bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II trial of the oral mTOR inhibitor everolimus (RAD001) for patients with relapsed or refractory lymphoma
Authors: Johnston P. B. , Ansell S. M. , Colgan J. P. , Habermann T. M. , Inwards D. J. , Markovic S. N. , Micallef I. N. , Porrata L. F. , LaPlant B. R. , Geyer S. M. , Witzig T. E.
Published: March 2020

8055

Background: mTOR inhibition with intravenous temsirolimus (Wyeth Pharmaceuticals) has been associated with responses in mantle cell lymphoma (J Clin Oncol 23;5347, 2005) as well as other lymphomas (Blood 108 (11) 2483; 2006). This phase II study tested the oral mTOR inhibitor everolimus (RAD001, Novartis Pharmaceuticals) in three simultaneous two-stage phase II lymphoma studies - aggressive (group 1), indolent (group 2), or uncommon (group 3). The goals were to learn the toxicity profile and to assess the anti-tumor response. Planned interim analysis for groups 1 and 3 have been completed and are the subject of this report. Methods: Patients (pts) received 10 mg PO daily for each 28 day cycle (up to 12) and restaged after 2, 6, and 12 cycles. The primary endpoint is the confirmed response rate, including CR, CRu or PR. 12 pts were enrolled in stage 1 of each study. At least 1 success in 12 is required to proceed to stage 2, to a total of 37 pts. Overall, the treatment will be considered promising if 4 or more successes are observed in all 37 pts in each group. Results: The median age of the 12 pts in group 1 was 68.5 yrs (range: 53–80), with a median of 3 (range, 1–15) prior therapies. Four pts had a prior stem cell transplant (SCT). Pts completed a median of 7 (range, 1–12) cycles of therapy. 6 confirmed responses have been achieved (1 CR, 5 PR), meeting the overall criteria for promising results in this study. Common grade 3 adverse events (AEs) include thrombocytopenia (3 pts) and anemia (2 pts). For group 3, the median age was 49 yrs (range, 27–78), with a median of 7 (range, 1–13) prior therapies and 6 pts had a prior SCT. Pts have completed a median of 6.5 cycles (range, 1–11). 5 confirmed responses have been achieved (5 PR), meeting the criteria for this regimen to be considered promising. Of these 5 patients, 3 had HD, 1 T-cell NHL, and 1 had macroglobulinemia. Common grade 3 AEs include anemia (3 pts) and thrombocytopenia (2 pts). No grade 4 AEs were reported. Conclusions: Oral everolimus has activity in a spectrum of lymphomas with acceptable toxicity. The responses observed in both group 1 and group 3 met the criteria to continue accrual. These results provide the rationale for additional studies with this novel class of agents and to integrate mTOR inhibitors into salvage treatment regimens.

No significant financial relationships to disclose.
R-HCVAD/R-MTX-ARAC is an effective regimen for untreated diffuse large B-cell lymphoma (DLBCL) with aggressive features: M. D. Anderson experience in 40 patients
Authors: Fayad L. , Temple S. , Pro B. , Hagemeister F. , Cabanillas F. , Samaiego F. , McLaughlin P. , Wang M. , Kwak L. , Romaguera J. , Rodriguez M. A.
Published: March 2020

8058

Background: R-HCVAD (rituximab-cyclphosphamide, vincristine, dexamethasone, doxorubicin) alternating with R-MTX-ARAC (rituximab, methotrexate-cytarabine) is a chemoimmunotherapy regimen with activity in ALL, mantle cell, and Burkitt’s lymphomas (BL). Histological differentiation between BL, atypical BL, and DLBCL with high-grade features can be difficult. We thus have treated patients with DLBCL with high-grade histological features and/or poor-risk IPI with R-HCVAD. Methods: Forty consecutive patients with information collected prospectively in the NCCN database, treated between 7/2002 and 10/05 at M.D Anderson Cancer Center, and who received at least one cycle are included in this cohort analysis. Characteristics: 18 (45%) male; 18 (45%) HI and High IPI; 25 (62.5%) ↑LDH; 26 (65%) with Stage III/IV; 2 (5%) with PS>1; 8 (20%) with >60 years; 25 (62%) a Ki-67 >90%. Four patients received less than 4 cycles of treatment. Results: ORR was of 100%, with 95% CR/CRu. With a median follow-up of 26 months, 6 patients failed: 1 died in CR of pulmonary embolism while on treatment; 1 patient who achieved CR, had PD before the end of treatment; 1 achieved a PR and was transplanted (is alive in remission); 1 achieved a PR and progressed died of disease; and 2 relapsed (one is in remission after an ASCT). Four patients have died: 3 of disease, 1 of pulmonary embolism. The 3-year OS is 88% (95% CI 77%-99%); 3-year FFS is 71% (95% CI 47%-95%). The 3-year FFS for patients with L/LI risk (3-failures of 22 pts) was 78% (95% CI 52%-100%); and for patients with HI/H IPI (3 failures of 18 pts) 65% (95% CI 27%-100%). Conclusions: R-HCVAD/R-MTC-ARAC is a very active regimen for DLBCL of high grade. Toxicity was mostly hematological. We are currently doing a prospective randomized phase II study comparing this regimen to standard R-CHOP in patients with poor-risk IPI scores.

No significant financial relationships to disclose.
Retrospective analysis of P-STAT6 expression as a predictive marker in primary nervous system lymphoma patients assigned to high-dose methotrexate
Authors: Altavilla G. G. , Pitini V. V. , Arrigo C. C. , Marabello G. G. , Naro C. C. , Tomasello C. C. , Righi M. M. , la Torre D. D.
Published: March 2020

8059

Background: Recent immunohistochemical data and gene expression values have demonstrated that a majority of Primary Nervous System Lymphoma (PCNSL) express both bcl-6 as well as MUM-1, suggesting an overlapping histogenetic time slot of B-cell differentiation. In addition, an increased expression of P-STAT6 seems to predict short survival in patients (pts.) treated with high-dose Methotrexate (HD-MTX)-based chemotherapy. To investigate the clinical impact of the P-STAT6 expression in this setting we have analyzed P- STAT6 expression in available tumor tissue blocks of 25 PCNSL pts. treated with HD-MTX who have had follow up for at least 2.5 years. Methods: Immunohistochemistry for P-STAT6 was performed using an indirect immunoperoxidase method. Responses were evaluated according to the International Workshop criteria for PCNSL. Progression-free survival (PFS) and overall survival (OS) were calculated according to the Kaplan-Meier Method. Results: 15 male, 10 female; mean age 52.1 years, were included in the analysis. The immunohistochemical analysis showed three different patterns of P-STAT6 expression: 7 pts. had absent P-STAT6 expression and low tumor cellular density (group A); 8 pts. had sparse positive P-STAT6 expression and low cellular density (group B), 10 pts. had strong P-STAT6 nuclear expression in tumor cells and on vascular endothelia and high cellular density (group C). The overall response rates to treatment (CR+PR) were 83% for both group A and B compared to 5% of group C. Furthermore the pts. with intense P-STAT6 expression experienced an impressive early progression (PFS median 2.5 months) and an OS very short (median 10 months). To date pts. of groups A and B have not reached median OS and PFS. Conclusions: PCNSL pts. with intense P-STAT6 expression experienced short survival when treated with HD-MTX- chemotherapy.

No significant financial relationships to disclose.
The choice of first-line therapy in advanced Hodgkin lymphoma: Retrospective comparison of ABVD and escalated BEACOPP regimen
Authors: Jurczak W. , Krochmalczyk D. , Giza A. , Węgrzyn J. , Sobocinski M. , Gawelko J. , Malkowski B. , Czyz J. , Pawlega J. , Skotnicki A. B.
Published: March 2020

8063

Background: HD patients with high risk have a relatively poor prognosis with less than 50% 5-year overall survival (OS) if treated with ABVD regimen. Methods: Therapy results of all 105 patients with advanced HL (CS IIBX -IV) treated from diagnosis at our Department in the last decade, are presented. The choice of initial 3 cycles between ABVD and escalated BEACOPP was done at the patients preferal and physician's adivice. Further 3 chemotherapy cycles depended on initial response assessment: poorly responding ABVD treated patients were offered therapy escalation. Patients with a good response (over 80% regression) after the first 3 cycles were later treated with ABVD. EFS and OS were primary endpoints of the study. Results: We divided patients into 2 treatment groups, depending on the first 3 cycles (escalated BEACOPP n = 57 or ABVD n = 48). Poor response resulting in therapy intensification was not considered as an event defined only as a relapse or progression during therapy. There was a statistically insignificant imbalance between the risk factor distribution with less favorable prognosis in patients treated with esc BEACOPP: 38 % of pts in IV th clinical stage (as compared to 31% in ABVD group), 3,08 EORTC risk factors (as compared to 2,64 in ABVD group) and 2,19 according to German Hodgkin Study Group (1.93 respectively). Increased toxicity of esc BEACOPP regimen was due to grade 3/4 cytopaenia (present in all patients) resulting in more infection episodes (according to WHO scale stage 3 - 16 pts , stage 4 - 8 pts; in ABVD group, 2 and 1 pt respectively). There were no treatment related mortalities. In esc BEACOPP projected 5 y OS was 96% and EFS 89% , which is comparable to GHSG results. 5 y OS and EFS in ABVD group are 87% and 66% respectively. The difference in EFS is statistically significant (p< 0.05). Conclusions: In our study we checked the feasibility of esc BEACOPP regimen in high risk HD pts. The results show the importance of the intensity of the first line approach. In the poor responders after the initial 3 cycles, even early treatment intensification, didn’t improve the outcome. De-escalation of therapy after the first 3 cycles, in good responders, didn’t make OS and EFS inferior to GHSG results in which they recommend 6 cycles of esc BEACOPP therapy.

No significant financial relationships to disclose.
Preliminary results from a phase II study of lenalidomide oral monotherapy in relapsed/refractory indolent non-Hodgkin lymphoma
Authors: Witzig T. E. , Vose J. , Pietronigro D. , Takeshita K. , Ervin-Haynes A. , Zeldis J. , Wiernik P. H.
Published: March 2020

8066

Background: Lenalidomide, an immunomodulatory drug, is approved in the US for treatment of relapsed/refractory multiple myeloma and myelodysplastic syndromes associated with a deletion 5q[31] cytogenetic abnormality. Lenalidomide also has activity in chronic lymphocytic leukemia and cutaneous T-cell lymphoma. This study was designed to assess the safety and efficacy of lenalidomide monotherapy in patients with relapsed/refractory indolent non-Hodgkin's lymphoma (NHL). Methods: Patients with relapsed/refractory indolent NHL with measurable disease after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Results: As of enrollment cut-off, 43 patients received drug and 27 were evaluable for response. The median age was 63 (43–82) and 12 were female. Histology was small lymphocytic lymphoma [SLL] (n=12), follicular center lymphoma grades 1,2 [FCL] (n=12) and nodal marginal B-cell lymphoma [NML] (n=3). Median time from diagnosis to lenalidomide was 4.3 (0.4- 24) years and median number of prior treatment regimens was 3 (1–17). Seven patients (26%) exhibited an objective response (2 complete responses (CR), 1 complete response unconfirmed (CRu) and 4 partial responses (PR)), 9 had stable disease (SD) for a tumor control rate (TCR) of 59% and 11 progressive disease (PD). Responses were produced in each of the indolent histologic subtypes studied: SLL (3/12), FCL (3/12) and NML (1/3). Since most responses develop at ≥ 4 months, additional responses may be seen in early SD patients with longer follow-up. Five patients (12%) exhibited Grade 4 neutropenia, and Grade 3 adverse events were neutropenia (16%) and thrombocytopenia (14%). Conclusion: Lenalidomide oral monotherapy is active with manageable side effects in relapsed/refractory indolent NHL.

[Table: see text]
Non-Hodgkin lymphoma of the Waldeyer's ring: Is a higher radiotherapy dose required?
Authors: Bahl G. , Laskar S. , Muckaden M. A. , Nair R. , Gupta S. , Bakshi A. , Gujral S. , Parikh P. M. , Shrivastava S. K. , Dinshaw K. A.
Published: March 2020

8067

Background: To evaluate the prognostic factors and treatment outcome of Indian patients with primary Non-Hodgkins Lymphoma (NHL) of the Waldeyer's Ring (WR) region treated at a single institute. Methods: 269 patients with NHL of the WR treated at Tata Memorial Hospital, Mumbai from January 1990 to December 2002 were included. The median age was 45 years and majority of the patients (67%) were males. Systemic symptoms were present in only 16% of patients, primary site was the tonsil in 58%, nasopharynx in 42% and base tongue in 5% of patients. Majority had Diffuse Large B-Cell Lymphoma (85%); 26% patients presented with stage I disease and 66% had stage II disease. Treatment comprised of a combination of chemotherapy (CTh) and radiotherapy (RT) in majority of the patients (71%). Among these patients, 63% received an RT dose of =45Gy. Results: The complete response rate was 68%. After a median follow-up of 57 months, the 5 year DFS & OS for the whole group were 62.2% and 70.1% respectively. Multivariate analysis showed that; age >30 years (HR=4.05, 95%CI=1.53–10.7, p=0.005), WHO performance score =2 (HR=2.36, 95%CI=1.12–4.95, p=0.023), T-cell lymphomas (HR=5.55, 95%CI=2.43–12.7, p<0.001), bulky tumors (HR=2.08, 95%CI=1.02–4.257, p=0.045), and nasopharyngeal primary (HR=3.26, 95%CI=1.51–7.02, p=0.003), had a negative influence on survival. Patients treated with a combination of CTh & RT had a significantly better outcome than those treated with CTh alone (OS: 78.9% vs. 48.1%, p<0.00001). The hazard ratio for death (HR) in the chemotherapy alone group was 3.50 (95% CI=2.17–5.65). The CR (p=0.01), DFS (p<0.0001) and OS (p=0.002) rates were significantly better for patients receiving a RT dose of =45Gy. The HR in the subgroup that received a RT dose of < 45Gy was 5.09 (95% CI=2.39–10.86). Conclusions: Age at diagnosis, WHO performance score, T-cell histological type, size and site of the tumor significantly influence outcome in patients with primary NHL of the Waldeyer's Ring. Combined modality treatment, comprising of CTh & RT (with an RT dose of =45Gy), results in satisfactory outcome in patients with this rare neoplasm.

No significant financial relationships to disclose.
Somatically mutated immunoglobulin VH genes without intraclonal heterogeneity indicate a post germinal center origin of primary intraocular diffuse large B-cell lymphomas
Authors: Malumbres R. , Davis J. , Ruiz P. , Lossos I. S.
Published: March 2020

8072

Background: Primary intraocular lymphoma (PIOL) is a very rare high grade malignant non-Hodgkin lymphoma, usually of the diffuse large B cell lymphoma (DLBCL) type, which presents in the vitreous, retina and/or the optic nerve. Sixty to 80% of patients with PIOL eventually disseminate to the brain, whereas up to 15% of primary central nervous system lymphoma (PCNSL) patients exhibit ocular involvement. For these reasons, PIOL is regarded as a subtype of PCNSL. Analysis of the immunoglobulin heavy chain (VH) sequences in PCNSL tumors demonstrated biased overrepresentation of the VH4–34 gene and indicated derivation of these tumors from highly mutated germinal center (GC) B cells with ongoing mutational activity. Whether PIOL tumors are of similar or different origin is presently unknown. Methods: Immunoglobulin VH genes were examined in vitrectomy specimens of 4 PIOL patients, 1 patient with concomitant PCNSL and 1 patient with systemic DLBCL involving the eye. The extracted DNA was amplified by PCR using VH family specific primers, cloned and sequenced. Results: Seven clonal VH rearrangements belonging to the VH4, VH3 and VH1 families were cloned from the analyzed cases. In concordance with previous reports, the lymphomatous eye infiltrate from the PCNSL patient revealed a mutated clonal VH4–34 gene with intraclonal heterogeneity -a manifestation of active ongoing mutational activity. All the PIOL clonal VH rearrangements also exhibited mutated sequences with homology to the germline sequences ranging between 76 to 95%. However, in contrast to PCNSL, 3 out of 4 PIOL cases exhibited no intraclonal heterogeneity while the remaining case demonstrated ongoing somatic mutations in one of the 2 clonal VH rearrangements detected in this tumor. Interestingly, the clinical course of this patient was highly unusual, since he exhibited systemic dissemination during follow-up. Conclusions: Analysis of VH gene sequences from PIOL tumors indicate a post- GC derivation and suggest that they belong to the activated B cell (ABC)-like subtype of DLBCL. This is in contrast to the GC-origin of closely related PCNSL.

No significant financial relationships to disclose.
Improved outcome after sequential brief induction conventional chemotherapy, concurrent chemoradiation (cCRT), consolidation high-dose chemotherapy (HDCT) or further conventional chemotherapy for early stage CD56+ natural killer (NK)/T-cell lymphoma
Authors: Yiu H. , Ngan R. K. , Cheng H. , Wong K. , Cheung M. , Lau W.
Published: March 2020

8075

Background: Nasal NK/T lymphoma is uncommon but prognosis is universally poor even in early stage disease. Chemotherapy is often added to radiation for improving outcome although its role has not been well defined. Methods: Since 1998, an intensive protocol has been introduced for pts with stage I or II disease, which consists of 3 cycles of anthracycline-based (CHOP or ProMACE-CytaBOM) chemotherapy to be followed by cCRT (50–54Gy radiotherapy with weekly cisplatin at 40mg/m2) for pts with adequate renal function, and then consolidation HDCT. Cyclophosphamide, BCNU & Etoposide HDCT was offered to pts <60 years with adequate organ functions. Otherwise, 3 more cycles of conventional chemotherapy were given. Results: Out of the 27 pts recruited into the intensive protocol up till 2005, 23 completed cCRT & 14 received HDCT. Six pts had failed either locally or systemically, among whom 2 local failures were salvaged by further local radiotherapy. Eight patients had died with 4 related to lymphoma progression, 3 due to treatment complications and 1 died of prevailing medical illness. A preceding cohort of 35 pts intended to be treated with combined sequential conventional chemotherapy and radiotherapy only (sCRT: n=35) from 1986 to 1997 was also analyzed and compared with the current cohort (cCRT: n=27). Pts in both groups had similar characteristics. The type of intended treatment was a statistically significant factor for 6-year failure-free survival (sCRT 22.9%, cCRT 65.9%; p=0.0049, log-rank test) and overall survival (sCRT 36.4%, cCRT 69.8%; p=0.05, log-rank test), so are B symptoms (present Vs absent) and stage (I Vs II). Conclusions: The intensive protocol with sequential brief induction conventional chemotherapy, cCRT, and consolidation HDCT / conventional chemotherapy in appropriate pts was feasible, leading to better outcome than the combination of sequential conventional chemotherapy and radiation alone. The relative contributions of cCRT and HDCT to the improved outcome should be further explored.

No significant financial relationships to disclose.
A phase IB safety and pharmacokinetic (PK) study of recombinant human Apo2L/TRAIL in combination with rituximab in patients with low-grade non-Hodgkin lymphoma
Authors: Yee L. , Fanale M. , Dimick K. , Calvert S. , Robins C. , Ing J. , Ling J. , Novotny W. , Ashkenazi A. , Burris H.
Published: March 2020

8078

Background: Recombinant human Apo2L/TRAIL (rhApo2L/TRAIL) induces apoptosis (programmed cell death) through binding to the pro-apoptotic receptors DR4 and DR5. Preclinical studies show that rhApo2L/TRAIL selectively induces apoptosis in many cancer cell lines derived from various malignancies including NHL, while sparing most normal cells. In vivo, rhApo2L/TRAIL and Rituximab cooperate to shrink or attenuate the growth of various NHL tumor xenografts in SCID mice. RhApo2L/TRAIL is being co-developed by Genentech and Amgen as a targeted therapy for solid tumors and hematologic malignancies. Methods: Subjects were eligible to participate if they had CD20+ follicular NHL or small lymphocytic lymphoma or marginal zone B-cell lymphoma that had progressed following stable disease or an objective response lasting > 6 months duration to the most recent rituximab-contain regimen. RhApo2L/TRAIL is administered intravenously over 1 hour for 5 consecutive days every three weeks up to 4 cycles at dose levels of 4 and 8 mg/kg. Rituximab is administered intravenously at 375 mg/m2 weekly for up to eight doses. Results: Six subjects with low grade NHL (4 with follicular NHL and 2 with small cell NHL) have been enrolled and treated with 4 mg/kg rhApo2L/TRAIL and rituximab, and one subject (with follicular NHL) has been enrolled and treated with 8 mg/kg rhApo2L/TRAIL and rituximab. The enrolled subjects range in age from 39–82 years; there are 6 male and 1 females. The number of prior therapies for NHL range from 1–8. Four subjects have received all protocol specified therapy. There have been no DLTs or SAEs or Grade 3/4 adverse events reported to date. To date, five subjects have undergone tumor response assessment: there have been 2 patients with complete response, 1 with partial response and 2 with stable disease. Conclusion: The combination of rhApo2L/TRAIL at 4 mg/kg/day and rituximab appears safe and shows evidence of activity in subjects with low grade NHL that has relapsed following previous rituximab-containing therapy. Enrollment is continuing to test rhApo2L/TRAIL at 8 mg/kg plus rituximab for expanded safety data and further dose optimization.

No significant financial relationships to disclose.
Cost-effectiveness of tositumomab and iodine I-131 tositumomab (Bexxar therapeutic regimen (BTR)), in treatment of non- Hodgkin lymphoma (NHL)
Authors: Flowers C. R. , Sambrook J. C. , Briggs A. , Osenenko K. , Wang H. , Dalal M. R.
Published: March 2020

8089

Background: BTR has demonstrated efficacy in NHL patients and it has potential to prolong time to progression (TTP) in relapsed/refractory, low grade, follicular, or transformed NHL. This study assessed effectiveness and cost-effectiveness of BTR compared to alternative therapies in first, second, and third line NHL therapy. Methods: Time-to-event models were constructed with 2 events: progression and death. Patient data from 8 BTR clinical trials were combined to fit Weibull models for TTP and overall survival (OS) by including FLIPI covariates. Estimates for BTR were compared with estimates for alternatives from Weibull models fitted to published TTP and BTR OS data by lines of therapy and measured in life-years (LY). Estimated pre-progression costs included drug costs, lab tests, monitoring, and adverse events; post progression costs included NHL costs until death, all valued in 2006 $US and discounted at 3%. Indirect comparisons yielded incremental cost-effectiveness ratios (ICER=Δ cost/Δ LYs) in each line of therapy. Results: As observed in the table , cost of care estimates in BTR were often comparable with alternative therapies, but typically LY gain favored BTR. Mostly in first and third line, a BTR strategy had an ICER less than the cost-effectiveness threshold of $50,000 per LY gained. Conclusion: Overall, a BTR strategy has a favorable cost-effectiveness profile to alternative strategies including rituximab maintenance (RXM) in first, second, and third line NHL therapy. Results imply both a possible survival gain with early BTR use, and the cost-effectiveness of BTR. This modeling approach can aid in clinical decision making regarding the sequence and timing of therapy for patients with follicular NHL.

No significant financial relationships to disclose.

[Table: see text]
Contribution of constitutive activation of Akt to the pathogenesis of mantle cell lymphoma (MCL) independent of PTEN protein expression
Authors: Economopoulou C. , Psyrri A. , Liakata E. , Papageorgiou S. , Economopoulou P. , Kontsioti F. , Pappa V. , Economopoulos T.
Published: March 2020

8101

Background: To determine whether the PI3K/Akt signaling pathway is involved in the pathogenesis of mantle cell lymphoma (MCL), we investigated the phosphorylation status of Akt in primary MCL cases and cell lines. We also sought to determine whether loss of the phosphatase PTEN is the mechanism of Akt activation in MCL. Methods: We evaluated the protein levels of Akt, phosphorylated Akt and PTEN in 15 primary MCL cases and 2 cell lines by immunoblotting Results: Akt was phosphorylated in 3 of 15 MCL cases and in 2 of 2 mantle cell lymphoma cell lines. PTEN protein was expressed in 15 of 15 primary mantle cell lymphoma cases and in 2 of 2 MCL cell lines. Conclusions: We conclude that constitutive activation of the PI3K/Akt pathway contributes to the pathogenesis of MCL. Loss of PTEN protein expression is not the responsible mechanism for Akt activation. Alternative mechanisms of Akt activation are being evaluated to identify markers predictive for response to PI3K/Akt inhibitors in MCL.

No significant financial relationships to disclose.
The effect of induction therapy with novel agents on stem cell mobilization in multiple myeloma
Authors: Mazumder A. , Jagannath S. , Vesole D.
Published: March 2020

8102

Background: Thalidomide or bortezomib combined with dexamethasone (TD or BD respectively) are now being increasingly used as induction regimens for newly diagnosed multiple myeloma. There are conflicting reports on the effects of T on stem cell mobilization. Since we have used both these regimens at our center, we performed a retrospective analysis of stem cell mobilization after induction therapy with either TD (n = 22) or BD (n = 18). Methods: The patients were balanced with respect to initial Durie-Salmon stage, median number of cycles of induction therapy prior to collection, response to induction therapy, bone marrow cellularity and involvement, and time from end of therapy to collection. All patients were mobilized with G-CSF 10mcg/kg and collected in a large volume pheresis, with a goal of at least 6x10(6) CD34+ cells/kg (for tandem transplant). Results: To achieve our stem cell goal, the number of patients who required 3 or more phereses in the TD group was 17/22 whereas it was only 4/18 in the BD group. (p<0.005). 3/3 patients who had received lenalidomide also required 3 or more phereses. Also, the number of CD34+ cells/kg obtained in the TD group was less–mean of 2.8x10(6) per pheresis, as compared to a mean of 5.2x10(6) per pheresis in the BD group (p<0.01). Time to neutrophil engraftment was similar in both groups. However in the TD group there was a 1 day delay in platelets > 20,000/ul (p<0.05). Conclusions: Thus, thalidomide induction led to a lower yield of stem cells when compared to bortezomib. Differences in stem cell markers are being investigated. This may become especially important when limiting numbers of stem cells are available from elderly patients, those with prior radiation or bulk disease and when used for in vitro manipulation. It is possible that agents such as bortezomib may alter the bone marrow microenviroment differently from imids such as thalidomide.

No significant financial relationships to disclose.
Risk of renal failure associated with IV bisphosphonate use in patients with multiple myeloma
Authors: Joyce A. T. , Harrison D. J. , Jun S. , Feliu A. L. , Anthony M.
Published: March 2020

8104

Background: IV Bisphosphonates including zoledronic acid (ZA) and pamidroniate are frequently used to delay time to skeletal related events in patients with multiple myeloma. The risk of renal toxicity with these agents is well known and regular monitoring of kidney function is required. Despite regular monitoring of creatinine, patients taking IV bisphosphonates may experience decreased renal functioning and renal failure. The purpose of this study was to determine the relative risk of renal failure in patients with multiple myeloma treated with ZA or pamidronate relative to patients whose lytic lesions remained untreated with medications. Methods: Commercially insured adults newly diagnosed with multiple myeloma 7/1/2002–6/2006 were identified using ICD-9 codes within the PHARMetrics Integrated Outcomes Database. Patients were stratified based on evidence of IV bisphosphonate use (treated) or no such evidence (untreated) following initial qualifying diagnosis. For treated patients, the date of first administration of an IV bisphosphonate was the patient's index date. Treated patients were matched to untreated patients based on use of radiation therapy or chemotherapy, year of cancer diagnosis, and health plan enrollment duration.The incidence rate (IR) for renal failure defined using ICD-9 codes was based on number of incident cases identified among the total person-years at risk and expressed as a rate per patient year. IRs and incidence rate ratios (IRR) (comparing the treated to untreated cohorts), with corresponding 95% confidence intervals are reported. Results: Treated (n=401) and untreated (n=431) patients were similar with respect to age (mean 56 years in both cohorts), but treated patients were more likely to be female (54% vs. 47%; p = 0.04) and less likely to have a history of anemia (48% vs. 51%; p=0.002). IV bisphosphonate use was associated with an 8.5% incidence of developing renal failure per patient year versus 4.9% in the untreated cohort (IRR 1.72; 95% CI 1.22–2.42). The risk was similar whether patients were treated with ZA or pamidronate. Conclusions: IV bisphosphonate use was associated with a significantly increased risk (72%) of developing renal failure in patients with multiple myeloma.

No significant financial relationships to disclose.
An analysis of erythropoietin (EPO) and venous thromboembolic events (VTE) in multiple myeloma (MM) patients (pts) treated with anthracycline-based chemotherapy and the immunomodulator agent thalidomide
Authors: Baz R. C. , Walker E. , Kelly M. , Hussein M. A.
Published: March 2020

8107

Background: The use of EPO has recently been reported to be associated with higher rates of VTE in MM pts receiving lenalidomide or thalidomide and dexamethasone (Knight et al. NEJM 2006). Uncontrolled erythrocytosis, a recognized risk factor for VTE, may complicate therapy with EPO when the hemoglobin is not carefully monitored. Other risk factors such as renal failure in this pt population might contribute to hypercoagulability. We sought to evaluate the contribution of EPO use to the development of VTEs in pts with MM treated with the immunomodulator agent thalidomide in combination with chemotherapy. Methods: We retrospectively reviewed records of 105 pts enrolled on a clinical trial for newly diagnosed or relapsed MM pts with pegylated liposomal doxorubicin, vincristine, dexamethasone and thalidomide (DVd-T). In this study pts pts were aggressively monitored for VTE as previously described (Hussein et al Mayo Clin.Proc. 81 (7):889–895, 2006). Demographic variables, aspirin therapy (on intent to treat basis), EPO therapy, as well as the occurrence of VTEs were extracted. Results: The median age was 63 years and 62 (59%) received EPO in conjunction with their MM therapy. VTE prophylaxis with aspirin (81mg daily) was administered to all but 21 pts. Of the 62 pts receiving EPO, 15 (24%) had a VTE compared to 11 (26%) who did not receive EPO (OR 0.928, 95% CI 0.38 - 2.3). Among the 21 pts who did not receive aspirin as VTE prophylaxis, 11 (52%) experienced a VTE compared to 18% (15/84) in those who did receive aspirin as VTE prophylaxis (OR 5.1, 95% CI 1.8 - 14). In the subgroup of 62 pts that received EPO, 54% (7/13) of pts who did not receive aspirin developed a VTE compared to 16% (8/49) who received aspirin and developed a VTE (OR 6, 95% CI 1.6 - 22.6), which is comparable to the overall study population. Conclusions: These results do not indicate an association between EPO use and VTE in MM pts receiving anthracycline-based chemotherapy with the immunomodulator thalidomide and on intent to treat basis low dose aspirin is effective in reducing the incidence of VTE with this complex regimen.

[Table: see text]
ZIO-101 (S-dimethylarsino-glutathione): Phase I/II trials in advanced/progressive multiple myeloma
Authors: Berenson J. R. , Jaganath S. , Reece D. , Boccia R. , Soebel R. , Belch A. , Schwartz B. , Gale R. P. , Hussein M.
Published: March 2020

8109

Background: ZIO-101(S-dimethylarsino-glutathione), a novel organic arsenic, is active against multiple cancers including myeloma in vitro and in animal models. In vitro, it is active at low concentrations in cancers resistant to arsenic trioxide. Anti-cancer activity is multifaceted and is mediated by disrupted mitochondrial function, increased reactive oxygen species (ROS) production, modified signal transduction and anti-angiogenesis. Methods: (1) Phase I/II study to determine maximum tolerated dose (MTD), dose- limiting toxicity (DLT), safety-profile and preliminary efficacy in patients with advanced/progressive myeloma receiving ZIO-101 daily for 5 consecutive d every 4 w; (2) comparison of this schedule at MTD with a schedule of 420 mg/me2/d twice/w for 3 w every 4 w. Results: (1) phase I/ II: 19 patients have been treated so far. Median age is 61 y (range, 41–84 y). Median N prior therapies was 8 (range, 4–10). ZIO-101 was well-tolerated; MTD was 420 mg/me2/d for the 5 d schedule, and DLT was transient confusion /ataxia. No clinically- important biochemical, bone marrow, or cardiac toxicities were seen and there was neither neuropathy nor QTc-prolongation. Pain during peripheral infusion was reported in some patients. Anemia was the only adverse event = grade-3 in 25% of subjects. 6 of 14 evaluable subjects had stable disease (SD) =8 w and 2, SD > 6 mo. Accrual to the phase II portion continues. Conclusions: ZIO-101 was well- tolerated. In the daily for 5 consecutive d every 4 w schedule, the MTD is 420 mg/me2/d and DLT, transient confusion /ataxia. There was SD in 43% of patients with advanced/progressive myeloma, of whom half are beyond 6 months. Accrual into the phase II part of this study continues.

No significant financial relationships to disclose.
Expression and immunogenicity of the cancer-testis antigen CT7 (MAGE-C1) in patients with multiple myeloma
Authors: Curioni Fontecedro A. , Knights A. J. , Tinguely M. , de la Rosa O. , Lopes B. , Moch H. , Renner C. , Zippelius A. , Knuth A.
Published: March 2020

8112

Introduction: CT7 (MAGE-C1) is an antigen with restricted expression in cancer and testis (CT antigen). It has been demonstrated to be expressed in more than 55% of Multiple Myeloma (MM) bone marrow biopsies (BMB). CT7 immunogenicity was so far unknown. Thus we aimed to analyse the immune response of MM patients towards CT7. Moreover, we evaluated correlations between CT7 expression and prognostic features. Methods: The CT7 gene was cloned from a MM cell line by RT-PCR; the protein has been expressed in E. coli, purified by affinity FPLC and analysed by Mass Spectrometry. MM patients’ sera (1:200 dilution) were analysed towards the CT7 full length protein by Western Blot (WB) and against truncated CT7 by WB and ELISA. BMB were analyzed by immunohistochemistry (IC) for CT7 expression and for proliferation/differentiation markers. Specific chromosomal aberrations were investigated by FISH analysis. Results: Both full-length and truncated proteins have been produced and fully sequenced. Out of 55 patients’ sera 12 typed positive for the full length protein by WB analysis. Ten of sixteen (62.5%) BMB were positive for CT7. So far no correlation with prognostic features was established. Conclusions: For the first time the in vivo immunogenicity of CT7 was demonstrated. Our preliminary data indicate that spontaneous anti-CT7 humoral responses occur in a significant proportion of MM patients. All detectable humoral responses observed to date are in patients with advanced disease. Characterization of antibody-binding sites and specific CD8/CD4 T cell responses in MM patients is on-going. Our data support the broad and strong expression of CT7 in patients with MM. To date CT7 represent the most immunogenic cancer testis antigen in MM.

No significant financial relationships to disclose.
Prognostic values of lung resistance protein (LRP) and P53 in patients with multiple myeloma (MM)
Authors: Elsawy W. H. , Abdel Kader M. , Gharib A. F. , Elnemr M. M. , Eltarhony S. A. , Gendia A. Y. , Abdullah M. , Dorgham Y. T.
Published: March 2020

8113

Background: This study was undertaken to assess the significance of lung-resistance related protein (LRP) expression and p53 mutations in plasma cells from untreated multiple myeloma (MM) patients and to determine whether LRP expression and p53 deletions was associated with a poor response and survival in patients treated with a conventional dose of melphalan. Methods: We have studied LRP expression by immunocytochemistry and p53 deletions by interphase fluorescence in situ hybridization (FISH) with a DNA probe specific for the p53 locus at 17p13 in bone marrow plasma cells from 38 untreated patients with MM received conventional oral dose melphalan (0.25 mg/kg, day 1 to 4) combined with prednisone (MP). We also studied their association with both response to chemotherapy and survival of the patients. Results: By FISH, deletions of p53, were detected in 31.5% of patients and LRP was found positive in 36.8%. Patients with a p53 deletion were predominantly at stage III (p53 deletion in 83.4% of stage III patients vs. 8.3% of patients at stages I and II respectively; P = 0.04). Both p53 deletion and LRP expression were correlated with other laboratory and clinical parameters. The overall response rate of all of the evaluable patients was 63.2%. The response rate was 79.2% for patients without LRP expression but only 35.7% for patients with LRP expression (P = 0.01). Among the 12 patients with a p53 deletion by FISH, 25% responded compared with 75% of patients without p53 deletion (P = 0.001). With the exception of LRP expression and p53 deletions, there was no other prognostic variable sharing any correlation with response. The median survival of LRP-positive patients was 11 months (95%-Cl: 9 to 24), whereas the median survival duration of LRP negative patients was not reached (Cl: 26 to 82; P < .002; hazard ratio [HR] = 2.9 (1.4–5.7). Patients with and without p53 deletions had significantly different overall survival times (median 13.9 months, 95%-CI: 8 to 26 and median not reached, CI: 24 to84, respectively; P < .0001; hazard ratio [HR] = 2.6). Conclusions: For patients with MM who were treated with conventional-dose chemotherapy, LRP expression and p53 deletions provides prognostically relevant information in addition to that provided by standard prognostic factors.

No significant financial relationships to disclose.
Quantitative bone ultrasonography at phalanges in patients with high-risk monoclonal gammopathy of unknown significance (MGUS) and myeloma treated with zoledronic acid
Authors: Iuliano F. , Guzzo I. , Deterlizi F. , Di Maio M. , Infusino S. , Perricelli A. , Pomillo A. , Molica S. , Baserga M.
Published: March 2020

8115

Background: Bisphosphonates are commonly used for metastatic bone disease in order to prevent skeletal-related events, to reduce bone pain and to improve quality of life. Zoledronic acid is commonly used in myeloma patients (pts), but additional studies are needed to determine the optimal timing, schedule and duration of treatment. Aim of the present study is to assess bone mineral density (BMD) in patients with high-risk MGUS and myeloma receiving zoledronic acid, using quantitative ultrasound analysis in transmission through phalanges. Methods: DBM Sonic Bone Profiler is the only ultrasound device that applies the method of signal analysis in transmission through phalanges. This technique has proven to be particularly effective in the diagnosis and treatment monitoring of post-menopausal osteoporosis. Measurements of BMD were performed by ultrasonography at distal metaphysis of the first phalanx of the II, III, IV and V hand finger, at baseline and at 1, 3, 6, 9, 12, 15 and 18 months. Results: 12 pts with high-risk MGUS (8 IgG k, 4 IgG lambda) and 4 pts with myeloma IIIA (3 IgG k, 1 IgA lambda), 6 males/ 10 females, median age 69 years, received zoledronic acid 4 mg intravenously every 4 weeks for at least 12 courses. All subjects took daily oral supplements containing elemental calcium (1 g) and vitamin D (400 IU). Myeloma patients also received chemotherapy. 4/6 males (66%) and 5/10 females (50%) improved amplitude-dependent speed of sound (AD-SoS) over the least significant change after 6 months. Mean difference from baseline value of AD-SoS shows a trend after 4 months of treatment, and became significant after 16 months (p<0.005). Conclusions: Densitometric-structural evaluation of bone tissue at phalanges is safe and useful to evaluate bone quality changes during treatment with zoledronic acid, that determines a significant and sustained increase in ultrasonographic parameters of bone density and structure.

No significant financial relationships to disclose.
A randomized phase III trial of 1 month versus 1 year adjuvant high-dose interferon alfa-2b in patients with resected high risk melanoma
Authors: Gogas H. , Dafni U. , Bafaloukos D. , Polyzos A. , Kokkalis G. , Kalofonos H. P. , Fountzilas G. , Skarlos D. , Tsoutsos D. , Pectasides D.
Published: March 2020

8505

Background: High dose IFNa regimen as reported in E1684 was unique for the incorporation of an induction phase of maximally-tolerated dosages of IV therapy for the initial 4 weeks. This is the only trial that has shown prolongation of overall survival and disease-free survival in comparison to observation. Analysis of the hazard curves for DFS and OS in E1684 reveal early and durable separation of the high-dose and observation arms suggesting that the induction phase may represent a critical component of the high-dose regimen, although this has not been tested prospectively. Methods: We conducted a prospective randomized study of IV induction therapy vs a full year of high-dose IFN with primary endpoints of DFS and OS for stage IIB, IIC and III melanoma patients within 56 days of curative surgery. Patients were randomized to receive IFN alfa-2b 15×106 U/m2 IV × 5/7 days weekly × 4 weeks (arm A) versus the same regimen followed by 10×106 U(flat dose) SC 3 times a week for 48 weeks (arm B). The proposed treatment would be considered at least as good as the conventional treatment, if the relapse rate at 3 years from study entry is at most 15% higher in the former arm (power 85%, one-sided test a=0.05, required sample size: 340). Results: Between 1998 and 2004, 364 patients were enrolled (355 eligible: 178 arm A and 177 arm B). Patients′ and tumor characteristics were well balanced between the two arms. At a median follow up of 51 months (95% CI 46–55), the median DFS is 32 months vs 31 months (p=0.836) and the median OS is 61 months vs 63 months (p=0.444). Eleven patients discontinued treatment in arm A and 54 in arm B. The discontinuation rate is significantly higher in group B (p<0.001), possibly due to the longer duration. Reasons for discontinuation were disease progression (69%) and toxicity (19%). Patients in arm B had more grade 3–4 hematologic, constitutional and neurologic toxicity. Conclusions: There are no significant differences in OS and DFS between the regimen of 1 month and 1 year treatment tested.

[Table: see text]
Role of ultrasound (US) and US-guided fine needle aspiration cytology (US-FNAC) prior to sentinel lymph node biopsy (SLNB) in 500 melanoma patients: Reduction of need for SNLB by high US-FNAC SN positive identification rate
Authors: Voit C. A. , van Akkooi A. C. , Schäfer-Hesterberg G. , Schoengen A. , Sterry W. , Eggermont A. M.
Published: March 2020

8512

Background: SN status as the important prognostic factor reflects the likelihood of metastatic melanoma and the MSLT-1 trial showed similar 5ys-survival rates of ∼85% both in the SN-staged group and in the watch&wait group. SN-staging far outperforms PET-scanning, since PET is only reliable for detection of metastatic lesions > 125 mm3. SN-staging is an invasive procedure and better screening methods are required to identify early disease in SNs. This ongoing study examines the role of US to demonstrate SN metastasis thus avoiding surgical SN- staging in a proportion of melanoma pts. Methods: In this prospective study 503 consecutive melanoma pts. underwent scintigraphy and then US-exam prior to scheduled SLNB. When US was suspicious for malignant deposits in the SN, pts underwent a FNAC. So far we determined outcome in 400 AJCC staged pts (median Br 2.7 mm). Interim FU-data are updated until 10/06 (mean/median FU 26/24 (1 - 64) mo. For pts with a positive SN we considered the pre-SN US/US-FNAC pos. if either US and/or FNAC were positive. If both were only suspicious, it was considered negative. Results: US identified the SN in 52/80 (86%). Specificity was 99% (317/320) with a PPV of 95% and NPV of 92%. SN identification rate by FNAC increased from 40% in stage pT1a/b to 79% in stage pT4a/b according to the higher probability for nodal disease in higher pT stages (4% in pT1ab vs 57% in pT4ab). FNAC became more sensitive with increasing tu load: SN with deposits of 0.50–1.99 mm were verified in 13/25 (52%), whereas with deposits > 2 mm in 13/16 (83%). 80/400 SNs were histologically malignant with 15/80 (22%) submicroscopic involvement (<0.1 mm), an identical percentage as in the Rotterdam series (van Akkooi, Ann Oncol 2006). Of the node pos. pts, 50% (40/80) already found positive on US guided FNAC could have avoided undergoing a SLNB and proceeded straight to TLND. Histolog. patterns of involvement in 68 SNs were examined: 26/68 showed subcapsular, 6/68 parenchymal and 20/68 combined. Updated DFS and OS will be reported. Conclusions: US of the SN and US-guided FNAC is highly accurate. In this prospective study 50% of the SN positive pts could have been spared the need to undergo a SLNB.

No significant financial relationships to disclose.
Prospective center-randomized trial of melanoma surveillance in 3,833 patients: An analysis of the early detection of recurrences
Authors: Garbe C. , Leiter U. M. , Weichenthal M. , Figl A. , Schadendorf D. , Hauschild A.
Published: March 2020

8516

Prospective center-randomized trial of melanoma surveillance in 3,833 patients: An analysis of the early detection of recurrences Garbe C, Leiter U, Weichenthal M, Figl A, Schadendorf D and Hauschild A Background: A follow up strategy with reduced imaging techniques in melanoma = 1.0mm, performed at the department of dermatology in Tuebingen (arm A) was compared to the previous more extended follow up schedule at the departments of dermatology in Kiel and Mannheim (arm B), table 1 . Methods: Follow up examinations were evaluated in stage I-III melanoma patients for a time period of two years. The early detection of recurrences (size of metastasis = 2 cm in diameter, <10 metastases, R0 resection) was the primary endpoint of the study. Results: 2,577 (arm A) and 1,256 (arm B) patients were documented with 12,965 physical examinations, 7,610 blood tests and 10,599 examinations with imaging techniques. 211 patients (112 arm A, 99 arm B) presented with 452 recurrences (240 arm A, 212 arm B). Of these 55.4 % were classified as early detected (arm A 64.3%, arm B 45.5%). A reduction of clinical and technical examinations in stage I melanoma (= 1.0 mm) did not have an effect on the early detection of recurrences. Loco-regional recurrences were mainly detected by physical examinations and lymph node ultrasound and were discovered earlier in arm A (P=0.01). This may be attributed to lymph node ultrasound which is more frequently applied in melanoma >1.0mm and stage III patients. No difference was observed in the detection of distant metastases, where CT scans and S100 blood tests had the highest diagnostic impact. Conclusions: A reduction of physical and technical examinations in primary melanoma =1.0mm, application of lymph node ultrasound in melanoma > 1.0 mm and an intensified follow up program in stage III may be considered as appropriate follow-up strategy.

No significant financial relationships to disclose.

[Table: see text]