Yulia Volchek

Imatinib plasma trough levels in chronic myeloid leukaemia: results of a multicentre study CSTI571AIL11TGLIVEC

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. Copyright

Phase 1/2 study of nilotinib prophylaxis after allogeneic stem cell transplantation in patients with advanced chronic myeloid leukemia or philadelphia chromosome-positive acute lymphoblastic leukemia

Allogeneic stem cell transplantation (SCT) remains the standard treatment for advanced chronic myeloid leukemia (CML) and Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+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.

Nilotinib-Associated Acute Pancreatitis:

OBJECTIVE To report a case of acute pancreatitis in a patient receiving nilotinib for chronic myelogenous leukemia (CML). CASE SUMMARY A 69-year-old man recently diagnosed with chronic phase CML received nilotinib 300 mg twice daily and was admitted with acute pancreatitis that appeared the day after the first dose. The patient had normal levels of triglycerides and denied alcohol use. Serum pancreatic enzymes were within normal limits the day before nilotinib initiation. Abdominal computed tomography demonstrated a normal liver, bile duct without stones, and findings that were consistent with focal pancreatitis. The patients history was significant for concomitant use of enalapril and simvastatin; both have been associated with pancreatitis, but the patient had been taking these medications for at least 5 years without adverse effects. Nilotinib was immediately discontinued. Abdominal pain resolved and serum pancreatic enzymes levels returned to normal 2 weeks later. DISCUSSION One of the adverse effects of some tyrosine kinase inhibitors is increased levels of serum pancreatic enzymes. Accordingly, nilotinib labeling includes “high lipase levels in serum” as an adverse event. There are few case reports of acute pancreatitis associated with nilotinib in the literature and some are incomplete. We present a well-documented case of nilotinib-associated acute pancreatitis. Consistent with Badalovs new classification system for drug-induced acute pancreatitis and with the Naranjo probability scale, this case represents a possible adverse reaction of pancreatitis associated with nilotinib therapy. As rechallenge is unethical, treatment with nilotinib has not been resumed. CONCLUSIONS This case demonstrates a possible association between acute pancreatitis and nilotinib use. Although a rare phenomenon, clinicians should be alert for signs and symptoms of pancreatitis, as treatment with nilotinib for CML is becoming more common.

Sensitive Replicate Real-Time Quantitative PCR of BCR-ABL Shows Deep Molecular Responses in Long-Term Post–Allogeneic Stem Cell Transplantation Chronic Myeloid Leukemia Patients

Real-time quantitative PCR (RT-qPCR) is commonly used for follow-up of chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors, but its current sensitivity does not allow detection of very low BCR-ABL levels. Therefore RT-qPCR negativity is not synonymous with complete molecular response. Replicate RT-qPCR had shown increased sensitivity in tyrosine kinase inhibitor-treated patients and was, therefore, used here to evaluate whether RT-qPCR-negative post-allogeneic stem cell transplantation (SCT) patients harbor detectable disease. Samples from 12 patients were tested at 2 time points using 82 replicates of BCR-ABL RT-qPCR. One patient (38 months after SCT) had detectable transcripts at baseline and none at the follow-up test, done at a median of 107 months after SCT. This suggests cure from CML in the majority of allogeneic SCT patients who have no transcripts detectable by replicate RT-qPCR for BCR-ABL.

Real-life Experience With Ponatinib in Chronic Myeloid Leukemia: A Multicenter Observational Study

Background: The strict recruitment criteria of patients for clinical trials often lead to reduced generalizability of the findings. We studied how ponatinib is used outside clinical trials in patients with chronic myeloid leukemia (CML). Patients and Methods: The present retrospective study included all patients with a diagnosis of CML who had received ponatinib in 7 medical centers in Israel. Results: From 2011 to 2016, we identified 37 patients with CML who had received ponatinib, 21 in the chronic phase and 16 in the advanced phase. Only 9 patients (26%) harbored the T315I (threonine to isoleucine mutation at position 315) mutation. All patients had received ≥ 1 previous tyrosine kinase inhibitor. The median age in our cohort was 43 years (range, 9–82 years), significantly younger than expected for patients with relapsed or refractory CML and 20 years younger than the median age of patients who participated in the PACE (ponatinib Philadelphia‐positive acute lymphoblastic leukemia and CML evaluation) trial. During a median follow‐up of 14 months (range, 1–51 months), the overall response rate was 85%. Of 34 patients, 16 (47%) experienced at least a major molecular response. Of the 37 total patients, another 16 patients (43%) discontinued treatment because of disease progression (n = 6), vascular complications (n = 1), severe cytopenia (n = 2), or for other reasons (n = 7). Conclusion: In real life, ponatinib is a “niche‐drug” reserved for a unique population of exceptionally young patients with CML with or without the T315I mutation. In this highly selected group, very different from the PACE cohort, ponatinib achieved high overall response rates. Micro‐Abstract In the present study, we identified 37 patients with chronic myeloid leukemia in 7 medical centers to study how ponatinib is used outside of clinical trials. At least 1 previous tyrosine kinase inhibitor had failed in all 37 patients. Their median age was 43 years (range, 9–82 years), and the overall response rate was 85%. Outside of clinical trials, ponatinib has been reserved for exceptionally young patients; however, responses can be expected even in heavily pretreated patients.