Key Points• Prescribing appropriately for age and cardiovascular risk is likely to result in minimal permanent toxicity-related dasatinib cessation.• CML patients on dasatinib with pleural effusion are more likely to have achieved MR4.5 after 6-month therapy than those without effusion.Dasatinib has shown superiority over imatinib in achieving molecular responses (MRs) in chronic phase chronic myeloid leukemia but with a different toxicity profile, which may impact its overall benefit. Reported toxicities include pleural effusions and pulmonary hypertension, and although the incidence of these events is well described, response to therapy and impact of dose modifications on toxicity has not been comprehensively characterized in a real-world setting. We retrospectively reviewed the incidence of dasatinib adverse events in 212 chronic phase chronic myeloid leukemia patients at 17 Australian institutions. Adverse events were reported in 116 patients (55%), most commonly pleural effusions (53 patients, 25%), which was the predominant cause of permanent drug cessation.Age and dose were risk factors for pleural effusion (P , .01 and .047, respectively).Recurrence rates were higher in those who remained on 100 mg compared with those who dose reduced (P 5 .041); however, recurrence still occurred at 50 mg. Patients who developed pleural effusions were more likely to have achieved MR4.5 after 6 months of dasatinib than those without effusions (P 5 .008). Pulmonary hypertension occurred in 5% of patients, frequently in association with pleural effusion, and was reversible upon dasatinib cessation in 6 of 7 patients. Dose reductions and temporary cessations had minimal impact on MR rates. Our observations suggest that by using the lowest effective dose in older patients to minimize the effusion risk, dose modification for cytopenias, and care with concomitant antiplatelet therapy, the necessity for permanent dasatinib cessation due to toxicity is likely to be minimal in immunologically competent patients.

Key Points• In contrast to other AEs, there is a high risk of recurrent vascular AEs with continuing nilotinib therapy for CML.Although second-generation tyrosine kinase inhibitors (TKIs) show superiority in achieving deep molecular responses in chronic myeloid leukemia in chronic phase (CML-CP) compared with imatinib, the differing adverse effect (AE) profiles need consideration when deciding the best drug for individual patients. Long-term data from randomized trials of nilotinib demonstrate an increased risk of vascular AEs (VAEs) compared with other TKIs, although the natural history of these events in response to dose modifications or cessation has not been fully characterized. We retrospectively reviewed the incidence of nilotinibassociated AEs in 220 patients with CML-CP at 17 Australian institutions. Overall, AEs of any grade were reported in 95 patients (43%) and prompted nilotinib cessation in 46 (21%).VAEs occurred in 26 patients (12%), with an incidence of 4.1 events per 100 patient-years.Multivariate analysis identified age (P 5 .022) and dyslipidemia (P 5 .007) as independent variables for their development. There was 1 fatal first VAE, whereas the remaining patients either continued nilotinib (14 patients) or stopped it immediately (11 patients). Recurrent VAEs were associated with ongoing therapy in 7 of 14 who continued (with 2 fatal VAEs) vs 1 of 11 who discontinued (P 5 .04). Nineteen of the 23 evaluable patients surviving a VAE ultimately stopped nilotinib, of whom 14 received an alternative TKI. Dose reduction or cessation because of VAEs did not adversely affect maintenance of major molecular response. These findings demonstrate that in contrast to other AEs, VAEs are ideally managed with nilotinib cessation because of the increased risk of additional events with its ongoing use.Nilotinib has a unique adverse effect (AE) profile, including both hematological and nonhematological AEs. 2 Five-year follow-up of phase 3 data documented grade 3 to 4 AEs of any kind in 61% and 72% of

thromboembolism (VTE) in SCD, with a higher mortality observed in patients with VTE compared to those without this complication [5].There are few studies specifically addressing treatment of PHT in SCD. Current strategies include optimizing SCD therapy and identifying potentially modifiable etiologies such as obstructive sleep apnea, pulmonary thrombosis, and left ventricular dysfunction. Hydroxyurea, approved for treatment of severe anemia and frequent vaso-occlusive episodes, has the potential benefit of being an NO donor. Endothelin receptor antagonists and prostaglandin therapy are approved for treatment of pulmonary arterial hypertension and have been recommended for select SCD patients with marked elevation of pulmonary vascular resistance and normal pulmonary artery occlusion pressure on RHC, and related symptoms [1]. Phosphodiesterase-5 inhibitor therapy is presently not recommended as first-line treatment for RHC-confirmed PHT due to the association of sildenafil with increased hospitalizations for pain crises. Riociguat, a soluble guanylate cyclase stimulator, is a vasodilator that bypasses the NO pathway. It has shown promise in CTEPH and PAH, but has not yet been studied in SCD. Although a study of the low molecular weight heparin, tinzaparin showed a reduction in the duration of pain crisis and hospitalization [6], most studies of anticoagulants in SCD have been small and poorly controlled. Treatment with the factor Xa inhibitor, rivaroxaban, as well as PAR-2 or IL-6 deficiency have been reported to attenuate PHT in animal models [7]. A study of rivaroxaban in SCD is ongoing to assess its pharmacodynamics effects (www.clinical trials.gov. identifier NCT02072668). Finally, pulmonary endarterectomy is standard for non-SCD patients with CTEPH, but the experience in SCD is limited, possibly due to concerns for a high risk of perioperative complications. Pulmonary endarterectomy requires cardiopulmonary bypass, hypothermia, and periods of circulatory arrest, which will likely increase the risk of sickling. These two cases, along with the previously published reports of four patients who underwent pulmonary endarterectomy [8][9][10], demonstrate that patients can undergo this procedure safely, with symptomatic and hemodynamic benefit. In summary, SCD patients with CTEPH, should be considered for pulmonary endarterectomy. AcknowledgmentAuthors thank Ertan Pamuklar, MD for help with the figure.

Aim/Background Imatinib, a tyrosine-kinase inhibitor (TKI), first line therapy for chronic myeloid leukemia in chronic phase (CML-CP) for over a decade, has an established side-effect profile. Clinical trials with 2nd generation (2G) TKIs have significantly deeper and faster cytogenetic and major molecular responses (MMR), though impact on long-term toxicity and survival remains to be determined. Dasatinib (DAS), an oral 2G TKI 350x more potent than imatinib in vitro, is generally well tolerated, with <15% patients in clinical trials requiring change in therapy due to adverse events (AE). However, potentially life-threatening PHT or pleural effusions can occur in up to 10% and 25% respectively. Little is known about this important toxicity, in terms of risk factors and natural history (including reversibility post drug cessation or dose modifications). We present our local experience with DAS, with a focus on pulmonary toxicity. Methods Retrospective review of all patients treated with DAS at PMCC (Melbourne, Australia) April 2003-July 2013. Patient data including demographics, disease characteristics, co-morbidities, pathology, radiology, TKI regimens, clinical course and AE were extracted from institution electronic records. Results Cohort included 37 patients: 33 CML-CP, 1 CML in accelerated phase, 1 post allograft relapsed Ph+ Acute Lymphoblastic Leukemia, 2 Ph+ Acute Myeloid Leukemia. 13/37 (35%) developed clinically significant pulmonary toxicity, including 9 (24%) patients with transthoracic echocardiography (TTE) evidence of elevated resting right ventricular pulmonary venous pressures (RVSP) whilst on DAS: 5 (14%) confirmed PHT (RVSP>36 mmHg), 3 (8%) RVSP in upper limit of normal (RVSP 30-36mmHg) and 1 with RVSP>30 post DAS cessation (RVSP not available during therapy). 7 (19%) were symptomatic of PHT, 4 (11%) required medical management. 12/37 (32%) had radiological evidence of pleural effusion: 10 (27%) symptomatic, 5 (14%) bilateral, 5 (14%) right sided, 2 (5%) left sided. 7 (19%) patients with PHT had associated pleural effusion (5/5 with RVSP >36, 2 RVSP>30), however 5 (14%) developed symptomatic pleural effusions without evidence of PHT. 6 (16%) patients required surgical intervention (5 drainage, 1 pleurodesis). 2 (5%) had persistent symptoms despite DAS cessation. RVSP normalised in 3 patients post DAS cessation (median time 24 months, range 1-26) but did not in 1 patient (follow up: 38 months). Serial TTEs were not performed in 5 patients. Risk factors (e.g. cardiovascular, pulmonary, other medications, vasculitides, disease status) were not more prominent in the PHT group, though a statistically significant difference in age between the two groups was noted. Of the entire cohort, 23/37 (62%) have ceased DAS for the following reasons: 8 (22%) disease progression, 5 (14%) PHT, 1 (3%) pleural effusion (without associated PHT), 4 (11%) other DAS-related toxicity, 2 (5%) sustained MMR, 1 (3%) sepsis, 1 (3%) pregnancy, 1 (3%) acute coronary syndrome. Conclusion The current model of TKIs use in CML requires life-long therapy, which demands durable tolerability and safety. We found clinically relevant pulmonary complications of DAS therapy to be more frequent than previously reported, perhaps due to non-specific symptoms and low levels of awareness. We now recommend obtaining baseline chest X-ray and TTE prior to DAS therapy. Any new pulmonary signs or symptoms warrant early investigation, including repeat TTE for assessment of pulmonary arterial pressures. Moreover, the patient’s capacity to tolerate PHT or pleural effusions, although difficult to predict, should be considered in choice of TKI agent. Disclosures: No relevant conflicts of interest to declare.

We report an 82-year-old male presenting to his general practitioner with an 18-month history of abdominal cramps and diarrhea. Th e patient was otherwise well, with the only notable medical history being Gilbert ' s disease and treated hypertension. Physical examination was unremarkable, although mild splenomegaly was subsequently identifi ed on ultrasound (craniocaudal length 15 cm).Full blood count revealed a mild lymphocytosis of 5.5 ϫ 10 9 /L (1 -4 ϫ 10 9 ), normal hemoglobin (Hb 139 g/L [125 -175 g/L]) and mild thrombocytopenia (platelets 139 ϫ 10 9 /L [150 -400 ϫ 10 9 ]). Examination of the blood fi lm showed medium-to-large lymphocytes with moderately condensed chromatin, large single prominent nucleoli and no cytoplasmic projections [ Figure 1(a)]. Flow cytometry demonstrated a homogeneous population of abnormal lymphocytes which were CD5 Ϫ , CD19 ϩ , CD20 ϩ (bright), CD22 ϩ (strong), CD23 ϩ , CD25 ϩ , DBA-44 Ϫ , FMC7 ϩ , CD79b ϩ , CD103 Ϫ with strong κ -restricted surface immunoglobulin expression. Based on the morphological and immunophenotypic fi ndings, the patient was diagnosed with de novo B-prolymphocytic leukemia (B-PLL) [1]. Th ere was no morphological or immunophenotypic evidence of underlying chronic lymphocytic leukemia (CLL).Due to progressive fatigue, thrombocytopenia and lymphocytosis, he was commenced on chlorambucil and prednisolone 10 months after diagnosis. Th is regimen was poorly tolerated and only two cycles were administered. Th e patient was subsequently commenced on cyclophosphamide, vincristine and prednisolone; however, this was also poorly tolerated. Th e patient was then referred to our institution for further management.When assessed at our institution 21 months after diagnosis, the patient was anorexic, cachectic and highly symptomatic from massive splenomegaly. Computed tomography (CT) scan of the abdomen demonstrated gross splenomegaly, measuring 22.5 ϫ 11.6 ϫ 24 cm, with mild portocaval lymphadenopathy. Notable blood investigations at this time were: Hb 123 g/L (125 -175 g/L), white cell count (WCC) 189.3 ϫ 10 9 /L (4 -11 ϫ 10 9 ), platelets 121 ϫ 10 9 /L (150 -400 ϫ 10 9 ), normal renal function, bilirubin 23 μ mol/L (0 -17 μ mol/L), alkaline phosphatase (ALP) 453 U/L (30 -120 U/L), gamma glutamyl transpeptidase (GGT) 362 U/L (11 -50 U/L), alanine transaminase (ALT) 114 U/L (0 -50 U/L), protein 71 g/L (60 -80 g/L), serum β 2 -microglobulin 6.3 mg/L (0.8 -3.0 mg/L), lactate dehydrogenase (LDH) 1216 U/L (230 -460 U/L) and no paraprotein on serum protein electrophoresis. Multiple cytogenetic analyses of peripheral blood did not yield any mitoses. Bone marrow aspirate and trephine showed extensive involvement by an abnormal lymphoid infi ltrate with morphological and immunohistochemical features of B-PLL. Immunohistochemistry demonstrated p53 positivity in Ͼ 50% of cells. Cytogenetic analysis was not performed.Due to symptomatic splenomegaly, the patient underwent an uneventful open surgical splenectomy. Th e spleen weighed 3.2 kg, and on histological examination showed ext...