bluuebunny/crossref_metadata_2025 huggingface dataset:
Reactivity of an Anti NS3-HCV-Induced Autoantibody in HCV-Positive Gastric Tissue by 2D Gel Immunoblot.
Authors: Spina Michele , Caggiari Laura , Cannizzaro Renato , Gloghini Annunziata , De Re Vallì
Published: April 2020

In a previous study we demonstrated an IgM cross reactivity against Fc region of human IgG and HCV-NS3 antigen in HCV-induced type II mixed cryoglobulinemia (MC). We identified NS3 and Fc epitopes recognized by these IgM by epitope excision approach. HLA determination confirms their ability to present these epitopes. The same cross reactivity has been observed with a monoclonal antibody, (mAb B3-18), obtained after immunization of a mouse with one of the identified NS3 epitopes. Previous, observations indicate that HCV may localize in several tissues besides the liver (such as gastric mucosa) possibly inducing some of the extra hepatic manifestations of chronic HCV infection. The aim of this study is to characterize the mAb B3-18 reactivity by an immuno-proteomic approach. Such novel information may be of interest to identify new potential antigens implicated in HCV pathogenesis useful to design new molecules for diagnostic or therapeutic approaches. Proteins were extracted from 12 gastric biopsies of patients with gastric disturb and HCV-infection (one of them with a concomitant malt lymphoma of the stomach) and from 3 patients with gastric disturb but without HCV infection as control. Proteins were analysed by 2D gel electrophoresis and mAb B3-18 immunoblot. Proteins recognized by mAb B3-18 were identified by MALDI-TOF mass spectrometry. Differential protein expression levels between patients and controls were detected by 2D-DIGE. Samples were also tested by immunohistochemistry with the mAb B3-18, by VDJ-BCR and VDJ-TCR genscan analysis and by KIR/ligands haplotypes. MAb B3-18 is functional both in 2D gel electrophoresis and in immunohistochemistry. Two specific proteins were identified by B3-18 immunoblot in HCV-infected patients: 18 kDa antrum mucosa protein (AMP 18) and TFIZ1. Both proteins function as growth factors at least partly responsible for maintaining a functional gastric epithelium by seeking evidence of epithelial cell mitogenic activity. They are expressed and secreted in normal gastric mucosa but down-regulated in gastric cancer. These proteins, as well as some others, also showed an up-regulation in gastric mucosa from HCV-infected patients. Mab B3–18 reactivity in immunohistochemistry was restricted to gastric tissue surrounding the NHL lesion. An oligo/monoclonal B cell pattern was found in 3 patients. The characterization of KIR/ligand is in course. The use of a monoclonal antibody miming IgM autoantibodies from HCV+ patients with type II MC and a concomitant immunocytoma, is useful to identify autoantigens that could sustain HCV-related B cell proliferations and HCV infection-associated antigens.
Fludarabine, Mitoxantrone and Dexamethasone for the First Line Treatment of Patients with Indolent Non-Hodgkin Lymphoma (NHL): GATLA First Interim Report (Grupo Argentino de Tratamiento de la Leucemia Aguda).
Authors: Milone Gustavo , Rodriguez A. , Milone Jorge , Bezares R.F. , Rudoy S. , Palmer Luis , Cerruti I. , Lastiri Francisco
Published: April 2020

Background: fludarabine (F) is licensed for the management of indolent non-Hodgkin lymphoma in countries such as Canada and Switzerland. Clinical evidence suggests that fludarabine monotherapy is as least as effective, than conventional therapies such as cyclophosphamide, vincristine, prednisone (CVP) for the first and second line treatment of B-cell low grade NHL achieving objective response rates. Better response rates can be achieved combining F with Mitoxantrone (N) and Dexamethasone (D) in indolent NHL patients (pts). The GATLA (Grupo Argentino de Tratamiento de la Leucemia Aguda) started a prospective multicenter national study to evaluate the use FND as a first line treatment for low grade NHL.

Aims: to assess the response rate, safety, disease free survival (DFS) and overall survival (OS) of FND as first line treatment for indolent NHL during (2002–2006).

Methods: Ninety-six patients in the period of January 2002 to April 2006 were recruited. Sixty-nine patients were valuable at the time of analysis. Median age 54 years old (range: 21–79). Gender: male 51% and female 49%. Inclusion criteria for low grade NHL-LG was: non-previous, age > 18 years old with symptomatic disease, ECOG performance status 0–2 and written informed consent. Ann Arbor staging:

5,8%, 14,5%, 24,6% and 55%.

FND treatment consisted of F 25 mg/m2 i.v. (days 1–3), N 10 mg/m m2 i.v. (day 1) and D 20 mg (days 1–5) each 28 days for 6 cycles. All patients received oral antibiotics for intestinal decontamination, antifungal prophylaxis and Trimethoprim-Sulfamethoxazole as P. carinii prophylaxis for one year.

Results: on this low grade NHL cohort the overall response rate (ORR) was 93% (ORR) with 70% (48 pts) with complete response (CR) and 23% (16 pts) with partial response; progressive disease and non-response 7% (5 pts). The probability of event free survival (EFS) and overall survival (OS) at 24 months was 60% and 90% respectively. Two patients developed secondary malignancies after treatment and one died. Only one patient died in CR.

Conclusions: in this population FND treatment demonstrate a high CR rate with low toxicity and high probability of EFS and OS as previous experience published in the literature.
Short Duration Filgrastim (G-CSF) Therapy (2–4 Days) Is Adequate To Maintain Dose Intensity in Hodgkin’s Lymphoma Patients Treated with Adriamycin, Bleomycin, Vinblastine and Dacarbazine (ABVD).
Authors: Kaminer Lynne S. , Bavisi Seema , Lawton Jessica , Uhlig William , Carro George , Grinblatt David L.
Published: April 2020

Maintaining dose intensity in Hodgkin’s Lymphoma (HL) correlates with an improved outcome in patients treated with combination chemotherapy. Filgrastim is commonly used as secondary prophylaxis for neutropenia to avoid dose delays and dose reductions. Results from a retrospective review at the Mayo Clinic (Blood104(11):abs 1317, 2004) demonstrated an increased frequency of pulmonary toxicity in patients with HL treated with bleomycin who had received G-CSF. Thus, using the minimum amount of filgrastim required to maintain dose intensity may be beneficial. We describe below our results using a shortened regimen of filgrastim in conjunction with ABVD chemotherapy.

The electronic and/or paper charts of twenty-one adult patients with HL receiving ABVD at KCCC between January 2002 and May 2005 were reviewed. All patients completed at least 2 cycles of ABVD, with a median of 6 (range 2–8) cycles per patient. Of the 21 patients evaluated, 18 required administration of filgrastim as secondary prophylaxis. The precipitating factor requiring administration of filgrastim was a low ANC, which resulted in treatment being held or delayed in all patients. The filgrastim dosing regimen utilized consisted of a median of 3 doses (range 2–4) given days 6–10 post ABVD treatment. The chart review included 21 patients who received a total of 213 treatments with ABVD. Of these treatments, 78 were not preceded by filgrastim, while 135 included filgrastim. When filgrastim was not given, a subsequent dose delay occurred in 16 instances (20.5%) and dose reduction occurred in one (1.33%) instance. Of the 135 ABVD treatments with filgrastim prior to treatment, a subsequent dose delay occurred only once (0.74%) and there were five (3.7%) dose reductions. Filgrastim was dosed at 5 mcg/kg, rounded to the nearest vial size. Five patients received 300 mcg, while the remaining 13 were dosed at 480 mcg. Using this shorter dosing regimen, there is a potential cost savings of $2420 per treatment when compared to 10 doses of filgrastim. Similarly, when compared to pegfilgrastim, there is a potential cost savings of $2470 per treatment.

In conclusion, using 2–4 doses of filgrastim is a cost effective method that allows patients who are receiving ABVD to sustain dose intensity. This shortened course of filgrastim may also decrease the risk of lung toxicity. These results identify a valuable approach to potentially improve outcomes in patients with Hodgkin’s lymphoma.
Intensive Induction Is Beneficial for High Risk Younger Patients with Aggressive B-Cell Lymphoma, While Frontline ASCT Brings No Benefit: Final Analysis of MegaCHOP-BEAM and MegaCHOP-ESHAP-BEAM Studies.
Authors: Pytlik Robert , Belada David , Kubackova Katerina , Kozak Tomas , Jankovska Milada , Pirnos Jan , Bolomska Ingrid , Vasova Ingrid , Papajik Tomas , Sykorova Alena , Siffnerova Hana , Hamouzova Michaela , Klener Pavel , Trneny Marek
Published: April 2020

Objectives. Both high-dose induction and front-line ASCT have been tested for improvement of treatment results in younger patients with aggressive lymphomas. Since 1998, Czech Lymphoma Study Group is testing these approaches in Phase II prospective studies. We present mature data from two studies conducted in the pre-Rituximab era.

Methods. In 1998–1999, patients up to 65 years of age with all types of aggressive lymphomas except Burkitt and lymphoblastic lymphoma and age-adjusted (aa)IPI 2 or 3 were recruited to MegaCHOP-BEAM protocol, which consisted of 3–4 cycles of high-dose CHOP (cyclophosphamide, 3 g/m2, adriamycine, 75 mg/m2, vincristine, 2 mg and prednisolone 300 mg/m2 + G-CSF every two weeks) followed with BEAM and ASCT. From 2000, 3 cycles of MegaCHOP were followed with 3 cycles of ESHAP and BEAM consolidation. Peripheral blood progenitor cells were collected after 2nd or 3rd MegaCHOP in first and after 1st ESHAP in the second protocol. Analyses were performed on intention to treat principle.

Results. 21 patients were recruited to MegaCHOP-BEAM and 30 patients to MegaCHOP-ESHAP-BEAM protocol, respectively. Median age was 41 years (range, 21–66 years), 29 patients were males (57%). 47% of patients had diffuse large B-cell lymphoma (DLBCL), 33% primary mediastinal B-cell lymphoma (PMBCL), 16% peripheral T-cell lymphoma and 4% grade 3 follicular lymphoma. 53 % of patients had aaIPI 2 and 47% of patients had IPI 3. Overall response rate was 93% and 70% of patients achieved complete remission. Treatment related mortality was 4% (2 patients). 67% of patients proceeded to transplant and in 21%, protocol was changed because of toxicity. Median follow up is 63 months (range, 32–96) for living patients. Median overall survival or progression-free survival have not been reached and actuarial overall survival is 66 ± 13% in three years with no differences between the two protocols. Patients with PMBCL had better outcome than patients with DLBCL and patients of other histologies (3-year survival 94% v. 60% v. 30%, p = 0,001). Interestingly, patients with aaIPI 3 apparently benefited from addition of ESHAP (3-year survival 77% in MegaCHOP-ESHAP-BEAM v. 30% in MegaCHOP-BEAM, p = 0,03) while aaIPI 2 patients had the same survival with both protocols. Omission of ASCT or protocol change because of toxicity did not seem to influence patients outcome.

Conclusions. Full-lenght intensified induction improved treatment results in high-risk patients with aggressive B-cell lymphomas, particularly with aaIPI 3, while ASCT did not seem to have an impact. For T-cell lymphomas, other treatment strategies have to be sought.
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

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

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

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 =>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

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

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; < 25% bone marrow involvement by lymphoma; prior radiation to <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

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

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

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

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.
IRL-1620 Increases the Efficacy of Radiation Treatment in Mice Bearing Lymphoma Cell Induced Tumors.
Authors: Lenaz Luigi , Gulati Anil , Sunila E.
Published: April 2020

PURPOSE. IRL-1620, a selective ETB receptor agonist, has been reported to selectively enhance tumor blood flow and potentiate the efficacy of chemotherapeutics in various tumor models. Improved tumor perfusion is associated with a net increase in tumor oxygenation, which may be exploited to increase the effectiveness of radiotherapy. Since tumor oxygenation increases the radiation-induced cellular damage, IRL-1620 may be helpful to increase radiation sensitivity of tumor. The present study was conducted to determine whether administration of IRL-1620 prior to radiation enhances the efficacy of radiotherapy.

STUDY DESIGN. Male Swiss albino mice (6–8 weeks old; 25–30 g) were used for the study. Tumor was induced by the subcutaneous inoculation of Dalton’s Lymphoma cells (1 million) on the right hind limb. Tumor volume was measured using a digital caliper. Animals with a tumor volume of about 1cc were selected for the study and were divided into six groups (10 mice per group). Group I: No treatment; Group II: IRL-1620 (9 nmol/kg, 5 doses on alternate days); Group III: Radiation (5 × 4 Gy using Cobalt-60 Teletherapy unit (Theratron 780, Canada) on alternate days administered at 1 Gy/min); Group VI: IRL-1620 (1 nmol/kg) + radiation, 5 doses on alternate days; Group V: IRL-1620 (3 nmol/kg) + radiation, 5 doses on alternate days; Group VI: IRL-1620 (9 nmol/kg) + radiation, 5 doses on alternate days. Mice were shielded with lead except for a 3-cm-diameter circular field where the tumor was centered. IRL-1620 was administered via tail vein 15 minutes prior to radiation administration. Tumor diameter was measured twice a week for a total of 70 days.

RESULTS. Tumor bearing mice without any treatment showed a progressive increase in tumor volume and all the animals died by 53 days after tumor induction. Radiation alone did not significantly reduce tumor volume when compared to controls (possible due to hypoxic condition). There was no significant increase in the survival. All the animals (10 out of 10) died by 56 days after tumor induction. Animals treated with radiation 15 min after administration of 9 nmol/kg IRL-1620 reduced the tumor volume significantly and there was significant increase in life span. It was found that only 4 out 10 animals died by 70 days after tumor induction. Animals treated with radiation 15 min after administration of 3 nmol/kg IRL-1620 delayed the development of tumors. It was found that 7 out 10 animals died by 70 days after tumor induction. Animals treated with radiation 15 min after administration of 1 nmol/kg IRL-1620 along with radiation delayed tumor development. It was found that 9 out 10 animals died by 70 days after tumor induction.

CONCLUSION. It is concluded that IRL-1620 significantly enhanced the efficacy of radiation treatment in Dalton’s Lymphoma cells induced tumor model by reducing tumor volumes and increasing the survival.
Long-Term Dosing of AMG 531 in Thrombocytopenic Patients with Immune Thrombocytopenic Purpura: 48-Week Update.
Authors: Kuter David , Bussel James , George James , Aledort Louis , Lichtin Alan , Lyons Roger , Nieva Jorge , Wasser Jeffrey , Bourgeois Emanuelle , Kappers-Klunne Mies , Lefrere Francois , Schipperus Martin , Kelly Reggie , Christal Jenny , Guo Matthew , Nichol Janet
Published: April 2020

AMG 531 is a novel thrombopoiesis-stimulating peptibody that increases platelet production by targeting the TPO receptor. The study described here is an ongoing, open-label extension assessing the safety and efficacy of long-term, weekly, subcutaneous administration of AMG 531 in ITP patients who have completed a previous AMG 531 study. Patients previously treated with AMG 531 receive the same starting dose as the final dose given in the previous study; placebo-treated patients begin the extension with a 1 μg/kg dose. Doses may be skipped, decreased, maintained, or increased based on platelet response. Patients who achieve a stable dose for at least 3 weeks (later amended to 4 weeks) may be allowed to self-administer the drug. A total of 104 patients have been enrolled; the longest AMG 531 treatment duration is 96 weeks. This planned interim analysis includes 36 patients (safety subset) whose previous study was a phase 2 trial. Data for patients previously enrolled in a phase 3 trial are still blinded. The 25 women and 11 men have a mean age of 50±13 (SD) years; 30 (83%) have had a splenectomy. Twelve patients entered the study using concurrent corticosteroids, which were tapered when the platelet count was >50x109/L. Adverse event (AE) profiles were similar for the intervals of weeks 1–24 vs 25–48 and beyond. The most frequent were headache (incidence of 2.0 per 100 weeks of subject exposure for weeks 1–24 vs 1.7 for weeks 25–48), upper respiratory infection (1.3 vs 0.8), and fatigue (0.9 vs 1.0). Four patients had serious treatment-related AEs: vaginal hemorrhage/anemia (withdrawn from treatment), diffuse reticulin formation in the bone marrow (withdrawn), bone pain (continues on treatment), and transverse sinus thrombosis with papilledema and temporary decrease in visual acuity (64-year-old patient with diabetes mellitus and a platelet count of 293x109/L at the time of the AE; this patient continues on treatment). No neutralizing antibodies have been detected to date. The efficacy subset consists of 27 patients who completed week 48 or beyond. Both the mean platelet count and the mean dose of AMG 531 have remained stable between weeks 24–48. The mean platelet count was 100x109/L ± 4.4 (SE) during weeks 1–24 and 131x109/L ± 5.3 (SE) during weeks 25–48. Eleven patients (41%) have had at least one platelet count >450x109/L, excluding counts associated with ITP rescue medication. Six of 12 patients were able to discontinue concurrent corticosteroids, and 2 had a >25% dose reduction. Individualized weekly doses of AMG 531 provide a therapeutic option for ITP. Most patients have been able to maintain a safe platelet count and to decrease or discontinue concurrent corticosteroid therapy.
Telomere-Based Pre-Clinical Therapy of Human Lymphoid Malignancy in a SCID Xenograft Model.
Authors: Longe Harold O. , Sinha Anupama , Faller Douglas V. , Denis Gerald V.
Published: April 2020

We continue to develop and extend our novel adjuvant therapy approach to lymphoid malignancy. We supplement CHOP with DNA oligonucleotides that mimic the chromosomal telomere, which we call a “T oligo.” These agents are homologous to the 3′ overhang nucleotide sequence of telomeres and have previously been shown to have anti-tumor activity in animal models of malignant melanoma and breast cancer. They are currently being evaluated in melanoma and breast cancer patients. If introduced into human or murine normal, proliferating primary B cells or T cells, T oligo causes transient cell cycle arrest, while exerting no toxicity, but if introduced into human or murine malignant B cells or T cells, the arrest is followed by p53 phosphorylation, p21 message induction and ultimately p53-dependent apoptosis. Other p53-related effector molecules, such as p73, are also likely to be involved. The mechanism immediately suggests a novel method of chemotherapy for leukemia and lymphoma as an adjuvant with CHOP. Furthermore, we have previously shown with in vitro assay and in vivo mouse models of diffuse large B cell lymphoma (DLCL) that T oligo produces a more-than-additive toxicity towards lymphoma cells when combined with vincristine. T oligo alone or in combination with sub-therapeutic doses of CHOP, the standard of care for DLCL, dramatically reduced lymphoma burden in spleen, lung, bone marrow and peritoneum. In combination, which we refer to as T-CHOP, there was a greater reduction in tumor burden than with either therapy alone. We now show in SCID mouse xenograft models of human T cell malignancies, using a Jurkat T cell leukemic line or a MOLT-4 T cell leukemic line that T oligo also works alone to reduce tumor burden dramatically and increase survival. Interestingly, because T oligo-driven apoptosis occurs in p53-null, human lymphoid tumors, even chemotherapy-resistant lymphoid tumors are nevertheless sensitive to T oligo treatment, which may have profound benefit for relapsed leukemia or lymphoma patients.
The European Leukemia Net CML Registry - Objectives, Achievements and First Results.
Authors: Hasford Joerg , Rosti Gianantonio , Baccarani Michele , Hehlmann Rudiger , Guilhot Joelle , Rousselot Phillippe , Cervantes Francisco , Hellmann Andrzej , Steegmann Juan L. , Colita Adriana , Markl Gertraud , Pfirrmann Markus , Simonsson Bengt
Published: April 2020

In 2004/2005, the European Chronic Myeloid Leukemia (CML) Registry was established within the European Leukemia Net (ELN) which is funded by the EU. The purpose is to collect prospectively baseline, follow-up and outcome data of CML patients treated with imatinib or with more recent tyrosine kinase inhibitors in a standardized format. Among the objectives are the development and validation of prognostic scores, the analysis of various prespecified subgroups, e.g. of patients with imatinib failure or of patients who discontinued imatinib after complete cytogenetic remission and to support the design and analysis of future clinical trials. At present individual patient data of about 1460 bcr/abl positive CML patients from France, Germany, Italy, Poland, Romania and Spain are in the data bank. Patients were treated either with 400 or 800 mg imatinib/day as mono or combination treatment. About 40% of the patients are female. Using the New CML Score the proportion of low risk patients varies between 35% – 89% (high risk: 0% – 13%) among the participating countries. First analyses of outcome data, here the proportion of cytogenetic remissions at month 12, indicate that the results of the IRIS trial can be reproduced. With more countries participating and longer observation times the European CML Registry promises to provide highly interesting data.
Downregulation of Receptor Activator of Nuclear Factor kB Ligand (RANKL) in Chronic Myeloid Leukemia Patients Receiving Imatinib Mesylate Is Dose-Dependent.
Authors: Albano Francesco , Zagaria Antonella , Anelli Luisa , Guastadisegni Maria , Pannunzio Alessandra , Spinosa Giuseppina , Rocchi Mariano , Liso Vincenzo , Specchia Giorgina
Published: April 2020

The receptor activator of the nuclear factor kB ligand (RANKL) is a key molecule in the pathogenesis of malignant osteolytic lesions in multiple myeloma or bone metastases in prostate and breast cancer. Inhibition of RANKL is therefore a promising new therapy for controlling bone loss and pain in bone tumors and associated osteolysis. Changes in bone and mineral metabolism developing in a proportion of patients taking imatinib for either chronic myeloid leukemia (CML) or gastrointestinal stromal tumors have previously been described. The aim of our study was to verify in CML patients the effect of imatinib on RANKL bone marrow molecular expression.

The study included 13 CML patients (7 males, 6 females, median age 37 yrs). Six were treated with imatinib at standard dosage (400 mg) and the remaining 7 at higher doses (> 400 mg). The median duration of imatinib therapy was 28 months (range 13 – 44 months).

The RANKL gene expression level was determined by Real-Time PCR using 1X Platinum SYBR Green qPCR SuperMix-UDG. Variations in RANKL gene expression level were estimated by comparing the values of 2−Δ Δ Ct obtained in CML patients at diagnosis and during imatinib treatment. For each of the tested cases the sample at diagnosis was utilized as calibrator and 28S rRNA was used as reference gene.

Eight (62%) patients showed a downregulation of RANKL gene expression, the fold decrease ranging from 0.01 to 0.47 as compared to the value at diagnosis; among these 8 patients, 6 (75%) were treated with imatinib at standard dosage. Instead, 5 (38%) patients showed an upregulation of RANKL, the gene expression fold increase ranging from 1.43 to 4.94 as compared to the gene level observed at CML onset; all these 5 patients were treated with high doses of imatinib. There was no association between RANKL expression and the duration of imatinib treatment.

These findings suggest that imatinib mesylate could control RANKL expression. At standard dosage, imatinib can downregulate RANKL production. The RANKL upregulation observed in CML patients treated with high doses of imatinib could be explained by the possible activation of the immune system cells, such as T and B cells, induced by the tyrosine kinases inhibitor. Further studies are needed to verify the minimal effective dose of imatinib on RANKL expression, with the aim of administering it as an antiosteolytic agent in such diseases as osteoporosis, metastatic bone disease, and multiple myeloma.