Atsuko Mugitani

CD138-negative clonogenic cells are plasma cells but not B cells in some multiple myeloma patients

Clonogenic multiple myeloma (MM) cells reportedly lacked expression of plasma cell marker CD138. It was also shown that CD19+ clonotypic B cells can serve as MM progenitor cells in some patients. However, it is unclear whether CD138-negative clonogenic MM plasma cells are identical to clonotypic CD19+ B cells. We found that in vitro MM colony-forming cells were enriched in CD138−CD19−CD38++ plasma cells, while CD19+ B cells never formed MM colonies in 16 samples examined in this study. We next used the SCID-rab model, which enables engraftment of human MM in vivo. CD138−CD19−CD38++ plasma cells engrafted in this model rapidly propagated MM in 3 out of 9 cases, while no engraftment of CD19+ B cells was detected. In 4 out of 9 cases, CD138+ plasma cells propagated MM, although more slowly than CD138− cells. Finally, we transplanted CD19+ B cells from 13 MM patients into NOD/SCID IL2Rγc−/− mice, but MM did not develop. These results suggest that at least in some MM patients CD138-negative clonogenic cells are plasma cells rather than B cells, and that MM plasma cells including CD138− and CD138+ cells have the potential to propagate MM clones in vivo in the absence of CD19+ B cells.

Impact of relative dose intensity (RDI) in CHOP combined with rituximab (R-CHOP) on survival in diffuse large B-cell lymphoma

BackgroundRecently, maintaining higher relative dose intensity (RDI) of chemotherapeutic drugs has become a widespread practice in an attempt to achieve better outcomes in the treatment of aggressive lymphoma. The addition of rituximab to chemotherapy regimens has significantly improved outcome in diffuse large B-cell lymphoma (DLBL). However, it is unknown if higher RDI in chemotherapy when combined with rituximab leads to a better outcome in aggressive B-cell lymphoma.MethodsWe retrospectively evaluated the impact of the RDI of initial chemotherapy (consisting of cyclophosphamide, doxorubicin, vincristine and prednisolone with rituximab (R-CHOP) on outcome in 100 newly diagnosed DLBL patients.ResultsA multivariate Cox regression model showed that RDI trended towards a significant association with mortality [hazard ratio per 0.1 of RDI = 0.8; 95% confidence interval 0.6–1.0; P = 0.08]. Additionally, on multivariate logistic analysis, advanced age was a significant factor for reduced RDI.ConclusionOur data suggest that in DLBL patients, mortality was affected by RDI of R-CHOP as the initial treatment, and the retention of a high RDI could therefore be crucial.

A multicenter clinical study evaluating the confirmed complete molecular response rate in imatinib-treated patients with chronic phase chronic myeloid leukemia by using the international scale of real-time quantitative polymerase chain reaction

Achievement of complete molecular response in patients with chronic phase chronic myeloid leukemia has been recognized as an important milestone in therapy cessation and treatment-free remission; the identification of predictors of complete molecular response in these patients is, therefore, important. This study evaluated complete molecular response rates in imatinib-treated chronic phase chronic myeloid leukemia patients with major molecular response by using the international standardization for quantitative polymerase chain reaction analysis of the breakpoint cluster region-Abelson1 gene. The correlation of complete molecular response with various clinical, pharmacokinetic, and immunological parameters was determined. Complete molecular response was observed in 75/152 patients (49.3%). In the univariate analysis, Sokal score, median time to major molecular response, ABCG2 421C>A, and regulatory T cells were significantly lower in chronic phase chronic myeloid leukemia patients with complete molecular response than in those without complete molecular response. In the multivariate analysis, duration of imatinib treatment (odds ratio: 1.0287, P=0.0003), time to major molecular response from imatinib therapy (odds ratio: 0.9652, P=0.0020), and ABCG2 421C/C genotype (odds ratio: 0.3953, P=0.0284) were independent predictors of complete molecular response. In contrast, number of natural killer cells, BIM deletion polymorphisms, and plasma trough imatinib concentration were not significantly associated with achieving a complete molecular response. Several predictive markers for achieving complete molecular response were identified in this study. According to our findings, some chronic myeloid leukemia patients treated with imatinib may benefit from a switch to second-generation tyrosine kinase inhibitors (ClinicalTrials.gov, UMIN000004935).

The prophylactic effect of itraconazole capsules and fluconazole capsules for systemic fungal infections in patients with acute myeloid leukemia and myelodysplastic syndromes: A Japanese multicenter randomized, controlled study

We performed a randomized, controlled study comparing the prophylactic effects of capsule forms of fluconazole (n = 110) and itraconazole (n = 108) in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) during and after chemotherapy.There were 4 cases with possible systemic fungal infection in the itraconazole group, and there were 8 possible and 3 probable cases in the fluconazole group. Adverse events did not significantly differ in the 2 groups. In patients with MDS or in the remission-induction phase of chemotherapy, the numbers of cases with probable or possible infections were lower in the itraconazole group than in the fluconazole group, whereas no difference was seen in patients with AML or in the consolidation phase of therapy. In patients with neutrophil counts of <0.1 * 109/L lasting for more than 4 weeks, the frequency of infection in the fluconazole group (5 of 9 patients) was significantly higher than in the itraconazole group (0 of 7 patients; P = .03). Our results suggest that both drugs were well tolerated in patients with AML or MDS who received chemotherapy and that the efficacy of itraconazole for prophylaxis against systemic fungal disease is not inferior to that of fluconazole.

The activated conformation of integrin β7 is a novel multiple myeloma-specific target for CAR T cell therapy

Cancer-specific cell-surface antigens are ideal targets for monoclonal antibody (mAb)-based immunotherapy but are likely to have previously been identified in transcriptome or proteome analyses. Here, we show that the active conformer of an integrin can serve as a specific therapeutic target for multiple myeloma (MM). We screened >10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb specifically recognizing a subset of integrin β7 molecules. The MMG49 epitope, in the N-terminal region of the β7 chain, is predicted to be inaccessible in the resting integrin conformer but exposed in the active conformation. Elevated expression and constitutive activation of integrin β7 conferred high MMG49 reactivity on MM cells, whereas MMG49 binding was scarcely detectable in other cell types including normal integrin β7+ lymphocytes. T cells transduced with MMG49-derived chimeric antigen receptor (CAR) exerted anti-MM effects without damaging normal hematopoietic cells. Thus, MMG49 CAR T cell therapy is promising for MM, and a receptor protein with a rare but physiologically relevant conformation can serve as a cancer immunotherapy target.

VNCOP-B plus rituximab therapy in elderly patients with aggressive B-cell non-Hodgkin lymphoma: a multicenter experience.

CHOP (cyclophosphamide, adriamycin, vincristine, and prednisolone) plus rituximab is a standard chemotherapy used to treat patients with aggressive B-cell non-Hodgkin lymphoma (B-NHL). However, among elderly patients, this regimen has not been completely satisfactory in its efficacy and safety. We report our clinical experience in 8 collaborative institutions to determine if the VNCOP-B (etoposide, mitoxantrone, cyclophosphamide, vincristine, prednisolone, and bleomycin) combination therapy plus rituximab was effective and safe to treat elderly patients with aggressive B-NHL. Between September 2004 and December 2007, 23 previously untreated patients, median age 73 years, 50.0% classified as high-intermediate/high-risk on the standard International Prognostic Index (IPI) entered this trial. Complete remission rate was 90.5%, with a 100% overall response rate (RR) at the end of induction therapy; overall survival (OS) rate at 3 years was 76.4% (median follow-up 744 days), with an 82.6% 3-year progression-free survival (PFS) rate (median follow-up 744 days). The most common grade 3/4 toxicities were hematologic, including neutropenia in 75.0% of the patients despite prophylactic administration of granulocyte colony-stimulating factor (G-CSF), febrile neutropenia in 30.0%, respectively. There was no treatment-related mortality (TRM). Rituximab not only combined with chemotherapy but also given sequentially improved survival. R-VNCOP-B could be another option for elderly patients who are not considered to tolerate in receiving R-CHOP.

Wilms Tumor 1 (WT1) mRNA Expression Level at Diagnosis Is a Significant Prognostic Marker in Elderly Patients with Myelodysplastic Syndrome

Background/Aims: A high expression of Wilms tumor 1 (WT1) mRNA occurs in most cases of acute leukemia and myelodysplastic syndrome (MDS). Although there are many reports suggesting that acute myeloid leukemia patients with high expression levels of WT1 mRNA have a relatively poor long-term survival, there are few reports addressing the relationship between WT1 levels and prognosis in MDS. Methods: We retrospectively analyzed 42 elderly patients with MDS whose WT1 levels at diagnosis were available, and we assessed the relationships between WT1 levels in peripheral blood and preexisting prognostic factors such as World Health Organization prognostic scores and Revised International Prognostic Scoring System risk categories, bone marrow blast percentages, and chromosomal abnormalities linked to a poor prognosis. We also evaluated the relationship between WT1 levels and prognosis. Results:WT1 levels were significantly different between high- and low-risk MDS patients (p < 0.05). There was a trend towards a significant difference between those with and those without poor prognostic chromosomal rearrangements (p = 0.051). Moreover, the overall survival and progression-free survival were significantly worse in elderly patients with higher levels of WT1 (p = 0.00039 and p = 0.00077, respectively). Conclusions: The WT1 mRNA expression level at diagnosis may be a significant independent prognostic marker for elderly patients with MDS.

der(5;17)(p10;q10) Is a Recurrent But Rare Whole-Arm Translocation in Patients with Hematological Neoplasms: A Report of Three Cases

We report the cases of 3 patients with hematological malignancies and complex karyotypes involving der(5;17)(p10;q10), which results in the loss of 5q and 17p. Although deletions of 5q and 17p are recurrent abnormalities in hematological disease, only about 20 cases harboring der(5;17)(p10;q10) have been reported. We address the tumorigenesis and morphological characteristics of hematological malignancies involving der(5;17)(p10;q10), along with a review of the literature.

Validation of previous prognostic models for thrombosis and exploration of modified models in patients with essential thrombocythemia

We examined the prognostic factors to validate previous prognostic models for survival and thrombosis with large‐scale data on Japanese patients with essential thrombocythemia (ET).

Clinical Significance of Wt1 mRNA Levels in Japanese Acute Lymphoblastic Leukemia Patients

This study enrolled 49 patients with de novo childhood acute lymphoblastic leukemia (ALL) and 19 adult patients with ALL. WT1 mRNA showed high positive expression rates of 90% or more in ALL patients, and fusion gene transcripts were detected in 22.4% of childhood ALL cases prior to treatment. During follow-up at 4-6 months, WT1 mRNA levels in childhood ALL cases were observed to be lower in patients undergoing hematological remission after treatment when compared to the initial stages. We also assessed hematological remission via ROC analysis. The upper cut-off values were calculated to be 220 and 1,820 copies/μg RNA in the peripheral blood (PB) and bone marrow (BM) samples, respectively. Since 50 copies/μg RNA was determined to be both, the limit of detection (LOD) and minimal residual disease (MRD) threshold, WT1 mRNA regions below the upper cut-off values indicated remission depth. The detection of high WT1 mRNA levels, even in patients without fusion gene transcripts, reflected the treatment effects and remission depth, demonstrating its capacity to be a useful MRD monitoring marker in ALL.