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Peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) are common subtypes of T-cell lymphoma. Although CHOP is a standard regimen for T-cell lymphoma, it has unsatisfactory outcomes. Pirarubicin is an anthracycline antibiotic with lower cardiotoxicity than doxorubicin. THP-COP (pirarubicin, cyclophosphamide, vincristine, and prednisone) is sometimes used for elderly patients with non-Hodgkin’s lymphoma in Japan. We performed a retrospective analysis using data from the population-based Osaka Cancer Registry as well as administrative data from 2010 to 2015. Of 82 enrolled patients, 51 received CHOP and 31 received THP-COP. The median age was 65 years in the CHOP group and 75 years in the THP-COP group. The probability of 3-year overall survival (OS) was 49.0% in the CHOP group and 44.9% in the THP-COP group. In the propensity score-adjusted analysis, there was no significant difference between the THP-COP and CHOP groups in the OS of the total sample [hazard ratio (HR) 0.46, 95% CI 0.14–1.55, P = 0.2]. Although our study was limited by its retrospective nature, it showed that clinical outcomes with the THP-COP regimen were comparable to those with the CHOP regimen in PTCL-NOS and AITL. Our findings should be re-assessed in larger studies in the future.

Although the overall clinical outcome of patients with diffuse large B cell lymphoma (DLBCL) has significantly improved, some patients still experience relapsed/refractory disease. In the rituximab era, real-world data about relapsed/refractory DLBCL are limited. To clarify the clinical outcome and prognostic factors in these patients, we conducted a retrospective analysis using data from the population-based Osaka Cancer Registry (OCR) from 2010 to 2015. In total, 189 adult patients aged up to 70 years who received CHOP or a CHOP-like regimen in combination with rituximab, as well as a subsequent second-line therapy, were included in the analysis. The median age was 63 years (range, 24–70). Age (> 63 years), the duration of first progression-free survival (PFS), and the use of rituximab in the second-line chemotherapy were prognostic factors for overall survival (OS) after the second-line treatment. In this cohort, 48 and 11 patients received autologous and allogeneic hematopoietic stem cell transplantation (HSCT), respectively. The probabilities of 3-year OS after autologous and allogeneic HSCT were 55.7% and 18.2%, respectively. In conclusion, we found that the clinical outcome of patients with relapsed/refractory DLBCL in the rituximab era was unsatisfactory. Further improvements in treatment strategies, including novel agents, are needed.

CAR T cells targeting CLL-1 have shown antileukemia efficacy in patients with acute myeloid leukemia (AML). However, CLL-1 low/− AML cells are present in some patients, suggesting that the development of CAR T cells with high sensitivity is necessary to eradicate all AML clones in these patients. Here, we identified CAR T cells derived from a novel, high-affinity anti-CLL-1 monoclonal antibody (mAb) that exhibited a significant anti-AML effect in vivo. We generated 13 new mAbs against CLL-1 and established CAR T cells from them. Of these, CAR T cells derived from mAb 2–23, which demonstrated greater affinity for CLL-1 than M26, the anti-CLL-1 mAb used in many previous studies, exhibited significant potential for cytokine production and cytotoxicity when co-cultured with AML cells. Treatment with 2–23 CAR T cells eradicated AML cells and significantly prolonged survival in AML xenograft models. Additionally, treatment with revumenib, a menin inhibitor, increased CLL-1 expression in AML cells harboring mixed-lineage leukemia (MLL) fusion genes or the NPM1 mutation, making them more susceptible to 2–23 CAR T cell-mediated cytotoxicity in vitro. These findings suggest that the clinical efficacy of CAR T cells derived from the novel, high-affinity anti-CLL-1 mAb 2–23 should be tested in patients with CLL-1-positive AML and also that combining 2–23 CAR T cells with revumenib may benefit some patients with CLL-1 low/− AML.

Cord blood (CB)-derived chimeric antigen receptor (CAR) natural killer (NK) cells have demonstrated significant antitumor efficacy. We recently reported that CB-derived CAR NK cells predominantly originate from CD7 + CD56 − CD34 − HLA-DR − Lin − NK cell precursors in CB. Here, we demonstrate that stimulating the interleukin (IL)-15 receptor on these NK precursors enhances the production of CAR NK cells from CB cells. In CB CD56 − CD34 − HLA-DR − Lin − cells, the IL-15 receptor was exclusively expressed on CD7 + NK cell precursors. Using K562 feeder cells that express not only 4-1BB ligand and membrane-bound (mb) IL-21 but also mbIL-15 significantly increased the production of mature NK cells from the purified NK cell precursors or T cell-depleted CB cells. The in vitro and in vivo antitumor effects of CAR NK cells generated using K562 feeder cells that express mbIL-15 were comparable to those of CAR NK cells produced using K562 feeder cells that do not express mbIL-15. These results suggest that K562 feeder cells expressing 4-1BBL, mbIL-21, and mbIL-15 can increase the production of CAR NK cells from CB cells while maintaining their cytotoxic potential. This method could also be useful for expanding NK cells from CB for any type of adoptive NK cell therapy with or without CAR transduction.

Tacrolimus (TAC) combined with short-term methotrexate (MTX) is widely used to prevent graft-versus-host disease (GVHD) in cord blood transplantation (CBT). As short-term MTX aggravates mucositis and delays engraftment, we reduced the dose of MTX, as previously reported in the non-CBT setting. Here, we retrospectively analyze outcomes of 20 patients who received CBT from April 2017 to December 2018. All patients received TAC with mini-MTX as GVHD prophylaxis. Mini-MTX was administered at a dose of 5 mg/m2 of MTX on days 1, 3 and 6 after CBT. Median age was 54.5 years. Median follow-up time in surviving patients was 396 days. The primary disease was acute leukemia (n = 12) or malignant lymphoma (n = 8). Three patients and 17 patients received myeloablative and reduced-intensity conditioning, respectively. Rate and median time to engraftment of neutrophils were 90.0% and 20.5 days, respectively. Cumulative incidences of grade II–IV and grade III–IV acute GVHD were 35.0% and 5.0%, respectively. At one year after CBT, the overall survival rate was 80.5%, cumulative incidence of relapse/progression was 15.0%, and non-relapse mortality rate was 5.0%. In conclusion, TAC with mini-MTX may be a promising GVHD prophylaxis regimen in single-unit CBT.

We evaluated the survival patterns for acute myeloid leukemia (AML) patients registered in the Osaka Cancer Registry from 1975 to 2017. During this period, 9706 patients were diagnosed with AML, with a median age of 60 years (range, 0–100). Patients were grouped by age (≤ 20, 21–40, 41–60, 61–70, and ≥ 71) and the year of their diagnosis (1975–1989, 1990–2001, 2002–2010, and 2011–2017). The overall survival (OS) rates of patients of ≤ 60 years of age improved significantly from the period 1975–1989 up to 1990–2001. However, there was a stagnation from 2002–2010 to 2011–2017. In terms of non-acute promyelocytic leukemia patients of > 60 years of age, the improvement of OS was limited during a very long period. In conclusion, the clinical outcome of patients with AML dramatically improved from 1975 to 2001. However, our dataset revealed stagnation in the improvement since 2002. Novel treatment options are needed to further improve the survival of elderly patients.

Peripheral T cell lymphomas (PTCL) are a heterogeneous group of non-Hodgkin lymphomas with poor outcomes. Adult T cell leukemia-lymphoma (ATL) and PTCL—not otherwise specified (PTCL-NOS)—are 2 common mature T cell lymphomas in Japan. Since it is unclear whether novel agents and treatment strategies incorporating hematopoietic cell transplantation have contributed to improved clinical outcomes in the real world, we performed a retrospective analysis using data from the population-based Osaka Cancer Registry. From 1977 to 2014, 1274 and 1143 patients were diagnosed with ATL or PTCL-NOS, respectively. Recently, the incidence of both diseases has gradually increased, and the age at diagnosis has risen. The 3-year overall survival (OS) rates in ATL patients were 12.0% in era 1 (1977–1999), 12.4% in era 2 (2000–2008), and 17.5% in era 3 (2009–2014) (P < 0.001). The 3-year OS rates in PTCL-NOS patients were 27.6% in era 1, 36.2% in era 2, and 35.0% in era 3 (P = 0.049). In conclusion, the incidences of ATL and PTCL-NOS have been increasing, particularly in elderly individuals. Clinical outcomes have improved in recent decades but are still unsatisfactory in both diseases. Thus, effective new treatment strategies incorporating novel agents are needed to further improve clinical outcomes in patients with ATL and PTCL-NOS.

A Correction to this paper has been published: https://doi.org/10.1007/s00277-020-04308-8

Acute myeloid leukemia (AML)-specific target antigens are difficult to identify. Here we demonstrate that HLA-DRB1 can serve as a leukemia-specific target of chimeric antigen receptor (CAR) T cells in patients with AML after allogeneic hematopoietic stem cell transplantation (allo-HCT). We identified KG2032 as a monoclonal antibody specifically bound to AML cells in about half of patients, but not to normal leukocytes other than B lymphocytes. KG2032 reacted with a subset of HLA-DRB1 molecules, specifically those in which the 86th amino acid was not aspartic acid. KG2032 reacted minimally with nonhematopoietic tissues. These results indicate that KG2032 reactivity is highly specific for AML cells in patients who carry KG2032-reactive HLA-DRB1 alleles and who received allo-HCT from a donor carrying KG2032-nonreactive HLA-DRB1 alleles. KG2032-derived CAR T or natural killer cells showed significant anti-leukemic activity in preclinical models in female mice, suggesting that they may cure patients with AML who are incurable with allo-HCT. Ikeda et al. report that HLA-DRB1 can serve as a leukemia-specific target for CAR T or natural killer cell-based therapy in patients with AML after allogeneic hematopoietic stem cell transplantation.