bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolution of Rituximab as “Standard” Therapy in Patients (pts) with Newly Diagnosed Diffuse Large B Cell Lymphoma (DLBCL) in Japan: An Analysis from West-Japan Hematology/Oncology Group (West-JHOG) NHL Outcomes Project.
Authors: Nawa Yuichiro , Matsuo Keitaro , Sunami Kazuki , Togitani Kazuto , Takimoto Hidetaka , Nishimori Hisakazu , Maeda Yoshinobu , Hiramatsu Yasushi , Kiguchi Toru , Yano Tomofumi , Yamane Hiromichi , Tabayashi Takayuki , Takeuchi Makoto , Makita Masanori , Sezaki Nobuo , Ikeda Kazuma , Ishimaru Fumihiko , Shinagawa Katsuji , Hara Masamichi , Tanimoto Mitsune 
Published: April 2020

Abstract
The addition of rituximab to the CHOP (R-CHOP) regimen has had a dramatic impact on therapy of B-NHL. To clarify the effect of rituximab plus CHOP, we conducted a retrospective multicenter analysis to compare clinical outcomes of R-CHOP and CHOP in Japanese patients with diffuse large B cell lymphoma (DLBCL). Between 1/2000 and 6/2005, unselected 293 Japanese patients with DLBCL recruited from 13 institution, received CHOP with or without rituximab as the first line therapy. CHOP or R-CHOP was given 3 courses following radiotherapy for localized, and 6–8 courses for advanced disease. Rituximab was given at 375 mg/m2 concurrently with each course. The median age of total patients was 68 (range 26–99). After median follow-up of 21 months, PFS at 1, 2 year was 70.7% (95% confidence interval [CI]; 64.9–75.8), 59.1%(95%CI;64.9–75.8), respectively. Ninety-six patients received rituximab in combination with CHOP and 197 patients received CHOP alone. No statistically significantly differences of clinical characteristics such as sex, age and international prognostic index (IPI) were documented between two groups. The median follow-up for living patients was 15 and 28 months for R-CHOP and CHOP, respectively. In multivariate analysis, R-CHOP therapy significantly reduced the risk of treatment failure (hazard ratio [HR] 0.62; 95%CI 0.40–0.96, p=0.033), although the risk of death was similar in both group (HR0.78; 95%CI 0.44–1.37, p=0.38). In conclusion, in this multicenter analysis, R-CHOP therapy prolongs progression-free survival in Japanese DLBCL patients. There was a trend to better OS with rituximab than without rituximab at 2-year, however, this was not statistically significant. Longer follow-up will be required to assess the effect rituximab plus CHOP on survival.
Retrospective comparison of R-CHOP versus CHOP R-CHOP (n=96) CHOP(n=197) P HR 95%CI PFS;progression free survival, OS;overall survival, HR;hazard ratio, CI;confidence interval. PFS(2yr) 62.9% 57.2% 0.033 0.62 0.40–0.96 OS(2yr) 77.5% 70.4% 0.38 0.78 0.44–1.37
Maintenance Treatment with Rituximab in Follicular NHL.
Authors: Rubio-Martinez Araceli , Recasens Valle , Giraldo Pilar 
Published: April 2020

Abstract
Introduction: Preceding studies have shown that Rituximab ® prolongs relapsed free time (TFR) and response duration (RD) in follicular NHL (FNHL) when given either together with chemotherapy or alone as maintenance after therapy. The best schedule of maintenance with R still remains unknown.
Aim of study: to evaluate the relapsed free time in FNHL patients using R as maintenance after being treated with an induction schedule that included R.
Design: observational, prospective trial in previously patients with FL treated with chemotherapy + R in complete remission (CR).
Patients and methods: Since January 2002 to December 2005, 23 previously treated FL grade I or II patients with one R-chemotherapy line were included. At diagnosis baseline assessment: age, gender, clinical and physical exam, blood counts, serum and urine biochemistry, albumin, β2-microglobuline and LDH level, body scan, bone marrow biopsy. Patients were classified according to ECOG, clinical stage and FLIPI. Patients in complete remission (CR) after chemotherapy received R 375 mg/m2 × 4 weekly every 6 months for 2 years. Re-staging studies were performed at every cycle: CR, partial remission (PR) and relapse ®. Toxicity events have been noted.
Statistical analysis: Overall survival (OS), relapsed free survival (RFS). Survival analysis was performed using Kaplan-Meier and Cox regression.
Results: Mean age 53.1 (35–75), 12 F/11M; ECOG 0(14), 1(8), 2(1); B symptoms 10; FLIPI score 0(2 patients), 1(10), 2(7), 3(4); stage I (2 patients), II(4), III(9), IV(8); grade I(10), II(13).
Therapy schedules: R-CHOP (69.5%), R-CHOP+RTP (8,7%), R-CMF (17,3%), R-CF (4.3%). At present 21,7% of patients have completed maintenance for two years, 30,4% have received 3 courses, 60,8% two and 1 100%. None of them have relapsed.
Adverse events: two patients were excluded because of grade 3–4 neutropenia and two referred erythema while infusion of R. OS: mean 28.2 months (10–61); RFS: mean 22 months (4–53).
Conclusions: R maintenance seems to be effective in FL. The tolerance has been good in most of the patients and only two cases presented severe adverse events, neutropenia, in those patients who had received QTP with fludarabine+R. It is necessary a longer follow-up to consider the magnitude of the effect obtained with R maintenance.
A Phase IIIb Study of Rituximab Maintenance Therapy in Patients with Follicular Non-Hodgkin’s Lymphoma Who Have Responded to Induction Therapy - MAXIMA-Protocol.
Authors: Hensel Manfred , Witzens-Harig Mathias , Dreger Peter , Ho Anthony D. , Thurley Daniel , Oertel Stephan 
Published: April 2020

Abstract
Five randomized trials (four Phase III and one phase II) have confirmed that rituximab maintenance therapy provides clinical meaningful improvements in terms of Progression Free Survival, Event Free Survival and response duration for patients. Two studies have also found an overall survival advantage for rituximab maintenance therapy (Hoechster et al. 2005, van Oers et al. 2005) and a third study could demonstrate a strong trend towards overall survival advantage (Dreyling et al. 2006). A Cochrane meta-analysis of several randomised Phase III trials (Schulz et al. 2005) demonstrated that rituximab plus-chemotherapy for first-line treatment of Follicular Lymphoma is superior to chemotherapy alone and significantly prolongs overall survival. To further broaden the available basis for maintenance treatment in the first-line and relapsed setting, the MAXIMA (MAintenance rituXImab in Follicular LymphoMA) trial has been started in August 2006 and will last 5 years. Patients with first line or relapsed/refractory advanced Follicular Lymphoma are included in this trial. In total 500 patients are planned for this international trial running in 23 countries.
Patients who achieve a Complete Remission, Complete Remission unconfirmed or Partial Remission after rituximab containing induction therapy (rituximab with or without chemotherapy) are eligible to enter the study to receive rituximab maintenance therapy administered at the standard dose of 375 mg/m2 every 2 months for 2 years. This regimen is also investigated in the ongoing PRIMA study, and also in an ongoing SAKK study which investigates the benefit of rituximab maintenance therapy for up to five years.
The previous five randomized trials did not detect significant safety issues for rituximab maintenance therapy. The main objective of the MAXIMA trial is to confirm this safety data in a wider patient population.
Secondary objectives of the study include standard time dependent parameters (PFS, EF, OS). In addition, the effect of rituximab maintenance therapy on improving response quality (PR =&gt;CR) after induction therapy will be evaluated.
A Multi-Center, Open-Label Study To Evaluate the Safety and Efficacy of Pentostatin, Cytoxan, and Rituxan (PCR) in the Treatment of Previously Untreated or Treated, Bulky Stage II, Stage III or IV, Low-Grade B-Cell NHL.
Authors: Mena Raul R. , Christiansen Neal P. , Markan Yudishtra , Pandit Lalita 
Published: April 2020

Abstract
The decision to treat indolent B-cell NHL is often based on progressive disease, worsening symptoms, and increasing hematological derangement. When treatment is indicated, these lymphoproliferative disorders are very sensitive to combination chemotherapies utilizing pentostatin (P), a purine analog, cyclophosphamide (C), a DNA alkylator, and rituximab (R), an anti-CD20 monoclonal antibody. P+C+R represents a promising approach in the treatment of these patients. Most regimens have utilized fludarabine (F) as the purine analog but the myelosuppression and immunosuppression of (F) combinations frequently results in severe infections. Eligibility criteria allow both treated and treatment-naïve patients diagnosed with Bulky Stage II or low-grade stage III/IV NHL (REAL classification) to be enrolled. Treatment consisted of intravenous infusions of P (4 mg/m2), C (600 mg/m2), and R (375 mg/m2) on day 1 of a 21-day cycle for a total of up to 10 cycles. Clinical evaluation was performed after cycles 2, 4, 6, 8 and 10 (if necessary). The intent-to-treat (ITT) population consisted of 76 NHL patients (median age 65, range 29–84) who received a total of 385 cycles (median 6 per patient). The ECOG status was 0 (64%), 1 (36%) and 2 (0%). The overall response rate (CR+Cru+PR) of the 69 evaluable patients was 72% (CR 11.6%, Cru 11.6%, PR 47.8%, SD 27.5% and PD or RD 1.4%). 12 grade 4 and 23 grade 3 neutropenias were documented. There were a total of 5 deaths due to acute myocardial infarction, NSCLC, a suspected cardiac event and 2 unknown cause of death. This immunochemotherapeutic regimen is active in indolent Grade III/IV NHL and the incidence of significant toxicities was low. Future trials evaluating the use of R as maintenance therapy following this PCR regimen may also be warranted with an eye toward increasing the overall survival of patients with NHL. The results will be updated at the meeting.
Phase I Trial of Combination Therapy with 90Y Ibritumomab Tiuxetan and Gemcitabine in Patients with Non-Hodgkin’s Lymphoma.
Authors: Borghaei Hossein , Smith Mitchell , Millenson Michael , Shafer Danielle , Thibodeau Linda , Schilder Russell 
Published: April 2020

Abstract
Y90-ibritumomab tiuxetan, or Zevalin (Z), is an effective therapy against CD20+ lymphomas and is approved for use in patients with relapsed or refractory low grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma (NHL). Gemcitabine also is active against NHL and is a potent radiation sensitizer. We are conducting a phase I trial to assess the safety of concomitant administration of Z and gemcitabine in patients with NHL. Nine patients in three cohorts will be treated with 250 mg/m2 of gemcitabine IV on days 1 and 8 of the Z treatment program of rituximab + In 111-ibritumomab on day 1 and rituximab + Y90 ibritumomab on day 8, with Z at 0.2, 0.3 or 0.4 mCi/kg respectively. The next cohort can only accrue after all patients in the prior cohort have hematologic toxicity that has recovered to grade 0–2 or after 60 days from the date of the last treated patient in the previous cohort. Once it is confirmed that a Z dose of 0.4 mg/kg can be safely administered with gemcitabine 250 mg/m2, Z will remain constant at 0.4 mCi/kg while gemcitabine will be escalated according to a Bayesian based system. Response evaluation is by standard criteria. Eligibility criteria include: any histology of recurrent NHL (not candidates for high dose therapy), platelets ≥ 150,000/ul; &lt; 25% bone marrow involvement by lymphoma; prior radiation to &lt;25% radiation of bone marrow and no prior bone marrow or stem cell transplant. Seven patients have been treated thus far, four with follicular NHL (FL) and three with diffuse large B cell (DLBCL). Median age is 74 (range 55–82). The median number of prior treatments is 3 (range 1–6). The first three patients received Z at 0.2 mCi/kg, next three patients 0.3 mCi/kg and the seventh patient has received standard 0.4 mCi/kg of Z, all with 250 mg/m2 of gemcitabine on days 1 and 8. Toxicity has consisted of: one grade 3 and two grade 2 neutropenia in the first three weeks, three grade 3 leukopenia and one grade 2 in the first 4 weeks of the trial, three grade 2 anemia (one patient has remained with grade 2 anemia for 14 weeks), four grade 2 thrombocytopenia in weeks 6 through 12, and one grade 3 thrombocytopenia in weeks 8&9 resolving to grade 2 (this patient received standard dose of Z). One grade 3 infection occurred, unrelated to the protocol or the study drugs. No grade 3 or 4 non-hematologic toxicity has been seen. In follow up, two patients with FL and one with DLBCL achieved CRu. Two patients with DLBCL and one with FL have progressed. One patient with FL is not yet evaluable. Conclusion: Our preliminary findings suggest that Zevalin can be safely combined with gemcitabine 250 mg/m2 in the treatment of patients with NHL. Accrual to the cohort with full dose Zevalin and gemcitabine is continuing.
Treatment of Low-Grade Non-Hodgkin Lymphomas with Fludarabine and Mitoxantrone Followed by Rituximab Maintenance: Results of a Phase II Study.
Authors: Psyrri Amanda , Dimopoulos Meletios A. , Fountzilas George , Tsatalas Constantinos , Anagnostopoulos Athanasios , Papageorgiou Sotirios , Xiros Nikolaos , Economopoulos Theofanis 
Published: April 2020

Abstract
The combination of fludarabine and mitoxantrone (FN) has been a well-tolerated and effective regimen for the treatment of indolent lymphomas. Rituximab is an active agent for the treatment of CD20-positive B-cell lymphomas. In the present study, we sought to determine the activity of FN chemotherapy followed by maintenance Rituximab in indolent lymphomas. Patients with indolent lymphoma received fludarabine 25 mg/m2 day 1–3 and mitoxantrone 10mg/m2 every 28 days. Patients who attained a response (CR or PR) received 4 weekly doses of Mabthera 375mg/m2 1 month and 3 months after completion of treatment. The primary endpoint of the study was to evaluate the response to this regimen and secondary endpoints were survival and toxicity. Forty-six patients were included in the study. The median follow-up time was 29 months. Six patients were stage I, 8 stage II, 3 stage III and 29 stage IV. Histology was distributed as follows: small lymphocytic lymphoma (SLL) 15 patients, splenic marginal zone lymphoma 3, lymphoplasmocytic lymphoma 1, marginal zone B-cell lymphoma 16 (extranodal 12 and nodal 4), follicular grade I 6 and follicular grade II 5 patients. The median number of delivered cycles was 6. Fifty-two percent of patients attained a complete response (CR) and 39% a partial response (PR) for an overall response rate of 91%. One patient had stable disease, one had progression of the disease, whereas 2 were non-evaluable. After a median follow-up of 29 months, 34 of 46 patients (74%) are alive and disease-free. Grade III and IV toxicities included neutropenia (28%), thrombocytopenia (7%), anemia (4%), and diarrhea (2%). In conclusion, FN followed by Rituximab maintenance is an active and well-tolerated regimen in the treatment of patients with indolent lymphomas.
Long-Term Followup of Patients with Follicular Lymphoma (FL) Treated with Two Years of Maintenance Rituximab: Response to Rituximab Retreatment at Progression.
Authors: Hainsworth John D. , Meng Christina , Spigel David R. , Raefsky Eric L. , Barton John H. , Greco F. Anthony 
Published: April 2020

Abstract
Background: Maintenance treatment with rituximab prolongs progression-free survival (PFS) in patients with FL when administered following single agent rituximab, chemotherapy, or rituximab/chemotherapy combinations. However, the possible induction of lymphoma resistance by prolonged rituximab treatment has been a cause for concern. To address this issue, we obtained long-term followup on patients who had received 2 years of maintenance rituximab and had objective response or stable disease when treatment was discontinued. With a median followup of 7 years, we evaluated the subsequent course of these patients, with particular attention to:
treatment administered at relapse, sensitivity to retreatment with rituximab at progression, and survival.
Methods: Between March 1998 and August 2002, we treated a total of 106 patients in 2 sequential studies with single-agent rituximab, followed by rituximab maintenance therapy (repeated 4-week courses every 6 months for 2 years). In both studies (JCO20:4261, 2002; JCO23:1088JCO23:2005), rituximab maintenance was arbitrarily discontinued after 2 years. Fifty-eight of 106 patients (55%) in these 2 trials had objective response or stable disease following completion of 2 years of maintenance rituximab. Followup regarding the subsequent course and treatment was obtained in all 58 patients.
Results: Nineteen of 58 patients (33%; 18% of all 106 patients treated) remain in continuous remission after a median followup of 7 years (range 4–8 years). Thirty-five patients progressed, while 4 patients died of intercurrent illnesses while in remission. Of the 35 patients who progressed, 24 patients received single-agent rituximab as the next therapy, while 2 patients received rituximab in combination with chemotherapy. Eight of 24 patients (33%) had objective responses to single-agent rituximab (CR 5, PR 3), 14 patients (58%) had stable disease, and 2 patients progressed. Six of the responding patients again received maintenance rituximab. Median PFS in the 22 responding/stable patients was 47 months (95% CI = 39–52 months) with 27% of patients progression-free at 5 years. Both patients receiving rituximab plus chemotherapy had complete remissions (durations 33, 64 months). Transformation to a more aggressive histology was not documented in any patient. The median survival of all 35 relapsing patients, measured from the time of relapse, is 63 months, (95% CI = 40-N.R.).
Conclusions: The majority of patients who relapse after 2 years of maintenance rituximab therapy remain sensitive to rituximab. Retreatment with rituximab, either as a single agent or in combination with chemotherapy, is a reasonable therapeutic option at the time of progression. Further investigation of more prolonged rituximab maintenance schedules is indicated.
Lack of Correlation between CD 52 Expression and Treatment Outcome in PTCL Patients Treated with CHOP Chemotherapy Plus Campath-1h (CHOP-C) as First Line Treatment.
Authors: Gallamini Andrea , Campidelli C. , Zaja F. , Billio A. , Gargantini L. , Manna A. , Secondo V. , Levis A. , Rigacci L. , Mazza P. , Iannitto E. , Pinto A. , Tucci A. , Patti C. , Zoli V. , Torchio P. , Ascani S. , Pileri S. 
Published: April 2020

Abstract
Prognosis for PTCL patients is poor; the 5-year overall survival rate ranges from 25 to 40%. Despite variable CD52 expression in T-cell malignancies, promising results have been demonstrated with alemtuzumab (Campath ®). We report preliminary results of standard CHOP therapy plus alemtuzumab (CHOP-C) in a cohort of untreated PTCL patients (pts). Beginning Jan 03, 25 consecutive PTCL pts were treated with 8 courses of CHOP. In the first cohort, 4 pts received alemtuzumab 30 mg. sc 1 day prior to the first 4 courses of CHOP, whereas in cohort 2 (N=21) alemtuzumab 30 mg was given one day prior to all 8 CHOP courses administered. The histopathology was centrally reviewed and included 16 patients with PTCL-U, 6 patients with AILD-T, and 3 patients with ALCL Alk. CD52 expression was checked by immunohistochemisty on paraffin-embedded material. Median age of patients was 51.2 years (range: 28–69), 22 (88%) were stage III–IV, 3 (12%) had bulky disease, 11 (44%) had bone marrow involvement, and 13 (52%) had high LDH values. The age-adjusted IPI values were 0 in 5 pts, 1 in 8 pts, 2 in 9 pts, and 3 in 3 pts. All 25 pts completed therapy.
Results: at a mean follow-up of 436 days (range:105–1124) 14/25 pts. are still alive and 11/25 have died, mostly of progressive disease (10/11). 17/25 pts achieved CR, 1 PR and 1 minimal response (MR); 6 pts. progressed. Of these 6 pts, 1 pt achieved a PR, and 1 pt in MR and 2 pts in CR died despite salvage treatment; one patient died +198 d. in CR due to pneumonia. Three pts relapsed +62, +119 and +145 days after achieving a CR. The mean duration of response was 273 days. The 2-year OS and FFS (Failure Free Survival) were 45% and 50% days, respectively (Figure). CD52 expression was available for 16 of 25 pts. Of 11 pts who progressed on, or relapsed after therapy, CD52 was positive in 5, negative in 2 and not available for 4 pts. Among the 14 responding pts, 7 were positive, 2 negative, and not available in 5.
Conclusions: CHOP-C seems to be a feasible chemoimmunotherapy regimen: the efficacy of this therapy seems fairly good with a CR rate of 68%; however 6/25 pts showed disease progression during therapy, most frequently after the third C-CHOP course. Although most pts were positive for CD52 expression (12/16), no relationship between CD52 expression and treatment outcome was identified.
Failure free survival (25 pts.) Failure free survival (25 pts.)
Expression of NTB-A in Normal Tissue, Non-Hodgkin Lymphomas and Investigation of Its Potential Therapeutic Impact for Chronic Lymphocytic Leukemia.
Authors: Zhao Xiaoxian , Korver Wouter , Prescott Nichole , Abo Arie , Hsi Eric 
Published: April 2020

Abstract
Introduction: Expressed on T, B, NK cells and neutrophils, NTB-A belongs to the signaling lymphocytic activation molecule (SLAM) family of immune receptors. It was reported recently that cross-linking of NTB-A induces T cell activation and Ly108 (the presumed mouse orthologue of NTB-A) controls the production of reactive oxygen species in neutrophils. To date, little is known about its expression at the protein level in normal tissues, or in hematologic malignancies.
Methods: We have generated monoclonal antibodies (mAbs) to NTB-A and used tissue microarrays (TMAs) to screen normal tissues and lymphomas. Western blotting and flow cytometry were used for confirmation of selected entities. Complement dependent cytotoxicity (CDC) assays were performed using the CellTiter-Glo Luminescent Cell Viability Assay kit (Promega).
Results: NTB-A was not detected in normal tissues including heart, liver, breast, kidney, brain, lung, uterus, small intestine, skin, prostate, pancreas, ovary, bladder, testis and stomach (5/5 negative cases for all above tissues) by IHC. Expression was observed in lymphocytes of normal tonsil and spleen. In lymphomas, we found NTB-A expression in diffuse large B-cell lymphoma (DLBL), follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma and Burkitt lymphoma. Western blotting and flow cytometry of B-cell lymphoma cell lines DOHH2 (DLBL) and Raji (Burkitt) confirmed NTB-A expression in these lines. Myeloma cell lines were negative for expression. Flow cytometry of normal blood cells showed expression of NTB-A in B-cells, T-cells and NK cells (95.5 ± 6.7%, 62.6 ± 29.5% and 72.7 ± 26.5%, respectively) but not in CD66+ granulocytes. Furthermore, CD34+ progenitor cells from bone marrow were negative. Because of the expression in SLL, we focused on chronic lymphocytic leykemia (CLL) cells. All (15/15) patient samples were confirmed positive by flow cytometry. No significant differences in expression levels were observed comparing CLL B-cells vs normal B-cells (n = 10). However, anti-NTB-A antibodies were capable of inducing CDC in white blood cells from CLL patients (n=5) but not in normal white blood cells (n=5), in addition to CDC activity against Raji cells. Preliminary data also suggests that the CDC effect is greater in purified CLL B-cells than purified normal B-cells.
Conclusions: These results show that NTB-A is expressed in normal lymphocytes but not in other solid tissues or in CD34+ progenitor cells. B cell malignancies, including Non-Hodgkin lymphoma cells appear to express NTB-A. In particular CLL patient cells express NTB-A, and an anti-NTB-A mouse mAb is capable of inducing CDC, suggesting NTB-A may be a potential immunotherapeutic target. Further studies examining the expression patterns in hematologic malignancies are ongoing.