Bendamustine treatment of Chinese patients with relapsed indolent non-Hodgkin lymphoma: a multicenter, open-label, single-arm, phase 3 study.

BACKGROUND: Bendamustine was approved in China on May 26th, 2019 by the National Medical Product Administration for the treatment of indolent B-cell non-Hodgkin lymphoma (NHL). The current study was the registration trial and the first reported evaluation of the efficacy, safety, and pharmacokinetics of bendamustine in Chinese adult patients with indolent B-cell NHL following relapse after chemotherapy and rituximab treatment. METHODS: This was a prospective, multicenter, open-label, single-arm, phase 3 study (NCT01596621; C18083/3076) with a 2-year follow-up period. Eligible patients received bendamustine hydrochloride 120 mg/m2 infused intravenously on days 1 and 2 of each 21-day treatment cycle for at least six planned cycles (and up to eight cycles). The primary endpoint was the overall response rate (ORR); and secondary endpoints were duration of response (DoR), progression-free survival (PFS), safety, and pharmacokinetics. Patients were classified according to their best overall response after initiation of therapy. Proportions of patients in each response category (complete response [CR], partial response [PR], stable disease, or progressive disease) were summarized along with a two-sided binomial exact 95% confidence intervals (CIs) for the ORR. RESULTS: A total of 102 patients were enrolled from 20 centers between August 6th, 2012, and June 18th, 2015. At the time of the primary analysis, the ORR was 73% (95% CI: 63%-81%) per Independent Review Committee (IRC) including 19% CR and 54% PR. With the follow-up period, the median DoR was 16.2 months by IRC and 13.4 months by investigator assessment; the median PFS was 18.6 months and 15.3 months, respectively. The most common non-hematologic adverse events (AEs) were gastrointestinal toxicity, pyrexia, and rash. Grade 3/4 neutropenia was reported in 76% of patients. Serious AEs were reported in 29 patients and five patients died during the study. Pharmacokinetic analysis indicated that the characteristics of bendamustine and its metabolites M3 and M4 were generally consistent with those reported for other ethnicities. CONCLUSION: Bendamustine is an active and effective therapy in Chinese patients with relapsed, indolent B-cell NHL, with a comparable risk/benefit relationship to that reported in North American patients. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, No. NCT01596621; https://clinicaltrials.gov/ct2/show/NCT01596621.

ADAM28 promotes tumor growth and dissemination of acute myeloid leukemia through IGFBP-3 degradation and IGF-I-induced cell proliferation.

ADAM28 has been shown to relate with tumor proliferation and prognosis. The expression of ADAM28 is up-regulated in acute myeloid leukemia (AML). However, the mechanism by which ADAM28 regulates the leukemic cell and the prognostic relevance with AML remain unknown. Here, we found that the expression level of ADAM28 was significantly elevated in AML patients suffering a relapse compared with those remaining in complete remission (CR). ADAM28 promoted the proliferation, migration and invasion in leukemic cells in vitro. Additionally, the increased expression of ADAM28 led to more IGFBP-3 degradation and IGF-I-induced cell proliferation. In a xenotransplantation mouse model, knockout of ADAM28 alleviated HL-60 cells growth and dissemination. The cumulative incidence of relapse (CIR) was significantly higher in patients with high ADAM28 expression. When separately considering the impact of ADAM28 on prognosis within the risk stratifications, patients with high ADAM28 expression levels had a significantly higher CIR in the favorable and intermediate-risk group but not in poor-risk group. Taken together, these data suggest a pivotal role for ADAM28 in regulating the proliferation and invasion of leukemic cells and in the prediction of relapse in AML patients.

Clinicopathological features of splenic tumours of lymphoid tissue.

BACKGROUND: To study the effects of splenectomy on treatment and diagnosis of tumours of lymphoid tissue of the spleen. METHODS: Fifty-three cases were reviewed from Peking University People's Hospital from 2002 to 2017. According to WHO classification of tumours of haematopoietic and lymphoid tissues (2008) and classification updated (2016), the cases were studied by microscopy, immunohistochemistry and in situ hybridization, combined with the bone marrow biopsy and clinical examination. RESULTS: In 53 cases, the male to female ratio was 3.4:1, the mean age was 55.4 years old, the median survival time was 17.0 months, and all patients present with variable degree of splenomegaly. The elevated percentage of lymphocyte in peripheral blood can be seen in 22 cases, and elevated LDH level in 24 cases. Abnormal blood counts can be seen in 26 cases before operation, and 22 cases remission to normal level partly or completely after operation. The clinical symptoms included abdominal pain or distension, fatigue, fever, and weight loss, etc. Seventeen cases present with lymphoadenopathy of abdomen or other sites. Fourteen cases were stage I or II, whereas 6 were stage III, 28 were stage IV. Forty-three cases were splenic B-cell marginal zone lymphoma (SMZL)(48.8%,21/43), DLBCL(23.3%,10/43), splenic diffuse red pulp small B-cell lymphoma (SDRPSBL)(11.6%,5/43), mantle cell lymphoma (MCL)(9.3%,4/43), follicular lymphoma (FL)(4.7%,2/43), composite lymphoma (CL, DLBCL and classical Hodgkin lymphoma)(2.3%,1/43) in turn, and the remaining 10 cases were chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) (n = 4), hairy cell leukaemia (HCL) (n = 1), hepatosplenic T-cell lymphoma (HSTL) (n = 5). The survival period of SMZL and DLBCL was 25.7, 18.6 months, respectively. Thirteen cases were dead (27.1%, 13/48). The chemotherapy protocol included Hyper-CVAD A/B with/without R (Rituximab), COP, CHOP with/without R etc. The prognosis of those with elevated LDH level, high clinical staging, B symptom, and older than 60 year old was obviously worse, and the prognosis of DLBCL was worse than that of SMZL. CONCLUSIONS: Most splenic lymphoid tumors present with splenomegaly and abnormal blood counts, and complete or part remission of blood counts can be seen after splenectomy, and splenectomy is also helpful for pathological diagnosis. The most common pathological types are SMZL and DLBCL. The definite diagnosis can be made by combining with clinical features, histopathology, immunophenotype, genetics, bone marrow biopsy and laboratory examination.

ADAM28 overexpression regulated via the PI3K/Akt pathway is associated with relapse in de novo adult B-cell acute lymphoblastic leukemia.

B-cell acute lymphoblastic leukemia (B-ALL) in adults is a very challenging disease. Relapse following remission after induction chemotherapy remains the major barrier to patient survival. ADAM28 is overexpressed in several human tumors and is related to cell proliferation and lymph node metastasis. To date, no information has been available on the prognostic role of ADAM28 in B-ALL. Fifty consecutive patients with de novo B-ALL and 22 healthy donors were enrolled in this study and were followed for 2.8 years. Our data suggested that ADAM28 expression in B-ALL patients was significantly increased (P<0.0001). Patients experiencing disease relapse exhibited significantly increased ADAM28 expression, compared with those with favorable outcomes (P=0.0094). Notably, ADAM28 overexpression was associated with lower probabilities of relapse-free survival (RFS) and event-free survival (EFS) (P<0.001) and was a significant prognostic factor (P<0.001). In vitro, the PI3K/Akt pathway inhibitor, as well as arsenic trioxide (ATO), down-regulated ADAM28 expression. Our results were the first to indicate that ADAM28 overexpression in B-ALL patients is correlated with relapse. ADAM28 overexpression is potentially regulated by the PI3K/Akt pathway. These data demonstrate that ADAM28 might serve as a novel biomarker for evaluating relapse in B-ALL and as a potential therapeutic target in B-ALL patients.

The mystery of chronic lymphocytic leukemia (CLL): Why is it absent in Asians and what does this tell us about etiology, pathogenesis and biology?

Chronic lymphocytic leukemia/small lymphocytic lymphoma is common in persons of predominately European descent but rare in Asians. Why is unknown but is likely genetically-determined. Environmental factors may also operate but are likely to be less important. When CLL occurs in Asians it has different features than CLL in persons of predominately European descent. The reason(s) for this is also not understood. We reviewed data on CLL in Asians (mostly Han Chinese but also other ethnic groups) and compared these data with those from persons of predominately European descent with CLL. CLL incidence was about 5-10-fold less in Asians. Asians with CLL are younger, have atypical morphologic and immunologic features, an increased proportion of IGHV mutations and rearrangements and briefer freedom-from-progression than persons of predominately European descent with CLL. These observations provide clues to the etiology and biology of CLL. But the mystery continues; more research is needed.

[Clinical characteristics of splenic marginal zone lymphoma with abnormal complete blood count].

The aim of this study was to investigate the clinical and laboratorial characteristics of splenic marginal zone lymphoma (SMZL) with an abnormal complete blood count (CBC). Data of 19 newly diagnosed SMZL patients with abnormal CBC were analyzed retrospectively. Seven patients were diagnosed by using splenic histology, 12 patients who did not undergo splenectomy were diagnosed on the basis of typical clinical presentation and cytologic, immunophenotypic and histologic characteristics of peripheral blood and bone marrow, according to SBLG guidelines. The results showed that leukocytosis (≥ 10.0×10(9)/L) was seen in 5 cases (26.3%); leukocytopenia (< 4.0×10(9)/L) was found in 6 cases (31.6%), hemoglobin concentration less than 120 g/L was found in 14 cases (73.7%) and thrombocytopenia was found in 11 (57.9%) patients. Fourteen (73.7%) patients had cytopenia in one or more lineage. As a specific morphologic character, villous lymphocytes were found in 10 (52.6%) patients. Similar immunophenotype was determined by histology in both bone marrow and spleen. Various histological infiltration patterns including intrasinusoidal pattern were found in bone marrow. Nine out of 16 (56.3%) patients displayed an increase of serum monoclonal immunoglobin. Autoimmune phenomena was found in 12 out of 15 (80.0%) patients. Splenectomy, as the only treatment could not achieve a ≥ 50% improvement of CBC in 4 patients, and then was judged as no response. Splenectomy followed by chemotherapy achieved partial response (PR) in 1 patient. Overall response rate of the therapeutic strategies with Rituximab was 100.0% (11/11). Furthermore, complete response was achieved in 9 out of 11 (81.8%) patients. It is concluded that SMZL with abnormal CBC has a higher incidence of cytopenia, bone marrow involvement and autoimmune phenomena. Therapeutic strategies consisting of Rituximab show a better efficacy.

The more, the less: age and chemotherapy load are predictive of poor stem cell mobilization in patients with hematologic malignancies.

BACKGROUND: Intensive treatment such as autologous peripheral blood stem cell (PBSC) transplantation is an important therapeutic strategy in many hematologic malignancies. A number of factors have been reported to impact PBSC mobilization, but the predictive factors varied from one study to another. This retrospective study assessed our current mobilization and collection protocols, and explored the factors predictive of PBSC mobilization in patients with hematologic malignancies. METHODS: Data of 64 consecutive patients with hematologic malignancies (multiple myeloma, n = 22; acute leukemia, n = 27; lymphoma, n = 15) who underwent PBSC mobilization for over 1 year were analyzed. Four patients with response to treatment of near complete remission or better were administered granulocyte colony-stimulating factor (G-CSF) to mobilize PBSCs. Sixty patients received G-CSF followed by chemotherapy mobilizing regimens. Poor mobilization (PM) was defined as when ≤ 2.0'10(6) CD34(+) cells/kg body weight were collected within three leukapheresis procedures. RESULTS: The incidence of PM at the first mobilization attempt was 19% (12/64). The PM group was older than the non-PM group (median age, 51 vs. 40 years; P = 0.013). In univariate analysis, there were no significant differences in gender, diagnosis, and body weight between the PM and non-PM groups. A combination of chemotherapy and G-CSF was more effective than G-CSF alone as a mobilizing regimen (P = 0.019). Grade III or IV hematopoietic toxicity of chemotherapy had no significant effect on the mobilization efficacy. Supportive care and the incidence of febrile neutropenia were not significantly different between the two groups. In multivariate analysis, age (odds ratio (OR), 9.536; P = 0.002) and number of previous chemotherapy courses (OR 3.132; P = 0.024) were two independent negative predictive factors for CD34(+) cell yield. PM patients could be managed well by remobilization. CONCLUSION: Older age and a heavy load of previous chemotherapy are the negative risk factors for PBSC mobilization.

Dynamics of monocyte count: a good predictor for timing of peripheral blood stem cell collection.

To investigate potential predictive parameters for successful collection of autologous peripheral blood stem cells (PBSC), 60 consecutive first mobilization attempts and 145 leukapheresis procedures for patients with hematologic malignancies (multiple myeloma: n = 20; acute leukemia: n = 27; lymphoma: n = 13) were analyzed. All patients underwent chemotherapy and granulocyte-colony stimulating factor combined mobilization protocols. PBSC collection began when white blood cell (WBC) count rebounded to >1.0 × 10(9)/L. Poor mobilization (PM) was defined as <2.0 × 10(6)/kg of ideal body weight CD34+ cells were collected from at least three leukapheresis procedures. PM incidence was 15% (9/60). On the first apheresis day, CD34+ cell yield was closely associated with the final yield. Failure to reach the first-day target of 0.7 × 10(6) CD34+ cells/kg was perfectly matched with PM. Circulating WBC and monocyte (MO) counts preleukapheresis had a positive correlation with final CD34+ cell yield. For the first-day apheresis target, receiver operator characteristic (ROC) curve analysis showed that MO count had an area under the curve (AUC) of 0.806 (P = 0.004). An optimal predictive cutoff value for MO count was 1.455 × 10(9)/L with both high sensitivity and specificity of 0.739 and 0.899, respectively. Patients who began leukapheresis with an MO count of ≥1.455 × 10(9)/L accomplished more successful first-day collections than those of their counterparts (P = 0.021). ROC analysis also showed preapheresis WBC count had a high AUC of 0.768 (P = 0.012). However, we could not find a WBC indicator to initiate leukapheresis. In conclusion, circulating MO count after mobilization is a helpful parameter to determine the optimal time point for starting a PBSC collection.

[Diffuse alveolar hemorrhage as a complication in patients with hematologic malignancies after chemotherapy: report of two cases and literature review].

OBJECTIVE: To study diffuse alveolar hemorrhage (DAH) in patients with hematologic malignancies after chemotherapy and discuss the possible etiology and appropriate therapy. METHODS: Symptoms, physical examinations, laboratory examination, chest radiographs or computed tomographic (CT) scans, treatments and outcomes of two patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) each after chemotherapy were presented. RESULTS: Both of the patients developed cough, progressive dyspnea, a drop of hemoglobin level, hypoxemia and widespread pulmonary infiltrate on chest radiographs or CT scans after chemotherapy. Moreover, case 1 (ALL) had high fever and bloody fluid drained from the intubation of mechanical ventilation, case 2 (NHL) developed continual hemoptysis. They were diagnosed as DAH and improved significantly after intermediate- or high-dose corticosteroid therapy. CONCLUSIONS: DAH is a rare fatal acute noninfectious pulmonary complication in patients with hematologic malignancies after chemotherapy. Early accurate diagnosis, identifying the underlying cause and appropriate treatment are critical for the management of DAH.

[Cytogenetic study on eosinophilia].

The aim of study was to investigate the importance of chromosome aberration in differential diagnosis of eosinophilia and the chromosomal aberrations involved in patients with clonal eosinophilia. 65 cases of eosinophilia were collected and chromosome specimens of bone marrow cells were prepared by 24-hour culture, and G-banding technique was used for karyotyping. The results showed that out of 65 cases, chromosome 16 inversion was detected in 9 patients suspected as M(4Eo), and among the other 56 cases, 5 were detected with chromosomal aberrations (8.9%). Combining clinical, hematological and cytogenetical data, the 5 patients were diagnosed as acute myeloid leukemia with eosinophilia, chronic eosinophilic leukemia, 8p11 myeloproliferative syndrome, chronic myeloid leukemia in acute phase and acute myeloid leukemia-M(4Eo) respectively. The detected chromosomal aberrations were +14, t (5; 12) (q31; p13), t (8; 9) (p11; q32), t (9; 22) (q34; q11) and inv (16) (p13 q22). In conclusion, cytogenetical detection is very important in differential diagnosis of clonal eosinophilic disorders and chronic eosinophilic leukemia, which is suggested to be done routinely in clinic.

[Comparison of the effect of Cobe Spectra and Fenwal CS 3000 plus blood cell separators in collection of peripheral blood stem cell components].

To evaluate the hematopoietic stem/progenitor cell apheresis effect of Cobe Spectra (Version 6.1) and Fenwal CS 3000 Plus cell separators, fourty-two procedures on twenty donors using Cobe Spectra cell separator and twenty-two procedures on sixteen donors using Fenwal CS 3000 Plus cell separator were retrospectively analyzed. The number of CD34(+) cells collected, the collection efficiency (CE) of CD34(+) cells and the contaminations of red blood cell and platelet in the stem/progenitor cell products of two devices were compared. The results showed that there were no significant differences in the total number of CD34(+) cells collected and the CD34(+) cell CE between the two devices. There were positive correlations between the count of peripheral blood cells including leukocyte, monocyte, hematopoietic progenitor cell and CD34(+) cell after mobilization and the total number of CD34(+) cells collected. The stepwise multiple variable analyses revealed the peripheral blood stem/progenitor cell count emerged as the only significant independent predictive factor for CE. A negative correlation was seen between the peripheral blood monocyte count and the CD34(+) cell CE for the Fenwal CS 3000 Plus. The Fenwal CS 3000 Plus product contained more red blood cells than that of the Cobe Spectra. The decrease in the peripheral platelet count after Fenwal CS 3000 Plus apheresis was also greater. It is concluded that collection efficacy of Cobe Spectra (Version 6.1) and Fenwal CS 3000 Plus was similar. Cobe Spectra shall be used preferably to assure higher CD34(+) cell CE at a high peripheral blood monocyte count. The Cobe Spectra cell separator is better for the donors with mismatched blood type and the donors with thrombocytopenia.

[Allogeneic hematopoietic stem cell transplantation for acute lymphocytic leukemia].

OBJECTIVE: To retrospectively analyze the results of a consecutive series of 100 ALL patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT) in our center. METHODS: Of the 100 ALL patients, 69 were male and 31 female, with a median age of 29.5 (4 - 47) years. Sixty-nine cases were in the first complete remission (CR(1)), 13 in more than CR(1) and 18 in relapse before transplant. Allo-HSCT from HLA identical siblings was performed for 86 patients, of whom 64 received bone marrow transplantation (BMT) and 22 peripheral blood stem cell transplantation (PBSCT). HLA matched unrelated BMT was performed for 8 patients, cord-blood transplantation from unrelated donor for 6 patients. Forty-five patients underwent allo-HSCT with conditioning regimen of Cy/TBI, 55 with BUCY. Prophylaxis of graft-versus-host disease (GVHD) included long-term MTX regimen (4 cases) and CsA + MTX regimen (96 cases). The average follow-up was 38.1 months. RESULTS: The 5-year overall survival (OS) and disease-free survival (DFS) of the 100 cases of ALL was 53.4% and 50.5%. The 5-year OS and DFS were significantly longer for patients in CR(1) than in >CR(1) and relapse patients before allo-HSCT (P < 0.001). The outcome of PBSCT seemed superior to that of BMT, but there was no difference between them. Multivariate analysis showed the most significant factor associated with long post allo-HSCT survival was that the patient underwent transplantation in CR(1). There was no significant difference in 5-year OS, DFS, cumulative incidences of relapse rate and treatment related mortality between the two cohorts prepared with TBI or BUCY. CONCLUSIONS: Allo-HSCT can cure a significant proportion of ALL patients, especially for those in CR(1). There was no significant difference in OS, DFS between the two different conditioning regimens and the different transplant choices.

[Significance of monitoring hematopoietic progenitor cells in peripheral blood stem cell during mobilization and harvest].

To achieve efficient peripheral blood stem cell harvest (PBSCH), a simple method to monitor peripheral blood stem/progenitor cells was evaluated. The Sysmex XE-2100 hematology analyzer with an immature information (IMI) channel was used to identify and count the hematopoietic progenitor cell (HPC). Twenty-five donors mobilized with G-CSF in allogeneic and 11 patients in autologous peripheral blood stem cell transplantation (allo-PBSCT and auto-PBSCT) were involved. The HPC, CD34(+) cell and CFU-GM in the peripheral blood and leukapheresis samples were detected during mobilization and harvest. The results showed that HPC amount had a positive correlation with both the CD34(+) cell and CFU-GM in the peripheral blood. The peripheral blood hematopoietic stem/progenitor cells in allo-PBSCT donors remarkably increased on day 5 of the mobilization, followed the leukocytes increased. However, a fast increase of hematopoietic stem/progenitor cells was earlier than leukocytes in the peripheral blood. The HPC positively correlated with the CD34(+) cell or CFU-GM in the PBSCH. On the days of collection, the count of HPC and CD34(+) cell in peripheral blood was highly correlated with the CD34(+) cell yield. It is concluded that HPC as an estimate of progenitor cells in collected blood sample could be used to determine the optimal time of PBSCH and minimize the risk of missing an adequate harvest.