reductions due to AEs, with 63% of dose-reduced pts able to successfully re-escalate to nilotinib 300 mg BID and safely continue therapy. Disclosures: Lipton: Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Meillon:Bayer: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria. Louw:Novartis: Congress attendance support Other, Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Congress attendance support, Congress attendance support Other, Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Pavlovsky:Novartis: Research Funding, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Jin:Novartis: Employment. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Woodman:Novartis: Employment, Equity Ownership. Hughes:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; CSL: Research Funding. Turkina:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria.