Trough plasma concentration of imatinib reflects BCR-ABL kinase inhibitory activity and clinical response in chronic-phase chronic myeloid leukemia: a report from the BINGO study.

Pharmacokinetic (PK) factors have been suggested to be involved in the unfavorable clinical responses of chronic myeloid leukemia (CML) patients treated with imatinib. The purpose of this study was to clarify prognostic implications of PK factors in CML patients treated with imatinib. The plasma trough (C(min)) level of imatinib and serum α(1)-acid glycoprotein (AGP) level were measured on two different days in 65 CML patients treated with imatinib for more than 12 months. We further examined whether the C(min) level of imatinib actually reflects inhibitory activity against BCR-ABL kinase using the plasma inhibitory activity (PIA) assay. Since the differences of five patients were statistically rejected by the Smirnov-Grubbs' test, we excluded them for further analysis. The C(min) level was strongly associated with the achievement of MMR at the 12th month, and ROC analysis demonstrated C(min) levels and their discrimination potential for major molecular response (MMR) with the best sensitivity (63.2%) and specificity (68.2%) at a C(min) threshold of 974 ng/mL. The α(1)-Acid glycoprotein (AGP) level was within the normal range in 57 of 60 patients, indicating little impact of AGP on our study. There was a weak correlation between PIA against phospho (P)-BCR-ABL and the C(min) level of imatinib (r(2) = 0.2501, P = 0.0007), and patient plasma containing >974 ng/mL imatinib sufficiently inhibited P-BCR-ABL. These results collectively indicated that maintaining ∼1000 ng/mL of C(min) was clinically and biologically important for the optimal response in CML patients treated with imatinib. A prospective intervention study is required to establish PK-based management in CML patients treated with imatinib.

A unique case of nasal NK/T cell lymphoma with frequent remission and relapse showing different histological features during 12 years of follow up.

Nasal natural killer (NK)/T cell lymphoma is an aggressive subtype of non-Hodgkin lymphomas, usually with a broad morphological spectrum, necrosis and angioinvasion, and is closely associated with Epstein-Barr virus (EBV) infection. We herein report a unique case of nasal NK/T cell lymphoma with frequent complete remission and relapse 12 years of follow up. A 9-year-old girl was diagnosed as having nasal NK/T cell lymphoma in 1995. The histological features were typical with diffuse lymphoid cell infiltration and angiocentric destruction. At the time of third relapse, however, biopsy showed infiltration of small sized lymphoid cells without necrosis and ulceration. These lymphoid cells were positive for both NK/T cell phenotype and EBV-encoded small RNAs. The tumor regressed spontaneously after biopsy and her clinical symptoms subsided. When she was admitted to the hospital in 2006 she had an extensive destructive lesion in the nasal cavity. These findings represent a rare case, in which histological findings changed in each time of relapse.

Irrespective of CD34 expression, lineage-committed cell fraction reconstitutes and re-establishes transformed Philadelphia chromosome-positive leukemia in NOD/SCID/IL-2Rgammac-/- mice.

Stem cells of acute myeloid leukemia (AML) have been identified as immunodeficient mouse-repopulating cells with a Lin(-)CD34(+)38(-) phenotype similar to normal hematopoietic stem cells. To identify the leukemia-propagating stem cell fraction of Philadelphia chromosome-positive (Ph(+)) leukemia, we serially transplanted human leukemia cells from patients with chronic myeloid leukemia blast crisis (n = 3) or Ph(+) acute lymphoblastic leukemia (n = 3) into NOD/SCID/IL-2Rgammac(-/-) mice. Engrafted cells were almost identical to the original leukemia cells as to phenotypes, IGH rearrangements, and karyotypes. CD34(+)CD38(-)CD19(+), CD34(+)38(+)CD19(+), and CD34(-)CD38(+)CD19(+) fractions could self-renew and transfer the leukemia, whereas the CD34(-)CD38(+)CD19(+) fraction did not stably propagate in NOD/SCID mice. These findings suggest that leukemia-repopulating cells in transformed Ph(+) leukemia are included in a lineage-committed but multilayered fraction, and that CD34(+) leukemia cells potentially emerge from CD34(-) populations.

[Mantle cell lymphoma mimicking chronic lymphocytic leukemia].

A 62-year-old male was admitted to our hospital complaining of dyspnea in March, 2002. He had remarkable bone marrow invasion with a significant number of leukemic cells, anemia and thrombocytopenia. In addition he had generalized lymphadenopathy including a bulky mass in the left cervix. Surface marker analysis of abnormal cells showed CD 5+, 10-, 19+, 20+, 23+, and kappa+, and immunohistochemistry revealed cyclin D1-positive cells. Chromosome analysis showed del(11q). The patient was diagnosed as having mantle cell lymphoma, stage IVB, and received combination chemotherapy. He could not obtain complete remission and died after 29 months. We found it very difficult in this case to make a differential diagnosis between mantle cell lymphoma and chronic lymphocytic leukemia. We report on this case and summarize the problem of the differential diagnosis.