bluuebunny/crossref_metadata_2025_split huggingface dataset:
Erythroid Response (ER) Rates in Myelodysplastic Syndromes (MDS) Patients Treated with Epoetin Alfa (EPO) or Darbepoetin Alfa (DARB) Using International Working Group Response Criteria (IWGc): Comparative Meta-Analysis.
Authors: Mundle Suneel , Lefebvre Patrick , Duh Mei S. , Bourezak Ahmed , Yektashenas Behin , Moyo Victor 
Published: October 2019

Abstract
Background: EPO has been used in the treatment of refractory anemia in MDS patients for many years. Recently, with the identification of definitive patient selection criteria (low serum EPO [sEPO] levels and receipt of minimal transfusions) and standardization of ER rate evaluation methods using the IWGc, response to EPO therapy has been shown to be significantly enhanced in low/int-1 risk MDS patients. The present meta-analysis was conducted to compare ER rates (defined as major + minor response) of the two erythropoiesis-stimulating therapies (ESTs) currently available in the US, EPO and DARB, in MDS patients who were selected and evaluated for ER using the aforementioned uniform criteria.
Methods: A systematic review and data extraction of studies from PubMed and ASCO/ASH proceedings from 1990–2006 in MDS patients treated with EPO monotherapy and from 2003–2006 in those treated with DARB monotherapy was performed. Pooled estimates of ER rates were calculated in each group using random-effects meta-analysis methods, which incorporated both between- and within-group variations. Multivariate meta-regression analysis was further conducted to control for differences in baseline characteristics between the two groups.
Results: Nine EPO studies (N=619 patients, N evaluable for ER rate =589) and 8 DARB studies (N=442, N evaluable for ER rate =389) were identified. Baseline characteristics were comparable between the two groups with respect to age, gender, mean baseline hemoglobin, transfusion dependency rates, and proportion of patients with refractory anemia/refractory anemia with ringed sideroblasts. The mean baseline sEPO levels were significantly higher in the EPO group, compared to the DARB group (376: range 43–418; vs. 133: range 68–303 mU/mL, p=0.0026). The average initial weekly dose in the EPO studies was 47,851 (range: 30,000–80,000) Units, while that in the DARB studies was 176 (range: 100–315) mcg. There was no significant difference in the pooled estimate of the ER rates for either EST (57.6%: 95% CI; 45–70) for the EPO studies vs. (59.4%: 95% CI; 49–70) for the DARB studies, (p=0.8282). Further, as compared to the studies with standard doses of the two ESTs per week (EPO 30,000–40,000 Units; DARB ≤ 150 mcg), those using higher doses of EPO (60,000–80,000 Units) or DARB (>150 mcg) per week showed significantly higher ER rates (EPO- 47.8% vs. 63.3%, p<0.001; DARB −52.6% vs. 71.1%, p<0.001).
Conclusions: This current meta-analysis demonstrates that, with the use of standardized patient selection and response evaluation methods, the two clinically available ESTs yield comparable ER rates in MDS patients.
Clinical Activity of the Immunoconjugate CMC-544 in B-Cell Malignancies: Preliminary Report of the Expanded Maximum Tolerated Dose (MTD) Cohort of a Phase 1 Study.
Authors: Fayad Luis , Patel Hemant , Verhoef Gregor , Czuczman Myron , Foran James , Gine Eva , Rohatiner Ama , Smith Mitchell R. , Shapiro Mark , Advani Anjali 
Published: October 2019

Abstract
Introduction: CMC-544 is an antibody-targeted chemotherapy agent composed of a humanized antibody that specifically targets the CD22 antigen, conjugated to calicheamicin, a potent cytotoxic antitumor agent. Malignant cells of mature B-lymphocyte lineage express CD22, suggesting that CMC-544 may be useful for treating lymphomas of B-cell origin. A phase 1 dose-escalation trial of CMC-544 was performed at 14 European and US sites with 36 patients in the dose escalation portion and 48 in the expanded MTD portion. The MTD dose was 1.8 mg/m2 every 4 weeks. In the dose escalation phase the main toxicities observed were thrombocytopenia, asthenia, nausea, neutropenia, elevated liver function tests (LFTs) and anorexia. Grade 3–4 levels were only seen for thrombocytopenia, asthenia, neutropenia and LFTs (incidence of 40%, 13%, 9% and 9% respectively). Responses were seen in 8/22 (36%) patients (Advani A, et. al. Blood, abstract# 230, 2005:106). We now report the results of the expanded cohort at the MTD.
Patients and Methods: Relapsed/refractory lymphoma patients were treated at the 1.8 mg/m2 dose level every 4 weeks. In addition to safety data, preliminary efficacy data (assessed using the International Workshop to Standardize Response Criteria for NHL) were collected.
Results: As of July 2006, 48 patients were treated: median age 57 years (range 26–75); 51% females; 61% with ≥ 4 prior lines of therapy; 22 (46%) follicular lymphomas (FL) and 26 (54%) diffuse large B-cell lymphomas (DLBCL). Data were available on 48 patients evaluable for safety and 34 patients (19 FL and 15 DLBCL) evaluable for response. The overall safety profile was manageable; the most common drug-related adverse events (all grades) included thrombocytopenia (90%; the only bleeding noted was grade 1–2 epistaxis [12%]), asthenia (57%), nausea (39%), neutropenia (37%) and elevated levels of AST/SGOT (41%), ALT/SGPT (18%), alkaline phosphatase (27%) and bilirubin (18%). Grade 3–4 AEs that occurred with a frequency ≥ 10% included thrombocytopenia (57%) and neutropenia (29%). Responses in evaluable patients are shown in Table 1. The objective response rate was 69% and 33% for patients with FL and DLBCL, respectively.
Conclusions: CMC-544 exhibits effficacy against recurrent/refractory B-cell lymphomas, with the main toxicity being clinically manageable, self limited thrombocytopenia. These encouraging data support the continuing development of CMC-544.
Number (%) of Responses in Evaluable Patients: Response Follicular Lymphoma (n=19) DLBCL (n=15) ORR = Overall Remission Rate, (CR/CRu+PR) CR/CRu 6 (31.7) 2 (13.3) PR 7 (36.8) 3 (20.0) ORR 13 (68.5) 5 (33.3)
The Risk of Venous and Arterial Thrombosis in Hyperhomocysteinemic Subjects Is Caused by Elevated Factor VIII:C Levels.
Authors: Lijfering Willem M. , Veeger Nic J.G.M. , Brouwer Jan-Leendert P. , van de Poel Marlene H.W. , van der Meer Jan 
Published: October 2019

Abstract
Hyperhomocysteinemia is demonstrated as a risk factor for venous and arterial thrombosis. Experimental evidence suggests that its thrombogenic propensity results from endothelial dysfunction and injury followed by platelet and fibrin formation. However, lowering homocysteine concentrations with vitamin B6, B12 or folic acid has not resulted in a reduced risk of recurrent venous and arterial thrombosis in large prospective clinical trials. This suggests that hyperhomocysteinemia is a surrogate for another thrombophilic related specimen. As high factor VIII:C levels are associated with an increased risk of both venous and arterial thrombosis, and with endothelial injury, we hypothesize that hyperhomocysteinemia and factor VIII:C levels are closely related to each other. Therefore, we performed a study to assess the absolute risk of thrombosis in hyperhomocysteinemia and the effects of elevated factor VIII:C levels on this risk in a large cohort of families with hereditary (index) deficiencies of protein S, protein C or antithrombin. Hyperhomocysteinemia was defined as a fasting plasma homocysteine level above 18.5 μmol/l and factor VIII:C levels were elevated when higher than 150%. A total of 405 relatives were included. Median factor VIII:C levels in hyperhomocysteinemic relatives (n=26, 6%) were 169%, compared to 136% in normohomocysteinemic relatives (P=0.004) (Figure) and were more often elevated (65 vs. 38%, P=0.006). Other thrombophilic defects, including the index deficiencies, factor V Leiden and the prothrombin mutation were equally divided. Hyperhomocysteinemia was associated with an increased risk of venous and arterial thrombosis (relative risk’s 2.6 [1.3–4.8] and 3.7 [1.5–8.4)], respectively). Relatives with elevated factor VIII:C levels were also at risk; relative risk 2.3 (1.4–4.0) for venous thrombosis and 2.3 (1.0–5.1) for arterial thrombosis. After excluding all relatives with elevated factor VIII:C levels, relative risk for venous thrombosis and hyperhomocysteinemia dropped to 1.3 (0.2–9.8) and nil relatives had arterial thrombosis. These results suggest that hyperhomocysteinemia indeed is an epiphenomenon for elevated factor VIII:C levels and therefore homocysteine measurements can be omitted in risk assessment for venous and arterial thrombosis when factor VIII:C measurements are incorporated in thrombophilia screening.
Figure Figure
Immuno-Chemotherapy (IC) and Autologous Stem Cell Transplant (ASCT) for Untreated Patients (pts) with Mantle Cell Lymphoma (MCL): CALGB 59909.
Authors: Damon Lloyd E. , Johnson Jeff , Niedzwiecki Donna , Cheson Bruce D. , Hurd David Duane , Bartlett Nancy L. , Byrd John C. , Kelly Michael , Linker Charles , Canellos George P. 
Published: October 2019

Abstract
We evaluated the feasibility, safety, and effectiveness of an intense IC regimen including ASCT in pts with untreated MCL up to age 70. The primary end-point was 2-year progression free survival (PFS). A successful protocol would demonstrate a 2-year PFS of 50% (95% CI 37, 63%) or better. MCL was confirmed by central pathology review plus either compatible immunophenotype, cyclin D1 over-expression, t(11;14) or bcl-1/IgH rearrangement. Treatment consisted of 2 cycles (3 if marrow has >=15% MCL after 2 cycles) of rituximab (R), methotrexate 300 mg/m2 (M) and augmented CHOP (2 g/m2 cyclophosphamide [C]) followed by consolidation and stem cell collection with EAR (etoposide [E] 40 mg/kg, cytarabine [A] 2 g/m2 for 8 doses, R for 2 doses, and filgrastim 10 mcg/kg/day beginning day14 until completion of stem cell collection). EAR was followed by ASCT using CBV (carmustine [B] 15 mg/kg, E 60 mg/kg, and C 100 mg/kg) followed by R 6 and 7 weeks after ASCT. 79 pts were enrolled in 40 months: median age 57 (37–69); 79% male; 33% elevated serum LDH; 73% bone marrow (+); 5% cerebrospinal fluid (+). 1 pt never received protocol therapy, 1 pt came off study for an allogeneic stem cell transplant, and 7 pts never underwent ASCT. Stem cell collection was excellent, with a median CD34-cell dose of 12x106/kg in median of 1 apheresis. There were 2 treatment-related deaths. The complete and partial response rates were 62% (49,74%) and 27% (17, 40%), respectively. With a median follow-up of 27.5 months, the PFS is 75% (61, 84%) at 2 years and 56% (39, 69%) at 3 years (intention to treat analysis). The overall survival is 82% (68, 90%) at 3 years. Intense IC plus ASCT is feasible, safe, and effective in pts with MCL. These results are comparable to single institution outcomes. Maintenance bortezomib will be added to this regimen post-ASCT in a successor CALGB trial.
Does Rituximab Influence the Prognostic Effect of Germinal Centre Phenotype in Diffuse Large B-Cell Lymphoma?.
Authors: Nyman Heidi , Karjalainen-Lindsberg Marja-Liisa , Taskinen Minna , Berglund Mattias , Adde Magdalena , Amini Rose-Marie , Blomqvist Carl , Enblad Gunilla , Leppä Sirpa 
Published: October 2019

Abstract
PURPOSE: Germinal centre (GC) and non-GC phenotypes are predictors of outcome in diffuse large B-cell lymphoma (DLBCL), and can be used to stratify chemotherapy-treated patients into low- and high-risk groups. Our aim was to determine how combination of rituximab with chemotherapy influences GC-associated clinical outcome.
METHODS: 95 DLBCL patients treated with rituximab in combination with CHOP or CHOEP regimen (immunochemotherapy) were included in the study. The median follow-up time was 27 months. 107 patients previously treated with chemotherapy served as a historical control group. BCL-6, CD10, and MUM1 expression was analyzed immunohistochemically by means of identifying GC and non-GC phenotypes. In addition, BCL-2 expression was determined. Expression data was correlated with survival parameters.
RESULTS: Consistent with previous studies, chemotherapy-treated patients with GC phenotype displayed a significantly better overall survival (OS) than the non-GC group (70% vs 47% p=0.012). In contrast, GC-phenotype did not predict outcome in immunochemotherapy-treated patients. The OS for GC-group was 82% compared with 80% for those with non-GC phenotype (p=ns). Conversely, the relapse free survival (RFS) for patients with GC and non-GC phenotypes were 74% and 65% (p=ns), respectively. When the patients were grouped according to BCL-2 expression, survival rates among the group of BCL-2 negative patients tended to be better than in BCL-2 positive patients (OS, 94% vs 77%, p=0.097; RFS, 94% vs 66%, p=0.029).
CONCLUSIONS: Rituximab in combination with chemotherapy seems to interfere with the prognostic value of GC- and non-GC phenotypes in DLBCL. However, rituximab may have a positive impact on outcome among the patients with BCL-2 negativity.
Serum Levels and Pharmacokinetic of Rituximab in Bi-Weekly R-CHOP in Elderly Patients with DLBCL Treated in the RICOVER-60 Trial.
Authors: Reiser Marcel , Wenger Michael K. , Nickenig Christina , Peter N. , Kuhn Christian , Metzner Bernd , Theisohn Martin , Pfreundschuh Michael 
Published: October 2019

Abstract
Background: The combination of Rituximab and CHOP is considered the standard of treatment for DLBCL in elderly patients (pts) but there is hardly any data on the pharmacokinetic of Rituximab in aggressive lymphoma pts.
Objective: To study serum levels and pharmacokinetic properties of Rituximab when combined with dose dense CHOP-14 in elderly DLBCL patients
Methods: Blood samples of 18 pts were taken before and after Rituximab-infusion at each chemotherapy cycle. Additional samples were taken after the end of treatment and at the following timepoints: after 1 week, 1 month, 2 months, 3 months, 6 months and 9 months, respectively. Serum samples were taken within a maximum of 30 min, centrifuged at 1000 g for 10 min (room temperature) and stored at −20 degrees C. Batch samples were shipped to Xendo Lab., Groningen, The Netherlands, and analysed. The measured values were analysed by pharmakokinetic software MW/PHARM, version 3.50; (MediWare, 9800 AB Zuidhorn, The Netherlands) Additionally, a simulation of expected Rituximab-PK was performed taking into account 5 clinical trials, totalling 3777 observations in 264 patients mostly FL.
Results: Median (range) age of pts was 69 (61–79) years. 10/18 pts had advanced stage (III/IV), 4/18 pts had bulky disease. Pts received a median (range) dose of 683 (545–791) mg Rituximab/cycle. Response to treatment was 15/18 CR/Cru, 2/18 PR,1/18 PD. The median (range) of trough serum Rituximab-levels (μg/ml) before each cycle were: #1 0(0–0); #2 39(18–61); #3 74(47–109); #4 95(40–136); #5 113(55–157); #6 114(12–518); #7 125(72–207);#8 117(75–304). After therapy Rituximab-levels were: 163(68–248) at 1 week; 101(44–163) at 1 month, 55(11–122) at 2 months, 33(6–577) at 3 months; 5(0–103) at 6 months, 0.7(0–128) at 9 months. 7 pts were evaluable at 9 months with 4/7 pts showed detectable Rituximab-levels. Thus, actual serum levels detected fit exactly the model calculated from data of patients with FL. A preliminary PK analysis of Rituximab according to a two-compartment model showed a long median (range) serum half-life (t 1/2) of 765 h (543–1092).
Conclusion: In the dose dense bi-weekly regimen R-CHOP-14 Rituximab-serum levels increased slowly up to cyle 5. During cycle 5– 8 the serum Rituximab-levels reached a plateau and decreased constantly after the end of treatment with detectable levels even after 9 months and a long serum half-life. Increasing serum levels in the first four cycles are due to saturation kinetics of Rituximab. Based on this data the German High Grade NHL Study Group (DSHNHL) further investigates a dose escalation of Rituximab in the first cycles in order to improve treatment outcome.
Induction with Fludarabine, Cyclophosphamide and Rituximab Followed by Maintenance with Rituximab: Results of a Prospective Study in 75 Patients (LNHF-03).
Authors: Tomas Jose F. , Montalban Carlos , Martinez-Lopez Joaquin , Paz Jose , Canales Miguel , Diaz-Mediavilla Joaquin , Godoy Pedro Sanchez , de Sevilla Alberto Fdez , Penalver Javier , Caballero MDolores , Prieto Elena , Salar Jose , de Ona Raquel , de la Serna Javier 
Published: October 2019

Abstract
Objectives. To evaluate clinical efficacy, molecular response and safety following the use of a regimen of fludarabine (25 mg/m2 x 3 days) Cy (1g/m2 x 1 day) and Rituximab (375 mg/m2/ x 1 day) (FCR)x 6 cycles, followed by maintenance with rituximab (375 mg/m2/week/x 4 weeks every 6 months x 2 years). (LNHF-03 Study).
Patients and methods. Seventy-five (75) patients with a diagnosis of follicular NHL were included in the study between October 2004 and January 2006. The median age was 54 years (30–75). Twenty-one per cent (21%) of the patients had bulky disease. According to the FLIPI index: (0–1): 22.6%; 2: 40,3%; 3: 37,1%. Minimal residual disease (MRD): A clonal population on diagnosis was identified by means of the bcl–2/IgH major and minor rearrangement study by means of quantitative PCR rearrangements of the Igs by means of fluorescent PCR. Subsequently, samples were studied following the induction treatment and during the maintenance treatment. The analysis is performed in the 70 patients that completed the six induction regimens and were evaluated.
Results. 64/70 patients were given the six cycles planned (91%). The presence of persistent cytopenia limited the cycles given in the other 6 patients to 4 or 5. Three hundred and thirty-eight (338) adverse effects were documented in the 414 cycles given to the 70 patients evaluated, almost all of them being mild, and 26 severe (degree 3–4), and almost all the cases were neutropenias. Infectious complications were frequent and many were severe: herpes zoster (5), pneumonia (5), cerebral toxoplasmosis (1), aspergillosis (1), infection by CMV (2). One patient developed erythroleukaemia within the first year following completion of the treatment. Three patients died ( CMV + aspergillosis, pneumonia, erythroleukaemia). 86% of the patients reached CR following induction, 6% unconfirmed CR and 8% partial response. On diagnosis, a clonal population was identified in 63% (45/71) of the cases. Of these 45 patients, samples are available following induction treatment in 35 cases. The molecular disease was negativised in all the cases, except one case with persistence of positive bcl2/IgH (0.3% as opposed to diagnosis) and is in uncertain CR. Of the 34 cases with negative ER, 32 are in CR or uncertain CR and 2 PR.
Conclusions. The FCR regimen has proven to have a potent antitumoral activity in recently diagnosed follicular lymphoma patients with very high clinical (86% CR) and molecular (95%) responses. The immunosuppression caused is profound, with the appearance of opportunistic infections, and in some cases prolonged lymphopenias and neutropenias that call for future assessment and follow-up.
Combined Immuno-Chemotherapy Followed by Rituximab Maintenance Is an Effective Salvage Treatment after Prior Rituximab Containing Therapy: Results of a GLSG-Subgroup Analysis in Patients with Relapsed Indolent Lymphoma.
Authors: Dreyling Martin H. , Forstpointner Roswitha , Boeck Hans-Peter , Repp Roland , Wandt Hannes , Pott Christiane , Seymour John Francis , Metzner Bernd , Haenel Annette , Lehmann Tanja , Hartmann Frank , Einsele Hermann , Unterhalt Michael , Hiddemann Wolfgang 
Published: October 2019

Abstract
Background: Combined immuno-chemotherapy incorporating Rituximab with various chemotherapy regimens has resulted in increased response rates and prolonged progression-free and even overall survival in numerous trials. However, a constant relapse pattern has been observed even after such an optimized first line treatment.
Methods: In a subgroup analysis of the GLSG trial for relapsed indolent lymphoma (R-FCM followed by Rituximab maintenance), response and long term results of patients with previous Rituximab containing treatment were compared with the Rituximab naive control group. Induction comprised of 4 courses of chemotherapy with Fludarabine, Cyclophosphamide and Mitoxantrone (FCM) plus Rituximab. Patients responding with a complete (CR) or partial remission (PR) were randomized for observation only versus Rituximab maintenance (4 applications at month 3 and 9).
Results: 18 of 268 patients (arm A) with relapsed lymphoma had already previously received a R-containing regimen, the remainder 250 patients (arm B) were Rituximab naive. Overall response (arm A: 83 % vs. group B: 77%) and CR rate (arm A: 39% vs. arm B: 23%) were comparable in both subsets of study patients. Accordingly, progression-free survival after R-FCM was comparable in both subgroups of patients (median PFS in arm A: 15 months, arm B: 27 months) and overall survival as well. Especially, no disadvantage in the Rituximab pretreated patient group was detectable. 9 of the Rituximab pretreated patients responding to R-FCM induction therapy were randomized to maintenance treatment. After a median observation time of 20 months, 3 patients had relapsed and 6 patients remained in remission (3 of them for >20 months) resulting in a similar PFS after rituximab maintenance as in patients who were Rituximab naive.
Conclusion: This subgroup analysis strongly suggests that a Rituximab containing salvage therapy induction as well as maintenance is a highly effective treatment option even in patients who received Rituximab in first line therapy.
Favorable Results of Rituximab in Combination with CHOP in the Front-Line Treatment of Follicular Lymphoma Grade 3.
Authors: Fayad Luis , Overman Michael , Pro Barbara , McLaughlin Peter , Samaniego Felipe , Younes Anas , Romaguera Jorge Enrique , Hagemeister F.B. , Kwak Larry , Rodriguez Maria Alma 
Published: October 2019

Background: Follicular lymphoma grade 3 has a natural history that is more akin to that of diffuse large B-cell lymphoma. The addition of rituximab to standard CHOP has resulted in improved response and survival in diffuse large B-cell lymphoma. Information about outcomes in follicular lymphoma grade 3 is lacking.
Methods: A single institution retrospective review of patients with follicular grade 3 lymphoma evaluated at the UTMDACC from 1999 to 2004. Patients were located from the UTMDACC lymphoma database. All patients were initially treated with R-CHOP.
Results: Forty-five patients were identified: 51% male, 47% ≥60 years, and 87% follicular grade 3b. The LDH was elevated in 24%, ECOG performance status was >1 in 2%, and >1 site of extranodal involvement was present in 10%. Stage distribution was 11% stage I, 11% stage II, 42% stage III, and 36% stage IV, bulky disease (>7cm) was present in 11%, and B symptoms occurred in 13%. Beta-2 microglobulin was elevated in 57% with values >3 μg/dL in over 50%. IPI distribution was: 46% IPI Low, 38% LI, 11% IH, and 4% IPI High. Overall response rate was 100% with 96% complete responses. Relapse rate by IPI category was 24% for Low IPI, 18% for IPI LI, and 40% for IPI IH, and 100% for the two patients with High IPI. With median follow-up of 33 months, three year failure-free survival (FFS) is 73% (95% CI: 59 to 87%). One patient died (2%) with an overall survival (OS) at three years of 97% (95% CI: 93 to 100%).
Conclusion: The addition of rituximab to CHOP provided a high response rate and excellent early survival in this group of mostly good prognosis patients. Relapses were still seen; longer follow-up is needed.