Overexposure to venetoclax is associated with prolonged-duration of neutropenia during venetoclax and azacitidine therapy in Japanese patients with acute myeloid leukemia.

PURPOSE: An observational study was conducted to evaluate the pharmacokinetics of venetoclax and its impact on the efficacy and safety for Japanese patients with acute myeloid leukemia (AML) treated with venetoclax and azacitidine therapy. METHODS: The association between the plasma concentration, after the first cycle of azacitidine and venetoclax therapy, and the efficacy and safety was evaluated in 33 patients with untreated or relapsed/refractory AML. RESULTS: Full dose of venetoclax was administered to all patients. Venetoclax treatment was 28 day long in 82% of patients; the relative dose intensity of azacitidine was 82%. Trough concentration was significantly higher among patients with complete remission (CR) and CR with incomplete hematologic recovery (CRi) than those with the morphologic leukemia-free state and partial remission, and no response groups (P = 0.01). Median duration of grade 3 neutropenia was 28 days (range 8-46 days). Area under the concentration-time curve (AUC0-24) was significantly higher among patients with protracted grade 3 neutropenia (≥ 28 days) than those with a shorter duration (< 28 days) (P = 0.03); multivariate analysis revealed that a higher AUC0-24 was a significant predictor of a longer duration of neutropenia (odds ratio 54.3, P = 0.007). CONCLUSION: Plasma concentrations of venetoclax were variable in Japanese patients with AML. Higher plasma concentrations were associated with CR/CRi and protracted grade 3 neutropenia. Therefore, it is essential to adjust the duration of venetoclax administration based on individual pharmacokinetic data to limit total drug exposure, reduce severe neutropenia, and achieve higher efficacy.

Prognostic impact of peripheral blood WT1 mRNA dynamics in patients with acute myeloid leukemia treated with venetoclax combination therapy.

BACKGROUND: Wilms' tumor gene 1 (WT1) mRNA quantification is a useful marker of measurable residual disease in acute myeloid leukemia (AML). However, whether monitoring the WT1 mRNA levels may predict the outcome of venetoclax (VEN) combination therapy in AML is not reported. This study aims to elucidate whether WT1 mRNA dynamics could predict long-term prognosis. METHODS: 33 patients with untreated or relapsed/refractory AML evaluated for peripheral blood WT1 dynamics in VEN combination therapy were analyzed. RESULTS: The median age was 73 years (range 39-87). Azacitidine was combined with VEN in 91% of patients. Overall, the median overall survival (OS) was 334 days (95% CI 210-482), and the complete remission (CR) plus CR with incomplete hematologic recovery rate was 59%. A 1-log reduction of WT1 mRNA values by the end of cycle 2 of treatment was associated with significantly better OS and event-free survival (EFS) (median OS 482 days vs. 237 days, p = 0.049; median EFS 270 days vs. 125 days, p = 0.02). The negativity of post-treatment WT1 mRNA value during the treatment was associated with significantly better OS and EFS (median OS 482 days vs. 256 days, p = 0.02; median EFS not reached vs. 150 days, p = 0.005). Multivariate analysis confirmed the significance of these two parameters as strong EFS predictors (HR 0.26, p = 0.024 and HR 0.15, p = 0.013, respectively). The increase in WT1 mRNA values was correlated with relapse. CONCLUSION: This study demonstrates that WT1 mRNA dynamics can be a useful marker for assessing long-term prognosis of VEN combination therapy for AML.

[Successful cord blood transplantation for refractory gamma-delta hepatosplenic T-cell lymphoma developed during treatment of Crohn's disease].

The patient was a 21-year-old man who had been diagnosed with Crohn's disease and received infliximab and azathioprine six years earlier. He was admitted with fever and fatigue. Peripheral blood examination showed LDH 2,473 U/l and thrombocytopenia, and contrast-enhanced computed tomography (CT) showed hepatosplenomegaly. Bone marrow biopsy and liver biopsy showed CD4+CD56+TCRγδ＋CD8- atypical cells, leading to a diagnosis of hepatosplenic T-cell lymphoma (HSTCL). The patient was refractory to CHOP and DA-EPOCH, and therefore received cord blood transplantation with myeloablative conditioning. CT showed reduced in hepatosplenomegaly and peripheral blood examination showed LDH 165 U/l and plt 180,000/µl, so the patient was discharged on day117. HSTCL is a tumor of immature γδT cells with a Vδ1 mutation in the spleen, and immunodeficiency has been implicated in its pathogenesis. Patients with inflammatory bowel disease treated with azathioprine are known to have an increased risk of lymphoproliferative disease. In this case, use of immunosuppressive drugs for Crohn's disease may have caused malignant transformation of γδ cells in the intestinal epithelium. Although the patient was refractory to chemotherapy, he was able to achieve remission with early cord blood transplantation and long-term survival is expected.

Long-term follow-up after R-High CHOP/CHASER/LEED with Auto-PBSCT in untreated mantle cell lymphoma-Final analysis of JCOG0406.

Progression-free survival after R-High CHOP/CHASER/LEED with auto-PBSCT in untreated mantle cell lymphoma in JCOG0406 study. A continuous pattern of relapse was observed.

Outcomes of adult patients with early T-cell precursor (ETP) acute lymphoblastic leukemia/lymphoma (ALL) and non-ETP T-ALL.

Early T-cell precursor (ETP) acute lymphoblastic leukemia/lymphoma (ALL) is generally considered to be a high-risk subtype. We retrospectively analyzed the clinical outcomes of adult patients diagnosed with ETP-ALL or other T-cell ALL (non-ETP T-ALL). The subjects were 82 patients (ETP-ALL: n = 18, non-ETP T-ALL: n = 64) for whom relevant immunophenotype data needed for classification were available. ETP-ALL patients were older (median age, 50.5 vs. 33.5 years, P = 0.042) and had less mediastinal involvement (27.8 vs. 73.4%, P < 0.001). The rate of complete remission (CR) with the first induction therapy was significantly lower in the ETP group (33.3 vs. 64.0%, P = 0.03), but the CR rate within 2 cycles of chemotherapy did not differ significantly (61.1 vs. 76.6%, P = 0.232). The 3-year overall survival (OS) rate was also similar in both groups (43.2 vs. 45.8%, P = 0.992). The ETP phenotype had no impact on survival in the transplant group or the non-transplant group. A multivariate analysis identified the male sex as a poor prognostic factor (HR: 4.43, P < 0.01), but not the immunophenotype of ETP. The prognosis for adult patients with ETP-ALL was comparable to that of non-ETP T-ALL patients. However, further studies aimed at improving the remission rate for ETP-ALL are needed.

Effects of ABCB1 polymorphisms on the transport of ponatinib into the cerebrospinal fluid in Japanese Philadelphia chromosome-positive acute lymphoblastic leukaemia patients.

The effects of polymorphisms of ABCB1 and ABCG2 on the dose-adjusted plasma trough concentrations and cerebrospinal fluid (CSF)-to-plasma ratios of ponatinib were evaluated. Blood (C4 ) and CSF (CSF4 ) concentrations at 4 h after administration were determined. The median (95% confidence interval) CSF4 -to-C4 ratio of ponatinib in subjects homozygous for ABCB1 variants 1236T/T, 2677T/T + T/A or 3435T/T were significantly higher than that in a group of subjects with other genotypes (P = .026, .012 and .015, respectively). The median (95% confidence interval) CSF4 -to-C4 ratio of ponatinib in 4 patients with the combination of ABCB1 variants 1236T/T-2677T/T + T/A-3435T/T was 2.62% (1.42-3.42%); this ratio was significantly higher than that in subjects with other genotypes (1.08% [0.89-1.47%]; P = .006). The brain distribution of ponatinib was affected by ABCB1 polymorphisms and therefore seems to be modulated by P-glycoprotein at the blood-brain and blood-CSF barriers.

Deep molecular response in patients with chronic phase chronic myeloid leukemia treated with the plasminogen activator inhibitor-1 inhibitor TM5614 combined with a tyrosine kinase inhibitor.

BACKGROUND: We recently showed that pharmacological inhibition of plasminogen activator inhibitor-1 (PAI-1) activity, based on TM5614, increases cell motility and induces the detachment of hematopoietic stem cells from their niches. In this TM5614 phase II clinical trial, we investigated whether the combination of a PAI-1 inhibitor and tyrosine kinase inhibitors (TKIs) would induce a deep molecular response (DMR) in patients affected by chronic myeloid leukemia (CML) by quantifying BCR-ABL1 transcripts. METHODS: Patients with chronic phase CML treated with a stable daily dose of TKIs for at least 1 year and yielding a major molecular response (MMR) but not achieving MR4.5 were eligible for this study. After inclusion, patients began to receive TM5614 as well as a TKI. The primary objective was an evaluation of the cumulative incidence of patient progression from an MMR/MR4 to MR4.5 by 12 months. RESULTS: Thirty-three patients were enrolled in the study. The median age was 59.0 years and 58% were male. No Sokal high-risk patients were enrolled in this trial. The median TKI treatment duration was 4.8 years. At the start of this study, seven patients and 26 patients received imatinib and second-generation TKIs, respectively. The cumulative MR4.5 incidence by 12 months was 33.3% (95% confidence interval, 18.0%-51.8%). The cumulative MR4.5 spontaneous conversion over 12 months was estimated as 8% with TKIs alone based on historical controls. The halving time of BCR-ABL1 at 2 months was significantly shorter for patients who achieved an MR4.5 , by 12 months than for the other patients (cutoff value: 48 days; sensitivity: 0.80; specificity: 0.91; ROC-AUC: 0.83). During this study, bleeding events and abnormal coagulation related to the drug were not reported, and TM5614 was found to be highly safe. CONCLUSION: TM5614 combined with TKI was well tolerated and induced MR4.5 in more patients than stand-alone TKI treatment.

Ponatinib Improved the Prognosis of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Japanese Single-Center Cohort Study.

Introduction The overall survival (OS) of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) has improved with the combination of tyrosine kinase inhibitor (TKI) with intensive chemotherapy. In recent years, there has been increased interest in the possibility of long-term survival without allogeneic hematopoietic stem cell transplantation (HSCT) or maintenance therapy. The aim of this study was to determine the effectiveness of treatment and the resultant outcomes in Ph+ALL patients using real-world data. Methods We performed a single-center retrospective analysis utilizing Akita University Hospital data (Akita, Japan) from November 2000 to June 2023 to evaluate the outcomes of TKI with intensive chemotherapy for Ph+ALL. Results Twenty-three patients with Ph+ALL were treated with intensive chemotherapy combined with TKI, including six imatinib, four dasatinib, and 13 ponatinib. The median patient age was 53 years (range; 28-67). Eighteen patients (78%) achieved complete molecular remission (CMR) within three months. HSCT was performed in 16 patients (70%), all of whom did not receive post-transplant TKI maintenance therapy. Six of the seven patients who did not undergo HSCT received maintenance therapy with ponatinib after intensive chemotherapy. The three-year OS was 81%. Ponatinib treatment resulted in a much higher OS rate than imatinib/dasatinib (100% vs. 60%; P=0.011). CMR within three months was identified as a prognostic factor for molecular relapse-free survival (hazard ratio (HR)=0.22; P=0.027). CD20 positivity was identified as a risk factor for hematological relapse (HR=5.2, P=0.032). Conclusion Even in a single-center cohort study, ponatinib, as a combination TKI with intensive chemotherapy or maintenance therapy, may improve the prognosis of Ph+ALL. Patients with CMR within three months might not necessarily need to receive HSCT, but a subsequent treatment-free status could have been achieved only by HSCT. Furthermore, CD20 positivity may be a useful biomarker for future treatment decisions in patients with Ph+ALL.

[Standard treatment and future perspectives for follicular lymphoma].

Follicular lymphoma (FL) is the most common type of low-grade, non-Hodgkin lymphoma. Although FL is generally a chemo-sensitive disease, current treatment strategies cannot cure patients with advanced-stage FL. Therefore, FL patients experience remission and relapse many times and generally have a long clinical course. The treatment goals for FL focus on improving subjective symptoms, recovery of cytopenia, and improvement in the quality of life. Careful watch and wait is an important treatment for asymptomatic FL with a low tumor burden. Rituximab monotherapy is also an important option for patients who have mild symptoms. The standard treatment for FL with a high tumor burden includes a combination of anti-CD20 antibodies, like rituximab or obinutuzumab, and chemotherapy like bendamustine and CHOP. The group with poor prognosis FL, such as POD24, should be considered for high-intensity therapies that include hematopoietic cell transplantation. In recent years, the development of molecular targeted therapies for recurrent FL has been vigorously promoted. Recently, lenalidomide and tazemetostat have been approved in Japan. This manuscript outlines the treatment strategy for untreated and relapsed FL and discusses future issues.

Safe administration and pharmacokinetic monitoring of crushed venetoclax tablets with posaconazole and clarithromycin via percutaneous endoscopic gastrostomy tube in a patient with acute myeloid leukemia.

PURPOSE: Leukemic stem cells in acute myeloid leukemia (AML) express high B cell lymphoma 2 (BCL2) levels, which contribute to leukemic cell survival and resistance to therapy. Venetoclax-a BCL-2 inhibitor-is indicated for the treatment of AML, which may also target leukemic stem cells; however, it is only available as a tablet. There are no reports of venetoclax use in patients who cannot take oral drugs; therefore, the efficacy, safety, and pharmacokinetics (PK) of venetoclax administered through a gastrostomy tube is unknown. CASE PRESENTATION: We report, for the first time, a case of relapsed Japanese AML patient treated with crushed venetoclax tablets through a percutaneous endoscopic gastrostomy (PEG) tube because of esophageal stricture due to complications of stem cell transplantation. The patient was also taking posaconazole and clarithromycin concomitantly. We evaluated the plasma concentrations of venetoclax administered through a PEG tube. Time to maximum concentration, maximum plasma concentration, and the area under the plasma concentration-time curve were similar to the previously reported PK parameters after oral administration of intact venetoclax tablets in Japanese patients with AML. The clinical course passed safely without the occurrence of unexpected adverse events during the administration of crushed venetoclax tablets in combination with azacitidine. CONCLUSIONS: The PK parameters of the crushed administered venetoclax via PEG tube was similar to the previously reported PK parameters of the orally administered venetoclax. Therefore, administration of crushed venetoclax tablets through a PEG tube could be an alternate route for patients who have difficulty with oral administration.

A phase I/II study of 10-min dosing of bendamustine hydrochloride (rapid infusion formulation) in patients with previously untreated indolent B-cell non-Hodgkin lymphoma, mantle cell lymphoma, or relapsed/refractory diffuse large B-cell lymphoma in Japan.

PURPOSE: This phase I/II clinical study was conducted to examine the safety, tolerability, pharmacokinetics, and efficacy of 10-min dosing of bendamustine in patients with previously untreated indolent B-cell non-Hodgkin lymphoma (iNHL) or mantle cell lymphoma (MCL) (Group 1) and patients with relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL) (Group 2). METHODS: Rituximab 375 mg/m2 was administered intravenously every 28 days to Group 1 patients on day 1 and every 21 days to Group 2 patients on day 1. Bendamustine 90 mg/m2/day was administered to the former on days 1 and 2; bendamustine 120 mg/m2/day was administered to the latter on days 2 and 3. Each regimen was delivered up to six cycles for both groups. The primary endpoints were safety and tolerability in Groups 1 and 2, respectively. RESULTS: Among 37 enrolled patients, safety was assessed in 36. In Group 1 (n = 30), 27 patients (90%) had follicular lymphoma. Adverse events (AEs) were observed in all 30 patients in Group 1. Dose-limiting toxicities were observed in two of six patients in Group 2. Common AEs included lymphocyte count decreased (86.7%, 100%). In Group 1, overall response and complete response rates were 93.1% (95% confidence interval [CI] 77.2-99.2%) and 75.9% (95% CI 56.5-89.7%), respectively. The Cmax and AUC of bendamustine tended to be higher in Group 2 than in Group 1. CONCLUSIONS: This study showed that bendamustine is safe, well-tolerated and effective for patients with previously untreated iNHL, MCL or rrDLBCL. Pharmacokinetic data were equivalent to those obtained outside of Japan. REGISTRATION NUMBERS: Registration NCT03900377; registered April 3, 2019.

High baseline total lesion glycolysis predicts early progression of disease within 24 months in patients with high-tumor-burden follicular lymphoma.

Despite the introduction of rituximab-containing regimens, approximately 20% of patients with follicular lymphoma (FL) still experience progression of disease within 24 months (POD24) and have poor overall survival. Therefore, a more accurate risk assessment tool is required. We investigated the predictive value of two new volume-based parameters determined from baseline 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT), baseline total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG), in 45 patients with high-tumor-burden FL who underwent baseline PET/CT. We observed that high TMTV, high TLG, and poor initial treatment response (less than complete [metabolic] response [non-CR/CMR] at the end of induction therapy) independently predicted poor PFS. Notably, POD24-positive patients were more common in the high-TLG group than in the high-TMTV group, which suggests that TLG is a stronger predictor of outcomes than TMTV. Combining baseline TLG and initial treatment response showed that patients with both high TLG and non-CR/CMR experienced significantly poorer outcomes, with a 2 year PFS of 0% (hazard ratio 60.39, P = 0.000002). This combination had 56% sensitivity and 100% specificity for detecting patients who would experience POD24. Baseline TLG and initial treatment response can precisely identify patients at high risk of POD24.

Relationship between achievement of major molecular response or deep molecular response and nilotinib plasma concentration in patients with chronic myeloid leukemia receiving first-line nilotinib therapy.

PURPOSE: We evaluated the plasma exposure and response relationships of nilotinib for patients with newly diagnosed chronic myeloid leukemia (CML) in real-world practice. METHODS: For the 26 patients enrolled in this study, at 3, 6, 12, and 24 months after nilotinib administration, the trough plasma concentrations (Ctrough) of nilotinib were analyzed. The relationships between nilotinib Ctrough and the molecular response to nilotinib treatment at each point (each n = 26) were evaluated. RESULTS: Median nilotinib Ctrough values were significantly higher in patients with a major molecular response (MMR) at 3 months than in patients without an MMR (809 and 420 ng/mL, respectively; P = 0.046). Based on the area under the receiver-operating characteristic curve, the threshold value of the nilotinib Ctrough at 3 months for predicting MMR achievement was 619 ng/mL at the best sensitivity (71.4%) and specificity (77.8%). Patients with a nilotinib Ctrough of above 619 ng/mL had a significantly shorter time to achievement of a deep molecular response (DMR; 9.0 and 18.0 months, respectively; P = 0.020) and higher rates of DMR by 2 years in Kaplan-Meier plots (P = 0.025) compared with that in patients with a nilotinib Ctrough of less than 619 ng/mL. CONCLUSION: For patients with newly diagnosed CML, the nilotinib dose may be adjusted using a Ctrough of above 619 ng/mL as the minimum effective concentration, i.e., the lowest concentration required for MMR or DMR achievement within a shorter time, during early stages after beginning therapy to obtain faster and deeper clinical responses.

Bendamustine plus rituximab in Japanese patients with relapsed or refractory diffuse large B-cell lymphoma.

This single-arm phase 3 study was conducted to confirm the results of our phase 2 study of bendamustine (B)-rituximab (R) in patients with relapsed/refractory diffuse large B cell lymphoma (rrDLBCL). The primary endpoint was overall response rate (ORR). Autologous stem cell transplantation-ineligible rrDLBCL patients with ≤ 2 prior chemotherapy regimens received R 375 mg/m2 IV on day 1 and B 120 mg/m2/day IV on days 2 and 3 every 21 days up to 6 cycles. Thirty-eight patients with a median age of 74 years (range, 43-86) received BR. The ORR and complete response rates were 76.3% and 47.4%, respectively. With a median follow-up of 19.5 months including long-term follow-up, median progression-free survival was 11.9 months. Median OS was 29.2 months. Discontinuation of treatment due to Gr3-5 TEAE was observed among 13 of 38 patients (34.2%). One patient with cytomegalovirus enterocolitis died during follow-up. This BR regimen was confirmed to be effective and tolerable in studied patients. ClinicalTrials.gov Identifier: NCT03372837 registered on 14 December 2017, NCT04354402 registered on 21 April, 2020.

Long-term outcomes and central nervous system relapse in extranodal natural killer/T-cell lymphoma.

To elucidate the long-term outcomes of non-anthracycline-containing therapies and central nervous system (CNS) events in patients with extranodal NK/T-cell lymphoma, nasal type (ENKTL), the clinical data of 313 patients with ENKTL diagnosed between 2000 and 2013 in a nationwide retrospective study in Japan were updated and analyzed. At a median follow-up of 8.4 years, the 5-year overall survival (OS) and progression-free survival (PFS) were 71% and 64%, respectively, in 140 localized ENKTL patients who received radiotherapy-dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) in clinical practice. Nine (6.4%) patients experienced second malignancies. In 155 localized ENKTL patients treated with RT-DeVIC, 10 (6.5%) experienced CNS relapse (median, 12.8 months after diagnosis). In five of them, the events were confined to the CNS. Nine of the 10 patients who experienced CNS relapse died within 1 year after CNS relapse. Multivariate analysis identified gingival (hazard ratio [HR], 54.35; 95% confidence interval [CI], 8.60-343.35) and paranasal involvement (HR, 7.42; 95% CI, 1.78-30.89) as independent risk factors for CNS relapse. In 80 advanced ENKTL patients, 18 received steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy as first-line treatment. Patients who received SMILE as their first-line treatment tended to have better OS than those who did not (p = 0.071). Six (7.5%) advanced ENKTL patients experienced isolated CNS relapse (median, 2.6 months after diagnosis) and died within 4 months of relapse. No second malignancies were documented in advanced ENKTL patients. In the entire cohort, the median OS after first relapse or progression was 4.6 months. 12 patients who survived 5 years after PFS events were disease-free at the last follow-up. Of those, 11 (92%) underwent hematopoietic stem cell transplantation. Our 8-year follow-up revealed the long-term efficacy and safety of RT-DeVIC and SMILE. The risk of CNS relapse is an important consideration in advanced ENKTL.

Single response assessment of transplant-ineligible multiple myeloma: a supplementary analysis of JCOG1105 (JCOG1105S1).

BACKGROUND: The International Myeloma Working Group response criteria require two consecutive assessments of paraprotein levels. We conducted an exploratory analysis to evaluate whether a single response assessment could be a substitute for the International Myeloma Working Group criteria using data from JCOG1105, a randomized phase II study on melphalan, prednisolone and bortezomib. METHODS: Of 91 patients with transplant-ineligible newly diagnosed multiple myeloma, 79 patients were included. We calculated the kappa coefficient to evaluate the degree of agreement between the International Myeloma Working Group criteria and the single response assessment. RESULTS: Based on the International Myeloma Working Group criteria, 11 (13.9%), 20 (25.3%), 36 (45.6%) and 12 (15.2%) patients had stringent complete response/complete response, very good partial response, partial response and stable disease, respectively. Based on the single response assessment, 17 (21.5%), 19 (24.1%), 35 (44.3%) and 8 (10.1%) patients had stringent complete response/complete response, very good partial response, partial response and stable disease, respectively. The kappa coefficient was 0.76 (95% confidence interval, 0.65-0.88), demonstrating good agreement. The single response assessment was not inferior to the International Myeloma Working Group criteria in the median progression-free survival (3.8 and 2.9 years) in stringent complete response/complete response patients, suggesting that the single response assessment was not an overestimation. CONCLUSIONS: The single response assessment could be a substitute for the current International Myeloma Working Group criteria for transplant-ineligible newly diagnosed multiple myeloma.

Effects of SLC22A2 808G>T polymorphism and bosutinib concentrations on serum creatinine in patients with chronic myeloid leukemia receiving bosutinib therapy.

The purpose of this study was to investigate the effects of SLC22A2 808G>T polymorphism and trough concentrations (C0) of bosutinib on serum creatinine in 28 patients taking bosutinib. At 1, 3, 6, 12, 24, and 36 months after administration, analysis of bosutinib C0 and creatinine was performed at the same time of day. Significant correlations were observed between bosutinib C0 and the change rate of serum creatinine or the estimated glomerular filtration rate (eGFR; r = 0.328, P < 0.001 and r = - 0.315, P < 0.001, respectively). These correlations were particularly high in patients having the SLC22A2 808G/G genotype (r = 0.345 and r = - 0.329, respectively); however, in patients having the 808T allele, there were no significant differences. In multivariate analyses, the SLC22A2 808G/G genotype, patient age, bosutinib C0 and second-line or later bosutinib were independent factors influencing the change rate of creatinine. Bosutinib elevated serum creatinine through organic cation transporter 2 (OCT2). We observed a 20% increase in serum creatinine with a median bosutinib C0 of 63.4-73.2 ng/mL. Periodic measurement of serum creatinine after bosutinib therapy is necessary to avoid progression to severe renal dysfunction from simple elevation of creatinine mediated by OCT2 following bosutinib treatment.

Evaluation of the plasma concentration of ponatinib in a chronic myeloid leukaemia patient with ponatinib intolerance.

WHAT IS KNOWN AND OBJECTIVE: Some patients with chronic myeloid leukaemia (CML) cannot continue tyrosine kinase inhibitor (TKI) treatment due to intolerance associated with higher plasma concentration. CASE SUMMARY: A 76-year-old woman with chronic-phase CML who showed resistance/intolerance to pre-TKIs has been treated with ponatinib. A high ponatinib bioavailability was noted; therefore, we administered ponatinib 15 mg/3 d to avoid adverse events due to high exposure. Eventually, the patient achieved a major molecular response. WHAT IS NEW AND CONCLUSION: Monitoring of the ponatinib plasma concentration led to safe and effective CML management in a patient with higher drug bioavailability.

Effects of proprotein convertase subtilisin/kexin type 9 and nilotinib plasma concentrations on nilotinib-induced hypercholesterolaemia in patients with chronic myeloid leukaemia.

WHAT IS KNOWN AND OBJECTIVE: The purpose of this study was to investigate the relationships among nilotinib plasma trough concentration (C0 ), low-density lipoprotein (LDL) cholesterol, and PCSK9 plasma concentration in 31 patients with chronic myeloid leukaemia. METHODS: Plasma concentrations of nilotinib and PCSK9 were measured by high-performance liquid chromatography and enzyme-linked immunosorbent assays, respectively. RESULTS AND DISCUSSION: LDL cholesterol concentrations at 1 month after nilotinib treatment were significantly increased compared with those before therapy. The mean C0 (±SD) of nilotinib at 1, 2, and 3 months after nilotinib treatment were 645 ± 516, 902 ± 623, and 951 ± 1088 ng/mL, respectively. Mean PCSK9 concentrations at 3 months after nilotinib treatment were significantly higher than those at the start of therapy (320 vs 257 ng/mL, respectively, P = .019). When the change rate in the PCSK9 concentration induced by nilotinib was classified with a cut-off value of +40%, the change rate in LDL cholesterol in patients with a change rate in PCSK9 of ≥40% was significantly higher than that in patients with a PCSK9 change rate of <40% (67.1% vs 38.0%, P = .043); however, there were no differences in mean nilotinib C0 . WHAT IS NEW AND CONCLUSION: Nilotinib may lead to hypercholesterolaemia by increasing plasma concentrations of PCSK9 after indirect inhibition of mammalian target of rapamycin (mTOR) complex 1. In addition, certain patients seem to have high sensitivity for nilotinib in a signalling cascade of the PI3K/Akt/mTOR pathway, despite low plasma concentrations of nilotinib. Consequently, nilotinib-induced hypercholesterolaemia could not be predicted based on the plasma concentration of nilotinib.