Dai Chihara

Differences in incidence and trends of haematological malignancies in Japan and the United States

The incidence of a malignant disease reflects the genetic and cumulative exposure to the environment of a population. Therefore, evaluation of the incidence and trends of a disease in different populations may provide insights into its aetiology and pathogenesis. To evaluate the incidence of haematological malignancies according to specific subtypes, we used population‐based registry data in Japan (N = 125 148) and the United States (US; N = 172 925) from 1993 to 2008. The age‐adjusted incidence of haematological malignancies in Japan was approximately one‐half that in the US but has been increasing significantly, whereas no significant change was seen in the US [annual percent change (95% C confidence interval): Japan, +2·4% (1·7, 3·1); US, +0·1% (−0·1, 0·2)]. Hodgkin lymphoma (HL) and non‐Hodgkin lymphoma (NHL) showed the largest differences in incidence, with the most remarkable differences observed for chronic lymphocytic leukaemia, HL‐nodular sclerosis, mycosis fungoides and cutaneous T‐cell lymphoma. HL and NHL are increasing substantially in Japan but not in the US, suggesting that environmental exposures, such as Westernization of the life style may be causing this increase. Differences in the incidence and trends for specific subtypes also showed a marked contrast across subtypes, which, in turn, may provide significant new insights into disease aetiology in the future.

Patients with mantle cell lymphoma failing ibrutinib are unlikely to respond to salvage chemotherapy and have poor outcomes

BACKGROUND Although ibrutinib is highly effective in patients with relapsed/refractory mantle cell lymphoma (MCL), a substantial proportion of patients have resistant disease. The subsequent outcomes of such patients are unknown. PATIENTS AND METHODS We carried out a retrospective review of all patients with MCL treated with ibrutinib at MD Anderson Cancer Center between January 2011 and January 2014 using pharmacy and clinical databases. Patients who had discontinued ibrutinib for any reason were included in the study. RESULTS We identified 42 patients with MCL who discontinued therapy due to disease progression on treatment (n = 28), toxicity (n = 6), elective stem-cell transplant in remission (n = 4) or withdrawn consent (n = 4). The median age was 69 years, 35 (83%) were male; the median number of prior treatments was 2 (range 1-8) and the median time from initial diagnosis of MCL to commencing ibrutinib was 3.0 (range 0.5-15.5) years. Patients had received a median of 6.5 (range 1-43) cycles of ibrutinib. Among 31 patients who experienced disease progression following ibrutinib and underwent salvage therapy, the overall and complete response rates were 32% and 19%, respectively. After a median follow-up of 10.7 (range 2.4-38.9) months from discontinuation of ibrutinib, the median overall survival (OS) among patients with disease progression was 8.4 months. By univariate analysis, elevated serum lactate dehydrogenase at progression was associated with inferior OS. CONCLUSION The outcome of patients with MCL who experience disease progression following ibrutinib therapy is poor, with both low response rates to salvage therapy and short duration of responses. Further studies to better understand and overcome ibrutinib resistance are urgently needed.BACKGROUND Although ibrutinib is highly effective in patients with relapsed/refractory mantle cell lymphoma (MCL), a substantial proportion of patients have resistant disease. The subsequent outcomes of such patients are unknown. PATIENTS AND METHODS We carried out a retrospective review of all patients with MCL treated with ibrutinib at MD Anderson Cancer Center between January 2011 and January 2014 using pharmacy and clinical databases. Patients who had discontinued ibrutinib for any reason were included in the study. RESULTS We identified 42 patients with MCL who discontinued therapy due to disease progression on treatment (n = 28), toxicity (n = 6), elective stem-cell transplant in remission (n = 4) or withdrawn consent (n = 4). The median age was 69 years, 35 (83%) were male; the median number of prior treatments was 2 (range 1-8) and the median time from initial diagnosis of MCL to commencing ibrutinib was 3.0 (range 0.5-15.5) years. Patients had received a median of 6.5 (range 1-43) cycles of ibrutinib. Among 31 patients who experienced disease progression following ibrutinib and underwent salvage therapy, the overall and complete response rates were 32% and 19%, respectively. After a median follow-up of 10.7 (range 2.4-38.9) months from discontinuation of ibrutinib, the median overall survival (OS) among patients with disease progression was 8.4 months. By univariate analysis, elevated serum lactate dehydrogenase at progression was associated with inferior OS. CONCLUSION The outcome of patients with MCL who experience disease progression following ibrutinib therapy is poor, with both low response rates to salvage therapy and short duration of responses. Further studies to better understand and overcome ibrutinib resistance are urgently needed.

Retrospective analysis of prognostic factors for angioimmunoblastic T-cell lymphoma: a multicenter cooperative study in Japan

Angioimmunoblastic T-cell lymphoma (AITL) is a major type of peripheral T-cell lymphoma (PTCL). To elucidate the clinicopathologic characteristics and prognosis of AITL in Japan, we retrospectively analyzed 207 patients with AITL. The median patient age was 67 years (range, 34-91 years), with 73% of patients older than 60 years. With a median follow-up of 42 months in surviving patients, 3-year overall survival (OS) was 54% and progression-free survival (PFS) was 38%. The International Prognostic Index (IPI) and the prognostic index for PTCL, not otherwise specified (PIT) were predictive for OS in this analysis. Multivariate analysis found that age older than 60 years, elevated white blood cell (WBC) and IgA levels, the presence of anemia and thrombocytopenia, and extranodal involvement at > 1 site were significant prognostic factors for OS, and IgA, anemia, and mediastinal lymphadenopathy were significant prognostic factors for PFS. A novel prognostic model consisting of the prognostic factors for OS was successfully constructed. In conclusion, IPI and PIT were still useful for prognostication of AITL, and other factors, including those not used in IPI, such as IgA, anemia, WBC count, thrombocytopenia, and mediastinal lymphadenopathy, also significantly affected prognosis. Future investigations for IgA as a unique prognostic factor are warranted.

High maximum standard uptake value (SUVmax) on PET scan is associated with shorter survival in patients with diffuse large B cell lymphoma

FDG-PET scan plays an important role in response assessment in diffuse large B cell lymphoma (DLBCL). In this study, we evaluated the prognostic value of maximum standard uptake (SUVmax) on pretreatment PET scan in DLBCL. Among 169 patients with DLBCL newly diagnosed and treated with R-CHOP between 2003 and 2008, 110 patients who had undergone pretreatment PET scan in single institute using an identical protocol were reviewed and analyzed. SUVmax at the predominant lesion on PET scan and other patient characteristics were evaluated for their association with complete response (CR) rate, overall survival (OS) and progression-free survival (PFS). The median SUVmax was 18.1 (2.0–36.4). There was no significant association between high SUV and other characteristics with the exception of PS ≥ 2 and Ki-67. Multivariate analysis revealed the independent association between high SUVmax and lower CR rate. The 3-year PFS rates in patients with SUV < 30 and those with SUV ≥ 30 were 78 and 51%, respectively (p = 0.06). The 3-year OS rates were 86 and 71%, respectively (p = 0.03). Multivariate analysis revealed that high SUVmax is a significant poor prognostic factor for both PFS and OS, independent of IPI. We showed the important prognostic value of pretreatment SUVmax of PET scan in DLBCL.

Recent advances in the treatment of adult T‐cell leukemia‐lymphomas

Recent advances in treatment for adult T‐cell leukemia‐lymphoma (ATL) are reviewed herein. It is currently possible to select a therapeutic strategy for ATL and predict prognosis by classification of patients by clinical subtypes and clinicopathological factors. Although the overall survival (OS) of patients with ATL has increased marginally because of advances in chemotherapy, further prolongation of survival might be difficult with conventional chemotherapy alone. Promising results have been reported for antiviral therapy using zidovudine and interferon‐α, and, indeed, antiviral therapy is currently the standard treatment for patients with ATL in western countries. Remarkably, the 5‐year OS rates are 100% for both the smoldering‐type and chronic‐type ATL. Recently, treatments for ATL have included allogeneic hematopoietic stem cell transplantation and molecular targeted therapies. Furthermore, the anti‐CCR4 monoclonal antibody mogamulizumab has been shown to have marked cytotoxic effects on ATL cells, especially in the leukemic type of ATL. In the lymphoma type of ATL, the response rate may be improved by combining mogamulizumab with chemotherapy. It should be recognized that prevention of infection from carriers of human T‐cell leukemia virus type‐I and transfer of the virus from mother to infant are crucial issues for the eradication of ATL.

Malignancy-associated hemophagocytic lymphohistiocytosis in adults: Relation to hemophagocytosis, characteristics, and outcomes.

Malignancy‐associated hemophagocytic lymphohistiocytosis (HLH) in adults is a highly lethal disorder. Knowledge gaps have resulted in under diagnosis or delayed diagnosis.

Malignancy-associated hemophagocytic lymphohistiocytosis in adults

Malignancy‐associated hemophagocytic lymphohistiocytosis (HLH) in adults is a highly lethal disorder. Knowledge gaps have resulted in under diagnosis or delayed diagnosis.

Normalization of free light chain kappa/lambda ratio is a robust prognostic indicator of favorable outcome in patients with multiple myeloma

To clarify the impact of serum free light chain (sFLC) ratio normalization in patients with multiple myeloma (MM) treated with novel agents.

Incidence and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: analyses with competing risk regression model

Abstract Central nervous system (CNS) relapse is a challenging complication in patients with diffuse large B-cell lymphoma (DLBCL). Thus, identification of the high-risk population, in whom prophylactic treatment may play a significant role, is critical. We calculated the incidence of CNS relapse and evaluated the risk factors for CNS relapse using competing risk regression analysis. A total of 386 patients who received CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) with (n = 203) or without (n = 183) rituximab were analyzed. The 5-year cumulative incidence of CNS relapse was 6.7%. Multivariate analysis identified three independent risk factors: bulky disease (subhazard ratio [SHR] 3.34, 95% confidence interval [1.45–7.66], p = 0.004), absolute lymphocyte count <1.0 × 109/L (SHR 2.38 [1.05–5.39], p = 0.037) and extranodal involvement (SHR 2.90 [1.01–8.33], p = 0.047). Patients with three risk factors represented 6% of patients, in whom the 5-year cumulative incidence was 26%. Larger scale studies are needed to validate our results. A better management strategy in patients with high-risk disease is critically needed.

Rituximab plus hyper-CVAD alternating with MTX/Ara-C in patients with newly diagnosed mantle cell lymphoma: 15-year follow-up of a phase II study from the MD Anderson Cancer Center

Intensive chemotherapy regimens containing cytarabine have substantially improved remission durability and overall survival in younger adults with mantle cell lymphoma (MCL). However, there have been no long‐term follow‐up results for patients treated with these regimens. We present long‐term survival outcomes from a pivotal phase II trial of rituximab, hyper‐fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine (R‐HCVAD/MA). At 15 years of follow‐up (median: 13·4 years), the median failure‐free survival (FFS) and overall survival (OS) for all patients was 4·8 years and 10·7 years, respectively. The FFS seems to have plateaued after 10 years, with an estimated 15‐year FFS of 30% in younger patients (≤65 years). Patients who achieved complete response (CR) after 2 cycles had a favourable median FFS of 8·8 years. Six patients developed myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) whilst in first CR. The 10‐year cumulative incidence of MDS/AML of patients in first remission was 6·2% (95% confidence interval: 2·5–12·2%). In patients with newly diagnosed MCL, R‐HCVAD/MA showed sustained efficacy, with a median OS exceeding 10 years in all patients and freedom from disease recurrence of nearly 15 years in almost one‐third of the younger patients (≤65 years).