[Listeria meningitis during daratumumab/bortezomib/dexamethasone therapy in a patient with multiple myeloma].

An 88-year-old woman was diagnosed with multiple myeloma received third-line chemotherapy, including DBd (daratumumab [DARA], bortezomib, and dexamethasone [Dex]), and the myeloma was in remission. Sulfamethoxazole/trimethoprim (ST) prophylaxis was discontinued because the dose of Dex was reduced to 20 mg every 4 weeks after 21 cycles of DBd. After 28 cycles of DBd, altered consciousness with fever ensued, and she was referred to the emergency department where Listeria monocytogenes (LM) meningitis was diagnosed. CD38 inactivation is associated with increased LM susceptibility. In patients on Dara-based chemotherapy, antibiotic prophylaxis should be considered using ST, which has activity against Listeria.

[Acquired thrombotic thrombocytopenic purpura following COVID-19].

COVID-19 often contributes to thrombus formation in microvessels, resulting in damaged vital organs. In this study, we report a case of COVID-19 associated with acquired thrombotic thrombocytopenic purpura (TTP). A 44-year-old man with a history of systemic lupus erythematosus presented with COVID-19 and concomitant hemolytic anemia and a marked thrombocytopenia. The patient was diagnosed with acquired TTP because ADAMTS13 inhibitor was detected and ADAMTS13 activity below the sensitivity level. The patient developed agitated neuropsychiatric symptoms, such as aphasia, disorientation, and delirium, which improved after a plasma exchange, prednisolone, and rituximab administration. Only a few reports have revealed COVID-19 with TTP, and this is the first case in Japan. Although acquired TTP rarely develops, it is an important complication of COVID-19, and thus, it should be promptly diagnosed and treated as soon as possible.

[Extranodal NK/T cell lymphoma, nasal type with local recurrence in the contralateral nasal cavity 15 years after initial sequential chemoradiotherapy].

A 72-year-old woman was diagnosed with extranodal NK/T cell lymphoma of the right nasal cavity and received sequential radiochemotherapy comprising focal radiotherapy and THP-COP chemotherapy. Showed a complete tumor response to the treatment; however, the tumor recurred in the contralateral right nasal cavity 15 years after the initial treatment. This was judged to be a marginal recurrence in the radiation field. After four cycles of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy, a second complete response was achieved. It is possible that another recurrence occurs in the future, and if the lesion is localized at the time of recurrence, it may be possible to control the disease again. Careful follow-up is considered necessary.

[Successful treatment with imatinib for a patient with myeloid neoplasms with eosinophilia and abnormalities of PDGFRB due to t (5;14)(q33;q22)].

A 50-year old man with a 1-year history of eosinophilia presented with an eosinophil count exceeding 13,800/mm3 in the peripheral blood at the first visit. Bone marrow examination revealed that eosinophils accounted for 30% of the nucleated cell count, and G-band karyotyping analysis detected t (5;14)(q33;q22). Using peripheral blood FISH test, he was found to have platelet-derived growth factor receptor ß (PDGFRB) locus rearrangement at 5q32-33. The level of eosinophils in the peripheral blood reduced markedly 3 days after the initiation of Imatinib mesylate, 400 mg daily. This treatment was administered for 2 years, after which the peripheral blood FISH test was negative for PDGFRB. In this disease, although most cases are with t (5;12), those with t (5;14) are relatively rare, and the long-term course of this translocation is unknown.

[Survey of Methotrexate Prescription and Blood Concentration in Patients Treated with High-Dose Methotrexate].

High-dose methotrexate therapy(HDMTX)is effective against lymphoid malignancies. However, delayed elimination of methotrexate(MTX)after HDMTX administration may lead to severe adverse drug reactions. We surveyed the drugs coadministered with MTX and the incidence of delayed MTX elimination in patients treated with HDMTX in a clinical setting. We analyzed the plasma MTX concentration in 110 samples after 55 cycles of HDMTX in 33 patients. Delayed MTX elimination was defined as a plasma MTX concentration ≥1.0 mmol/L at 48 h after the start of HDMTX administration or ≥0.1 mmol/L at 72 h after the start of HDMTX administration. The incidence of the combined use of drugs affecting MTX excretion and drugs that exhibited typical renal excretion was 84.8%(n=28). The incidence of delayed MTX elimination was 39.4%(n=13). MTX-induced acute kidney injury occurred in 9 patients, all of whom also exhibited delayed MTX elimination. Therefore, when prescribing HDMTX, it is important to monitor adverse events, including acute kidney injury, which may be induced by prolonged MTX blood concentrations.

[Case of Primary Mediastinal Non-Seminomatous Germ Cell Tumor with Pathological Complete Response after Induction Chemotherapy and Residual Tumor Resection Accompanied by Late-Onset Bilateral Pneumothorax].

A man in his late teens presented to our hospital with left-sided chest pain. CT showed a 12 cm sized anterior mediastinal tumor and tiny nodules in the bilateral lower lobe of the lungs. The patient also had elevated serum AFP and hCG levels. Pathological findings of the CT-guided biopsy specimen suggested a yolk sac tumor, and no testicular abnormality was seen on ultrasound. Following whole body examination, he was diagnosed with primary mediastinal non-seminomatous germ cell tumor. After sperm cryopreservation, 4 courses of BEP(bleomycin[BLM]plus etoposide[ETP]plus cisplatin[CDDP]) chemotherapy were administered to normalize the tumor markers. The mediastinal tumor shrank but was still widely in contact with the left pulmonary artery. He underwent mediastinal tumor resection and segmentectomy of the left upper lobe via a median sternotomy. The maximum tumor size was 9 cm in diameter, and pathological examination of the specimen revealed only an immature teratoma with no malignant findings. At the same time, both the lower lung nodules were resected and pathologically identified as intrapulmonary lymph nodes. No recurrence was observed, but 6 months after surgery, he made an emergency visit to our department due to dyspnea. Bilateral pneumothorax was detected, and chest tube insertion was rapidly performed that improved with only right chest drainage. Cytology of the right hemorrhagic pleural effusion showed no evidence of malignancy. It was possible that a postoperative right-to-left shunt of the anterior mediastinum was present, leading to bilateral pneumothorax.

[A Case of Philadelphia Chromosome-Positive Acute Myeloid Leukemia Extramedullary Recurrence in a Patient Undergoing Thoracoscopy for Massive Pleural Effusion].

A man in his early 70s visited a previous hospital because of pancytopenia and was diagnosed with acute myeloid leukemia based on a bone marrowexamination. The karyotype was 46,XY, t(9;22)(q34;q11.2)[2/20], and real-time polymerase chain reaction(PCR)revealed minor bcr-abl chimeric mRNA. Finally, the patient was judged as having Philadelphia chromosome- positive acute myeloid leukemia, and remission induction chemotherapy with the JALSG AML 201 protocol was initiated in combination with dasatinib to achieve complete remission. After 3 courses of consolidation chemotherapy, the anticancer drugs were discontinued because of deterioration of his general condition and renal insufficiency. Six months after the initial treatment, he was referred to our department, and no evidence of recurrence was confirmed on bone marrow examination. However, 2 months later, right massive pleural effusion was detected, and he was admitted to the department of pneumology at our hospital. Thoracoscopic pleural biopsy was performed at the time of chest tube insertion, and he was diagnosed with acute myeloid leukemia extramedullary recurrence. Peripheral myeloblasts appeared and increased rapidly, accompanied by further exacerbation of renal function; thus, he received palliative care at the department of hematology and oncology.

[A Case of Synchronous Diffuse Large B-Cell Lymphoma of the Right Breast and Invasive Ductal Carcinoma of the Left Breast].

A woman in her early 60s noticed bilateral breast masses and visited a different hospital. Core needle biopsy showed diffuse large B-cell lymphoma of the right breast and invasive ductal carcinoma of the left breast. After referral to our department, PET-CT was performed. Compared with mild fluorodeoxyglucose accumulation in left breast cancer(BC), highly accumulated lesions were found on the right breast, left anterior chest wall, nasopharynx, and tonsil. The right breast lesion was the largest with a diameter of 30mm and was considered the primary lesion of malignant lymphoma(ML). The ML was classified as stage Ⅳ, pathologically proven with erythema of the left breast and nasopharynx. Three courses of R-CHOP were performed. However, due to suspicion of heart failure, chemotherapy was changed to R-CEOP(non-anthracycline-containing regimen)and 3 courses were additionally performed. The therapeutic effect of R-Chemo for ML was CR. Left BC showed a tendency of shrinkage. After intrathecal administration of anticancer drugs to prevent infiltration of ML into the central nervous system and preoperative endocrine therapy with aromatase inhibitor, left lumpectomy and sentinel lymph node biopsy were performed. BC was classified as clinical stage ⅠA and had an estrogen receptor score of 3b. Postoperative whole breast radiotherapy was completed, and the planned internal use of exemestane was more than 5 years. With multidisciplinary therapy, 3.5 years had passed since the initial treatment without recurrence.

[A Case of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Achieving Complete Molecular Response with Ponatinib Therapy despite the Development of Hemorrhagic Stroke during Remission Induction Chemotherapy].

A man in his late 50s had lumbago and thrombocytopenia. He was diagnosed with Philadelphia chromosome-positive acute lymphoblastic leukemia(Ph plus ALL). Remission induction chemotherapy was initiated with JALSG Ph plus ALL 208 protocol, but cerebral infarction in the right occipital lobe developed on day 2 and, to make matters worse, was accompanied by hemorrhagic cerebral infarction in the left occipital lobe on day 9. We decided that chemotherapy with multiple drugs was difficult to continue, and it was stopped. After improvement of the general condition, dasatinib therapy was started on day 52. After about 5 months, Ph plus ALL relapsed. Although mild disorientation and visual field defects remained due to old cerebral infarction, organ function was maintained, and patient performance status(PS)was classified as 1. Introduction of ponatinib was considered feasible, and ponatinib was started from a dose of 15mg/day to prevent the occurrence of vaso- occlusive adverse events. It was gradually increased to 30mg /day and continued about 4 months without recurrence of cerebral infarction. Complete molecular response was achieved with ponatinib therapy. It was suggested that, in patients with Ph plus ALL with a history of cerebral infarction, ponatinib could be a treatment option under careful risk management.

[A Case of POEMS Syndrome Treated by Ld Prior to HDCTx Followed by aPBSCT].

A man in his late 40s was presented to a hospital with complaints of peripheral numbness and fatigue. Systemic edema, pleural effusion and ascites, pigmentation, splenomegaly, and CT findings of osteoplastic changes suggested POEMS syndrome. He was referred to our division, and a bone marrow examination indicated MGUS. However, his serum level of vascular endothelial growth factor(VEGF)was elevated to 1,520 pg/mL, and IgA-l type M protein was detected. He was diagnosed with POEMS syndrome and received four cycles of induction chemotherapy containing lenalidomide and dexamethasone( Ld). All symptoms improved gradually, and after auto peripheral blood stem cell harvest(aPBSCH), high-dose melphalan was administered, followed by auto peripheral blood stem cell transplantation(aPBSCT)being performed. Pleural effusion and ascites disappeared, while numbness remained slightly. His serum level of VEGF decreased to 68 pg/mL when the planned primary treatment was completed. Many cases of POEMS syndrome involve peripheral neuropathy; therefore, a lenalidomide-containing regimen may be a more adequate strategy than ones containing thalidomide and bortezomib.

[A Patient Surviving More Than Five Years Due to the Effect of Sequential Alternating Chemotherapy Administered to Metachronous Overlapping Cancer of Multiple Myeloma and Stageâ £ EGFR Positive Non-Small Cell Lung Cancer].

A woman in her late 50s visited our department because an abnormal shadow of her right lung was seen on her chest radiographs. She was diagnosed with Stage ⅠA primary lung adenocarcinoma with EGFR exon 19 deletion mutation by performing thoracoscopic middle lobe resection and lymph node dissection. After 1 and a half years, the lung metastasis recurred and she received gefitinib(GEF)monotherapy for 9 months and withdrew because of the sustained complete response(CR). Three years and 7 months after the first visit, she was diagnosed as having complication of revised international staging system(R-ISS)Ⅱ multiple myeloma with anemia, retinal vein occlusion, and M proteinemia. It was decided that treatment for myeloma should be given priority and hence, Bd, high dose chemotherapy with auto-peripheral blood stem cell transplantation(aPBSCT), Ld, ELd and Pd therapy were performed sequentially until progressive disease(PD)and survival benefit were evident. As lung metastasis of adenocarcinoma also progressed, myeloma treatment was terminated, GEF was administered intermittently and consequently, shrinkage of the lung metastasis was confirmed. Depending on sequential alternating chemotherapy for both malignancies, a relatively long survival time of 5.4 years from the initiation of treatment for myeloma and 7.5 years from the recurrence of lung adenocarcinoma was achieved.

Monocyte subsets and their phenotypes during treatment with BCR-ABL1 tyrosine kinase inhibitors for Philadelphia chromosome-positive leukemia.

BCR-ABL1 tyrosine kinase inhibitors (TKIs) are effective agents in the treatment of Philadelphia chromosome-positive leukemia. However, vascular events have developed in some patients receiving each TKI. The perturbation of circulating monocyte subsets and their expressions of chemokine and scavenger receptors are associated with the development of cardiovascular events. Here, we examined the subsets of circulating monocytes and their phenotypes in 51 patients treated with imatinib, nilotinib, and dasatinib, and 11 healthy subjects in our institute. Except for a negative association between the number of classical monocytes and imatinib treatment, the proportions and numbers of monocyte subsets were not significantly associated with TKI treatment. However, chemokine receptors, CCR2, CX3CR1 on classical monocytes, and scavenger receptor, CD204, on intermediate and non-classical monocytes were significantly associated with TKIs. These data demonstrated the relationships between alterations of chemokine and scavenger receptors on different monocyte subsets and the TKI treatments.

The Experience of Persons With Hematological Malignancy When Communicating With Health Care Professionals.

This study aimed to elucidate the experiences of Japanese persons with hematological malignancy (PHMs) in communicating with health care professionals (HCPs), from diagnosis to the end of life, as recalled by their families. We interviewed 14 bereaved families and analyzed the data using the basic techniques of grounded theory. We found that PHMs lived to the fullest possible when they experienced ownership of their illness process despite their disease. The ownership was made possible by active communication from HCPs: first, acknowledging the PHM's way of life, including reaching out from the HCPs and appreciating sincerely PHMs' hopes and will; and second, paving the way ahead, including giving prospects and offering choices. The study underlines that rather than just providing information about the disease, HCPs need to actively ask about and show respect for the PHM's way of life. Only after achieving this can HCPs communicate possible future pathways with PHMs.

[Effect of the Administration Period of Rasburicase in Japanese Adult Hematological Malignancy Patients at High-Risk for Tumor Lysis Syndrome].

Tumor lysis syndrome (TLS) is a life-threatening metabolic complication caused by the rapid breakdown of malignant cells. It is an oncologic emergency and occurs spontaneously after the initiation of chemotherapy for hematological malignancies. Therefore, the management of TLS is important. Rasburicase (RSB) has been shown to be effective for the management of TLS. We retrospectively investigated the optimal administration period of RSB (1 to 7 days) for 38 adult patients with a hematological malignancy who were at high risk for TLS. In all patients, the serum uric acid (sUA) value did not increase beyond the upper limit of normal. Clinical TLS did not occur in any patients. Seven patients were administered a single-dose of RSB and sUA remained within normal limits. These results suggested that single-dose RSB administration was efficacious for Japanese adult patients with hematological malignancies who are at high risk for TLS.

[Azacitidine for Therapy-Related Myelodysplastic Syndrome Following Oxaliplatin (L-OHP)Therapy for Metastatic Rectal Cancer].

Therapy-related myelodysplasticsyndrome(t-MDS)has been reported to occur after treatment with cytotoxic agents and radiation. Here, we report a case of t-MDS following oxaliplatin(L-OHP)exposure, which was successfully treated with azacitidine(AZA). A 71-year-old man was referred to our department because of pancytopenia. He had been diagnosed with rectal cancer(cT4aNXM0, stage II B-III C, RAS gene status wild-type)3 years ago and had received 8 courses of capecitabine(CAP)and L-OHP(XELOX regimen), followed by 48 courses of CAP and bevacizumab. Before referral, recurrence of rectal cancer was detected using CT after the last course of chemotherapy. A bone marrow examination revealed multilineage dysplasia and 9.0%myeloblasts. Cytogenetic analysis disclosed a chromosome 7 abnormality. The diagnosis of t- MDS was made and treatment with AZA was initiated. Subsequently, temporary but significant hematological improvements were observed, which enabled the patient to receive additional palliative radiation therapy against the locally relapsed rectal cancer. AZA might be useful in t-MDS because of its efficacy and low toxicity.

Hypersensitivity reaction to ß-lactam antibiotics in patients with adult T-cell leukemia/lymphoma treated with mogamulizumab
.

Mogamulizumab (MOG) is a humanized anti-CCR4 monoclonal antibody that is highly cytotoxic for adult T-cell leukemia/lymphoma (ATL) cells. Most non-hematological adverse events are cutaneous adverse reactions in ATL patients. We reviewed the medical records of 24 patients with CCR4-positive aggressive ATL who had received MOG treatment. The incidence of MOG-induced cutaneous adverse reactions (MCARs) was 25% (6 patients). Four patients with MCAR had an interesting clinical course, compared with MCARs reported in previous reports. The factors causing MCAR were suspected to be cefepime, cefozopran, and piperacillin/tazobactam. We consider that hypersensitivity reaction to ß-lactam antibiotics is involved in a significant proportion of MCARs.
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Splenic marginal zone lymphoma complicated by cold agglutinin disease.

Splenic marginal zone lymphoma (SMZL) is a rare low-grade B-cell lymphoma accounting for less than 1% of lymphoid neoplasms and is often associated with autoimmune disorders. A 48-year-old woman presented with severe anemia due to steroid-refractory cold agglutinin disease (CAD), and was referred to our hospital for management of progressive systemic illness and high fever. On admission, she showed elevated serum soluble IL-2R and mild splenomegaly. PET/CT revealed FDG accumulation in the spleen and bone. She was pathologically diagnosed as having splenic marginal zone lymphoma by splenectomy and received 8 cycles of rituximab every 2 weeks, resulting in marked improvement of anemia. Lymphoma cells were positive for CD20/CD11c/CD13, phenotypically compatible with SMZL. We report herein the characteristic features of SMZL, and appropriate procedures for diagnosis and treatment.

[Autologous peripheral blood stem cell transplantation for double-refractory myeloma with K-RAS and N-RAS mutations].

The prognosis of multiple myeloma (MM) has been improved due to the introduction of novel agents like proteasome inhibitors and immunomodulatory drugs (IMiDs). However, some cases are refractory to the use of novel agents, and the prognosis of such cases is poor. A 53-year-old male was diagnosed with MM and categorized as follows: Bence-Jones protein lambda type MM, Durie-Salmon IIIA, international staging system (ISS) stage II, and revised ISS stage II. Mutations in K-RAS and IGH/FGFR3 translocation were detected at diagnosis. His tumor was refractory to seven therapeutic regimens including bortezomib, IMiDs (lenalidomide, thalidomide, pomalidomide), conventional chemotherapy, and radiation therapy. N-RAS mutations, CKS1B gains, and C-MYC split signals were detected after treatment. We performed high-dose melphalan/autologous stem cell transplantation (HD-MEL/ASCT) as a salvage therapy and achieved very good partial response. The correlation between K-RAS mutations and poor prognosis or between N-RAS mutations and reduced sensitivity to bortezomib is reported. However, RAS mutations are reported as a favorable factor for HD-MEL/ASCT. In general, mutations of both the K-RAS and N-RAS are known to be mutually exclusive. This rare MM case has mutations in both K-RAS and N-RAS, and the possible relevance of these mutations to both the refractoriness to novel therapies and sensitivity to HD-MEL/ASCT is suggested.

Vincristine-induced paralytic ileus during induction therapy of treatment protocols for acute lymphoblastic leukemia in adult patients.

Vincristine (VCR) is an important drug used in the treatment of acute lymphoblastic leukemia (ALL). VCR-induced neurotoxicity can manifest as peripheral neuropathy, constipation, or paralytic ileus. While there are some case reports describing VCR-induced paralytic ileus (VIPI) in pediatric ALL, there are fewer publication on adult ALL patients. Therefore, we retrospectively investigated VIPI during induction therapy of treatment protocols for ALL in 19 adult patients. The incidence of VIPI was 32%. VIPI was significantly increased in patients receiving concomitant itraconazole (ITCZ) (p = 0.04). We recommend avoidance of the combination of VCR and ITCZ.

Advanced human T-cell leukemia virus type 1 carriers and early-stage indolent adult T-cell leukemia-lymphoma are indistinguishable based on CADM1 positivity in flow cytometry.

We previously reported that the cell adhesion molecule 1 (CADM1) versus CD7 plot in flow cytometry reflects disease progression in human T-cell leukemia virus type 1 (HTLV-1) infection. In CD4(+) cells from peripheral blood, CADM1(-) CD7(+) (P), CADM1(+) CD7(dim) (D) and CADM1(+) CD7(-) (N) subpopulations are observed. The D and N subpopulations increase as asymptomatic HTLV-1 carriers (AC) progress to indolent adult T-cell leukemia-lymphoma (ATL) and the N subpopulation then expands in aggressive ATL. In the present study we examined whether the analysis can estimate the risk of developing ATL in advanced AC. Peripheral blood samples from AC (N = 41) and indolent ATL patients (N = 19) were analyzed by flow cytometry using the CADM1 versus CD7 plot for CD4(+) cells and inverse long PCR (clonality analysis) of FACS-sorted subpopulations. Almost all AC with a high HTLV-1 proviral load (>4 copies/100 cells) had a CADM1(+) (D + N) frequency of >10%. AC with 25% < CADM1(+) ≤ 50% contained expanded clones similar to smoldering-type ATL. In many patients in the 25% < CADM1(+) ≤ 50% group, the proportion of abnormal lymphocytes was distributed around the 5% line, which divides AC and smoldering-type ATL in Shimoyama's classification. In conclusion, the CADM1 versus CD7 plot is useful for selection of putative high-risk AC. The characteristics of some AC and smoldering ATL are said to be similar; however, long-term follow up is required and the clinical outcome (e.g. rate of transformation) of these cases should be used to determine whether to include them in the same clinical category.