bluuebunny/crossref_metadata_2025 huggingface dataset:
2-Methoxyestradiol Sensitizes B-NHL Cells to TRAIL-Mediated Apoptosis Via Inhibition of HIF-1α, NF-κ B, YY1 and Induction of DR5 Expression.
Authors: Huerta-Yepez Sara , Vega Mario I. , Baritaki Stavroula , Suzuki Eriko , La Vallee Theresa , Bonavida Benjamin
Published: April 2020

There have been many advances in the treatment of B-NHL by both chemotherapy and immunotherapy. However, many patients experience recurrences and relapses and develop resistance to further treatments. Therefore, there is a need for new therapies. TRAIL and mAbs directed against DR4 or DR5 are currently being examined clinically, either alone or in combination with other therapies, for the treatment of resistant cancers. The objective of our study is to examine whether B-NHL can be sensitized to respond to TRAIL. 2-Methoxyestradiol (2ME2), a naturally occurring metabolite of estradiol, is known to have apoptotic activity and anti-angiogenic activity and has been examined for its therapeutic efficacy, both preclinically and in humans. Further, we and others have shown that 2ME2 can sensitize solid tumors to TRAIL-induced apoptosis. Thus, we hypothesized that 2ME2 may also sensitize B-NHL cells to TRAIL-induced apoptosis and that 2ME2-induced microtubule disruption and inhibition of NF-κ B activity may be involved in 2ME2-induced sensitization. The present study examined the role of 2ME2 in TRAIL-sensitization of the B-NHL cell line, Ramos, as a model for B-NHL. Ramos cells were treated with 2ME2 (0.1, 1.0 μ m for 5 h) and then treated with TRAIL (2.5–10 ng/ml for 18 h). The cells were harvested and examined for apoptosis by Annexin V/PI and for activation of caspase-3. The findings demonstrate that, while single agents were not cytotoxic, the combination treatment resulted in significant cytotoxicity demonstrating synergy in apoptosis. The synergy was obtained with very low concentrations of 2ME2 (0.1μ m) and TRAIL (2.5 ng/ml), concentrations that were not effective in other tumor cell lines studied. We examined the potential mechanism involved in synergy induced by 2ME2 and TRAIL. Surface DR-5 expression was upregulated following treatment with 2ME2. In addition, the transcription repressor YY1 protein expression was inhibited as assessed by Western and immunohistochemistry (IHC). Microtubule disruption by 2ME2 results in inhibition of HIF-1α transcriptional activity through impairment of HIF-1α nuclear accumulation. Additionally, we have found that 2ME2 inhibits HIF-1α accumulation in the nucleus as assessed by IHC. Inhibition of HIF-1α has been shown to regulate apoptosis via upregulation of BID and phosphorylyzation of Bcl-2. The present findings demonstrate, for the first time, that 2ME2 sensitizes B-NHL cells to TRAIL-induced apoptosis via inhibition of both HIF-1α and YY1 and upregulation of DR5. The findings support potential therapeutic combination studies of 2ME2 with TRAIL for the treatment of resistant B-NHL In addition, we suggest that HIF-1α, YY1, and DR5 may serve as targets for therapeutic intervention and potentially as biomarkers for activity.
International Prognostic Score (IPS) Is Not Useful in Stages I–II Hodgkin’s Lymphoma (HL) - An Experience of the Buenos Aires Leukemia Group (BALG).
Authors: Tartas Norma E. , Zerga Marta , Santos Maria I. , Alfonso Graciela , Amoroso Maria
Published: April 2020

The International Prognostic Factors Project on advanced HL developed a prognostic score to predict treatment outcome in patients with advanced disease treated with modern chemotherapy,with or without radiotherapy (RT).The score incorporates seven adverse prognostic factors (APF): age ≥45yrs old, male sex, stage IV, hemoglobin<10.5,serum albumin <4 g/dl,leukocytosis≥ 15×109/L and lymphocytopenia (< 0.6× 109/L). Patients with ≤ 2 APF have a two year freedom from progression of 80% while those with 3 or more APF have a worse outcome, each additional factor reduces the prognosis by about 8%.

To study the utility of IPS in less advanced disease, we looked into our patients included in the HD 98 protocol for stages I–II HL.According to this protocol, patients without bulky disease,B symptoms or N< 3, received 4 cycles of standard ABVD plus IFRT.Patients with one or more of the unfavourable characteristics received 6–8 cycles of standard ABVD plus RT in areas of bulky or residual disease.Since December 98, ninety two patients have been included, 91 are evaluable for this report.Patient characteristics were as follows: 44 males,47 females, Age 30yr (15–80).Histologic subtypes were: LP:5, NS:64, MC:21, LR:1. Clinical stages IA:13, IAX: 3, IB:1, IBX:3, IIA:34, IIAX:13, IIB:19, IIBX:5.

Looking to IPS impact in freedom from progression we have simply considered two subgroup of patients: low risk (<3APF) and high risk (≥ 3APF).Only 6/91 patients belonged to the high risk group. With ABVD 92% of the patients got a CR.Four patients were considered to be primary resistant, we have lost follow up of two patients, three persons have relapsed and two of them got a second CR. Currently 85/91 are alive, with a median FU of 56 months .All patients with a high IPS obtained a prolonged CR . Three patients have relapsed at 7,13 and 30 months;all belonged to the low risk IPS group.Four patients with primary resistant HL have died, three of them had had an autologus bone marrow transplant .All primary resistant HL belonged to the low risk IPS group.

We think that IPS is not useful in stages I–II HL, because it is only significantly altered in less than 10% of the patients. One possible explanation might be, that IPS relies on laboratory parameters such as white cell counts in peripheral blood, hemoglobin levels and serum albumin which are less affected, in early stages of the disease .Interestingly 5/6 patients with high risk IPS had B symptoms and 3/5 had bulky or N3 disease, consequently they received 6–8 cycles of ABVD. These facts, might have had influence in our results.

In our experience resistance to ABVD have a dismal prognosis in HL. IPS was not a good predictor of progression or resistance in this cohort of patients.
Hodgkin’s Lymphoma Reed Sternberg Cells over Express the T-Cell Inhibitory Carbohydrate-Binding Lectin, Galectin 1: Role of AP-1 and Likely Mechanism of Tumor Immune Escape.
Authors: Juszczynski Przemyslaw , Ouyang Jing , Kutok Jeffery L. , Monti Stefano , Chen Wen , Cin Paola Dal , Abramson Jeremy S. , Takeyama Kunihiko , Golub Todd R. , Aster Jon C. , Rabinovich Gabriel A. , Shipp Margaret A.
Published: April 2020

Primary Hodgkin lymphomas (HL) contain small numbers of neoplastic Reed-Sternberg (RS) cells within an extensive host inflammatory infiltrate, which includes few cytotoxic T-cells. The lack of an effective host anti-tumor response prompts speculation regarding the mechanisms that HL RS cells use to evade immune surveillance. To identify novel HL-specific T-cell inhibitory molecules, we compared the gene expression profiles of a series of HL and diffuse large B-cell lymphoma (DLBCL) cell lines. The HL cell lines overexpressed galectin-1 (GAL1), a carbohydrate-binding lectin that selectively induces the apoptosis of cytotoxic T cells. GAL1 mRNA abundance was 5- to 33- fold higher in HL cell lines than in DLBCL lines. GAL1 protein expression was also uniformly high in HL cell lines and low or undectable in DLBCL lines by western blotting.

Immunohistochemical staining of primary tumors revealed abundant GAL1 expression in HL RS cells whereas DLBCLs were uniformly negative. To elucidate the mechanisms responsible for GAL1 over expression in HL, we analyzed the GAL1 locus and identified a candidate AP1 enhancer element 1.5 kb downstream of the GAL1 transcription start site. The predicted enhancer element increased the expression of a reporter gene (luciferase) 5-fold in a HL cell line but had no effect in either a DLBCL or fibroblast cell line. In electrophoretic mobility studies, AP1 bound to the predicted GAL1 enhancer element in a cell-type specific manner. In addition, mutation of the AP1 binding site in the GAL1 enhancer abolished its activity. Since the AP1 components, cJUN and JUN-B, are known to be overexpressed in HL, we analyzed cJUN and JUN-B copy numbers and transcript abundance in the HL cell lines using 100K high-density SNP arrays and oligonucleotide RNA microarrays. We found increased copy numbers of cJUN and/or JUN-B in all HL cell lines tested and confirmed these findings using fluorescence in situ hybridization (FISH). Increased cJUN and JUN-B copy numbers were associated with significantly higher transcript abundance in the HL cell lines. In additional functional assays, we confirmed previous reports that recombinant GAL1 induced the apoptosis of CD3+ PHA-stimulated lymphoblasts in a dose- and time-dependent manner. Taken together, these studies indicate that HL RS cells selectively over express GAL1, at least in part, via AP1-mediated induction of the GAL1 enhancer. Given the profound effects of GAL1 on cytotoxic T cells, RS-specific expression of GAL1 likely inhibits the host anti-tumor response in HL.
Rituximab Combined with M/VACOP-B and Radiotherapy in Primary Mediastinal Large B-Cell Lymphoma (PMLBCL): A Prospective Italian Phase II IIL Study.
Authors: Martelli Maurizio , Stefoni Vittorio , Cabras Giuseppina , Cortellazzo Sergio , Brusamolino Ercole , Levis Alessandro , Botto Barbara , De Vivo Antonio , Natalino Fiammetta , Erica Finolezzi , Foa Robert , Zinzani Pier Luigi
Published: April 2020

Background: Third generation regimens such as MACOP-B or VACOP-B (M/VACOP-B) in combination with involved-field radiotherapy (IFRT) seem to improve lymphoma-free survival of PMLBCL. The superiority of R-CHOP over CHOP-like regimens has been recently demonstrated in younger low risk DLBCL. Recently, the addition of Rituximab to CHOP has also improved survival in PMBLCL.

Aims: To evaluate the effectiveness and safety of Rituximab added to the standard M/VACOP-B regimens (R-M/VACOP-B) +/− IFRT in PMLBCL.

Patients and Methods: A total of 40 patients with PMLBCL has so far been treated in the six participating centers between February 2002 and July 2005. The median age was 38 years (range 17–54); 21/19 (53%) were females; 30 patients had stage II and 10 stage IV; 38 (95%) presented a bulky disease; LDH was increased in 26 (65%) and 21(53%) had a superior vena cava syndrome. According to the age-adjusted IPI score, 24 patients had an IPI = 0–1 and 16 an IPI = 2–3. All patients were treated with standard MACOP-B (30 patients) or VACOP-B (10 patients) regimens plus six cycles of Rituximab (375mg/m2) given at weeks 3, 5, 7, 9, 11 and 13. Twenty-six patients (65%) received mediastinal IFRT at a median dose of 36 Gy. The response was evaluated in all patients after six cycles of chemo-immunotherapy, at the end of the planned chemotherapy and after IFRT.

Results: The response rate after six cycles of the scheduled R-M/VACOP-B regimen was CR/CRu = 20 (50%), PR = 19 (47%) and NR = 1 (3%). Eight of the 40 patients received a second line therapy followed by HDT-ASCT (6/8 patients) because considered as low responders (PR = 7 and NR = 1). At the end of the chemo-immunotherapy program, 28 patients witnessed a CR/CRu (70%) and 12 a PR (30%). Seven of the 12 PR patients obtained a CR/CRu following IFRT for an overall CR/CRu rate of 87% (35/40). After a median follow-up of 13 months, the 2-year OS and PFS are 75% and 78%, respectively. No additional toxicities other than those related to chemotherapy were observed during and after Rituximab infusion.

Conclusions: R-M/VACOP-B are active therapeutic regimens devoid of severe toxicity for the management of patients with PMLBCL. The addition of Rituximab to M/VACOP-B regimens does not seem to improve the lymphoma-free survival of this group of patients. An update of these results on a broader number of patients will be presented at the meeting.
Single Institution Experience with Y-90 Ibritumomab Tiuxetan in the Treatment of Non-Hodgkin Lymphoma.
Authors: Martin Peter , Michel Rene , Galal Ahmed
Published: April 2020

Background: Radioimmunotherapy (RIT) is an effective treatment of Non-Hodgkin Lymphoma (NHL). Nonetheless, the use of RIT outside of clinical trials has been limited. We report here the experience in 25 patients treated with Y-90 ibritumomab tiuxetan off-protocol at a single institution.

Patients and Methods: The charts of all patients treated with RIT between October, 2004 and May, 2006 were retrospectively reviewed in accordance with Good Clinical Practice guidelines. 19 patients were treated with RIT alone while 6 were treated with RIT in combination with high-dose chemotherapy and autologous hematopoietic stem cell transplant (HSCT). Dosimetry was not performed.

Results: The median age of patients was 56 years (range 43–71 years). 13 of 25 had high-grade lymphoma (either transformed lymphoma or diffuse large B-cell lymphoma). The median IPI was 3. The median number of prior regimens was 3 (range 1–6). 6 patients had received fludarabine. 3 patients had undergone prior autologous HSCT and one had undergone allogeneic HSCT. The median time to platelet recovery >20 × 109/L was 35 days. One patient continues to have platelets <20 × 109/L 380 days post-RIT. The median time to recover platelets to >20 × 109/L was 72 among patients who had previously received fludarabine. Prior HSCT also appeared to be associated with prolonged thrombocytopenia. 7 patients remained neutropenic (ANC<0.5 × 109/L) for >30 days. One patient who had been treated with 4 lines of prior chemotherapy, including prolonged chlorambucil, developed acute myeloid leukemia at 6 months post-RIT. There have been 3 deaths to date, all due to disease progression at 1, 1, and 3 months post-RIT. The overall response rate in 21 of 25 patients was 84% with 9 patients achieving CR. With a median follow-up of 7 months, 5 patients have progressed.

Conclusion: The use of off-protocol RIT in our institution was associated with similar response rates to those reported in patients treated on-protocol. Off concern, however, is the significant hematologic toxicity. There was an association between prior fludarabine and prolonged thrombocytopenia that has not been reported previously.
Late Onset Neutropenia like a Complication of Treatment with Anti-CD20.
Authors: Rubio-Martinez Araceli , Recasens Valle , Godoy Ana , Padron Noelia , Giraldo Pilar
Published: April 2020

Introduction: The occurrence of unexplained peripheral blood cytopenia, particularly neutropenia, has been recently reported after rituximab ®. Its prevalence may be underestimated since it may occur late after treatment (Cattaneo C et al Leuk Lymphoma. 2006 Jun;47(6):965–6, Chaiwatanatorn K et al Br J Haematol 2003). Apparently the risk is higher when R is associated with Fludarabine in combination therapy, producing a decrease in bone marrow precursors. Patients and methods: observational and retrospective study in order to determine the incidence of WHO grade III – IV neutropenia (neutrophils: ≤ 0.6×109/L) and the development of infection complications in patients treated with R-CMF or R-CF in our hospital from 6/8/2003 to 20/3/2006. We have compared these data with the incidence of delayed neutropenia during 621 courses of R or R-CHOP administered as outpatient schedule in the same period.

Data source: clinical reports. Variables: demographic data (age, gender), date of diagnosis, histological type, schedule therapy, number of cycles, clinical response (complete remission (CR), partial remission (PR), and non response (NR), prophylaxis with G-CSF, blood counts (leucocytes, neutrophils, hemoglobin and platelets) during all treatment and follow-up, infections and number of admissions in the hospital. Kaplan-Meier survival and Cox regression were calculated.

Results: From 78 courses of Immuno-chemotherapy in 16 consecutive patients diagnosed of follicular NHL: 10, B-CLL: 5, mantle NHL: 1. R-CMF (14 patients), R-CF (2 patients). (9 males/7 females), mean age 58.75 (20–78). In first line 8, second line 6 and third line 2. Number of courses received: mean 4,8 (1–6). Response: CR:13, NR: 1, Non valuable: 2. G-CSF prophylaxis during therapy in 50%. 9 patients (56.2%) developed neutropenia during the treatment or in the following year, one of them had also anemia and thrombocytopenia. In 4 patients the combination therapy was administered in first line, 3 as second line and 2 as third line therapy. Patients received 5 (6 courses), 1 (5 courses), 1 (3 courses), 1 (2 courses) and 1 (1 course), 8 developed infections that required admission into hospital (1 died after third course by sepsis). Another two patients developed severe infections without neutropenia. A late and persistent neutropenia after to finish therapy (1–6 months later), was observed in 4 patients (duration:3, 12, 11 and 4 months); 2 patients got over at 11 and 12 months after and in two of them is present now. They were treated with G-CSF, prednisone and cyclosporine in 2 cases without response and reached normal values when we associated IV immunoglobulins extract. OS: mean 26.4 months (6–49), RFS: 10.6 months (1–30).

Conclusions: Delayed-onset cytopenia, particularly neutropenia, is a clinically significant complication of rituximab treatment when it is administered in combination with Fludarabine increasing the risk of severe infections.
Comprehensive Analysis of Homeobox Genes in Hodgkin Lymphoma Cell Lines Identified Dysregulated Expression of HOXB9 Mediated by Constitutive Active ERK5 Signalling Pathway and BMI1.
Authors: Nagel Stefan , Burek Cristof , Venturini Letizia , Scherr Michaela , Quentmeier Hilmar , Meier Corinna , Rosenwald Andreas , Drexler Hans G. , MacLeod Roderick A.F.
Published: April 2020

Within the human genome nearly 200 homeobox genes have been identified. These are functionally involved in distinct developmental processes during embryogenesis and in the adult. Many have been implicated in cancer mostly following ectopic expression. In this study, we analyzed homeobox gene expression in Hodgkin lymphoma (HL) cell lines using degenerate primers for RT-PCR and Affymetrix U133A expression arrays followed by extended RT-PCR analysis of candidate homeobox genes in additional hematopoietic cell lines. We identified upregulated HOXB9 expression in HL, as well as in anaplastic large cell lymphoma and mediastinal B-cell lymphoma cell lines. Analysis of HOXB9 regulation in HL cells revealed activation by E2F3A, and repression by BMI1, respectively. Constitutive ERK5 pathway activation was identified in all HL cell lines analyzed together with primary HL lymph nodes biopsies. Our data show that ERK5 regulates HOXB9 expression, probably mediated via BMI1 repression. Expression analysis of microRNA gene mir-196a1 which is located upstream of HOXB9 indicated coregulation together with HOXB9. Functional analysis of HOXB9 by knockdown or overexpression assays revealed its influence in both proliferation and apoptosis in HL cells. In summary we identified upregulated expression of HOXB9 in HL, and its regulation mediated by constitutively active ERK5 signalling, thus representing novel therapeutic targets in both HL and NHL subtypes.
Response to Re-Treatment with Rituximab Plus Salvage-Chemotherapy in Refractory or Relapsed Aggressive Non-Hodgkin’s Lymphoma.
Authors: Borgerding Andrea , Hasenkamp Justin , Chapuy Bjoern , Truemper Lorenz , Wulf Gerald , Glass Bertram
Published: April 2020

The efficacy of re-therapy with rituximab immuno-chemotherapy was analysed in 20 consecutive patients with relapsed or progressive aggressive Non Hodgkin’s lymphoma after initial treatment with rituximab plus chemotherapy. Ten patients had a diffuse large B-cell lymphoma, seven had a mantle cell lymphoma and three a grade III follicular lymphoma. At primary diagnosis, the IPI was high-intermediate or high in 75% of the patients and the median age was 55 years (range 36–72 years). The overall response rate of primary immuno-chemotherapy was 75% (15/20 patients) with a complete remission in 8/20 patients (40%). After relapse, 53 % of these patients (8/15) responded again to immunochemotherapy: two patients had a second complete and six a second partial remission. None of the five patients with primary progressive disease responded to a conventional immuno-chemo salvage therapy. After re-therapy with rituximab plus salvage chemotherapy, ten patients received at least one cycle of high dose chemotherapy followed by SCT. One patient did receive HD-chemotherapy and an autologous graft solely, two patients did receive HD-radio-immunotherapy followed by an autologous graft and seven patients finally received HDT and an allogeneic transplant. Allogeneic SCT resulted in a CR in 6 out of 7 patients. One of these ten patients relapsed after HDT consolidation. Six out of ten patients without HDT consolidation after immuno-chemotherapy progressed after secondary treatment, 4 patients are alive without progression (SD, PR) but follow up is short (7, 10, 13 and 16 months). Conclusion: A substantial proportion (53%) of patients with relapse after rituximab immuno-chemotherapy did response to rituximab containing salvage therapy. Patients with progressive disease under immuno-chemotherapy did not respond to such salvage therapy. Without additional consolidation by HDT the risk of progression after successful salvage with rituximab and salvage-chemotherapy is high.
Pentostatin Combined with Cyclophosphamide, and Rituximab Induces High Response Rates in Patients with Untreated Indolent B-Cell Lymphoma.
Authors: Samaniego Felipe , Fayad Luis E. , Pro Barbara , McLaughlin Peter , Rodriguez Maria Alma , Hagemeister F.B. , Fanale Michelle , Neelapu Sattva , Younes Anas , Kwak Larry W.
Published: April 2020

The addition of rituximab to combination chemotherapy has improved treatment outcomes of indolent lymphomas. Combination therapy with purine analogs, akylating agents, and monoclonal antibodies is a promising approach for treating indolent B-cell lymphoma. Nucleoside analog-based regimens selectively target lymphoid cells, making them attractive drugs for lymphoid cancers. Pentostatin is a nucleoside analog that compared with other nucleoside analogs appears to have less bone marrow cell toxicity. The combination of pentostatin, cyclophosphamide, and rituximab (PCR) is an effective regimen for relapsed chronic lymphocytic leukemia and relapsed indolent B-cell lymphoma. In this study, we examined the efficacy of pentostatin, cyclophosphamide, and rituximab for the treatment of B-cell lymphoma. Pentostatin (4 mg/m2), cyclophosphamide (600 mg/m2), and rituximab (375 mg/m2) were given on day 1 of a 21-day cycle with restaging after every 3 cycles. Patients received prophylaxis with acyclovir 400 mg/po bid and trimethoprim-sulfamethoxazole 3 times per week. Small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL), was stained for ZAP70 staining and immunoglobulin heavy chain gene mutations. At the time of abstract submission, 29 patients are eligible for response and toxicity. There were 12 patients with follicular lymphoma, 13 with SLL/CLL, and 4 with mucosa-associated lymphoid tissue (MALT), and the median age was 63 years. This regimen was used as first-line therapy for 26 patients and second-line therapy in 3 patients. We observed an overall response of 27 out of 29 (93%), CR/CRu in 19 out of 29 (65%), PR in 8 out of 29 (27%), and mixed response in 2 out of 29 (7%). The main toxicities were nausea and vomiting. No prolonged pancytopenia or myelodysplasia were observed. The correlation of ZAP70 and immunoglobulin heavy chain gene mutations with response is ongoing. Our preliminary data demonstrate that PCR therapy is an effective regimen in previously untreated indolent lymphoma.
Phase II Study of Denileukin Diftitox (ONTAK®) in Patients with Relapsed/Refractory B-Cell Non-Hodgkin’s Lymphoma (B-NHL) and Poor Bone Marrow Reserve.
Authors: Czuczman Myron S. , Pinter-Brown Lauren , Lechowicz Mary Jo , Bartlett Nancy , Lazarus Hillard , Lister John , Goy Andre , Kahanic Stephen , Rosen Peter , Acosta Mark
Published: April 2020

Therapeutic options for patients (pts) with relapsed/refractory B-NHL and poor bone marrow reserve are limited. Denileukin diftitox (DD), a recombinant fusion protein, which when given at the standard dose, is not myelosuppressive and achieved a response rate of 25% in pts with relapsed/refractory B-NHL (Dang JCO22:4095–4102, 2004). We conducted a phase II, open label, multi-site study to evaluate efficacy and tolerability of DD given weekly in pts with relapsed/refractory B-NHL who had diminished bone marrow reserve. This is the first study of DD in NHL to use a dosing regimen other than the standard 18 mcg/kg/day for 5 days repeated every 21 days. Pts were required to have failed to respond or have progressive disease (PD) after ≥2 prior treatment regimens, bi-dimensional disease of at least 4cm2, and mild to moderate cytopenia defined as one or more of the following: ANC ≥1000 but <1500, platelets ≥40,000 but <150,000, and WBC ≥2000 but <4000, or have relapsed after prior stem cell transplantation (SCT). Denileukin diftitox was administered at 18 mcg/kg/day ×3 days followed by 21 mcg/kg weekly. Evaluation of response was performed after 8 wks of treatment, and pts with stable disease or objective response were to receive another 8 weekly infusions. Twenty-two pts enrolled; the median age was 67 yrs (range 45–78), median number of previous treatments was 4 (range 2–9), 12 had prior SCT. There were 14 pts with diffuse large cell lymphoma (DLCL), 5 follicular lymphoma (FL), and 3 small lymphocytic lymphoma (SLL). The median lesion size at entry was 21cm2 (range 10–598cm2). Twenty of 22 pts discontinued therapy prematurely, 14 due to PD, 1 with SD, and 5 due to toxicity. The median number of weekly doses given was 4 (range 1–16). No objective responses have been observed to date and enrollment has been suspended. Fourteen pts are alive (10 DLCL, 3 FL, 1 SLL) ranging from 2–14 months from entry. Adverse events observed with weekly dosing were similar to those seen with the standard regimen; however, incidence of most common grade 3–4 toxicities was less, with fatigue 24%, transaminase elevation 18%, and hypoalbuminemia 12%. Although all pts had mild to moderate cytopenia at enrollment, only 2 pts (9%) experienced grade 3–4 neutropenia, none with neutropenic infection, and 1 pt had worsening of thrombocytopenia from grade 3 at study entry to grade 4. In conclusion, weekly dosing of DD is well tolerated, even in pts with diminished marrow reserve, but has not demonstrated significant anti-tumor activity in this heavily pretreated B-NHL population with bulky disease. Follow-up will continue for survival analysis.
CHOP-Rituximab-Interferon Therapy in Follicular Lmphoma (FL): High Remissions with Reasonable Toxicity.
Authors: Bseiso Ali W. , Hocking William G. , Mercier Richard J. , Krawisz Bruce , Birhiray Ruemu
Published: April 2020

Background: Rituximab (R) plus chemotherapy (CTP) results in highly durable remissions in FL. IFN-α-2b has activity against FL and may demonstrate synergism when given concurrently with CTP. Some studies showed clinical benefit to adding IFN to CTP concurrently or as maintenance. We hypothesized that adding IFN to RCHOP may enhance the anti-lymphoma effect via enhancing the ADCC effect of R by generating effector NK and T-cells.

Methods: pts ages ≤75, stages II-IV, classified as B, C and D on IWF were enrolled.

Treatment: 6 cycles of CHOP with R added prior to cycles 1, 3 and 5. Growth factor support was allowed. IFN at 3× 106 U TIW SQ was concurrently given. Subsequently, 4 weekly R doses were given followed by 1 year of maintenance IFN at 5× 106 U TIW SQ for a total of 80 wks of therapy.

Results: 15 pts were enrolled. 1 pt with MZL was taken off study. Among 14 pts with FL, there were 8 males and 6 females. 10 pts were stage IV, 4 stage III, 3 had PS of 0, 9 PS of 1, and 1 PS of 2. Age was 29 to 72 (median 62). 11/14 achieved CR, 2 had PR. At median f/u of 62 mo (36–67), 10/14 pts remain alive and progression-free, including 1 pt with PR who later developed ovarian ca. 2 died of PD, 1 at 13 months after stopping therapy, and the other of CNS transformation during CTP. 1 patient had molecular progression while in clinical CR, responding to additional R and 1 was lost to follow-up. At diagnosis, 8 showed bcl-2 translocation by PCR in BM. AT week 29, 6 of the 8 showed disappearance of the bcl-2 translocation while 1 (who had PR) had persistence of the translocation. 7 completed maintenance; 5 withdrew during maintenance due to IFN toxicity. Grade 3–4 toxicities, included fatigue in 3 pts, neutropenic fever in 2 patients, sensory neuropathy in 1 patient, rash in 1 pt and depression in 1 pt.

Conclusions: treatment of FL with RCHOP plus IFN was reasonably tolerated with high durable responses. Five of 12 pts had to discontinue IFN in the maintenance phase due to toxicity.
Intestinal Marginal Zone B-Cell Lymphoma of MALT Type: Clinical Manifestation and Outcome of a Rare Disease.
Authors: Oh Sung Yong , Kim Won Seog , Ryoo Baek-Yeol , Kang Hye Jin , Park Yeon Hee , Kim Kihyun , Ko Young Hye , Kwon Hyuk-Chan , Nam Eunmi , Lee Jae-Hoon , Kim Jung Han , Kim Hyo-Jin
Published: April 2020

Purpose: Intestinal marginal zone B-cell lymphoma of MALT type (I-MZL) is a relatively uncommon type of lymphoma. Because of the rarity, the natural history and optimal treatment modality has not been well defined. Therefore, we performed a retrospective analysis of the clinical features and treatment outcomes of I-MZL.

Methods: From 1990 to 2005, a total of 27 patients with histologically confirmed I-MZL were analyzed.

Results: The median age was 51 (range: 19–83) years. The study involved 16 males (59%) and 11 females (41%). Patients initially presented with abdominal pain (62.9%), diarrhea (22.2%) and various symptoms. The most common involving site was ileo-cecal area (40.7%) followed by small intestine (25.9%), colorectal (18.5%), multiple intestine involvements (14.8%) in the decreasing order of frequency. Musshoff stage IE, IIE1, IIE2, IIIE, and IV were present in 44%, 15%, 11%, 7.4%, and 22%, respectively. B symptom was observed in 11%. Twenty one (78%) and five (19%) patients were in low or low-intermediate risk group according to international prognostic index (IPI). Sixty-three percents (17/27) were in low risk group in follicular lymphoma international prognostic index (FLIPI). Treatment was mainly combined with surgical modality. Complete and partial remissions were achieved in 22 (82%) and 1(4%). After the median follow-up duration of 56.1 months, Median progression free survival (PFS) were 8.8 (95% CI: 3.8–13.8) years. The estimated 5-year overall survival (OS) and PFS were 86% and 54%, respectively. Stage ≥ IIE2 was poor prognostic factor of PFS and OS.

Conclusion: I-MZL trends to be an indolent disease - prolonged survival with frequent relapse like other site MZL of MALT type. They present commonly early stage, low risk state and respond well local and systemic treatment. I-MZL has favorable prognosis.
Extranodal-NHL: Outcomeand Comparison with Nodal NHL. Single Institution Experience Year: 1988–2004.
Authors: Lal Amar , Masood Nehal , Adil Salman
Published: April 2020

Background & Objective: Non-Hodgkin’s lymphoma (NHL) arising in an extra nodal (EN) site is not uncommon and its natural history and treatment is clearly characterized in the literature. Data on EN-NHL and comparison with N-NHL with relation to survival and prognostic factors is scarce in our part of the world. The primary objective of this study was to analyze the anatomic distribution, clinical features and outcome of Diffuse large B-cell lymphoma (DLBCL) patients according to the primary site (extra nodal vs nodal) with applicability of International Prognostic Index (IPI).

Methods: From 1988 to 2004, 711 cases of NHL were diagnosed at our Institute. Out of these 145 (20%) patients were excluded as they were other than DLBCL hitopathology. Five hundreds fifty-seven (80%) patients were analyzed for the clinico-pathologic characteristics, treatment outcome and prognostic factors affecting overall survival.

Ann Arbor staging system was used for staging with bone marrow biopsy, chest and abdominal radiography/CT.

Results: Median age was 48.7 ± 15.3 years; the M: F ratio was 2:1. The distribution according to the primary site was: lymph node, 322 cases (58%) of these 145 cases (44%) stage IV, 76 cases (23%) Stage III, 60 cases (18%) stage II and 47 cases(15%) stage I; and EN sites, 235 (42%), including gastro-intestinal tract (44%) followed by upper aerodigestive tract (19%), bones (08%), spine (05%), and unusual sites less than 3% each as breast, CNS, testis, lungs and skin.

The median survival rate was 4.8 and 6.3 years in NL and ENL respectively vary according to primary site/stage of the lymphoma.

In the univariate analysis age less than 60 years, early stage I -II, extra nodal involvement primarily gastric or bone, 0–1 extra nodal site, 0–1 PS, lack of B symptoms, normal LDH level has been associated with good prognosis.

In the multivariate analysis age, PS, stage and level of LDH were the main variables to predict OS; no nodal or extranodal site maintained their prognostic value.

Conclusion: Our data correspond with series from west increasing incidence extranodal lymphoma due to improved diagnostic techniques and superior results with chemotherapy by preserving the organ. Few patients with bowel obstruction or cord compression lymphoma required surgery for diagnosis or relief of symptoms. There is significant difference from western data in histologies DLBC-NHL is the most common histologies in our study. Overall survival patients with EN-NHL were similar to nodal NH-Lymphoma but largely depended on IPI.
Synergic Effects of Proteasome Inhibitor PS-341 and Tyrosine Kinase Inhibitor STI571 on Chronic Myeloid Leukemia Cells and BCR-ABL Oncoprotein In Vitro and In Vivo.
Authors: Zhou Guangbiao , Hu Zheng , Liu Dapeng , Wu Fuqun , Zhu Jiang , Chen Saijuan , Liu Xiaoli , Li Juan , Li Xiaofeng , Zhang Fengxiang
Published: April 2020

STI571/Gleevec/imatinib, a rationally-designed agent that occupies the ATP-binding site of BCR-ABL and stabilizes the protein in its closed, inactive conformation, has been a remarkable success for the treatment of chronic myeloid leukemia (CML). However, a significant proportion of patients chronically treated with STI571 develop resistance because of the acquisition of mutations in the kinase domain of BCR-ABL. Furthermore, the effects of STI571 on CML patients in accelerated phase or blastic crisis are unsatisfactory since many patients relapse after transient remission. Hence, additional drugs or STI571-based combination regimens are desired to circumvent resistance and to improve response rates. Here we reported that PS-341, a proteasome inhibitor which offers great promise to patients with multiple myeloma (MM), significantly enhanced the antileukemia activity of STI571 in vitro and in vivo. We found a synergy exists between low concentrations of PS-341 (5–10 nM) and STI571 (0.1–0.2 μM) in inhibition of cell growth and induction of apoptosis in K562 cell line and CD34+ leukemic cells isolated from CML patients. In K562 cells, combined use of PS-341 and STI571 accelerated activation of caspase-3, 9, and facilitated cleavage of poly-(ADP-ribose) polymerase (PARP) as compared to those in cells treated with PS-341 or STI571 alone. Moreover, PS-341/STI571 combination resulted in potentiated degradation of BCR-ABL and downregulation of phosphorylated BCR-ABL as compared to those in mono treatment. In nude mice inoculated subcutaneously with K562 cells, treatment with PS-341 (injected intraperitoneally, ip) alone (at doses of 0.05, 0.5, 1 mg/kg/d, twice a week for 4 weeks, respectively) decreased tumor growth in a dose-dependent manner. STI571 (ip) at 10 mg/kg/d also inhibited tumor growth. Intriguingly, combinatory administration of low dose PS-341 (0.05 mg/kg/d, twice a week for 4 weeks) and STI571 (10 mg/kg/d) yielded a much more profound inhibition of tumor growth and even clearance of leukemic cells in mice compared to either monotherapy. Taken together, these results demonstrate synergic effects of PS-341 and STI571, and provide the rationale to evaluate PS-341/STI571 combination in treating CML aiming to further improve clinical outcome of patients.
A Prospective Study in Ph+ Chronic Myeloid Leukemia (CML) Patients Showing That Interphase Fluorescence in Situ Hybridization (FISH) Is Effective as Conventional Cytogenetics for Definition of Cytogenetic Response. Correlation with Molecular Response (by the GIMEMA CML WP).
Authors: Testoni Nicoletta , Luatti S. , Marzocchi G. , Amabile M. , Gamberini C. , Buontempo F. , Baldazzi C. , Iacobucci I. , Mancini M. , Cuneo A. , Specchia G. , Kerim S. , Rege-Cambrin G. , Giugliano E. , Giussani U. , Abruzzese E. , Grimoldi M.G. , Modaferri B. , Castagnetti F. , Palandri F. , Mecucci C. , Bernasconi P. , Gozzetti A. , Palka G. , Zanatta L. , Zaccaria A. , Martinelli G. , Rosti G. , Baccarani Michele
Published: April 2020

We planned a prospective analysis involving 3 multicentric national studies of the GIMEMA (Gruppo Italiano Malattie Ematologiche Adulto) CML Working Party (WP) to evaluate the correlation between conventional cytogenetics (CC) and FISH response in CML pts in chronic phase (CP) treated with Imatinib. Karyotype and FISH analyses were performed on bone marrow (BM) cells in 26 local laboratories and in 12 WP reference labs. Peripheral blood samples for quantitative RT-PCR were centralized in Bologna. The data are reported in Figure 1 and in Table 1. Fig 1 shows the relationship between CC and FISH (r=0.91;p=0.008). Tab 1 shows the demonstration of FISH data according to CC data and the number of metaphases available for CC. Of 217 pts in CCgR by CC and > 20 metaphases studied, 81.6% were FISH negative, 15.2% showed a low rate of FISH positive cells (1–5%) and 3.2% an higher rate. Of 94 pts in CCgR by CC but with < 20 metaphases studied, 71.3% were FISH negative, 21.3% showed a low rate of FISH positive cells (1–5%) and 7.4% an higher rate. Of 43 pts in PCgR by CC and FISH positive, 48.8% showed 1– 5% positive cells. Moreover, 358 samples were performed simultaneously by CC, FISH and quantitative RT-PCR: 179 (50%) samples in CCgR showed major molecular response (MMolR, defined as a BCR-ABL × 100 ratio < 0.1%): 164 (91.6%) were FISH negative and 15 (8.4%) were FISH positive (1.3–10% positive cells). We conclude that interphase FISH is a very releable method of monitoring the CCgR once it has been achieved. The relationship of FISH on BM cells with molecular response is at least as good as the relationship of CC with molecular response. It remains to be shown if the same results can be obtained on peripheral blood cells, that are already widely used for molecular monitoring.

No FISH negative FISH 1–5% FISH > 5% CCgR ≥ 20 met 217 177 (81.6%) 33 (15.2%) 7 (3.2%) CCgR < 20 met 94 67 (71.3%) 20 (21.3%) 7 (7.4%) PCgR ≥ 20 met 43 0 21 (48.8%) 22 (51.2%) CCgR and MMolR 179 164 (91.6%) 12 (6.7%) 3 (1.7%) Figure Figure
Rituximab Is an Alternative to Splenectomy in Adults with Chronic Immune Thrombocytopenic Purpura: Results of a Multicenter Prospective Phase 2 Study.
Authors: Godeau Bertrand , Fain Olivier , Porcher Raphael , Lefrere Francois , Fenaux Pierre , Cheze Stephane , Vekhoff Anne , Chauveheid Marie-Paule , Stirnemann Jerome , Galicier Lionel , Bourgeois Emmanuelle , Haiat Stephanie , Varet Bruno , Leporrier Michel , Papo Thomas , Michel Marc , Bierling Philippe
Published: April 2020

Background : Rituximab, a monoclonal anti-CD20 antibody, is a promising therapeutic agent for adults with immune thrombocytopenic purpura (ITP). Pooling results of the published literature suggest that rituximab achieves an initial response in about 50 % of adults with chronic ITP, with a 25–40% rate of sustained response. However, heterogeneity of patient pre-treatment status, short follow up and bias due to retrospective studies limit the interpretation of the data.

Objective : To assess the safety and efficacy of rituximab in adults with chronic ITP (duration ≥ 6 months) and platelet count ≤ 30x109/L candidate to splenectomy.

Methods : a multicenter prospective open-label single arm phase 2 trial designed according to Fleming’s single stage procedure was conducted. After informed consent, non splenectomized adults received 4 weekly intravenous infusions of rituximab at a dose of 375 mg/m2. All other ITP treatments were stopped. Treatment success was defined as a platelet count ≥ 50 x109/L with at least a 2 fold increase of the initial value at one year after the first rituximab infusion. Patients who received another treatment during follow up were considered as non responders. A sample size of at least 56 patients was calculated by Fleming’s single-stage design to ensure 90 % power for proving lack of efficacy if the true complete response rate was below 25%.

Results : Sixty consecutive patients (40F/20M) were included over a 21 months period. Mean age was 48 years (range 18–84). Mean ITP duration was 4.8 years. Mean platelet count at inclusion was 16±10x109/L. All but one patient, in whom reversible serum sickness disease was diagnosed after 2 infusions, received 4 infusions of rituximab. Fifteen other patients experienced transient side effects that did not lead to treatment discontinuation. No patient was lost to follow up. Success was achieved in 40 % (24/60 patients) (95 % confidence interval 28% to 52%) and was found significantly different from 25% (p=0.007). Among the 24 long term responders, platelet count at one year was ≥ 150x109/L in 18 and between 50 and 150 x109/L in 6. Two other patients (3%) had and incomplete response defined as a platelet count at one year between 30 and 50 x109/L but at least 2 fold the initial value. Thirty four (57%) patients failed to respond and amongst them, 18 have already undergone splenectomy.

Conclusion: rituximab appears to be a safe and good splenectomy-sparing strategy in adults with chronic ITP leading to a significant and durable response in 40% of the cases.
The Clinical Significance of Biphenotypia in Blastic Phase CML.
Authors: Tam Constantine S. , Kantarjian Hagop M. , Verstovsek Srdan , Wierda William G. , Shan Jenny , Otero-Palacios Joselle , Awais Ahmed , Ravandi-Kashani Farhad , Cortes Jorge
Published: April 2020

The characteristics and clinical outcomes of CML blast phase (CML-BP) patients whose blasts express antigens from more than one lineage are currently unknown. We systemically assessed lineage fidelity among patients with CML-BP using the definition of biphenotypic leukemia as proposed by the European Group for the Immunological Characterization of Leukemias (EGIL; Leukemia1995; 9:1783). Briefly, individual antigens are assigned scores based on known specificity for one of three lineages (myeloid, B-lymphoid or T-lymphoid); biphenotypic leukemia is defined by a score of >2 points for two lineages. Between 02/97 and 01/06, 163 patients were treated for CML-BP at the MD Anderson Cancer Center, of which 120 had adequate flow cytometric assessment for calculation of EGIL score. The number of patients by lineages was: 89 myeloid (74%), 21 lymphoid (17.5%; B 14%, T 3.5%), 9 biphenotypic (7.5%), 1 unclassifiable (<1%). Four of nine biphenotypic BP patients had a history of antecedent myeloid BP (n=3) or lymphoid BP (n=1). Lymphoid BP patients had lower mean white cell count (p=0.04), lower mean platelets (p=0.007) and higher mean bone marow blast percentage (p<0.001) than myeloid BP patients; those with biphenotypic BP had values between the lymphoid and myeloid groups. Seven imatinib-naïve biphenotypic patients received imatinib as initial therapy for CML-BP, with six regaining a second chronic phase; however, median time to failure was only 2 months and, with the exception of one patient censored for allogeneic transplantation, all patients progressed within 4 months. The patient who underwent allogeneic transplantation died of transplant-related complications. An additional patient who had previously failed imatinib and nilotinib in chronic phase had no response to dasatinib in biphenotypic BP. The final patient developed biphenotypia during resistant relapse of previous B-lymphoid BP, and received supportive therapy only. Overall survival for lymphoid, myeloid and biphenotypic BP were 13, 8 and 6 months respectively (p=0.04). In order to determine the significance of minor degrees of lineage aberrancy, we examined the survival of myeloid and lymphoid BP patients with EGIL score 1.0 – 2.0 in a second lineage. For lymphoid BP patients, minor expression of myeloid antigens did not affect survival; in contradistinction, myeloid BP patients with minor expression of lymphoid antigens had a trend to inferior survival. Biphenotypic BP may either be de-novo or may emerge from previous unilineage CML-BP, highlighting the trend for lineal infidelity in CML-BP. Responses to tyrosine kinase inhibitors are short-lived, and survival using current therapeutic strategies is very poor.

Overall Survival Overall Survival
Cost-Effectiveness Analysis for Integral Treatment of Chronic Myeloid Leukemia in Chronic Phase at the Instituto Mexicano del Seguro Social (IMSS) Mexico.
Authors: Tenorio Luisa , Vargas E Juan , Baez Enrique , Afanador Carolina , Zapata Leon , Gomez-Morales Enrique
Published: April 2020

The economic analysis has become a priority for health institutions as a result of the increase in medical care costs. Therefore, an analysis model was developed integrating clinical and economic outcomes for the Medical care of chronic myeloid leukemia (CML) in chronic pahse.

Objective: To perform a cost-effectiveness assessment of the therapeutic alternatives for CML at UMAE No.25 IMSS.

Methodology: Economic evaluation of the use of imatinib mesylate (IM) vs. interferon + citarabine (INF/AraC), using as an effectiveness indicator, the number needed for treatment (NNT), to achieve a complete cytogenetic response (CCR) at 24 and 30 months was used. The integral care was obtained from the revision of clinical records in the UMAE 25, and from disease related-costs published by the IMSS.

Results: The NNT reveals the amount of patients that need to be treated with one or the other of the therapies to obtain the desired result (CCR), which means that for every 1.15 patients IC 95% (1.06–1.25) treated with IM for 24 months, one will reach the CCR, with a cost of $867,729 mexican pesos (mx), in comparison to the care cost for 7.14 patients IC 95 % (5.75–8.88) patients that are required to be treated with IFN/AraC for 24 months to obtain the same result, with a cost of mx $4,454,565. This difference is higher when results are assessed at 30 months: A cost of NNT care of 1.27 patients IC 95% (1.07–1.50) of mx $1,178,848 for IM vs. mx $10,182,116 for NNT care of the 13.5 patients, CI 95% (9.40–19.43) required to achieve a CCR with IFN/AraC.

Discussion: Comparing these results with the cost of the main treatment used during the same time, the expense effectiveness is evident. In other words, for each peso spent on IM at 24 months, mx $0.63 are effective, whilst for each peso spent on IFN/AraC, only mx $0.02 are beneficial for the patient. When this same reasoning is applied to the success cost at 30 months, we see that for each peso spent on IM, $0.58 are effective vs mx $0.01 per peso effectiveness spent on IFN/AraC.

Conclusions: The superiority of IM is evident compared to INF/AraC in regards to the effectiveness of achieving CCR at 24 and 30 months. This positive difference in favor of imatinib mesylate is reflected on the cost that Health Institutions have to spend, in order to obtain a successful CCR, due to the decreased number of patients necessary to treat with IM, in order to achieve this success.