[Successful immunosuppressive therapy in female hemophilia A developing inhibitor after perioperative administration of factor VIII products].

A 62-year-old woman was diagnosed as a hemophilia A carrier (factor VIII activity 35%) on preoperative examination of an ovarian tumor. A total of 35,600 units of recombinant factor VIII products was administered perioperatively. On postoperative day 95, a subcutaneous hematoma formed and immunosuppressive therapy with prednisolone was started based on an APTT of 66 seconds, factor VIII (FVIII) activity of 3%, and FVIII inhibitor of 1 BU/ml. During this treatment, the patient was hospitalized due to ankle joint bleeds and required hemostatic treatment, but the inhibitor disappeared and FVIII activity recovered to 30% after postoperative day 438 with cyclophosphamide. F8 analysis revealed the patient carried a heterozygosity of p.Arg391Cys, which has previously been categorized as cross-reacting material (CRM)-positive severe hemophilia A. No high-risk mutations for inhibitor development were found. We also report the results of a desmopressin acetate hydrate test administered to the patient to prepare for future treatment in case of hemorrhage, since high-dose FVIII administration may have been a factor in inhibitor development.

[Successful induction therapy for acute myeloid leukemia under management with extracorporeal membrane oxygenation].

A 53-year-old woman presented with shortness of breath and hyperleukocytosis and was admitted to our hospital. Shortly after, she went into cardiopulmonary arrest and was resuscitated. Her white blood cell count was 566,000/µl, with 94.5% cup-like blasts positive for MPO staining and FLT3-ITD positive, so she was diagnosed with acute myeloid leukemia (AML) M1. She also had disseminated intravascular coagulation and tumor lysis syndrome. Extracorporeal membrane oxygenation (ECMO) was started to manage bilateral pulmonary thromboembolism that had developed due to deep vein thrombosis, and induction therapy was performed under ECMO. On the third day of illness, the patient developed cerebral hemorrhage. Hematological remission was confirmed on the 39th day of illness. After consolidation therapy with chemotherapy and an FLT3 inhibitor, she underwent allogeneic hematopoietic stem cell transplantation, and remains alive. Case reports suggest strong evidence of mortality benefit from ECMO in patients with hematologic malignancies, particularly when ECMO served as a bridge through chemotherapy. Our patient suffered from cardiopulmonary arrest due to hyperleukocytosis and pulmonary thromboembolism, but was saved by induction of remission under ECMO. Improvements in supportive care should lead to reduction in early deaths during induction therapy.

Repurposing a novel anti-cancer RXR agonist to attenuate murine acute GVHD and maintain graft-versus-leukemia responses.

The nuclear receptor (NR) subclass, retinoid X receptors (RXRs), exert immunomodulatory functions that control inflammation and metabolism via homodimers and heterodimers, with several other NRs, including retinoic acid receptors. IRX4204 is a novel, highly specific RXR agonist in clinical trials that potently and selectively activates RXR homodimers, but not heterodimers. In this study, in vivo IRX4204 compared favorably with FK506 in abrogating acute graft-versus-host disease (GVHD), which was associated with inhibiting allogeneic donor T-cell proliferation, reducing T-helper 1 differentiation, and promoting regulatory T-cell (Treg) generation. Recipient IRX4204 treatment reduced intestinal injury and decreased IFN-γ and TNF-α serum levels. Transcriptional analysis of donor T cells isolated from intestines of GVHD mice treated with IRX4204 revealed significant decreases in transcripts regulating proinflammatory pathways. In vitro, inducible Treg differentiation from naive CD4+ T cells was enhanced by IRX4204. In vivo, IRX4204 increased the conversion of donor Foxp3- T cells into peripheral Foxp3+ Tregs in GVHD mice. Using Foxp3 lineage-tracer mice in which both the origin and current FoxP3 expression of Tregs can be tracked, we demonstrated that IRX4204 supports Treg stability. Despite favoring Tregs and reducing Th1 differentiation, IRX4204-treated recipients maintained graft-versus-leukemia responses against both leukemia and lymphoma cells. Notably, IRX4204 reduced in vitro human T-cell proliferation and enhanced Treg generation in mixed lymphocyte reaction cultures. Collectively, these beneficial effects indicate that targeting RXRs with IRX4204 could be a novel approach to preventing acute GVHD in the clinic.

[Allogeneic hematopoietic stem cell transplantations for relapsed and refractory acute lymphoblastic leukemia following inotuzumab ozogamicin treatment].

Inotuzumab ozogamicin (InO) was administered in three cases of relapsed/refractory adult acute lymphoblastic leukemia (ALL) before allogeneic hematopoietic stem cell transplantation (allo-SCT). One case developed extremely severe sinusoidal obstruction syndrome (SOS) but recovered after receiving defibrotide therapy. A gap of 63 days in the SOS case was noted from the last administration of InO to allo-SCT, the duration was 133 and 86 days for the other two cases, and the remaining risk factors for SOS were comparable in the three cases. In contrast to gemtuzumab ozogamicin (GO), the interval between InO exposure and allo-SCT has not been reported as a risk for SOS. Nevertheless, this case suggests that the intervals should be as long as possible.

[FLT3-ITD and NPM1 mutation positive acute myeloid leukemia with cuplike blasts mimicking acute promyelocytic leukemia].

FMS-like tyrosine kinase 3 (FLT3) inhibitors improve the prognosis of FLT3-internal tandem duplication (ITD)-positive acute myeloid leukemia (AML). Case 1 is a 47-year-old male patient who presented with a white blood cell count (WBC) of 95,700/ml with 94% blast accompanied by cuplike nuclei, lactate dehydrogenase (LDH) of 2,434 IU/l, fibrin degradation products (FDP) of 476 mg/ml, and a bone marrow examination that revealed blastic marrow with chromosome 46, XY, positive FLT3-ITD, and positive nucleophosmin 1 (NPM1) mutation type A. Flow cytometry revealed that blasts were positive for CD33 and negative for CD34, CD117, and human leukocyte antigen-DR isotype (HLA-DR). The patient had no response to idarubicin combined cytarabine; however, qiuzartinib administration resulted in the first complete remission. Case 2 is a 71-year-old female patient, who presented with 94,900/ml of WBC with a 91% blast accompanied with cup-like nuclei, LDH of 19,03 IU/l, FDP of 112 mg/ml, and a peripheral blood examination that revealed chromosome 46, XX, positive FLT3-ITD, and positive NPM1 mutation type B. Flow cytometry revealed that blasts were positive for CD33 and negative for CD34, CD117, and HLA-DR. She had a partial response to venetoclax combined with azacytidine, and qiuzartinib administration resulted in the first complete remission. Both cases were CD34- and HLA-DR-negative with disseminated intravascular coagulation mimicking acute promyelocytic leukemia (APL). Additionally, recognizing the cuplike blasts is useful to differentiate FLT3 mutant AML from APL for the proper use of FLT3 inhibitors.

[Use of pegylated granulocyte colony-stimulating factor in dose-adjusted EPOCH-R therapy].

Dose-adjusted (DA)-EPOCH-R causes profound neutropenia requiring relatively long hospital stays with multiple doses of granulocyte colony-stimulating factor (G-CSF). A single-dose pegylated G-CSF (PEG-G-CSF) has been used for the treatment of chemotherapy-induced neutropenia. We retrospectively examined 15 patients (median age 61, range 33-75 years) treated with DA-EPOCH-R. In the first cycle of the DA-EPOCH-R therapy, a G-CSF preparation was used, and since the second cycle, the G-CSF and PEG-G-CSF use groups were divided. The median length of hospitalization after starting chemotherapy in the second-cycle DA-EPOCH-R was significantly shorter with PEG-G-CSF group (n=9) of 9 (7-13) days compared with G-CSF group (n=6) of 18 (15-22) days (P<0.001). Risk factors of febrile neutropenia, such as bone marrow invasion, performance status, serum albumin, and history of febrile neutropenia at the first DA-EPOCH-R cycle or previous chemotherapy were not significantly different for both groups, and the incidence of febrile neutropenia in PEG-G-CSF and G-CSF groups was 2.6% and 46.9%, respectively. These analyses suggest that PEG-G-CSF can be combined with DA-EPOCH-R without compromising treatment outcomes as compared with the daily dose of G-CSF.

Myeloid differentiation factor 88 signaling in donor T cells accelerates graft-versus-host disease.

Myeloid differentiation factor 88 (MyD88) signaling has a crucial role in activation of both innate and adoptive immunity. MyD88 transduces signals via Toll-like receptor and interleukin-1 receptor superfamily to the NFκB pathway and inflammasome by forming a molecular complex with interleukin-1 receptor-associated kinase 4. The MyD88/interleukin-1 receptor-associated kinase 4 pathway plays an important role, not only in innate immunity, but also T-cell immunity; however, its role in donor T cells on the pathophysiology of graft-versus-host disease (GvHD) remains to be elucidated. We addressed this issue by using MyD88-deficient T cells in a mouse model of allogeneic hematopoietic stem cell transplantation (allo-SCT). While MyD88-deficient and wild-type T cells proliferated equivalently after transplantation, MyD88-deficient T cells demonstrated impaired survival and differentiation toward Th1, Tc1, and Th17, and induced less severe GvHD compared to wild-type T cells. Administration of interleukin-1 receptor-associated kinase 4 inhibitor PF-06650833 significantly ameliorated GvHD after allo-SCT. These results thus demonstrate that donor T-cell MyD88/interleukin-1 receptor-associated kinase 4 pathway is a novel therapeutic target against GvHD after allo-SCT.

Successful correction of factor V deficiency of patient-derived iPSCs by CRISPR/Cas9-mediated gene editing.

BACKGROUND: Factor V (FV) deficiency is a monogenic inherited coagulation disorder considered to be an ideal indication for gene therapy. To investigate the possibility of therapeutic application of genome editing, we generated induced pluripotent stem cells (iPSCs) from a FV-deficient patient and repaired the mutation of factor V gene (F5) using a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9). METHODS: The patient's peripheral blood mononuclear cells were reprogrammed for iPSCs. The targeting vector was designed with homology arms against F5 containing the corrected sequence. Cas9 ribonucleoprotein (RNP) complex and targeting vector were electroporated into iPSCs. Gene-edited iPSCs were differentiated into hepatocyte-like cells (HLCs). RESULTS: The mutation of F5 in patient-derived iPSCs was repaired by CRISPR/Cas9. In concentrated culture supernatants of patient-derived iPS-HLCs, neither FV antigen nor activity was detected, while in those of gene-corrected iPS-HLCs, FV antigen and specific activity were 67.0 ± 13.1 ng/mL and 173.2 ± 41.1 U/mg, respectively. CONCLUSIONS: We successfully repaired the mutation of F5 using the CRISPR/Cas9 and confirmed the recovery of FV activity with gene-corrected iPS-HLCs. Gene-edited iPSCs are promising for elucidating the pathophysiology as well as for a modality of gene therapy.

[Interleukin-6-producing paraganglioma mimicking multicentric Castleman disease].

Multicentric Castleman disease (MCD) comprises a heterogeneous group of lymphoproliferative disorders. Interleukin 6 (IL-6) plays an important role in the MCD pathophysiology. Here, we report the case of a 17-year-old Japanese man who presented with fever, headache, fatigue, and weight loss, with normal blood pressure. A movable mass was palpated in his lower abdomen. Laboratory tests revealed microcytic anemia and hypoalbuminemia, with elevated IL-6, sIL-2R, and vascular endothelial growth factor. Computed tomography of the abdomen demonstrated a 55-mm-diameter pelvic tumor and enlarged mesenteric lymph nodes. MCD was suspected, and the pelvic tumor resected. After the operation, his blood pressure rose slowly, and resulted to seizures of posterior reversible encephalopathy syndrome. Evaluation of hypertension revealed that plasma norepinephrine and normetanephrine concentrations were elevated, and pathological examinations showed that the resected tumor was positive for IL-6 and chromogranin-A. Therefore, we diagnosed the patient with IL-6-producing paraganglioma with MCD-mimicking symptoms. Moreover, IL-6-producing pheochromocytoma and paraganglioma should be included in differential diagnoses of MCD, even in normotensive patients.

A Host-Dependent Prognostic Model for Elderly Patients with Diffuse Large B-Cell Lymphoma.

BACKGROUND: Decision-making models for elderly patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) are in great demand. PATIENTS AND METHODS: The Society of Lymphoma Treatment in Japan (SoLT-J), in collaboration with the West-Japan Hematology and Oncology Group (West-JHOG), collected and retrospectively analyzed the clinical records of ≥65-year-old patients with DLBCL treated with R-CHOP from 19 sites across Japan to build an algorithm that can stratify adherence to R-CHOP. RESULTS: A total of 836 patients with a median age of 74 years (range, 65-96 years) were analyzed. In the SoLT-J cohort (n = 555), age >75 years, serum albumin level <3.7 g/dL, and Charlson Comorbidity Index score ≥3 were independent adverse risk factors and were defined as the Age, Comorbidities, and Albumin (ACA) index. Based on their ACA index score, patients were categorized into "excellent" (0 points), "good" (1 point), "moderate" (2 points), and "poor" (3 points) groups. This grouping effectively discriminated the 3-year overall survival rates, mean relative total doses (or relative dose intensity) of anthracycline and cyclophosphamide, unanticipated R-CHOP discontinuance rates, febrile neutropenia rates, and treatment-related death rates. Additionally, the ACA index showed comparable results for these clinical parameters when it was applied to the West-JHOG cohort (n = 281). CONCLUSION: The ACA index has the ability to stratify the prognosis, tolerability to cytotoxic drugs, and adherence to treatment of elderly patients with DLBCL treated with R-CHOP. The Oncologist 2017;22:554-560 IMPLICATIONS FOR PRACTICE: Currently, little is known regarding how to identify elderly patients with diffuse large B-cell lymphoma who may tolerate a full dose of chemotherapy or to what extent cytotoxic drugs should be reduced in some specific conditions. The Society of Lymphoma Treatment in Japan developed a host-dependent prognostic model consisting of higher age (>75 years), hypoalbuminemia (<3.7 g/dL), and higher Charlson Comorbidity Index score (≥3) for such elderly patients. This model can stratify the prognosis, tolerability to cytotoxic drugs, and adherence to treatment of these patients and thus help clinicians in formulating personalized treatment strategies for this growing patient population.

Inhibiting retinoic acid signaling ameliorates graft-versus-host disease by modifying T-cell differentiation and intestinal migration.

Graft-versus-host disease (GVHD) is a critical complication after allogeneic bone marrow transplantation. During GVHD, donor T cells are activated by host antigen-presenting cells and differentiate into T-effector cells (Teffs) that migrate to GVHD target organs. However, local environmental factors influencing Teff differentiation and migration are largely unknown. Vitamin A metabolism within the intestine produces retinoic acid, which contributes to intestinal homeostasis and tolerance induction. Here, we show that the expression and function of vitamin A-metabolizing enzymes were increased in the intestine and mesenteric lymph nodes in mice with active GVHD. Moreover, transgenic donor T cells expressing a retinoic acid receptor (RAR) response element luciferase reporter responded to increased vitamin A metabolites in GVHD-affected organs. Increasing RAR signaling accelerated GVHD lethality, whereas donor T cells expressing a dominant-negative RARα (dnRARα) showed markedly diminished lethality. The dnRARα transgenic T cells showed reduced Th1 differentiation and α4ß7 and CCR9 expression associated with poor intestinal migration, low GVHD pathology, and reduced intestinal permeability, primarily via CD4(+) T cells. The inhibition of RAR signaling augmented donor-induced Treg generation and expansion in vivo, while preserving graft-versus-leukemia effects. Together, these results suggested that reagents blunting donor T-cell RAR signaling may possess therapeutic anti-GVHD properties.

Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality.

Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, play an important role in the maintenance of peripheral tolerance. We explored the role of PD-1 ligands in regulating graft-versus-host disease (GVHD). Both PD-L1 and PD-L2 expression were upregulated in the spleen, liver, colon, and ileum of GVHD mice. Whereas PD-L2 expression was limited to hematopoietic cells, hematopoietic and endothelial cells expressed PD-L1. PD-1/PD-L1, but not PD-1/PD-L2, blockade markedly accelerated GVHD-induced lethality. Chimera studies suggest that PD-L1 expression on host parenchymal cells is more critical than hematopoietic cells in regulating acute GVHD. Rapid mortality onset in PD-L1-deficient hosts was associated with increased gut T-cell homing and loss of intestinal epithelial integrity, along with increased donor T-cell proliferation, activation, Th1 cytokine production, and reduced apoptosis. Bioenergetics profile analysis of proliferating alloreactive donor T-cells demonstrated increased aerobic glycolysis and oxidative phosphorylation in PD-L1-deficient hosts. Donor T-cells exhibited a hyperpolarized mitochondrial membrane potential, increased superoxide production, and increased expression of a glucose transporter in PD-L1-deficient hosts. Taken together, these data provide new insight into the differential roles of host PD-L1 and PD-L2 and their associated cellular and metabolic mechanisms controlling acute GVHD.

CRISPR/Cas9 gene editing clarifies the role of CD33 SNP rs12459419 in gemtuzumab ozogamicin-mediated cytotoxicity.

The single-nucleotide polymorphism (SNP) rs12459419 is located at the intron/exon junction of CD33 exon2. When exon2 is skipped by this CD33 SNP, the full-length CD33 (CD33FL) is converted to a short CD33 isoform (CD33D2). Since gemtuzumab ozogamicin (GO) only recognizes CD33FL, the CD33 SNP may affect the clinical efficacy of GO. To elucidate the significance of CD33 SNP on GO reactivity, we leveraged the CRISPR/Cas9 genome-editing system to create OCI-AML3 cell lines with specifically modified CD33 SNPs. Levels of CD33 D2 mRNA were significantly higher in the T/T clone (p < 0.001), but CD33D2 protein was not detectable in any clones. There was no significant difference in CD33FL mRNA expression across edited clones, and CD33FL protein expression was lowest in T/T clones, followed by T/C and C/C. Cytotoxicity assays revealed that the IC50 of GO was significantly lower in T/C and C/C clones than in the T/T clone (p < 0.001). Our study demonstrated a difference in GO-induced cytotoxicity in CD33 SNP-edited clones, clearly indicating that at least one CD33 SNP allele, rs12459419 C, is important for sensitivity to GO.

High-dose cytarabine plus gemtuzumab ozogamicin as consolidation therapy in patients with favorable- or intermediate-risk acute myeloid leukemia.

Previous prospective randomized trials have investigated the efficacy of gemtuzumab ozogamicin in the frontline treatment of acute myeloid leukemia (AML). We evaluated the efficacy of high-dose cytarabine with GO as consolidation therapy in 20 patients with favorable- or intermediate-risk AML in first complete remission. They included six patients with wild-type nucleophosmin (NPM1) core binding factor (CBF), ten with NPM1-mutated non-CBF, and four with wild-type NPM1 non-CBF. The median follow-up for the entire cohort was 62.0 months. The three-year overall survival (OS) and relapse-free survival (RFS) rates were 72.2% and 77.8%, respectively. OS and RFS were significantly higher for NPM1-mutated non-CBF AML than for wild-type NPM1 non-CBF AML (p = 0.001). We also examined the CD33 single-nucleotide polymorphism (SNP) rs12459419, which has been reported to influence the therapeutic efficacy of GO and CD33 expression. The CD33 expression ratio was higher in CD33 SNP C/C than in C/T (83.1% vs. 49.8%, p = 0.035), but 3-year OS and RFS did not differ significantly. These results suggest that consolidation therapy with high-dose cytarabine plus GO is highly effective in transplant-ineligible elderly patients and may be a reasonable treatment, especially for NPM1-mutated AML.

Correlation of ex vivo and in vivo ammonia production with L-asparaginase biological activity in adults with lymphoid malignancies.

Silent inactivation of L-asparaginase (L-Asp) represents rapid clearance of L-Asp by anti-L-Asp IgG antibodies without clinical symptoms. Measurement of L-Asp activity is the gold standard for diagnosis of silent inactivation, but this test is not commercially available in Japan as of 2023. We evaluated ex vivo and in vivo ammonia production in relation to L-Asp activity. Blood samples from ten adult patients treated with L-Asp were collected to measure ammonia levels and L-Asp activity before the first dose and 24 h after the last dose of L-Asp, during each cycle of treatment. Plasma ammonia levels were analyzed immediately and 1 h after incubation at room temperature, and ex vivo ammonia production was defined as the increase in ammonia concentration. Ex vivo ammonia production correlated with L-Asp activity (R2 = 0.741), and ammonia levels measured immediately after blood collection were moderately correlated with L-Asp activity (R2 = 0.709). One patient with extranodal NK/T-cell lymphoma showed an increase in ammonia levels during the first cycle, but no increase in ammonia levels or L-Asp activity after L-Asp administration during the second cycle. Both ex vivo and in vivo ammonia production and surrogate markers are used for L-Asp biological activity.

Histological and immunohistochemical features of gingival enlargement in a patient with AML.

Here, we discuss the pathophysiology of leukemia-associated gingival enlargement based on a case of acute myelomonocytic leukemia (AML-M4) with typical gingival enlargement. Uniquely, this patient was well enough to allow full periodontal examination and incisional gingival biopsy to be performed both before and after chemotherapy. The patient was a 39-year-old Japanese woman with AML-M4 showing gingival enlargement. Histological and immunohistochemical features of gingiva and bacterial counts in the periodontal pockets were examined before and after chemotherapy. The results were as follows: (1) infiltration of myelomonocytic blasts in enlarged gingiva; (2) resolution of gingival enlargement with complete remission of AML by anticancer chemotherapy; and (3) the numbers of bacteria in the periodontal pockets were not high and were not altered before or after chemotherapy. In patients with AML-M4, remarkable mucosal enlargement is not generally observed in the body except in the gingiva. We hypothesized that antigens derived from periodontal bacteria, even if they are not present in large numbers, could act as chemoattractants for myelomonocytic leukemic cells.

Plasmacytoid dendritic cells prime alloreactive T cells to mediate graft-versus-host disease as antigen-presenting cells.

Dendritic cells (DCs) can be classified into 2 distinct subsets: conventional DCs (cDCs) and plasmacytoid DCs (pDCs). cDCs can prime antigen-specific T-cell immunity, whereas in vivo function of pDCs as antigen-presenting cells remains controversial. We evaluated the contribution of pDCs to allogeneic T-cell responses in vivo in mouse models of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation by an add-back study of MHC-expressing pDCs into major histocompatibility complex-deficient mice that were resistant to GVHD. Alloantigen expression on pDCs alone was sufficient to prime alloreactive T cells and cause GVHD. An inflammatory environment created by host irradiation has the decisive role in maturing pDCs for T-cell priming but this process does not require Toll-like receptor signaling. Thus, functional outcomes of pDC-T-cell interactions depend on the immunologic context of encounter. To our knowledge, these results are the first to directly demonstrate an in vivo pathogenic role of pDCs as antigen-presenting cells in an antigen-specific T cell-mediated disease in the absence of other DC subsets and to provide important insight into developing strategies for tolerance induction in transplantation.

Improved outcome of allogeneic bone marrow transplantation due to breastfeeding-induced tolerance to maternal antigens.

Exposure of offspring to noninherited maternal antigens (NIMAs) during pregnancy may have an impact on transplantations performed later in life. Using a mouse model, we recently showed that bone marrow transplantation (BMT) from NIMA-exposed offspring to the mother led to a reduction of graft-versus-host disease (GVHD). Since offspring can also be exposed to NIMAs by breastfeeding after birth, we tested whether breast milk could mediate the tolerogenic NIMA effect. We found that oral exposure to NIMAs by breastfeeding alone was sufficient to reduce GVHD, and that in utero exposure to NIMAs is required for maximum reduction of GVHD. The tolerogenic milk effects disappeared when donor mice were injected with CD25 monoclonal antibodies during the lactation period, suggesting a CD4(+)CD25(+) regulatory T cell-dependent mechanism. Our results suggest a previously unknown impact of breastfeeding on the outcome of transplantation.

Beneficial tyrosine kinase inhibitor therapy in a patient with relapsed BCR-ABL1-like acute lymphoblastic leukemia with CCDC88C-PDGFRB fusion.

BCR-ABL1-like acute lymphoblastic leukemia (ALL) is a neoplasm of lymphoblasts committed to the B-cell lineage that lack the BCR-ABL1 translocation but show a pattern of gene expression very similar to that seen in ALL with BCR-ABL1 with poor prognosis. A 22-year-old female was diagnosed with common-B-cell-ALL positive for CD10, CD19, CD22, CD79a, CD34, HLA-DR, and TdT in January 2017, and achieved complete remission (CR) with induction therapy, followed by consolidation therapy and maintenance therapy. In March 2020, 6 months after the completion of maintenance therapy, she relapsed. Inotuzumab ozogamicin (IO) was administered, and on day 28, bone marrow evaluation showed a morphologic CR. She had an HLA-identical sibling, and transplantation in her 2nd CR was planned. Because her ALL had been identified as BCR-ABL1-like ALL with CCDC88C-PDGFRB fusion, she was treated with imatinib for 2 months accompanied by 2 intrathecal methotrexate therapies, and 1 course of L-asparaginase, vincristine, and prednisolone in an outpatient setting. MRD analysis revealed potent efficacy of 2 months imatinib therapy; IgH MRD decreased from 1 × 10-2 to 1 × 10-3, and CCDC88C-PDGFRB/104ABL from 37.3 to 0. It is earnestly desired that well-designed clinical trials of TKI in ABL class-mutant BCR-ABL1-like ALL be conducted in Japan.

A case of lymphomatoid granulomatosis with central nervous system involvement successfully treated with IFNα.

Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)-driven B-cell lymphoproliferative disease affecting mainly extranodal sites such as the lung, central nervous system (CNS), skin, kidney, and liver. We report a case of low-grade LYG involving the CNS that was successfully treated with interferon alpha (IFNα). A 69-year-old woman developed necrotic erythema of the skin and was initially diagnosed with pyoderma gangrenosum based on skin biopsy. She showed a limited response to prednisolone. Approximately 6 months after the initial onset, low-grade LYG was diagnosed after detection of CNS lesions on brain biopsy. The whole blood EBV-DNA load determined by real-time polymerase chain reaction was slightly elevated. Two months into IFNα therapy, skin and CNS lesions had responded favorably and the EBV-DNA load decreased. IFNα plays an important role in treatment of LYG through its antiproliferative, immunomodulatory, and anti-EBV effects. To our knowledge, this is the first case report of successful treatment with IFNα in Japan. Further investigation is necessary to determine optimal use of IFNα for LYG.