Background: ENESTfreedom (NCT01784068) is a single‐arm, open‐label, phase 2 study evaluating TFR in patients with CML in chronic phase who achieved a sustained deep molecular response (DMR) with 1L nilotinib. In the primary analysis, 51.6% of patients remained in TFR 48 wks after stopping nilotinib. Analyses at 144 wks showed durability of TFR. Aims: To assess longer‐term maintenance and safety of TFR after 192 wks of follow‐up. Methods: Eligible patients had been treated with ≥2 y of 1L nilotinib and achieved MR 4.5 ( BCR‐ABL1 IS ≤0.0032%). After 1 y of consolidation treatment, patients with sustained DMR could attempt TFR. Nilotinib was resumed upon loss of major molecular response (MMR; BCR‐ABL1 IS ≤0.1%). As of 17 Sep 2018 (data cut‐off), all patients had either completed ≥192 wks of TFR, resumed nilotinib, or discontinued the study. Results: Of 190 patients who had entered TFR, 87 remained in TFR, 91 had resumed nilotinib and 12 had discontinued the study by the data cut‐off. At 192 wks, the TFR rate was 44.2% (84/190, 95% CI: 37.0–51.6%). Of patients in TFR at 144 wks, 5/89 were not evaluable for TFR at 192 wks as 2 had discontinued by 192 wks due to patient/physician decision, and 3 who were previously in MR 4.5 did not have 192‐wk PCR data. A total of 90/91 (98.9%) and 84/91 (92.3%) patients who resumed nilotinib regained MMR and MR 4.5 , respectively. At 48 wks after regaining MMR or MR 4.5 , 75/90 and 73/84 patients, respectively, had stable responses. There were no disease progressions or deaths due to CML. A total of 10 deaths were reported in the 144‐wk analysis, with no new deaths reported subsequently. The treatment‐free survival rate at 192 wks was 48.7% (95% CI 41.4–55.6%; Figure ). Rates of all‐grade AEs were 84.3% during consolidation and 77.5%, 70.8%, 48.3% and 52.8% during each subsequent 48‐wk period of TFR, respectively, among the 89 patients who remained in TFR for >144 wks (including 87 patients for >192 wks). Rates of musculoskeletal pain AEs (all‐grade) were 15.7% during consolidation, then increased during the first 48 wks of TFR (40.4%) and subsequently decreased during TFR to below levels seen during consolidation (9.0%, 3.4% and 3.4%, respectively). Rates of cardiovascular events were low across all periods (3.4%, 2.2%, 1.1%, 2.2% and 0%). Among the 91 patients who resumed nilotinib, the most common AEs were nasopharyngitis (18.7%) as well as pruritus, fatigue and increased lipase (14.3% each); the majority of AEs were grade 1/2. To further explore AEs that may affect quality of life, incidences of AEs grouped by category (rate >10% on treatment) were analyzed during consolidation and the 1 st , 2 nd , 3 rd , and 4 th 48‐wk periods of TFR, respectively: gastrointestinal disorders, 29.2%, 28.1%, 16.9%, 6.7% and 3.4%; infections and infestations, 39.3%, 34.8%, 24.7%, 19.1% and 20.2%; musculoskeletal and connective tissue disorders: 27.0%, 50.6%, 22.5%, 7.9% and 10.1%; and general disorders and administration site conditions (eg, asthenia, pyrexia): 14.6%, 11.2%, 10.1%, 6.7% and 4.5%. In these AE categories, similar trends toward decreasing incidences during TFR compared with consolidation were observed. Summary/Conclusion: These results demonstrate the long‐term durability and safety of TFR following 1L nilotinib. There were no disease progressions or CML‐related deaths, and musculoskeletal pain AEs were transient. AEs that may adversely affect patients’ quality of life tended to decrease in frequency during TFR vs during consolidation. Patients should continue to be regularly monitored during TFR. image

BACKGROUND:The role of ureteric stenting in kidney transplant recipients is still debatable. Stenting can reduce the incidence of urine leaks and ureter stenosis, but can be also associated with specific complications, particularly urinary tract infections (UTIs). MATERIAL AND METHODS:To estimate the influence of ureteric stenting on urological complications in kidney transplantation (KTx), we retrospectively analyzed all KTx performed between January 2011 and December 2016 in Gdansk Transplantation Centre, a total of 628 patients. Ureteric stenting was used in 502 patients (80%)-double-J (DJ) group. Catheters were implanted during the surgical procedure and left in situ for a mean time of 30 days. RESULT:The frequency of urinary leaks was 10 times higher in patients without stenting (10%). Ureter stenosis was also more frequent in the non-DJ group (8.7% vs 1.6%, P < .05). Multiple-regression modeling showed that the urinary not stenting was a risk factor for urinary leak (adjusted odds ratio [AOR] = 0,1; 95% confidence interval [CI]: 0.03-0.26; P < .01), ureter stenosis (AOR = 0,16; 95% CI: 0.06-0.41; P < .01), and generally reoperation after KTx (AOR = 0,46; 95% CI: 0.28-0.77; P < .01). Acute rejection and delayed graft function were equal in both groups. Mean serum creatinine concentration 1 month after transplantation was similar in both groups (1.5 mg/dL in the DJ group and 1.44 mg/dL in the non-DJ group, P > .05). UTIs were more frequent in the DJ group (22.1% vs 16.7%), but the difference was not significant. Time of hospitalization was longer in patients with UTI (34 vs 22 days, P < .05). CONCLUSIONS:Ureteric stenting can protect patients from most frequent urological complications like urine leaks and ureter stenosis. The influence of ureteric stenting on UTI development is not strong in our material.

The single-arm, phase 2 ENESTfreedom trial assessed the potential for treatment-free remission (TFR; i.e., the ability to maintain a molecular response after stopping therapy) following frontline nilotinib treatment. Patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase with MR4.5 (BCR-ABL1⩽0.0032% on the International Scale (BCR-ABL1IS)) and ⩾2 years of frontline nilotinib therapy were enrolled. Patients with sustained deep molecular response during the 1-year nilotinib consolidation phase were eligible to stop treatment and enter the TFR phase. Patients with loss of major molecular response (MMR; BCR-ABL1IS⩽0.1%) during the TFR phase reinitiated nilotinib. In total, 215 patients entered the consolidation phase, of whom 190 entered the TFR phase. The median duration of nilotinib before stopping treatment was 43.5 months. At 48 weeks after stopping nilotinib, 98 patients (51.6%; 95% confidence interval, 44.2–58.9%) remained in MMR or better (primary end point). Of the 86 patients who restarted nilotinib in the treatment reinitiation phase after loss of MMR, 98.8% and 88.4%, respectively, regained MMR and MR4.5 by the data cutoff date. Consistent with prior reports of imatinib-treated patients, musculoskeletal pain-related events were reported in 24.7% of patients in the TFR phase (consolidation phase, 16.3%).

BACKGROUND:The purpose of renal transplantation is to achieve a maximal improvement in quality of life (QoL) and life expectancy in patients with end-stage renal disease (ESRD) while minimizing the potential side effects of this procedure. It is important to achieve an optimal balance between graft function and the patient's QoL. This study was designed to assess the changes in the QoL after kidney transplantation (KTx) in patients with ESRD previously treated with hemodialysis (HD) or peritoneal dialysis (PD).METHODS:QoL was prospectively analyzed in 69 patients after kidney transplantation in a single-center study. Patients with ESRD were divided into 2 groups: those previously treated with HD (n = 44 patients; group 1) or PD (n = 25 patients; group 2). Both groups were asked to complete the KDQOL-SFtm questionnaire before and 12 months after kidney transplantation.RESULTS:We observed significant differences in many parameters of QoL in both groups after KTx but more positive changes of most parameters in question exhibited by patients previously treated by means of HD than PD. Patients treated with HD and PD demonstrated improvement after KTx in 74% of dimensions. There were no statistical differences in the QoL between group 1 and group 2 before or after KTx.CONCLUSIONS:The study demonstrated post- to pre-transplant improvements of QoL independently of previous treatment.

Abstract Introduction: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) primarily affects older patients (pts) who often have medical comorbidities along with disease-related immunosuppression and myelosuppression. Although alkylating agents such as chlorambucil (clb) have been commonly used in these pts, novel therapies are needed. Ibrutinib (ibr) is a first-in-class, oral, covalent inhibitor of Bruton's tyrosine kinase FDA-approved for pts with CLL who received ≥1 prior therapy and for del17p CLL (including first-line). Ibr showed high activity in treatment-naïve pts age ≥65 years, with an overall response rate (ORR) of 84% (complete response [CR] in 23%) and 30-month progression-free survival (PFS) of 96% (Byrd et al. Blood 2015). We conducted a randomized, open-label phase 3 trial to evaluate efficacy and safety of single-agent ibr vs clb in treatment-naïve older pts with CLL/SLL. Methods: Pts aged ≥65 years with treatment-naïve CLL/SLL were randomized 1:1 to receive 420 mg ibr daily until progression or clb 0.5 mg/kg (up to maximum of 0.8 mg/kg) on days 1 and 15 of a 28-day cycle for up to 12 cycles. Pts with del17p were excluded. Primary endpoint was independent review committee (IRC)-assessed PFS per iwCLL 2008 criteria, with 2012 clarification for treatment-related lymphocytosis. Secondary endpoints included overall survival (OS), ORR, event-free survival (EFS), rate of hematologic improvement, and safety. Pts with IRC-confirmed progression could transfer to an extension study where next-line therapy (including ibr) could be initiated if they had an iwCLL indication for treatment. Results: Among 269 pts enrolled, median age was 73 years (70% ≥70 years). Baseline characteristics were balanced between arms; 45% had advanced Rai stage, 20% had del11q, and 69% had comorbidities at baseline including CIRS score >6, reduced creatinine clearance, or ECOG status of 2. For pts treated with clb, 40% completed 12 cycles of therapy (mean dose 0.6 mg/kg). At a median follow-up of 18.4 months (mos), ibr significantly prolonged IRC-assessed PFS vs clb (median not reached [NR] vs 18.9 mos; HR 0.16, 95% CI 0.09-0.28, P<0.0001); this was consistent within subgroups including age ≥70 years, del11q, and unmutated IGHV. As assessed by investigator, ibr reduced the risk of progression or death by 91% (HR 0.09; 95% CI, 0.04-0.17; P<0.0001; Figure 1A), with an 18-mo PFS of 93.9% vs 44.8%. Ibr significantly prolonged OS vs clb (median NR for either arm; HR 0.16, 95% CI 0.05-0.56, P=0.0010; Figure 1B); 24-mo OS was 97.8% vs 85.3%, respectively. Three deaths occurred on the ibr arm vs 17 deaths on clb arm. The IRC-assessed ORR was 86.0% with ibr (4.4% CR/CRi) vs 35.3% with clb (1.5% CR/CRi). ORR with ibr was higher than clb at all evaluated time points; at 8 mos, ORR was 84% and 31%, respectively. Investigator-assessed ORR was 90.4% (9.6% CR/CRi) vs 35.3% (4.5% CR/CRi), respectively. Median EFS was also prolonged with ibr (NR vs 12 mos; HR 0.17, 95% CI 0.10-0.26; P<0.0001). A ≥50% reduction in lymph node burden was observed in 91.2% vs 36.8% (P<0.0001), and reduction in spleen enlargement in 75.7% vs 39.1% (P<0.0001), for ibr and clb, respectively. Rates of sustained hematologic improvements were significantly higher with ibr vs clb, including in pts with baseline anemia (84% vs 45%; P<0.0001) or thrombocytopenia (77% vs 43%; P=0.0054). Median duration of treatment was 17.4 mos with ibr and 7.1 mos with clb. Most frequent (≥20% of pts) adverse events (AEs) with ibr included diarrhea, fatigue, cough and nausea. Most frequent AEs with clb included nausea, fatigue, neutropenia, anemia and vomiting. AEs leading to treatment discontinuation were less frequent with ibr (9% vs 23%). Atrial fibrillation occurred in 6% (6 pts grade 2 and 2 pts grade 3) with ibr and 1% with clb. Hypertension was noted more frequently on ibr, but was limited to grade 1-3 and managed without ibr dose modification or discontinuation. Major hemorrhage occurred in 4% (1 pt grade 2, 4 pts grade 3, 1 pt grade 4) with ibr over median follow-up of approximately 1.5 years, and in 2% with clb. At the time of study closure, 87% of pts randomized to ibr continue to receive ibr. Conclusions: Treatment with single-agent ibr was superior to clb in terms of PFS, OS, ORR, EFS and hematologic improvement in treatment-naïve older CLL/SLL patients, with an 84% reduction in risk of death, and an acceptable safety profile. Disclosures Off Label Use: ibrutinib in first-line CLL (including non-del17p CLL). Barr:Gilead: Consultancy; Abbvie: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Robak:Janssen: Consultancy, Research Funding; MorphoSys AG: Consultancy, Honoraria, Research Funding. Owen:Janssen: Honoraria; Lundbeck: Honoraria; Gilead: Honoraria; Roche: Honoraria. Ghia:Adaptive: Consultancy; Pharmacyclics: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; GSK: Research Funding; AbbVie: Consultancy; Janssen: Consultancy; Roche: Consultancy, Research Funding; Acerta Pharma BV: Research Funding. Hillmen:Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Roche Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Bartlett:Novartis: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Gilead: Consultancy, Research Funding; Genentech: Research Funding; MERC: Research Funding; Insight: Research Funding; Colgene: Research Funding; Medimmune: Research Funding; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Kite: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding. Coutre:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding. Quach:Celgene Corp, ONYX, Janssen, Takeda, Novartis, BMS: Honoraria, Research Funding. Janssens:Mundipharma: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy. O'Dwyer:Celgene: Honoraria, Research Funding. Hellmann:BMS: Consultancy, Other: funding of travel, accomodations or expenses, Speakers Bureau; Novartis: Consultancy, Other: funding of travel, accomodations or expenses, Research Funding, Speakers Bureau. Schuh:Acerta Pharma BV: Research Funding. Siddiqi:Seattle Genetics: Speakers Bureau; Pharmacyclics/Jannsen: Speakers Bureau; Kite pharma: Other: attended advisory board meeting. Tam:AbbVie: Honoraria; Roche: Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Keating:Glaxo-Smith-Kline Inc.: Other: Advisory board; Celgene Corp.: Consultancy. Suri:Pharmacyclics LLC, an AbbVie Company: Employment. Zhou:Pharmacyclics LLC, an AbbVie Company: Employment. Clow:Pharmacyclics LLC, an AbbVie Company: Employment. Styles:Pharmacyclics LLC, an AbbVie Company: Employment. James:Pharmacyclics LLC, an AbbVie Company: Employment. Kipps:Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor; Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor. Burger:Pharmacyclics LLC, an AbbVie Company: Research Funding.

The EUTOS population-based registry includes data of all adult patients newly diagnosed with Ph+ and/or BCR-ABL1+ CML in 20 predefined countries and regions of Europe. Registration time ranged from 12 to 60 months between January 2008 and December 2013. Median age was 55 years and median observation time 29 months. 80% of patients were treated first-line with imatinib, and 17% with a second generation tyrosine kinase inhibitor, mostly according to European LeukemiaNet recommendations. After 12 months CCyR and MMR were achieved in 57 and 41% of patients, respectively. Patients with high EUTOS risk scores achieved CCyR and MMR significantly later than patients with low EUTOS risk. Probabilities of OS and PFS for all patients at 12, 24 and 30 months was 97%, 94% and 92%, and 95%, 92% and 90%, respectively. The new ELTS score was validated: the OS of patients differed significantly between the three risk groups. The probability of dying in remission was 1% after 24 months. The current management of patients with TKIs resulted in responses and outcomes in the range reported from clinical trials. These data from a large population-based, patient sample provides a solid benchmark for the evaluation of new treatment policies.

The European Treatment and Outcome Study (EUTOS) population-based registry includes data of all adult patients newly diagnosed with Philadelphia chromosome-positive and/or BCR-ABL1+ chronic myeloid leukemia (CML) in 20 predefined countries and regions of Europe. Registration time ranged from 12 to 60 months between January 2008 and December 2013. Median age was 55 years and median observation time was 29 months. Eighty percent of patients were treated first line with imatinib, and 17% with a second-generation tyrosine kinase inhibitor, mostly according to European LeukemiaNet recommendations. After 12 months, complete cytogenetic remission (CCyR) and major molecular response (MMR) were achieved in 57% and 41% of patients, respectively. Patients with high EUTOS risk scores achieved CCyR and MMR significantly later than patients with low EUTOS risk. Probabilities of overall survival (OS) and progression-free survival for all patients at 12, 24 and 30 months was 97%, 94% and 92%, and 95%, 92% and 90%, respectively. The new EUTOS long-term survival score was validated: the OS of patients differed significantly between the three risk groups. The probability of dying in remission was 1% after 24 months. The current management of patients with tyrosine kinase inhibitors resulted in responses and outcomes in the range reported from clinical trials. These data from a large population-based, patient sample provide a solid benchmark for the evaluation of new treatment policies.

This population-based registry was designed to provide robust and updated information on the characteristics and the epidemiology of chronic myeloid leukemia (CML). All cases of newly diagnosed Philadelphia positive, BCR-ABL1+ CML that occurred in a sample of 92.5 million adults living in 20 European countries, were registered over a median period of 39 months. 94.3% of the 2904 CML patients were diagnosed in chronic phase (CP). Median age was 56 years. 55.5% of patients had comorbidities, mainly cardiovascular (41.9%). High-risk patients were 24.7% by Sokal, 10.8% by EURO, and 11.8% by EUTOS risk scores. The raw incidence increased with age from 0.39/100 000/year in people 20–29 years old to 1.52 in those >70 years old, and showed a maximum of 1.39 in Italy and a minimum of 0.69 in Poland (all countries together: 0.99). The proportion of Sokal and Euro score high-risk patients seen in many countries indicates that trial patients were not a positive selection. Thus from a clinical point of view the results of most trials can be generalized to most countries. The incidences observed among European countries did not differ substantially. The estimated number of new CML cases per year in Europe is about 6370.

Tyrosine kinase inhibitors represent today’s treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69–0.82) vs 0.69 (95% CI: 0.61–0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (P<0.001) and non-high-risk disease (P=0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56% vs 39%; P=0.005) and free of drug treatment (56% vs 6%; P<0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered.