Selective targeting of multiple myeloma cells with a monoclonal antibody recognizing the ubiquitous protein CD98 heavy chain.

Cancer-specific cell surface antigens are ideal therapeutic targets for monoclonal antibody (mAb)-based therapy. Here, we report that multiple myeloma (MM), an incurable hematological malignancy, can be specifically targeted by an mAb that recognizes a ubiquitously present protein, CD98 heavy chain (hc) (also known as SLC3A2). We screened more than 10,000 mAb clones raised against MM cells and identified R8H283, an mAb that bound MM cells but not normal hematopoietic or nonhematopoietic cells. R8H283 specifically recognized CD98hc. R8H283 did not react with monomers of CD98hc; instead, it bound CD98hc in heterodimers with a CD98 light chain (CD98lc), a complex that functions as an amino acid transporter. CD98 heterodimers were abundant on MM cells and took up amino acids for constitutive production of immunoglobulin. Although CD98 heterodimers were also present on normal leukocytes, R8H283 did not react with them. The glycoforms of CD98hc present on normal leukocytes were distinct from those present on MM cells, which may explain the lack of R8H283 reactivity to normal leukocytes. R8H283 exerted anti-MM effects without damaging normal hematopoietic cells. These findings suggested that R8H283 is a candidate for mAb-based therapies for MM. In addition, our findings showed that a cancer-specific conformational epitope in a ubiquitous protein, which cannot be identified by transcriptome or proteome analyses, can be found by extensive screening of primary human tumor samples.

[Hypomagnesemia induced by gastrointestinal losses due to carfilzomib].

A 67-year-old man with multiple myeloma had been treated with carfilzomib, lenalidomide, and dexamethasone (KRd) therapy. During the second course, he developed dyspnea, which gradually worsened. After admission, gastrointestinal losses of magnesium were confirmed, and intravenous magnesium was administered, which consequently improved his symptoms. Although KRd therapy was resumed, hypomagnesemia was recurring. Therefore, carfilzomib was replaced with ixazomib, which improved the patient's hypomagnesemia. The major causes of hypomagnesemia are gastrointestinal and renal losses; our case appeared to have gastrointestinal losses of magnesium and was successfully treated by discontinuing carfilzomib. Hypomagnesemia should be considered in patients receiving carfilzomib; furthermore, clinicians should consider discontinuing carfilzomib as its treatment.

The activated conformation of integrin ß7 is a novel multiple myeloma-specific target for CAR T cell therapy.

Cancer-specific cell-surface antigens are ideal targets for monoclonal antibody (mAb)-based immunotherapy but are likely to have previously been identified in transcriptome or proteome analyses. Here, we show that the active conformer of an integrin can serve as a specific therapeutic target for multiple myeloma (MM). We screened >10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb specifically recognizing a subset of integrin ß7 molecules. The MMG49 epitope, in the N-terminal region of the ß7 chain, is predicted to be inaccessible in the resting integrin conformer but exposed in the active conformation. Elevated expression and constitutive activation of integrin ß7 conferred high MMG49 reactivity on MM cells, whereas MMG49 binding was scarcely detectable in other cell types including normal integrin ß7+ lymphocytes. T cells transduced with MMG49-derived chimeric antigen receptor (CAR) exerted anti-MM effects without damaging normal hematopoietic cells. Thus, MMG49 CAR T cell therapy is promising for MM, and a receptor protein with a rare but physiologically relevant conformation can serve as a cancer immunotherapy target.

Pulmonary Involvement of Acute Myeloid Leukemia Mimicking Transfusion-related Acute Lung Injury.

Transfusion-related acute lung injury (TRALI) is defined as a new episode of acute lung injury (ALI) occurring during transfusion or within 6 hours of transfusion completion. A 66-year-old man suffering from acute myeloid leukemia developed acute respiratory distress syndrome after platelet transfusion. TRALI was diagnosed clinically, but an autopsy showed leukemic cells in diffuse pulmonary edema. Anti-human neutrophil antigen (HNA)-3a antibodies were detected in the donor serum, and the HNA-3 genotype of the patient was identified as a/a. This case was considered to represent pulmonary involvement of acute myeloid leukemia, rather than TRALI. A revision of the definition of TRALI accounting for hematological malignancies should therefore be considered.

Wilms Tumor 1 (WT1) mRNA Expression Level at Diagnosis Is a Significant Prognostic Marker in Elderly Patients with Myelodysplastic Syndrome.

BACKGROUND/AIMS: A high expression of Wilms tumor 1 (WT1) mRNA occurs in most cases of acute leukemia and myelodysplastic syndrome (MDS). Although there are many reports suggesting that acute myeloid leukemia patients with high expression levels of WT1 mRNA have a relatively poor long-term survival, there are few reports addressing the relationship between WT1 levels and prognosis in MDS. METHODS: We retrospectively analyzed 42 elderly patients with MDS whose WT1 levels at diagnosis were available, and we assessed the relationships between WT1 levels in peripheral blood and preexisting prognostic factors such as World Health Organization prognostic scores and Revised International Prognostic Scoring System risk categories, bone marrow blast percentages, and chromosomal abnormalities linked to a poor prognosis. We also evaluated the relationship between WT1 levels and prognosis. RESULTS: WT1 levels were significantly different between high- and low-risk MDS patients (p < 0.05). There was a trend towards a significant difference between those with and those without poor prognostic chromosomal rearrangements (p = 0.051). Moreover, the overall survival and progression-free survival were significantly worse in elderly patients with higher levels of WT1 (p = 0.00039 and p = 0.00077, respectively). CONCLUSIONS: The WT1 mRNA expression level at diagnosis may be a significant independent prognostic marker for elderly patients with MDS.

Reversible dasatinib-related pulmonary arterial hypertension in a CML patient.

A 59-year-old man diagnosed with the chronic phase of chronic myeloid leukemia (CML) in June 2011 was started on dasatinib (100 mg/day). He had no signs of pleural effusion (PE) or right heart failure before treatment, but symptoms of PE and dyspnea (New York Heart Association class III) appeared in January 2013 and May 2014, respectively. Doppler transthoracic echocardiography and right heart catheterization revealed pulmonary arterial hypertension (PAH) with an estimated pulmonary artery systolic pressure (PASP) of 80 mmHg and estimated mean pulmonary artery pressure of 29 mmHg. Rheumatoid factor, antinuclear antibody, dsDNA antibody, and SCL70 were not elevated, and computed tomography confirmed the absence of a pulmonary embolism. Therefore, dasatinib-related PAH was diagnosed and treatment with this agent was discontinued. The PASP had decreased to 51 and 40 mmHg at one month and one year, respectively, after dasatinib discontinuation. This patient developed PAH while receiving dasatinib administration and only discontinuation of this agent improved his symptoms. The possibility that dasatinib can cause PAH must be considered before administering this agent to patients with CML.

Postinfluenza Vaccination Idiopathic Thrombocytopenic Purpura in Three Elderly Patients.

The etiologies of secondary idiopathic thrombocytopenic purpura (ITP) include infection, autoimmune disease, and immunodeficiency. We report the cases of three elderly patients who developed ITP after receiving influenza vaccinations. The platelet count of an 81-year-old woman fell to 27,000/µL after she received an influenza vaccination. A 75-year-old woman developed thrombocytopenia (5,000 platelets/µL) after receiving an influenza vaccination. An 87-year-old woman whose laboratory test values included a platelet count of 2,000/µL experienced genital bleeding after receiving an influenza vaccination. After Helicobacter pylori (HP) eradication or corticosteroid treatment, all of the patients' platelet counts increased. Influenza vaccination is an underlying etiology of ITP in elderly patients. HP eradication or corticosteroid treatment is effective for these patients. Clinicians should be aware of the association between ITP and influenza vaccinations.

[Usefulness of measuring serum procalcitonin levels by immunochromatographic assay in febrile neutropenia].

In order to clarify the usefulness of measuring procalcitonin (PCT) values under the extreme condition called febrile neutropenia (FN), PCT was measured with immunochromatographic assay (ICA) and electro-chemi-luminescence immunoassay (ECLIA) at two time points: upon FN occurrence and 12 to 24 hours after FN occurrence, and correlations and associations between the two methods were reviewed. A strong correlation between the ICA and ECLIA results was observed when Spearman's rank correlation coefficient was 0.878, and the association was also demonstrated by Fisher's direct test since P=4.68×10(-10). Special equipment is not required, the operations are simple, and the ICA method currently adopted by many facilities can be used as the standard method even for the clinical condition known as FN.

[Complication of pernicious anemia during interferon-ß treatment for type C chronic hepatitis].

A 62-year-old man with chronic hepatitis C underwent interferon (IFN)-ß therapy. After treatment for a period comprising 29 months and 2 weeks, hematological results showed a decrease in white blood cell, hemoglobin, and platelet counts (WBC 2,300/µl, Hb 7.2 g/dl, PLT 4.7×10(4)/µl), and IFN therapy was stopped. Despite therapy discontinuation, the pancytopenia continued to progress with elevation of LDH (LDH 4,898 IU/l), and the patient was admitted to our hospital with suspected hematological disease. The patient underwent clinical screening, and pernicious anemia caused by vitamin B12 deficiency was diagnosed. The anemia rapidly improved with vitamin B12 treatment. Interferon is the mainstay of treatment for patients with viral hepatitis. While the adverse effects of interferon therapy are widely recognized, only a few reports have documented pernicious anemia developing during IFN-therapy. We recommend that particular attention be paid to such clinical and laboratory conditions as megaloblastic anemia when administering IFN. We also recommend checking the vitamin B12 level, as a deficiency of this vitamin may lead to the development of megaloblastic anemia.

Eosinophilia, regardless of degree, is related to better outcomes after allogeneic hematopoietic stem cell transplantation.

OBJECTIVE: Several recent studies report that, after allogeneic hematopoietic cell transplantation (allo-HCT), eosinophilia is a favorable factor for transplant outcomes. However, whether the degree of eosinophilia influences transplant outcomes is yet to be established. METHODS: We studied 144 patients with hematological malignancy who received allo-HCT at our institution. The stem cell sources were bone marrow in 84 patients, peripheral blood stem cells in 32 patients, and cord blood in 28 patients. One hundred and twelve patients underwent myeloablative conditioning and 49 patients had high-risk disease. We performed semi-landmark analysis to examine the influence of eosinophilia. RESULTS: Eosinophilia developed at a median of 47 days after transplantation in 63 patients (44%). The patients with eosinophilia showed significantly better overall survival (OS) and a lower relapse rate at three years, compared to those without eosinophilia (66% vs 55%, p=0.04 and 30% vs 50%, p=0.002). On analysis following division into groups with mild (500-1,500×10(6)/L) and hyper- (>1,500×10(6)/L) eosinophilia, three-year OS and relapse rates were 68% and 65% (p=0.92), and 31% and 28% (p=0.90), respectively. On multivariate analysis, eosinophilia was significantly associated with lower relapse rates [HR: 0.5 (95% CI: 0.3-0.9), p=0.01] and the same trend was preserved in the analysis of the mild and hyper-eosinophilic groups. CONCLUSION: The results suggest that eosinophilia after allo-HCT was associated with better OS and a lower relapse rate, regardless of the levels. The mechanism of this effect is still unclear, and requires study of the pathophysiological process to clarify the relationship between the higher levels of eosinophilia after allo-HCT and organ infiltration.

CD48 as a novel molecular target for antibody therapy in multiple myeloma.

Monoclonal antibody (mAb) drugs are desirable for the improvement of multiple myeloma (MM) treatment. In this study, we found for the first time that CD48 was highly expressed on MM plasma cells. In 22 out of 24 MM patients, CD48 was expressed on more than 90% of MM plasma cells at significantly higher levels than it was on normal lymphocytes and monocytes. CD48 was only weakly expressed on some CD34(+) haematopoietic stem/progenitor cells, and not expressed on erythrocytes or platelets. We next examined whether CD48 could serve as a target antigen for mAb therapy against MM. A newly generated in-house anti-CD48 mAb induced mild antibody-dependent cell-mediated cytotoxicity and marked complement-dependent cytotoxicity against not only MM cell lines but also primary MM plasma cells in vitro. Administration of the anti-CD48 mAb significantly inhibited tumour growth in severe combined immunodeficient mice inoculated subcutaneously with MM cells. Furthermore, anti-CD48 mAb treatment inhibited growth of MM cells transplanted directly into murine bone marrow. Finally and importantly, we demonstrated that the anti-CD48 mAb did not damage normal CD34(+) haematopoietic stem/progenitor cells. These results suggest that the anti-CD48 mAb has the potential to become an effective therapeutic mAb against MM.

[Successful treatment with the combination of recombinant human soluble thrombomodulin and gabexate mesilate in three patients with obstetric disseminated intravascular coagulation].

Recombinant human soluble thrombomodulin (rTM) is a new drug for the treatment of disseminated intravascular coagulation (DIC), although the effects on obstetric DIC have not yet been fully elucidated. We report herein three patients with obstetric DIC caused by placental abruption, hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, and atonic bleeding, respectively. In all three cases, treatment with rTM proved successful, suggesting that rTM is an efficient method for treating obstetric DIC.

[Improved outcome in brain abscess during induction in acute myelocytic leukemia].

A 31-year-old female with acute myelocytic leukemia was admitted to our hospital in June 2004. She had complications of brain abscess at the WBC nadir after the second course of induction therapy. However,because the platelet count was low, neurosurgical procedures, including craniotomy/abscess resection, or abscess drainage, were not performed, and we could not detect bacteria or fungus as the cause of brain abscess. Combination therapy with meropenem trihydrate and fosfluconazole was effective. Thereafter, she underwent related peripheral blood stem cell transplantation, and has had no recurrence of brain abscess. Brain abscess during chemotherapy for patients with acute leukemia is commonly due to fungus,particularly Aspergillus, which has a very high fatality rate. Therefore, the treatment of brain abscess without the detection of bacteria and fungus requires combination therapy with antifungal agents and antibiotics. In this case, methionine-positron emission tomography was useful for the evaluation of therapeutic effectiveness for brain abscess.