Double-unit cord blood transplantation after myeloablative conditioning for patients with hematologic malignancies: a multicenter phase II study in Japan.

We analyzed the outcomes of 61 patients with hematologic malignancies who underwent double-unit cord blood transplantation (dCBT) after myeloablative conditioning performed as part of a prospective multicenter phase II study. The conditioning regimen for dCBT included total body irradiation, cyclophosphamide, and granulocyte colony-stimulating factor combined with cytosine arabinoside for myeloid malignancies and with total body irradiation and cyclophosphamide for lymphoid malignancies. The cumulative incidence of neutrophil engraftment after dCBT was 85% (95% confidence interval [CI], 73%-92%). All 51 of the patients who engrafted had complete chimerism derived from a single donor by day +60. Only the degree of HLA disparity in the host-versus-graft direction had an impact on unit dominance. The cumulative incidence of grade II-IV acute graft-versus-host disease was 25% (95% CI, 15%-37%), and that of chronic graft-versus-host disease was 32% (95% CI, 20%-44%). The 1-year cumulative incidence of relapse was 23% (95% CI, 13%-34%), and that of transplantation-related mortality was 28% (95% CI, 17%-39%). With a median follow-up of 41 months, event-free survival was 48% (90% CI, 37%-58%) at 1 year and 46% (90% CI, 35%-56%) at 3 years. Event-free survival at 3 years was 67% (95% CI, 46%-81%) for patients with standard risk and 29% (95% CI, 15%-45%) for those with advanced risk. This study suggests that dCBT after myeloablative conditioning is a promising alternative for adults and large children with hematologic malignancies who need stem cell transplantation but lack a suitable adult donor or an adequate single-unit cord blood graft.

Clinical evaluation of WT1 mRNA expression levels in peripheral blood and bone marrow in patients with myelodysplastic syndromes.

A study to evaluate WT1 mRNA expression levels in peripheral blood (PB) and bone marrow aspirate (BM) was conducted in 172 patients, including 115 with myelodysplastic syndromes (MDS), in Japan. The level of WT1 mRNA expression was evaluated according to the French-American-British (FAB) and World Health Organization (WHO) classifications (2001, 2008) and using the International Prognostic Scoring System and the WHO Prognostic Scoring System scales. WT1 mRNA expression levels in PB and BM were well correlated (r = 0.85), and they tended to increase with disease stage progression and in those at higher risk of leukemic transformation. WT1 mRNA expression can be a useful marker for the diagnosis and risk evaluation of MDS.

Phase II study of intensive post-remission chemotherapy and stem cell transplantation for adult acute lymphoblastic leukemia and lymphoblastic lymphoma: Japan Clinical Oncology Group Study, JCOG9402.

OBJECTIVE: To evaluate the efficacy and safety of intensive post-remission chemotherapy for untreated patients aged 15-69 years with adult acute lymphoblastic leukemia and lymphoblastic lymphoma in a multicenter Phase II study. METHODS: The chemotherapy regimen consisted of induction, post-remission and maintenance for 2 years. The primary endpoint was 5-year progression-free survival, and secondary endpoints included complete remission rate, overall survival and adverse events. Among 115 patients enrolled, 108 eligible patients [median age, 33.5 years (range, 15-69)] including 96 acute lymphoblastic leukemia and 12 lymphoblastic lymphoma were assessed. Other major characteristics were male 50%, T-cell phenotype 21%, Philadelphia chromosome 22%, B-symptom+ 35% and performance status 2/3 22%. RESULTS: Eighty-seven patients achieved complete remission (81%; 95% confidence interval 72-88%), while five (5%) died during the chemotherapy protocol. The median overall survival and progression-free survival were 1.8 years (95% confidence interval, 1.5-2.6) and 1.2 years (95% confidence interval, 0.8-1.6), respectively. Their 5-year overall survival and progression-free survival were 29 and 28%, respectively. The 5-year overall survival of 31 patients who underwent allogeneic (n = 19) or autologous (n = 12) stem cell transplantation during first complete response was 51%. Major non-hematologic toxicities of Grade 3 or greater were infections (21%) and pulmonary complications (6%). When compared with the investigators' previous Phase II trials, JCOG9402 improved progression-free survival and overall survival when compared with JCOG8702; however, it did not show improvement when compared with JCOG9004. CONCLUSIONS: Although the intensified induction and post-remission chemotherapy was feasible and 28% of the patients with adult acute lymphoblastic leukemia or lymphoblastic lymphoma achieved long-term progression-free survival, JCOG9402 did not show improvement.

[A case of advanced gastric cancer with liver metastases successively treated with S-1/CDDP combination therapy followed by curative resection].

The patient was a 67-year-old male with type-3 gastric cancer from the upper body of the stomach to the cardia. An abdominal computed tomography scan revealed liver metastases(S8)(T2N0M0H1, Stage IV). The patient received neoadjuvant combined chemotherapy with S-1 and CDDP. S-1(120mg/body/day)was orally administered for 3 weeks followed by 2 drug-free weeks as a course, and CDDP(60mg/m2)was administered by intravenous infusion on day 8. After the second course, significant tumor reduction and disappearance of liver metastases resulted. Total gastrectomy, splenectomy, cholecystectomy, and D2 nodal dissection were performed. The histological diagnosis revealed no metastases in all lymph nodes: Stage I B. The combined neoadjuvant chemotherapy with S-1 and CDDP can be considered an effective treatment for advanced gastric cancer.

Repeated donor lymphocyte infusions overcome a myeloid sarcoma of the stomach resulting from a relapse of acute myeloid leukemia after allogeneic cell transplantation in long-term survival of more than 10 years.

A patient with acute myeloid leukemia had a relapse with a myeloid sarcoma of the stomach 32 months after allogeneic bone marrow transplantation. The patient was treated with the first donor lymphocyte infusion (DLI) and one course of induction chemotherapy. Due to severe infectious complication after chemotherapy, the patient could not continue chemotherapy. Subsequently, the patient was treated with a total of 13 cycles of DLI at 1-2 month intervals. Complete remission was achieved and neither relapse nor graft versus host disease has occurred during a follow-up of more than 10 years.

Feasibility of reduced-intensity cord blood transplantation as salvage therapy for graft failure: results of a nationwide survey of adult patients.

To evaluate whether rescue with cord blood transplantation (CBT) could improve the poor survival after graft failure (GF), we surveyed the data of 80 adult patients (median age, 51 years) who received CBT within 3 months of GF (primary 64, secondary 16), with fludarabine-based reduced-intensity regimens with or without melphalan, busulfan, cyclophosphamide, and/or 2-4 Gy total-body irradiation (TBI). A median number of 2.4 × 10(7)/kg total nucleated cells (TNC) were infused, and among the 61 evaluable patients who survived for more than 28 days, 45 (74%) engrafted. The median follow-up of surviving patients was 325 days, and the 1-year overall survival rate was 33% despite poor performance status (2-4, 60%), carryover organ toxicities (grade 3/4, 14%), and infections (82%) prior to CBT. Day 100 transplantation-related mortality was 45%, with 60% related to infectious complications. Multivariate analysis showed that the infusion of TNC ≥2.5 × 10(7)/kg and an alkylating agent-containing regimen were associated with a higher probability of engraftment, and that high risk-status at the preceding transplantation and grade 3/4 organ toxicities before CBT were associated with an increased risk of mortality. In conclusion, in an older population of patients, our data support the feasibility of CBT with a reduced-intensity conditioning regimen for GF.

Clinical significance of minimal residual disease in adult acute lymphoblastic leukemia.

Monitoring minimal residual disease (MRD) in patients with acute lymphoblastic leukemia (ALL) is a useful way for assessing treatment response and relapse. We studied the value of MRD and showed a correlation with relapse for 34 adult patients with ALL. MRD was evaluated by real-time quantitative polymerase chain reaction (RQ-PCR) with probes derived from fusion chimeric genes (BCR/ABL) (n = 12) or PCR-based detection of clonal immunoglobulin and T cell receptor gene rearrangements (n = 16), or both (n = 6). We analyzed 27 of the 34 patients who could be examined for MRD on day 100 after induction therapy. The overall survival (OS) rate (45.0%) and relapse-free survival (RFS) rate (40.0%) at 2 years in complete remission (CR) patients with MRD level ≥ 10⁻³ (n = 12) were significantly lower than those in CR patients with MRD level <10(-3) (n = 15) (OS rate 79.0%, RFS rate 79.4%) (log-rank test, P = 0.017 and 0.0007). We also applied multicolor flow cytometry for comparison with MRD results analyzed by PCR methods. The comparison of results obtained in 27 follow-up samples showed consistency in 17 samples (63.0%) (P = 0.057). MRD analysis on day 100 is important for treatment decision in adult ALL.

Pretreatment total serum protein is a significant prognostic factor for the outcome of patients with peripheral T/natural killer-cell lymphomas.

Peripheral T- and NK-cell lymphomas (PT/NKCLs) are relatively rare, and few studies have validated the International Prognostic Index (IPI) for PT/NKCLs in prospective clinical trials. Histopathological specimens from 136 patients, enrolled in six prospective multicenter trials of doxorubicin-containing regimens, with PT/NKCLs were reviewed by six hematopathologists following the WHO classification. This combined analysis demonstrated that the IPI was not predictive of prognosis for patients with PT/NKCLs as previously shown by GELA. In a univariate analysis, low total serum protein (TP) and albumin levels, gastrointestinal tract involvement, and histologic subtype (extranodal NK/T-cell lymphoma, nasal type, and peripheral T-cell lymphoma, unspecified) were significantly associated with reduced survival. In a multivariate analysis, TP (p = 0.004) and histologic subtype (p = 0.024) remained significant. We discuss the need to establish the importance and meaning of TP and to develop new strategies for patients with PT/NKCLs allowing for TP, especially with worse histologic subtypes.

Prognostic analysis and a new risk model for Hodgkin lymphoma in Japan.

The Japan Clinical Oncology Group conducted two multicenter phase II trials in 200 patients with advanced Hodgkin lymphoma (HL) in the 1990s. Among 181 patients whose histopathological specimens were available and reviewed by 6 hematopathologists, 167 (92.3%) were diagnosed with HL. Five-year overall survival (OS) among these 167 patients was 88.3%, including 89.2% among nodular sclerosis and 82.2% among mixed cellularity cases. International prognostic score was not closely associated with OS. Seven unfavorable prognostic factors for OS on univariate analysis were male, B symptoms, clinical stage of III or IV, elevated serum LDH, elevated alkaline phosphatase, elevated beta2-microglobulin, and pathological subtype (mixed cellularity and lymphocyte depletion). On multivariate analysis, male [HR 3.30 (95% CI 1.15-9.52, p = 0.027)] and elevated serum LDH [HR 2.41 (95% CI 1.07-5.43, p = 0.034)] were independent factors for OS. Based on these prognostic factors, the 5-year OS was 95.7% in the low-risk group (no adverse factor), 87.9% in the intermediate-risk group (1 adverse factor) and 73.3% in the high-risk group (2 adverse factors). This simple prognostic model for HL warrants further validation studies.

[Cost benefit analysis for prophylactic use of itraconazole versus fluconazole after hematopoietic stem cell transplantation].

Systemic fungal infection (SFI) is now one of the main causes of death from infective complications after hematopoietic stem cell transplantation (HSCT) and the role of prophylaxis of fungal infection has been established. However, there is no evidence evaluating the cost-benefit ratio of SFI management in Japan. To estimate the medical costs on prophylaxis and treatment of SFI in HSCT, we embarked on a randomized control prospective study of the medical cost-benefit ratio comparing fluconazole with itraconazole for antifungal prophylaxis in 40 patients who received HSCT in our hospital. Despite the similarity of efficacy for prophylaxis, the median cost of itraconazole prophylaxis between Day-10 and Day+28 was significantly less than that of fluconazole. There are many patients who require an i.v. formulation because of non-compliance with oral administration after HSCT and these cases cause increased medical costs. Therefore, further investigation is needed not only regarding differences among prophylactic agents but also regarding differences in administration routes focusing on the cost-effectiveness of treatment.

Successful voriconazole treatment of invasive pulmonary aspergillosis in a patient with acute biphenotypic leukemia.

A 23-year old woman with acute biphenotypic leukemia (ABL) complained of chest pain with cough, high fever and hemoptysis during induction chemotherapy, although she had been treated with anti-biotics and micafungin. We made a clinical diagnosis of invasive pulmonary aspergillosis (IPA) based on a consolidation in the right upper lung field on a chest radiograph as well as a high level of serum beta-D-glucan (with no evidence of tuberculosis and candidiasis). We changed her treatment from micafungin to voriconazole. Later, we discovered an air-crescent sign by CT scan that supported the diagnosis of IPA. Following voriconazole treatment, clinical symptoms ceased and abnormal chest shadows improved gradually and concurrently with a recovery of neutrophils. IPA must be considered in immunocompromised patients with pulmonary infiltrates who do not respond to broad-spectrum antibiotics. Serological tests and CT findings can aid in early diagnosis of IPA, which, along with treatment for IPA, will improve clinical outcomes.

Mesenchymal stem cells for treatment and prevention of graft-versus-host disease after allogeneic hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective therapy for hematological malignancies and inherited diseases. However, acute graft-versus-host-disease (aGVHD) is a major life-threatening complication after allo-HCT and there are few therapeutic options for severe steroid-refractory aGVHD. Preliminary studies on co-transplantation of mesenchymal stem cells (MSCs) have shown an improvement in or resolution of severe aGVHD. However, the mechanism underlying this immunosuppressive effect has not been elucidated. Most of the data suggest that the immunosuppressive effect involves soluble factors such as IL-6 or TGF-beta as well as cell-cell contact dependence. MSCs interact either directly with T cells or indirectly via other immune cells such as dendritic cells and NK cells. Here we review the immunomodulatory function of MSCs in allo-HCT and their potential usefulness in the treatment or prevention of severe acute GVHD.

Diffuse large B-cell lymphoma with massive portal vein tumor thrombosis in a patient with alcoholic cirrhosis: a case report and literature review.

We describe a case of diffuse large B-cell lymphoma with massive portal vein tumor thrombosis in a patient with alcoholic cirrhosis. The tumor was detected only in the intrahepatic portal vein and the spermatic cord by FDG-PET/CT. Percutaneous liver biopsy and orchiectomy were performed and histological examination revealed diffuse large B-cell lymphoma. The tumor showed complete response after six courses of the combination chemotherapy. Portal vein tumor thrombosis of malignant lymphoma is extremely rare; moreover, it is possible that this is the first case of malignant lymphoma originating from the spermatic cord producing portal vein tumor thrombosis.

Phase I/II and pharmacokinetic study of cladribine with 2-h infusion in Japanese patients with relapsed indolent B-cell lymphoma mostly pretreated with rituximab.

We conducted a phase I/II study to investigate the toxicity, pharmacokinetics, and efficacy profiles of cladribine with 2-h intravenous infusion for five consecutive days every four weeks in Japanese patients with relapsed indolent B-cell lymphoma. This was a dose-escalation study to confirm the safety of the doses which have been recommended for Caucasian patients (phase I), and to further evaluate the efficacy and safety (phase II). In the phase I portion for nine patients, no dose-limiting toxicities were observed at levels 1 (0.09 mg/kg/day, n = 3) and 2 (0.12 mg/kg/day, n = 6). No appreciable accumulation of plasma cladribine concentration was suggested. We enrolled a total of 20 patients, and an additional 14 patients in the phase II portion at level 2 (0.12 mg/kg/day). Eighteen patients, including 13 with follicular lymphoma, were eligible for efficacy evaluation, and 15 (83%) were pretreated with rituximab. The overall response rate was 50% (9/18; 80% confidence interval, 35-65%), with 11% (2/18) complete response. With a median follow-up of 296 days, the estimated median time to progression for 18 eligible patients was 382 days. The most frequent adverse events were hematologic toxicities, including grade 4 neutropenia. Non-hematologic toxicities were mild. In conclusion, cladribine with 2-h intravenous infusion for five consecutive days every four weeks is effective with acceptable toxicities for Japanese patients with relapsed indolent B-cell lymphoma, including those pretreated with rituximab.

[A case report--gastric stenosis due to primary gastric malignant lymphoma after administration of R-CHOP].

A 67-year-old man was diagnosed with primary gastric malignant lymphoma by an endoscopic examination. Endoscopy revealed irregular ulcerative regions from body to antrum of the stomach. With a diagnosis of diffuse large B-cell lymphoma based on the biopsy finding, the patient was treated with R-CHOP chemotherapy. After three cycles of chemotherapy, a tight stenosis was located at the antrum of the stomach. Total gastrectomy was performed due to an obstruction. Pathological diagnosis was complete response. It was thought that the tumor organization rapidly disappeared due to the effectiveness of the chemotherapy, and that the origin of the stricture caused fibrosis.

Hematopoietic stem cell transplantation for core binding factor acute myeloid leukemia: t(8;21) and inv(16) represent different clinical outcomes.

We analyzed 338 adult patients with acute myeloid leukemia (AML) with t(8;21) and inv(16) undergoing stem cell transplantation (SCT) who were registered in the Japan Society for Hematopoietic Cell Transplantation database. At 3 years, overall survival (OS) of patients with t(8;21) and inv(16) was 50% and 72%, respectively (P= .002). Although no difference was observed when restricted to allogeneic SCT in first complete remission (CR; 84% and 74%), OS of patients with t(8;21) and inv(16) undergoing allogeneic SCT in second or third CR (45% and 86% at 3 years; P= .008) was different. OS was not different between patients in first CR who received allogeneic SCT and those who received autologous SCT for both t(8;21) AML (84% vs 77%; P= .49) and inv(16) AML (74% vs 59%; P= .86). Patients with inv(16) not in CR did better after allogeneic SCT than those with t(8;21) (70% and 18%; P= .03). Patients with t(8;21) and inv(16) should be managed differently as to the application of SCT. SCT in first CR is not necessarily recommended for inv(16). For t(8;21) patients in first CR, a prospective trial is needed to clarify the significance of autologous SCT and allogeneic SCT over chemotherapy.

Disease-specific analyses of unrelated cord blood transplantation compared with unrelated bone marrow transplantation in adult patients with acute leukemia.

We made a disease-specific comparison of unrelated cord blood (CB) recipients and human leukocyte antigen allele-matched unrelated bone marrow (BM) recipients among 484 patients with acute myeloid leukemia (AML; 173 CB and 311 BM) and 336 patients with acute lymphoblastic leukemia (ALL; 114 CB and 222 BM) who received myeloablative transplantations. In multivariate analyses, among AML cases, lower overall survival (hazard ratio [HR]=1.5; 95% confidence interval [CI], 1.0-2.0, P= .028) and leukemia-free survival (HR=1.5; 95% CI, 1.1-2.0, P= .012) were observed in CB recipients. The relapse rate did not differ between the 2 groups of AML (HR=1.2; 95% CI, 0.8-1.9, P= .38); however, the treatment-related mortality rate showed higher trend in CB recipients (HR=1.5; 95% CI, 1.0-2.3, P= .085). In ALL, there was no significant difference between the groups for relapse (HR=1.4, 95% CI, 0.8-2.4, P= .19) and treatment-related mortality (HR=1.0; 95% CI, 0.6-1.7, P= .98), which contributed to similar overall survival (HR=1.1; 95% CI, 0.7-1.6, P= .78) and leukemia-free survival (HR=1.2; 95% CI, 0.9-1.8, P= .28). Matched or mismatched single-unit CB is a favorable alternative stem cell source for patients without a human leukocyte antigen-matched related or unrelated donor. For patients with AML, decreasing mortality, especially in the early phase of transplantation, is required to improve the outcome for CB recipients.

Prolongation of survival and improvement in performance status following palliative chemotherapy in gastrointestinal cancer patients with a poor performance status.

BACKGROUND: The prognosis of advanced gastrointestinal cancer, especially in patients with poor performance status (PS), is generally dismal. Patients with PS 3-4 are almost ineligible for participation in clinical studies. PATIENTS AND METHODS: From June 2000 to February 2007, 116 patients with poor PS (PS 3 = 73 and PS 4 = 43) were treated with chemotherapy. Retrospective analysis was performed. RESULTS: Of the 107 patients with at least one measurable lesion, a partial response was obtained in 15 patients (14.0%). Of 65 patients with ascites and/or pleural effusion, 12 patients achieved decreased fluid accumulation. A decline in tumor markers was observed in 30 patients. As a result, 38 patients (32.7%) achieved tumor response, a decrease in fluid accumulation or a decline in tumor markers (responders), which resulted in a survival benefit compared to the other 78 patients without effect (6.9 vs. 2.2 months, p < 0.001). PS improvement was seen in 16 patients (13.8%). CONCLUSIONS: The results suggest that chemotherapy may be beneficial in gastrointestinal cancer patients with poor PS, as demonstrated by a certain degree of improvement in PS and survival in responders. Further study is required to confirm the benefit of chemotherapy in this patient population.

A case of advanced breast cancer associated with development of liver atrophy with progressive liver failure during treatment.

A 44-year-old-female came to our hospital with abdominal distension in April 2005. She had been diagnosed with breast cancer in 1991, which was treated with mastectomy, postoperative radiation therapy,and a five-year course of hormonal therapy. An abdominal computed tomography (CT) scan revealed multiple hypoattenuated lesions in both lobes of her liver, which were diagnosed as metastatic breast cancer by liver biopsy. Weekly chemotherapy with paclitaxel was initiated on May 13. Trastuzumab and tamoxifen were added after two weeks. After six months of treatment, the CT scans showed reductions in the size of her multiple liver metastases along with the development of slight irregularities in the liver surface. Liver dysfunction was improved,and tumor marker BCA225 levels significantly decreased. After ten months of treatment, the CT scan showed nodular irregularity of the hepatic borders with deformation and atrophic changes. After twelve months of treatment,she was readmitted with abdominal distension and lower extremity edema. Increased ascites and appearance of esophageal varices were observed. Laboratory values were compatible with decompensation of liver function,although BCA225 levels still remained low. Despite discontinuation of chemotherapy and hormonal therapy at this time, she died from liver failure less than two weeks later. The atrophic changes and liver failure are suspected to have resulted from the chemotherapy and/or hormonal therapy.

A retrospective analysis of allogeneic hematopoietic stem cell transplantation for adult T cell leukemia/lymphoma (ATL): clinical impact of graft-versus-leukemia/lymphoma effect.

Adult T cell leukemia/lymphoma (ATL) is a highly aggressive T cell malignancy, and has a poor prognosis. Recently, allogeneic-hematopoietic stem cell transplantation (allo-HSCT) has been suggested to improve the outcome. We retrospectively analyzed 15 patients with ATL who had received allo-HSCT in 2 institutions in Hokkaido, Japan. The median age of the patients was 57 years. The estimated 3-year overall survival (OS) and progression-free survival (PFS) rates were 73.3% and 66.7%, respectively. Calcineurin inhibitor dosage was reduced and administration was discontinued abruptly in 6 of the 15 patients for disease control; as a result, 4 (66.7%) of the 6 patients achieved complete response (CR) or partial response. Therefore, a graft-versus-leukemia/lymphoma (GVL) effect might be induced by discontinuation of immunosuppression. Thirteen of the 15 patients were followed up by monitoring HTLV-1 proviral DNA levels. In 10 of the 11 patients with positive HTLV-1 proviral DNA before allo-HSCT, HTLV-1 proviral DNA became undetectable at least once after allo-HSCT, and only 1 of the 5 patients in whom HTLV-1 proviral DNA became detectable after allo-HSCT relapsed. Compared to the results of past studies, these results show that allo-HSCT greatly improved the prognosis of ATL and suggest a contribution of the induction of a GVL effect.