Reina Watanabe

Central nervous system involvement in diffuse large B‐cell lymphoma

Background: Malignant lymphoma with central nervous system (CNS) involvement has an extremely poor prognosis. We retrospectively studied the risk factors for CNS involvement in patients with diffuse large B‐cell lymphoma (DLBCL) treated by cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or rituximab (R) ‐CHOP chemotherapy.

Central nervous system event in patients with diffuse large B-cell lymphoma in the rituximab era

Central nervous system (CNS) events, including CNS relapse and progression to CNS, are known to be serious complications in the clinical course of patients with lymphoma. This study aimed to evaluate the risk of CNS events in patients with diffuse large B‐cell lymphoma in the rituximab era. We performed a retrospective survey of Japanese patients diagnosed with diffuse large B‐cell lymphoma who underwent primary therapy with R‐CHOP chemoimmunotherapy between September 2003 and December 2006. Patients who had received any prophylactic CNS treatment were excluded. Clinical data from 1221 patients were collected from 47 institutions. The median age of patients was 64 years (range, 15–91 years). We noted 82 CNS events (6.7%) and the cumulative 5‐year probability of CNS events was 8.4%. Patients with a CNS event demonstrated significantly worse overall survival (P < 0.001). The 2‐year overall survival rate after a CNS event was 27.1%. In a multivariate analysis, involvement of breast (relative risk [RR] 10.5), adrenal gland (RR 4.6) and bone (RR 2.0) were identified as independent risk factors for CNS events. We conclude that patients with these risk factors, in addition to patients with testicular involvement in whom CNS prophylaxis has been already justified, are at high risk for CNS events in the rituximab era. The efficacy and manner of CNS prophylaxis in patients for each involvement site should be evaluated further. (Cancer Sci 2012; 103: 245–251)

SUVmax in FDG-PET at the biopsy site correlates with the proliferation potential of tumor cells in non-Hodgkin lymphoma

The maximum standard uptake value (SUVmax) of the whole body on 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) reflects the tumor aggressiveness in non-Hodgkin lymphoma (NHL). To clarify the correlation between SUVmax at the biopsy site and the proliferation potential of tumor cells, we studied 36 patients with untreated NHL and five with untreated Hodgkin lymphoma (HL) by measuring the Ki-67 proliferation index (MIB-1 labeling index) in biopsy specimens. The measured MIB-1 labeling index was categorized into seven levels: nearly 0%, 5–20%, 21–40%, 41–60%, 61–80%, 81–95%, and nearly 100%. Twenty-four lymph nodes (LNs) and 17 extranodal (EN) sites were biopsied. The reviewed diagnosis was eight indolent lymphomas, two mantle-cell lymphomas, 26 aggressive lymphomas, and five HLs. A positive correlation was observed between the SUVmax at the biopsy site and the MIB-1 labeling index in the 36 patients with NHL (r = 0.69, p < 0.001). The correlations were also observed in LN group (r = 0.60, p = 0.006) and EN group (r = 0.87, p < 0.001), respectively. In the five patients with HL, the MIB-1 labeling index was uniformly categorized in nearly 100%. The SUVmax correlates with the proliferation potential in the case of NHL.

Peripheral blood absolute lymphocyte/monocyte ratio as a useful prognostic factor in diffuse large B-cell lymphoma in the rituximab era

The tumor microenvironment, including tumor‐infiltrating lymphocytes and myeloid‐derived cells, is an important factor in the pathogenesis and clinical behavior of malignant lymphoma. However, the prognostic significance of peripheral lymphocytes and monocytes in lymphoma remains unclear.

Clinical significance of minimal residual disease detected by multidimensional flow cytometry: Serial monitoring after allogeneic stem cell transplantation for acute leukemia

We analyzed minimal residual disease (MRD) by multidimensional flow cytometry (MFC) after allogeneic stem cell transplantation in 41 patients with acute myeloid leukemia (AML) (n=31) or acute lymphoblastic leukemia (ALL) (n=10). Aberrant antigen expression was compared with the results of quantitative PCR for WT1 mRNA (n=41) and leukemia-specific fusion transcripts (n=12; AML in seven, ALL in five). There was a significant correlation between detection of MRD by MFC and WT1 mRNA, as well as between MFC and fusion transcripts. Serial monitoring of MRD by the three techniques correlated in parallel to the clinical course in most of the patients, but three patients were only positive for WT1 during hematological remission. The overall survival time of patients with complete remission was significantly associated with the appearance of aberrant expression after transplantation. In conclusion, MFC is valuable for clinical management decisions after transplantation.

Pretransplant serum ferritin is associated with bloodstream infections within 100 days of allogeneic stem cell transplantation for myeloid malignancies

We retrospectively studied the association between iron overload and bloodstream infections (BSI) in the 100-day period following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia or myelodysplastic syndromes. Serum ferritin was measured before transplantation to evaluate iron overload. Of 114 adult patients who underwent transplantation between 2000 and 2008, 36 (32%) developed BSI. Of the 44 isolates, 63% were Gram-positive bacteria, 32% were Gram-negative bacteria, and 4% were fungi. The median time to the onset of the first BSI was day 28 (range day 0–95) after transplantation. Univariate analysis revealed a significantly higher incidence of BSI in the high (≥1,000 ng/ml, n = 57) than in the low (<1,000 ng/ml, n = 57) ferritin group (42.1 versus 21.1%, respectively, P = 0.017). Peripheral blood stem cell transplantation (PBSCT) (n = 23) showed a greater protective effect against BSI compared with bone marrow (n = 71) and cord blood (n = 20) transplantation. Pretransplantation serum ferritin (HR = 2.844, 95% CI: 1.180–6.859, P = 0.020) and PBSCT (HR = 0.135, 95% CI: 0.025–0.717, P = 0.019) were significant factors on multivariate analysis. In conclusion, pretransplantation serum ferritin significantly predicts BSI within the 100-day period after allo-HSCT.

Absolute monocyte count in follicular lymphoma patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.

Elevated absolute monocyte counts (AMCs) have been reported to indicate poor prognosis for patients with lymphoproliferative disease, including those with follicular lymphoma (FL) receiving various treatments. We evaluated the prognostic impact of AMC in 150 consecutive FL patients who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Progression-free survival (PFS) did not differ significantly according to the AMC level. Univariate and multivariate analyses did not indicate a prognostic significance of AMC for PFS. Thus, the AMC is not a prognostic factor for FL patients treated with R-CHOP. However, immunochemotherapy might influence the prognostic impact of AMC.

Human leukocyte antigen-DR expression on flow cytometry and tumor-associated macrophages in diffuse large B-cell lymphoma treated by rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone therapy: retrospective cohort study

Abstract Loss of human leukocyte antigen (HLA)-DR expression may be related to a poor prognosis of diffuse large B-cell lymphoma (DLBCL), and tumor-associated macrophages (TAMs) may influence tumor progression. We retrospectively reviewed 36 patients with newly diagnosed DLBCL who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) therapy at Kanagawa Cancer Center in Japan from 2004 to 2010. HLA-DR expression by lymphoma cells was evaluated using flow cytometry, and TAMs in lymphoma tissue were detected by immunohistochemistry for CD68 as a marker of macrophages and CD163 as a marker of M2 TAMs. Three-year overall survival was, respectively, 100% versus 69.6% in the HLA-DR “bright” and “not bright” groups (p = 0.012). Patients from the HLA-DR “not bright” group with strong CD163 expression had a much worse prognosis than other patients. The HLA-DR status shown by flow cytometry can be used to predict the prognosis of patients with DLBCL receiving R-CHOP therapy and prognostic accuracy can be increased by also assessing TAMs.

Intrathecal methotrexate prophylaxis and central nervous system relapse in patients with diffuse large B-cell lymphoma following rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone

Abstract This study evaluated the efficacy of central nervous system (CNS) prophylaxis using intrathecal methotrexate (IT-MTX) in patients with diffuse large B-cell lymphoma (DLBCL). We retrospectively studied 322 patients who achieved first complete remission (CR) after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. The CNS prophylaxis consisted of four doses of IT-MTX (15 mg) with hydrocortisone (25 mg) administered after CR was achieved. Forty patients (12%) received CNS prophylaxis (group A) and 282 patients (88%) did not (group B). Three patients in group A (8%) and eight in group B (3%) experienced isolated CNS relapse during the first CR, although this difference was not statistically significant (p = 0.14). Ten of 11 CNS relapses occurred in the brain parenchyma with (n = 3) or without (n = 7) leptomeningeal involvement, and the remaining patient had exclusive leptomeningeal involvement. In patients with DLBCL attaining CR after R-CHOP, IT-MTX administration was insufficient to prevent CNS relapse.

The standard international prognostic index for predicting the risk of CNS involvement in DLBCL without specific prophylaxis

Abstract Central nervous system (CNS) involvement is a serious complication in patients with diffuse large B-cell lymphoma (DLBCL) and evaluating CNS risk is an important issue. Using the standard international prognostic index (IPI) and CNS-IPI, a recently proposed model including IPI risk factors and adrenal/kidney involvement, we assessed CNS risk in 1220 untreated DLBCL patients who received R-CHOP without prophylaxis. According to the standard IPI, the cumulative incidences of CNS involvement at 2 years were 1.3, 4.6, 8.8, and 12.7% in the low-, low-intermediate-, high-intermediate-, and high-risk groups, respectively (p <.001). This result is comparable with that of the CNS-IPI. Patients with breast involvement tended to have lower risk according to the standard IPI but showed frequent CNS involvement, similar to patients with testis involvement. The standard IPI is also a useful predictor of CNS involvement. Patients with breast/testis involvement would be candidates for prophylaxis regardless of the standard IPI risk.