Posttransplantation cyclophosphamide mediates effective reconstitution of memory B cells after allogeneic hematopoietic cell transplantation.

OBJECTIVES: Impaired B-cell reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT) contributes to the pathogenesis of chronic graft-versus-host disease (cGVHD). Therefore, methods to consistently achieve effective B cell lymphogenesis are required. We assessed the long-term effects of posttransplantation cyclophosphamide (PTCy) use on immune reconstitution in clinical settings, an emerging strategy to suppress allogeneic immunological inflammation early after allo-HCT and prevent subsequent GVHD. METHODS: We comprehensively analyzed peripheral immune cell subsets and measured serum immunoglobulin G (IgG) or cytokine levels in 39 patients who survived for >1 year after allo-HCT. RESULTS: The absolute counts of B1 and IgM memory B cells were significantly lower in patients with severe cGVHD than in those without. The absolute count and percentage (among total CD19+ B cells) of switched memory B cells and serum IgG levels were significantly higher in patients transplanted with PTCy than in those transplanted with conventional GVHD prophylaxis. Interestingly, increased percentages of switched memory B cells and serum IgG levels were observed only in patients transplanted with PTCy and not in those transplanted with umbilical cord blood. CONCLUSIONS: PTCy administration can mediate favorable memory B-cell reconstitution long after allo-HCT and may therefore suppress cGVHD.

[Usefulness of web-based application for health surveys before and after peripheral blood stem cell harvest from healthy donors].

Health surveys to assess adverse events after peripheral blood stem cell harvest (PBSCH) have conventionally been conducted by phone, but phone calls are suboptimal for conducting frequent surveys. We developed a web-based application (donor app) that enables donors to inform healthcare professionals (HCPs) of their health status as an electronic patient-reported outcome (ePRO). In this prospective observational study, we compared the usefulness of this donor app to phone calls for conducting health surveys. App users reported ePRO daily, and patients called by HCPs reported their health status at least once a week when called. The observation period was from the first administration of granulocyte colony-stimulating factor to the first follow-up visit after PBSCH, excluding the hospitalization period. Each group consisted of eight donors with a median age of 32 years (range: 19-58). Nine (56.3%) were female. There were eight related donors in the phone call group and four in the donor app group. During the observation period, HCPs obtained health status reports more frequently from app users than from phone call recipients (mean proportion of days with reports made during the observation period, 27.0% vs 53.5%; p<0.05). Average time spent by the HCPs for one follow-up and total follow-ups were both significantly shorter when the donor app was used. There were no differences in donor burden or satisfaction with donation. Our study suggests that use of a donor app could provide more detailed health survey data without increasing the burden on donors and HCPs.

[Retrospective Analysis of Bortezomib or Lenalidomide for Very Elderly Patients with Newly Diagnosed Multiple Myeloma].

In elderly patients aged≥80 with newly diagnosed multiple myeloma(NDMM), the optimal initial doses of bortezomib (Bor)and lenalidomide(Len)remain unclear. We performed a retrospective analysis that included 20 patients with NDMM aged≥80 years who underwent treatment with Bor or Len at our hospital from July 2010 to December 2019. Among the patients treated with Bor, the median time to next treatment(TTNT)was 4.2 months, and the median dose was 1.0 mg/m2 per injection. While patients with International Staging System(ISS)Ⅲ or an estimated glomerular filtration rate of < 40 mL/ min/1.73 m2 required dose reductions, dose intensity did not significantly affect TTNT. Among the patients treated with Len, the median TTNT was 14.6 months, and the median dose of Len was 10.0 mg/day. All patients who started with6le;10 mg Len continued the initial dose; the others required a dose reduction. Treatment was discontinued in 2 patients because of disease progression and in other 15 patients because of adverse events(AEs). In conclusion, initial doses of Bor at 1.0 mg/ m2 per injection and Len at 10 mg per day may provide potent disease control and permit continuing treatment with few AEs in elderly patients with MM.

[Human herpes virus 8-negative primary effusion lymphoma-like lymphoma recurring as a tumor adjacent to the left atrium].

Primary effusion lymphoma (PEL) is a rare type of non-Hodgkin lymphoma, usually presenting as serous effusions without detectable tumor masses, and it is universally associated with the human herpesvirus 8 (HHV8). In contrast, cases of HHV8-negative effusion lymphoma have been reported and termed as HHV8-negative PEL-like lymphoma. Here, we have reported a rare case of HHV8-negative PEL-like lymphoma that developed in the left atrium tumor 4 years after the pericardial drainage. A 74-year-old female was admitted due to cardiac tamponade caused by massive pericardial effusion. Pericardial drainage was performed, and cytopathologic examination of the fluid revealed atypical lymphoid cells consistent with an effusion lymphoma of B-cell lineage. The pericardial effusion was completely drained, and complete remission was achieved. After 4 years of the drainage, she developed syncope caused by arrhythmia. A computed tomography scan revealed a large tumor in the left atrium and multiple swollen mediastinal lymph nodes. Biopsy of one of the lymph nodes was performed, and its histology was consistent with diffuse large B-cell lymphoma. She was treated with chemotherapy, including rituximab, and complete remission was achieved again. Thus, our experience suggests that careful follow-up may be required in patients with HHV8-negative PEL-like lymphoma after complete remission has been achieved by the drainage.

[Durable remission of Langerhans cell sarcoma attained by autologous hematopoietic stem cell transplantation following surgical resection].

Langerhans cell sarcoma (LCS) is a rare neoplastic proliferation of Langerhans cells with a poor prognosis. Owing to its rarity, standard treatment for LCS has not been established to date. Here, we report a case of LCS occurring in multiple lymph nodes in the right cervix in which remission is maintained by autologous hematopoietic stem cell transplantation (auto-HSCT) after surgical resection. A 58-year-old male presented with enlarged right submandibular lymph nodes. Positron-emission tomography/computed tomography (PET/CT) revealed multiple lymphadenopathies in his right cervix. We performed a lymph node biopsy, and he was diagnosed with LCS. We selected the CHOP regimen as the first-line chemotherapy; however, rapid disease progression was observed soon after the first cycle of the therapy. The neck dissection was performed on day 16 of the CHOP therapy. As the residual tumor was suspected, we started the second-line chemotherapy with a combination of etoposide, cisplatin, ifosfamide, and gemcitabine; complete remission was confirmed by PET/CT. Subsequently, the patient was administered high-dose chemotherapy with auto-HSCT. After 2 years of auto-HSCT, complete remission has been maintained. Although there is no report of auto-HSCT for LCS, it could be an effective therapeutic tool for the disease.

Validation of previous prognostic models for thrombosis and exploration of modified models in patients with essential thrombocythemia.

OBJECTIVE: We examined the prognostic factors to validate previous prognostic models for survival and thrombosis with large-scale data on Japanese patients with essential thrombocythemia (ET). METHOD: We conducted a study in 352 patients with ET to validate previous prognostic models and search for new prognostic factors. RESULTS: The International Prognostic Score for essential thrombocythemia (IPSET), the conventional risk classification and the International Prognostic Score for thrombosis in essential thrombocythemia (IPSET-T) were confirmed to be reproducible in Japanese patients. However, no significant difference was observed between the low-risk and intermediate-risk categories according to the revised IPSET-T, which does not allow direct comparison of the four risk groups. We reevaluated the risk using a modified revised IPSET-T, which was derived from the revised IPSET-T by scoring the factors as follows: one point for age > 60 years, two points for past history of thrombosis, two points for JAK2 gene mutation-positive; total points of 0 = very low risk, 1 =  low risk, 2 =  intermediate risk, 3 and above = high risk, with significantly different thrombosis-free survival. CONCLUSION: The modified revised IPSET-T has been useful for 4-group stratification to predict a population that requires therapeutic intervention, irrespective of the treatment regimens.

[Long-term remission with mogamulizumab monotherapy in a patient with refractory adult T-cell leukemia-lymphoma].

A 73-year-old female with malaise, anorexia, and hydrodipsia was referred to our department. Peripheral blood tests revealed leukocytosis with 51% blast cells exhibiting flower-shaped nuclei. Flow-cytometry to detect tumor cells in peripheral blood indicated CD3+, CD4+, CD8-, and CD25- expression, but those in the lymph nodes expressed CD25+. Southern blots revealed clonal HTLV-1 provirus in the tumor cells, consistent with adult T-cell leukemia-lymphoma. Cytotoxic chemotherapy was ineffective, but eight cycles of mogamulizumab induced complete remission (CR). A relapse lesion appeared on the right breast but disappeared spontaneously. The patient has currently maintained CR for over five years.

Peripheral T-cell lymphoma, not otherwise specified accompanied by central nervous system involvement with features of lymphomatosis cerebri.

Lymphomatosis cerebri (LC) is a rare variant of primary central nervous system lymphoma, and it is characterized by diffuse cerebral infiltration of malignant lymphoma cells without evidence of a mass lesion. Herein, we report a patient with systemic peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) who had central nervous system involvement mimicking LC. A 72-year-old immunocompetent male presented with rapidly progressive dementia. Fluor-deoxy-glucose (FDG) -positron emission tomography revealed increased FDG uptake in the bone and skin. Histopathological examination of the skin lesion revealed PTCL-NOS infiltration. A FLAIR MRI scan of the brain revealed diffuse hyperintense lesions in the cerebral white matter of both hemispheres. These lesions were not enhanced with gadolinium, and there was no perceptible mass effect. We performed a brain biopsy, and the histology results were consistent with PTCL-NOS. The patient was treated with corticosteroid and chemotherapy; however the disease progressed, and he died 4 months after the diagnosis. This was a rare case of systemic lymphoma accompanied with central nervous system involvement mimicking LC.

Analysis of elderly patients with diffuse large B-cell lymphoma: aggressive therapy is a reasonable approach for 'unfit' patients classified by comprehensive geriatric assessment.

BACKGROUND: The treatment strategy for diffuse large B-cell lymphoma (DLBCL) in elderly patients is problematic. Although several researchers have reported the effectiveness of comprehensive geriatric assessment (CGA) and the futility of curative treatment in 'unfit' patients with DLBCL, these propositions are not firmly established. PATIENTS AND METHODS: We conducted a retrospective analysis using a database. Patients with DLBCL were eligible if ≧ 60 yr old. CGA stratification was performed using medical records. RESULTS: One hundred and 35 patients were identified. Anthracycline-based chemotherapy with curative intent was performed in 115 (85%) patients. According to CGA, 82 (61%) patients were classified as 'fit'. Their 1-yr overall survival (OS) was significantly better than that of 'unfit' patients [91.3% vs. 53.8%, P < 0.001]. Patients classified as 'unfit' treated with curative intent had a significantly better 1-yr OS when compared with those receiving palliative measures [66.1% vs. 19.0%, P < 0.001]. CONCLUSIONS: CGA is an effective tool for predicting outcomes in older patients with DLBCL. The patients treated with curative intent had significantly better outcomes compared with those receiving palliation, irrespective of CGA stratification. Curative treatment should be considered even for 'unfit' patients.

[Double-Hit Follicular Lymphoma with BCL2 and MYC Translocations].

Double-hit lymphomas are rare tumors that are defined by a chromosomal breakpoint affecting the MYC/8q24 locus in combination with another recurrent breakpoint, mainly a t(14; 18)(q32;q21)involving BCL2. We report a case of a 38-yearold woman with a 2-month history of abdominaldistention. 18F-FDG PET showed multiple positive systemic lymph nodes, positive peritoneum, and multiple positive intra-abdominal masses. Histopathology results of the cervical lymph node were compatible with double-hit follicular lymphoma(Grade 3A)because fluorescence in situ hybridization(FISH)demonstrated both MYC rearrangement and BCL2 gene fusion. She was initially started on R-CHOP(rituximab and doxorubicin, vincristine, cyclophosphamide, and prednisolone), but after one course the regimen was changed to dose-adjusted EPOCH-R(rituximab and doxorubicin, etoposide, vincristine, cyclophosphamide, and prednisolone). However, she showed no response to this chemotherapy regimen or haploidentical stem cell transplantation. The treatment strategy included salvage chemothera- py. An autologous and/or allogeneic hematopoietic transplantation is important for non-responders to DA-EPOCH-R.

[Peripheral T-Cell Lymphoma, Not Otherwise Specified Occurring After the Treatment of Relapsed Follicular Lymphoma].

A 77-year-old-man was diagnosed with follicular lymphoma (FL), grade 3A. After six courses of R-THP-COP (rituximab, pirarubicin, cyclophosphamide, vincristine and prednisolone) therapy, he achieved complete remission (CR). He achieved a second CR after radiotherapy, a third CR after six courses of bendamustine /rituximab (BR) therapy, and a fourth CR after six courses of BR therapy. However 2 months after the last chemotherapy, his tumor progressed rapidly and he died. Autopsy results showed medium and large lymphoid cells with pleomorphic, irregular nuclei and prominent nucleoli infiltrated in multiple lymph nodes, the liver, the lung, and the spleen. The lymphoid cells were positive for CD3, CD8, granzymeB, TIA-1 and negative for CD4, CD20, CD79a, CD10, and CD56. Autopsy diagnosis was peripheral T-cell lymphoma, not otherwise specified. Occurrence of lymphoma in T-cell lineage should be considered, if the course of low-grade B-cell lymphomas, such as FL rapidly progresses.

[Cutaneous extramedullary hematopoiesis associated with myelodysplastic/myeloproliferative neoplasm, unclassifiable].

Cutaneous extramedullary hematopoiesis has been reported in a small number of patients with myelofibrosis. A 79-year-old male with JAK2V617F-positive myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS-MPN-U), presented with multiple skin lesions. The skin lesions were papulonodular, reddish brown, and elastic hard on palpation. Based on a lesion biopsy, cutaneous extramedullary hematopoiesis associated with MDS/MPN-U was diagnosed. He died four months later due to exacerbation of MDS/MPN-U. Cutaneous invasion might be associated with progressive disease and a poor prognosis for MDS/MPN-U, as it is for myelofibrosis.

[Leukostasis during Chronic Myelogenous Leukemia Resolved Following Leukapheresis].

Patients with hyperleucocytic leukemia (WBC count>10×10(4) mL) are at high risk of early mortality owing to pulmonary or cerebral leukostasis. Several researchers have reported the efficacy of immediate leukapheresis. Here, we report of a patient with chronic myelogenous leukemia in blast crisis and with pulmonary failure due to leukostasis who recovered after a combination therapy of leukapheresis and imatinib treatment.

Efficacy and safety of low-dose imatinib in an elderly patient with mixed phenotype acute leukemia with t(9;22)(q34;q11.2);BCR-ABL1.

Low-dose imatinib with monitoring of drug concentrations in blood may successfully control Philadelphia chromosome-positive mixed phenotype acute leukemia (Ph+MPAL), particularly in elderly patients with comorbidities.

Extracorporeal Membrane Oxygenation with rituximab-combined chemotherapy in AIDS-associated primary cardiac lymphoma: A case report.

Although effective combination of antiretroviral medications is being developed, the incidence of non-Hodgkin lymphoma (NHL) with human immunodeficiency/acquired immunodeficiency syndrome (HIV/AIDS) still remains significantly higher than that in individuals without infection. Primary cardiac lymphoma (PCL) is an NHL that involves the heart and/or the pericardium. PCL is very rare and often causes serious complications, which can be a diagnostic challenge. To our knowledge, no study has reported the measurement of rituximab concentration under venoarterial extracorporeal membrane oxygenation (VA-ECMO). Herein, we report the case of a 54-year-old male patient with AIDS-associated primary cardiac NHL who developed right ventricular outflow tract obstruction. The patient experienced fatigue and dyspnea on exertion. Contrast-enhanced computed tomography showed a bulky tumor mass in his right atrium and ventricle, and an echocardiogram revealed severe hypokinesis of his heart and poor cardiac output. A biopsy was performed, and immunohistochemistry revealed diffuse large B-cell lymphoma. Therefore, he was treated with rituximab-combined chemotherapy under VA-ECMO. Blood levels of rituximab were measured during chemotherapy with VA-ECMO. Thereafter, he was temporarily discharged from the hospital. This clinical case suggests that VA-ECMO and rituximab-combined chemotherapy are useful in rescuing patients with severe cardiopulmonary failure due to AIDS-associated PCL.

Importance of diagnosis-to-treatment interval in newly diagnosed patients with diffuse large B-cell lymphoma.

Treatment of patients with malignancy sometimes be delayed due to various reasons. Several studies revealed that an influence of diagnosis-to-treatment interval (DTI) on outcomes differs depending on the type of malignancy. In this study, we evaluated the influence of DTI on clinical outcomes in newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL). A total of 199 patients were identified with a median DTI of 22 days. At 2 years, patients with short DTI (0-22 days) showed significantly poorer OS (62.7% vs 86.4%) and PFS (55.1% vs 75.9%) compared to those with long DTI (over 22 days). Although short DTI was strongly correlated with several known adverse factors, it remained to be an independent prognostic factor by multivariate analysis. In conclusion, our study confirmed the importance of DTI in patients with DLBCL. Researchers should consider DTI as one of the important prognostic factors and plan clinical trials to be able to enroll patients with aggressive disease requiring urgent treatment.

Diagnosis of a difficult to differentiate case of early-onset hyperviscosity syndrome caused by IgM type multiple myeloma: a case report.

Hyperviscosity syndrome (HVS) can cause multiple organ damage if not treated immediately. IgM multiple myeloma (IgM MM) is a very rare form of myeloma with clinical features such as elevated serum IgM, and anemia, that resemble Waldenström macroglobulinemia (WM). Distinguishing between these two diseases is important, but can be a challenging problem. It is well known that MyD88 mutations and t(11;14) translocations are useful for differential diagnosis. We diagnosed HVS in a 29-year-old male with IgM MM. He was treated with triplet therapy, autologous hematopoietic stem cell transplantation, and carfilzomib consolidation therapy. His clinical course was monitored by serum IgM levels, and bone marrow myeloma cell counts by multiparameter flow cytometry analysis. After this series of treatments, his HSV disappeared and he reached stringent complete response. In cases of early onset of HVS, IgM MM should be considered in addition to WM.

Hodgkin-like adult T-cell leukemia/lymphoma that developed during the follow-up of HTLV-1 associated myelopathy/tropical spastic paraparesis.

Hodgkin-like adult T-cell leukemia/lymphoma (ATLL) is a rare variant of ATLL, which represents the early neoplastic phase of ATLL that follows an indolent clinical course compared with typical ATLL. Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurological disorder characterized by the paralysis of lower limbs and urinary disturbance. Although these diseases are caused by HTLV-1 infection, there are no reports describing the coexistence of Hodgkin-like ATLL and HAM/TSP. Here, we report the first case of Hodgkin-like ATLL complicated by HAM/TSP. The patient was a 56-year-old man with right inguinal lymphadenopathy who had been using the neurology outpatient service for 13 years after being diagnosed with HAM/TSP. He was unable to receive intensive chemotherapy or allogeneic stem cell transplantation due to a poor performance status, but his condition was stable for approximately two years.