Masaharu Kamoshita

Adherence to the standard dose of imatinib, rather than dose adjustment based on its plasma concentration, is critical to achieve a deep molecular response in patients with chronic myeloid leukemia

The correlation between imatinib (IM) trough plasma concentration (Cmin) and clinical response was assessed in patients with chronic-phase chronic myeloid leukemia. The Cmin correlated with neither the achievement of complete cytogenetic response (977 vs. 993 ng/ml, P = 0.48) nor a major molecular response (1,044 vs. 818 ng/ml, P = 0.17). Although this was significantly higher in patients with complete molecular response (CMR) than in those without (1,430 vs. 859 ng/ml, P = 0.04), the difference was not significant in the sub-population treated with a standard dose of IM (400 mg/day). Finally, multivariate analysis showed that the IM standard dose, but not Cmin, was predictive of the achievement of CMR. We thus suggest that, in practical clinics at least, adherence to the standard dose is the most important factor for the achievement of CMR.

Effects of anti-platelet glycoprotein Ib and/or IIb/IIIa autoantibodies on the size of megakaryocytes in patients with immune thrombocytopenia.

Abstract: To determine whether anti‐platelet autoantibodies react with megakaryocytes, as well as with platelets, in immune thrombocytopenia (ITP), 38 ITP patients were studied. They were classified into four groups; anti‐platelet glycoprotein lb‐positive (group A, n> = 5), anti‐platelet glycoprotein II/b/IIIa‐positive (group B, n = 2), positive to both antibodies (group C, n = 3), and negative to both antibodies (group D, n = 28). The number and size of megakaryocytes in each group were compared. The number of megakaryocytes in groups A, B, C, and D was 12.8 ± 8.9, 75.2, 29.1, and 17.0 ± 21.7/mm2, respectively. The mean cytoplasmic area of megakaryocytes in groups A, B, C, and D was 1001 ± 26.3, 1621, 1109, and 1311 ± 235.6/μm2, respectively. This finding indicated that, in the presence of anti‐platelet glycoprotein Ib, megakaryocytes were not increased in number and were small in size, whereas, in the presence of anti‐platelet glycoprotein Ilb/IIIa, megakaryocytes were increased in number and in cytoplasmic area. Our study suggested that anti‐platelet glycoprotein Ib may impair platelet production by megakaryocytes in ITP.

Megakaryopoiesis in patients with cyclic thrombocytopenia

Summary Megakaryopoiesis was examined in 10 patients (eight females and two males) with cyclic thrombocytopenia (CT) to investigate the underlying pathogenesis. Numbers of CFU‐Meg and megakaryocytes and the mean cytoplasmic area (mean area) of megakaryocytes at the peak, nadir, ascent mid phase, and descent mid phase of the platelet cycle were determined. The patients were classified as female cases group I (cases 1–4; previously diagnosed as ITP and CT occurred during remission), female cases group II (cases 5–8; persistent CT from initial diagnosis), and male CT (cases 9 and 10). In three of the four female cases in group I, numbers of CFU‐Meg and megakaryocytes were normal or increased persistently during the platelet cycle, whereas the mean area fluctuated in synchrony with the platelet cycle, suggesting failure of cyclic production rather than platelet destruction. In the female cases in group II and one female case in group I, numbers of CFU‐Meg and megakaryocytes were also normal or increased at four phases of the cycle, but the mean area did not fluctuate, remaining large during the cycle, suggesting cyclic destruction or platelet clearance. In contrast, in the male patients values for numbers of CFU‐Meg, megakaryocytes and mean cytoplasmic area fluctuated during the platelet cycle, indicating that cyclic changes in megakaryopoiesis generated the platelet cycle. These findings indicate that the measurement of cytoplasmic area is useful for distinguishing cyclic platelet production from cyclic destruction or clearance in CT.

Measurement of Proteasome Activity in Peripheral Blood Mononuclear Cells as an Indicator of Susceptibility to Bortezomib-Induced Severe Neurological Adverse Events in Patients with Multiple Myeloma

Aims: To explore the biomarker for predicting the occurrence of adverse events in myeloma patients treated by intravenous bortezomib, we measured proteasome activity in peripheral blood mononuclear cells. Methods: Samples were obtained from 34 bortezomib-naïve patients. Proteasome activity was measured at pre- and postchemotherapy phase by using a synthetic substrate. Results: Bortezomib injection resulted in a dramatic decrease in proteasome activity, reaching 32.4 ± 18.79% (mean ± SD) of the pretreatment level at 1 h, but it generally recovered at the end of the first course. In total, 6 patients manifested with severe bortezomib-induced peripheral neuropathy (sBIPN) in the second-third course. There was a nonsignificant trend for these patients to have lower levels of the relative proteasome activity at the end of the first course than those without sBIPN (median: 74.03 vs. 103.2%, p = 0.052). Moreover, in all of them, proteasome activity did not recover to the pretreatment level, whereas no patients with complete recovery manifested with sBIPN. Analysis with Fishers exact test demonstrated that incomplete recovery of proteasome activity is a significant risk factor for sBIPN (p = 0.014). Conclusion: Patients with incomplete recovery of proteasome activity are at high risk for developing sBIPN, and the susceptible patients can be indicated by monitoring proteasome activity.

Targeting complete response with upfront bortezomib consolidation versus observation after the achievement of complete response following autologous transplantation for multiple myeloma (TUBA study)

Complete response (CR) after treatment for multiple myeloma is associated with superior progression‐free survival (PFS). Multiple myeloma patients were prospectively recruited for induction treatment with bortezomib and dexamethasone (BD) followed by autologous hematopoietic cell transplantation (auto‐HCT) between 2010 and 2012. If patients did not achieve CR after auto‐HCT, BD consolidation therapy was added to target CR.