bluuebunny/crossref_metadata_2025 huggingface dataset:
Bi-weekly dosing preserves the efficacy of rituximab in elderly patients with poor-prognosis DLBCL: Results from the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study group (DSHNHL)
Authors: Schubert J. , Reiser M. , Wenger M. , Kloess M. , Lengfelder E. , Franke A. , Steinhauer H. B. , Clemens M. , Schmitz N. , Loeffler M. , Pfreundschuh M.
Published: March 2020

7536

Background: The addition of rituximab (R) to 3-weekly CHOP-21 improved overall results in elderly patients with DLBCL, but was more effective in good-prognosis (g-p: IPI = 1,2) than poor-prognosis (p-p: IPI = 3,4,5) patients (JCO 23:4117, 2005). Similarly, addition of R to bi-weekly CHOP-14 in the RICOVER-60 trial resulted in improved time to treatment failure (TTF) in 828 elderly (61–80 years) DLBCL patients (Blood 106:9a, 2005). To study the effects of R when combined with CHOP-14 in different subgroups of elderly DLBCL patients. Methods: Intention-to-treat-analysis of the primary endpoint time-to-treatment-failure (TTF) and the secondary endpoint overall survival (OS) in the subgroup of g-p and p-p patients treated within the RICOVER trial which compared 6 and 8 cycles of CHOP-14, both with and without R. Results: Of 828 evaluable patients (61–80 years, stage I-IV), 503 had g-p (CHOP-14 = 252; R-CHOP-14 = 251) and 325 p-p (CHOP-14 = 161; R-CHOP-14 = 163). After a median observation of 26 months, there was no difference between 6 and 8 cycles in either subgroup. In contrast, addition of R resulted in a similar improvement of TTF in both g-p (67% vs. 81%, p = 0.001) and p-p (36% vs. 52%, p = 0.004) patients. The improvement of survival is not yet different in either group: g-p: 82% (CHOP-14) vs. 88% (R-CHOP-14), p = 0.458; p-p: 58% (CHOP-14) vs. 64% (R-CHOP-14), p = 0.146. Pharmacokinetic studies show a pronounced nadir of R levels after the first R-CHOP-14, with R levels increasing after each subsequent cycle. The R nadir after the first R-CHOP is expected to be even more pronounced in a 3-weekly schedule and might explain the small improvement reproted for 3-weekly R in elderly patients with p-p DLBCL. Conclusions: Our subgroup and pharmacokinetic analysis indicate that not only dose-dense chemotherapy, but also dose-dense rituximab contribute to the excellent results of the RICOVER-60 trial. Supported by Deutsche Krebshilfe.

[Table: see text]
Weekly bortezomib in the treatment of patients (pts) with previously treated multiple myeloma: A phase II trial of the Minnie Pearl Cancer Research Network
Authors: Greco F. A. , Spigel D. R. , Barton J. H. , Farley C. , Schreeder M. T. , Hermann R. C. , Hainsworth J. D.
Published: March 2020

7547

Background: Bortezomib, administered on a twice-weekly schedule, is now a standard part of treatment for patients with multiple myeloma. Weekly bortezomib schedules have shown activity in other cancer types, and are more convenient than twice weekly schedules. In this multicenter, community-based phase II trial, we evaluate the feasibility, toxicity, and efficacy of weekly bortezomib in pts with previously treated multiple myeloma. Methods: Eligibility criteria included a diagnosis of multiple myeloma treated with 1 or 2 previous systemic regimens (only 1 if first-line therapy included high-dose therapy); ECOG PS 0–2; creatinine < 2.0 mg/dL; WBC ≥ 3000/μL; ANC > 1000/μL; platelets ≥ 50,000/μL; no peripheral neuropathy > grade 1; informed consent. All pts received bortezomib 1.6mg/m2 IV on days 1, 8, 15, and 22 of each 5-week cycle. Pts were reevaluated at 10-week intervals; treatment continued for 8 cycles (40 weeks) or until myeloma progression. Results: Between 5/04 and 12/05, 37 pts entered this trial. Pt characteristics: median age 70 years; male/female, 20/17; 24 pts (65%) had received 2 previous regimens (previous high dose therapy, 2 pts); elevated β-2 microglobulin, 27 pts (73%). Of 26 pts evaluated, 13 pts (50%) had major responses, 11 pts (42%) stable disease, and 2 pts (8%) had progression. After a median follow-up of 7 months, projected median PFS is 9.6 months; overall survival at 1 year is 81%. Weekly bortezomib was well tolerated by most pts. Grade 3/4 toxicities included fatigue (21%), diarrhea (11%), neutropenia (7%), thrombocytopenia (4%), all others < 5%. No grade 3/4 neuropathy occurred. Only 1 pt required bortezomib dose reduction during treatment, and 2 pts discontinued treatment because of toxicity (myelosuppression, 1; fatigue/dehydration, 1). Conclusions: Weekly bortezomib is a convenient, well tolerated treatment for pts with previously treated multiple myeloma. Overall response rates with this schedule are similar to those previously reported with the standard twice-weekly schedule. Further followup is necessary to better evaluate the duration of response and the incidence of cumulative toxicities.

[Table: see text]
JC human polyomavirus (JCV) and Epstein-Barr virus (EBV) replicative activities are detected in Hodgkin/Reed Sternberg cells (HRS) and circulating lymphocytes (PBL) of Hodgkin lymphoma (HL) and associated with relapse, especially in younger patients
Authors: Carde P. , Andreoletti L. , Koscielny S. , Assaf E. , Girinsky T. , Bosq J. , Bernheim A. , Flamant S. , Violot D. , Parmentier C. , M’Kacher R.
Published: March 2020

7551

Background: The HRS derive from germinal-center B-cells, potential sites for latency and reactivation of JCV in immunosuppressed individuals. Replication of human polyomaviruses (JC, BK, SV40) and EBV was assessed in Hodgkin (HL) and B cell non-Hodgkin (B-NHL) lymphomas. Methods: FISH, immunohistochemistry for oncogenic proteins, PCR and DNA sequencing to identify polyomaviruses and EBV on involved nodes and in PBL before, during and after treatment (N = 73 HL, 91 B-NHL). Controls were 30 healthy donors, 70 solid tumors and 14 acute leukemia patients. Results: using FISH, JCV and EBV DNA were detected in all lymphoma nodes. High genome copy number of JCV and EBV were present in 60% and 63%, respectively, in HL patients versus 11% and 14% in B-NHL patients (P < 10−6; P < 10−5). Using nest-PCR, JCV DNA sequencing after laser capture microdissection identified the presence and specificity of JCV sequences in HRS. T antigen and LMP1 co-expression, in 34% of HRS, was associated with early HL relapse (P < 10−4), particularly in young patients (P < 10−5). Only in HL patients PBL, genome copy number of JCV increased significantly during treatment (42%). Rogue cells (cultured lymphocytes with multiple complex chromosomal aberrations indicative of genomic instability) appeared in 40% of patients, and correlated with relapse (p < 10−4). The same JCV sequences were found in tumor cells and PBL of HL patients. Co-genomic replication of EBV and JCV was highly correlated in lymph nodes and in PBL in HL. Conclusions: JCV genomic replication was detected for the first time in HRS, and associated to rogue cell emergence in PBL. Co-detections of JCV and EBV genomic replication in HRS and PBL are associated with relapse, especially in young patients. HRS and PBL JCV/EBV infections are linked and worth further studies.

No significant financial relationships to disclose.
High dose chemotherapy followed by autologous stem cell transplantation for relapsed or refractory Hodgkin’s lymphoma
Authors: Holland D. W. , Engelhardt B. G. , Goodman S. A. , Greer J. P. , Morgan D. S. , Schuening F. G. , Wolff S. , Bitting R. , Sulur P. , Stein R. S.
Published: March 2020

7552

Background: High dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) can produce long-term durable remissions in patients (PTS) with relapsed or refractory Hodgkin’s lymphoma (HL). We investigated whether previously reported prognostic factors could predict overall survival (OS) and progression free survival (PFS) in a modern cohort of PTS, and attempted to identify any subgroup with a particularly inferior survival. Methods: A retrospective chart review was performed on all PTS with relapsed or refractory HL who received HDT and ASCT at a single institution. Results: From 1990 to 2001, 115 PTS received HDT followed by ASCT for relapsed or refractory HL. 76/109 PTS (70%) had achieved a complete response to initial therapy. Median time from initial therapy to relapse (TTR) was 18 months (range, 0–220 months). 105 PTS (91%) received HDT with cyclophosphamide, BCNU, and VP-16. The source of stem cells was bone marrow in 68 PTS (59%) and peripheral blood in 47 PTS (41%). Five year PFS and OS were 46% and 58%, respectively, with a median follow-up of 58 months (range, 1–175 months). The five year PFS and OS of the 13 PTS (11%) with primary refractory disease was 39% and 54%, respectively, not significantly different. 59 PTS (51%) died after HDT and ASCT. The most common cause of death was relapsed HL. Regimen related mortality accounted for 8 deaths (7%). Male gender and TTR <12 months were associated with decreased OS by univariate analysis (P = 0.04 and P = 0.03, respectively). Similar, but non-significant trends were noted in PFS. In multivariate analysis, only TTR <12 months was associated with a statistically significant decrease in OS (P = 0.04). Five year OS for patients with TTR <12 and ≥12 months was 44% and 63%, respectively. Second malignancies occurred in 9 PTS (8%). The most common diagnosis was myelodysplastic syndrome/acute myelogenous leukemia [n = 6 (67%)]. Conclusions: We have confirmed that HDT and ASCT produces long-term PFS and OS in a proportion of PTS with relapsed or refractory HL. TTR <12 months was associated with a statistically significant decrease in OS by multivariate analysis; however, no group of PTS, including those with primary refractory disease, could be identified who did not benefit from HDT and ASCT.

No significant financial relationships to disclose.
Impact of rituximab on outcome of autologous transplantation for mantle cell lymphoma
Authors: Naing A. , Palmer J. , Tsai N. , Kogut N. , Popplewell L. , Rodriguez R. , Krishnan A. , Nakamura R. , Forman S. J. , Nademanee A.
Published: March 2020

7555

Background: Currently, Mantle Cell Lymphoma (MCL) is an incurable disease. Patients treated with chemotherapy alone experience only transient responses, with no long-term improvement in disease-free/overall survival. While autologous hematopoietic stem cell transplantation (ASCT) in MCL patients has demonstrated prolonged survival, relapse remains the major issue. We evaluate the impact of rituximab (Rituxan, Rtx) on relapse and survival following ASCT. Method: A case-series of 83 MCL patients treated with ASCT at City of Hope (from 02/1991 to 04/2005) were examined; a total of 52 patients received Rtx (with-Rtx) as part of their induction/salvage treatment (pre-ASCT) and/or maintenance therapy (post-ASCT), 31 patients did not receive Rtx (no-Rtx) at any point pre-/post-ASCT. An assessment of baseline patient and disease characteristics (gender, age, KPS, % of pts with bone marrow involvement at diagnosis, disease stage/status at ASCT, % of pts with bulky disease B-symptoms at ASCT, and # of regimens administered prior to ASCT) showed no significant differences among the two groups. Result: To date, 23 patients have relapsed/progressed post-ASCT; 61% of the patients in the no-Rtx group remain disease free at last contact, while 79% in the with-Rtx group remain disease free. The median survival in the no-Rtx group is 77.63 months; the median survival time point for the with-Rtx group has not been reached due to shorter follow-up period. The 2-yr relapse rate for the with-Rtx/no-Rtx groups among 1st CR/PR patients were 19% (95% CI: 10–33%) and 26% (95% CI: 14–43%) (p > 0.05) respectively and the 2-yr relapse rate for the with-Rtx/no-Rtx groups among the beyond 1st CR pts were 33% and 40% respectively (p > 0.05). The survival endpoint showed similar results. The 2-yr survival probability for the with-Rtx/no-Rtx groups among the 1st CR/PR patients were 91% (95% CI: 76–97%) and 82% (95% CI: 64–91%) (p > 0.05) respectively and the 2-yr survival probability for the with-Rtx/no-Rtx groups among the patients beyond 1st CR/PR were 59% and 63% respectively (p > 0.05). Conclusion: Using Rtx as induction/salvage and/or maintenance before and after ASCT therapy may not be associated with decreased relapse and improved survival. Nevertheless, our data indicate that outcome is better when ASCT is carried out at 1st CR/PR.

No significant financial relationships to disclose.
Sildenafil citrate suppresses disease progression in patients with Waldenstrom’s macroglobulinemia
Authors: Patterson C. J. , Soumerai J. , Hunter Z. , Leleu X. , Ghobrial I. , Treon S. P.
Published: March 2020

7556

Background: Responses to sildenafil citrate (Viagra), a phosphodiesterase-5 inhibitor used to treat erectile dysfunction, have been observed in patients with Waldenstrom’s Macroglobulinemia (WM). Moreover, sildenafil citrate induces apoptosis of WM lymphoplasmacytic cells (Clin Lymphoma 5:205, 2004). We therefore conducted a prospective phase II study of sildenafil citrate in patients with slowly progressing WM who did not meet consensus eligibility for active therapy (Semin Oncol 2003; 30:116). Intended therapy was as follows: Week 1 25 mg po qD Week 2 50 mg po qD Week 3 75 mg po qD Week 4, then Months 2–24 100mg po qD or Maximum Tolerated Dose Methods: Thirty patients were enrolled, 18 of whom were previously untreated. All patients demonstrated progressing disease prior to enrollment. Median age was 66 (range 43–85 yrs), baseline BM involvement was 30% (range 5–90%), serum IgM was 3,640 (range 790–6,720 mg/dL), hematocrit was 37.1% (range 32.7–58.5%), and B2M was 2.3 (range 1.5–8.9 mg/dL). Patients were evaluable for response after 3 months of therapy. Results: At a median of 3 months, serum IgM levels declined in 19/30 (63%) patients from a median of 3,640 (range 790–6,720 mg/dL) to 2,965 (range 1,170–6,110 mg/dL). 5/30 patients (17%) demonstrated at least a minor response (≥25% IgM decrease). Two patients were taken off study for non-response to therapy. Toxicities were mild and included headaches, sinus congestion, facial flushing, dyspepsia, and generally resolved on their own with prolonged sildenafil citrate usage. Only two patients required dose modification to 25 mg and 75 mg po qD, respectively. Corollary studies to determine putative mechanisms of action for sildenafil citrate in WM were also performed and will be updated at the meeting. Conclusions: This prospective clinical trial provides preliminary evidence for activity of sildenafil citrate in patients with advancing WM. With minimal toxicity, sildenafil citrate appears to have suppressed disease progression in more than half of patients and has resulted in objective responses, thus warranting further investigation in WM and possibly other B-cell disorders.

No significant financial relationships to disclose.
Long-term results of high-dose chemotherapy (HDCT) supported by hematopoietic circulating (ASCT) or bone marrow (BMT) stem cell autografting as first salvage treatment for refractory or relapsed Hodgkin’s lymphoma
Authors: Viviani S. , Bonfante V. , Di Nicola M. , Cortelazzo S. , Carlostella C. , Valagussa P. , Bonadonna G. , Barbui T. , Gianni A. M.
Published: March 2020

7567

Background: The aim of this retrospective study was to evaluate with a long follow-up the efficacy of HDCT + ASCT or ABMT for refractory or relapsed HL. Methods: Data were collected from 99 pts who failed or relapsed after first-line CT± radiotherapy and were treated with HDCT+ASCT or ABMT between Oct 1984 and Dec 2003. Thirty-two pts had late relapse (CR≥12 months), 31 had early relapse (CR<12 months), while 36 had primary refractory (IF) HL.The main pts characteristics at relapse/progression were as follows: M/F: 50/49; median age 28 years; stage III-IV:54%; B symptoms: 33%; bulky disease 22%; extranodal ± nodal disease 54%; IPI≥3 39%. HDCT program consisted in a debulking phase with sequential high-dose chemotherapy (Cyclophosphamide 7gr/mq followed by ASC or BM harvest, Methotrexate 8 gr/mq+ Vincristine 1.4 mg/mq, VP16 2 gr/mq) in 71 cases; 3–4 courses of Ifosfamide (3gr/mq × 4 days)+ Vinorelbine (25mg/mq day 1+5) in 28 cases. Final myeloablative course was BEAM (63%), or high-dose Melphalan combined with high-dose Mitoxantrone (11%) or with high-dose Carmustine (9%) or TBI (17%) followed by ABMT or ASCT. Results: Ninety-two pts (93%) completed the HDCT program, while seven pts (7%) progressed during debulking CT. Early and late toxicity were mild. After a median follow-up of 66 months both 10-year freedom from second progression (FF2P) and overall survival (OS) were 61% for all pts. FF2P and OS were respectively 70% and 66% for pts with late relapse; 64% and 60% for pts with early relapse; 52% and 56% for primary refractory pts. Multivariate analysis showed that prognostic factors for FF2P were stage III-IV vs I-II (HR 2.09; p=0.04), response to first-line CT: CR≥12 vs CR<12 vs IF (HR 2.19; p=0.058) and bulky vs non bulky (HR 1.96; p=0.07). Prognostic factors for OS were response to first-line CT (HR 2.59; p=0.05), stage III-IV vs I-II (HR 1.37; p=0.39) and bulky vs non bulky (HR 2.06; p=0.06).Conclusion: These long-term results confirm that HDCT + ASCT or ABMT was feasible, safe and very effective for the treatment of relapsed/refractory HL.Our data support the use of this strategy for the salvage therapy even in the unfavourable group of primary refractory pts.

No significant financial relationships to disclose.
Association between Chlamydia psittaci infection and extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT)-lymphomas
Authors: Aigelsreiter A. , Stelzl E. , Deutsch A. , Beham-Schmid C. , Beham A. , Lanzer G. , Linkesch W. , Kessler H. , Neumeister P.
Published: March 2020

7568

Background: MALT-lymphomas are often associated with infectious organisms. Microbial species associated with MALT lymphomas are: Helicobacter pylori (H.pylori), Campylobacter jejuni, Borrelia burgdorferi, and Hepatitis C Virus. Recent studies showed evidence of Chlamydia psittaci (C. psittaci) infection in 80% of ocular adnexal lymphoma and tumor regression following eradication therapy. We studied the presence of C. trachomatis, C. pneumoniae, and C. psittaci DNAs in MALT lymphomas of various sites and in non-malignant controls. Methods: MALT lymphomas from the following sites were selected for analysis: salivary gland (n=13), thyroid gland (n=4), skin (n=2), ocular adnexa (n=2), stomach (n=6), intestinum (n=4). Samples of Sjoegren syndrome (n=10) and samples of H. pylori positive gastritis (n=7) were included as non-malignant controls. Macrodissected tissue containing >80% lymphoma cells from paraffin embedded tissue was processed for DNA isolation. For the presence of C. psittaci and C. pneumoniae DNA real time PCR assays were used. For C. trachomatis a commercially available PCR assay (Roche Molecular Diagnostics) was employed. All samples were tested twice. A sample was regarded as positive if at least one positive result was obtained. Results: C. psittaci was found at variable frequencies in MALT lymphomas of different sites: 4/13 (31%) salivary gland, 2/4 (50%) thyroid gland, 2/2 (100%) skin, 2/2 (100%) ocular adnexa, 1/6 (17%) gastric, and 0/4 intestinal MALT lymphomas. Among the non-malignant specimens, C. psittaci DNA was detected in 4/10 (40%) samples of Sjoegren syndrome and in 0/7 samples of H. pylori positive gastritis. All nongastric MALT lymphomas tested were negative for C. trachomatis and C. pneumoniae. Conclusion: Our data reveal a clear association of C. psittaci infection with extragastric MALT lymphoma. However, no evidence could be established for C. trachomatis and C. pneumoniae infection. Moreover, the high prevalence of Sjoegren syndromes - the most frequent precursor lesion for MALT lymphomas of salivary gland and ocular adnexa - may suggest an involvement of C. psittaci induced antigenic driven lymphomagenesis in a significant proportion of extragastric MALT lymphomas.

No significant financial relationships to disclose.
Imaging results after CHOP-rituximab followed by 90Y ibritumomab tiuxetan and rituximab (R) in patients with previously-untreated follicular lymphoma (FL)
Authors: Demonaco N. A. , Wu M. , Osborn J. , Evans T. , Foon K. A. , Swerdlow S. , Kant J. , Joyce J. , Land S. , Jacobs S. A.
Published: March 2020

7589

Background: There has been some question regarding the predictive value of 111In scans in FL. We report imaging results with fusion PET-CT scans and 111In scans in a single-institution, non-randomized, phase II trial in patients with FL treated with CHOP-R followed by 90Y ibritumomab tiuxetan (Zevalin (Z)) and R. Methods: Eligible patients have CD20 positive FL, Grade 1–3 or transformed, Stage II-IV, no prior treatment with monoclonal antibody or chemotherapy, and symptomatic disease (if grade 1–2). CHOP-R is given every 21 days for 3 cycles. Four weeks after the last dose of CHOP-R, patients receive the Zevalin regimen, which includes 111In imaging and 90Y therapy. One week after Z, patients receive R 375 mg/m2 IV weekly for 4 doses. Bone marrow examination and fusion PET-CT scans are performed at baseline, after CHOP-R, and 12 weeks after Z. The primary endpoint is CR, and responses are reported using the International Working Group (IWG) criteria with the additional requirement of a negative PET scan for CR/CRu. Results: Thirty-six FL patients have been accrued, and 16 patients have completed therapy and follow-up studies. One patient did not have a positive PET scan at baseline. Following therapy, the proportion with a negative PET scan improved from 8 of 15 (53.3%) after CHOP-R to 15 of 15 (100%) after Z. Using IWG criteria in combination with PET scan results, the CR rate increased from 4 of 15 (26.7%) after CHOP-R to 12 of 15 (80%) after Z. Five of 6 patients (83%) with tumor uptake by 111In scan and 7 of 9 (78%) with a 111In scan negative for tumor achieved a CR. Conclusions: There was no significant difference in CR between those patients with 111In tumor uptake versus patients with a negative 111In scan. Functional imaging with PET-CT may be a more sensitive method than CT alone in determining residual disease in FL. This trial continues to accrue patients, and more time is needed to determine the duration of response and time to next therapy.

No significant financial relationships to disclose.
Flavopiridol, fludarabine and rituximab (FFR) is an active regimen in indolent B-cell lymphoproliferative disorders and mantle cell lymphoma (MCL)
Authors: Lin T. S. , Fischer B. , Moran M. E. , Shank R. S. , Kraut E. , Porcu P. , Farag S. S. , Blum K. A. , Colevas A. D. , Grever M. R. , Byrd J. C.
Published: March 2020

7599

Background: The cyclin-dependent kinase inhibitor flavopiridol is active in MCL and chronic lymphocytic leukemia (CLL) when given by 1-hr IV bolus dosing. Flavopiridol induces apoptosis independent of p53 and may eliminate tumor cells resistant to fludarabine and rituximab. Methods: We performed a phase I dose escalation study of flavopiridol, fludarabine and rituximab (FFR) in patients (pts) with MCL, CLL and indolent B-cell non-Hodgkin’s lymphoma (NHL). Pts received fludarabine 25 mg/m2 IV day 1–5 and rituximab 375 mg/m2 day 1 every 28 days for up to 6 cycles. Flavopiridol was given 50 mg/m2 by 1-hr IV bolus day 1 (cohort 1), day 1–2 (cohort 2), or day 1–3 (cohort 3) of each cycle. Growth factor support was prohibited. Results: Twenty-one pts were enrolled and are evaluable for toxicity and response. Median age was 62 years (range, 43–81); 8 pts had CLL, 5 MCL, 4 follicular NHL (FL), and 4 other low-grade NHL. Nine pts had received 1–2 prior therapies; 12 pts were previously untreated. CLL pts were Rai stage III/IV (5) or required treatment for stage I/II disease (3). NHL pts had stage III/IV (10) or progressive stage II disease (3). Dose limiting toxicity (DLT) was not observed in 3 pts in cohort 1. Two of 6 pts in cohort 2 developed DLT (grade 3 seizures; grade 3 renal failure due to nausea and diarrhea). Twelve additional pts were enrolled at the cohort 1 dose level, to define toxicity and efficacy. Pts received a median of 4 cycles (range 1–6), and 9 of 21 pts completed 6 cycles. Therapy was stopped early due to cytopenias (7), infection (2), DLT (2) or progressive disease (1). Response was graded by NCI 96 (CLL) or IWG (NHL) criteria. Overall response rate was 90%, and 14 pts achieved CR (67%). Six pts relapsed a median of 7.5 months (range 4–18) after finishing therapy; 13 pts remain in remission a median of 13.5 months (range 4–25) after therapy. All 9 MCL/FL pts responded (8 CR, 1 PR), and 8 pts remain in remission a median of 17 months (range 6–25) after therapy. Conclusions: FFR showed significant clinical activity in a small group of pts, but cytopenias limited therapy. We are currently studying a modified FFR regimen using a more active flavopiridol schedule (30-min IV bolus followed by 4-hr IV infusion) and allowing the use of prophylactic filgrastim.

[Table: see text]
Lenalidomide and bortezomib induce osteoclast cytotoxicity and decrease BAFF secretion in osteoclasts in human multiple myeloma: Clinical implications
Authors: Breitkreutz I. , Tai Y. , Li X. , Coffey R. , Raab M. S. , Song W. , Hideshima T. , Chauhan D. , Munshi N. , Anderson K. C.
Published: March 2020

7606

Background: Myeloma bone disease is caused by an enhanced osteoclast (OCL) activation, leading to osteolytic bone lesions. OCL have recently been reported to produce abundant B-cell activating factor (BAFF) in the bone marrow microenvironment that is important for myeloma cell growth and survival (Blood 106, 1021–30, 2005; ASH2005, #627). The proteasome inhibitor bortezomib (PS341, Velcade) has potent anti-myeloma activity with impressive clinical responses. A recent study indicated that bortezomib has inhibitory effects on OCL (ASH 2005, #2488). Lenalidomide (CC-5013, Revlimid) is an immunomodulatory derivative of thalidomide that has shown promising anti-myeloma effects in patients with relapsed or refractory multiple myeloma (MM) (ASH 2005, #6 & #1565). However, the effect of lenalidomide on human OCL lineage is unknown. Therefore, the aim of this study is to investigate the effect of lenalidomide and bortezomib on human OCL. Methods: OCL formation from healthy donors and MM patients were stimulated with RANKL (50ng/ml) and GM-CSF (10ng/ml) in 20% FBS/RPMI. Cells were incubated with lenalidomide 2μM or bortezomib 2nM, alone and in combination, for two weeks followed by [3H]thymidine uptake assay to measure growth inhibition of OCL. Similar experiments were also performed in cocultures of CD138-purified cells from MM patients with OCL, in the presence or absence of lenalidomide and bortezomib. In addition, ELISA was performed to measure cytokine release of BAFF produced by OCL in these cultures. Results: OCL growth was decreased by lenalidomide (n=6) (median 49.2%, range 20–62.5%; coculture: 53% and 35%) as well as bortezomib (96 and 49%; coculture 63 and 59%) and by the combination of both drugs (95 and 55%; coculture 42 and 44%). BAFF secretion was dramatically decreased in cultures treated with lenalidomide 2μM (n=3) (median 72%, range 61–75.9%). Conclusions: These results indicate that lenalidomide and bortezomib inhibit OCL growth and survival. Importantly, lenalidomide and bortezomib also block growth and survival of MM cells cocultured with OCL, suggesting that lenalidomide may inhibit OCL growth and survival through inhibition of BAFF and may prevent development of osteolytic lesions in MM.

No significant financial relationships to disclose.
Phase I study of bortezomib and 153Sm-lexidronam combination for refractory and relapsed multiple myeloma
Authors: Yeh H. S. , Swift R. A. , Ferretti D. , Mapes R. A. , Goeckeler W. F. , Berenson J. R.
Published: March 2020

7614

Background: Multiple myeloma (MM) is a highly radiosensitive B-cell malignancy and radiation therapy has been an effective treatment for these patients. Recent preclinical studies have demonstrated that the bone-seeking radionuclide, Samarium Sm153 lexidronam (Sam) in combination with the proteasome inhibitor, bortezomib (Vel), can synergistically inhibit proliferation of myeloma cell lines in vitro and reduce MM growth in mice bearing human MM without significant myelotoxicity. These results provide the basis for a new therapeutic approach of combining Vel and Sam to overcome resistance and to minimize nontumor tissue toxicity among refractory and relapsed MM patients. Methods: The primary objective of this Phase I study is to determine the response rate and tolerability of Vel + Sam combination in patients with relapsed or refractory MM. Patients will be enrolled on this Phase I dose-escalation trial which involves six cohorts. Previous treatment with Vel is permissible. Dose escalation in parallel arms is as follows: A complete treatment cycle is 8 weeks. Vel is given on days 1, 4, 8 and 11 followed by a 45-day rest period. Sam is administered on day 4. The cycle is repeated on Day 57 if disease is stable or improved and platelets and neutrophils recover to at least grade 1 toxicity. DLT is defined as cycle 1 grade 4 hematologic or grade ≥3 non-hematologic toxicity. Results: Cohorts 1 and 4 have been enrolled (3 patients per cohort). One cycle of treatment has been completed thus far. No significant toxicity has been observed except a transient fever in one patient. There have been no dose limiting toxicities to date. The first six patients will be evaluated for response within the next two weeks. Conclusions: The trial will continue to enroll patients in cohorts 2 and 5. Updated results from the trial will be presented at the meeting.

[Table: see text]

[Table: see text]
Bendamustine in combination with thalidomide and prednisolone (BPT) in patients with refractory or relapsed multiple myeloma: Results of a phase I clinical trial
Authors: Poenisch W. , Rozanski M. , Hoffmann F. , Boldt T. , Schwarzer A. , Ruffert U. , Rohrberg R. , Kreibich U. , Niederwieser D.
Published: March 2020

7620

Background: Thalidomide is an active single agent in advanced relapsed or refractory multiple myeloma (MM). Combination of low dose thalidomide with bendamustine and prednisolone might be a way to maintain efficacy of the drug without dose limiting toxicity (DLT). Methods: The treatment consists of a fixed dose of bendamustine (60mg/qm) day 1, 8, and 15 and prednisolone (100 mg) day 1, 8, 15, and 22. At the same time, thalidomide was given in patients cohorts with escalating doses, starting with 50 mg to a maximum of 200 mg daily. 8 patients (4 after conventional chemotherapy and 4 after APBSCT) were enrolled at each dose level. Cycles were repeated every 28 days for a minimum of 2 and a maximum of 10 cycles until a maximal response was achieved, a DLT or a disease progression were observed. 23 patients ( 8 in the first dose level with 50 mg thalidomide, 8 in the second dose level with 100 mg and 7 patients in the third dose level with 200 mg) are enrolled until now. The number of prior treatment regimens was 2 or more in all patients. 6 patients were refractory for the last treatment. Median age was 67 years (range: 40 - 78). Results: All patients completed 2 cycles of BPT-treatment and were hence evaluable. Response was assessed using EBMT criteria modified to include near complete remission (nCR) and very good partial remission (VGPR). 20 of 23 patients responded after at least 2 cycles of chemotherapy with 3 CR, 5 VGPR, 11 PR and 2 MR. 2 patients had stable disease. With a median follow up of ten months, EFS and OS at twelfe months were 36 % and 85 %, respectively. Most common site effects were constipation (10 patients WHO grade 1, 8 patients WHO grade 2), polyneuropathy (14 patients WHO grade 1, 2 patients WHO grade 2) and somnolence (4 patients WHO grade 1). None of the 23 patients developed dose-limiting hematoxicity as defined by an ANC < 1,0 Gpt/l for > 7 days or an ANC < 0,5 Gpt/l for > 3 days or platelet count < 25 Gpt/l. Short neutropenia was reported in 8 patients (WHO grade 3 and 4) but no thrombocytopenia was observed. Conclusions: BPT with a dose between 50 and 200 mg thalidomide daily is well tolerated in patients with relapsed or refractory MM.

No significant financial relationships to disclose.
Long-term outcome of high-dose chemotherapy and autologous stem cell transplantation in relapsed/refractory Hodgkin’s disease: A cohort of 199 pts from Royal Marsden Hospital
Authors: Sirohi B. , Cunningham D. , Norman A. R. , Oates J. , Wotherspoon A. , Chong G. , Arkenau T. , Horwich A.
Published: March 2020

7622

Background: The purpose was to assess prognostic factors and outcome of pts with relapsed/refractory Hodgkin disease (HD) who have received high-dose chemotherapy and autologous stem cell transplant (ASCT). Methods: The retrospective study was approved by Research Ethics Committee. Primary end-point was overall (OS) and progression free survival (PFS). OS was defined as death from any cause measured from date of transplant and PFS defined as disease progression or death from any cause. Data on 199 pts who received ASCT between 1985–6/05 was reviewed. Results: Median time from 1st treatment(tx) to ASCT was 2.5 y (0.5–27.3). Demography at ASCT:61% Stage IV, median age 31y(18–69); median prior tx regimens 3 (1–7); median Hasenclever index 3 (0–6); 150 pts had responding disease (53 CR, 97 PR), 49 pts had stable/untested relapse/refractory disease. 62% pts received MBE as conditioning tx and bone marrow was source of stem cells in 57%. Post-ASCT, 61% (122/199) pts attained CR with an overall response (CR+PR) of 85%. 12 pts had non-relapse mortality;10 died before 1990 of interstitial pneumonitis (with higher dose BCNU). Of 122 pts attaining CR, 27 relapsed;3 after attaining CR for >5y and 1 after attaining CR for>10-y. 5-y risk of relapse in patients attaining CR was 21%. Median OS/PFS from ASCT was 9y/2.6y. 105 pts are alive at median follow-up of 10.3y. 5-y OS/PFS was 52/45% and 10-y OS/PFS was 49.5/41% for whole group. 10-y OS/PFS for pts in CR vs PR vs rest at ASCT was 72/66% vs 55/44% vs 11/5%. 20(10%) pts developed 2nd cancer (7 secondary AML/MDS). Probability of developing 2nd cancer at 10y is 6.9% (95%CI 3.6–13%) and 19.8% (95%CI 12–32%) at 20-y. Conclusions: These data provide the longest followup reported for patients receiving ASCT for relapsed/refractory HD. In addition to previously described prognostic factors, our data shows that Hasenclever index <3 influences outcome favorably and attaining CR at ASCT leads to a significantly better outcome.

[Table: see text]

No significant financial relationships to disclose.
ITCC phase II study of imatinib mesylate in children with solid tumors expressing imatinib-sensitive tyrosine kinase receptors
Authors: Vassal G. , Geoerger B. , Le Deley M. , Doz F. , Pichon F. , Frappaz D. , Gentet J. , Landman-Parker J. , Berthaud P. , Morland B.
Published: March 2020

9003

Background: Imatinib mesylate inhibits selectively specific activations of the platelet-derived growth factor receptor (PDGFR), c-KIT and BCR/ABL tyrosine kinases and is approved for the treatment of chronic myeloid leukemia and gastro-intestinal stromal tumors (GIST). This study evaluated efficacy of imatinib in solid childhood tumors. Methods: Phase II study of imatinib as single agent in children and adolescents with refractory or relapsing solid tumor expressing at least one of the receptors. Patients were to be treated at 340 mg/m2, a dose escalation allowed to 440 mg/m2 after 2 months in case of insignificant improvement. C-KIT, PDGFRα and β expression was determined on archive tissue sections by immunohistochemistry prior to study entry. Gene mutations, pharmacokinetics, pharmacogenetics, and positron emission tomography imaging were assessed. Results: 36 patients, 21 boys, median age 13.7 years (2.2–22.5 y), 12 with brain tumors, 6 fibromatosis, 8 mesenchymal/bone tumors, and 10 other solid tumors, including 1 GIST and 3 chordoma, were treated at 340 mg/m2 daily during a total of 168 months (median 1.9 month/patient, range 0.5–19). 18/36 expressed c-KIT, 10 PDGFRα, 21 PDGRβ; 12 expressed more than one receptor. Ten patients were escalated to 440 mg/m2 due to lack of efficacy. During the 1st month, 17 patients experienced mild toxicity (grade 1 and 2) related to study treatment: gastro-intestinal (n=22), face edema (n=7), asthenia (n=5), tumor induration (n=2), skin toxicity (n=2), thrombocytopenia (n=1). No partial or complete response was observed; 5 patients (2 fibromatosis, 1 GIST, 1 medulloblastoma, 1 pseudo-inflammatory tumor) experiencing durable stable disease have been under treatment for more than 12 months. Interesting tumor stabilization during 10 and 7 months, respectively, was achieved in a brain stem glioma and a renal carcinoma. Glucose uptake on 18FDG PET scan was reduced in a chordoma, although the child progressed and died due to disease. Pharmacokinetic and genetic data are currently evaluated. Conclusions: Imatinib as single agent was well tolerated, but—as used in our study —failed to show measurable anti-tumor effects according the standard criteria in the pediatric malignancies studied.

No significant financial relationships to disclose.
Immunotherapy for HER2-positive medulloblastoma: Regression of experimental tumors by transfer of HER2-redirected T cells in vivo
Authors: Ahmed N. M. , Ratnayake M. K. , Savoldo B. , Perlaky L. , Dotti G. P. , Wels W. , Bhattacharjee M. , Shine D. H. , Rooney C. M. , Heslop H. E. , Gottschalk S.
Published: March 2020

9008

Background: The long-term objective of this project is to develop an innovative HER2-targeted immunotherapeutic approach for medulloblastoma, the most common malignant brain tumor of childhood. HER2 is expressed in 40% of medulloblastomas and at present less than one third of patients with HER2-positive tumors are cured by conventional therapies. The aim of this study was to determine if T cells grafted with a HER2-specific chimeric antigen receptor (CAR) recognize and kill HER2-positive medulloblastomas. Methods: Mitogen-activated T cells from healthy donors and medulloblastoma patients were transduced with a retroviral vector encoding a HER2-specific CAR with a ζ-signaling domain (HER2T-cells). We analyzed the ability of HER2T-cells to 1) proliferate, 2) produce immunostimulatory cytokines (IFN-γ and IL-2), and 3) kill HER2-positive targets in cytoxicity assays upon exposure to HER2-positive primary medulloblastoma cells and cell lines. The in vivo function was tested in an orthotopic murine xenograft model of human medulloblastoma, which allows for serial imaging by bioluminescence. Results: HER2T-cells killed both HER2-positive primary medulloblastoma cells and cell lines in cytotoxicity assays, whereas HER2-negative tumor cells were not killed. Stimulation of HER2T-cells resulted in T-cell proliferation and secretion of IFN-γ and IL-2 in a HER2-dependent manner. No functional difference was observed between cells generated from medulloblastoma patients receiving dexamethasone and healthy donors. In vivo, the adoptive transfer of HER2T-cells resulted in sustained regression of established medulloblastomas in an orthotopic murine xenograft model as judged by bioluminescence imaging. In contrast, delivery of non-transduced T cells did not change tumor growth in comparison to untreated tumors. Conclusions: This study shows for the first time that HER2 is a target antigen for the immunotherapy of medulloblastoma. HER2-redirected T-cells not only recognized and killed HER2-positive medulloblastomas ex vivo, but also induced regression of experimental medulloblastoma in vivo. Hence, adoptive transfer of HER2-redirected T-cells may represent a promising immunotherapeutic approach for medulloblastoma.

No significant financial relationships to disclose.
Vascular endothelial growth factor (VEGF-A) serum levels in standard risk ALL pediatric patients (CCG-1962 study)
Authors: Avramis I. A. , Panosyan E. H. , Dorey F. , Holcenberg J. S. , Avramis V. I.
Published: March 2020

9026

Background: Many molecular pathways including cell-cycle control, angiogenesis & drug resistance mediate tumor growth and survival. Activation of Akt, PI3K and Ras can be induced by the activation of receptor tyrosine kinases, such as the VEGF-R and related growth factor receptors. VEGF-A serum levels <40 and >100 pg/ml have been associated with good and poor prognoses, respectively. The higher the VEGF-A levels the greater the chance of MRD blasts surviving chemotherapy. ALL blasts secrete VEGF-A and express VEGF-R. The hypothesis was that serum VEGF-A levels in SR ALL pediatric patients at entry of Induction (IND) are predictive of Event-Free Survival (EFS). Methods: 117 patients were entered in CCG-1962 study and were randomized into the Native & PEG-ASNase arms. VEGF-A serum levels in Induction were quantified by an ELISA assay. Results: . All patients had a decrease in VEGF-A levels by Day 14 of IND, but they later dichotomized; with EFS group levels remained low and Event group increasing. The VEGF-A levels at the end of IND remained unchanged in all patients in the DI1 and DI2 treatment phases. A linear relationship exists between high VEGF-A levels at entry to IND and time to Event. Moreover, 7 yr EFS patients have lower VEGF-A average levels of 28±2 pg/ml than Event patients, >100 pg/ml (P<0.01). VEGF-A levels were analyzed by STATA-9 to yield Kaplan-Meier curves. Various cut-off values of VEGF-A were used, with the 30 and 60 pg/ml being the most significant. Low VEGF-A levels at entry or at the end of IND had superior EFS (P<0.0001). In addition, these patients were examined for Δ-VEGF-A positive or not positive. These analyses produced a significant difference, in that patients who had an increase in serum levels of VEGF-A from IND to a later treatment phase had an Event and the patients who had a decrease or no change were EFS (P<1E-6). Bifurcation by Native or PEG-ASNase arm did not alter these results. Conclusions: These results taken together with the results from other studies, strongly support that high VEGF-A serum concentrations in IND and no increase in Δ-VEGF-A are treatment-independent surrogate markers for EFS. Since many studies have demonstrated the same fact, an anti-VEGF-A modality may be useful to enhance the outcome of the ALL patients.

No significant financial relationships to disclose.
The outcome of infant ALL: Experience at King Abdulaziz Medical City, Jeddah, western Region of Kingdom of Saudi Arabia
Authors: Khattab T. M. , Felimban S. K. , Atra A.
Published: March 2020

9038

Background: Infants with ALL have a worse prognosis than older children. Several regimens has been used with a 4 years event free survival ranging from 25%-40%. An international collaborative treatment protocol (Interfant 99) based on the understanding of the biology of infant ALL was introduced aiming to improve the outcome and study the role of allogeneic bone marrow transplantation (BMT). To review the clinical features, treatment outcome and causes of treatment failure of all infant ALL treated at our center. Methods: We retrospectively reviewed all case notes of children with ALL diagnosed between 1986–2005 to identify infants <12 months with ALL. The age, WBC and CNS disease at diagnosis were reviewed. Treatment details and survival were studied. Results: Among 351 patients with ALL, 12 were infants (4.2%). Patients charachteristics are shown in table below. Six were boys and 6 were < 6 month at diagnosis. Nine patients (75%) had WBC count >100,000 and 4/12 CNS disease at presentation. Immunophenotyping showing lacking CD10 7/12, biphentyping 3/12, unknown 2/12 and t (4:11) found in 2/12. Treatment consisted of UKALL-based in 7 patients and Interfant 99 protocol in 5. Two patients received BMT, one from unrelated donor and the other with one antigen mismatch from his mother. Six patients (50%) died of toxicity and 3(25%) of recurrent leukemia including one who had unrelated donor BMT. Three patients survive in full remission including one who had BMT from his mother. Conclusions: This small single center study confirms the inferior outcome of infant ALL. Toxic death remains a major cause of treatment failure. Because of the rarity of infant ALL, international collaboration is required to study the role of different chemotherapy regimens and assess the role of allogeneic BMT.

[Table: see text]

No significant financial relationships to disclose.
Chemotherapy followed by low dose radiotherapy in childhood Hodgkin’s disease. Retrospective analysis of results and prognostic factors
Authors: Viani G. , Novaes P. , Salvajoli J. , Ferrigno R. , Pellizzon C. , Fogaroli R. , Maia M.
Published: March 2020

9039

Background: To report on treatment results and prognostic factors of young patients with Hodgkin’s disease treated with chemotherapy (CT) followed by low dose radiotherapy (RT). Methods: This retrospective series analysed 166 patients under 18 years old, treated from January 1985 to December 2003. Median age was 10 years (range 2–18). The male to female ratio was 2,3:1. Adenomegalia was the most frequent complaint (68%), and the time of symptom duration was smaller than 6 months in 55% of the patients. In histological analysis Nodular Sclerosis was the most prevalent type (43%) followed by Mixed Celularity (41%). The disease was restricted to two nodal group ( stage II) in 60% and to adjacent groups in 55% (stage III). The most frequent site of metastasis ware the bone marrow (38%) and lungs (42%). Standard treatment consisted of chemotherapy (drug combination varied according to treatment protocols vigent). Radiotherapy consisted of 21 Gy dose in 17 fractions in most part of patients (90.2%), delivered to involved field or mantle field. 13,86% patients did not receive RT. Results: The OS and EFS in 10 years were 88.6% and 82.4%.Survival according to clinical stage as 94.4%, 94.25%, 90.6% and 71.5% for stages I to IV (p=0.0215). The OS in 90.5% of patients who received RT and in 75.6% of patients who did not (p=0.001). Multivariate analysis showed presence of B symptoms and low platelet count to be associated with a worse prognosis. Conclusions: This study shows that combining chemotherapy and low dose RT is an effective treatment for HL in childhood, providing high rates of cure and disease control (88.6% in 10 years), and that so far it is not possible to abdicar RT. And yet, attention to platelet count should be payed in order to improve survival. Also, B symptom presenting children may be involved in more aggressive protocols so survival can be improved. As the disease is highly curable, any data of long term follow-up should be presented in order to better direct therapy, improving outcome and lowering side effects.

No significant financial relationships to disclose.