Pathological landscape of tumor flare reaction to epcoritamab treatment.

Tumor flare reaction (TFR) is characterized by an increase in lesion size during immune-based therapy, often resembling disease progression. It signifies inflammation at the tumor site and is frequently seen in immunotherapy, where it is termed "tumor pseudoprogression." The exact mechanisms behind TFR remain unclear. We report the case of a 62-year-old Japanese man with relapsed and refractory diffuse large B cell lymphoma treated with epcoritamab. On day 10 of the first epcoritamab cycle, after two subcutaneous injections of epcoritamab, the cutaneous lymphoma lesions became swollen. This was identified as TFR, and was managed with a three-day course of intravenous dexamethasone at 12 mg/day. The third injection, scheduled for day 15, was delayed by 1 week. Four doses of epcoritamab were completed over the initial 35-day period. A skin biopsy was performed on day 30. Histopathological examination showed CD20+ large atypical lymphocytes forming residual nodules, encircled by CD4+ and CD8+ lymphocytes, with a predominance of CD8+ T cells over CD4+ T cells. Although infrequent, TFR may be a significant indicator of tumor response to epcoritamab therapy. The diagnosis of TFR could be underestimated, and proper identification and understanding of its clinicopathological features are crucial for its effective management.

Comprehensive procedure for injecting Evusheld® for hematological diseases in a single institute.

Tixagevimab and cilgavimab (EVA, Evusheld®), monoclonal antibody combination treatments, consisted of two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). EVA showed prophylactic and therapeutic effects against coronavirus disease 2019. The Japanese Society of Hematology recommended EVA for such patients with active treatment, but each institution decided on comprehensive administration. We develop a systematic procedure for comprehensive EVA injection prophylactically in patients with hematological malignancies without any over/under-indication. We listed all patients with the required indications from November 2022 to March 2023. We included 178 cases, 84 females and 94 males, with a median age of 70 (range: 19-90) years. Underlying diseases are myeloid neoplasms in 36 (20%), lymphoid neoplasms in 75 (73%), and others. Indications were intensively hematological malignancy treatment, rituximab treatment within 12 months, burton kinase inhibitor treatment, after chimeric antigen receptor T cell immunotherapy, and after stem cell transplantation in 74 (41%), 73 (41%), 3 (2%), 5 (3%), and 23 (13%) cases, respectively. Of the 178 cases, 22 (12.4%) refused EVA injection. Further, 42 and 136 cases were administered outpatient and inpatient, respectively. Over 95% of the listed cases received EVA injection within 3 months. No severe toxicities were observed among them (N = 156), and 8 (5.2%) cases had breakthrough SARS-CoV-2 infection, which was significantly lower (P = 0.02) than those without EVA (4 [18.2%] of 22 cases). Both groups showed no moderate or severe infection cases. This single-center experience showed that comprehensive EVA injection management effectively generated safer completion with preferable clinical impact.

Graft-versus-host disease after autologous stem cell transplantation in a recipient who underwent allogeneic stem cell transplantation 20 years earlier.

A literature review does not provide information about the safety of autologous hematopoietic stem cell transplantation (HSCT) in a recipient who has previously received allogeneic HSCT. We treated a 69-year-old woman with diffuse large B cell lymphoma. The patient received autologous stem cell transplantation (ASCT) in the second complete remission of malignant lymphoma. The patient had undergone allogeneic hematopoietic SCT (allo-HSCT) for chronic myeloid leukemia 20 years ago. Chronic myeloid leukemia had been in complete remission for the previous 20 years. Thus, the patient received autologous and allogenic HSCT 20 years apart. ASCT involves the patient receiving "self" hematopoietic cells from an allogeneic donor. In other words, this is immunologically the second allo-HSCT. The allo-HSCT 20 years ago was undergone by a related healthy brother, a human leukocyte antigen (HLA) 8/8 full matched donor. The conditioning regimen was reduced-intensity consisting of fludarabine and busulfan. The patient did not experience acute or chronic graft-versus-host disease (GVHD) after allo-HSCT. The second transplantation, ASCT was performed to the MEAM conditioning regimen. Engraftment was uneventful, and complete donor chimerism had been achieved even after ASCT. She suffered from an acute gastric mucosal lesion 52 days after ASCT. Pathological finding of gastric mucosa was nonspecific acute gastritis with significant neutrophil infiltration. Sex chromosome analysis of gastric mucosa demonstrated that mucosal cells had XX signals, whereas infiltrating neutrophils had XY signals. We speculated the patient onset of an acute gastric GVHD in this recipient after the second transplantation. This case remarked infiltration of neutrophils triggered GVHD reaction by resetting allogeneic immune reaction after the second transplantation. We describe a rare occurrence of GVHD reaction in a recipient of ASCT following allo-HSCT.

Clinical effects of tacrolimus blood concentrations early after allogeneic hematopoietic stem cell transplantation.

BACKGROUND AIMS: Tacrolimus (TAC) plus short-term methotrexate (stMTX) is used for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). TAC blood concentrations are frequently adjusted to enhance the graft-versus-leukemia/lymphoma effect or attenuate severe GVHD. Limited information is available on the clinical impact of these adjustments and the optimal time to perform them in order to achieve good clinical outcomes. METHODS: We retrospectively analyzed 211 patients who underwent allo-HSCT at our institutes. RESULTS: Higher TAC concentrations in week 3 correlated with a significantly higher cumulative incidence of relapse (CIR) (P = 0.03) and lower nonrelapse mortality (P = 0.04). The clinical impact of high TAC concentrations in week 3 on CIR was detected in the refined disease risk index: low/intermediate (P = 0.04) and high (P < 0.01), and conditioning regimens other than cyclophosphamide/total body irradiation and busulfan/cyclophosphamide (P = 0.07). Higher TAC concentrations in week 1 correlated with a lower grade 2-4 acute GVHD rate (P = 0.01). Higher TAC concentrations in weeks 2 and 3 correlated with slightly lower (P = 0.05) and significantly lower (P = 0.02) grade 3-4 acute GVHD rates, respectively. Higher TAC concentrations in weeks 1 and 3 were beneficial for severe acute GVHD in patients with a human leukocyte antigen-matched donor (P = 0.03 and P < 0.01, respectively), not treated with anti-thymocyte globulin (P = 0.02 and P = 0.02, respectively), and receiving three stMTX doses (P = 0.03 and P = 0.02, respectively). CONCLUSIONS: The clinical impact of TAC concentrations varied according to patient characteristics, including disease malignancy, conditioning regimens, donor sources, and GVHD prophylaxis. These results suggest that TAC management needs to be based on patient profiles.

Negative Impact of Gemtuzumab Ozogamicin on CD33-Positive Early T-Cell Precursor Acute Lymphoblastic Leukemia: A Case Report.

Introduction: Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a rare subtype of T-cell leukemia that phenotypically expresses mature T-cell markers and immature myeloid markers such as CD33. Gemtuzumab ozogamicin (GO) is a novel agent for the CD33 molecular targeting antibody conjugated to the cytotoxic agent calicheamicin. GO is anticipated to be effective against ETP-ALL. In vivo studies promise antileukemic effects in cell lines; however, clinical reports to support this research are lacking. We treated a patient who suffered from CD33-positive ETP-ALL using GO. Case Presentation: We treated an 81-year-old man who suffered from ETP-ALL. The patient's leukemia expressed T cell and myeloid markers including cyCD3, CD5, CD7, CD33, and HLA-DR. Initially, the patient was treated using a standard chemotherapy regimen for acute lymphoblastic leukemia comprising cyclophosphamide, daunorubicin, vincristine, l-asparaginase, and prednisolone. The induction chemotherapy produced the expected complete hematological response; however, bone marrow blasts remained. Following consolidation chemotherapy, the patient maintained a full hematological response. Thereafter, we changed the consolidation regimen to nelarabine, which did not reduce bone marrow blasts effectively. After two courses of nelarabine therapy, we finally used GO at an 8 mg/m2 weekly dose after confirming that CD33 expression was still positive in the patient's residual leukemic cells. GO was ineffective in treating the patient's leukemia, and peripheral blasts increased 30 days following treatment. The patient died 81 days after initiating GO therapy. Conclusion: This is the first clinical case of GO having a negative impact on ETP-ALL. Because the GO resistance mechanism for ETP-ALL has not been fully elucidated, treatment modification should be considered to achieve optimal clinical efficacy.

Potential factors for and the prognostic impact of ascites after allogeneic hematopoietic stem cell transplantation.

Ascites is sometimes detected after allogeneic hematopoietic stem cell transplantation (allo-HSCT); however, since limited information is currently available, its clinical meaning remains unclear. Therefore, we herein examined potential factors for and the impact of ascites on the prognosis of patients after allo-HSCT at our institutes. Fifty-eight patients developed ascites within 90 days of allo-HSCT (small in 34 (16%), moderate-large in 24 (11%)). A multivariate analysis identified veno-occlusive disease/sinusoidal obstruction syndrome (p = 0.01) and myeloablative conditioning (p = 0.01) as significant potential factors for the development of small ascites. Thrombotic microangiopathy (TMA) (p < 0.01) was a significant potential factor for moderate-large ascites. The incidence of both small and moderate-large ascites correlated with lower overall survival (p = 0.03 for small ascites and p < 0.01 for moderate-large ascites) and higher non-relapse mortality rates (p = 0.03 for small ascites and p < 0.01 for moderate-large ascites). Lower OS and higher NRM rates correlated with the incidence of both small and moderate-large ascites. Further investigation is warranted to establish whether the clinical sign of ascites improves the diagnostic quality of TMA in a large-scale study.

Repeated spontaneous remission of acute myeloid leukemia in response to various infections: a case report.

BACKGROUND: Acute myeloid leukemia (AML) is a progressive hematological malignancy that can be fatal when left untreated. However, spontaneous remission is rarely observed in the presence of infectious diseases. CASE PRESENTATION: We treated an 80-year-old woman with AML who spontaneously underwent remission after infections. Spontaneous remission was observed after each of three independent clinical infections caused by different pathogens-nontuberculous Mycobacterium infection, pulmonary aspergillosis, and Escherichia coli bacteremia. All infections were treated promptly with antimicrobials. Mycobacterium avium infection was treated with azithromycin, rifampin, and ethambutol. Pulmonary aspergillosis was treated with itraconazole followed by voriconazole. E. coli infection was treated with meropenem. During each infectious episode, leukemic cells disappeared from the patient's peripheral blood and pancytopenia improved without routine blood transfusion. These clinical effects lasted for several months. The patient has survived for > 2 years beyond the median survival time of end-stage AML. Thus, this case represents an immunological antileukemic effect of systemic infections. CONCLUSIONS: We have discussed a common mechanism of spontaneous remission of AML without chemotherapy, clinically exhibited by infection immunology. We believe that infections exert a limited immunological effect against AML, which may prolong survival among elderly individuals with AML.

Metabolic Steal of the Myocardium by Primary Cardiac Lymphoma.

Less than 1.0% of malignant lymphomas are primary cardiac lymphoma (PCL), a rare malignant lymphoma. Due to its infrequency, the metabolic dynamics of the treatment have not been completely analyzed. A 62-year-old man who had been complaining of exertional dyspnea for a month arrived at our emergency room. He developed right cardiac failure as a result of a mass in the right atrium, according to a computed tomography (CT) scan. According to an echocardiogram, the mass was obstructing his blood flow and affecting how his heart worked. The lump was pathologically determined to be diffuse large B-cell lymphoma after he underwent urgent heart surgery. The lesion was only localized in the heart, according to a postoperative 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET)/CT scan, indicating that the disease was in clinical stage IE. An 18F-FDG-PET/CT scan showed a thickness of the right atrial wall as residual disease despite the majority of the cardiac lymphomatous mass being removed during surgery; it also showed that the usual uptake of 18F-FDG in healthy myocardium had diminished. Following chemotherapy, 18F-FDG uptake recovered in the patient's normal myocardium of the heart in remission. In conclusion, a sort of "metabolic steal phenomenon" that may be connected to PCL is the difference in uptake between tumor-involved and healthy myocardium.

Prognostic impact of the simple L-index and absolute lymphocyte count early after allogeneic hematopoietic stem cell transplantation.

BACKGROUND AIMS: The L-index, designed as a quantitative parameter to simultaneously assess the duration and severity of lymphopenia, and absolute lymphocyte count (ALC) have a prognostic impact after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, discrepancies have been reported in the impact of ALC, and limited information is currently available on the L-index. METHODS: To search for a better clinical tool, the authors retrospectively compared the simple L-index at 30 days (sL-index(30)), which aims to make the original L-index more compact, and ALC at 30 days (ALC(30)) after allo-HSCT in 217 patients who underwent allo-HSCT at the authors' institutions. RESULTS: Median sL-index(30) was 11 712 (range, 4419-18 511) and median ALC(30) was 404 (range, 0-3754). In a multivariate analysis, higher sL-index(30) was associated with a significantly higher cumulative incidence of relapse (CIR) (hazard ratio [HR], 1.01, 95% confidence interval [CI], 1.00-1.02, P = 0.02 for every increase of 100 in sL-index(30)) as well as non-relapse mortality (NRM) (HR, 1.02, 95% CI, 1.00-1.03, P = 0.01 for every increase of 100 in sL-index(30)). Although higher ALC(30) was associated with significantly lower CIR (HR, 0.94, 95% CI, 0.89-1.00, P = 0.04 for every increase of 100/µL in ALC(30)), it was not extracted as an independent risk factor for NRM (HR, 0.96, 95% CI, 0.88-1.05, P = 0.39). Higher sL-index(30) was associated with a slightly higher rate of grade 3-4 acute graft-versus-host disease (GVHD) (HR, 1.02, 95% CI, 1.00-1.04, P = 0.12 for every increase of 100 in sL-index(30)) but not chronic GVHD (HR, 1.00, 95% CI, 0.99-1.01, P = 0.63). ALC(30) was not associated with rates of grade 3-4 acute GVHD (HR, 1.02, 95% CI, 0.88-1.17, P = 0.81) or chronic GVHD (HR, 1.02, 95% CI, 0.98-1.06, P = 0.34). In a receiver operating characteristic curve, the cutoff values of sL-index(30) and ALC(30) for CIR were 9000 and 500, respectively, and the cutoff value of sL-index(30) for NRM was 12 000. CONCLUSIONS: sL-index(30) is a promising tool that may be applied to various survival outcomes. A large-scale prospective study is needed to clarify whether medical interventions based on sL-index(30) values will improve the clinical prognosis of patients.

Cost-Effectiveness Analysis of Transplantation-Ineligible Elderly Patients With Acute Leukemia Harboring a Molecular Target: Ph-Positive Acute Leukemia and FLT3-Mutated Acute Myeloid Leukemia.

Background: Tyrosine kinase inhibitors (TKIs) and FMS-like tyrosine kinase 3 (FLT3) inhibitors are promising agents for Ph-positive acute leukemia (Ph+ AL) and FLT3 mutated acute myeloid leukemia (FLT3-AML), respectively. Methods: We examined the cost-effectiveness ratio (CER) of dasatinib and ponatinib for Ph+ AL and the cost-effectiveness of gilteritinib and quizartinib for FLT3-AML in elderly patients. Molecular therapy can fit the elderly population better than chemotherapy (CT). Results: The daily drug cost of dasatinib, ponatinib, gilteritinib, and quizartinib was $240, $170, $524, and $479 in terms of treatment maintenance dose, respectively. Treatment of Ph+ AL with stem cell transplantation (SCT), CT, dasatinib, and ponatinib yielded CERs of $322,375, $34,928, $61,104, and $46,234, respectively. The CERs for FLT3-AML treated with SCT, CT, gilteritinib, and quizartinib were $355,270, $42,717, $94,987, and $90,080, respectively. Treatment of elderly patients with TKIs and FLT3 inhibitors remained expensive and inferior to conventional CT. Conclusion: Although TKIs and FLT3 inhibitors have an inferior CER than does conventional CT, their promising survival benefit with better QOL can offer a profound advantage. TKI or FLT3 inhibitor monotherapy is recommended as an alternative treatment option for unfit (vulnerable) elderly patients with Ph+ AL or FLT3-AML.

Application of PD-L1 blockade in refractory histiocytic sarcoma: A case report.

Histiocytic sarcoma (HS) is a rare hematological malignancy, which exhibits morphological and immunophenotypic features of histiocytes. A standard therapy for HS has not yet been established due to its rareness; therefore, disease control is not always possible. A multimodal treatment strategy has been suggested for HS. The present study reported on a case of a 43-year-old female patient who complained of left femoral pain, which was caused by left femoral bone mass. A biopsy of their left femoral bone tumor revealed that the patient had HS. Their sarcoma was localized in the femoral bone and was not considered to be curable, due to local infiltration of the bone tumor beyond the periosteum. The patient then underwent two types of HS-specific chemotherapy; however, both regimens were ineffective. As a result, they underwent radiation therapy at the sites of progressive disease. Because the HS cells of the patient expressed PD-L1, they were treated with nivolumab (240 mg/body, biweekly) for residual diseases in the right occipital bone, multiple lung nodules, intrapelvic right lymph node and primary site. Nivolumab treatment resulted in a complete response at all sites, with the exception of the primary site, which was confirmed by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography. The patient received additional nivolumab treatment as consolidation therapy for 1 year. In addition, residual disease of the femoral head was completely resected. The surgically resected refractory tumor revealed the tumor cells no longer pathologically expressed PD-L1 . In conclusion, for refractory and recurrent HS in which surgical resection is not appropriate, treatment with immune-checkpoint inhibitors, such as nivolumab, may be considered an optional but promising immunotherapy if the tumor histologically expresses PD-L1. The present study detected one of the refractory mechanisms of ICI treatment.

Distinct Characteristics of Sweet's Syndrome of the Scrotum Caused by All-trans Retinoic Acid in a Patient with Acute Promyelocytic Leukemia.

Induction therapy with all-trans retinoic acid (ATRA) is effective for acute promyelocytic leukemia (APL). ATRA induces neutrophil differentiation and its associated side effects. The differentiation syndrome is the most characterized ATRA-induced adverse effect. Sweet's syndrome, also known as neutrophilic dermatosis, is another form of ATRA-associated disease characterized by neutrophil infiltrating erythema that develops with fever. This is a case of a 34-year-old Japanese man diagnosed with APL. At the onset, the patient did not have skin involvement of APL cells. He was treated with ATRA and induction chemotherapy with idarubicin and cytarabine. Scrotal skin rash occurred at day 14, which developed into scrotal ulceration up to day 28 even after eliminating APL cells in his peripheral blood. Sweet's syndrome is a pathological diagnosis of scrotal skin ulceration representing neutrophil infiltration. The infiltrating neutrophils showed PML-RARα rearrangement. The patient was diagnosed with ATRA-associated Sweet's syndrome with skin ulcer. His cutaneous lesion did not respond to intravenous prednisolone therapy; thereby, ATRA was discontinued. After the cessation of ATRA, the skin lesion improved in the next week. We confirmed he achieved a complete response after induction chemotherapy. In our observation, ATRA-associated Sweet's syndrome is characterized by the following clinical manifestations: preferable occurrence in the scrota, tend to progress into skin ulcer, and pathogenicity associated with PML-RARα-positive matured neutrophils. The etiology, pathogenesis, and risk factors of ATRA-associated scrotal ulceration were discussed in the literature review.

Risk Factors for and the Prognostic Impact of Pericardial Effusion after Allogeneic Hematopoietic Stem Cell Transplantation.

Pericardial effusion (PE) is a rare complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although the mechanisms underlying the onset of PE remain unclear, patients with PE after allo-HSCT have poor clinical outcomes. However, the prognostic impact of PE remains controversial, and risk factors have varied among studies. Therefore, we examined contributing as well as prognostic factors for PE. We retrospectively examined 243 patients who underwent allo-HSCT at the Faculty of Medicine, Kagawa University and Takamatsu Red Cross Hospital, Kagawa, Japan between 2000 and 2020. Forty-three patients (18%) were excluded owing to a lack of data on PE, and thus we ultimately analyzed 200 patients. We reviewed the findings of computed tomography (CT) scans, including chest CT, and echocardiography after allo-HSCT. Only cases in which a radiologist or echocardiography technician detected PE were assessed. PE was stratified into localized PE and whole-circumference PE. The median age at transplantation was 52 years (range, 16 to 74 years). The study cohort comprised 106 patients (53%) age more than 50 years, 88 females (44%), and 112 males (56%). Primary diseases were myeloid neoplasms in 122 patients (61%) and lymphoid neoplasms in 78 (39%). The conditioning regimen was myeloablative in 142 patients (71%) and nonmyeloablative in 58 (29%). The median duration of follow-up was 47 months (range, 1 to 209 months). Forty patients developed PE within 100 days; localized in 23 (12%) and whole circumference in 17 (9%). In a multivariate analysis, significant risk factors for the development of PE within 100 days were late neutrophil engraftment (hazard ratio [HR], 5.24; 95% CI, 1.92 to 14.30; P < .01) and thrombotic microangiopathy (TMA) (HR, 8.23; 95% CI, 1.42 to 47.60; P = .02). The incidence of whole- circumference PE correlated with a lower overall survival (OS) rate (HR, 3.10; 95% CI, 1.34 to 7.17; P < .01) and higher nonrelapse mortality (NRM) rate (HR, 2.94; 95% CI, 1.18 to 7.32; P = .02). In the subgroup analysis, significant risk factors for the development of PE within 365 days were late neutrophil engraftment (HR, 3.13; 95% CI, 1.08 to 9.02; P = .04), the occurrence of chronic graft-versus-host disease (GVHD) (HR, 3.57; 95% CI, 1.19 to 10.70; P = .02), and disease recurrence (HR, 4.98; 95% CI, 1.43 to 17.30; P = .01). The development of whole-circumference PE also correlated with a lower OS rate (HR, 3.83; 95% CI, 1.65 to 8.89; P < .01) and a higher NRM rate (HR, 83.21; 95% CI, 17.75 to 390.10; P < .01). The overall occurrence of acute (grade II to IV) GVHD, chronic GVHD, and TMA were 36% (72 of 200), 39% (78 of 200), and 10% (19 of 200), respectively. In the entire cohort, the 3-year OS rate was 55%, and 3-year relapse and NRM rates were 37 and 14%, respectively. The present results demonstrate that risk factors for PE varied according to the time after allo-HSCT, and that whole-circumference PE at any time correlated with lower OS and higher NRM rates. A large-scale prospective study is needed to verify risk factors for PE and clarify whether immunosuppressive interventions based on the onset of PE improve the clinical prognosis of patients.

Correction to: Histologic transformation of t(11;18)-positive MALT lymphoma presented with aberrant T-cell marker expression.

M. Nishikori receives honoraria from Eisai and funding from Eisai and Sumitomo Dainippon Pharmaceutical.

Histologic transformation of t(11;18)-positive MALT lymphoma presented with aberrant T-cell marker expression.

Mucosa-associated lymphoid tissue (MALT) lymphoma with t(11;18)(q21;q21), resulting in an API2-MALT1 fusion transcript, is reported to rarely transform into aggressive lymphoma. Here, we report the clinical course of a patient who experienced histologic transformation after 20 years' disease history of t(11;18)-positive MALT lymphoma. The patient suddenly developed a large intrapelvic mass and ascites with a rapid increase in lactate dehydrogenase. Cytology of the ascites detected large abnormal cells, and flow cytometric analysis revealed that the cells were positive for cytoplasmic CD3, CD4, and CD38, and partially positive for CD7, but negative for CD19 and CD20. Antigen receptor gene rearrangement analysis and in situ hybridization of the immunoglobulin light chains confirmed that the tumor cells were of B-cell lineage. Chromosomal analysis showed complex karyotypes with intraclonal variation, and in addition to t(11;18), t(8;14) and heterozygous loss of the TP53 were demonstrated. Although histological and phenotypic features were significantly altered from the original MALT lymphoma, the presence of t(11;18) led us to the diagnosis of histologic transformation of MALT lymphoma. Although transformation of t(11;18)-positive MALT lymphoma into aggressive lymphoma is extremely rare, it may occur, probably with additional genetic abnormalities such as cMYC rearrangement and/or the loss of TP53.