bluuebunny/crossref_metadata_2025 huggingface dataset:
Infectious Disease Associations in Advanced Stage, Indolent Lymphoma (Follicular, FL and Non-Follicular, nFL): Developing a Lymphoma Prevention Strategy.
Authors: Portlock Carol S. , Hamlin Paul A. , Noy Ariela , Palomba Maria Lia , Rosenzweig Lisa , Walker Darren , Corcoran Stacie , Chey William D. , Gaydos Charlotte A. , Schwartz Ira , Papanicolaou Genovefa , Markowitz Arnold
Published: October 2019

Background: The antigen-drive association of gastric MALT lymphoma with H. pylori is well recognized. Successful antibiotic therapy can result in lymphoma remission, and with it, lymphoma prevention. We have sought to prospectively identify possible associated infections in patients with non-bulky, advanced stage indolent lymphoma as the first step to such a lymphoma treatment/prevention strategy. These patients are often candidates for “watch and wait” and it is during this period that a window of opportunity may exist to identify and treat related infections.

Methods: Patients with a new diagnosis of indolent lymphoma (FL and nFL), stages II (intra-abdominal), III and IV fulfilling GELF criteria for observation were eligible. Studies performed: Stool H. pylori, Hepatitis C and Borrelia serologies, Borrelia and Chlamydia fixed tissue PCR, peripheral blood mononuclear cell PCR for Chlamydia, and a hydrogen breath test for small bowel bacterial overgrowth.

Results: 55 patients have been enrolled with IRB informed consent: 32 females, 23 males; median age, 54 years (21–77); 30 FL, 25 nFL; stage II (4 pt), III (22), and IV (29). All met GELF criteria for observation. Infections tested include: H. pylori (13 positive: 6 FL, 7 nFL); Hepatitis C (3+; 1 FL, 2 nFL); and small bowel bacterial overgrowth (10+; 4 FL, 6 nFL). Borrelia serologies and tissue PCR were negative in all 13 pts tested. Chlamydia psittaci tissue PCR positive in 1 FL (12 negative). Thus, 20 of 54 (37%) patients have had at least one positive study; and, to date we have observed lymphoma responses after successful antibiotic therapy alone in 6 of 20: H. pylori (1 FL with CRu for 20+ months; 1 nFL with transient near CR); Hepatitis C (1 FL with PR but HCV persistent; 2 nFL (1 CR for 24+ mos; 1 stable, currently on HCV therapy); SBBO (1 FL in PR for 28+ mos). Of interest, the patients with associated infections but without lymphoma response to antibiotics, appear to have required institution of lymphoma treatment sooner than those without initial associated infections (Treatment free survival 48% vs. 87.5%, p=0.08; 33 months median f/u from diagnosis), possibly suggesting a different biology.

Conclusion: Infections are common in advanced stage indolent lymphoma (37% in our series). Anecdotal lymphoma responses have been seen and 2 have been durable CRs (10%) ongoing for 20+ mos following infection eradication alone. The identification and treatment of associated infections may be a first step toward developing a lymphoma prevention strategy.
Acquired Immunodeficiency and Malnutrition in Patients Treated with Bi-Weekly CHOP-Based Chemotherapy for Diffuse Large B-Cell Lymphoma.
Authors: Tholstrup Dorte , Hansen Mads , De Nully Brown Peter , Jurlander Jesper
Published: October 2019

During the recent years CHOP-14/CHOEP-14 in combination with the monoclonal anti-CD20 antibody Rituximab has become the standard choice of treatment for non-localized, poor risk Diffuse Large B-Cell Lymphoma. We, and others, have observed a relative high incidence of opportunistic infections not normally associated with the short neutropenic periods of CHOP-based treatment. We therefore introduced a prospective risk-assessment study in February 2005. The aim of the study is to assess the degree of malnutrition and immunodeficiency that may be associated with bi-weekly regimens. This is a preliminary evaluation of the first 27 patients included. Median age was 60 (31–80), 21 (78%) had CS III/IV disease, 14 (52%) extranodal involvement, 19 (70%) elevated LDH, 9 (33%) a Performance Score ≥2, i.e.13 (48%) presented with IPI 3–5 disease. Furthermore, 7 (26%) had bone marrow involvement, 8 (30%) bulky disease and 17 (63%) B-symptoms. All patients received 6 or 8 cycles of CHOP-14/CHOEP-14, and 15 patients received Rituximab at day 1 of each cycle. Patients were examined four times: 1) before 1st cycle, 2) 14 days after 4th cycle, 3) 14 days after last cycle (i.e. 6th or 8th), and 4) 3 months after treatment. Examination included blood tests, bodyweight and DEXA-scans. 20 patients (74%) had a significant weight loss during treatment. However, 3/4 had regained normal weight three months later. Consistently, DEXA-scans demonstrated a significant reduction in total lean body mass in 12 (44%) patients. P-protein, p-albumin, and selected trace elements were decreased in about 1/4 of patients during treatment. However, most patients had significant declines in T-cell levels during treatment, and interestingly about 1/4 presented with very low T-cell levels at diagnosis. Thus, total CD3-count was low in 7 (26%) patients at diagnosis, and reduced under treatment in 23 (85%). Both CD4- and CD8-count was low in 6 patients at diagnosis, while CD4 was reduced under treatment in 24 and CD8 in 16 patients. Likewise, a significant decrease of IgA, IgM, and IgG subclasses developed during treatment (Table 1). We conclude that patients treated with bi-weekly CHOP-chemotherapy may develop severely decreased levels of T-cells and severe hypogammaglobulinemia, which may be related to an increased incidence of opportunistic infections such as PCP or CMV reactivation.
GMCLI, Goelams Mantle Cell Lymphoma Index, a New Prognostic Index of Survival for MCL Patients Treated with VAD-C and Autologous PBSCT.
Authors: Gressin Remy , Maugendre Sylvie Caulet , Deconinck Eric , Tournilhac Olivier , Dartigeas Martine , Moles Marie Pierre , Lepeu Gerard , Guyotat Denis , Legouffe Eric , Dugay Jacqueline , Martin Claude , Casassus Philippe , Pierre Jean , Ghandour Christiane , Grulois Isabelle , Maloisel Frederic , Le Maignan Christine , De Jaureguiberry Jean Pierre , Thyss Antoine , Lucas Virginie , Cailleres Sylvie , Rodon Philippe , Dutel Jean Luc , Colombat Philippe , Gyan Emmanuel
Published: October 2019

The treatment of Mantle Cell Lymphoma (MCL) and the predictive variables of response to chemotherapy and survival are largely discussed. The French Goelams group conducted between 1996 and 2000, a first line phase II prospective trial for MCL patients to test the efficacy of the VAD+C regimen, explore the effect of ASCT on patients under 60 and identify prognostic factors.

Treatment: it consisted for the first step of 4 cycles of VAD+C regimen (classical VAD with vincristine, adriblastine, dexamethasone associated with chlorambucil 12 mg/D from D20 to D29. interval between two cycles 35 days). The responders (cheson criteria) went to the second step wich consisted of 4 other VAD+C regimen for patients over 60 years or for patients under 61 years, 2 other VAD+C regimen followed by a ASCT with preparative regimen including Alkeran 140 and a 8 grays TBI.

Results: 90 patients were included and finally 74 retained after the pathologic review. Fifty (78%) were common forms and 24 blastoid variants. For the 74 eligible patients (40 under 61years and 34 over 60), the ORR after 4 cycles of VAD+C was 73% and 46% of the patients were in CR/CRu. ASCT influenced significantly the PFS, with a median survival of 20 months for non transplanted patients versus 37 months for ASCT recipients (p=0,001) and showed a tendency for a better OS (p=0.07). Six independent prognostic factors (PF) were identified as influencing OS: blastic variants, LDH level, lymphocytosis>5G/L, MIB1proliferation index, performance status and B symptoms. This allows to propose a new prognostic index which stratifies patients at diagnosis into 3 prognostic groups, with 0 or 1 PF (n=34, 46%), 2 or 3 PF (n=29, 39%) and 4 or more PF (n=11, 15%). For these three groups, median OS was respectively of 68, 41 and 7 months (p=0.0001).

Conclusion: The VAD+C regimen thus appears as a good regimen for MCL with few prognosis factors, which can effectively be completed by an ASCT for young responders’ patients.
FcγRIIIa Gene Polymorphisms May Correlate with Response to Frontline R-CHOP Therapy for Diffuse Large B-Cell Lymphoma.
Authors: Kim Dong Hwan , Jung Hee Du , Sohn Sang Kyun , Lee Je-Jung , Yang Deok-Hwan , Park Yeon Hee , Do Young Rok , Shin Ho Jin , Hyun Myung Soo
Published: October 2019

Background: The precise mechanism of rituximab (R) plus CHOP (R-CHOP) therapy in diffuse large B-cell lymphoma (DLBCL) is not fully elucidated. Besides overcoming bcl-2 mediated chemoresistance, antibody-dependent cellular cytotoxicity (ADCC), which is activated by effector cells via IgG fragment C receptors (FcR), was also proposed as a mechanism of Rituximab. The current study evaluated the impact of FcR polymorphism on the response to R-CHOP therapy for DLBCL with the basis that FcR polymorphism can affect R’s affinity for ADCC effector cells.

Patients and Methods: The FcγRIIIa and FcγRIIa gene polymorphisms were determined in DLBCL patients receiving R-CHOP (n=113) comparing to CHOP therapy (n=85).

Results: The FcγRIIIa valine (V) allele was significantly correlated with higher complete response rate to R-CHOP compared to phenylalalnine (F) allele (88% in V/V versus 79% in V/F versus 50% in F/F, p=0.002), while no difference was found between FcγRIIa polymorphism. In addition, V/V allele was associated with faster achievement of response than other alleles. The impact of FcγRIIIa gene polymorphism on response rate was not noted in CHOP group. In terms of overall or event-free survival, no difference was found according to FcγRIIIa or FcγRIIa alleles.

Conclusion: The FcγRIIIa SNP is predictive of response to R-CHOP, but does not correlate with survival in DLBCL patients.
Peripheral T-Cell Lymphoma, Not Otherwise Specified: A Clinicopathologic Study of 340 Cases from the International T-Cell Lymphoma Project.
Authors: Weisenburger Dennis D. , Wilson Wyndham H. , Vose Julie M.
Published: October 2019

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), is an uncommon lymphoma in which the clinical and pathological features of prognostic importance are not well understood. Therefore, we collected 340 cases of PTCL-NOS from 21 centers in 13 countries around the world to study this entity. PTCL-NOS was the most common subtype of PTCL in the project (29.3%) and consisted mainly of PTCL unspecified (88.5%) and the lymphoepithelial type (8.2%). The median age of the patients was 60 years, 66% were males, and 69% had stage III/IV disease at diagnosis. Anthracycline-based chemotherapy was given in 80% and a complete response was obtained in 56% of the patients. However, the 5-year overall and failure-free survivals for the entire group were only 32% and 20%, respectively. The International Prognostic Index (IPI) was highly predictive of survival (p<0.001). Other clinical prognostic factors identified in multivariate analysis (MVA) included hypergammaglobulinemia (HR 0.5), mass >10 cm (HR 2.5), and platelets <150,000/mm3 (HR 2.2). Pathologic features predictive of survival included >70% transformed cells (HR 1.7) and <10% CD8+ background T-cells (HR 1.8). However, in final MVA, only the IPI and >70% transformed cells were predictive of survival. In conclusion, PTCL-NOS is an aggressive disease in which the IPI and the percentage of transformed cells could be used to select patients for risk-adapted therapies.
The Genetic Contribution to the Aetiology of Thalidomide Associated VTE.
Authors: Morgan Gareth J. , Johnson David C. , Crowley John , Shaughnessy John , Sonneveld Pieter , Durie Brian , Ramos Christine , Van Ness Brian G. , Barlogie Bart , Hoering Antje , Haessler Jeff , Baris Dalsu , Katz Michael , Rajkumar Vincent S. , Goldschmidt H.
Published: October 2019

We have taken a genetic strategy to define the mechanisms underlying the increased risk of VTE in myeloma patient treated with thalidomide using clinical trial data derived from the MRC, ECOG, Little Rock and HOVON trial groups. Baseline VTE rates in the MRC IX study, (CTD vs CVAD; n=748 no prophylactic anticoagulation), were 14%. Rates in both arms were equal but in the thalidomide arm, thrombotic events were all DVT’s or PE’s, whereas in the CVAD arm they split equally between line related and VTE’s. In the other comparison (CTD vs MP; n=542), the VTE rate was 17%, all in the thalidomide arm. Rates were similar or higher (30%) in the other trials depending on the intensity of treatment used.

We carried out a nested case control on DNA from MRC IX on 90 VTE (45 thalidomide, 45 non-thalidomide related), matched to 180 controls. SNPlex analysis for 60 SNPs in the coagulation cascade, DNA repair, thalidomide, metabolism and myeloma specific pathways, identified 7 genes which affected risk (NBS1, MTHFR, Ku80, Cyp3A5, LGAL52 and IL12B). This suggests three major pathways contribute to the risk of thalidomide related VTE, metabolism of thalidomide, tumour responsiveness and some pro-thrombotic factors. These factors differ from non-thalidomide related risk where a strong pro-inflammatory response is most relevant. We tested this hypothesis further using an expanded panel of 3,404 SNPs (BOAC panel), using the Megalle system. Statistical analysis of this data defined the top 20 thalidomide and non-thalidomide associated SNPs, which were consistent with the initial hypothesis, the results of which exclude variation in the coagulation cascade as being a significant risk factor. We explored this hypothesis further using pathway-based analysis focussing on the MTHFR, DNA repair and WNT pathways on data from the ECOG, HOVON and Little Rock data sets. The biological relevance of the SNPs and genes identified was validated by correlating the level of expression using the Affymetrix U133 CHIP with genetic variation at the DNA level. To verify the relevance of DNA repair variability to tumour response further, we correlated gene expression profiling with response and again Ku80 was identified as one of a cluster of genes defining increased risk. The data suggests that the risk of thalidomide related VTE relates to rapid tumour lysis combined with a prothrombotic tendency, whereas in line related thrombosis, risk is dependent upon a strong proinflammatory response. We are building this genetic data into a clinical risk model in order to allow us to develop a rationale for intervention strategies.
Surgical Resection Alone in Children with Limited Stage Lymphocyte Predominant Hodgkin’s Lymphoma - The Experience of the EuroNet-PHL Group.
Authors: Mauz-Koerholz Christine , Hasenclever Dirk , Gorde-Grosjean Stephanie , Dörffel Wolfgang , Schellong Günther , Shankar Ananth , Hall Georgina , Wallace William H. , Korholz Dieter , Landman-Parker Judith
Published: October 2019

Introduction: Lymphocyte predominant Hodgkin’s lymphoma (LP) is a rare CD20-positive subtype of Hodgkin’s lymphoma which was only recently recognised as a separate disease entity. Most patients present with localised stage IA or IIA disease and usually, the disease has a relatively indolent clinical course. Up until recently, children with LP were treated alike classical Hodgkin’s lymphoma and received chemotherapy +/− radiotherapy. Two published reports of surgical resection alone in 19 children with LP (Pellegrino 2003, Murphy 2003) suggest that this may be an effective therapeutic option for a select group of children with limited stage disease. Study objectives: Can a proportion of children with limited LP be cured by surgery alone if resection is complete? Is a watch and wait strategy after surgery alone safe for those patients with residual disease after resection? What is the risk of relevant upstaging at relapse and of transformation into an aggressive B-cell lymphoma?

Methods: European study groups participating in the EuroNet-PHL inter-group were requested to report their experience of surgery alone in children with LP. Surgery as single treatment modality has been used on a case by case basis for several years by the SFCE (France), the DAL / GPOH (Germany), and more recently by the UKCCSG (UK). Individual data of 57 patients were collected using a common CRF. 11 cases already published by Pellegrino were updated and are included.

Results: 49 patients with initial stage IA achieved a CR after surgery. In 8 patients (5 in IA, 1 in IIA, 2 in IIIA) resection was incomplete. At a median observation time of 43 months (max. 172 months) all patients are alive. In the CR group 13 relapses were observed, all occurring early within 26 months of resection. Freedom from progression is estimated to be 67% (95% CI [59%; 75%]). Of the 8 patients who had incomplete resection 6 patients relapsed (p=0.008), of whom one (initial stage IIIA) relapsed as non-Hodgkin lymphoma. Of the 16 stage IA patients who experienced a relapse, 9 had a local relapse alone and the remaining 7 relapsed with stage II A. The rate of upstaging (B-symptoms or relapse stage > II) was 0% (95%-CI: [0%; 21%]).

Conclusion: If complete resection is achieved, a substantial proportion (about 2/3 in our series) of surgically treated stage IA patients experience long-term remission and may be actually cured. Nevertheless, as most of the relapses occurred in the initially involved lymph node region, a better evaluation of the remission status after surgery may be obtained if FDG-PET is combined with CT/MRI. Based on these data we have designed a Europe-wide study in FDG-PET-negative stage IA-IIA LP to prospectively confirm these promising results in a larger cohort.
Identification of Prognostic Factors in Early Unfavorable Stage Hodgkin’s Lymphoma (HL): An Individual Patient Data Meta-Analysis.
Authors: Bohlius Julia , Haverkamp Heinz , Diehl Volker , Eghbali Houchingue , Ferme Christopher , Franklin Jeremy , Pfistner Beate , Schiller Petra , Raemaekers John , Engert Andreas , Henry-Amar Michel
Published: October 2019

Background: In patients with early unfavorable stage HL, generally defined as stage I and II patients with mediastinal bulk, elevated ESR, 3 3 involved nodal regions, older age or extranodal involvement, progression-free-survival (PFS) is low compared to patients with early favorable or advanced stages disease. This indicates suboptimal treatment strategies and clinical heterogeneity within the group of patients with early unfavorable stage HL. An international collaborative study was initiated to identify factors that may predict for poor prognosis in this patient group.

Methods: Medline and Cochrane Library were systematically searched for randomized controlled trials (n>100 patients per study arm) in early stage HL patients with one or more risk factors receiving 4–6 cycles of ABVD or similar chemotherapy plus radiotherapy. Individual patient data were collected and risk factors for PFS (including disease progression, relapse or death) identified using multivariate analysis (linear stepwise proportional hazards) stratified by study.

Results: Six studies were identified; data from 4,490 adult patients enrolled between 08/1982 and 01/2003 were available for analysis. The median follow up was 64 months; 663 patients experienced an event leading to an overall 5-year PFS rate of 85% (95% CI 83%–88%). Six factors were significantly (P<0.01) associated with poor PFS: male gender (Hazard ratio (HR) 1.69), age (HR per additional life year 1.03), B symptoms (HR 1.25), anemia (HR per 1 g/dL Hb decrease 1.09), WBC (HR per 1000 WBC increase 1.02) and large mediastinal tumor (HR 1.54). Split into quintiles by predicted risk, observed 5-year PFS rates differed significantly (p<0.001): 80% of patients with early unfavorable stage HL achieved 5-year PFS rates ranging from 84% (95% CI 81%–87%) to 92% (95% CI 90%–94%) while 20% of patients had poor 5-year PFS, i.e. 76% (95% CI 73%–79%). Compared to low risk patients, those with high risk were more often male (81% vs 40%), older (median age 50 vs 29 years) and presented more often with B symptoms (62% vs 28%) and large mediastinal tumor (42% vs 27%). These data show that among stage I and II patients with at least one risk factor heterogeneity exists.

Conclusion: Using basic characteristics and routine tests, it is possible to identify a subgroup of early unfavorable stage patients with poor PFS while receiving 4–6 cycles of ABVD or similar chemotherapy plus radiotherapy. For these patients, treatment optimization is open to discussion in particular when compared to that of patients with advanced stage disease.
A Phase II Trial of FM (Oral Fludarabine and Mitoxantrone) Chemotherapy Followed by Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin®) for Previously Untreated Follicular Lymphoma (FL) Patients.
Authors: Zinzani Pier Luigi , Pulsoni Alessandro , Balocco Manuela , Tani Monica , Fanti Stefano , Perrotti Alessio , Castellucci Paolo , Zaja Francesco , Fabbri Alberto , Zaccaria Alfonso , Voso Maria Teresa , Fattori Pierpaolo , Guardigni Luciano , Gentilini Patrizia , Cabras Maria Giuseppina , De Renzo Amalia , Rigacci Luigi
Published: October 2019

We conducted a prospective, multicenter, single-arm, open-label, non-randomized, phase II study to evaluate the efficacy and safety of 90Y Ibritumomab Tiuxetan of a new approach combining induction chemotherapy with oral Fludarabine and Mitoxantrone (FM) followed by consolidation with 90Y Ibritumomab Tiuxetan for patients with previously untreated FL. Patient eligibility was represented by: age ≥ 18 years with biopsy-proven, untreated; stage II – IV FL grade I–II; WHO performance status of 0 to 2. All patients signed a written informed consent. Patients were treated with standard FM chemotherapy (Fludarabine was administered orally at the dose 40 mg/m2/day for 3 consecutive days) every 28 days for 6 cycles. Patients were restaged 4 to 8 weeks after completion of the sixth cycle of FM. Patients achieving at least a PR after 6 cycles of FM chemotherapy were eligible for consolidation with 90Y Ibritumomab Tiuxetan provided the granulocyte count was > 1500/μL, the platelet count >100.000/μL, lymphocytes expressing the CD20 antigen and the bone marrow examination at the completion of FM demonstrated < 25% involvement with lymphoma. All patients were to receive a single dose of 90Y Ibritumomab Tiuxetan 14.8 MBq/kg (0.4 mCi/kg) up to a maximum dose of 1184 MBq (32 mCi). At data reporting for this abstract, 62 patients were enrolled and 41 were evaluable for response. Of these 41 patients, all are evaluable for induction FM regimen and 19 of them also are evaluable after 90Y Ibritumomab Tiuxetan treatment. 15 were male and 26 female; the median age was 52.5 years (range 36–70); 5 were stage II, 12 stage III, and 24 stage IV. After the FM treatment the OR rate was 100%, including 73% complete remissions (CR + CRu) and 27% PR. Time to event analyses, including TTP and duration of response are pending further follow-up. Treatment was well tolerated; grade ≥ 3 AEs were seen in 20 patients; the most common grade ≥ 3 AEs was neutropenia. Among the actual 19 evaluable patients subsequentially treated with 90Y Ibritumomab Tiuxetan, 3/5 (60%) patients improved their remission status from PR to CR. The 90Y Ibritumomab Tiuxetan toxicity included grade ≥ 3 hematologic AEs in 12 patients. These preliminary data indicate: 1) FM regimen including oral fludarabine presents the same activity of i.v. formulation one without significant gastrointestinal toxicity and with a better patient compliance; 2) feasibility, tolerability, and efficacy of the FM plus 90Y Ibritumomab Tiuxetan regimen for untreated FL. Final efficacy and safety data will be presented.
Molecular Inhibition of mTOR with Temsirolimus (TORISEL™, CCI-779) Is a Promising Strategy in Relapsed NHL: The University of Chicago Phase II Consortium.
Authors: Smith Sonali M. , Pro Barbara , Smith Scott , Stiff Patrick , Lester Eric , Modi Sanjiv , Dancey Janet , Vokes Everett E. , van Besien Koen
Published: October 2019

Mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine kinase positioned at the juncture of several signal transduction pathways frequently disrupted in cancer. Downstream effectors, S6KI and 4EBP1, regulate cell cycle kinetics and cell growth via translational modulation, and this is effectively halted by rapamycin. Temsirolimus (TORISEL™, CCI-779) is a rapamycin ester derivative with cell cycle inhibitory properties. We conducted a phase II study of temsirolimus 25 mg IV over 30 minutes weekly in three cohorts of patients with relapsed/refractory NHL: Group A (diffuse large B-cell lymphoma, DLCL), Group B (follicular lymphoma, FL), Group C (small lymphocytic lymphoma/chronic lymphocytic leukemia [SLL/CLL] and other indolent B-cell lymphomas). Correlative studies in primary tumor tissue and in peripheral blood samples include phosphorylated p70S6K, total and phosphorylated 4EBP1, PTEN status, p21 status, and p27 status. Forty patients are registered, of which 21 are evaluable for response. Six patients are inevaluable and 13 too early for response evaluation; all patients were included in toxicity evaluation. There were 22 males/18 females with a median age of 59 (range, 29–83). Primary tumor samples were collected in 10 patients, with biomarker analysis pending. Histologic subtypes include 7 DLCL, 14 FL, and 13 CLL/SLL. Of 21 evaluable patients for response, there were 3 complete remissions (all FL) and 5 partial remissions (1 DLCL, 3 FL, 1 SLL), for an overall response rate of 40%. An additional 10 patients (5 FL, 6 CLL/SLL) had minor responses or stable disease; only 3 pts had progressive disease as their best response. The median follow-up is 4 months (range, 1–15 months). Grade 1–2 non-hematologic toxicities (except where noted) include increased hepatic enzymes (10 pts), skin rash (13 pts), fatigue (18 pts; grade 3 in 2 pts), hypercholesterolemia (22 pts), hyperglycemia (21 pts; grade 3 in 1 pt), hypertriglyceridemia (20 pts; grade 3 in 1 pt). Six patients were removed from study due to pneumonitis; 4 of these patients were symptomatic (cough, fevers, dyspnea) and 2 were asymptomatic but had pulmonary abnormalities on staging CT scans. Grade 3 and 4 hematologic toxicities include thrombocytopenia (5 pts), lymphopenia (5 pts), and leucopenia (2 pts). In summary, temsirolimus shows preliminary but encouraging activity across multiple B-NHL subtypes, complementing the published activity in mantle cell lymphoma. Careful attention must be paid to pulmonary toxicity. However, the early activity, including disease regression and stabilization, suggests that future combinations with cytotoxics or other biologics may be warranted, and that mTOR inhibition in NHL is a promising strategy.
Preclinical In Vitro and In Vivo Evidence Support a Therapeutic Role for the CD70 Directed Monoclonal Antibody (SGN-70) in Waldenström’s Macroglobulinemia (WM).
Authors: Hatjiharissi Evdoxia , Ho Allen W. , Xu Lian , O’Connor Kelly E. , Hunter Zachary R. , Santos Daniel D. , Manning Robert , Leleu Xavier , Moreau Anne-Sophie , Patterson Christopher J. , McEarchern Julie A. , Law Che-Leung , Grewal Iqbal S. , Munshi Nikhil C. , Treon Steven P.
Published: October 2019

Introduction: WM is a B-cell disorder characterized by bone marrow (BM) infiltration of lymphoplasmacytic cells (LPC), along with excess mast cells (MC) which support the growth and survival of BM LPC through multiple TNF-family ligands including CD40L, APRIL and BLyS/BAFF. Importantly, BM LPC stimulate cell surface expression of TNF-family ligands through release of sCD27 which induces CD70 on MC. We therefore have sought the development of agents which could target CD27-CD70 interactions. As such, we examined the therapeutic potential of directly targeting CD70 using the fully humanized monoclonal antibody SGN-70 (Seattle Genetics, Inc., Bothell WA).

Methods-Results: As part of these studies, we used flow cytometric analysis to evaluate the expression of CD70 on primary WM patient BM LPC and MC, as well as 2 WM cell lines (BCWM.1 and WM-WSU). These studies demonstrated cell surface expression of CD70 on BM LPC and MC from 20/26 (77%) and 10/11 (90%) WM patients, respectively. We next assessed the ability of the SGN-70 antibody to eradicate primary WM LPC (n=5) and WM cell lines by assessing for direct induction of apoptosis, complement dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) as well as induction of TNF family ligands on primary WM MC and the LAD2 MC line. Following incubation of WM LPC with SGN-70 (0.01–20 μg/ml), no direct induction of apoptosis or CDC activity was observed. However, SGN-70 mediated significant dose-dependent ADCC against WM LPC and MC at concentrations of 0.1–20 ug/ml. Importantly, SGN-70 blocked sCD27-induced expression of CD40L and APRIL on primary WM MC and LAD2 MC. To further evaluate the therapeutic potential of SGN-70 in an in vivo model, SCID-hu mice bearing BCWM.1 WM cells were treated with SGN-70 (1 mg/kg, i.p., qOD) Serum human IgM and sCD27 levels were measured by ELISA to monitor for tumor engraftment and disease progression. SGN-70 initiated 6 weeks following tumor engraftment blocked tumor growth in 12/12 treated mice, whereas all 5 untreated mice demonstrated disease progression. The results of these studies provide the framework for clinical trials to examine the therapeutic potential of the SGN-70 monoclonal antibody in WM.
Long Term Clinical Benefit of Lenalidomide (Revlimid) Treatment in Patients with Myelodysplastic Syndrome without Del 5q Cytogenetic Abnormalities.
Authors: Raza Azra , Reeves James E. , Feldman Eric J. , Deeg H. Joachim , Dreisbach Luke , Schiffer Charles A. , Shammo Jamile M. , Klimek Virginia M. , Greenberg Peter L. , Bennett John M. , DeWald Gordon W. , Zeldis Jerome B. , Wride Kenton , Schmidt Michele , Knight Robert D. , List Alan F.
Published: October 2019

Background: MDSs are clonal hematopoietic stem cell malignancies characterized by cytopenias resulting from ineffective hematopoiesis. A phase 2 study of lenalidomide (MDS-002) demonstrated hematological improvement in patients with MDS without an associated deletion 5q cytogenetic abnormality (List AF, et al. Haematologica2006;91[suppl1]:379[abst 1032]). We now report multicenter results after 〉2 yrs follow-up.

Methods: A total of 214 pts with transfusion-dependent anemia were categorized into the following IPSS MDS risk groups after central review of bone marrow morphology, karyotype, and peripheral blood findings: Low/Int-1 (168 [78%]); Int-2/High (8 [4%]); and unclassified (38 [18%]). Patients were unclassified for missing or inadequate marrow studies for central review (morphology [29] or cytogenetic [7]) or other diagnoses (AML [1], atypical CML [1]). Patients were evaluated for frequency and duration of red blood cell transfusion independence (RBC-TI) (IWG criteria), hemoglobin (Hgb) response, and safety. The starting dose of lenalidomide was 10 mg (daily or daily × 3 wks q28d cycle).

Results: Overall, 56 (26%) of 214 enrolled patients achieved RBC-TI. Median time to RBC-TI was 5 wks, median duration of RBC-TI response was 41.0 wks (range, 8.0–136.4), and median Hgb increase achieved during RBC-TI was 3.2 g/dL (range, 1.0–9.8). An additional 36 patients experienced a ≥ 50% reduction in RBC transfusions (overall hematological improvement in 92 [43%] patients). Overall, 47 (22%) patients had an abnormal karyotype at baseline and 9 (19%) patients achieved a cytogenetic response (4 complete). The most common drug-related grade 3/4 adverse events (AEs) were neutropenia and thrombocytopenia (25% and 20%, respectively). Deep vein thrombosis occurred in only 2 (1%) patients. The duration of RBC-TI was ≥ 52 weeks in 21 (38%) patients. Among these 21 patients, 14 (67%) did not require a lenalidomide dose reduction during the first 52 weeks of treatment. Analyses of response variables will be presented. Dose-limiting neutropenia/thrombocytopenia was not reported after 52 weeks. The most commonly reported AEs after 52 weeks were mild-moderate diarrhea and fatigue (38% and 29%, respectively).

Conclusion: Lenalidomide is an active, well-tolerated treatment in MDS patients with transfusion-dependent anemia that is not associated with a deletion 5q abnormality. The rate of erythroid hematologic improvement and duration of RBC-TI is encouraging and offers a possible alternative to cytokine therapy.
Treatment with the Anti-CD20 Antibody (B1) and Irradiation Result in Synergistic Cytotoxicity That Is Dependent on MAPK Activation.
Authors: Ivanov Andrei , Cragg Mark S. , Illidge Tim M.
Published: October 2019

Radioimmunotherapy using radiolabeled anti-CD20 antibodies (mAb) is an effective new treatment in non-Hodgkin lymphoma with high response rates. However, the molecular mechanisms behind these impressive clinical responses are poorly understood. To elucidate these mechanisms we studied the signaling events evoked in a panel of lymphoma cell lines following treatment with anti-CD20 mAb alone or in combination with irradiation. In all three lymphoma cell-lines tested a synergistic cytotoxic effect was observed when the anti-CD20 mAb B1 was combined with irradiation. The additive effect seen with B1 mAb and radiation was not observed with Rituximab and could be reversed with MEK inhibitors U0126 and PD98059 as well as siRNA targeting MEK1 or 2. Moreover, addition of U0126 reversed the decrease in clonogenic survival triggered by treatment with B1 and irradiation. To further probe the mechanism of this synergistic cell death we used cell lines over-expressing BCL2 or crmA, to block mitochondrial and death receptor pathways, respectively. Although BCL2 and crmA over-expression mediated protection against radiation alone, it had no impact on the increased cytotoxicity induced by B1+irradiation. Morphological studies revealed gross vacuolization of the cytoplasm, yet relatively well preserved nuclei in cells treated with B1+irradiation. Taken together our data indicate that activation of the MAPK cascade is an important factor that contributes to the synergistic effect of anti-CD20 (B1) antibody and irradiation and provides important new insights into how this treatment may work in the clinic.
Synergistic Interaction of the Histone Deacetylase Inhibitor SAHA with the Proteasome Inhibitor Bortezomib in Mantle Cell Lymphoma.
Authors: Heider Ulrike , Kaiser Martin , Zavrski Ivana , Sterz Jan , Jakob Christian , Fleissner Claudia , Hecht Monica , Kleeberg Lorenz , Braun Christian , Possinger Kurt , Sezer Orhan
Published: October 2019

Mantle cell lymphoma (MCL) is an incurable B cell lymphoma and novel treatment strategies are urgently needed. Proteasome inhibitors, e.g. bortezomib, act by targeting the catalytic 20S core of the proteasome and induce apoptosis in tumor cells. Among other mechanisms, they lead to cytoplasmic accumulation of the IκBa protein, resulting in a reduced NF-κB activity. Histone deacetylase inhibitors (HDAI), e.g. SAHA, promote histone acetylation, chromatin uncoiling, and transcription of a variety of genes. Previous studies have indicated that HDAIs also interfere with NF-κB signaling. Since NF-κB is constitutively activated MCL cells and plays a major role in a variety of cellular processes, we hypothesized synergist effects of bortezomib and HDAI in MCL cells. Human mantle cell lymphoma cell lines (JeKo-1 and Granta-519) were exposed to bortezomib and/ or SAHA for 4 to 48 hours. Cell viability and apoptosis were quantified by the MTT and annexin-V assay, respectively. The effect of the combination of both agents was analyzed using the median effect method of Chou and Talalay. Reactive oxygen species (ROS) were quantified by the fluorophore H2DCFDA. The functional role of ROS generation was assessed using the free radical scavenger N-acetyl-l-cysteine (LNAC). In addition, activated caspases, proteasome- and NF-κB activity were quantified. After 48 hours of incubation, IC50 of SAHA and bortezomib were noted at 0.8μM and 7.7nm in JeKo-1 cells and at 3.9μM and 5.7nm in Granta-519 cells, respectively. Combined incubation resulted in synergistic cytotoxic effects, as indicated by CI values <1. This was accompanied by an increase of caspase-3, -8 and -9 activity. In addition, coexposure of bortezomib and SAHA led to an enhanced ROS generation (5.4 fold in Jeko-1 and 9.2 fold in Granta-519 as compared to untreated controls), while the agents alone only modestly induced reactive oxygen species. LNAC could block the ROS generation and reduced the apoptosis significantly. As expected, bortezomib reduced the NF-κB activity. Interestingly, exposure to SAHA led to an increase of NF-κB activity after 4 hours and a decrease after 24 hours. The combination of both drugs resulted in a decrease of NF-κB activity. Moreover, combined treatment with bortezomib and SAHA resulted in a marked reduction of proteasome activity that was more pronounced than the proteasome inhibition by the single agents. In conclusion, this is the first report giving evidence that SAHA and bortezomib synergistically induce apoptosis in mantle cell lymphoma cells through the generation of reactive oxygen species and disruption of the NF-κB pathway. Our data provide a framework for clinical studies with the combination of both agents in patients with mantle cell lymphoma.
Long-Term Clinical Benefit of Lenalidomide (Revlimid) Treatment in Patients with Myelodysplastic Syndrome and Chromosome Deletion 5q.
Authors: List Alan F. , Dewald Gordon W. , Bennett John M. , Giagounidis Aristoteles , Raza Azra , Feldman Eric J. , Powell Bayard L. , Greenberg Peter L. , Nimer Stephen D. , Zeldis Jerome B. , Wride Kenton , Schmidt Michele , Knight Robert D.
Published: October 2019

Background: Myelodysplastic syndromes (MDS) are hematological disorders characterized by chronic anemia, and are often refractory to cytokine therapy. Two phase 2 studies evaluating lenalidomide in MDS (MDS-001 and MDS-003), demonstrated a high frequency of erythroid response in patients with a chromosome 5q31 deletion (List AF et al., N Eng J Med2005; 352:549–557 and List AF et al., in press). Herein we report on the durability of response with long term follow-up approaching 4 years.

Methods: All enrolled subjects were evaluated for frequency and duration of red blood cell transfusion independence (RBC-TI), change in hemoglobin (Hgb), pathologic and cytogenetic response, and safety.

Results: Ten 5q31- patients achieved a cytogenetic and/or major erythroid response in MDS-001. Four of these patients have maintained a major response for at least 2 years (range 2.2 to 3.7 years). In MDS-003, 99 (67%) of 148 enrolled patients achieved RBC-TI. Of the 99 responders 83 were Low/Int-1, 3 were Int-2/High and 13 were not classified. Median increase in Hgb from baseline to maximum achieved during RBC-TI was 5.4 g/dL (range 1.1, 11.4). The estimated median duration of response was 115.9 weeks, and 52 (53%) of 99 responders remain on study with ongoing RBC-TI response as of 30 June 2006. Duration of response was at least 52 weeks for 63 (64%), 78 weeks for 52 (53%), and 104 weeks for 36 (36%) of 99 responding patients. Variables (or co-variates) associated with longer duration of TI in multivariate analysis included low baseline transfusion requirement (<4 units per 8 wks, p=0.002), 5q- syndrome (p=0.01) and low IPSS (p=0.02) classifications. Among 85 evaluable patients, major cytogenetic responses were achieved in 37 (44%) and minor responses in 24 (28%). Cytogenetic responses occurred in patients with complex karyotypes as well as those with an isolated 5q31 deletion. The frequencies of major and minor cytogenetic responses were similar among patients with and without 5q- syndrome. The most common drug-related adverse events (AE) were Grade 3/4 neutropenia and thrombocytopenia, reported in 87 (59%) and 74 (50%) of 148 patients, respectively although hematologic AEs led to study discontinuation in only 13 (9%) of patients. Pneumonia was the only serious adverse event that occurred in >10% of patients (15/148; 10%). Adverse events were manageable through supportive treatment and dose reduction.

Conclusion: Lenalidomide is an effective treatment in MDS patients with an associated chromosome 5q31 deletion, with RBC-TI and major erythroid response maintained for median duration > 2 years.
Mistargeting of Normal Cells in Anti-CD30 Immunotherapy of Lymphoma Cells Is Blocked by Selective Metalloproteinase Inhibitor.
Authors: Simhadri Vijaya L. , von Strandmann Elke Pogge , Eichenhauer Dennis A. , Ludwig Andreas , Reiners Katrin S. , Engert Andreas , Hansen Hinrich P.
Published: October 2019

CD30 is a transmembrane receptor which is selectively overexpressed on Hodgkin lymphoma and large cell anaplastic lymphoma and therefore an interesting target for antibody-based immunotherapy. However, the receptor is cleaved by metalloproteinases and the ectodomain is released in the environment where it competes with the CD30-based immunotherapy. Moreover, therapeutic anti-CD30 antibodies stimulate this cleavage which results in a loss of target antigen and an enhanced release of the soluble ectodomain (sCD30). In order to improve immunotherapy, we analyzed the mechanism of the release and the function of resulting sCD30. By means of FACS analysis, we demonstrate that sCD30, like membrane-anchored CD30, binds to CD30 ligand (CD153)-expressing cells. Since monoclonal antibodies bind to both CD30 and sCD30, this results in unwanted targeting of these “non-target” cells via sCD30 bridging. To overcome the damage of normal cells in immunotherapy as a consequence of sCD30-binding, we analyzed the mechanism involved in the release of sCD30. Shedding of CD30 can be enhanced by PKC activation involving the disintegrin metalloproteinase ADAM17 but not free cytoplasmic calcium. In contrast, antibody-induced CD30 shedding is calcium-dependent and PKC-independent. Using the ADAM10 inhibitor GI254023X and a ADAM10-deficient cell line generated from embryonically lethal ADAM10−/−mouse we demonstrate that antibody-mediated shedding involves the related metalloproteinase ADAM10. In co-culture experiments, the antibody-induced transfer of sCD30 from the Hodgkin lymphoma cell line L540 to the CD30-negative but CD153-expressing mast cell line HMC-1 was inhibited by GI254023X.

These findings suggest that selective metalloproteinase inhibitors blocking antibody-induced shedding of target antigens could be of therapeutic value to increase the specificity and reduce side-effects of immunotherapy with monoclonal antibodies.
Anti-Adult T-Cell Leukemia Effects of a Novel Synthetic Retinoid, Am80 (Tamibarotene) through Inhibition of NF-κB.
Authors: Nakazato Tetsuro , Ishikawa Chie , Okudaira Taeko , Tomita Mariko , Mori Naoki
Published: October 2019

Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type I (HTLV-I) and remains incurable. Retinoid is a collective term for compounds, which bind to and activate retinoic acid receptors (RARα, β, γ and RXRα, β, γ), members of nuclear hormone receptor superfamily. It is involved in cell differentiation, morphogenesis, proliferation, and anti-neoplastic processes. The most important endogenous retinoid is all-trans-retinoic acid (ATRA), which is an RARα, β, and γ ligand. ATRA and its mimics have been in clinical use for treatment of acute promyelocytic leukemia (APL) and adult T-cell leukemia (ATL). Many synthetic retinoids have been developed and attempts to improve their medicinal properties have been made. Among them, a novel synthetic retinoid, Am80 (Tamibarotene) is an RARα- and RARβ-specific (but RARγ- and RXRs-nonbinding) synthetic retinoid that is expected to overcome ATRA resistance, because of several times more potent differentiation activity than ATRA and sustained plasma level during continuous administration due to a lower affinity for cellular retinoic acid binding protein. On this background, we examined the inhibitory effect of Am80 on HTLV-I-infected T-cell lines and primary ATL cells. Am80 showed little growth inhibition of peripheral blood mononuclear cells, but it markedly inhibited the growth of both HTLV-I-infected T-cell lines and primary ATL cells. Am 80 could arrest cells in the G1 phase of the cell cycle and induced apoptosis in HTLV-I-infected T-cell lines. The NF-κB pathway is critical for the immortalization and survival of HTLV-I-infected T cells. Therefore, NF-κB pathway was examined as potential targets of Am80 signaling. Am80 significantly inhibited phosphorylation of IκBα and NF-κB-DNA binding, in conjunction with the reduction of expression of proteins involved in the G1-S cell cycle transition and apoptosis. Furthermore, in animal studies, treatment with Am80 produced partial inhibition of growth of tumors of an HTLV-I-infected T-cell line transplanted subcutaneously in severe combined immunodeficient mice. These findings clearly demonstrate that Am80 is a potential inhibitor of NF-κB in ATL cells, and might be a useful therapeutic agent against ATL.
Survivin Isoforms and HSP90 Are Downregulated in Erythropoiesis during Lineage Specific Differentiation of MDS Hematopoietic Progenitor Cells.
Authors: Hopfer Olaf J. , Komor Martina , Koehler Ina S. , Schulze Matthias , Freitag Claudia , Hoelzer Dieter , Thiel Eckhard , Hofmann Wolf-Karsten
Published: October 2019

Survivin has recently been shown to critically regulate erythroid versus megakaryocytic differentiation in mouse hematopoietic stem cells. Its role in human hematopoiesis has not been fully elucidated yet. To answer the question whether dysregulation of expression of survivin and its protein stabilisator HSP90 contributes to the ineffective erythropoiesis in myelodysplastic syndrome (MDS), we have generated an in vitro model of MDS lineage-specific hematopoietic differentiation by culturing CD34+ cells from healthy donors (n=7) and MDS patients (low risk: RA/n=6, RARS/n=3; high risk: RAEB/n=4, RAEB-T/n=2) with EPO, TPO and GCSF. Cell harvest was at days 0, 4, 7 and 11. Expression analysis of survivin splicing variants (wt, 2a, d3ex) and of HSP90 was done by real time RT-PCR (qPCR) for each lineage at each time point. Furthermore, epigenetic analysis of key regulatory genes by methylation specific PCR and qPCR to detect DNMT1 (maintenance methylation) and DNMT3a and 3b (de novo methylation) expression was performed for each of the experimental conditions. RNA expression of all survivin isoforms and of HSP90 was continously upregulated during normal erythropoiesis. During late megakaryopoiesis of normal hematopoietic stem cells a significant downregulation was seen with elevated expression values for survivin wt and survivin 2b during early thrombopoiesis. In contrast, during MDS erythropoiesis a significant downregulation of expression of all survivin isoforms and HSP90 during late erythropoiesis was observed. Lower expression for survivin wt, survivin 2b and HSP90 was seen during early MDS megakaryopoiesis. Promotor methylation analyisis revealed MDS specific aberrant methylation for survivin, particularly during MDS high risk erythropoiesis (p=0.02). However, expression of DNMT1 was only elevated during erythropoiesis and in low risk MDS. A significant inverse correlation between RNA expression of DNMT enzymes and survivin splicing variants could not be detected. In conclusion our data support the essential role for survivin in regulation of erythropoietic versus megakaryopoietic differentiation of hematopoietic precursor cells. The dysregulation of survivin expression during MDS erythropoiesis may therefore account for the ineffective erythropoiesis known in MDS. Furthermore, downregulation of survivin (protein) stabilisator HSP90 might additionally contribute to this effect. Although an inverse correlation with overexpression of DNMTs and downregulation of survivin splicing variants was not seen, the aberrant survivin promoter methylation during MDS erythropoiesis indicates that epigenetic dysregulation results in low survivin expression.