bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel Diagnostic Scheme for Follicular Dendritic Cell Neoplasm: Clinicopathologic Analysis of 146 Cases.
Authors: Kim Tae-Jung , Moon Yeonsook , Lee Kyungji , Park Gyeongsin , Lee Youn-Soo , Kang Chang-Suk , Shim Sang-In , Lee Kyo-Young
Published: October 2019

Follicular dendritic cell neoplasm(FDCN), a rare tumor exhibiting a broad histopathological spectrum and unpredictable biologic behavior, has been classified into follicular dendritic cell tumor(FDCT) and follicular dendritic cell sarcoma(FDCS) regarded as borderline lesion and malignant tumor, respectively, by World Health Organization. But still no definite diagnostic criteria distinguishing FDCT from FDCS was established. Here in, as an approach to the differential diagnostic criteria, we performed clinicopathological analysis for 146 cases of FDCN, documented in English literature from January 1986 to May 2006. Through PubMED search with key words of FDC or dendritic cell tumor, we collected and reviewed 73 articles out of more than six thousands candidates, which contained 146 FDCNs with clinicopathological informations. We analyzed the carefully selected cases with parameters including age, gender, tumor location, tumor size, tumor margin, EBV association, mitosis, nuclear atypism, hemorrhage, necrosis and Castleman’s disease association. Recurrence, metastasis and death of disease were referred as event. Kaplan-Meier model was used for overall event-free survival analysis and the log-rank test was used to assess statistical significance.

Mitotic Index (MI, ≥ 5/10HPF vs <5/10HPF, P=0.0182) and tumor location (intraabdominal vs extraabdominal, P=0.007) showed significant association with event-free survival. But the other parameters have failed to achieve statistical significance as predictors of adverse events. For proposing diagnostic scheme, the risk groups were designated as follows: high risk group(n=7), MI ≥ 5/10HPF and intraabdominal; low risk group(n=26), MI <5/10HPF and extraabdominal; intermediate risk group(n=35), all others. These three risk groups had distinctly different median event-free survivals, 11 months, 24 months and 96 months for high, intermediate and low risk groups, respectively. And each group showed significantly different overall event-free survivals(P=0.0007). In conclusion, this novel diagnostic scheme might be a useful tool for predicting biologic behavior of FDCN.
Adult Weight Gain and Risk of Developing Non-Hodgkin Lymphoma (NHL): Results from a Large Prospective Cohort Study of Older Women.
Authors: Bardia Aditya , Habermann Thomas M. , Vierkant Robert A. , Wang Alice H. , Cerhan James R.
Published: October 2019

Background: Obesity has been associated with risk of non-Hodgkin lymphoma (NHL) in several recent studies. However, the effect of weight gain during adulthood, a potentially modifiable risk factor, on the incidence of NHL is not clear. We therefore examined the association of weight gain since age 18 years with the risk of NHL among older women.

Methods: We examined this association in the Iowa Women’s Health Study, a prospective study of 37,762 Iowa women aged 55 to 69 years at enrollment in 1986. Lifestyle and other risk factors, including weight at age 18 and at enrollment, were self-reported on a mailed questionnaire. We defined stable weight as no increase in weight or up to a 10% weight loss from age 18 to enrollment, while percent weight gain was divided into tertiles based on the distribution observed in the cohort. NHL incidence through 18 years of follow-up was ascertained by linkage with the Iowa SEER Cancer Registry. Cox proportional hazards models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) of percent weight gain with NHL incidence, adjusting for age (Age-adjusted model) and age, marital status, farm residence, transfusion history, diabetes, use of hormone replacement therapy, alcohol use, smoking, and intake of red meat and fruits (Multivariate model).

Results: The mean age of the women in the cohort in 1986 was 62.1 years. During 593,474 person-years of follow-up, 379 incident cases of NHL were observed. The mean age at diagnosis was 72.6 years (range 58–87 years). The main results are reported in the table. Similar results were found for absolute weight gain. Stratification of these results on body mass index at age 18 (using a cutpoint of 21 kg/m2) showed similar results, with the exception of >10% weight loss for women with a BMI of <21 at age 18 where we could not estimate a RR (no cases observed).

Conclusions: Weight gain or large weight loss (>10% of body weight) during adulthood were both associated with increased risk of NHL, although the RRs for percent weight gain were not statistically significant and there was no dose-response. This study suggests another potential benefit of avoiding adult weight gain, although further studies are needed to confirm these novel findings.

Association of percent weight change during adulthood (age 18 to age 55–69 years) and risk of NHL % Weight Change NHL Cases Person-years Age-Adjusted RR(95% CI) Multivariate RR (95% CI) >10% weight loss 15 17053 2.06 (1.05–4.02) 2.02 (1.03–3.95) Stable 20 45973 1 (reference) 1 (reference) 0–18.2% gain 115 175883 1.50 (0.94–2.42) 1.50 (0.93–2.41) 18.3–34.8% gain 119 176258 1.54 (0.96–2.47) 1.53 (0.95–2.47) >34.8% gain 110 178308 1.40 (0.87–2.25) 1.32 (0.82–2.14).
Induction of RKIP and Inhibition of the Transcription Repressor YY1 in B-NHL by the Novel Proteasome Inhibitor NPI-0052 and Sensitization to TRAIL-Induced Apoptosis.
Authors: Suzuki Eriko , Huerta-Yepez Sara , Baritaki Stavroula , Palladino Michael , Bonavida Benjamin
Published: October 2019

Proteasome inhibitors have been shown to exert multiple effects including direct cytotoxic activity in sensitive cancer cells. In addition, proteasome inhibitors have recently been used therapeutically for certain cancers such as multiple myeloma and mantle cell lymphoma. We have recently reported that the novel proteasome inhibitor, NPI-0052 (Nereus Pharmaceuticals), can sensitize drug-resistant B-NHL tumor cells to apoptosis by various chemotherapeutic drugs. Also, NPI-0052 inhibits the NF-κB survival pathway and inhibition of NF-κB sensitizes tumor cells to TRAIL-induced apoptosis. We hypothesized that inhibition of NF-κB by NPI-0052 may also lead to sensitization of TRAIL-resistant B-NHL cells to TRAIL-mediated apoptosis. Human Burkitt’s lymphoma,Ramos cells, were treated with various concentrations of NPI-0052 (0–10ng/ml for 24h) and were then treated with recombinant human TRAIL (0–100ng/ml for 24h). The cells were examined for apoptosis by Annexin V/PI. The combination treatment resulted in significant potentiation of cytotoxicity and synergy in apoptosis was achieved. We have then examined a potential underlying mechanism of NPI-0052-mediated sensitization. The transcription repressor YY1 was recently shown to negatively regulate the transcription of the TRAIL death receptor DR5 and thus overexpression of YY1 is a resistant factor for TRAIL-induced apoptosis. Hence, treatment of Ramos cells with NPI-0052 resulted in significant inhibition of YY1 expression and upregulation of surface DR5 expression. We have also examined the effect of NPI-0052 on RKIP (Raf-kinase inhibitor protein) (Yeung et al., Molecular Cellular Biology; 21:7207, 2001) expression. Since both NPI-0052 and RKIP inhibit the NF-κB pathway, we hypothesized that treatment of Ramos cells with NPI-0052 may result in significant upregulation of RKIP expression. The findings, indeed, demonstrate that NPI-0052 significantly induced RKIP expression in Ramos cells. Overall, the findings show, for the first time, that NPI-0052 sensitizes B-NHL tumor cells to TRAIL-mediated apoptosis. Sensitization by NPI-0052 was correlated with both the induction of RKIP expression and inhibition of YY1 and upregulation of DR5 expression. Currently, TRAIL or agonist monoclonal antibodies against DR4 or DR5 are being examined clinically for anti-tumor activity. Therefore, our findings suggest the potential application of the combination of NPI-0052 and TRAIL or agonistic monoclonal antibodies against DR4 or DR5 in the treatment of tumor cells that are resistant to drugs and TRAIL.
Host Immunogenetic Single Nucleotide Polymorphisms (SNPs) Predict Overall Survival in Small Lymphocytic Lymphoma.
Authors: Thompson Carrie A. , Wang Sophia , Maurer Matthew J. , Habermann Thomas M. , Severson Richard K. , Rothman Nathaniel , Lynch Charles F. , Davis Scott , Morton Lindsay M. , Cozen Wendy , Hartge Patricia , Geyer Susan M. , Chanock Stephen , Cerhan James R.
Published: October 2019

Small lymphocytic lymphoma (SLL) is an incurable indolent lymphoma, and there are relatively few prognostic biomarkers for this important NHL subtype. We evaluated the hypothesis that inherited variability in cytokine and immune-related genes was associated with overall survival in SLL. We genotyped 73 SNPs in 44 candidate genes in 140 SLL patients aged 20–70 years who participated in a population-based case-control study conducted from 1998–2000 through the Surveillance, Epidemiology, and End Results (SEER) cancer registries in Detroit, Seattle, Iowa, and Los Angeles. DNA was extracted from a venous blood sample or mouthwash buccal cell sample. All genotyping was conducted at the National Cancer Institute Core Genotyping Facility using the Taqman platform. Histology, stage, presence of B-symptoms, first course of therapy, date of last follow-up, and vital status were derived from linkage to registry databases at each study site in the spring of 2005. Cox proportional hazards analysis was used to estimate the hazard ratio (HR) and 95% confidence interval for the association between individual SNPs and overall survival, adjusted for age, demographic and clinical factors. Multiple simultaneous modeling strategies were used to identify the best summary multi-SNP risk score to predict survival. At last follow-up, there were 45 deaths in 140 patients (32%). The median follow-up of the 95 surviving patients was 58 months (range 24–75 months). In multivariate modeling, SNPs in IL13 (rs1800925; HRCC=2.36, 1.24–4.49), IL7R (rs1494555; HRGG =2.20, 0.84–5.76), and TNF-alpha (rs1800630; HRAC/AA=1.73, 0.95–3.17) were the strongest and most robust predictors of survival. Two or more deleterious genotypes from these three SNPs increased the risk of death (HR=2.2, 1.2–4.1) compared with one or fewer deleterious genotypes (p=0.009). Three groups (low, intermediate, and high risk) were defined by combining the SNP score and a clinical/demographic score. The 5-year Kaplan-Meier survival estimates for these groups were 85%, 65%, and 11%, respectively. Compared to patients with a low risk score, patients with intermediate (HR=2.5, 1.2–5.1) or high (HR=11, 4.3–27.7) risk scores had poorer overall survival (p=3.9 x 10−8). Our preliminary results suggest that SNPs in IL13, IL7R, and TNF-alpha alone and in combination predict overall survival in SLL, lending support to the hypothesis that host genetic background is a promising class of prognostic biomarkers in SLL.
Clinical Usefulness and Therapeutic Plan with Interim PET/CT Analysis in Malignant Lymphoma.
Authors: Yang Deok-Hwan , Lee Je-Jung , Min Jung-Joon , Lee Se-Ryeon , Kim Yeo-Kyeoung , Bom Hee-Seung , Kim Hyeoung-Joon
Published: October 2019

FDG-PET, a functional imaging modality used for staging and monitoring response to treatment of malignant lymphoma, has a higher sensitivity and specificity than conventional imaging. PET/CT may be more accurate than conventional imaging in assessing treatment effects to correctly identify patients with residual disease and predict therapy outcomes. We prospectively investigated that PET/CT may provide additional prognostic information in mid-response assessment prior to completion of chemotherapy.

Patients and Method: Eighty-six newly diagnosed patients with malignant lymphoma were enrolled from Aug. 2004 to July 2006. Both CT and PET/CT analysis were performed at the time of diagnosis and after the 3rd or 4th chemotherapy. The clinical stage of the patients was assessed according to International Workshop Criteria (IWC). PET/CT imaging was analyzed according to the combination of morphology using the CT portion and by the uptake and location of the FDG-PET portion. The cut off value of the positive in PET/CT was more than max SUV 3.0. We divided them into four different response groups using IWC and PET/CT (CRu-negative, Cru-positive, PR-negative, PR-positive). The limited-stage patients were treated with chemotherapy and involved field radiation therapy and the advanced-stage patients were treated with eight cycles of chemotherapy. However, advanced-stage patients who were older than sixty, if they had CRu-negative in interim analysis, were treated with only six cycles.

Results: Median age was 53.5 years (range: 19 – 85). Seventy five patients had Non-Hodgkin’s lymphoma [Indolent-11 (12.8%), Aggressive-64 (74.4%)] and eleven patients (12.8%) had Hodgkin’s lymphoma. Forty-two patients (48.8%) achieved CRu-negative, 6 patients (7.0%) achieved CRu-positive, 20 patients (23.3%) achieved PR-negative and 18 patients (20.9%) showed PR-positive by interim IWC and PET/CT. The relapse rate is significantly different between PET-positive (58.3%) and PET-negative (8.1%) (P=0.000), especially when 12 of 18 patients in PR-positive group (66.7%) relapsed after or during chemotherapy. Figures showed the Kaplan-Meier estimates of overall and progression free survival of 86 patients depending on the combined evaluation of interim IWC and PET/CT.

Conclusion: Interim PET/CT analysis was a significantly predictive value of disease progression and survival. The patients with PR-positive according to interim IWC and PET/CT analysis should be considered for an intensive therapeutic plan.

Figure Figure
Aberrant Somatic Hypermutation of Follicular Lymphoma Transformed To Diffuse Large B-Cell Lymphoma.
Authors: Fruehwirth Margareta , Deutsch Alexander J.A. , Staber Philipp B. , Aigelsreiter Ariane , Linkesch Werner , Beham-Schmid Christine , Neumeister Peter
Published: October 2019

Follicular Lymphoma (FL) accounts for approximately 20–30% of all malignant lymphomas and the frequency of histological transformation (HT) into diffuse large B-cell lymphomas (DLBCL) varies from 10% to 70%. Many genetic lesions have already been described in histological transformation, but a mechanism of genome-wide instability during histological transformation (HT) has not been reported. We have shown that the somatic hypermutation process (SHM) physiologically aimed at mutating the immunoglobulin variable gene (IgV) aberrantly targets multiple proto-oncogenes in >50% of DLCBL (Pasqualucci et al., Nature 412:341, 2001). Consequently, multiple mutations are introduced in the 5′ region of genes including known proto-oncogenes such as PIM-1, PAX-5, Rho/TTF and c-MYC. To further investigate whether aberrant somatic hypermutation (ASHM) also occurs in histological transformation of follicular lymphoma in DLBCL we studied the mutational profile of these genes in a total of 26 cases consisting of 10 paired samples of follicular lymphoma together with the corresponding DLBCL and 6 single cases of transformed DLBCL. Genomic DNA from histologically confirmed, macrodissected tissue obtained from formalin fixed and paraffin embedded tissue or cryoconserved samples was directly sequenced. Mutations in one or more genes were detected in 6 of 10 (60%) cases of pre-HT follicular lymphoma and in 13 of 16 (81.2%) post-HT cases. Two ore more genes were affected in 1 of 10 (10%) of FL and in 7 of 16 (43.7%) cases with DLBCL. Mutations in PIM-1 occurred in 3 of 10 (30%) cases of follicular lymphoma and in 9 of 16 (56.2%) in DLBCL. For PAX-5, the distribution of the mutated cases between FL and DLBCL was 2 of 10 (20%) and 7 of 16 (43.7%), for RhoH/TTF 2 of 10 (20%) and 3 of 16 (18.7%) and for c-MYC none of 10 (0%) FL and 2 of 16 (12.5%) DLBCL. A total of 38 single base pair substitutions were found in 19 cases, 10 sequence variants in 6 FL cases and 28 sequence variants in 13 DLBCL cases. The mutations were of somatic origin and share features of the IgV SHM process including bias for transition over transversion, elevated ratio of G+C over A+T substitutions and restriction to the first 1-2Kb from the promoter initiation site. The mean mutation frequency in mutated follicular lymphoma was with 0.024 ×10−2/bp 1.4 fold lower compared to 0.032 ×10−2/bp in the transformed DLBCLs. Further in PIM-1 and c-MYC some of the mutations were found to affect coding exons, leading to amino acid exchanges, thus potentially altering gene function. These data support a role of aberrant SHM in the histological transformation of FL to overt DLBCL.
Genomic Imbalances Are Associated with Outcome of Helicobacter pylori Eradication in t(11;18)(q21;q21)-Negative Gastric MALT Lymphomas.
Authors: Fukuhara Noriko , Tagawa Hiroyuki , Nakamura Tsuneya , Inagaki Hiroshi , Morishima Yasuo , Nakamura Shigeo , Seto Masao
Published: October 2019

Background: Approximately 70% of low grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma cases are successfully treated by H. pylori eradication. The MALT lymphoma resistant to this therapy needs an additional therapy. A part of the tumors transform to an aggressive lymphoma including diffuse large B-cell lymphoma (DLBCL). The t(11;18)(q21;q21) characteristic to MALT lymphoma is recognized as a marker for H. pylori independency, but this marker is found in only a half of the MALT lymphomas resistant to H. pylori eradication. Therefore the detailed genomic features of eradication resistant group as well as dependent group are needed to understand molecular basis.

Patients and Methods: We performed array-based comparative genomic hybridization for 30 gastric MALT lymphomas treated with H. pylori eradication. These included 10 cases of t(11;18)(q21;q21)-positive MALT group, 10 cases of t(11;18)(q21;q21)-negative MALT with H. pylori dependent group and 10 cases of t(11;18)(q21;q21)-negative MALT with H. pylori independent group. The presence of t(11;18)(q21;q21) was identified by a multiplex reverse transcriptase polymerase chain reaction of the API2-MALT1 chimeric transcript.

Results: Almost no significant genetic alterations were found in t(11;18)(q21;q21)-positive MALT lymphoma, whereas numerous genomic alterations were found in those without t(11;18)(q21;q21). These aberrations were mostly similar to those found in DLBCL (Tagawa et al., Blood 106:5, 2005). Trisomy 3 is most recurrent and 7q loss specific to SMZL is also recurrent. Within the t(11;18)(q21;q21)-negative MALT lymphoma group, presence of genomic imbalances is more frequent in H. pylori independent group (one of ten (10%) vs seven of ten (70%); p =0.019, two-sided fisher’s exact test). Neither locally advanced disease nor including large cell component is correlated with H. pylori independency, respectively.

Conclusions: Genomic imbalances are associated with H. pylori independency in t(11;18)(q21;q21)-negative gastric MALT lymphomas. Thus, the genomic imbalances may have a role in the acquisition of H. pylori-independent growth.
NOTCH2 Mutations in Marginal Zone Lymphoma.
Authors: Troen Gunhild , Wlodarska Iwona , Warsame Abdirashid , Llodrà Silvia H. , De Wolf-Peeters Christiane , Delabie Jan
Published: October 2019

Notch2 is a membrane receptor and transcription factor that is indispensable for marginal zone cell differentiation. Also, marginal zone cell lymphomas express increased levels of Notch2 when compared with other B-cell lymphomas. Of interest, activating mutations have previously been described for Notch1, a homologous transcription factor which is important for T-cell differentiation, in up to 50% of cases of acute T-lymphoblastic leukemia, and are thought to contribute to leukemogenesis. We therefore investigated whether activating mutations in the NOTCH2 gene could be identified, especially in marginal zone lymphoma (MZL). We analyzed 41 cases of MZL and 28 other B-cell lymphomas cases for the presence of potentially activating mutations in exons 26, 27 and 34 of the NOTCH2 gene. These exons code for the heterodimerization and the C-terminal transcriptional activation domains. We identified four cases with mutations among the MZL cases, but none in the other B-cell lymphoma cases. Mutations were found in two cases of splenic marginal zone lymphoma and two cases of extranodal marginal zone lymphoma of MALT type, respectively. To investigate whether elevated Notch2 expression in most of the other marginal zone lymphomas, as investigated by quantitative RT-PCR, was due to structural changes within the NOTCH2 locus, FISH analysis was performed. FISH analysis did not reveal structural changes of the NOTCH2 locus in any of the MZL cases. In conclusion, we have shown potentially oncogenic NOTCH2 mutations in 10% of MZL. It remains to be shown whether elevated Notch2 expression in most MZL can be caused by as yet other disease mechanisms.
An In Vivo Model To Investigate the Nature of the Cell-of-Origin of Multiple Myeloma.
Authors: Asimakopoulos Fotios , Varmus Harold
Published: October 2019

Multiple myeloma (MM) and related plasma cell dyscrasias are characterized by monoclonal expansion of terminally differentiated plasma cells. However, it is puzzling how the quiescent plasma cell can be the source of often aggressive and relapsing neoplasms. We and others have postulated that the myeloma clonogenic progenitor may reside in a more immature compartment with greater self-renewal capacity, most probably a maturing plasmablast precursor in the germinal center. To investigate the nature of cell-of-origin for these diseases and the genetic requirements for pathogenesis, we have created a novel flexible mouse model system that enables the delivery of stochastic, sequential, somatic mutations to precisely defined compartments of the germinal center in secondary lymphoid tissues. To this end, we have used BAC transgenic technology to express distinct types of avian leukosis virus (ALV) receptors, TVA and TVB, in the expanding centroblast of the dark zone and the committed plasmablast of the light zone, respectively. Mammalian tissues are refractory to transduction by retroviruses of the ALV family unless they ectopically express the cognate avian-derived receptors. Thus, the coding sequences for the TVA receptor, fused to a fluorescent protein tag were placed under the control of transcription factor A-myb, expressed in centroblasts of the dark zone. Similarly, sequences encoding a fluorescent-tagged TVB receptor were placed under the control of transcription factor Blimp1, expressed in the earliest committed plasmablasts as well as mature plasma cells. Analysis of the Blimp1: TVB mice showed that expression of the avian retroviral receptor in the hematopoietic system is limited to the light zone of germinal centers, extrafollicular collections of CD138+ cells in the spleen and lymph nodes as well as long-lived bone marrow plasma cells. Analysis of A-myb: TVA transgenic mice demonstrated expression of the fusion receptor to be restricted to B cells in the immunized spleen but not T cells. Both transgenic systems have been crossed into an Ink4a/Arf-deficient background. We have been transducing plasma cell precursors generated in the course of immune responses to T-dependent antigens with retroviral vectors carrying genes important in myelomagenesis, such as cyclin D1 or c-Myc. Animals are being monitored for development of plasma cell dyscrasias by periodical serum protein electrophoresis (SPEP) and other assays.
Clinicopathological Features of Pyothorax-Associated Lymphoma; a Retrospective Survey Involving 98 Patients.
Authors: Narimatsu Hiroto , Ota Yasunori , Kami Masahiro , Takeuchi Kengo , Suzuki Ritsuro , Matsuo Keitaro , Kishi Yukiko , Hamaki Tamae , Tanaka Yuji , Nakamura Shigeo
Published: October 2019

Pyothorax-associated lymphoma (PAL) is a lymphoproliferative disorder developing in the pleural cavity after a long-standing history of pyothorax. The pathogenesis, clinical features and optimal treatment have not been clarified. To investigate clinicopathological features of pyothorax-associated lymphoma (PAL), we examined medical records of 98 patients (88 males and 10 females) with PAL at a median age of 70 (range, 51–86). Seventy-nine patients had a history of artificial pneumothorax. Median interval between diagnosis and artificial pneumothorax was 43 years (range, 19–64). At diagnosis, performance status was 0–1 (n=56) and 2–4 (n=42). Clinical stages were I (n=42), II (n=26), III (n=8) and IV (n=22). In situ hybridization using a probe for EBV-encoded RNA-1 demonstrated the presence of the EBV genome in the nucleus of tumor cells in 28 of 29 (88%) patients. Immunohistochemical studies revealed that 12 of 14 (86%) and 11 of 17 (65%) were positive for EBNA-2 and LMP-1, respectively. Seventeen were treated supportively. The other 81 received aggressive treatments; chemotherapy (n=52), radiotherapy (n=7), surgery (n=4) and combination (n=18). Response rates to chemotherapy, radiotherapy, and chemoradiotherapy were 56%, 71%, and 83%, respectively. Five-year overall survival was 0.35 (95% confidence interval, 24–45%). The 5-year overall survival rates were 0.47 (95% CI, 0.30– 0.63), 0.35 (95% CI, 0.16– 0.54) and 0.15 (95% CI, 0.04–0.33) in patients with stages I, II and I-IV disease, respectively (Figure 1). Overall survival are different among the three groups (p <0.0001). Causes of deaths were PAL (n=39), respiratory failure (n=13), and others (n=12). Multivariate analysis identified prognostic factors for overall survival; lactate dehydrogenase levels (hazard ratio (HR)=2.36, p=0.013), sex (female vs. male) (HR=0.15, p=0.01), performance status (2–4 vs. 0–1) (HR=2.20, p=0.02), clinical stages (III/IV vs. I/II) (HR=1.95, p=0.037) and chemotherapy (HR=0.31, p=0.01). Most patients with PAL are elderly, and have comorbidities, while some of them achieve durable remission with appropriate treatments. These findings prompt us to establish an optimal treatment strategy based on risk stratification of individual patients.

Figure Figure
High Dose Cytarabine Salvage Regimen Combined with Bortezomib Is Feasible and Highly Effective in Relapsed Mantle Cell Lymphoma.
Authors: Weigert Oliver , Weidmann Eckhart , Mueck Rudolf , Bentz Martin , von Schilling Christoph , Rohrberg Robert , Jentsch-Ullrich Kathleen , Unterhalt Michael , Hiddemann Wolfgang , Dreyling Martin H.
Published: October 2019

Introduction: Mantle cell lymphoma (MCL) is a subtype of malignant lymphoma with an especially poor prognosis. However, molecular targeted therapy may alter the natural history of disease. Bortezomib (BZ) is a potent, selective and reversible inhibitor of the 26S proteasome thereby interfering with intracellular protein homeostasis. Various clinical phase II trials revealed significant efficacy of BZ monotherapy in relapsed MCL with approximately 40% response rate, but rare CR and short duration of response. Based on our preclinical data demonstrating synergy of BZ and cytarabine (Ara-C) we performed a pilot study to explore the clinical impact of such combined approach.

Treatment: 2 g/m2 Ara-C was applied on day 2 and 3 (1 g/m2 in patients with impaired hematopoiesis or age >60 years) combined with BZ 1.5 mg/m2 iv bolus (day 1 and 4). In addition, dexamethasone 40 mg was given over a 4 day period. R was added to the outlined regimen in 6 patients (375 mg/m2). Treatment was repeated in 3 week intervals for a total of 4 cycles with staging procedures performed after 2 and 4 cycles.

Results: After informed consent 8 patients with relapsed or refractory advanced stage MCL were treated accordingly to the outlined protocol. Median age was 65 years (54–76), 5 patients were male. Median number of prior systemic therapies was 4 (2–7). All patients had previously been treated with CHOP and at least one rituximab (R)-containing regimen, 2 patients previously failed BZ monotherapy, and none of them was considered eligible for myeloablative treatment. Currently data from 7 patients are available for analysis of toxicity and response. At time of analysis, a total of 22 cycles has been applied with a median follow-up of 214 days (119–366). As expected, hematologic toxicity CTC grade III/IV occurred in all 7 patients, but only one case of neutropenic fever (grade 3) and no major bleeding were observed. Ara-C dose was reduced in 5 patients. Two patients developed new onset or worsening of preexisting polyneuropathy. Dose of BZ had to be reduced in 1 patient and stopped after cycle 2 in another patient with preexisting polyneuropathy. Of note, 2 patients developed herpes zoster (grade 2). In 3 patients treatment was stopped after cycle 2 due to insufficient response (progressive disease, stable disease and minimal response, respectively). In the 4 patients completing 4 cycles 1 CR and 3 PR were archieved.

Conclusion: Salvage therapy with high-dose Ara-C combined with BZ in relapsed or refractory MCL was associated with considerable but manageable hematotoxicity and only few infectious complications. The high efficacy in heavily pretreated patients justifies a comparative trial of the European MCL Network evaluating a high-dose cytarabine containing regimen +/− BZ.
Oral Forodesine (Bcx-1777) Is Clinically Active in Refractory Cutaneous T-Cell Lymphoma: Results of a Phase I/II Study.
Authors: Duvic Madeleine , Forero-Torres Andres , Foss Francine , Olsen Elsie A. , Kim Youn
Published: October 2019

Background: Forodesine is a potent, rationally designed purine nucleoside phosphorylase (PNP) inhibitor that is orally bioavailable. IV forodesine has shown clinical activity in patients with cutaneous T-cell lymphoma (CTCL). The objective of this phase I/II study was to evaluate the safety, PK profile, and efficacy of oral forodesine in patients with refractory CTCL.

Methods: An open-label dose-escalation study of fordesine, 40 to 320 mg/m2 qd for 4 weeks, was undertaken to evaluate the safety and PK profile of oral forodesine, followed by an investigation of the expansion of the optimal biologic dose (dose with maximum PNP inhibition and elevation of plasma deoxyguanosine levels) to assess efficacy. Previously treated, refractory CTCL patients with stage IB or greater disease were eligible for participation. The primary end point was objective response (OR) = complete response [CR] plus partial response [PR], as measured by the severity-weighted assessment tool (SWAT; see Figure) and physicians’ global assessment (PGA)

Results: Overall, 37 patients were treated, including 14 patients in the dose-escalation portion of the study. No dose-limiting toxicities were observed with target doses of ≤320 mg/m2; thus, a maximum tolerated dose was never defined. Based on PK/PD results, an 80 mg/m2 qd dose was identified as the optimal biologic dose, and this ongoing study was expanded to enroll a total of 28 patients (median age, 64 yr; range, 28–81 yr). The OR rate was 53.6% (15/28 patients; 2 [7.1%] with a CR and 13 [46.4%] with a PR). The proportion of patients with stage IIB or greater disease was 19/28 (67.9%). Response in this population was seen in 10 (52.6%) of the 19 patients (1 [5.3%] with a CR and 9 [47.4%] with a PR). The percent change in SWAT score from baseline as a function of time demonstrated a progressive decrease over a 24-week period. To-date, 12 (42.9%) of 28 patients have completed ≥4 months of treatment. Safety data were recorded for all 37 patients treated with forodesine. The most common adverse events classified as grade 2 or less, without regard to causality, were nausea (30%), dizziness (22%), pruritus (22%), fatigue (19%), headache (19%), peripheral edema (19%), and pyrexia (16%). The only adverse event classified as grade 3 or greater, without regard to causality, and occurring in at least two patients, was lymphopenia, which was observed in two patients (5%).

Conclusions: Oral forodesine is effective in the treatment of refractory CTCL patients and has an encouraging safety profile.

SWAT SCORE: Percent Change from Baseline SWAT SCORE: Percent Change from Baseline
Romidepsin (Depsipeptide, FK228) Induces Clinically Significant Responses in Treatment-Refractory CTCL: Interim Report of a Phase II Multicenter Study.
Authors: Lerner Adam , Demierre M.F. , Whittaker S. , Robak T. , Baran E. , McCulloch W. , Prentice A.G.
Published: October 2019

Background: Romidepsin is a bicyclic peptide which inhibits Class I and II HDACs. An initial study by Piekarz et al noted frequent responses to romidepsin therapy in patients with CTCL (ASCO, 2004). The aim of the pivotal phase II study reported here is to confirm this clinical activity.

Methods: This single arm, open label study is enrolling mycosis fungoides (Stages IB-IVA) or Sezary syndrome patients from 30 centers in the UK, Germany, Poland and the US. Patients with biopsy-proven CTCL (centrally reviewed) that have failed at least one prior systemic therapy receive up to 6 cycles of romidepsin at 14 mg/m2 as a 4-hour IV infusion on Days 1, 8 and 15 q 28 days but may continue therapy if PR or CR is achieved. Eligibility criteria include adequate organ function and ECOG PS less than or equal to 1. Exclusion criteria include significant cardiovascular abnormalities or treatment with QTc-prolonging or CYP3A4-inhibiting drugs.

The primary endpoint is response rate as measured by a combination of imaging, circulating cell counts and a scoring instrument to determine average weighted skin involvement. Skin responses are confirmed by standardized photography. Where possible, correlative studies are performed including acetylation status, apoptotic markers and proteomic analyses. Target accrual is 64 evaluable patients.

Results: 45 patients have received treatment with 31 evaluable for efficacy. Preliminary results of responses are 1 CCR, 11 PRs, 17 SD and 2 PD for an ORR of 39% (duration 3–12 months). One PR became a CCR after more than 6 courses of treatment. In responding patients, time to response ranges from 1–3 cycles. In those patients with pruritus, relief of at least 30 mm from baseline (on a 100 mm VAS) or a VAS score of 0 (no itching) for at least 2 cycles, was seen in 14/26 patients (54%). Seven (7) patients withdrew with PD and 13 for other reasons. Most frequent toxicities are nausea/vomiting, fatigue, myelosuppression and asymptomatic ECG changes. 5 patients have withdrawn for toxicity and there have been no treatment-related deaths.

Conclusions: This study confirms the previously reported efficacy of romidepsin in treatment-refractory CTCL which includes relief of pruritus and a high response rate including one cCR. The low rate of treatment discontinuation due to side-effects and prolonged treatment duration of some patients illustrate that toxicity has been manageable. Accrual continues.
Treatment of Children & Adolescents with Early Stage Nodular Lymphocyte Predominant Hodgkin Lymphoma with a Low Intensity Short Duration Chemotherapy Regimen [CVP] - on Behalf of the EuroNet-PHL Group.
Authors: Shankar Ananth G. , Daw Stephen , Hall Georgina , Gorde-Grosjean Stephanie , Koerholz Christine Mauz , Korholz Dieter , Wallace William H. , Hasenclever Dirk , Landman-Parker Judith
Published: October 2019

Background: Nodular Lymphocyte Predominant Hodgkin’s Lymphoma (NLPHL) is a distinct clinicopathologic subtype of Hodgkin’s lymphoma [HL]. Reports in published literature suggest that very little, and occasionally, no chemotherapy is sufficient for long term survival in patients with LPHL and that this disease appears to have a more indolent course than classical HL. The optimum therapy for early stage NLPHL is not known, but it is likely that current therapy for classical Hodgkin’s lymphoma is unnecessarily toxic and intensive for this indolent, slowly progressive, CD 20 positive disease. Adverse treatment related late effects are the major causes of morbidity and death. Consequently children with early stage NLPHL represent ideal candidates for low intensity treatment.

Study Objectives: To assess whether a non-intensive chemotherapy regimen consisting of cyclophosphamide [500mg/m2 iv- day 1], vinblastine [6 mg/m2 iv-day1 & 8] and oral prednisolone [40 mg/m2 - days 1–7] (CVP) every 14–21 days, count dependent, could replace standard chemotherapy protocols used for classical HL without compromising efficacy in children and young people with NLPHL.

Patients and Methods: Between May 2004 and April 2006 18 patients with stages IA [n=12] and IIA [n=6] biopsy proven NLPHL were treated with 3 cycles of CVP chemotherapy. Three of the eighteen patients were initially treated with surgical resection alone and received CVP at first relapse. Ten patients were males and the median age at diagnosis was 10 years (range 7–15 years). Staging investigations at diagnosis included both conventional cross sectional as well as 18 fluro-deoxyglucose [FDG] PET imaging. Remission status at the end of 3 cycles of CVP was confirmed by both conventional cross sectional and PET imaging.

Results: 17 patients achieved a complete remission [CR] after 3 courses of CVP and 1 patient a very good partial remission [VGPR]. To date, only 1 patient has relapsed while all the remaining patients remain in continuous CR. Median duration of follow up is 12 months (range 2–26 months). The overall survival is 100% and event free survival is 94%. No significant early or late toxicity has been observed to date.

Conclusions: Nothithstanding the relatively short follow up period, CVP is an effective non toxic chemotherapy regimen with 95% of patients with early stage NLPHL achieving a CR after 3 courses. Based on these preliminary results, we have designed a prospective European study for patients with stage IA & IIA NLPHL to confirm these results in a larger cohort of patients.
High Anti-Lymphoma Activity of Bendamustine/Mitoxantrone/Rituximab (BMR) in Rituximab Pretreated Relapsed or Refractory Indolent Lymphomas. A Multicentre Phase II Study of the German Low Grade Lymphoma Study Group (GLSG).
Authors: Weide Rudolf , Hess Georg , Koeppler Hubert , Heymanns Jochen , Thomalla Joerg , Aldaoud Ali , Losem Christoph , Schmitz Stefan , Haak Ursula , Huber Christoph , Unterhalt Michael , Hiddemann Wolfgang , Dreyling Martin
Published: October 2019

Purpose: Bendamustine is a new anti-lymphoma agent with promising activity. Based on a preceeding phase I study the current trial explored Bendamustine in combination with Mitoxantrone and Rituximab (BMR) in patients with relapsed or refractory indolent lymphomas.

Patients and Methods: Patients with relapsed or refractory symptomatic stage III/IV indolent lymphomas with or without prior treatment with Rituximab were eligible. Therapy consisted of Bendamustine 90 mg/m2 days 1+2, Mitoxantrone 10 mg/m2 day 1, Rituximab 375 mg/m2 day 8. Treatment was repeated on day 29 for a total of 4 cycles.

Results: Between 04/03 and 07/04 62 patients were recruited from 24 participating institutions, 40% of whom had received prior Rituximab therapy. Median age was 67 years (40–83). Lymphoma subtypes were 30 follicular (FL), 18 mantle cell (MCL), 4 B-CLL with plasmacytic differentiation, 3 lymphoplasmacytic (LPL), 3 marginal zone (MZL), 2 diffuse large B-cell (DLBCL), 1 high grade lymphoma not otherwise specified and 1 hairy cell leukemia. The overall response rate (ORR) was 88% with 36% CR and 53% PR. ORR in Rituximab pretreated patients was 75% (38% CR, 38% PR). After a median observation time of 17 months (1 – 33), the estimated median progression free survival is 19 months. Treatment related toxicities of grade 3/4 comprized a reversible myelosuppression (10 % anemia, 78 % leukocytopenia, 46 % granulocytopenia, 16 % thrombocytopenia). However, unexpected hospitalisations were necessary after 10 of 231 cycles (4%) only.

Conclusion: BMR is a very effective new outpatient immuno-chemotherapy with low toxicity for patients with relapsed/refractory indolent lymphoma.

Response rates All patients FL MCL pretreated with Rituximab n 62 30 18 25 end of therapy without staging 3 3 0 1 evaluable patients 59 27 18 24 CR 21 (36%) 13 (48%) 6 (33%) 9 (38%) PR 31 (53%) 12 (44%) 8 (44%) 9 (38%) MR 1 (2%) 0 (0%) 1 (6%) 1 (4%) SD 0 (0%) 0 (0%) 0 (0%) 0 (0%) PD 6 (10%) 2 (7%) 3 (17%) 5 (21%) EX 0 (0%) 0 (0%) 0 (0%) 0 (0%) CR+PR 52 (88%) 25 (93%) 14 (78%) 18 (75%)

Figure Figure
Early Results from a Phase II Study of Lenalidomide Monotherapy in Relapsed/Refractory Indolent Non-Hodgkin’s Lymphoma.
Authors: Witzig Thomas E. , Vose Julie M. , Kaplan Henry P. , Wolf Jeffrey Lee , Pietronigro Dennis , Takeshita Kenichi , Ervin-Haynes Annette , Zeldis Jerome B. , Wiernik Peter H.
Published: October 2019

Background: Lenalidomide (Revlimid®), an immunomodulatory drug (IMiD®), was recently approved in the US for treatment of relapsed/refractory multiple myeloma and myelodysplastic syndromes associated with a deletion 5q[31] cytogenetic abnormality. Lenalidomide also has demonstrated activity in chronic lymphocytic leukemia and cutaneous T-cell lymphoma while thalidomide, a less potent IMiD®, has activity in non-Hodgkin’s lymphoma (NHL) as both monotherapy and in combination with rituximab.

Aim: To assess the safety and efficacy of lenalidomide monotherapy in subjects with relapsed/refractory indolent NHL.

Methods: Subjects with relapsed/refractory indolent NHL following at least 1 prior treatment regimen with measurable disease are eligible. Subjects receive 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continue therapy for 52 weeks as tolerated or until disease progression. Response and progression are evaluated using the IWLRC methodology.

Results: As of July 25, 2006, 23 subjects of a planned 40 have enrolled and received drug. Fifteen subjects are currently evaluable for tumor response. The median age of the 15 response-evaluable subjects is 64 (54–82) and 5 are female. Histology is small lymphocytic lymphoma [SLL] (n=8), follicular center lymphoma grades 1,2 [FL] (n=5) and nodal marginal B-cell lymphoma [NML] (n=2). Median time from diagnosis to lenalidomide monotherapy is 7.6 (3–14) years and median number of prior treatment regimens per subject is 3 (1–17). Two subjects (13%) exhibited an objective partial response (PR) at four months. Both responses, one FL and one NML, occurred in subjects with substantial tumor burden of 61.8 cm2 and 80.3 cm2, respectively. The 4-month time-to-response for these indolent NHL subjects is longer than the 2-month median time-to-response in aggressive NHL subjects (n=7) following lenalidomide monotherapy. Seven patients had stable disease (SD) for a tumor control rate (TCR) of 60% and 6 had progressive disease (PD). Grade 3 or 4 adverse events occurred in 9 (39%) subjects. These were predominantly Grade 3 hematological events (neutropenia, thrombocytopenia) with only 3 subjects (13%) experiencing a Grade 4 adverse reaction (all neutropenia).

Conclusion: Early results of lenalidomide monotherapy in indolent NHL show evidence of activity with a safety profile similar to that established previously in other hematological malignancies.
The C3b Component of Complement Inhibits NK Cell Activation Induced by Rituximab-Coated Target Cells.
Authors: Wang Siao-Yi , Racila Emilian , Taylor Ronald P. , Weiner George J.
Published: October 2019

Rituximab (RTX) is an accepted therapy for B cell malignancies, but there is still much to learn about the mechanisms responsible for the observed responses and the potential interactions between various mechanisms of action. Some studies suggest that complement fixation followed by lysis through the membrane attack complex contributes to the anti-tumor effects of RTX. Other investigations indicate that antibody dependent cellular cytotoxicity (ADCC) mediated by NK cells is central to the response of therapy. In prior studies, we found that RTX-coated target cells activate NK cells as indicated by NK cell modulation of CD16, upregulation of CD54 and CD69, and production of IFNγ. NK activation induced by RTX-coated target cells was dependent on the affinity of multivalent interactions between Fc γ receptors III (CD16) of the NK cell and Fc regions of cell-bound RTX molecules. We used these in vitro assays to assess the relationship between complement fixation, and the ability of RTX-coated target cells to activate NK cells. Normal human serum inhibited the modulation of NK cell CD16, and also blocked upregulation of CD54, induced by RTX-coated target cells. The ability of serum to inhibit NK activation was dose dependent and was abrogated upon heat inactivation. Serum depleted of C1q or C3 also failed to inhibit NK cell activation. The inhibitory activity of serum depleted of these complement components was restored when purified C1q or C3 were added back respectively. In addition, the level of NK cell inhibition was dependent on the amount of C3b deposited on the target cells. An antibody that stabilizes C3b on the target cell surface (3E7, DiLillo et al., Molec Immunol 2006) further enhanced the inhibition of NK cell activation induced by RTX-coated target cells. One possible explanation for these findings is that complement-mediated lysis destroyed the RTX-coated target cells before they had the opportunity to induce activation of the NK cells. To assess this possibility, lymphoma cells were killed, fixed with formaldehyde, and washed prior to their use as target cells. These RTX-coated and fixed target cells were able to induce modulation of CD16 on the NK cells, which was again inhibited by normal human serum. These findings indicate that the observed inhibition of NK activation by complement is unlikely to be a consequence of complement mediated lysis of the target cells. Instead, these data suggest that C3b deposition on RTX-coated target cells inhibits the interaction between the Fc portions of RTX and CD16 on the NK cells, and so limits the ability of RTX-coated target cells to induce NK activation. These results could have implications in our understanding of the relationship between complement fixation and ADCC, and their relative roles in potentiating destruction of malignant cells in the blood and tissues.