The IFM/DFCI group reported that VRD induction followed by up-front autologous peripheral blood stem cell transplantation (ASCT) and maintenance therapy led to median PFS of 50 months, which established up-front ASCT as the standard of care even in the era of novel agents. We conducted a retrospective analysis on outcomes of patients who received triplet induction therapy followed by up-front ASCT at our institution. A total of 124 patients received ASCT between November 2016 and December 2021 at Japanese Red Cross Medical Center. Patient characteristics, treatment response before and after ASCT, and PFS and OS were retrospectively analyzed. VRD-based induction therapy was used for 94%. Among 118 evaluable patients, 116 (98%) received either consolidation and/or maintenance therapy. Best responses were ≥CR 77% and ≥VGPR 94%, respectively. Sixty-eight out of 104 patients achieved MRD-negativity by multiparameter FCM (<10⁻⁵). Five-year estimated PFS and OS were 54.7% and 80.2%, respectively. Age ≥65, high-risk cytogenetic abnormalities, and <VGPR before ASCT were identified as worse prognostic factors for PFS. Patients who achieved MRD negativity had significantly PFS (p=0.0048, 4-yr PFS 86.4% vs. 49.8%). The negative impact on PFS in the high-risk group can be overcome by achieving MRD-negativity. Prospective research is warranted to evaluate the effectiveness of consolidation therapy.

A woman in her 70s who was undergoing treatment for an overlap syndrome of autoimmune hepatitis and primary biliary cirrhosis developed persistent genital bleeding. Coagulation tests revealed a longer activated partial thromboplastin time, a 7% decrease in coagulation factor IX activity (FIX:C) and a FIX inhibitor (of 3 BU/ml). Lupus anticoagulant (LA), anticardiolipin antibody, and anti-β2 glycoprotein I antibody were positive, and the activated partial thromboplastin time cross-mixing test suggested the presence of LA. Additionally, all intrinsic coagulation factors decreased, but activity of all factors except FIX showed dilution linearity, which suggested a false decrease in activity due to LA. Although definitive diagnosis was difficult due to concurrent LA, this case was strongly suspected to be autoimmune coagulation FIX deficiency complicated by LA. Bypass therapy was not performed because the patient had no anemia and was positive for LA, and immunosuppressive therapy with prednisolone was initiated immediately. Eleven weeks after diagnosis, FIX:C was 41% and zFIX inhibitor was less than 1 BU/ml, leading to remission.

An asymptomatic woman in her early 40s with a history of hyperferritinemia (5,412 ng/ml) was referred to our hospital after repeated phlebotomy for hemosiderosis. She had unexplained hyperferritinemia, low-normal transferrin saturation, and high hepcidin levels, in the absence of iron overload-induced organ injury. She was diagnosed with ferroportin disease based on detection of the SLC40A1 variant SLC40A1 c.485_487del (p.Val162del) on genetic analysis. Her ferritin levels remained stable during pregnancy, and postpartum anemia was successfully treated with 2-week oral iron therapy. Ferroportin disease is characterized by impaired iron export and preferential iron trapping in tissue macrophages. To reduce risk of anemia, a non-aggressive phlebotomy regimen is recommended in patients with ferroportin disease, which shows a milder clinical course compared with other classical hemochromatosis subtypes.

Here we describe two patients that required interruption of a busulfan (BU) containing conditioning regimen due to severe mental disorder before stem cell transplantation. The first patient was a 66-year-old man scheduled for unrelated peripheral blood stem cell transplantation with fludarabine/BU conditioning for myelodysplastic syndrome. He received 9.6 mg/kg BU and developed hallucinations that worsened the next day. BU was stopped on the final day, but the patient became comatose (grade 4). He recovered the next day. The second patient was a 69-year-old man scheduled for autologous peripheral blood stem cell transplantation with thiotepa (TT)/BU conditioning for cerebral nervous system relapse of mantle cell lymphoma. He received 12.8 mg/kg BU and developed hallucinations. His mental symptoms worsened on the next day, and thus administration was stopped on the second day of TT. His symptoms improved the next day. Both patients were over 65 years old, and their psychiatric symptoms worsened 1-2 days after the final dose of BU. Our findings suggest that BU may cause psychiatric disorders in elderly patients. When performing BU conditioning, it may be necessary to avoid azole antifungal medication and acetaminophen and to reduce the dose or perform therapeutic dose monitoring for elderly patients.

A 68-year-old man was referred to our hospital with dizziness and mild fever one week after receiving the second dose of the COVID-19 mRNA vaccine (BNT162b2). Laboratory tests showed hemolytic anemia and a positive direct Coombs test, and he was diagnosed with autoimmune hemolytic anemia (AIHA). On admission, the patient had impaired consciousness with auditory hallucinations, and a head MRI scan showed multiple high-signal areas on diffusion-weighted imaging, suggesting multiple recent infarctions. Echocardiography also showed decreased wall motion in the inferior and posterior walls. A skin biopsy to investigate the cause revealed many platelets and fibrin thrombi in the capillaries and small veins, which was considered the cause of the organ damage. After starting prednisolone (1 mg/kg) for AIHA, hemolytic anemia as well as impaired consciousness, and decreased wall motion rapidly improved. Microthrombosis after BNT162b2 mRNA vaccination is rare, and autoimmune abnormalities appeared to contribute to onset in this case.

A 43-year-old man presenting with oral bleeding was diagnosed with acute promyelocytic leukemia (APL). Induction chemotherapy consisting of all-trans retinoic acid and idarubicin was initiated, and disseminated intravascular coagulation (DIC) was treated with fresh frozen plasma and recombinant thrombomodulin infusions. The patient was free from neurological symptoms throughout the clinical course. However, cerebral hemorrhagic lesions were detected incidentally on magnetic resonance imaging performed to screen for leukemic central nervous system invasion at 2 weeks after treatment initiation. Imaging findings suggested subacute or later-phase cerebral hemorrhage. Platelet transfusions and other supportive care was provided. Serial imaging evaluations confirmed reduction of the hemorrhagic lesions. Hematological remission was achieved after induction chemotherapy, and no symptoms due to cerebral hemorrhage developed during the subsequent consolidation therapy. As patients with APL characteristically experience hemorrhagic events due to bleeding tendency caused by DIC, physicians should be aware of the possibility of asymptomatic cerebral hemorrhage in these patients.

Although adult B-cell acute lymphoblastic leukemia (B-ALL) responds to initial treatment, relapse and refractory cases are common. Even when these cases are treated with novel agents (blinatumomab, inotuzumab ozogamicin, etc.) and/or allogeneic stem cell transplantation, the prognosis remains poor. Recently, chimeric antigen receptor T-cell (CAR-T) therapy, targeting CD19, has demonstrated great potential in treating relapsed or refractory B-ALL. We have already used tisagenlecleucel in clinical practice, but it is limited to patients up to 25 years of age. This review summarizes the most recent evidence on CAR-T therapy for relapsed or refractory adult B-ALL, which has a poor prognosis when assessed in younger patients.

The prognosis of B-cell acute lymphoblastic leukemia in children, adolescents, and young adults has improved significantly over the second half of the last century, with long-term survival rates reaching 90%, due to risk factor stratification and risk-adjusted treatment intensity. On the contrary, there are relapsed/refractory cases, and antibody-mediated immunotherapy and chimeric antigen receptor T-cell therapy are now being used in combination with conventional chemotherapy and allogeneic hematopoietic cell transplantation; the development of this treatment is expected. Tisagenlecleucel is extensively used in Japan and abroad because of its high complete remission rate in high-risk relapsed/refractory cases, including unresponsive to chemotherapy, relapsed after transplantation, and transplant-unsuitable cases. Several studies have been published in the last 2-3 years that discuss risk factors for relapse after tisagenlecleucel and the need for consolidative therapy. This manuscript presents the direction of these discussions and perspectives.

B-cell non-Hodgkin’s lymphoma is a very heterogonous malignancy with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) as the most common subtypes. Recent advances in chimeric antigen receptor T-cell (CAR-T) therapy are changing the current landscape for management of relapsed or refractory (R/R) DLBCL and R/R FL, which have a poor prognosis. Pivotal trials leading to the FDA approval of three CD19 CAR-T cells (Yescarta^®, Kymriah^® and Breyanzi^®) showed complete response (CR) rates of 40-60%, with a significant subset of patients achieving long-term disease remission. Real-world studies have also confirmed this data. Notable toxicities include cytokine release syndrome and neurologic toxicities, which are usually treatable and reversible, as well as cytopenias and hypogammaglobulinemia. Salvage chemoimmunotherapy followed by high-dose chemotherapy and autologous stem cell rescue is the standard of care for chemo-sensitive and transplant-eligible R/R DLBCL. This review highlights the approved CAR-T constructs, including their efficacy, adverse effects, and real-world data.

Immune cell therapies targeting B-cell maturation antigen (BCMA) have been developed for relapsed and refractory multiple myeloma (RR-MM). Chimeric antigen receptor (CAR)-T cell therapies appear promising for RR-MM, and two BCMA-targeting CAR-T cell products, idecabtagene vicleucel and ciltacabtagene autoleucel, have achieved the highest response rates in heavily treated patients to date. These CAR-T products have been approved for RR-MM previously treated with 3 agents (proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies) in Japan. Despite the promising efficacy of CAR-T therapy, several issues remain to be resolved to establish its best use in routine clinical practice. In addition, most patients who receive CAR-T cell therapy eventually relapse after a long or short remission, and a better understanding of mechanisms of resistance and relapse following CAR T-cell therapy for MM will be necessary to overcome resistance to CAR-T therapy. In the near future, early initiation of CAR-T therapy for RR and development of next-generation CAR-T cell products should further improve prognosis in patients with MM.

Chimeric antigen receptor T cell (CAR-T) therapy has strong efficacy as well as characteristic complications. Although overshadowed by the glaring clinical picture of cytokine releasing syndrome and immune effector cell-associated neurotoxicity syndrome, there are many other side effects that are important to manage. In this article, CAR-T-specific adverse events will be reviewed based on the actual clinical experience.

The number of cases of chimeric antigen receptor T (CAR-T) cell therapy has been rapidly increasing in Japan since Tisagenlecleucel was approved in March 2019, and clinical experience with CAR-T therapy for CD19 has demonstrated that the therapy can be performed safely than initially expected. The current challenge for CAR-T therapy is insufficient response, as about 50% of patients who receive CD19 CAR-T therapy eventually relapse or become refractory. The causes can be generally classified as CAR-T cell exhaustion and lack of sufficient effector function, loss of the target antigen, and extremely rapid tumor growth, and countermeasures are being investigated and developed for each of these causes. Additionally, the development of novel CAR-T therapies is also desired. In this article, we discuss the current status and future prospects of these issues, including our own efforts.