bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic value of clinicopathological factors in operated stage I non-small cell lung cancer (NSCLC)
Authors: Nakahara R. , Suzuki H. , Matsuguma H. , Igarashi S. , Miyazawa N.
Published: March 2020

7222

Background: Recently adjuvant chemotherapy has improved survival in resected stage I, especially stage IB NSCLC. While some cases with stage IA NSCLC have poor prognosis, there are no reliable clinicopathological markers to predict cancer related death. This study was conducted to identify the prognostic factors for resected stage IA and IB patients. Methods: We retrospectively analyzed 318 cases that were diagnosed with pathological stage I NSCLC from 1986 to 2000 at Tochigi Cancer Center. Various clinical and pathologic factors were reviewed, and the risk of a cancer related death was investigated. Analyzed factors were as follows: sex, age, smoking status, preoperative serum CEA level, tumor histological type, pathological differentiation, tumor size, lymphatic invasion (ly), vascular invasion (v), and pleural invasion (p). Results: The cancer specific 5-year survival rate for each stage were estimated to be 91% foe stage IA (n = 198) and 66% for stage IB (n = 120). In the stage IA subset, the univariate analysis revealed the following five factors to be poor prognostic factors: age 65 < (p = 0.008, Risk Ratio = 1.76), high CEA level (p < 0.001, RR = 2.09), tumor size 2 cm < (p = 0.008, RR = 1.75), ly (+) (p = 0.007, RR = 1.87), and v (+) (p = 0.003, RR = 1.77). The 5-year survival rate for stage IA patients that have three or more factors was 67% (n = 43). In the stage IB subset, the univariate analysis of clinicopathological factors revealed tumor size 4 cm < (p = 0.004, RR = 1.53), v (+) (p = 0.02, RR = 1.45), and no pleural invasion (p0) (p = 0.004, RR = 0.64) to be prognostic factors. The 5-year survival rate for stage IB patients that have all the good prognostic factors (tumor size 4 cm ≥, v(-), and p0) was 96% (n = 26). Conclusion: Our analysis suggests that the combination of prognostic factors revealed the poor prognostic group equal to stage IB patients in stage IA group. On the other hand, combination of prognostic factors revealed the good prognostic group in stage IB patients. It should be considered to do adjuvant chemotherapy with poor prognostic stage IA patients and avoid with good prognostic stage IB patients.

No significant financial relationships to disclose.
Biomarker correlates of survival in NSCLC: Role of RXRβ and PPARγ in mediating bexarotene impact on patient survival
Authors: Negro-Vilar A. , Gatzemeier U. , Ramlau R. , Sun S. L. , Negro-Vilar R. , Hermann T. , Zhang J. K. , Dziewanowska Z.
Published: March 2020

7227

Background: Bexarotene is a selective modulator of retinoid X nuclear receptors (RXRs), which form heterodimers with many other nuclear receptors playing a critical role in cell growth, differentiation, and apoptosis. Loss of RXRs is seen in many advanced tumors, including NSCLC and higher RXR levels in NSCLC lung biopsies (stages I-III) have been correlated with longer overall survival. Two large first line NSCLC Phase III trials reported at ASCO 2005 (SPIRIT I and II) showed that while no benefit in overall survival was seen adding bexarotene to two chemo regimens, a large (36%) subpopulation of patients in both trials that had high grade hypertriglyceridemia in response to bexarotene had significantly longer survival. A retrospective analysis was conducted to evaluate the baseline characteristics of these patients and to examine the level of expression of RXR and one of its partners (PPARγ) in lung tumor tissue biopsies obtained from a subgroup of patients in both studies. Methods: RXRs (α,β,γ) and PPARγ expression levels in lung tumor tissue from patients in SPIRIT I and II trials (stage IIIB/IV) taken prior to study entry were assessed by Q-PCR analysis of RNA isolated from microdissected lung tumor tissue biopsies. Cox regression and Kaplan-Meier survival estimation were used for statistical evaluations. Results: In an initial subset of 41 patients, RXRβ expression in lung tumor showed positive correlation with survival. High RXRβ = longer survival (median survival 438 days), low RXR shorter (MS = 317). Treatment with bexarotene increased the differences (RXRβ Hi, MS = 627 days; RXRβ low = 211 days). PPARγ showed a negative correlation with survival and those patients with RXRβ Hi/PPARγ low ratios had the longest MS (627 days vs. 226 days for the RXRβ low/PPARγ high group), a difference that was magnified by bexarotene treatment. Conclusions: RXRβ expression level correlates with a positive survival in late stage NSCLC while PPARγ shows negative correlation. Bexarotene treatment enhances the survival differences, supporting an involvement of triglyceride and lipid metabolism as regulated by these two key nuclear receptors in the longer survival seen in the 215 patients in the high triglyceride subgroup.

[Table: see text]
A computer program designed to assist in NSCLC adjuvant therapy decision making
Authors: Ravdin P. M. , Davis G. J.
Published: March 2020

7230

Background: The goal the computer program, Adjuvant! for NSCLC, is provide the health professional, and the NSCLC patient with information that might be helpful when deciding about adjuvant chemotherapy for completely resected Stage 1 to Stage 3A disease. The 4 elements of this decision are: estimates of prognosis, estimates of the efficacy of adjuvant chemotherapy, estimates of completing mortality, and estimates of toxicity. Methods: Estimates of prognosis are based on an analysis of 17, 130 patients in the SEER registry. Estimates for 5 year disease specific mortality for Stage 1A, 1B, 2A, 2B, and 3A disease are 22%, 37%, 51%, 63%, and 70%. Multivariate analysis justifies using tumor size, histologic grade, and BAC histology for refinement of prognostic estimates for Stage 1 patients. A small subgroup of Stage 1 patients (with tumors < 10mm, low grade, BAC histology) could be identified with a 5 year disease specific mortality risk of <10%. Estimates of the efficacy of chemotherapy were derived from meta-analyses. A proportional risk reduction of 20% is used by the program as the default efficacy estimate for platinum-based therapy. Pop-ups and help files discuss areas of uncertainty and controversy. The user has the option to adjust the default efficacy estimate to the more optimistic efficacy estimates of some of the recent trials, or to take into account some of the uncertainty as to whether adjuvant chemotherapy works as well in Stage 1 disease. SEER data shows the average NSCLC patient has competing mortality rates higher than would be suggested by chronologic age. Regimen specific risks of treatment related toxicity is given by the program. In the over 100 pages of help files there is a detailed discussion of the clinical evidence, adjuvant therapy guidelines, ongoing clinical trials, and corollary areas (radiotherapy, neoadjuvant therapy, biomarkers, etc.) Results: The program projects that for patients with favorable Stage 1 tumors the absolute OS benefit of therapy may be as low as 1% (of the same size as the risk of treatment related mortality), but for patients with Stage 2 and 3A disease the 5 yr OS benefit may be ∼10%. Conclusions: The impact of this tool on physician and patient knowledge about the adjuvant therapy of NSCLC will be presented.

[Table: see text]
The impact of initial treatment of advanced stage indolent lymphoma on the risk of transformation
Authors: Al-Tourah A. J. , Gill K. K. , Hoskins P. J. , Klasa R. J. , Savage K. J. , Sehn L. H. , Shenkier T. N. , Gascoyne R. D. , Voss N. J. , Connors J. M.
Published: March 2020

7510

Background: The impact of initial treatment of indolent non-Hodgkin’s lymphoma (NHL) on the risk of transformation (TR) to aggressive NHL is unknown. High LDH and advanced stage at diagnosis have been shown to be predictive for TR; however, the effect of initial treatment is difficult to estimate as most series included heterogenous patient (pts) populations. Methods: As part of a large retrospective analysis examining TR (n = 698), we identified pts from 2 consecutive phase II studies conducted at the British Columbia Cancer Agency. Both studies had identical inclusion criteria: diagnosis of indolent NHL, no prior treatment, age16–60 y and advanced stage disease (III/ IV or I/ II with B symptoms or bulky disease ≥10cm). The first study included use of BPVACOP (bleomycin, cisplatin, etoposide, doxorubicin, cyclophosphamide,vincristine and prednisone, followed by involved field irradiation (RT) to original nodal sites of lymphoma. The second used combination alkylator-purine analogue (cyclophosphamide- cladrabine or fludaribine and prednisone). The definition of TR was based on either histological confirmation (HIST) or clinical features (CLIN), defined as one or more of the following: rapid discordant nodal or extranodal growth; sudden rise in LDH to > 2 x previous baseline; involvement of unusual extranodal sites; or hypercalcemia. Results: 260 pts were identified. BPVACOP+RT (n = 140), alkylator-purine analogue (n = 120). Median age 46 y (19–60). Follicular histology in 133 (94%) and 105 (87%), respectively. The majority were stage III/IV (89%) with equal proportions in each cohort. With a median follow-up (FU) for living pts of 90 months (1–225), 26 (18%) pts treated with BPVACOP+RT developed TR, 16 of which were confirmed with biopsy, versus 32 (27%) in the alkylator-purine group, of which 18 had biopsy confirmation. The 5 y risk of TR for BPVACOP+RT was 9% compared to 24% for the alkylator-purine analogue group (p < 0.0095). The annual risk of TR through 10 y of FU was 1.5% and 3.0%, respectively. The post-TR 5 y OS of all 58 pts with TR was 19%. Pts with TR based on CLIN vs HIST criteria did not differ in their outcome. Conclusions: The use of an anthracycline-based regimen as initial treatment for advanced stage indolent NHL is associated with a marked reduction in the risk of future TR.

No significant financial relationships to disclose.
Long-term follow-up of high-dose treatment (HDT) with autologous haematopoietic progenitor cell support in 702 patients (pts.) with follicular lymphoma (FL). An EBMT registry study
Authors: Montoto S. , Rohatiner A. Z. , Canals C. , Gisselbrecht C. , Fouillard L. , Milpied N. , Haioun C. , Taghipour G. , Schmitz N. , Goldstone A. H.
Published: March 2020

7526

Background: HDT with stem cell rescue has been increasingly used in pts. with FL. The aim of this retrospective analysis was to evaluate the outcome of a large series of pts. who received HDT for FL. Patients: From 1979 to 1995, 702 pts. (median age: 45, range: 17–68 yrs.) underwent HDT with a TBI-containing regimen in 407 cases and chemotherapy-based regimens in 276 (BEAM, 164). The median time from diagnosis to HDT was 2.2 yrs. Disease status at the time of HDT was as follows: CR, 323 pts. (1st: 138; 2nd: 141; 3rd: 44); PR, 170 pts.; recurrence/progression, 187 pts. (“sensitive”, 152; resistant, 20; untested, 15); primary refractory, 22 pts. The source of progenitor cells was bone marrow (BM) in 384 pts. (55%), peripheral blood progenitor cells (PBPC) in 288 (41%) and BM + PBPC in 30 (4%). Results: 353/702 pts. (50%) developed recurrent lymphoma at a median of 1.7 yrs. (range: 0.2 to 13.3) after HDT. 5-year PFS after HDT was 43%. On multivariate analysis, age at HDT <45 yrs. and HDT in CR1 correlated with longer PFS; refractory disease was the only variable predictive for risk of recurrence. 23 pts. developed secondary MDS/AML, in 18 cases after receiving TBI. With a median follow-up of 10.2 yrs., 338 patients have died, 96 without lymphoma progression. The 5-year non-relapse mortality (NRM) was 9%. On multivariate analysis, age > 45 at HDT, refractory disease at HDT and TBI were associated with a higher NRM. 5-yr and 10-yr OS from HDT were 64% and 52%, respectively. For pts. treated with HDT in CR1, 10-yr OS and PFS from HDT were 71% and 46%, respectively. The variables that predicted for a longer OS in the multivariate analysis were younger age at HDT, CR1 at HDT and the use of a non TBI-containing regimen. The effect of TBI on NRM and OS was mostly as a consequence of late mortality. Conclusions: This analysis confirms that the best outcome was associated with younger age and treatment in CR1. In addition, in this study TBI was associated with a negative impact on survival.

No significant financial relationships to disclose.
Phase I/II trial of Arginine Butyrate and ganciclovir in Epstein-Barr virus-associated lymphoid malignancies
Authors: Faller D. V. , Hermine O. , Small T. , Suarez F. , O’Reilly R. , Boulad F. , Fingeroth J. , Mentzer S. J. , Klein C. , Horwitz S. , Perrine S. P.
Published: March 2020

7542

Background: Malignancies associated with latent Epstein-Barr virus (EBV) are resistant to nucleoside-type anti-viral agents because the viral enzyme target of these drugs, thymidine kinase (TK), is not expressed. Short-chain fatty acids, such as butyrate, induce EBV-TK expression in latently-infected B cells. In preclinical studies, we have shown that butyrate sensitizes EBV(+) lymphoblastoid cells, tumor lines and primary lymphoma cultures to apoptosis induced by ganciclovir. Methods: We conducted a Phase I/II trial of Arginine Butyrate in combination with ganciclovir in patients with refractory EBV(+) lymphoid malignancies to evaluate toxicity, pharmacokinetic parameters, and clinical responses. Fifteen patients with heavily-pretreated, refractory EBV(+) lymphoid malignancies, consisting of monoclonal refractory lymphoproliferative disease (PTLD), B cell non-Hodgkin’s lymphomas (NHL) (including one HIV-associated anaplastic B cell lymphoma), T cell NHL (including one cutaneous lymphoma), T/NK cell lymphomas, and Hodgkin disease were studied. Ganciclovir was administered twice daily and Arginine Butyrate was administered in an intra-patient dose-escalation. Arginine Butyrate was instituted at 500 mg/kg/day by continuous infusion, and escalated to 2000 mg/kg/day, as tolerated. Results: The MTD for Arginine Butyrate was established as 1000 mg/kg/day. Overall the combination was well-tolerated, with the most common toxicities being nausea and headache. Complications from rapid tumor lysis occurred in three patients, including acute hepatic necrosis in one patient. Reversible grade 3–4 somnolence or stupor occurred in three patients at Arginine Butyrate doses of greater than 1000 mg/kg/day. Ten of fifteen patients showed significant anti-tumor responses, with 5 CR and 5 PR. In certain patients who demonstrated a clinical CR, subsequent pathological analysis showed elimination of all tumor cells. Conclusions: The combination of Arginine Butyrate and ganciclovir was reasonably well-tolerated and appears to have significant biological activity in vitro and in vivo against refractory EBV(+) lymphoid malignancies.

No significant financial relationships to disclose.
Defining Burkitt’s lymphoma (BL) with cytogenetics: LY10, a prospective clinicopathological study of dose-reduced (dr) CODOX-M/IVAC in patients with 100% Ki-67 staining B-cell non-Hodgkin’s lymphoma (NHL)
Authors: Walewski J. , Mead G. , Jack A. , Barrans S. , Radford J. , Clawson S. , Stenning S. , Qian W.
Published: March 2020

7557

Background: Previous studies suggest that CODOX-M/IVAC is effective therapy for BL (Ann Onc 2002 13:1264–74), however the diagnosis of BL in this and other studies was not based on modern immunochemistry and cytogenetics and is unreliable. To re-evaluate this question we prospectively studied a population of patients (pts) with aggressive B-cell lymphoma (100% Ki-67+) uniformly treated with dr CODOX-M/IVAC. Methods: Pts ≤65 years with B-cell lymphomas showing 100% Ki-67, considered fit for chemotherapy, received either dr CODOX-M x 3 or dr CODOX-M/IVAC x 4 according to a modified international prognostic index (IPI). Chemotherapy was modified by methotrexate dose reduction to 3g/m2. Pts >65 years had further dose reductions; unfit pts were studied pathologically only. Tumours were characterised using both an extended panel of antibodies and interphase FISH on paraffin sections for the presence of the C-MYC and BCL-2 rearrangements. Results: Of 126 pts reviewed centrally, 5 were ineligible; 53 were diagnosed as BL, each based on the combination of the presence of re-arrangement of C-MYC as a sole abnormality, germinal centre phenotype and p53 abnormality. The final 68 cases were highly heterogenous with respect to tumour phenotype and cytogenetics and were diagnosed as diffuse large B-cell lymphoma (DLBCL). Median age (all pts) was 44 years (range 17–83), with 23 aged >65. Compared with the DLBCL pts, BL pts were significantly younger (mean 38yrs vs 53 yrs, p < 0.001), had more marrow involvement (45% vs 24%, p = 0.02) and male predominance (83% vs 65%, p = 0.03). Of 104 pts entered into the clincal study, 32 pts (10 BL, 22 DLBCL, IPI 0,1) received dr CODOX-M x 3 and 72 (39 BL, 33 DLBCL, IPI >1) received dr CODOX-M/IVAC x 4. With median follow-up of 15 months (range 1 to 37), 1 year progression-free survival was 58%, 95% CI 48%-68% (54% BL vs 62% DLBCL) and 1 year survival 61% 95% CI 51%-71% (55% BL vs 66% DLBC). Conclusions: The study shows Ki67 is not an accurate approach to the diagnosis of BL and the use of immunocytochemistry and FISH is essential. BL and DLBCL as defined differ markedly clinically. Preliminary data suggest that dr CODOX-M/IVAC has similar activity in both histologies.

No significant financial relationships to disclose.
Phase II study of preemptive high dose chemotherapy and autologous stem cell transplantation for lymphoma based on early FDG-PET scanning
Authors: Kasamon Y. L. , Wahl R. , Ziessman H. , Garrett-Mayer E. , Jones R. J. , Ambinder R. F. , Flinn I. W. , Swinnen L. J.
Published: March 2020

7561

Background: [18F] FDG-PET after only 2–4 cycles of initial chemotherapy is highly prognostic in patients (pts) with aggressive lymphoma, with reported relapse rates of 71–100% if PET demonstrates residual viable disease. We hypothesized that midtreatment PET could optimize pt selection for preemptive transplantation through early risk stratification. Methods: A phase II, single center trial was activated in 2/2004. Pts with newly diagnosed aggressive non-Hodgkin’s lymphoma underwent PET-CT on days 11–20 of cycle 2 or 3 of (R)CHOP. Regardless of IPI, pts whose PET was considered positive for macroscopic residual lymphoma received 2 cycles of (R)ESHAP or (R)ICE, followed by autologous transplantation (busulfan-cyclophosphamide conditioning). Pts with negative interim PET completed standard therapy. We aimed to transplant ≥20 pts to detect a ≥25% absolute improvement in 2-year event-free survival (EFS) to 45%, versus 20% in a historical cohort of PET positive pts who did not receive early transplantation (85% power and two-sided alpha of 0.05). An ongoing imaging analysis of gradations of FDG uptake, scored as 0 to 4+, will be correlated with outcome. Results: As of 1/6/2006, 41 evaluable pts have been accrued, 39 with large B-cell lymphoma (8 primary mediastinal), 1 follicular large cell, 1 peripheral T-cell. Median age at diagnosis was 50 (20–78); 26 pts were stage III or IV. Twenty-five pts (61%) had a positive midtreatment PET. Of 26 pts with IPI of 0–2, 17 (65%) had positive PET; of 13 pts with IPI of ≥3, 8 (62%) were positive; 2 pts had undetermined IPI. The actuarial 1-year EFS from the time of midtreatment imaging is 78% for the group as a whole, 69% for PET positive pts, 81% for PET negative pts. Twenty pts have completed transplant, and 2 were ineligible because of early disease progression. Two transplant recipients have relapsed. Treatment-related mortality has been limited to 1 death from veno-occlusive disease. Conversion from PET positive to negative at initial post-transplant assessment occurred in 68%. The actuarial 1-year EFS after transplantation at 10 month median follow-up is 82%. Conclusions: Immediate intensification of therapy for poor-risk pts identified by midtreatment PET has been feasible and so far very promising.

[Table: see text]
Rituximab, gemcitabine and oxaliplatin (R-GEMOX): An effective regimen for relapsed and refractory B-cell lymphoma
Authors: El Gnaoui T. , Dupuis J. , Belhadj K. , Rahmouni A. , Copie-Bergman C. , Gaillard I. , Diviné M. , Tabah-Fisch I. M. , Reyes F. , Haioun C.
Published: March 2020

7562

Background: High-dose therapy with autologous stem cell support (HDT) is an established treatment for chemosensitive relapse in lymphoma. However, not all patients are candidates for HDT because of age, comorbidities or previous HDT. In addition,effective and less toxic alternatives to classical Cisplatin/ARA-C-based salvage regimens are needed. Methods: Based on the clinical activity, tolerability of rituximab (R), gemcitabine (G) and oxaliplatin (Ox) and synergy between these drugs, the R-GEMOX regimen was designed with R (375mg/m2 d 1), G (1,000 mg/m2 d 2) and Ox (100 mg/m2 d 2). Treatment was given every two weeks. Between January 2002 and June 2005, 46 patients with refractory/relapsing B-cell CD20+ lymphoma not eligible for HDT were enrolled in an unicenter pilot study whose primary objective was overall response rate (ORR) after 4 cycles (induction phase). Patients were planned to receive 8 cycles if at least PR was observed after 4 cycles. Median age was 64 years (range: 43–78) and histological subtypes were: diffuse large B-cell lymphoma (n = 33), follicular (n = 8) and mantle cell (n = 5). Prior treatments included anthracyclin in 45 patients, rituximab in 26 (56%) and HDT in 14 (30%). The median number of prior treatments was 2 (range: 1 to 5) and 13 patients (28%) had received at least 3 prior regimens. Results: 315 cycles were given. The dose administered was 100% of the intended dose for the three drugs in all patients but 8, for whom the dose of oxaliplatin was reduced due to neurotoxicity (n = 7) or preexisting renal insufficiency (n = 1). Eight patients progressed during the induction phase. After 4 cycles, responses were: 10 CR, 13 CRu and 15 PR resulting in an ORR of 83%. At the end of treatment, among the 38 responder-patients, 36 patients achieved CR (78% of the entire population), one patient remained in PR and one progressed. With a median follow-up of 27 months, the 2-year progression-free and overall survivals were 53% and 66%, respectively. NCIC grade 3–4 neutropenia and thrombocytopenia were reported in 48% and 22% of the cycles. A grade 4 infection was observed in only 3% of the cycles. There was no renal toxicity. Conclusions: The R-GEMOX regimen shows promising activity with an acceptable toxicity. It is currently evaluated in a multicentric phase II study.

[Table: see text]
Dose-modified oral chemotherapy for AIDS-related non-Hodgkin’s lymphoma (AR-NHL) in East Africa
Authors: Mwanda W. O. , Orem J. , Fu P. , Banura C. , Kakembo J. , Ness A. , Johnson J. , Black J. , Katongole-Mbidde E. , Remick S.
Published: March 2020

7564

Background: Dose-modified chemotherapy for AR-NHL in the pre-HAART era has been shown to be equally efficacious and less myelotoxic [N Engl J Med 1997;336:1641 (mBACOD); J Clin Oncol 2001;19:2171 (mCHOP)]. In resource-constrained settings, intravenous chemotherapy and supportive care of the AIDS/cancer patient are challenging (J Natl Cancer Inst 2002;94:718). Methods: We embarked on a pilot feasibility trial of dose-modified oral chemotherapy [lomustine 50 mg/m2 D1 (C1 only); VP-16 100 mg/m2 D1–3; and cyclophosphamide/procarbazine 50 mg/m2 each D22–26 at 6-week intervals (1 cycle) for 2 cycles] in HIV-infected patients with biopsy-proven AR-NHL in East Africa. Results: A total of 52 pts (23 Uganda; 29 Kenya) were registered to study. The majority of pts were female (56%) with median age 39 yrs (range 18–64); poor PS (2 or 3) - 62%; high grade lymphoma (65%); advanced stage (III or IV) - 67%; and B symptoms (79%). At study entry median CD4 count was 207/μL and HIV-1 viral load 98,857 copies/ml. Nineteen pts (37%) had access to ARV. A total of 74.5 cycles of therapy were administered to 49 pts (median 2; range 0.5–2). The regimen was well tolerated. There were 4 episodes of febrile neutropenia and 3 treatment-related deaths (6% mortality rate). Overall objective response rate is 67% (CR/uCR 49%); median survival 8.2 months (range <1.0 to 52.5+ mos.); and 22 patients remain alive as of 10/7/05. Conclusions: Dose-modified oral chemotherapy is efficacious, has comparable outcome to that in the US in pre-HAART era, an acceptable safety profile, and is pragmatic in the resource-limited setting. Further investigation of the oral regimen vs. mCHOP is warranted. [Supported in part by NIH grants: CA83528, AI36219, CA70081, and TW00011. Bristol-Myers Squibb and Sigma Tau Pharmaceuticals provided the chemotherapy drugs for this trial.] (J. Black, PhD, formerly DCTD, NCI, Bethesda, MD, USA).

No significant financial relationships to disclose.
BACOP/FR combination chemotherapy as front-line treatment of follicular lymphoma. A phase II study of the Gruppo Italiano Studio Linfomi (GISL)
Authors: Luminari S. , Lombardo M. , Mammi C. , Bellei M. , Merli F. , Stelitano C. , Lazzaro A. , Marasca R. , Brugiatelli M. , Federico M.
Published: March 2020

7571

Background: Doxorubicin, fludarabine and rituximab are all considered active drugs in the treatment of follicular lymphoma (FL). Howevere, the best induction regimen is still matter of debate. In 2003 the GISL started a phase II trial to assess efficacy and tolerability of a combination of bleomycin, adriamycin, ciclophosphamide, vincristine and prednisone (BACOP) followed by fludarabine and rituximab (FR). Methods: To be included in the study pts should have: histologically confirmed diagnosis of FL, stage II-IV disease, age 18–70, active disease. Pts were assessed for t(14:18) by PCR on bone marrow at diagnosis and at time of response assessment. Treatment consisted in three courses of BACOP followed by 4 courses of FR for pts in partial remission (PR) or complete remission with persistent t(14:18) positivity (CRM+). Pts achieving molecular complete remission (CRM-) stopped therapy after BACOP. The main endpoints of the study were overall response rate (CR+PR) (ORR) and failure free survival (FFS). A final accrual of 60 assessable pts was planned, however a faster accrual than expected allowed to enrol 91 pts between May 2003 and Dec 2005. Results: At time of present analysis 61 pts were valuable for final response: Median age was 56 yrs (25–70), male gender 56%, 18% with systemic symptoms, 88% in stage III-IV disease, 13% had elevated LDH and 21% bulky disease. Molecular marker was present in 30 out of 57 pts. 19 pts achieved a CR after three courses of BACOP; four of them, being in CRM- stopped therapy. 28 pts achieved CR with four additional courses of FR. At the end of treatment CR and ORR were 77% and 90% respectively; relatively to pts with molecular marker at diagnosis CRM- was 60%. Toxicity data are available for 57 patients: grade III/IV anemia and neutropenia were observed in two (3%) and 18 (32%) cases respectively; severe infections occurred in two cases, both bacterial pneumonia. After a median follow-up of 17 months (0.5–31) 12 events were observed: Major toxicity, four; non responders, two; relapse, six. Conclusions: BACOP/FR is a feasible and safe regimen for the treatment of patients with FL with promising efficacy. More mature follow-up is required to confirm these preliminary results.

No significant financial relationships to disclose.
A phase II study of bortezomib in relapsed Hodgkin lymphoma: Preliminary results of CALGB 50206
Authors: Blum K. A. , Johnson J. L. , Niedzwiecki D. , Cannellos G. P. , Cheson B. D. , Bartlett N. L.
Published: March 2020

7576

Background: Constitutive NF-κB activation has been described in both Hodgkin lymphoma (HL) cell lines and patient-derived Reed-Sternberg cells. In vitro, therapeutic targeting of NF-κB with proteasome inhibitors like bortezomib leads to apoptosis of HL cell lines, providing a rationale for clinical trials with this agent. Methods: From 3/15/2004 until 2/23/2005, the CALGB conducted a phase II trial of bortezomib in patients (pts) with relapsed and refractory classical HL to assess response rate and toxicity. Eligibility requirements included at least one prior systemic therapy, measurable disease, absolute neutrophil count ≥ 750/μL, platelets ≥ 75,000/μl, and creatinine ≤ 2.5 mg/dl. Pts able to undergo a stem cell transplant with curative intent or with pre-existing sensory neuropathy ≥ grade 2 were not eligible. Bortezomib was administered at 1.3 mg/m2 days 1, 4, 8, and 11 every 21 days for 2–8 cycles, or until disease progression. Results: 30 pts received a median of 2 cycles (range, 1–8). For 25 pts with available data, 80% had stage IV disease with a median of 4 prior therapies (range 2–8, 92% with prior stem cell transplant). For 29 pts with complete response data, 2 pts were not evaluable due to adverse events (bleeding gastric ulcer and grade 4 dyspnea) during cycle 1 leading to a discontinuation of therapy prior to restaging. In the remaining 27, no responses were observed [95% CI (0.0, 0.13)]; 18 pts progressed, and 9 pts had stable disease. Median follow-up is 4.4 (range, 0.6 -16.4) months. The median progression-free and overall survival times are 1.4 [95% CI (1.3, 2.8)] and 11.6 months [95% CI (6.6, ongoing)], respectively. Toxicity data are available for 26 pts. Grade 3–4 events included thrombocytopenia (27%), lymphopenia (8%), dyspnea (8%), anemia (4%), diarrhea (4%), hypotension (4%), rash (4%), and hyperbilirubinemia (4%). Both instances of grade 3–4 dyspnea occurred in pts with disease progression in the lung. 27% developed grade 2 sensory or motor neuropathy. Conclusions: Although well-tolerated, bortezomib has no single agent efficacy in relapsed classical HL at the current dose and schedule.

No significant financial relationships to disclose.
Absolute lymphocyte count prior to rituximab therapy predicts time to progression in patients with follicular grade 1 lymphoma
Authors: Behl D. , Markovic S. N. , Witzig T. E. , Colgan J. P. , Habermann T. M. , Inwards D. J. , Ansell S. M. , Micallef I. N. , Johnston P. B. , Porrata L. F.
Published: March 2020

7586

Background: The immunologic mechanisms of action of rituximab have been described as complement mediated lysis, vaccine like effect, antibody-dependent cellular cytotoxicity (ADCC) and the cellular microenvironment. We hypothesized that in the treatment of follicular grade 1 lymphoma (FL), the presence of a stronger host immune status prior to rituximab therapy would result in a prolonged time to progression (TTP). As a surrogate marker for immune status, we evaluated the absolute lymphocyte count (ALC) prior to rituximab treatment. Methods: Between 1996 and 2002, 1,104 consecutive FL patients were evaluated at Mayo Clinic Rochester. Of these patients, we retrospectively analyzed a group of all FL patients who received rituximab (375 mg/m2 once a week for four weeks) alone at any time during their lymphoma treatment at the Mayo Clinic (n=79). The primary end-point was to assess the impact of ALC just prior to rituximab therapy on TTP for FL. Results: The median age of the cohort was 56.6 years (range: 25–98 years). The median follow-up was 12.5 months (range: 1–76 months). An ALC count of ≥ 890 cells/μL prior to rituximab therapy predicted a longer TTP compared with an ALC < 890 cells/μl (25 months versus 8 months, respectively, p < 0.0124). A higher complete response rate was observed in the ALC ≥ 890 cells/μL group compared with the ALC < 890 cells/μL group [15/40 (38%) vs 5/39 (13%), p < 0.035]. The groups were balanced regarding the Follicular Lymphoma International Prognostic Index (FLIPI) (p = 0.794). Multivariate analysis demonstrated ALC ≥ 890 cells/μL prior to rituximab therapy as an independent prognostic factor for TTP when compared to hemoglobin, LDH, and Ann Arbor stage. The ALC was independent of the FLIPI in multivariate analysis. Conclusions: This data supports the hypothesis that a higher lymphocyte count, as a marker of the immune status of the patient, predicts for a longer TTP following rituximab therapy.

No significant financial relationships to disclose.
Patterns of mortality after prolonged follow-up of a randomized trial using granulocyte colony-stimulating factor (G-CSF) to maintain chemotherapy dose intensity in non-Hodgkin lymphoma (NHL)
Authors: Clamp A. R. , Bhattacharya S. , Ryder D. W. , Pettengell R. , Radford J. A.
Published: March 2020

7590

Background: Recombinant G-CSF is commonly used to maintain chemotherapy dose intensity and reduce the incidence of infective complications in the management of NHL. The possible impact of this effect on mortality patterns after prolonged follow-up is worthy of investigation. We investigated the long-term survival and incidence of second malignancies in the first randomized trial utilising recombinant G-CSF in NHL (Pettengell R et al Blood 1992, 80: 1430–1436). Methods: Data on overall survival (OS), progression-free survival (PFS), freedom from progression (FFP) and the incidence of second malignancies were extracted from medical records and cancer registry databases for 80 patients with aggressive subtypes of NHL, who had previously been randomised to receive either VAPEC-B chemotherapy alone (39 patients) or VAPEC-B with G-CSF (41 patients). 10 year survival figures were extracted and Kaplan-Meier survival curves were drawn for the above parameters and compared between treatment groups using the log-rank test. Results: Median follow-up was 11.8 years for surviving patients (range 7.8–13.1 yrs). Patients receiving G-CSF achieved a 12% higher median dose intensity of chemotherapy. No significant differences were found in PFS or OS but 10 year FFP appeared to be better in the G-CSF arm (60.8%) compared with the control arm (45.6%) (log-rank test p=0.12). Eleven deaths from non-NHL causes occurred in the G-CSF arm compared with three in the control arm (log- rank test p=0.06). Five second malignancies were detected on long-term follow-up in the G-CSF arm compared with two in the control arm. Conclusions: The demonstration of different mortality patterns in the two arms may be related to the greater dose intensity of chemotherapy received in the G-CSF arm. Although, our study has insufficient statistical power to draw definite conclusions, this finding warrants further investigation.

No significant financial relationships to disclose.
Manifestation and prognostic value of EBV serology in nasal/nasopharyngeal T and NK-cell lymphomas
Authors: Zhang Y. , Huang Y. , Xiao J. , Xia Y. , Lu T. , Lin T.
Published: March 2020

7596

Background: Extranodal nasal type T and NK-cell lymphoma is highly associated with the Epstein-Barr virus (EBV) infection which is usually found in tumor cells, but the serum manifestation of EBV and its prognostic value remains unclear. Methods: 151 patients with nasal/nasopharyngeal T and NK-cell lymphomas were reviewed, the diagnoses of which were confirmed by histology and immunohistochemistry from Jan, 1992 to Nov, 2004. In 40 patients, which included 30 males and 10 females and aged 24 to 73(median 46) years old, analyses were performed of serum titers of antibodies against virus-capsid antigen (VCA-IgA) and early antigen (EA-IgA) with immunoenzyme assay, and antibody against EBV DNAase (EDAb), with immunoradiological method. Positive criteria were identified as VCA-IgA ≥ 1: 10, EA-IgA≥ 1: 10, and EDAb ≥ 30%. Clinically, 87.5% of the 40 patients were staged as Ann Arbor I and II diseases. Most patients underwent combined chemo and radiotherapy. Results: Median follow-up time for survived patients was 17(6–136) months. Median survival time for the overall patients were 12 months. Highest serum VCA-IgA, EA-IgA, and EDAb levels were 1: 1280, 1: 40, and 86% respectively. Positive rates of the three parameters were 60%, 15%, and 50% respectively. 30 patients(75%) had at least one positive parameter. Positve EA-IgA was negatively correlated with survival (p=0.0245) in Kaplan-Meier analysis, neither positive VCA-IgA or elevated EDAb level showed significant correlation with survival (p=0.134 and 0.405 ). Conclusions: Most patients with nasal/nasopharyngeal T and NK-cell lymphomas showed serum evidences of EBV infection, higher EA-IgA level can be a poor prognostic factor for survival. The importance of EBV serology in patients with nasal/nasopharyngeal T and NK-cell Lymphoma deserves further investigation.

No significant financial relationships to disclose.
A phase II study of HCVIDDOXIL alternated with methotrexate-cytarabine in patients with newly diagnosed T-cell lymphoma
Authors: Pro B. , Fayad L. , Romaguera J. , Hagemeister F. H. , Samaniego F. , McLaughlin P. , Rodriguez A. M. , Kwak L. , Walker P. , Dang N. H.
Published: March 2020

7597

Background: T cell lymphomas (TCL) generally are more aggressive and have a poorer prognosis than the corresponding B cell lymphomas. A chemotherapeutic regimen that is effective in aggressive lymphoid malignancies is HCVAD alternating with methotrexate (MTX) and cytarabine (Ara-C). Pegylated liposomal doxorubicin (DOXIL) is associated with greater tumor penetration and less toxicity. We initiated a phase II study to evaluate the efficacy of the regimen HCVIDDOXIL, using DOXIL as a substitute for doxorubicin in the HCVAD regimen, alternated with MTX-Ara-C . Methods: Previously untreated patients (pts) with Zubrod performance status ≤3, age > 18 years, and adequate organ function were eligible. Pts with skin involvement alone, CD30+, ALK +, T-anaplastic large cell lymphoma (ALCL), HIV-1 positive serology, and evidence of CNS involvement were excluded. Pts received HCVIDDOXIL ( cyclophosphamide 300 mg/m2 iv Q 12 h × 6 doses d 1–3, mesna 600 mg/m2 iv daily over 24 hours by continuous infusion d 1–3, DOXIL 25 mg/m2/day iv on d 2, vincristine 1.4 mg/m2 (max. 2 mg) iv days 4 and 11, dexamethasone 40 mg iv or po daily × 4 d 1–4 and 11–14) alternated with MTX/Ara-C ( MTX 200 mg/m2 iv over 2 hours on d 1, then 800 mg/m2 iv over 22 hours on d1, Ara-C 3 g/m2 iv Q 12 hours × 4 doses on d 3–4) every 3 weeks for a maximum of 8 cycles. Endpoints were progression-free survival and response rate. Results: Between October 2003 and November 2005, 23 pts were enrolled. Median age 53 years (range, 23–68). Twelve pts had stage IV, 6 stage III, 3 stage I, and 2 stage II disease. Fourteen (60%) pts had extranodal disease, and 8 (36%) pts had an elevated LDH. In 21 evaluable pts, the ORR was 90% [CR n=12 (57%); PR n= 7 pts (33%)]. Common Grade 3–4 adverse events were thrombocytopenia in 17 pts (77%), neutropenia in 6 (27%), anemia in 5 (23%), and febrile neutropenia in 7 (32%). With a median follow-up of 13 months, the median progression-free survival is 8.3 months (95% CI: 6.5 to 14.2 months). Conclusions: In this high-risk population the regimen HCVIDDOXIL alternated with MTX-Ara-C induced a high response rate. As expected, the most common toxicity was myelosuppression. The efficacy of this regimen should be confirmed in a larger cohort of patients. Enrollment in this study continues.

No significant financial relationships to disclose.
The benefit of whole-body low-dose unenhanced multidetector computer tomography (WBLD-MDCT) for follow up and therapy response monitoring in patients with multiple myeloma: Correlation with hematologic parameters
Authors: Horger M. S. , Driessen C. , Brodoefel C. , Faul C. , Pereira P. , Vogel W. , Claussen C. D. , Kanz L.
Published: March 2020

7607

Background: To assessthe value of whole-body low-dose multidetector computer tomography (WBLD-MDCT) as diagnostic and survey modality in multiple myeloma (MM), and as a one-stop alternative (Horger et al. EJR 2005;54:289–297) to established imaging techniques (e.g. x-ray and MRI). Methods: Between 7/2001 and 2/2005, WBLD-MDCT scans were obtained in 90 consecutive patients with histologically proven stage II-III MM, all patients having 2 or more scans (mean = 3,8; range = 2–6). CT-scans were performed using a standardized low-dose protocol and the number, size and density of focal or diffuse medullary (in the appendicular skeleton and pelvis) and extra-medullary lesions as well as osteolysis were analysed for each examination and at follow up. Results were correlated with current standard MM laboratory data and at follow up in order to assess correct temporal recognition of significant myeloma changes by both methods. Results: Detection and follow up of medullary and extra-medullary MM lesions and osteolysis by WBLD-MDCT resulted in a sensitivity of 92%, a specificity of 93%, a NPV of 95%, a PPV of 85% and a likelihood ratio for patients with CT-abnormalities to present changes in the course of their disease of 12. Results of radiologic and hematologic analysis showed high agreement at follow up (median, 3 mo). However, agreement of both techniques at the time of investigation was only moderate (κ = 0.629), with CT being correct in 60% of mismatching cases. Thus, CT enabled earlier detection of MM changes. WBLD-MDCT assessed correctly the course of disease in all 4 patients with nonsecretory MM. Evaluation of stability was optimal in all patients. Conclusions: WBLD-MD represents a reliable, widespread, quick (75s acquisition time), and cost-effective imaging technique in MM, allowing detection of bone marrow involvement, extra-medullary tumors and lytic bone lesions in different clinical settings (staging, follow up, therapy monitoring, evaluation of stability). WBLD-MDCT repeatedly allowed detection of changes in the course of the disease prior to laboratory data, especially in extramedullary MM relapse and nonsecretory MM.

No significant financial relationships to disclose.
A phase I/II study of arsenic trioxide, bortezomib, and ascorbic acid in relapsed or refractory multiple myeloma
Authors: Berenson J. R. , Matous J. V. , Ferretti D. , Swift R. A. , Mapes R. A. , Morrison B. , Yeh H. S.
Published: March 2020

7611

Background: The combination of arsenic trioxide (ATO) and bortezomib (B) has shown synergistic anti-tumor activity against human multiple myeloma (MM) cells in preclinical studies, suggesting that this combination may effectively treat patients with MM. In addition, ascorbic acid (AA) can sensitize MM cells to the cytotoxic effects of ATO. Methods: Patients with relapsed or refractory MM were enrolled in this phase I/II dose-escalation trial in 6 cohorts. Patients were given ATO (0.125 or 0.250 mg/kg), B (0.7, 1.0, or 1.3 mg/m2), and a fixed dose of AA (1000 mg) IV on days 1, 4, 8, and 11 of a 21-day cycle for a maximum of 8 cycles. The planned sample size was a maximum of 27 evaluable patients. The primary endpoint was safety and tolerability of the ATO/B/AA regimen in patients with relapsed or refractory MM. Results: At the time of this interim analysis, 22 patients (median age, 63 years) have been enrolled, and accrual has been completed on all cohorts. This group had failed a median of 4 (range, 3–9) prior therapies. One occurrence of grade 4 thrombocytopenia was observed. One occurrence of asymptomatic arrhythmia led to patient withdrawal. All other adverse events were grade 1 or 2. For the 21 patients evaluable for efficacy, objective responses were observed in 10 patients (43%), including 2 complete (CR), 2 partial (PR), and 5 minor (MR) responses. Only 1 (1 MR) of 6 patients receiving the lowest dose of B (0.7 mg/m2) showed a response, whereas 8 (2 CR, 2 PR, and 4 MR) of 15 patients receiving the higher doses (1.0 or 1.3 mg/m2) responded. Conclusions: The ATO/B/AA regimen was well tolerated by the majority of patients, and produced objective responses in 43% of the patients in this heavily pretreated group. The results of this phase I/II study warrant further clinical evaluation of the ATO/B/AA combination regimen for the treatment of patients with relapsed or refractory MM.

[Table: see text]
Generation of T-cells reactive against CT-7 and BCMA peptides: Potential targets for T-cell immunotherapy of multiple myeloma
Authors: Anderson L. D. , Maloney D. G. , Riddell S. R.
Published: March 2020

7615

Background: Multiple myeloma is a malignant plasma cell disorder that is incurable with chemotherapy or autologous stem cell transplantation (SCT), and novel therapies with lower toxicity are needed. There is evidence that T-cells can recognize myeloma and mediate anti-tumor effects, but the lack of defined target antigens other than idiotype has hindered the development of myeloma-specific T-cell therapy. We are investigating cancer-testis antigens and overexpressed “self”-proteins as candidate myeloma antigens, including MAGE-C1 (CT-7), which is expressed by >80% of myelomas, and B-Cell Maturation Antigen (BCMA), a plasma cell differentiation antigen commonly over-expressed in myeloma. Methods: To identify potential T-cell epitopes from CT-7 and BCMA, we scanned the protein sequences with computer algorithms and synthesized peptides predicted to bind to HLA-A2 and A3. CT-7 and BCMA are both “self” proteins to which the T-cell repertoire may be relatively tolerant, so we have utilized culture conditions that facilitate the expansion of rare myeloma-reactive T-cells. CD8+ T cells were stimulated in vitro with autologous dendritic cells pulsed with CT-7 or BCMA peptides in the presence of cytokines that avoid excessive nonspecific expansion of T-cells. Wells were screened for reactivity against peptide-pulsed target cells and myeloma cell lines. Results: A specific CD8+ T-cell response by both ELISPOT and cytotoxicity assays to at least one HLA-A2 peptide from each of the CT-7 and BCMA proteins has been identified in normal donors. CT-7 and BCMA-specific T-cells are being cloned in order to determine their ability to recognize primary myeloma cells. Experiments are also in progress to elicit responses to these peptides in myeloma patient samples and to screen HLA A3-binding epitopes. Conclusions: T-cells recognizing CT-7 and BCMA are detectable in the normal T-cell repertoire and can be isolated and expanded in vitro. We are currently pursuing the identification of additional antigenic epitopes in these proteins to define their potential utility as targets for vaccination or adoptive T-cell therapy.

No significant financial relationships to disclose.
A pediatric phase I trial and pharmacokinetic (PK) study of erlotinib (ERL) followed by the combination of ERL with temozolomide (TMZ): A Children’s Oncology Group Study
Authors: Jakacki R. I. , Tersak J. , Blaney S. , Krailo M. , Hamilton M. , Dancy J. , Gilbertson R. , Ingle A. , Adamson P. C.
Published: March 2020

9015

Background: EGFR is potently inhibited by ERL. Aberrant cell signaling via the EGFR family has been implicated in the development of several human cancers, including certain pediatric solid tumors. Methods: A phase I dose escalation study in children with refractory solid tumors was conducted to define the maximal tolerated dose (MTD) and dose limiting toxicities (DLTs) of single agent ERL, determine the tolerability of the combination of ERL and TMZ, and to determine the PK of ERL. Pts received single agent ERL qd × 28 d followed by ERL qd continuously in combination with TMZ 180 mg/m2/day × 5d. Cycles were repeated q 28 d. ERL was initially administered using the IV formulation given orally. The tablet form was subsequently studied at the MTD to further evaluate PK. Results: 46 pts (36 fully evaluable for toxicity) median age 11.5 yrs (range 3–20 yrs), were enrolled in cohorts of 3–6 pts at ERL doses of 35, 50, 65, 85 and 110 mg/m2/d. At the 110 mg/m2/day dose level, 2/4 pts had DLT (1 rash, 1 hyperbilirubinemia). In the expanded cohort at the MTD of 85 mg/m2/d, (n=21), 3 pts had DLT (2 rash, 1 diarrhea). Non-DLTs observed during the single agent cycle included diarrhea (n=14), rash (n=9), hyperbilirubinemia (n=7), neutropenia and/or thrombocytopenia (n=5). 1 pt with a soft tissue sarcoma had a minor response after 28d of single agent ERL, continuing to a PR by cycle 4. 3 pts (2 neuroblastoma, 1 neurocytoma) had prolonged responses (13–20+ months) to the combination. Oral administration of the IV formulation resulted in a higher Cmax and a lower Cmin compared to the adult data using tablets. Median apparent clearance was 2.85 (range 1.61–6.37) L/hr/m2 with a terminal half of 8.45 (5.1–27.1) hr. No PK interaction was observed between ERL and TMZ and the combination was well tolerated. Conclusions: The pediatric recommended phase 2 dose of ERL of 85 mg/m2/day, either alone or in combination with TMZ, is well tolerated in children. A COG phase 2 trial is planned.

[Table: see text]