Tatsuya Katsurada

Polyclonal Proliferation of Plasma Cells Associated with Marked Hypergammaglobulinemia in an Elderly Patient

We describe an 89-year-old woman who presented with prominent plasmacytosis mimicking plasma cell leukemia. The apparent serum M-protein level of >7 g/dL of γ mobility was revealed to be a polyclonal increase of immunoglobulins. The plasma cells in the peripheral blood expressed polyclonal surface/cytoplasmic immunoglobulins as well as CD19, CD30, CD38, and CD138 antigens but lacked CD10, CD20, CD25, and CD56. The bone marrow plasma cells showed the CD45+, CD19+, CD56-, MPC-1-/+, and CD49e- immunophenotype, which was in clear contrast with the immunophenotypes of the neoplastic myeloma cells. Abdominal lymphadenopathy, splenomegaly, and a high level of soluble interleukin 2 receptor may have been reflections of an underlying lymphoproliferative disorder, potentially leading to the polyclonal proliferation of plasma cells.

A Japanese family with X-linked sideroblastic anemia affecting females and manifesting as macrocytic anemia

X-linked sideroblastic anemia (XLSA) is a rare hereditary disorder that typically manifests in males as microcytic anemia. Here, we report a family with XLSA that affects females and manifests as macrocytic anemia. The proband was a Japanese woman harboring a heterozygous mutation c.679C>T in the ALAS2 gene. This mutation causes the amino acid substitution R227C, which disrupts the enzymatic activity of erythroid-specific δ-aminolevulinic acid synthase. The mutation was not detected in the ALAS2 complementary DNA from peripheral blood red blood cells of the proband, indicating that the cells were mostly derived from erythroblasts expressing wild-type ALAS2. The proband’s mother, who had been diagnosed with myelodysplastic syndrome, also had XLSA with the same mutation. Clinicians should be aware that XLSA can occur not only in males but also in females, in whom it manifests as macrocytic anemia.

VNCOP-B plus rituximab therapy in elderly patients with aggressive B-cell non-Hodgkin lymphoma: a multicenter experience.

CHOP (cyclophosphamide, adriamycin, vincristine, and prednisolone) plus rituximab is a standard chemotherapy used to treat patients with aggressive B-cell non-Hodgkin lymphoma (B-NHL). However, among elderly patients, this regimen has not been completely satisfactory in its efficacy and safety. We report our clinical experience in 8 collaborative institutions to determine if the VNCOP-B (etoposide, mitoxantrone, cyclophosphamide, vincristine, prednisolone, and bleomycin) combination therapy plus rituximab was effective and safe to treat elderly patients with aggressive B-NHL. Between September 2004 and December 2007, 23 previously untreated patients, median age 73 years, 50.0% classified as high-intermediate/high-risk on the standard International Prognostic Index (IPI) entered this trial. Complete remission rate was 90.5%, with a 100% overall response rate (RR) at the end of induction therapy; overall survival (OS) rate at 3 years was 76.4% (median follow-up 744 days), with an 82.6% 3-year progression-free survival (PFS) rate (median follow-up 744 days). The most common grade 3/4 toxicities were hematologic, including neutropenia in 75.0% of the patients despite prophylactic administration of granulocyte colony-stimulating factor (G-CSF), febrile neutropenia in 30.0%, respectively. There was no treatment-related mortality (TRM). Rituximab not only combined with chemotherapy but also given sequentially improved survival. R-VNCOP-B could be another option for elderly patients who are not considered to tolerate in receiving R-CHOP.

Efficacy of interferon-alpha in essential thrombocythemia during pregnancy

Dear Editor, Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm associated with an increase in platelet counts and risk of vascular complications. When young women with ET become pregnant, an adverse outcome of pregnancy caused by thromboembolic complications is a matter of concern [1]. Reduction of platelet counts by conventional chemotherapeutic agents is not advisable due to their potential fetal toxicities. Two observational studies involving retrospective multicenter cases suggested a role of interferon-alpha in this clinical setting [1, 2]. Herein, we report four consecutive pregnancies in three ET patients (aged 22 to 32 years) successfully treated with interferon-alpha in our institution between 2001 and 2016. To our knowledge, this represents the largest single-center series. No patients had a prior history of pregnancy or thrombosis. The time from diagnosis of ET to pregnancy ranged from 19 to 77 months. Patient 1 became pregnant twice at the age of 22 and 27 years. All patients were prophylactically given acetylsalicylic acid (ASA) shortly after the diagnosis of ET. Patients 1 and 3 had calreticulin mutations but not Jak 2 mutation, while genetic data were not available for patient 2. Platelet counts ranged from 1095 to 1741 × 10/L at the time of diagnosis (Table 1) and decreased slightly when patients became pregnant. After obtaining informed consent and IRB approval, interferon-alpha was started from 26 to 29 weeks of gestation in patients 1 and 2, respectively. Because of the highly elevated platelet counts, interferon was started at 12 weeks of gestation in patient 3. The interferon dose was three million units given subcutaneously twice or three times per week. In all patients, platelet counts showed a gradual decrease during the treatment, which was well tolerated with no noteworthy adverse events except for a transient liver dysfunction in patient 3. Full-term delivery was obtained in all but patient 3, in whom a cesarean section was performed because of breech presentation. All the babies had normal birth weight and platelet counts (Table 1). Interferon-alpha is known to have anti-proliferative effect on pluripotent as well as lineage-committed progenitor cells. In addition, interferon-alpha induction of SOCS-1 impairs thrombopoietin signaling, leading to direct suppression of megakaryocyte growth [3]. Platelet count before conception may not correlate or predict the risk of pregnancy complication [4, 5]. However, reduction of platelet counts with interferon-alpha has yielded uneventful delivery in most cases. Indeed, an Italian registry [1] reported live births in 19 out of 20 pregnant ET patients given interferon, as did an UK multicenter study [2] in 9 out of 10 pregnant ET patients treated with pegylated interferon-alpha-2a. A systematic survey indicates that interferon-alpha does not significantly increase the fetal risks above that in general population rates [6]. In conclusion, our study supports that interferon-alpha is the treatment of choice in the management of ET patients in pregnancy [7]. * Yataro Yoshida yoshida@takedahp.or.jp

Numerous aggregates of “tiny” micromegakaryocytes in the bone marrow

A 70-year old male presented with leukocytosis (24.9 9 10/L) and thrombocytosis (727 9 10/L). Hb was 14.9 g/dL, neutrophils 81%, basophils 1%, eosinophils 4%, and myelocytes 1%. He had no splenomegaly. Serum LDH was 477 U/L, B12755 pg/m, and ferritin 104 ng/dL. Neutrophil alkaline phosphatase activity was normal. The marrow was moderately cellular with many aggregates of micromegakaryocytes, each aggregate comprising up to 20 ‘‘tiny’’ micromegakaryocytes (Fig. 1). Small cells were close to the size of lymphocytes. Although usual-sized micromegakaryocytes were occasionally seen, most ‘‘tiny’’ micromegakaryocytes were found to form aggregates accompanying many platelets (Fig. 2a, b) and such aggregates were scattered in the entire length of marrow film. Immature granulocytes showed hypogranulation (Fig. 3a), and occasional mature cells showed hypersegmentation (Fig. 3b, c) and cytoplasmic Dohle bodies (arrowheads Fig. 3d). Erythroid series showed mild megaloblastoid changes. These features resembled myelodysplastic syndromes (MDS). Blast cells were few. Normal marrow cytogenetic analysis and the lack of BCR-ABL in mRNA analysis excluded chronic myeloid leukemia (CML). Marrow WT1 mRNA level was 1600 copies/lg RNA. No marrow fibrosis was seen in biopsy. These findings excluded myeloproliferative neoplasm (MPN). Proliferation and marked dysplasia in megakaryocytic and myeloid lineages falls within the scope of MDS/MPN, unclassifiable, according to the current WHO system, rather than atypical BCR-ABL negative CML. The marrow findings remained essentially unchanged in repeat study although blood counts oscillated in response to the intermittent hydroxyurea (1000 mg) treatment. Y. Yoshida (&) Y. Hamakawa S. Oguma T. Katsurada The Center for Hematological Diseases, Takeda General Hospital, 28-1 Ishida-Moriminami, Fushimi-Ku, Kyoto 601-1495, Japan e-mail: yoshida@takedahp.or.jp