Allo-SCT with reduced-intensity conditioning (RIC) results in lower non-relapse mortality (NRM), but higher relapse rate than myeloablative conditioning (MAC) in AML/myelodysplastic syndromes (MDS). Novel regimens with intensive anti-leukemic activity, but with limited toxicity will be of benefit. In all, 85 patients with AML/MDS, not eligible for MAC, were given fludarabine-treosulfan conditioning (FT). Outcomes were compared with those in patients given fludarabine-BU RIC (FB2, n ¼ 106) or reduced-toxicity (RTC) conditioning (FB4, fludarabine and myeloablative BU dose, n ¼ 85). The 5-year NRM was 29%, 20% and 18% after FT, FB2 and FB4, respectively (P ¼ NS). Multivariate analysis (MVA) identified comorbidity score (HCT-CI) 42 and advanced disease as adverse factors with no independent impact of regimen. The 5-year relapse rate was 36%, 47% and 40%, respectively (P ¼ 0.17). MVA identified advanced disease as the major adverse factor, while FT had significantly lower relapse rate (hazard ratio 0.6, P ¼ 0.03). The 5-year survival (OS) was 37% with advanced disease. HCT-CI 42 and age X50 were found as adverse factors. The 5-year OS was 46%, 44% and 50% after FT, FB2 and FB4 in early-intermediate-stage disease (P ¼ NS) and 33%, 9% and 28% in advanced disease, respectively (P ¼ 0.02). FT is an RTC regimen with intensive anti-leukemia effect in MAC non-eligible patients.

BACKGROUND: Allogeneic stem cell transplantation (SCT) remains the standard treatment for advanced chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph 1 ALL). Relapsed disease is the major cause of treatment failure, especially when SCT is given in the setting of advanced disease. Tyrosine kinase inhibitors can be given after transplantation prophylactically or after the detection of minimal residual disease (MRD) to reduce the relapse risk. METHODS: Posttransplant nilotinib was started after the achievement of sustained engraftment and the resolution of transplant-related toxicities. Nilotinib was continued until progression or unacceptable toxicity. RESULTS: Twenty-two patients with advanced CML (n 5 15) or Ph 1 ALL (n 5 7) underwent SCT with human leukocyte antigen-matched siblings (n 5 11), unrelated donors (n 5 7), or alternative donors (n 5 4). Sixteen patients were given prophylactic nilotinib maintenance, which was started at a median of 38 days after transplantation. Six patients stopped the treatment because of toxicities (mostly gastrointestinal and hepatic). After nilotinib maintenance, 11 patients achieved (n 5 9) or maintained (n 5 2) a complete molecular response (CMR), and only 1 of them later relapsed. Four of the 5 patients not achieving CMR relapsed. At a median follow-up of 46 months, 9 patients were alive, and 13 had died. The 2-year overall and progression-free survival rates were 55% (95% confidence interval [CI], 34%-75%) and 45% (95% CI, 25%-66%), respectively. Among the 16 nilotinib recipients, the rates were 69% (95% CI, 46%-92%) and 56% (95% CI, 32%-81%), respectively. The 2-year nonrelapse mortality and relapse rates for all patients were 32% (95% CI, 17%-58%) and 23% (95% CI, 11%-49%), respectively. CONCLUSIONS: Nilotinib is relatively safe and effective prophylactic therapy for the prevention of relapse after SCT. It may control MRD and convert patients to CMR, which is associated with prolonged survival. These observations merit further study in larger scale studies. Cancer 2015;121:863-71.

The choice of a rituximab-based regimen and the prognostic significance of interim 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) in primary mediastinal large B cell lymphoma (PMBCL) are debatable. We evaluated the clinical features and outcomes of 95 consecutive patients with PMBCL who were treated between 1985 and 2009. Forty-three patients received rituximab-based chemotherapy, R-VACOP-B (N = 30) or R-CHOP21 (N = 13), whereas 52 patients were treated with VACOP-B (N = 47) or CHOP21 (N = 5). Radiotherapy was not given. Patients who received rituximab had a 5-year progression-free survival (PFS) of 79 % and overall survival (OS) of 97 % compared with 58 % (p = 0.06) and 88 % (p = 0.2), respectively, without rituximab. Five-year PFS in patients treated with R-VACOP-B, R-CHOP21, VACOP-B, and CHOP21 were 83, 69, 62, and 20 %, respectively (p = 0.039). However, direct comparison showed that the difference between PFS rates in patients receiving R-VACOP-B compared to R-CHOP21 was not statistically significant (p = 0.3). None of the standard clinical risk factors predicted for PFS and OS in patients receiving rituximab (R)-chemotherapy. Mid-interim FDG-PET/CT scans were performed in 30/43 patients who received R-chemotherapy. The negative predictive values of mid-PET activity were high (100 % for R-VACOP-B and 86 % for R-CHOP21) while the positive predictive values (PPV) were relatively low (30 and 75 %, respectively). Despite the low PPV, the 5-year PFS for mid-PET-negative patients (N = 16) was significantly higher (94 %) than that for mid-PET-positive (N = 14) patients (57 %, p = 0.015). This retrospective analysis demonstrates that the superiority of VACOP-B over CHOP21 for treatment of PMBCL disappeared once rituximab was added. The potential benefit of using interim PET activity as a guide for continuing therapy in patients with PMBCL remains unclear due to the relatively low PPV.

Secondary malignancies are well established complication in long-term survivors after allogeneic stem-cell transplantation (SCT) with myeloablative conditioning (MAC). Fludarabine-based reduced-intensity (RIC) and reduced-toxicity conditioning (RTC) regimens are increasingly used in the last decade; however, due to limited long-term follow-up, there is no data on secondary malignancies in this setting. The records of 931 consecutive patients given allogeneic SCT with MAC (n=257), RIC (n=449) or RTC (n=225), in a single institution over a 13-year period, were reviewed. Twenty-seven patients had secondary malignancy, diagnosed a median of 43 months (7 months-11.5 years) after SCT. The 10-year cumulative incidence was 5.6% (95% confidence interval (CI), 3.6-8.7), twice the expected rate in matched normal population. The incidence was 1.7, 7.4 and 5.7% after MAC, RIC and RTC, respectively (P=0.02). Multivariate analysis identified fludarabine-based conditioning (hazard ratio (HR) 3.5, P=0.05), moderate-severe chronic graft-versus-host disease (HR 2.8, P=0.01) and diagnosis of chronic myeloproliferative or non-malignant disease (HR 0.2, P=0.04) as risk-factors for secondary malignancy. The related 10-year mortality rate was 2.4% (95% CI, 1.0-5.4). In conclusion, the risk of secondary malignancies is not reduced and is even possibly increased in the era of fludarabine-based RIC/RTC. Patients and physicians should be aware of this association and life-long cancer screening is required for all transplant survivors.

Imatinib has been accepted as frontline treatment for patients with chronic myeloid leukaemia (CML), and patients generally receive doses ranging from 400 to 800 mg/day. Previous studies have demonstrated that maintaining imatinib plasma levels (IMPLs) >1000 ng/mL leads to improved responses and long-term outcomes. However, IMPLs vary among patients because of factors such as drug-drug interactions, adherence, toxicity and differential levels of expression of cellular efflux/influx proteins. In this study, IMPLs were analysed in 191 patients with CML and were compared with achievement of molecular and cytogenetic responses (CyR). IMPLs were also correlated with renal and hepatic dysfunction. Additionally, self-reported adherence was monitored. The median and mean IMPLs were 994 ng/mL and 1070 ± 686 ng/mL, respectively, with 96 patients (50%) achieving plasma levels >1000 ng/mL. Self-reported patient compliance was 98%. Patients who achieved a complete CyR (CCyR) had significantly higher IMPLs (1078 ± 545 ng/mL) than those without CyR (827 ± 323 ng/mL, p = 0.045). When grouped together, patients who achieved a CCyR or partial CyR had significantly higher IMPLs than patients who achieved a minimal CyR or did not achieve a CyR (1066 ng/mL vs 814 ng/mL, p = 0.002). There was no significant difference observed in the IMPLs between patients who achieved molecular responses (n = 177) on treatment (major molecular response, 976 ± 385 ng/mL versus complete molecular response, 1138 ± 809 ng/mL, p = 0.387). Mean IMPLs were similar in patients with or without renal or hepatic impairment. Overall, this study confirmed previous reports that higher IMPLs correlate with clinical responses and demonstrated that imatinib exposure did not differ in patients with or without liver and/or renal dysfunction. The use of IMPL testing and patient diaries may be practical tools for the management of imatinib therapy in patients with CML.