Early dynamics of chronic myeloid leukemia on nilotinib predicts deep molecular response.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by the BCR-ABL1 tyrosine kinase. Although ABL1-specific tyrosine kinase inhibitors (TKIs) including nilotinib have dramatically improved the prognosis of patients with CML, the TKI efficacy depends on the individual patient. In this work, we found that the patients with different nilotinib responses can be classified by using the estimated parameters of our simple dynamical model with two common laboratory findings. Furthermore, our proposed method identified patients who failed to achieve a treatment goal with high fidelity according to the data collected only at three initial time points during nilotinib therapy. Since our model relies on the general properties of TKI response, our framework would be applicable to CML patients who receive frontline nilotinib or other TKIs.

Optimal treatment strategy with nilotinib for patients with newly diagnosed chronic-phase chronic myeloid leukemia based on early achievement of deep molecular response (MR4.5 ): The phase 2, multicenter N-Road study.

For patients who have chronic myeloid leukemia (CML), one of the primary treatment options is administration of nilotinib 300 mg twice daily (BID). In previous studies which compared outcomes associated with nilotinib or imatinib treatment, nilotinib achieved a higher rate of deep molecular response (MR). We conducted a phase II, open-label, multicenter study to investigate an intrapatient nilotinib dose-escalation strategy for patients with newly diagnosed chronic-phase (CP) CML based on early MR4.5 achievement. The primary study endpoint was achievement of MR4.5 by 24 months following the initiation of nilotinib 300 mg BID. Fifty-three patients were enrolled, 51 received nilotinib, and 37 completed the treatment. An increase in the nilotinib dose (to 400 mg BID) was allowed when patients satisfied our criteria for no optimal response at any time point. The median (range) dose intensity was 600 (207-736) mg/day. Of 46 evaluable patients, 18 achieved an optimal response and 28 did not. Of the latter, nine patients underwent dose escalation to 400 mg BID, and none achieved MR4.5 . The remaining 19 patients could not undergo dose escalation, 12 (63%) because of adverse events (AEs), and 7 (37%) for non-AE related reasons. Four of these patients achieved MR4.5 . The MR4.5 rate by 24 months was 45.7%. The progression-free, overall and event-free survival were each 97.6%. No new safety concerns were observed. Our findings support the use of continuous nilotinib at a dose of 300 mg BID for newly diagnosed patients with CML-CP.

[Hypercalcemia associated with all-trans retinoic acid therapy for microgranular type acute promyelocytic leukemia].

A 24-year-old man was admitted to the hospital for pancytopenia. Peripheral blood test and bone marrow aspiration demonstrated an increase in hypogranular promyelocytes. Karyotype analysis and RT-PCR showed 47, XY, t(15;17)(q22;q12), +12, and PML-RARA, respectively. The patient was diagnosed as having acute promyelocytic leukemia microgranular type (M3v) and was therefore administered all-trans retinoic acid (ATRA). Idarubicin and Ara-C were later added to the treatment regimen because of an increased number of leukemic cells. Nausea, vomiting and general fatigue associated with hypercalcemia developed on day 30. There were no findings indicating infection. The administration of ATRA was thus suspected to have induced hypercalcemia. ATRA was therefore discontinued and prednisolone and elcatonin were administered instead. Five days after this change, the serum calcium level normalized. Complete remission was thereafter confirmed on day 45. Hypercalcemia associated with ATRA therapy for APL is rare, and to date, there have been no case reports describing hypercalcemia associated with M3v in the literature. Interaction of fosfluconazole was suspected of causing hypercalcemia when used concomitantly with ATRA.

[Hepatitis-associated aplastic anemia preceded by a hemophagocytic syndrome-like state].

A 21-year-old man was admitted to our hospital for acute hepatitis of unknown cause. His liver function improved with rest, but worsened 2 months later. He developed a high fever and pancytopenia. The serum level of cytokines including TNF-alpha, IFN-gamma, IL-6, and M-CSF was elevated, and hemophagocytes were seen in bone marrow. These findings suggested a hemophagocytic syndrome-like state. With prednisolone, gamma-globulin, and G-CSF, the high fever disappeared and the patient's liver function gradually recovered. However, the severe pancytopenia persisted. The bone marrow became acellular with a small number of hemophagocytes, and hepatitis-associated aplastic anemia was diagnosed. After immunosuppressive therapy with ATG, CyA and G-CSF was started, and the patient showed hematopoietic reconstitution. The bone marrow CD4+/CD8+ lymphocyte ratio recovered to within the normal range, and the serum cytokines including TNF-alpha and IFN-gamma decreased. The increase in serum cytokines, particularly TNF-alpha and INF-gamma, as well as the presence of activated T cells associated with the preceding hemophagocytic syndrome-like state may have predisposed this patient to aplastic anemia.

Elevated levels of cyclin A1 and A (A2) mRNA in acute myeloid leukaemia are associated with increased survival.

Cyclin A (A2) and cyclin A1 are members of the G2 cyclins, which are involved in the control of G2/M and G1/S transitions as well as mitosis. Human cyclin A1 was cloned as an A-type cyclin that is highly expressed in acute myeloid leukaemia (AML). The clinical significance of these cyclins in myeloid leukaemia remains to be clarified. We investigated the relative levels of these transcripts in 80 patients with de novo AML. Correlations with clinical parameters showed that the initial white blood cell count and serum lactate dehydrogenase levels were inversely associated with cyclin A (A2) mRNA levels (r = -0.276, P = 0.019) and cyclin A1 mRNA levels (r = -0.241, P = 0.042) respectively. They were independently associated with increased overall survival [P = 0.035 for cyclin A (A2) and P = 0.016 for cyclin A1]. Multivariate analysis using Cox's proportional hazard model showed that elevated cyclin A1 mRNA levels contributed significantly to the better prognosis of patients with AML. Furthermore, the analysis of survival probability showed that the group with high levels of both cyclin A (A2) and A1 survived significantly longer than the group with low expression of both these cyclins (P = 0.002). These data indicate that high expression levels of both cyclin A (A2) and A1 are associated with good prognosis in AML patients.

[Primary subcutaneous mantle cell lymphoma treated successfully with THP-COP therapy].

A 73-year-old man noticed a subcutaneous tumor on the left upper palpebra from April 1998, but did not seek therapy for it. Facial subcutaneous tumors appeared from November 1999, and multiple tumors appeared on the skin of the chest and both upper arms from January 2000. Tumor biopsy revealed that these tumors were non-Hodgkin lymphoma showing CD19 (+), CD20 (+), CD5 (+), CD10 (-), smIgM (+), sm lambda (+) and cyclin D1 (+). The karyotype was t(11;14) (q13;q32), but bcl-1 gene rearrangement was not detected. On the basis of these data, primary mantle cell lymphoma (MCL) of the subcutis was diagnosed. The patient underwent eight courses of THP-COP therapy, and complete remission was achieved. Primary subcutaneous B-cell lymphoma, especially MCL, is rare. MCL is aggressive and difficult to cure; the median survival of patients is 3 to 5 years, and the 5-year survival is 30%. However, the present patient showed a good response to chemotherapy, and complete remission has continued for 17 months since the MCL was first diagnosed.

Normal myelopoiesis but abnormal T lymphocyte responses in vitamin D receptor knockout mice.

The vitamin D receptor (VDR) is a transcription factor that mediates the actions of its ligand, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], which can promote monocyte/macrophage differentiation and inhibit proliferation and cytokine production by activated T lymphocytes. In this study, VDR knockout (KO) mice were used to investigate the possible role of VDR in hematopoiesis. The relative number of red and white peripheral blood cells and the percentage of bone marrow macrophages did not differ between VDR KO and wild-type mice. 12-O-tetradecanoylphorbol-13-acetate, but not 1,25(OH)(2)D(3), induced differentiation of bone marrow-committed myeloid stem cells from VDR KO mice to monocytes/macrophages. Production of IL-18, a Th1-promoting cytokine, was reduced in macrophages from these mice. Antigen-stimulated spleen cells from VDR KO mice showed an impaired Th1 cell response and had decreased expression of STAT4, a Th1 cell transcription factor. These results demonstrate the absolute requirement of VDR for 1,25(OH)(2)D(3)-induced monocyte/macrophage differentiation but show that monocyte/macrophage differentiation can occur in the absence of this receptor. The observed reduction in Th1 population in these mutant mice may be explained by a loss of macrophage IL-18 production or a suppression of STAT4 expression by activated splenocytes.