Masahiro Manabe

Factors that contribute to long-term survival in patients with leukemia not in remission at allogeneic hematopoietic cell transplantation

BackgroundThere has been insufficient examination of the factors affecting long-term survival of more than 5 years in patients with leukemia that is not in remission at transplantation.MethodWe retrospectively analyzed leukemia not in remission at allogeneic hematopoietic cell transplantation (allo-HCT) performed at our institution between January 1999 and July 2009. Forty-two patients with a median age of 39 years received intensified conditioning (n = 9), standard (n = 12) or reduced-intensity conditioning (n = 21) for allo-HCT. Fourteen patients received individual chemotherapy for cytoreduction during the three weeks prior to reduced-intensity conditioning. Diagnoses comprised acute leukemia (n = 29), chronic myeloid leukemia-accelerated phase (n = 2), myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) (n = 10) and plasma cell leukemia (n = 1). In those with acute leukemia, cytogenetic abnormalities were intermediate (44%) or poor (56%). The median number of blast cells in bone marrow (BM) was 26.0% (range; 0.2-100) before the start of chemotherapy for allo-HCT. Six patients had leukemic involvement of the central nervous system. Stem cell sources were related BM (7%), related peripheral blood (31%), unrelated BM (48%) and unrelated cord blood (CB) (14%).ResultsEngraftment was achieved in 33 (79%) of 42 patients. Median time to engraftment was 17 days (range: 9-32). At five years, the cumulative probabilities of acute graft-versus-host disease (GVHD) and chronic GVHD were 63% and 37%, respectively. With a median follow-up of 85 months for surviving patients, the five-year Kaplan-Meier estimates of leukemia-free survival rate and overall survival (OS) were 17% and 19%, respectively. At five years, the cumulative probability of non-relapse mortality was 38%. In the univariable analyses of the influence of pre-transplant variables on OS, poor-risk cytogenetics, number of BM blasts (>26%), MDS overt AML and CB as stem cell source were significantly associated with worse prognosis (p = .03, p = .01, p = .02 and p < .001, respectively). In addition, based on a landmark analysis at 6 months post-transplant, the five-year Kaplan-Meier estimates of OS in patients with and without prior history of chronic GVHD were 64% and 17% (p = .022), respectively.ConclusionGraft-versus-leukemia effects possibly mediated by chronic GVHD may have played a crucial role in long-term survival in, or cure of active leukemia.

Immunoglobulin Prophylaxis Against Cytomegalovirus Infection in Patients at High Risk of Infection Following Allogeneic Hematopoietic Cell Transplantation

Reports on the efficacy of intravenous immunoglobulin (IVIG) prophylaxis against cytomegalovirus (CMV) infection after allogeneic hematopoietic cell transplantation (HCT) have often sparked controversy. In addition, we are not aware of any study that has examined whether prophylaxis with IVIG affects the incidence of CMV infection in high-risk patients--those who are elderly or have received human leukocyte antigen (HLA) mismatched HCT. In the present open-label, phase II study, we addressed this question. We enrolled 106 patients in the study. The cumulative incidences of CMV infection at 100 days after HCT were similar in the intervention and the control groups (68% and 64%, P=.89; 89% and 87%, P=.79, respectively, for patients 55 years or older and those who received HLA-mismatched HCT). In those who received HLA-mismatched HCT, 1-year overall survival after HCT was 46% in the intervention group and 40% in the control group (P=.31); for age≥55 years, the corresponding values were 46% and 40% (P=.27). Our data showed that prophylaxis with regular polyvalent IVIG did not affect the incidence of CMV infections or survival among older patients or those who receive HLA-mismatched HCT.

Extramedullary plasmacytoma of the dura mimicking meningioma

In December 2005, a 59-year-old man presented at ourNeurosurgery Department with a 2-month history ofamnesia and gait disturbance. A solid mass lesion wasdetected in the right temporal region on magnetic reso-nance imaging (MRI), presumed to be a meningioma(Fig. 1). He underwent surgery via a right temporal frontalcraniotomy and partial resection of the mass. Biopsy of themass demonstrated a densely cellular tumor composed ofplasma cells, positive for IgG and kappa light chain(Fig. 2), and negative for lambda chain, CD56 and cyclinD1. These findings were consistent with intracranialplasmacytoma.No additional sites of plasmacytoma were identified oneither computed tomography or bone scintigraphy, and bonemarrow plasmacytosis was absent (1.8% plasma cells,morphologically normal), and bone marrow cells showed anormal karyotype. Serum immunoglobulin levels werealmost normal (IgG 1,374 mg/dL, IgA 443 mg/dL, IgM54 mg/dL, IgE 81 IU/mL, IgD 7.6 mg/dL), and postopera-tive serum protein immunoelectrophoresis showed a smallM-component only (IgG-j). Urine Bence-Jones protein wasnot detected. Other organopathies, such as nephropathy,hypercalcemia and bone region, were absent. Thus, a diag-nosis of extramedullary plasmacytoma was made accordingto the classification of the International Myeloma WorkingGroup (IMWG) [1]. He underwent external beam radio-therapy to the brain at a dosage of 50 Gy, which resulted inthe disappearance of the remaining tumor region.In January 2007, he developed hoarseness and thoracicpain. Since CT scans demonstrated new masses at other sites(rib and vertebral bones), he was diagnosed with diseaseprogression. Laboratory findings showed an increased totalserum protein of 8.6 g/dL, IgG 3,629 mg/dL, and serumprotein immunoelectrophoresis revealed an evidentM-component of IgG-j. Bone marrow examination showedno evidence of plasmacytosis (2.4% plasma cells, withoutatypia) and chromosomal analysis revealed a normalkaryotype. Thereafter, he received several courses of che-motherapy with vincristine, doxorubicin and dexametha-sone. Despite treatment, regrowth of the mass was observed.He refused further therapy and was discharged from ourhospital.Patients with a solitary dural plasmacytoma have beenreported with a female predominance of 84% and a meanage of 50.2 years. Clinically, combination therapy includ-ing surgical resection followed by at least 50 Gy radio-therapy is recommended, and long-term survival has beenobserved. On the other hand, patients with myelomatousmeningeal involvement have shown an extremely poorprognosis despite intensified treatment, including intrathe-cal and/or systemic chemotherapy and cranial radiotherapy[2]. Our patient showed a recurrence almost 1 year after theinitial diagnosis. We consider that postoperative radio-therapy was delayed by about 2 months because of inten-sive care, which might have caused the early recurrence.

BK virus-associated nephropathy in an HIV-positive patient with gingival plasmablastic lymphoma

BK virus (BKV) nephropathy is common after renal transplantation, but less well characterized in patients with human immunodeficiency virus (HIV). Here, we report a rare case of BKV nephropathy in a patient with acquired immunodeficiency syndrome (AIDS)-related plasmablastic lymphoma (PBL). A 32-year-old man was admitted to our hospital with a complaint of gingival swelling in the right lower jaw of 3-month duration in February 2006. He had been diagnosed with an AIDS-related cytomegalovirus (CMV) enteropathy, in January 2006, when his CD4-positive lymphocyte count was 40/lL and HIV RNA viral load was 84000 copies/mL. He had no prior history of homosexuality or drug abuse. Treatment with ganciclovir and highly active antiretroviral therapy (HAART) was begun 1 month before admission to our hospital. On examination, there was a small left anterior cervical adenopathy, but no other lymph node was palpable. Intraorally, a painful outgrowth from the gingiva was present in the right mandibular molar area (Fig. 1). Laboratory values available on admission included a white blood cell count of 2130/lL (76% polymorphonuclear leukocytes, 18% lymphocytes, 5% eosinophils), a hemoglobin concentration of 8.6 g/dL, and platelet count of 367000/lL. Lactate dehydrogenase was 428 IU/L, blood urea nitrogen was 8.8 mg/dL and serum creatinine was 0.78 mg/dL. Urine dipstick indicated neither proteinuria nor glycosuria, and specific gravity was 1.010. The CD4 count was 3/lL, and HIV viral load was 4400 copies/mL. Biopsy sample from the right mandible region showed monomorphic dense proliferation of lymphoid cells with large, central or eccentrically placed nuclei, prominent nucleoli and abundant mitotic figures (Fig. 2). Immunohistochemical stains revealed that the large atypical lymphocytes were positive for CD79a, kappa light chain and CD38, and weakly positive for CD20 and Epstein–Barr virus (EBV) latent membrane protein (LMP). Results were negative for CD3, CD10, lambda light chain and CD138. The proliferation rate, as assessed by Ki-67/MIB-1 staining, was over 90%. EBV was identified by in situ hybridization, but no evidence of human herpes virus-8 (HHV-8) was detected. A diagnosis of PBL was made based on the diagnostic criteria of WHO. Computed tomography (CT) scans of the neck revealed an infiltrative mass in the right mandible with swelling of the soft tissue, and a lymph node (23 9 15 mm) in the left neck. Additional imaging of the chest, abdomen, and pelvis, and bone marrow aspiration were negative for lymphoma. Clinically, he had stage 2 disease. Chemotherapy was begun with cyclophosphamide, doxorubicin, vincristine and prednisolone. After three cycles of chemotherapy, he underwent external beam radiotherapy to the neck at a dosage of 30 Gy, which resulted in the disappearance of the remaining tumor lesion; however, he developed severe cytopenia and kidney dysfunction that serum creatinine progressed from 0.9 to 5.5 mg/dL over a 3-month period. Antiretroviral drugs and ganciclovir were suspected as the etiology, but a trial to M. Manabe (&) Y. Yoshii S. Mukai E. Sakamoto H. Kanashima H. Teshima Department of Hematology, Osaka City General Hospital, 2-13-22 Miyakojimahondori, Miyakojima-Ku, Osaka 534-0021, Japan e-mail: m1153564@med.osaka-cu.ac.jp

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.

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.

der(5;17)(p10;q10) Is a Recurrent But Rare Whole-Arm Translocation in Patients with Hematological Neoplasms: A Report of Three Cases

We report the cases of 3 patients with hematological malignancies and complex karyotypes involving der(5;17)(p10;q10), which results in the loss of 5q and 17p. Although deletions of 5q and 17p are recurrent abnormalities in hematological disease, only about 20 cases harboring der(5;17)(p10;q10) have been reported. We address the tumorigenesis and morphological characteristics of hematological malignancies involving der(5;17)(p10;q10), along with a review of the literature.

P2-20-2DIFFUSE LARGE B-CELL LYMPHOMA DURING AZATHIOPRINE THERAPY FOR AUTOIMMUNE HEPATITIS: A CASE REPORT

Abstract Introduction: Autoimmune hepatitis (AIH) is a form of chronic hepatitis of unknown aetiology. As for therapeutic agents, corticosteroids and azathioprine have been the standard therapy for AIH. On the other hand, immunosuppressant involving azathioprine may cause immunodeficiency - associated lymphoproliferative disorders (LPD). Herein, we report a case of diffuse large B-cell lymphoma (DLBCL) during azathioprine therapy for AIH. Case report: A 64-year-female was referred to our hospital because of epigastralgia on September 2013. She was diagnosed as having AIH 10 years previously, and since then she had been treated with corticosteroid alone, followed by steroid in combination with azathioprine. Physical examination revealed pale and anaemic conjunctivae. Endoscopic examination revealed an irregularly elevated mass in her antrum of stomach. Biopsy of the mass showed DLBCL. Because of uncontrollable bleeding, the patient underwent emergent gastrectomy. Pathological examination revealed EBER negativity; hence, it seemed that her disease course might have been poorer outcome. Then the patient was started on R-CHOP therapy and subsequently there were no evidence of relapse. Discussion: Azathioprine is among the immunosuppressive agents for various diseases such as Crohns disease, systemic vasculitis, and systemic lupus erythematosus. And for AIH, azathioprine is recommended as a suitable treatment. As far as we know, only few cases of immunodeficiency - associated LPD following azathioprine therapy for AIH have been described. The frequency, clinical course and prognostic value of immunodeficiency-associated LPD associated AIH has not been clarified yet because of its rarity, and further accumulation of cases is necessary for evaluation of the therapeutic outcome of immunodeficiency - associated LPD patients.

A Rare t(9;22;16)(q34;q11;q24) Translocation in Chronic Myeloid Leukemia for Which Imatinib Mesylate Was Effective: A Case Report

The t(9;22)(q34;q11) translocation is found in about 90% of chronic myeloid leukemia (CML) patients. About 5–10% of CML patients have complex variant translocations involving a third chromosome in addition to chromosomes 9 and 22. Herein, we describe a CML-chronic phase male with a complex translocation involving chromosome 16, t(9;22;16)(q34;q11;q24). First, he was treated with interferon-alpha and intermittent hydroxyurea, but only a partial cytogenetic response was attained. Subsequently, the patient was treated with imatinib mesylate because of an additional chromosome abnormality, trisomy 8. A major molecular response was obtained after one years imatinib therapy, and the follow-up chromosomal analysis performed 4 years and 3 months after the initiation of imatinib therapy displayed a normal karyotype of 46,XY.

Transient efficacy of cord blood transplantation in acute myeloid leukemia with t(16;21)(p11;q22)

A 58-year-old woman presented with a 2-week history of coughing and purpura in October 2006. A physical exam only found purpura and anemic conjunctiva. Her laboratory values on admission included a white blood cell count of 10340/mL (73% blasts), a hemoglobin concentration of 8.5 g/dL, a platelet count of 4000/mL and a lactate dehydrogenase level of 676 IU/L. Her bone marrow aspirate revealed 78% blasts, some of which displayed hemophagocytosis and intracytoplasmic vacuolation or both (Fig. 1). Cytochemically, the blasts were positive for myeloperoxidase. In surface marker analysis, the blasts displayed CD13, CD33, CD41, CD34 and CD56 expression but were negative for HLA-DR. A chromosomal study of her bone marrow cells revealed her karyotype to be 46XX,t(16;21)(p11.2;q22)[19]/46XX[1]. A diagnosis of acute myeloid leukemia (AML) with maturation was made. The patient received induction chemotherapy involving 100 mg/m cytosine arabinoside (Ara-C) on days 1 to 7 and 12 mg/m idarubicin on days 1 to 3 but remission was not achieved. Therefore, re-induction with 7 mg/m mitoxantrone on days 1 to 3 and 200 mg/m Ara-C on days 1 to 5 was attempted twice, eventually achieving complete hematological remission with no detectable chromosomal abnormalities. She then underwent an unrelated cord blood transplantation with a serologically 2 loci mismatched graft in March 2007. Due to her age, reduced-intensity conditioning consisting of 25 mg/m fludarabine per day for 5 days, 80 mg/m melphalan per day, and total body irradiation (4 Gy in two doses) was employed as a preparative regimen to avoid transplant-related mortality. Her posttransplantation course was relatively uneventful except for grade II acute graft versus host disease (GvHD) of the gut, which was resolved with the addition of steroids. By day +100, she had achieved full donor chimerism in her bone marrow and no chronic GvHD was seen. In January 2009 she was found to have a decreased hemoglobin level and she subsequently suffered a hematological relapse. Owing to her poor performance status she was administered only palliative chemotherapy consisting of Ara-C 100 mg/m alone on days 1 to 7 and died from pneumonia 31 months after the initial diagnosis. To date, about 60 cases of AML harboring t(16;21)(p11;q22) have been reported, and interestingly, according to the review by Kim et al., most of the t(16;21)(p11;q22)-AML cases involved Asians, especially from Korea and Japan. It was reported that this type of AML displays characteristics including hemophagocytosis and vacuolation of leukemic cells as well as a poor prognosis. Imashuku et al. suggested that its characteristic bone marrow morphology could be used to aid the prompt identification of patients with high risk t(16;21)(p11;q22)-AML requiring a hematopoietic stem cell transplantation (HSCT) in the early stages of treatment. Concerning HSCT, to the best of our knowledge, around 15 patients with t(16;21)(p11;q22)-AML have undergone an allogenic HSCT. However, only a few long-term survivors were reported to be among these HSCT recipients as the others suffered relapses. Although we used cord blood as a stem cell source so that we could perform allogenic HSCT promptly, unfortunately her AML relapsed. However, complete remission was maintained for 22 months after the transplantation. As the prognosis of t(16;21)(p11;q22)-AML is extremely poor, this type of AML should be treated early using a powerful modality such as HSCT during the first remission. Although the significance of an association between the genesis of t(16;21)(p11;q22) and regional differences in the incidence of this disease have not been clarified, we suggest that hematologists in Asia, the area where t(16;21)(p11;q22)-AML occurs most frequently, should be aware of the diagnostic and clinical features of this type of AML in order to improve the prognosis of patients with this translocation. Asia–Pacific Journal of Clinical Oncology 2011; 7: 315–316 doi:10.1111/j.1743-7563.2011.01427.x