Clinical effects of recombinant thrombomodulin and defibrotide on sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation.

Sinusoidal obstruction syndrome (SOS) is a lethal complication after hematopoietic stem cell transplantation (HSCT). Defibrotide (DF) is the only drug internationally recommended for SOS treatment in Western countries. Recombinant human soluble thrombomodulin (rhTM), which is promising for the treatment of patients with disseminated intravascular coagulation, is also reported to be potentially effective for SOS. To clarify the safety and efficacy of DF and rhTM, we conducted a retrospective survey of these agents in Japan. Data from 65 patients who underwent allogeneic HSCT and received DF (n = 24) or rhTM (n = 41) for SOS treatment were collected. The complete response rates for SOS on day 100 were 50% and 54% in the DF and rhTM groups, respectively. The 100-day overall survival rates were 50% in the DF group, and 48% in the rhTM group. Several severe hemorrhagic adverse events were observed in one patient in the DF group and five patients in the rhTM group. The main causes of death were SOS-related death, and no patient died of direct adverse events of DF or rhTM. Our results suggest that rhTM, as well as DF, can be effective as a novel treatment option for SOS.

[Analysis of prognostic factors in transplant-eligeble newly diagnosed myeloma patients treated with bortezomib plus dexamethasone as induction therapy].

We retrospectively analyzed, and herein discuss, the outcomes of and prognostic factors for 35 untreated multiple myeloma patients less than 65 years of age who received induction therapies with bortezomib (Bor) and dexamethasone (BD) for the purpose of up-front autologous peripheral blood stem cell transplantation (SCT). The overall response rate was 77% (27 cases, including 4 [11%] complete response and 13 [37%] very good partial response cases). The rate of SCT accomplishment was 51% (18 cases). The 3 year-progression free survival (PFS) rate for the SCT group was significantly higher than that of the non-SCT group (41% vs 0%, P=0.0037). This result reflects the significantly more severe adverse effects of induction therapy for the non-SCT than the SCT group. Among reasons for SCT drop-out, 29% of cases suffered severe peripheral neuropathy with features such as irreversible numbness and pain. The analysis of PFS revealed a cytogenetic factor, favorable chromosomal type at diagnosis, to predict a better outcome (P values on univariate and multivariate analyses were 0.0004 and 0.0405, respectively). Our observations suggest establishment of induction therapy, aimed at reducing adverse effects and overcoming unfavorable cytogenetic abnormalities, to be necessary for improving the outcomes of patients with multiple myeloma.

Successful pregnancy and delivery via in vitro fertilization with cryopreserved and thawed embryo transfer in an acute myeloid leukemia patient after allogeneic bone marrow transplantation.

As the number of young long-term survivors of hematopoietic stem cell transplantation (HSCT) for acute leukemia continues to increase, post-transplant infertility is becoming a significant concern. HSCT, particularly with cyclophosphamide and total body irradiation conditioning, is known to cause secondary premature ovarian failure, resulting in infertility. To preserve post-transplant fertility, several methods have been proposed, including in vitro fertilization (IVF) with embryo cryopreservation. Due to the aggressiveness of acute leukemia, however, patients have little chance to undergo egg harvesting and IVF before they must begin receiving chemotherapy. To the best of our knowledge, there have been no detailed reports of successful pregnancy after HSCT using IVF with embryo cryopreservation and transfer in a patient with acute myeloid leukemia. Here, we report the case of a 42-year-old woman with acute myeloid leukemia who became pregnant 2 years and 2 months after allogeneic bone marrow transplantation via IVF-embryo transfer with an egg collected after induction therapy and delivered a full-term healthy infant.

Biweekly THP-COP therapy for newly diagnosed peripheral T-cell lymphoma patients.

Pirarubicin tetrahydropyranyl adriamycin (THP-ADR) is an analogue of doxorubicin. This agent exhibits activity against some doxorubicin-resistant cell lines. We performed a phase II study of biweekly THP-COP [50 mg/m(2) pirarubicin, 750 mg/m(2) cyclophosphamide, 1.4 mg/m(2) vincristine (2.0 mg maximum) on day 1, and 100 mg/body predonisolone on days 1-5] in patients with peripheral T-cell lymphoma (PTCL). Seventeen patients with newly diagnosed PTCL were enrolled. Histological diagnoses were of PTCL, not otherwise specified (n = 5), or angioimmunoblastic T-cell lymphoma (n = 12). All diagnostic specimens including those of the historical control group were centrally reviewed by hematological pathologists. All patients received six cycles of biweekly THP-COP. The patient group included 13 male and 4 female patients, with a median age of 62 years. The median follow-up time in surviving patients was 30 months. Overall response rate was 94% with 15 cases of complete remission (88%). The 3-year progression-free survival and overall survival rates were 57% and 75%, respectively. The most frequent adverse events associated with biweekly THP-COP were leukocytopenia (100%), neutropenia (100%), and lymphopenia (100%), followed by alopecia (92%) and anaemia (88%). All of these occurred only transiently, and the patients subsequently recovered. Biweekly THP-COP is a safe and promising therapy for patients with newly diagnosed PTCL. This study is registered in a public database (UMIN000010485).

Prognostic significance of serum beta-2 microglobulin level in Hodgkin lymphoma treated with ABVD-based therapy.

The levels of serum beta-2 microglobulin (ß2MG) are determined mainly from lymphoid tissue. To examine its prognostic value in Hodgkin lymphoma (HL), we conducted a retrospective analysis. We analyzed 67 patients with HL diagnosed and treated at seven institutes of the Yokohama City University Hematology Group between 1998 and 2011. The patients included 40 males and 27 females with a median age of 41 years (range 16-81 years). The HL subtypes were nodular sclerosis classical HL in 37 patients, mixed cellular classical HL in 23, lymphocyte-rich classical HL in 6, and nodular lymphocyte-predominant HL in 1. The 4-year overall survival (OS) rate of all 67 patients was 89 %. Patients with ß2MG levels ≥ 2.5 mg/L (n = 18) showed inferior progression-free survival (PFS; 4-year PFS rate, 42 %) and inferior OS (4-year OS rate, 60 %) compared to patients who had ß2MG levels <2.5 mg/L (n = 49; 4-year PFS rate, 87 %; 4-year OS rate, 98 %; P < 0.001). In multivariate analysis, only a serum ß2MG level ≥ 2.5 mg/L was a significant adverse prognostic factor in regard to PFS (P = 0.04; relative risk 3.57). However, it was not significant prognostic factor for OS (P = 0.16) in the multivariate analysis. The serum ß2MG level at diagnosis is a useful prognostic marker in patients with HL.

European Treatment and Outcome Study score does not predict imatinib treatment response and outcome in chronic myeloid leukemia patients.

The Sokal and Hasford scores were developed in the chemotherapy and interferon era and are widely used as prognostic indicators in patients with chronic myeloid leukemia (CML). Recently, a new European Treatment and Outcome Study (EUTOS) scoring system was developed. We performed a multicenter retrospective study to validate the effectiveness of each of the three scoring systems. The study cohort included 145 patients diagnosed with CML in chronic phase who were treated with imatinib. In the EUTOS low- and high-risk groups, the cumulative incidence of complete cytogenetic response (CCyR) at 18 months was 86.9% and 87.5% (P = 0.797) and the 5-year overall survival rate was 92.6% and 93.3% (P = 0.871), respectively. The cumulative incidence of CCyR at 12 months, 5-year event-free survival and 5-year progression-free survival were not predicted using the EUTOS scoring system. However, there were significant differences in both the Sokal score and Hasford score risk groups. In our retrospective validation study, the EUTOS score did not predict the prognosis of patients with CML in chronic phase treated with imatinib.

Drug-induced liver injury after allogeneic bone marrow transplantation.

A 23-year-old woman developed acute severe hepatitis and jaundice on day 183 after bone marrow transplantation from HLA-B antigen mismatched-related donor. The administration of prednisolone and cessation of the prescribed drugs resolved the liver injury. Drug lymphocyte stimulation test was positive for acyclovir, and liver biopsy indicated the characteristics of drug-induced liver injury (DILI) rather than graft-versus-host disease. Physicians should keep DILI in mind when considering differential diagnosis for liver complications after allogeneic cell transplantation.

Standard R-CHOP therapy in follicular lymphoma and diffuse large B-cell lymphoma.

The introduction of rituximab (R) has measurably improved the outcome of patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). To evaluate the outcome of patients with FL and DLBCL under R plus CHOP therapy, we performed a retrospective analysis in Yokohama City University Hematology Group in Japan. Five hundred and twenty-six patients (158, FL ; 368, DLBCL) were scheduled to undergo primary therapy with 6 cycles of full-dose R-CHOP therapy with curative intent. The median observation periods in living patients with FL and DLBCL were 45 months and 43 months, respectively. The complete response, 5-year progression-free survival (PFS), and 5-year overall survival (OS) rates were 86%, 50%, and 92% in the FL group, and 89%, 72%, and 80% in the DLBCL group, respectively. Although PFS was significantly better in the DLBCL group than in the FL group, OS was significantly better in FL patients. We also found that the OS and PFS of grade 3 FL patients were not statistically different from those with grade 1-2. These findings indicate that all grades of FL should be categorized simply as "FL" with regard to R-CHOP therapy. Our results also demonstrate the incurability of FL (grade 1-3B), even with R-CHOP therapy.

Absolute monocyte count in follicular lymphoma patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.

Elevated absolute monocyte counts (AMCs) have been reported to indicate poor prognosis for patients with lymphoproliferative disease, including those with follicular lymphoma (FL) receiving various treatments. We evaluated the prognostic impact of AMC in 150 consecutive FL patients who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Progression-free survival (PFS) did not differ significantly according to the AMC level. Univariate and multivariate analyses did not indicate a prognostic significance of AMC for PFS. Thus, the AMC is not a prognostic factor for FL patients treated with R-CHOP. However, immunochemotherapy might influence the prognostic impact of AMC.

Upfront autologous stem cell transplantation for untreated high-risk diffuse large B-cell lymphoma in patients up to 60 years of age.

BACKGROUND: Although rituximab added to CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) is the standard chemotherapy for untreated DLBCL, its therapeutic effect is limited in younger patients with high-intermediate risk or high-risk disease according to the age-adjusted international prognostic index. In fact, the efficacy and safety of HDT plus rituximab followed by ASCT for such patients remain unclear. PATIENTS AND METHODS: We retrospectively investigated the safety and effectiveness of HDT/ASCT in patients with untreated DLBCL. Twenty-two patients, aged 60 years and younger, with untreated DLBCL (classified as high-intermediate [n = 14 (64%)] or high [n = 8 (32%)] risk) underwent upfront HDT/ASCT between January 2004 and December 2008, achieving either a complete response (CR; n = 15 (68%)) or a partial response (PR; n = 7 (32%)). RESULTS: The 5-year overall survival rate was 81.0% and the progression-free survival rate was 73.0%, with no significant difference between risk groups based on the international prognostic index. The most common nonhematologic toxicity was febrile neutropenia [n = 9 (41%)]. The cause of all 3 fatalities was exacerbation of the underlying disease, and no treatment-related mortality was observed. No variables with a significant influence on overall survival were identified, but a correlation of the treatment response before transplanation with progression-free survival was suggested (CR vs. PR: 92% vs. 30%, P = .002). CONCLUSION: These results suggest that adding rituximab to upfront HDT/ASCT is feasible and can improve the outcome in untreated patients with poor-prognosis DLBCL. In the future, upfront HDT/ASCT should be more extensively evaluated in clinical trials.

Successful treatment of a patient with adult T cell leukemia/lymphoma using anti-CC chemokine receptor 4 monoclonal antibody mogamulizumab followed by allogeneic hematopoietic stem cell transplantation.

Adult T cell leukemia/lymphoma (ATLL) is an aggressive peripheral T cell neoplasm caused by human T cell lymphotropic/leukemia virus type-1 and has a poor prognosis. A new anti-CC chemokine receptor 4 monoclonal antibody (mogamulizumab) has been shown to be effective for ATLL. Although mogamulizumab is now available in Japan for patients with ATLL, the influence on allogeneic hematopoietic stem cell transplantation (HSCT) remains unclear. Here we report a woman with ATLL resistant to combination chemotherapy, who achieved complete remission following treatment with mogamulizumab and subsequently received allogeneic HSCT. The patient has remained in complete remission with controlled graft-versus-host disease. To our knowledge, this is the first report of an ATLL patient who received mogamulizumab treatment followed by allogeneic HSCT. We suggest that administration of mogamulizumab to chemotherapy-resistant patients with ATLL may improve their disease status before allogeneic HSCT and result in better survival.

Concentrated ascites reinfusion therapy for sinusoidal obstructive syndrome after hematopoietic stem cell transplantation.

Sinusoidal obstruction syndrome (SOS) is one of the severe complications of hematopoietic stem cell transplantation (HSCT). Systemic management including respiratory and circulatory support is necessary. In addition, abdominal paracentesis is often needed for pain relief and to reduce the pressure of tense ascites. Concentrated ascites reinfusion therapy (CART) involves the filtration, concentration, and reinfusion of drained ascites, which contributes to reuse of autologous proteins. CART has been reported as supportive therapy for patients with liver cirrhosis and cancer. We retrospectively reviewed the efficacy and safety of CART in three patients (two with acute myelogenous leukemia and one with chronic myeloid leukemia) who developed SOS after allo-HSCT. They all had symptomatic, tense, and diuretic-refractory ascites with right costal pain and marked weight gain. Two patients showed immediate improvement after CART. However, one patient experienced four CARTs with slow recovery. All patients are now alive and are being monitored as outpatients over 2 years with remission. No severe adverse event was observed related to CART, and 25.2-98.0 (median 30.2) grams of albumin was collected and reinfused. CART after paracentesis reduces protein loss in ascites by reinfusion of autologous protein instead of exogenous albumin preparations. Although transient fever is reported as a frequent adverse event, no events like severe bleeding or infection were observed. While its safety has not been fully established in patients with hematological disease after HSCT, CART may be a considerable supportive therapy for SOS with tense ascites.

R-CHOP therapy alone in limited stage diffuse large B-cell lymphoma.

Long-term observation has identified a pattern of continuing relapse in limited stage diffuse large B-cell lymphoma (DLBCL) treated by three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus involved-field irradiation. We retrospectively analysed 190 untreated patients with limited stage DLBCL treated by R-CHOP alone. All the patients were scheduled to undergo primary therapy with six cycles of full-dose R-CHOP. Cases with a dose reduction of more than 20% were excluded from the study. Additional local irradiation was allowed in patients with partial response (PR). Five patients received additional local irradiation after PR at the end of the R-CHOP therapy. The median observation period was 52 months. Median age at diagnosis was 63 years. The responses to therapy were 180 complete responses, eight PR, and two progression of disease (PD). The 5-year progression-free survival and 5-year overall survival rates were 84% and 90%, respectively, both in plateau. During the observation period, 29 patients experienced PD. The progression sites were the primary sites in 15 patients, outside the primary sites in 10, and undetermined in four patients. These results suggest that the 'standard' strategy of three cycles of R-CHOP followed by involved-field radiotherapy for limited stage DLBCL could be effectively replaced by six cycles of R-CHOP alone.

Successful treatment of a pregnant woman with Philadelphia chromosome-positive acute lymphoblastic leukemia.

The management of acute leukemia during pregnancy is challenging. Delays in treatment for acute leukemia can adversely affect maternal prognosis, but chemotherapy during pregnancy may induce severe adverse effects on the fetus. Here, we report a case of a pregnant woman with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) who underwent remission induction therapy and successfully delivered a live infant after chemotherapy. The case is a 36-year-old woman diagnosed with Ph(+)ALL in the 27th week of pregnancy. She underwent remission induction therapy including daunorubicin, vincristine, cyclophosphamide, and prednisolone. Imatinib was not used in the induction therapy. She delivered the infant after one course of chemotherapy. The infant and the patient are both alive now, without any major complications.

Clinical features of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue.

We newly diagnosed 131 patients with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue lymphoma between 1998 and 2010. We retrospectively studied 124 patients for whom complete clinical data were available at presentation and who had minimally undergone tumour staging by physical examination, computed tomography (CT), bone marrow aspiration, and biopsy. A slight female predominance (men, 58; women, 66) was observed in the study population; the median age was 67 years. The primary locations at presentation were the stomach (38%), orbita (20%), lung (12%), intestinal tract (8%), thyroid gland (6%), others (14%), and unknown (2%). Seventy per cent of patients had localized disease. Of the 124 patients, 14 (11%) had lymph node involvement, and 5 (4%) had bone marrow involvement. Five (4%) patients had both lung and gastric involvement. The 5-year overall survival rate for the 124 patients was 96.1%. The overall vital prognosis was excellent. Moreover, gastro-intestinal fiberscopic examination is essential, especially in cases with lung involvement at presentation.

[Biclonal co-existence of t(15;17) and t(9;22) chromosomal abnormalities in acute promyelocytic leukemia].

A 50-year-old male was admitted to our hospital with pancytopenia. Peripheral blood examination showed pancytopenia (WBC 450/µl, Hb 7.3 g/dl, Plt 3,000/µl) and elevated FDP. Bone marrow examination demonstrated 38% blasts, 20% promyelocytes and Faggot cells. Cytogenetic analysis demonstrated the following: 46, XY, t(15;17)(q22;q12)[9]/46, XY, del(6)(q?), t(9;22)(q34;q11.2)[1]/46, XY[10]. PML/RARA and minor BCR/ABL were also detected by quantitative reverse transcription polymerase chain reaction of bone marrow cells (52,000 copies/µgRNA and 650 copies/µgRNA, respectively). The patient was diagnosed with acute promyelocytic leukemia. He was treated with all-trans retinoic acid monotherapy and achieved complete hematological remission 51 days after the initial treatment. Post-induction bone marrow examination demonstrated 46, XY[20] and PML/RARA 240 copies/µgRNA, whereas minor BCR/ABL was not detected. The patient's initial cytogenetic analysis suggested the presence of two distinct clones with t(15;17) and t(9;22), which to our knowledge have not previously been reported.

Long-term outcome of human herpesvirus-6 encephalitis after allogeneic stem cell transplantation.

Human herpesvirus-6 (HHV-6) encephalitis is recognized as a relatively rare, but sometimes lethal, complication of allogeneic hematopoietic stem cell transplantation (HSCT). Although the development of new diagnostic techniques and antiviral therapy has improved, the prognosis of encephalitis is still unclear. We surveyed 197 patients who underwent allogeneic HSCT between January 2004 and March 2008 at our institution, and 8 (4.0%) were diagnosed as having HHV-6 encephalitis. Five were male and 3 were female, with a median age of 40.5 years. The median onset of HHV-6 encephalitis was 18 days after HSCT, and the median duration of antiviral therapy was 41 days. The median survival time from the onset of encephalitis was 23.1 months (range: 2.7-66.7), and 3 patients died of unrelated causes (sepsis in 2 and gastrointestinal tract bleeding in 1). Cord blood transplantation was identified as the only independent risk factor (relative risk [RR] = 4.98; P = .049) by multivariate analysis. There was no statistical significance of survival after HSCT between the patients with HHV-6 encephalitis and those without HHV-6 encephalitis (the 2-year survival rate was 60% and 52.6%, respectively; P = .617). Four of the 5 surviving patients were unable to return to society because of neuropsychological disorders, including anterograde amnesia and seizures with prominent hippocampal atrophy. Although HHV-6 encephalitis occurring after HSCT is now becoming a curable complication, its sequelae, such as neuropsychological disorders, have a marked influence on the quality of life of long-term survivors. Accordingly, it is necessary to identify risk factors for HHV-6 encephalitis and establish methods for prevention of this complication.

A retrospective analysis of obstetric patients with idiopathic thrombocytopenic purpura: a single center study.

Idiopathic thrombocytopenic purpura (ITP) commonly affects women of childbearing age. We studied the clinical characteristics of pregnant women with ITP to estimate their risks of bleeding. A retrospective chart review was performed for all obstetric patients with ITP who had delivery at our hospital, from 1 March 2000 to 31 March 2008. Twenty women with ITP delivered 24 children in 23 pregnancies. In all, eight women were treated with corticosteroid during their pregnancy period, and there was only one non-responder. There was no correlation between the maternal platelet count and the amount of blood loss at delivery. Two infants were revealed to have had platelet counts lower than 30 × 109/L, and were treated with high-dose IV IgG. One of them also received corticosteroid therapy. There was no relationship between maternal platelet count at delivery and infant platelet count at birth. Overall, no serious bleeding event was seen in either of the mothers or infants. For most women with ITP, pregnancy is uncomplicated, and even those with severe thrombocytopenia during pregnancy have good outcomes when under the strict care of a hematologist and gynecologist.