[Successful remission induction with reduced-dose all-trans retinoic acid for acute promyelocytic leukemia complicated by COVID-19].

A 43-year-old man with pancytopenia was diagnosed with acute promyelocytic leukemia (APL). On the first day of induction therapy with all-trans retinoic acid (ATRA) alone, he presented with high fever and was found to have coronavirus disease 2019 (COVID-19) infection by SARS-CoV2 antigen test. While it is generally recommended to delay treatment for APL patients with COVID-19 unless urgent APL treatment is required, this patient needed to continue treatment due to APL-induced disseminated intravascular coagulation (DIC). Considering the challenge of distinguishing between differentiation syndrome (DS) and COVID-19 exacerbation, the ATRA dosage was reduced to 50%. The patient was able to continue treatment without development of DS or exacerbation of DIC, leading to his recovery from COVID-19 and remission of APL.

Tandem autologous stem cell transplantation in elderly patients with myeloma: A multicenter retrospective analysis.

Tandem autologous stem cell transplantation (ASCT) has been reconsidered for high-risk patients with myeloma, and the eligibility criteria for up-front ASCT have been updated to include more elderly patients. This study aimed to evaluate the efficacy and tolerability of tandem ASCT in elderly patients with myeloma compared to tandem ASCT in young patients and single ASCT in elderly patients. A retrospective study using the Transplant Registry Unified Management Program database of the Japanese Society for Transplantation and Cellular Therapy, which included 64 elderly and 613 young patients who received tandem ASCT, and 891 elderly patients who received single ASCT, was conducted. The median overall survival (OS) over 38.5 months in the elderly and young patients who received tandem ASCT, and elderly patients who received single ASCT was 78.9, 92.5, and 77.1 months, respectively; no significant difference in the median OS was observed. The cumulative incidence of transplantation-related mortality was similar in the elderly and young patients receiving tandem ASCT. High-risk cytogenetic abnormality was not identified as a poor prognostic factor for OS in elderly patients who received tandem ASCT but in those who received single ASCT. Thus, tandem ASCT was effective and tolerable in elderly patients with myeloma.

[An elderly patient with lymphoplasmacytic lymphoma successfully treated with low-dose tirabrutinib].

A 93-year-old woman was diagnosed with lymphoplasmacytic lymphoma (LPL) with circulating tumor cells in her peripheral blood after presenting with anemia. LPL progressed eight months later, with anemia worsening and tumor cells increasing to 66% of leukocytes. She began tirabrutinib at a low dose (80 mg daily: 17% of the standard dose) because she preferred to maintain her quality of life (QOL). Within three weeks, she was free of transfusion dependency and had a partial response with the disappearance of peripheral tumor cells. The dosage of tirabrutinib was increased to 240 mg daily because it was well tolerated. She has been on the treatment for 13 months with no adverse effects. Tirabrutinib, a highly selective Bruton's tyrosine kinase inhibitor, has been reported to have promising efficacy for LPL, but it also has a high incidence of dermatological toxicity, which may impair QOL. Low-dose tirabrutinib initiation may be effective and assist elderly patients with LPL in maintaining their QOL.

[Multiple microthromboses with autoimmune hemolytic anemia after BNT162b2 mRNA vaccination].

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.

Plateau is a prognostic factor of lenalidomide therapy for previously treated multiple myeloma.

The plateau phase emerging during the treatment of multiple myeloma (MM) is known to last steadily for a certain period, even without treatment. Therefore, the treatment started at plateau phase is expected to be associated with a better outcome. In this study, this hypothesis was evaluated retrospectively for previously treated MM patients in Kansai Myeloma Forum database who received lenalidomide (LEN) with or without dexamethasone for the first time. Disease stability index (DSI) was defined as (maximum - minimum values of M protein during the 90 days before the start of LEN) divided by M-protein values at the start of LEN. The patients were classified into three groups: stable (S), DSI ≤ 0.25; increasing (I), DSI > 0.25 with increasing M protein; decreasing (D), DSI > 0.25 with decreasing M protein. In univariate analysis of 352 patients, DSI group "I", non-IgG type, serum albumin<3.5 g/dL, and age≥70 were statistically significant prognostic factors for both progression-free survival and overall survival. In multivariate analysis, the former 3 risk factors were statistically significant for poor overall survival. Thus, DSI is an independent prognostic factor for the treatment with LEN for previously treated MM.

[Development of classical Hodgkin lymphoma in a patient receiving tocilizumab for rheumatoid arthritis].

A 66-year-old woman was being treated with methotrexate and etanercept for rheumatoid arthritis (RA). Because her RA symptoms worsened, her medication was changed to tocilizumab (TCZ), and her symptoms improved. However, one year and six months later, she was referred to our hospital because of fever, cervical and para-aortic lymphadenopathy, and massive lesions of the liver/spleen. She was diagnosed with clinical stage IVB mixed cellularity classical Hodgkin lymphoma (cHL) on the basis of right cervical lymph node biopsy. Immunohistochemically, Hodgkin cells were positive for CD20, CD30, PAX-5, LMP-1, PD-L1, and EBER and were negative for CD5, CD15, and EBNA2. Her fever and lymphadenopathy did not improve after the discontinuation of TCZ. Therefore, she was administered ABVd therapy and achieved complete remission (CR) after six cycles of ABVd therapy. She was found to be alive and in CR on regular follow up till February 2021. To the best of our knowledge, there are limited reports of immunodeficiency-related lymphoproliferative disorders associated with TCZ in literature, and our case may be a valuable report on the association of TCZ with the development of cHL in patients with RA.

A multi-center retrospective analysis of patients with relapsed/refractory follicular lymphoma after third-line chemotherapy.

The overall outcome of patients with advanced-stage follicular lymphoma (FL) has improved significantly. However, some patients still develop multiple relapsed/refractory FL (RRFL). To address the still-limited data on this population, we performed this multi-center retrospective study. We analyzed 41 patients who received third-line treatment for RRFL at 8 institutes. The median age at diagnosis was 59 years (range, 38-70). The median progression-free survival (PFS) and probability of PFS at 2 years were 1.61 years and 39.4%, respectively, after third-line chemotherapy, and 0.45 years and 19.0%, respectively, after fourth-line chemotherapy. Objective response (OR) after third-line chemotherapy was achieved in 24 patients (53.7%). Bendamustine (Ben)-based regimens were associated with a significantly higher OR rate than other regimens (77.8% vs. 40.0%, respectively, P = 0.025). The median overall survival (OS) and probability of OS at 2 years were 4.71 years and 65.9%, respectively, after third-line chemotherapy, and 1.01 year and 45.1%, respectively, after fourth-line chemotherapy. In conclusion, this study had a small sample size and retrospective design, but it was able to demonstrate poor response rate and duration in patients with multiple RRFL, particularly after fourth-line chemotherapy. The optimal treatment strategy in this population should be clarified, including possibly hematopoietic stem cell transplantation.

[Sustained Complete Remission after Eradication Therapy in A Helicobacter pylori-Negative Cecum Mucosa-Associated Lymphoid Tissue Lymphoma].

Most primary gastric mucosa-associated lymphoid tissue(MALT)lymphomas are associated with a chronic Helicobacter pylori(H. pylori)infection. The eradication of H. pylori is the first-line treatment for H. pylori-positive cases with early-stage disease. In addition, successful treatment of H. pylori-negative early stage MALT lymphomas by eradication has been reported in several small cases series. However, the association of primary gastrointestinal MALT lymphomas with H. pylori in areas other than the stomach is not clear, and the efficacy of eradication therapy for these patients has not been established. We performed H. pylori eradication therapy for H. pylori-negative cecum MALT lymphoma. Three months later, a histopathological examination showed no evidence of MALT lymphoma, and the patient was classified as being in remission. So far, the patient has been in remission for 1 year and 6 months. Our case is the first report of successfully treating H. pylori- negative cecum MALT lymphoma with eradication therapy.

[Leucovorin Administration Allows Continued Pralatrexate Treatment in a Patient with Angioimmunoblastic T-Cell Lymphoma].

Pralatrexate(PDX)has been approved for the treatment of relapsed/refractory peripheral T-cell lymphoma(PTCL), including angioimmunoblastic T-cell lymphoma(AITL). Oral mucositis is the most common and severe adverse effect of PDX that often leads to dose reduction or omission. Herein, we report a 65-year-old man with AITL, who received PDX treatment after a second relapse. This drug was effective; however, the adverse effects, such as oral mucositis, were severe. Therefore, leucovorin(LV)was administered to prevent the adverse effect, resulting in continuation of the PDX treatment for 8 months. LV administration minimizes adverse effects for patients receiving high-dose methotrexate. However, the optimal dose and schedule of LV in PDX treatment has not yet been established. In the future, clinical trials on the use of LV for PDX-induced oral mucositis are needed.

[Development of chronic myelogenous leukemia during treatment with TPO receptor agonist for ITP].

We report a 77-year-old Japanese man with idiopathic thrombocytopenic purpura (ITP) which developed into chronic myelogenous leukemia (CML) during treatment with eltrombopag, a thrombopoetin (TPO) receptor agonist, because the disease was refractory to prednisolone. Eltrombopag can induce a good reaction in terms of the platelet count. However, CML in the chronic phase developed in about 19 months in our present case. Dasatinib was administered because he had diabetes. However, a blastic crisis immediately occurred. He died despite switching to Nilotinib. Recently, the occurrence of myelofibrosis and hematological malignancies due to long-term use of TPO receptor agonists has become a concern. This is the first report of a TPO receptor agonist possibly contributing to CML onset and crisis.

Tumor lysis syndrome followed by tumor regression after COVID-19 in a patient with chronic lymphocytic leukemia.

Coronavirus disease 2019 (COVID-19) can become lethal in patients with hematological malignancies; however, several cases of tumor regression after COVID-19 have been described, and the precise mechanism behind this paradoxical effect is unknown. Herein, we describe a case of Tumor lysis syndrome (TLS) followed by tumor regression after COVID-19. A 72-year-old woman with untreated chronic lymphocytic leukemia was admitted to our hospital with SARS-CoV-2 antigen-positive pneumonia. On admission, her anti-SARS-CoV-2 spike antibody was negative despite receiving two prior vaccinations. Immediately after admission, she developed confusion and ventricular tachycardia. Laboratory data showed acidosis, hyperkalemia, and a rapid decrease of tumor cells in peripheral blood, and she was diagnosed with clinical TLS. She was transferred to the intensive care unit and received continuous hemodialysis therapy. Although hyperferritinemia and bicytopenia, which suggest a cytokine storm followed, she recovered without steroids and additional COVID-19 treatment in 8 days. 2 months later, CT revealed a marked shrinking of lymphadenopathy, which was compatible with tumor regression after COVID-19. Considering the impaired humoral immunity and abrupt response, direct oncolysis caused by SARS-CoV-2 and cytokine storm-induced cell-mediated immune reaction may have been responsible for this paradoxical effect.

Real-world data on induction therapy in patients with transplant-ineligible newly diagnosed multiple myeloma: retrospective analysis of 598 cases from Kansai Myeloma Forum.

To investigate the real-world clinical outcomes and management of novel drug-containing therapies for newly diagnosed multiple myeloma (MM) patients, we retrospectively analyzed data on the first-line treatment for newly diagnosed transplant-ineligible MM patients from Kansai Myeloma Forum, a registry network in Japan. A total of 598 patients treated with novel drugs between March 2007 and February 2018 were analyzed. Regimens used were VD (n = 305), Rd (n = 103), VMP (n = 97), VCD (n = 71), and VRd (n = 22). Younger patients tended to receive VRd or VCD, whereas the regimen with the highest median patient age was Rd. More than three-quarters of patients in the Rd group received a reduced dose of lenalidomide. The Rd and VRd groups had a relatively high incidence of infection and skin complications, and the VMP group had the highest incidence of peripheral neuropathy. Overall response rate did not differ significantly between regimens. Multivariate analysis in all patients revealed several poor prognostic factors, such as poor performance status. Novel drug-containing regimens for newly diagnosed MM showed a durable response with manageable AEs in the real-world setting.

Phase II study of dose-modified busulfan by real-time targeting in allogeneic hematopoietic stem cell transplantation for myeloid malignancy.

We aimed to evaluate the efficacy and safety of allogeneic hematopoietic stem cell transplantation with targeted oral busulfan (BU) and cyclophosphamide (CY) in a phase II study. Busulfan (1.0 mg/kg) was given initially in six doses. Based on the estimated concentration at steady state after the first dose of BU, subsequent (7th-16th) doses were adjusted to obtain a targeted overall concentration at steady state of 700-900 ng/mL. The primary endpoint was 1-year overall survival (OS). Fifty patients were registered and 46 (median age, 53 years; range, 18-62 years) received planned transplant, including 24 with AML, 16 with myelodysplastic syndrome, and six with CML. Fourteen patients were categorized as standard risk. Nineteen patients received transplant from human leukocyte antigen-identical siblings, 27 from unrelated donors. The BU dose required reduction in 32 patients and escalation in six patients. One-year OS was 65% (95% confidence interval, 50-77%). Cumulative incidence of hepatic sinusoidal obstruction syndrome was 11%. One-year transplant-related mortality was 18%. Both OS and transplant-related mortality were favorable in this study, including patients of older age and with high risk diseases. Individual dose adjustment based on BU pharmacokinetics was feasible and effective in the current phase II study. This trial is registered in the University Hospital Medical Information Network Clinical Trial Registry System (UMIN-CTR, ID:C000000156).

Relationship between donor-specific HPA-15 antibodies and poor graft function in HPA-15 mismatched cord blood transplantation.

Poor graft function (PGF) is a fatal complication following hematopoietic stem cell transplantation and is influenced by multiple factors, such as donor-specific anti-HLA antibodies, a poor infused CD34+ cell count, and the donor source. Alloantibodies against human platelet antigen 15 (HPA-15) recognize platelet membrane glycoprotein CD109, which is expressed not only on platelets, but also on megakaryocytes and specific hematopoietic stem cells. HPA-15 antibodies are known to induce platelet transfusion refractoriness and neonatal alloimmune thrombocytopenia, but their effects on graft function following hematopoietic stem cell transplantation remain unknown. We encountered a case of HPA-15 mismatched cord blood transplantation with a high HPA-15b antibody titer. Prolonged PGF and megakaryocyte aplasia with sustained high-titer HPA-15b antibodies were attenuated by rituximab therapy, and rapid recovery of hematopoiesis was achieved. HPA-15-compatible platelet transfusions were highly effective for platelet recovery. Methylcellulose assays and megakaryocyte cultures revealed that patient serum inhibited in vitro hematopoietic development from patient bone marrow cells. These results suggest that HPA-15 antibodies might be a cause of PGF and that reducing the HPA-15 antibody titer might improve graft function in HPA-15 mismatched transplantation.

[A case of chronic myeloid leukemia occurring during treatment for chronic lymphocytic leukemia].

Since the progression of chronic lymphocytic leukemia(CLL)is long and requires lengthy primary disease management, the risk of double primary cancers and secondary cancer due to treatment has become an issue in western countries with a high incidence of CLL. However, the coexistence with chronic myeloid leukemia(CML)is rare even in the West, and no cases have been reported in Japan. At this time, we would like to report a rare case of CML coexisting during the progression of CLL. The patient was a 68-year-old woman. As she had entered the advanced stage of B-cell chronic lymphocytic leukemia(B-CLL), fludarabine, a purine analog agent, was administered. Two years later, a high-granulocyte dominant white blood cell count began to appear. BCR/ABL analysis by FISH was 97. 6%positive, and the chromosomal test was t(9:22)(q34:q11), so CML was diagnosed. Coexistence of CML in CLL can mainly be classified into three types; CML preceding CLL, CLL preceding CML, and simultaneous occurrence, and the most common, as in this case, long progression CLL preceding CML. At this time, we performed a mainly bibliographical consideration according to the main occurrence type, including the possibility of secondary CML due to fludarabine.

[Definitive diagnosis of intravascular large B-cell lymphoma by random skin biopsy].

A 69-year-old male was admitted to our hospital for high-grade-fever and body weight loss lasting for a few months. In a previous hospital, extensive laboratory examinations and imaging modalities had failed to establish the origin of the fever. On admission he showed mild anemia, and elevated LDH and CRP, together with a high sIL-2R level, suggesting a possibility of lymphoid malignancy without nodal or solid organ involvements, in particular, intravascular large B-cell lymphoma(IVLBCL). A bone marrow biopsy revealed no abnormal findings except minimal hemophagocytosis. A random skin biopsy was then performed, though no detectable skin lesion was seen. The histological results of the skin materials clearly showed a prominent intravascular large lymphoid cell proliferation with a phenotype of CD20+, CD79a+, CD3- and CD5- in the small vessels. On the basis of these findings, a diagnosis of IVLBCL was established and the patient was treated with(R-)CHOP regimen immediately, which resulted in complete remission following two courses of chemotherapy. Difficulties often arise in the diagnosis of IVLBCL when suspicious lesions suitable for biopsy are lacking. Random skin biopsy would therefore be a useful tool if less invasive measures fail.

Donor-derived myelodysplastic syndrome after allogeneic stem cell transplantation in a family with germline GATA2 mutation.

Germline GATA2 heterozygous mutations were identified as complex immunodeficiency and hematological syndromes characterized by cytopenia (monocytes, B-cells, NK-cells), susceptibility to mycobacterium, fungus, or Epstein-Barr virus (EBV) infection, and myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) development. Herein, we report a patient with AML who had a fatal infection after allogeneic hematopoietic stem cell transplantation (HSCT) due to impaired immune reconstitution associated with GATA2 mutation. A 15-year-old man was diagnosed with AML with monosomy 7. His family history was negative for immunodeficiency and hematological disorders. He attained complete remission after HSCT from an HLA-identical sister. Post-HSCT examinations performed 15 months later revealed pancytopenia, especially monocytopenia and the absence of B and NK cells, resulting in the occurrence of donor-type MDS. Twenty-one months after HSCT, he developed central nervous system aspergillosis and finally died of the disease. Two months later (24 months after PBSCT), the donor was diagnosed with persistent EBV infection accompanied by MDS with multilineage dysplasia. Genetic analysis of GATA2 revealed a novel heterozygous mutation (c.1023_1026dupCGCC) in both siblings. GATA2 mutations were highly prevalent among adolescent MDS/AML patients with monosomy 7. Therefore, the screening of GATA2 mutations in relatives is necessary when performing HSCT from a relative donor.

Pretreatment levels of serum soluble interleukin-2 receptor are useful in selecting the treatment regimen for newly diagnosed advanced-stage follicular lymphoma with low tumor burden.

High pre-treatment serum soluble interleukin-2 receptor (sIL-2R) levels are associated with poor overall survival (OS) of patients with newly diagnosed follicular lymphoma (FL). We evaluated the usefulness of pre-treatment sIL-2R levels in selecting a treatment regimen for advanced-stage FL with low tumor burden (FL-LTB). This retrospective, multicenter observational study enrolled consecutive patients who received a rituximab-containing regimen for newly diagnosed advanced stage FL-LTB (grade 1-3a) between 2008 and 2018. We applied a previously reported cut-off value of 1800 IU/mL for sIL-2R. A total of 211 patients were eligible for the analysis. Among patients with high sIL-2R (47 patients, 22.3%), the OS rates for patients treated by rituximab monotherapy (R-mono) (11 patients) were significantly lower than those treated by rituximab-combination chemotherapy (R-chemo) (36 patients): 5-year OS rates were 66.7% and 94.4%, respectively (P = 0.007). Among patients with low sIL-2R (164 patients, 77.7%), OS rates were comparably good between the R-mono group (34 patients) and the R-chemo group (130 patients): 5-year OS rates were 100% and 98.3%, respectively (P = 0.38). Our results suggest that R-chemo may yield better OS than R-mono for patients with newly diagnosed advanced-stage FL-LTB and high pre-treatment serum sIL-2R levels.

Double-Hit Primary Plasma Cell Leukemia with IGH/MYC and IGH/CCND1 Translocations.

Primary plasma cell leukemia (pPCL) is an aggressive variant of multiple myeloma (MM). Immunoglobulin heavy chain (IgH) translocations are found in a majority of pPCL cases, supporting a central relation to pathogenesis of pPCL. However, two independent IgH translocations are barely detected at the onset of pPCL, and their significance is yet to be elucidated. Here, we report a case of an aggressive pPCL with simultaneous IGH/MYC and IGH/CCND1 translocations. A 73-year-old man was referred to our hospital with back pain and diagnosed as having pPCL with more than 50% circulating plasma cells. Cytogenetic analysis revealed 47, Y, t (X; 8;14) (q24; q24; q32), t (11; 14) (q13; q32), and +18. IGH/MYC and IGH/CCND1 translocations were confirmed by fluorescence in situ hybridization analysis. Bortezomib and dexamethasone treatment achieved rapid elimination of peripheral malignant plasma cells, and the patient maintained a partial response for 18 months. After biological relapse, he received salvage therapy with ixazomib, lenalidomide, and dexamethasone, followed by pomalidomide and dexamethasone, and exhibited stable disease for an additional 14 months. Although IGH/MYC translocation in association with dysregulation of antiapoptotic pathway leads to worse prognosis in lymphomas, the novel agent-based regimen showed good efficacy, suggesting that IGH/MYC plays a different role in the pathogenesis of MM. IGH/CCND1 and IGH/MYC translocations may have contributed to abrupt onset of pPCL in this case.

Pretreatment serum soluble interleukin-2 receptor level predicts survival in patients with newly diagnosed follicular lymphoma.

This retrospective, multicenter observational study investigated the prognostic value of pretreatment serum soluble interleukin-2 receptor (sIL-2R) level for outcomes of newly diagnosed follicular lymphoma (FL) grade 1-3a who required treatment at diagnosis. A total of 628 patients were recorded, and 502 of these were eligible for analysis. Patients were divided into four quartiles, based on their serum sIL-2R levels as follows: Q1 (sIL-2R < 520 IU/mL), Q2 (520 ≤ sIL-2R < 1030 IU/mL), Q3 (1030 ≤ sIL-2R < 2530 IU/mL) and Q4 (sIL-2R ≥ 2530 IU/mL). Using a multivariable Cox proportional-hazards model, we showed the adjusted probability of overall survival (OS) decreased with increasing serum sIL-2R levels (p for trend = .007). Similar trends were observed for disease-specific survival (DSS) and progression-free survival (PFS). In conclusion, pretreatment serum sIL-2R levels significantly and dose-dependently associate with worse outcomes (OS, DSS and PFS) of patients with newly diagnosed FL.