bluuebunny/crossref_metadata_2025 huggingface dataset:
Clarithromycin, pomalidomide, and dexamethasone (ClaPD) in relapsed or refractory multiple myeloma.
Authors: Rossi Adriana C. , Mark Tomer Martin , Rodriguez Melissa , Shah Manan , Quinn Ryann , Pearse Roger N , Zafar Faiza , Pekle Karen , Speaker Stephanie , Jayabalan David , Ely Scott , Coleman Morton , Chen-Kiang Selina , Niesvizky Ruben
Published: March 2020

8036

Background: Clarithromycin has been shown to enhance anti-myeloma activity of lenalidomide+dexamethasone in the upfront treatment of multiple myeloma (MM). Pomalidomide is an immunomodulatory agent effective in relapsed/refractory MM (RRMM). We hypothesized that clarithromycin may similarly enhance pomalidomide + dexamethasone in RRMM. We now report updated results from a phase 2 trial of ClaPD in RRMM. Methods: 73 patients with RRMM were enrolled in a single-institution phase 2 study of ClaPD. All subjects had ≥ 3 prior lines of therapy, one of which must have included lenalidomide. ClaPD is clarithromycin 500mg twice daily; dexamethasone 40mg weekly; and pomalidomide 4mg for days 1-21 of a 28-day cycle. All patients had VTE prophylaxis with aspirin. Monthly disease response evaluation included immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM responses. Treatment continued as tolerated until disease progression. Results: The 66 patients who completed ≥ 1 cycle of ClaPD are reported. Median number of cycles was 6 (range 1-17). Responses were progressive disease: 10%, stable disease: 21%, minimal response: 12%, partial response: 33%, very good partial response: 18%, stringent complete remission: 5%, for an overall response rate (ORR) of 56% and ≥VGPR rate of 23%. Median time to PR was 1.25 cycles (range 1-8). Median PFS was 5 months. Response and PFS were not different in patients refractory to lenalidomide (85%), bortezomib (82%), or double-refractory patients (76%). After a median follow up of 12 months,28 pts (42%) remain on study without progression and 56pts (85%) are alive. Two pts withdrew due to toxicity (1 Grade 3 fatigue, 1 Grade 4 muscular weakness). One patient withdrew consent. Conclusions: ClaPD is highly effective for heavily pre-treated RRMM, particularly in lenalidomide-refractory disesase and compares favorably to previously published Phase 2 data of Pom/Dex (ORR 56% vs 40% - Lacy et. al JCO 2009) without excess toxicity. Response to ClaPD is rapid, well tolerated, and sustained over 7 months in most subjects. These data support the clinical efficacy of pomalidomide based regimens in RRMM.
Second cancer risk 40 years after cure for Hodgkin lymphoma.
Authors: Schaapveld Michael , Aleman Berthe M , Eggermond Anja M , Janus Cecile P , Krol Augustinus , Maazen RWM Van Der , Raemaekers John M. M. , De Boer J. P. , Zijlstra Jose M , Van Imhoff Gustaaf Willem , Beijert Max L , Poortmans Philip M. , Lybeert Marnix L. , Mulder Ina , Visser Otto , Louwman Marieke J. , Sombroek Cherita , Lugtenburg Pieternella , van Leeuwen Flora E.
Published: March 2020

8039

Background: During the last decades Hodgkin Lymphoma (HL) treatment changed towards less toxic chemotherapy schemes and smaller radiation fields. The impact of these changes on second cancer (SC) risk is still unknown. Methods: We calculated standardized incidence ratios (SIR), comparing SC risk after HL treatment with expected risk, based on cancer incidence in the general population, and compared SC risk between treatment modalities, accounting for competing events, in a large Dutch cohort comprising 3,390 5-years HL survivors, aged 15-51 years at HL treatment and diagnosed between 1965-2000. Results: The median follow-up was 18.2 years; 23% of the patients was followed ≥25 years. During follow-up 734 SCs and 92 third cancers (TC) occurred. The SIR for any SC was 4.5 (95% confidence interval (95%CI) 4.1-4.9). SC risk was still elevated after 35 years of follow-up (SIR 3.9; 95%CI 2.5-5.8) and cumulative incidence (CI) reached 47.1% (95%CI 43.6-50.5) at 40 years follow-up. For TCs the SIR was 5.5 (95%CI 4.4-6.9); the 20-year CI was 22.3% (95%CI 17.8-27.2). Risks of NHL and leukemia strongly decreased in more recent treatment periods (P-trend <0.001). The CI of solid tumors (ST) between 5-19 years after HL treatment did not differ for patients treated between 1965-1979, 1980-1989 or 1990-2000 (P=0.21; 19-year CI 9.1%, 11.6% and 11.4%, respectively). Radiotherapy (RT) above the diaphragm increased risk of STs above the diaphragm (hazard ratio (HR) 2.4, P<0.001), while subdiaphragmatic RT was associated with a 1.7-fold increased HR of a subdiaphragmatic ST (P=0.001). An incomplete mantle field was associated with significantly lower breast cancer (BC) risk (hazard ratio (HR) 0.4, 95%CI 0.2-0.8). A cumulative procarbazine dose >4.2 g/m2 yielded a 1.3-fold increased HR (95%CI 1.0-1.7) for non-breast STs and a 2-fold (95%CI 1.2-3.1) increased HR for gastrointestinal STs, but was associated with a strongly decreased BC risk (HR 0.3, 95%CI 0.2-0.6). Conclusions: SC risk after HL has decreased with treatment changes over the last decades, due to strongly decreasing risk of leukemia and NHL. Smaller radiation fields and procarbazine doses >4.2 g/m2 are associated with lower breast cancer risk, while high procarbazine doses increase risk of gastrointestinal STs.
Long-term follow-up results of a phase I/II study of concurrent chemoradiotherapy for localized nasal NK/T-cell lymphoma (NKTCL): JCOG0211.
Authors: Yamaguchi Motoko , Tobinai Kensei , Oguchi Masahiko , Ishizuka Naoki , Kobayashi Yukio , Isobe Yasushi , Ishizawa Kenichi , Maseki Nobuo , Itoh Kuniaki , Usui Noriko , Wasada Izumi , Ishikura Satoshi , Kagami Yoshikazu , Kinoshita Tomohiro , Hotta Tomomitsu , Tsukasaki Kunihiro , Oshimi Kazuo ,   Japan Clinical Oncology Group - Lymphoma Study Group (JCOG-LSG)
Published: March 2020

8050

Background: Concurrent chemoradiotherapy has been regarded as one of the standard management for localized nasal NKTCL. However, its long-term efficacy and toxicity is not known. Methods: The JCOG0211 trial is a phase I/II study of concurrent chemoradiotherapy consisting of radiotherapy (RT) of 50 Gy and 3 cycles of DeVIC (carboplatin, etoposide, ifosfamide, dexamethasone) for newly diagnosed, localized nasal NKTCL (JCO 2009). Patients (Pts) with newly diagnosed, localized diseases (IE & contiguous IIE with cervical node involvement) who were 20-69 yrs of age with PS 0-2 were eligible. 3-D conformal RT planning with a wide margin (+ 2 cm to the gross tumor, the entire nasal cavity and the nasopharynx) and a 2-step cone down were required. 33 pts were enrolled in the study, 27 of whom were treated with RT and a 2/3-dose of DeVIC, which was selected as the recommended phase II dose in the preceding phase I portion of the trial. All pts completed RT without any protocol violations. Long-term follow-up results on overall survival (OS), progression-free survival (PFS) and toxicity were evaluated. Results: The median follow-up was 69 months (range, 62-96). The pt (N=33) characteristics were as follows: median age 54 yrs (range, 21-68); stage IIE 33%; B symptom (+) 36%; elevated serum LDH 21%. %5-yr OS and PFS were 73% (95%CI, 54-85%) and 67% (95%CI, 48-80%), respectively. 11 pts (33%) experienced disease recurrence. Two achieved a 2nd CR by salvage chemotherapies followed by allogeneic stem cell transplantation, and the remaining 9 pts died of disease. There was no observed death and disease progression after 34 and 31 months, respectively. One pt experienced Grade 3 irregular menstruation for 3 years. No other Grade 3 or 4 late non-RT-associated adverse events (AEs) were observed. One pt received plastic surgery due to Grade 4 RT dermatitis. No other Grade 3 or greater RT-associated late AEs were encountered. Conclusions: Both survival benefit and disease control from concurrent chemoradiotherapy with RT and DeVIC are maintained during a 5-yr follow-up, indicating the excellent efficacy of this approach as a first-line therapy for localized nasal NKTCL. Long-term toxicity is acceptable.
Determinants of and outcomes associated with chemoimmunotherapy dose density in elderly subjects with diffuse large B-cell lymphoma (DLBCL).
Authors: Perepu Usha S. , Weibel Kelcy C , Button Anna M , Jacobus Laura S. , Smith Brian , Cerhan James R. , Link Brian K.
Published: March 2020

8061

Background: RCHOP is the standard first line therapy for DLBCL but elderly patients often receive suboptimal doses. Relative dose intensity (RDI) less than 70-90% has previously been associated with inferior survival in CHOP treated patients. We now investigate the clinical determinants of immunochemotherapy dose delivery and comparative effectiveness of dose intensity on lymphoma-specific outcomes in persons over the age of 60. Methods: SPORE MER (Molecular Epidemiology Resource) is a prospectively accrued observational study in which University of Iowa and Mayo Clinic patients with a diagnosis of Non Hodgkins lymphoma have been enrolled since 2003. We reviewed data from the Iowa patients along with medical records from DLBCL patients over the age of 60 treated with anthracycline based chemo immunotherapy consecutively enrolled up through to December 2009. Statistical tests of associations between RDI and clinicopathologic factors, as well as survival outcomes, were performed. Results: We identified 92 patients over the age of 60. The median age was 70. 47 subjects experienced at least 1 dose reduction, 26 subjects had dose delays, and 20 subjects were unable to complete therapy. RDI ranged from 0.30-1.70 (median 0.92) for doxorubicin and from 0.29-1.70 (median 0.97) for cyclophosphamide. 24 and 19% of subjects received < 80% of RDI for dox and cy respectively. Age (p< 0.001 for both dox and cy) and performance status (p=0.04 for dox) but not number of medications, ACE27 co-morbidity score, body surface area, nor need for acute care visits were associated with decreased RDI. Adjusted for IPI, RDI did NOT have a significant effect on event-free or lymphoma-specific survival. Conclusions: Among clinical variables, age is the dominant variable associated with delivery dose intensity for chemotherapy in elderly patients treated for DLBCL; and among elderly patients receiving chemo immunotherapy, we did not find an association between dose intensity and lymphoma-specific outcomes. [Table: see text]
Brentuximab vedotin for relapsed or refractory non-Hodgkin lymphoma: Preliminary results from a phase II study.
Authors: Advani Ranjana , Oki Yasuhiro , Shustov Andrei R. , Grove Laurie E. , Bartlett Nancy
Published: March 2020

8070

Background: Brentuximab vedotin is a CD30-directed antibody-drug conjugate approved for the treatment of Hodgkin lymphoma and systemic anaplastic large cell lymphoma (ALCL) after failure of other therapies. Based on the high objective response rate observed in patients with systemic ALCL, a type of non-Hodgkin lymphoma that is characterized by homogeneous CD30 expression, a study was initiated in other non-Hodgkin lymphomas that express the CD30 target. Methods: A phase 2 open-label single-arm study is underway in patients with relapsed or refractory CD30-positive non-Hodgkin lymphoma, excluding ALCL (NCT01421667). Brentuximab vedotin is administered IV at 1.8 mg/kg every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint is objective response rate assessed by the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Tumor specimens are assessed by central lab in order to characterize the relationship of CD30 expression with antitumor activity. Results: Ten patients (age range 28–83; 5 M, 5 F) have enrolled to date. Diagnoses include diffuse large B-cell lymphoma (DLBCL, n=2), EBV-positive DLBCL of the elderly (n=3), primary mediastinal B-cell lymphoma (n=2), peripheral T-cell lymphoma NOS (n=2), and angioimmunoblastic T-cell lymphoma (AITL). Patients had received 1–6 prior chemotherapy regimens; 3 patients had prior stem cell transplants. Of 6 patients who have completed the cycle 2 response assessment, 2 attained complete remission, 1 with DLBCL (90% CD30+) and 1 with AITL (8% CD30+), 1 had stable disease, and 3 had progressive disease. Treatment-related serious adverse events observed to date were rash, febrile neutropenia, and mastoiditis. Conclusions: Preliminary results suggest that brentuximab vedotin may have antitumor activity in patients with relapsed or refractory CD30-expressing non-Hodgkin lymphomas, in addition to the efficacy previously observed in systemic ALCL. Updated study results will be presented.
Use of exon-based transcriptome profiling to identify novel signaling pathways and survival-associated genes in diffuse large B-cell lymphoma.
Authors: Leppa Sirpa , Taskinen Minna , Koivula Satu , Chen Ping , Louhimo Riku , Delabie Jan , Karjalainen-Lindsberg Marja-Liisa , Bjorkholm Magnus , Fluge Oystein , Pedersen Lars Moeller , Rydstrom Karin , Jerkeman Mats , Eriksson Mikael , Hautaniemi Sampsa , Holte Harald ,   Nordic Lymphoma Group
Published: March 2020

8074

Background: Identification of biological prognostic factors that could be used to define poor risk diffuse large B-cell lymphoma (DLBCL) patients is a main concern. Methods: Study population consisted of 38 de novo high risk DLBCL patients less than 65 years old. The patients were treated in the Nordic phase II protocol with six courses of R-CHOEP14 followed by systemic central nervous system prophylaxis with one course of high dose methotrexate and one course of high dose cytarabine. Exon array-based profiling was used to screen signaling pathways and differentially expressed genes between the clinically high risk patients, who had relapsed or remained in remission in response to dose dense chemoimmunotherapy. At the time of the analysis, median follow up was 34 months, progression free survival (PFS) 78% and overall survival (OS) 78%. Results: The screen between relapsed patients and the patients in remission using criteria of p ≤ 0.05 and fold change ≥ 1.6 revealed 566 differentially expressed genes (131 protein coding), of which 24 were likely to be involved in conventional signaling pathways, including those regulating antigen processing and presentation (CIITA, HLA-DQA2, HLA-DQB1, RFXAP), Jak-STAT signaling (SOCS3), Notch signaling (NOTCH1) and Toll-like receptor signalling (IRF5). In cox univariate analysis, 12 of 24 genes were found to associate with PFS (p<0.05). Of these, high expression of CIITA, DLL4, HLA-DQA2, HLA-DQB1, IRF5, NOTCH1, PER1, RFXAP, SEMA4D and ZFP36 had a favorable impact on PFS, whereas high levels of ENPP3 and PRKAR2B were associated with adverse outcome. Differential expression of four genes was confirmed by quantitative PCR, and prognostic value of six genes validated using Lymphoma/Leukemia Molecular Profiling Project microarray data set. Immunohistochemical validation of the findings in a larger patient cohort is ongoing. Germinal centre B-cell signature did not predict survival in this cohort. Conclusions: The results provide evidence that exon-based transcriptome profiling can identify biologically relevant signaling pathways and genes that discriminate the outcome of homogenously treated young high risk DLBCL patients.
Prevention of adverse events during treatment of HIV-associated Hodgkin lymphoma with ritonavir and zidovudine.
Authors: Sandhu Sonia , Gupta Shweta , Itokazu Gail , Braik Tareq , Jain Shivi , French Audrey L. , Rubinstein Paul G.
Published: March 2020

8085

Background: In response to very high rates of neurologic and hematologic adverse events (AE) when ABVD was used in combination with ritonavir (RTV) or zidovudine (AZT) in HIV-associated Hodgkin (HL) we instituted a policy to use alternative antiretroviral agents during HL therapy in our HIV patients. In this study, we examined all AE in HIV-HL since the exclusion of RTV and AZT over 2 years ago. We also evaluated the AEs when HAART and chemotherapy for NHL were taken together in an expanded cohort of 52 pts. Methods: A screen of pharmacy and hospital databases between 1998-2012 identified all HIV-associated HL and NHL patients. Adverse events during chemotherapy were assessed by chart review and graded per the NCI Common Terminology Criteria for Adverse Events. Statistics: Fisher's exact test was used to examine the differences in AE incidence associated with use of specific antiretrovirals. Results: HAART use during chemotherapy was identified in 35/36 (96%) pts with HL and 52/108 (48%) of pts with NHL. Before RTV and AZT were prohibited, G3/4 neuropathy, neutropenia, and anemia developed in 31, 68, and 57% of 23 pts with HIV-HL respectively. Since then, 12 patients were treated with non-RTV and AZT based HAART. 0% neuropathy and only 20% G3/4 neutropenia and 10% anemia was observed, each statistically significant (p<0.01). Of the 54 patients with NHL, 64% received CHOPR like, HYPERCVADR (18%), and daEPOCHR (11%). All AEs for each NHL regimen were similar to historical controls and no anti HIV medication was found to correlate with any AE, despite 28% of the HAART regimens containing RTV. Conclusions: No relationship between any AE and anti HIV medications was identified during treatment for NHL. But, excluding RTV or AZT-based HIV therapy during HL treatment, decreased neuropathy, neutropenia, and anemia by 100%, 38%, and 28% respectively. We suggest that exclusion of ritonavir and zidovudine from HAART regimens used with ABVD become the standard.
Predictive value of baseline serum MIP-1α and CRP on symptom burden and tumor response to induction therapy in patients with multiple myeloma.
Authors: Cleeland Charles S. , Wang Xin Shelley , Thomas Sheeba K. , Liu Ping , Sailors Mary H , Mendoza Tito R. , Reuben James M. , Cohen Evan N. , Gilmore Katherine R. , Ilagan Venus M , Williams Loretta A. , Johnson Valen E.
Published: March 2020

8091

Background: Macrophage inflammatory protein-1α(MIP-1α) is a growth factor for human multiple myeloma (MM) cells. As an osteoclastic factor, its presence provides pathophysiological evidence of the development of lytic bone lesions in MM. C-reactive protein (CRP) indicates systemic inflammation. The relationship between disease-driven inflammatory markers and both patient-experienced symptoms and tumor response to induction therapy is unknown. Methods: MM patients (N=39) who were either newly diagnosed or had received fewer than 2 cycles of chemotherapy, and who also were to receive induction therapy, were enrolled. To test concentrations of MIP-1α and CRP, serum samples were collected before and after induction and assayed by Luminex. Multiple symptoms were measured twice a week via the M. D. Anderson Symptom Inventory MM module (MDASI-MM) from -8 to +112 days of induction. The MM-specific items of the MDASI-MM are bone aches, constipation, muscle weakness, diarrhea, sore mouth or throat, rash, and difficulty paying attention. Correlation between symptom severity and inflammatory markers at baseline was examined by linear regression modeling. Kruskal-Wallis significance test and Wilcoxon test were used to examine association between MIP-1α and tumor response. Results: Patients received either bortezomib-based (89%) or lenalidomide-based induction therapy. Baseline MIP-1α and CRP were significantly inversely related to the mean severity component score of the 5 most-severe symptoms (fatigue, pain, bone aches, poor sleep, drowsiness) (p=.03; p=.02), and significantly inversely related to the severity of a component score of the module-specific symptoms (p=0.04; p=.002). Change over time in MIP-1α differed significantly by tumor response category (p=.04), with the partial response group having a higher median score than the complete response group (1.483 vs. 0.016, p=.01). Conclusions: Our data suggest that higher baseline levels of serum MIP-1α and CRP predict effective chemotherapy-induced reduction of disease-related symptoms in MM patients. Higher serum MIP-1α expression after induction therapy was related to less-ideal tumor response.
Prognostic value of serum lactate dehydrogenase in symptomatic multiple myeloma.
Authors: Patel Krina K. , Orlowski Robert Z. , Weber Donna M. , Wang Michael , Thomas Sheeba K. , Shah Jatin J. , Turturro Francesco , Alexanian Raymond , Delasalle Kay
Published: March 2020

8093

Background: In patients with symptomatic multiple myeloma, the clinical features, responses to treatment, and survival times vary. Well established predictors of survival include the International Staging System (ISS), cytogenetic abnormalities, and response to therapy. Long recognized has been the association of high serum lactate dehydrogenase (LDH) with advanced disease and shorter survival. We focused here on the impact of high LDH on staging and prognosis in order to guide the role of recent advances in therapy. Methods: We evaluated 1,247 patients with newly diagnosed, symptomatic myeloma from 10/74 to 7/11. Our goal was to determine the prognostic value of high LDH (>300 IU/L) in relation to ISS stage. We also compared the frequencies of anemia, hypercalcemia, and response to therapy in patients with high LDH with those of patients with Stage III disease and normal LDH values. Results: All 1,139 patients with normal LDH lived significantly longer than the 108 patients with elevated values (47 vs. 16 months, p <.01). LDH was elevated in 9% of all patients, but in 2%, 6%, and 18% of patients with ISS-I, II, and III disease, respectively. Their survival times were also significantly shorter than those of comparable patients in each stage with normal LDH (table). Among the 108 patients with high LDH, the frequencies of hemoglobin <8.5 g/dl (54 vs. 41%, p=.03), and serum calcium>11.5 mg/dl (41 vs. 27%, p<.01) were significantly higher than those of 292 patients with Stage III disease and normal LDH, and the frequency of response to therapy was less (40 vs. 62%, p<.01). Conclusions: Serum lactate dehydrogenase provides a convenient and dependable prognostic indicator in patients with multiple myeloma. An elevated LDH value indicates a poor prognosis regardless of ISS stage, confirming the report by Gkotzamanidou, Terpos, and Dimopoulos et al, and should be included in the definition of stage III disease. Such patients require rapid control of disease with sequential combinations of effective drugs and intensive therapy in order to improve their outcome. [Table: see text]
Clinical profile of multiple myeloma in Asia: An Asian Myeloma Network (AMN) study.
Authors: Lee Jae Hoon , Kim Kihyun , Kim Jin Seok , Min Chang Ki , Shimizu Kazuyuki , Chou Takaaki , Kosugi Hiroshi , Suzuki Kenshi , Hata Hiroyuki , Chen Wenming , Hou Jian , Huang Shang-Yi , Chng Wee Joo , Tan Daryl C.L. , Teoh Gerrard , Chim James , Liang Raymond , Nawarawong Weerasak , Siritanaratkul Noppadol , Durie Brian G.
Published: March 2020

8097

Background: The incidence of multiple myeloma (MM) is known to be variable according to ethnicity. However the difference of clinical characteristics between ethnic groups is not well-defined. In Asian countries the incidence of MM has been lower compared with Western countries. However, there are growing evidences that MM is increasing very rapidly in this region. Until now, only few data of Asian patients has been reported. Asian myeloma network (AMN) decided to analyze the first multinational project to explore clinical characteristics of Asian MM patients and clinical practice performed in Asian countries. Methods: Data were collected from 21 centers from 7 countries and regions were collected retrospectively. Clinical characteristics of 2969 symptomatic MM patients at diagnosis were described. Overall survival (OS) and prognostic factors were analyzed for 2273 patients who have survival data. Results: Median OS was 54 months (95% CI 48.0-60.0). Patients who were diagnosed before 2000 were shorter survival. Transplantation was performed to 513 patients with better survival (84 vs. 45 months, p<0.001). First line treatment of 2339 evaluable patients was analyzed. Overall response rate was 71% with 30%, VGPR or better. New drugs including bortezomib, thalidomide or lenalidomide were combined for 32.5% of all 2339 patients without difference in response rate or OS according to combination. Conclusions: We successfully described clinical characteristics of Asian MM patients and this project will be the base for future studies or clinical trials for Asian MM patients. Updated analyses and comparison with Western data will be presented. AMN, supported by the International Myeloma Foundation (IMF) IMWG initiative.
Survival outcomes of early autologous stem cell transplant (ASCT) followed by lenalidomide, bortezomib, and dexamethasone (RVD) maintenance in patients with high-risk multiple myeloma (MM).
Authors: Kaufman Jonathan L. , Nooka Ajay K. , Muppidi Samatha , Heffner Leonard T. , Gleason Charise , Boise Lawrence , Lonial Sagar
Published: March 2020

8100

Background: Despite markedly improved survival rates for MM pts in the last decade, 15-20% of pts with high risk genetics continue to have dismal outcomes with a median PFS of 18.5 months (Kapoor P et al). In this subset of pts, efforts are needed to improve response rates and prolong the response duration, but doing so without genotoxic therapy as this has been shown not to improve outcomes (Barlogie et al). Methods: We evaluated 37 pts with high risk features [del17p (n=16), t(4;14) (n=1), t(14;16) (n=4) by FISH/CTG; hypodiploidy (n=9), del 13 (n=16); complex karyotype (n=14) by CTG; PCL (n=7) and atypical presentation (n=4)]. After completing induction therapy, all pts underwent ASCT followed by RVD maintenance. 60 days after ASCT following hematological recovery, pts began maintenance [lenalidomide 10 mg/day (days1–21), bortezomib 1.3 mg/m2 and dexamethasone 40 mg once a week (days 1, 8, 15) every 28 days]. Results: The response rates are summarized in the table. 7/36 pts progressed while on RVD maintenance. The median PFS and OS for pts on RVD maintenance has not been reached. Pts with <VGPR pre-ASCT and with <VGPR on RVD maintenance have median PFS of 28 months and 11 months, respectively. 4 pts with prior h/o DVT received anticoagulation, while all others received ASA for DVT prophylaxis. No thrombotic events were seen. There were no grade 3/4 toxicities or treatment-related mortality. The most common toxicities during maintenance schedule were: PN-40% (G1: 26%; G2:14%); G1 rash-10% and G1 fatigue in 78% pts. Cytopenias were seen in 25% pts and dose reductions were made in 50% pts. There is no report of secondary malignancies. Conclusions: Early ASCT followed by RVD maintenance delivers superior response rates in this high risk segment achieving sCR in 47% and ≥VGPR in 73% pts and prevents early relapses. The median PFS and OS have not been reached. RVD maintenance regimen is well tolerated and promising. [Table: see text]
Association of bone marrow plasma cell infiltration pre-auto transplant with adverse outcomes in multiple myeloma.
Authors: Bashir Qaiser , Parmar Simrit , Dinh Yvonne , Qureshi Sofia , Rondon Gabriela , Popat Uday R. , Nieto Yago , Jones Roy B. , Champlin Richard E. , Qazilbash Muzaffar , Shah Nina
Published: March 2020

8102

Background: Auto-stem cell transplantation (SCT) has become the standard of care for eligible patients (pts) with multiple myeloma (MM). However, the impact of bone marrow (BM) plasma cell (PC) percentage before SCT is not yet known. Methods: Retrospective review of 1489 MM pts who underwent auto-SCT from 7/8/98 – 12/31/2010 with post-induction, pre-SCT BM biopsy information available. Pts were divided into 2 groups: <10% PC infiltration (“PC low”) and >10% PC infiltration (“PC high”). Progression-free (PFS) and overall (OS) survivals were estimated by the Kaplan-Meier method. Log-rank test was performed to test differences in survival. Results: 1489 pts were studied. 1174 pts had <10% involvement of BM by PCs and 315 had > 10% involvement. For pts in the PC low group, 32% had a CR, 20% had a VGPR, 31% had a PR, 13% had <PR and 3% had progressive disease (PD) after SCT. For pts in the PC high group, 11% had a CR, 14% had a VGPR, 48% had a PR, 21% had <PR and 5% had PD after SCT. Median PFS was significantly shorter for the PC high group vs the PC low group (24.8 vs 29.5 months, p=0.05), as was median OS (52.5 vs 79.4 months respectively, p<0.001). When only pts who had a PR to induction were examined, there was a significant difference in both PFS (24.4 vs 33.2 months, p=0.04) and OS (58.3 vs 81.2 months, p =0.002) for the PC high vs PC low groups, respectively. For the 1299 (87%) pts treated in the era of novel therapeutics (after 2000), the differences between the PC high and PC low groups were maintained for both PFS (24.4 vs 29.5 months respectively (p=0.029)) and OS (54.8 vs 88.4 months respectively, p<0.001). Chemo-mobilization before SCT did not improve PFS or OS but this was done in only 44 (14%) of PC high pts. Conclusions: PC BM infiltration before auto-SCT is associated with a worse outcome. This finding persists in pts with a PR before SCT. Thus BM disease burden may further stratify pts with a PR. Though additional therapy did not significantly change the outcome for pts with high PC burden, this was done only in a minority of pts. Additionally, differences between PC high and PC low groups are maintained despite new salvage agents over the last 10 years. Further prospective study is warranted to determine the true impact of BM PC infiltration.
Use of whole genome sequencing to identify highly recurrent somatic mutations in Waldenström’s macroglobulinemia.
Authors: Hunter Zachary R , Xu Lian , Yang Guang , Zhou Yangsheng , Liu Xia , Cao Yang , Tripsas Christina , Manning Robert J , Patterson Christopher J , Sheehy Patricia S , Treon Steven P.
Published: March 2020

8107

Background: Waldenstrom’s Macroglobulinemia (WM) is an IgM secreting lymphoplasmacytic lymphoma. The genetic basis for this disease remains to be clarified. Methods: We performed whole genome sequencing (WGS) using CD19+ selected bone marrow lymphoplasmacytic cells (LPC) from 30 WM patients. For 10 of these patients, paired CD19+ depleted peripheral blood samples were used for WGS as normal controls. Results: The most common somatic variants identified and validated by Sanger sequencing included MYD88 L265P, an activating mutation for IRAK/TRAF6/NFKB and MAPK signaling, which was observed in 27/30 (90%) patients; the N-terminal domain of CXCR4, which included mutations associated with WHIM syndrome and confer constitutive CXCR4 signaling resulting from dysfunctional receptor endocytosis, a finding observed in 8/30 (27%) patients, and ARID1A (5/30; 17%), a tumor suppressor gene. Less common somatic variants were also identified in MUC16 (4/30; 13%), TRAF2 (3/30; 10%), TRRAP (3/30; 10%) and MYBBP1A (2/30; 7%). Conclusions: Using WGS and confirmatory Sanger sequencing, we have identified several somatic variants with oncogenic function, the most common of which include MYD88 L265P, the N-terminal domain of CXCR4, and ARID1A.
Analysis of molecular mechanisms of response and resistance to vemurafenib (vem) in BRAFV600E melanoma.
Authors: Sosman Jeffrey Alan , Pavlick Anna C. , Schuchter Lynn Mara , Lewis Karl D , McArthur Grant A. , Cowey Charles Lance , Moschos Stergios J , Flaherty Keith T. , Kim Kevin B. , Weber Jeffrey , Hersey Peter , Long Georgina V. , Lawrence Donald P. , Kockx Mark , Spleiss Olivia , Koehler Astrid , Bollag Gideon , Joe Andrew K. , Trunzer Kerstin , Ribas Antoni
Published: March 2020

8503^

Background: Vem induces frequent clinical responses (RR >50%) and improved survival in patients (pts) with BRAF-mutated metastatic melanoma. Multiple mechanisms of escape from vem have been proposed. We performed a centralized analysis of pretreatment, cycle 1, day 15 (D15), and progression (DP) tumor samples collected during the phase II BRIM-2 trial (Sosman et al, NEJM 2012). Methods: Of 132 pts enrolled, archival tumor samples, biopsies taken at baseline (BL), D15, and DP were obtained from 84, 38, 26, and 22 pts, respectively, and analyzed by immunohistochemistry (IHC) for signaling molecules in the MAPK, PI3K/AKT, and cell cycle pathways. Genetic analyses of signaling genes were performed using Sequenom MASSarray and direct DNA sequencing. Results: High levels of ERK phosphorylation were seen at BL indicating constitutive MAPK signaling due to the BRAF mutation. In 19/22 paired samples, pERK levels were reduced following vem (BL vs D15). Mean absolute pERK reduction in pts with clinical response (RECIST criteria) to vem (n=14) was significantly greater than in non-responders (n=8; p=0.013). Baseline cytoplasmic PTEN H-score was higher in responders vs non-responders (H-score=88 vs 68; p=0.042). At progression, upregulation of pERK (H-score=181) was frequently, but not uniformly found vs D15 tumors (H-score=48.5). At progression, increases in Cyclin D1 and Ki67 were seen, without obvious changes in PTEN or pAKT. NRAS mutations occurred in 3/13 DP; 2 had paired BL samples without NRAS mutations. Only 1/82 pts had a concomitant NRAS and BRAF mutation at BL, and did not respond to vem. MAP2K1 (MEK1) codon 124 mutations occurred in 7/92 BL and 1/20 DP samples. 2 pts with BL MEK1 mutations had partial responses. Conclusions: MAPK signaling was effectively inhibited by vem early in treatment, and in the subset of patients with matched tumor samples the degree of pathway inhibition correlated with clinical response. MAPK signaling is upregulated in many lesions at progression. NRAS mutations appear to be a mechanism of acquired resistance in a few tumors (3/13), while the role of MEK1 mutations in resistance is less clear.
Safety and efficacy of MET inhibitor tivantinib (ARQ 197) combined with sorafenib in patients (pts) with NRAS wild-type or mutant melanoma from a phase I study.
Authors: Means-Powell Julie Ann , Adjei Alex A. , Puzanov Igor , Dy Grace K. , Goff Laura Williams , Ma Wen Wee , Fetterly Gerald J. , Michael Shaunita A. , Chai Feng , Lamar Maria , Schwartz Brian E. , Sosman Jeffrey Alan
Published: March 2020

8519

Background: The MET receptor tyrosine kinase is implicated in tumor cell proliferation, invasion, and metastasis, and is activated in NRAS mutant melanoma. Tivantinib is an oral, selective MET inhibitor currently in phase II/III clinical trials. Tivantinib plus sorafenib exhibited synergistic antitumor activity vs single-agent activity in several tumor models. This phase I dose-escalation study assessed the safety of tivantinib plus sorafenib in pts with advanced solid tumors. Methods: Endpoints were safety, the recommended phase II dose (RP2D) of tivantinib plus sorafenib, and antitumor activity. Dose escalation previously established the RP2D as tivantinib 360 mg twice daily (BID) plus sorafenib 400 mg BID. Extension cohorts enrolled ≤ 20 pts each with melanoma or other tumors. Pts were treated until disease progression or unacceptable toxicity. Results: 16 pts with melanoma (median age, 66 yr) received treatment at the RP2D, and 3 pts are still on study. 12 pts received ≥ 1 previous systemic anticancer treatment (median, 1.2; range, 0-5) including ipilimumab (2 pts) or MEK inhibitor (1 pt). Common adverse events (≥ 25%) were rash (50%), diarrhea and fatigue (44% each), anorexia (38%), stomatitis and nausea (31% each), and anemia, weight decrease, and hypophosphatemia (25% each). Best responses were complete response (CR) in 1 pt, partial response (PR) in 3 pts, and stable disease (SD) in 3 pts. 4 pts had progressive disease and 5 pts were not evaluable (3 pts had not reached first assessment time, 1 pt withdrew consent, and 1 pt had unacceptable toxicity). The overall response rate and disease control rate were 25% and 44%, respectively. Median progression-free survival (mPFS) was 5.3 mo (95% CI, 1.6-12.9 mo). Among 8 pts with NRAS mutations, mPFS was 9.2 mo (95% CI, 5.3-12.9 mo) and responses were 1 CR, 1 PR, and 2 SD. Conclusions: Tivantinib plus sorafenib combination therapy was well tolerated and exhibited preliminary anticancer activity in pts with melanoma. Dual inhibition of MET and angiogenesis may be an effective treatment strategy in NRAS-mutant melanoma.
Clinical significance of genomic alterations of the CDK4-pathway and sensitivity to the CDK4 inhibitor PD 0332991 in melanoma.
Authors: McArthur Grant A. , Young Richard J. , Sheppard Karen E , Mar Victoria , Waldeck Kelly , Fox Stephen B. , Kelleher Fergal C , Liu Wendy , Dobrovic Alexander , Pearson Richard , Kelly John , Christensen James G. , Randolph Sophia
Published: March 2020

8520

Background: Activation of CDK4 by amplification, increased expression of Cyclin D1 (CCND1) or reduced expression of the CDK inhibitor p16 (CDKN2A) can contribute to transformation of melanocytes indicating that CDK4 can act as an oncogene in melanoma.To explore if CDK4 may be a viable target for the treatment of human melanoma we have analyzed the frequency and clinico-pathological associations of genomic alterations of the CDK4 pathway in primary human melanoma and examined the genomic predictors of sensitivity to the highly selective CDK4/6 inhibitor PD 0332991 (991) in a panel of melanoma cell lines. Methods: A series of 167 primary melanomas with clinical, molecular and pathological annotation, including median follow up of 6.6 years, were analyzed for copy number variation (CNV)- gain of CDK4 or CCND1 (average gene copy >2.4) or loss of CDKN2A (average gene copy <1.4), by fluorescence in situ hybridization. A panel of 39 cell lines were treated with 991 in vitro and GI50s calculated. The mean GI50 of the melanoma cell lines was used to define sensitivity. Gene expression profiling and mutation or CNV in CDKN2A were used to identify predictors of sensitivity. Results: 75% of primary melanomas had at least one CNV (75%, 70% and 82% for BRAF, NRAS or wild-type BRAF/NRAS mutation status respectively). 55% showed loss of CDKN2A. 28% of melanomas had two or more CNVs. Melanomas with two or more CNVs involving CCND1 had worse overall survival (HR 5.56, p=0.02). Low CDKN2A mRNA expression or mutation or loss of CDKN2A predicted sensitivity to 991 with 30/33 mutant/loss lines being sensitive compared to only 2/6 wild type lines (p<0.006). Expression of CDK4, CCND1 or other cyclins or CDK-inhibitors did not predict sensitivity to 991. Conclusions: Genomic alterations in the CDK4 pathway are frequent in melanoma and are associated with worse survival, particularly when melanomas harbor two or more CNVs involving CCND1. Mutation, loss or low expression of CDKN2A in melanoma cell lines predicted sensitivity to the CDK4 inhibitor 991. Taken together these data support evaluation of CDK4 inhibitors in melanoma and suggest that CDKN2A maybe a genomic predictor of sensitivity to these agents.
A Cancer Research UK two-stage multicenter phase II study of imatinib in the treatment of patients with c-kit positive metastatic uveal melanoma (ITEM).
Authors: Nathan Paul D. , Marshall Ernest , Smith Catrin Tudur , Bickerstaff Matthew , Escriu Carles , Marples Maria , Damato Bertil , Kalirai Helen , Coupland Sarah
Published: March 2020

8523

Background: The median overall survival (OS) for metastatic uveal melanoma is less than 6 months with a median progression free survival(PFS) of 3 months. No systemic or regional therapy has shown a survival advantage over best supportive care. Despite pre-clinical evidence suggesting anti-tumour activity for the KIT tyrosine kinase inhibitor imatinib, there are several negative phase II trials in unselected patients. Our primary aim was to test the efficacy of imatinib in patients with prospectively-tested c-kit immunopositive metastatic uveal melanoma. Secondary aims included assessment of toxicity and patient recruitment. Methods: A phase II UK multicentre single-arm, two-stage Gehan design recruited 25 evaluable patients receiving imatinib 400mg OD until progression/unacceptable toxicity. Primary efficacy outcome was PFS at 3 months. Secondary outcomes were OS, overall PFS, disease response (RECIST) and toxicity. Prospective sample collection for putative biomarkers was included. Results: After 16.6 months 37 patients were screened, with 25 were registered and included in final efficacy analyses. The sample included PS 0-1 patients with a median age of 63 yrs and a median 9.3 months from diagnosis of metastatic disease. 82% had high LDH levels (>460IU/L), 65% had no previous treatment for metastatic disease and 8% did not have liver involvement by metastasis. Preliminary final results indicate the estimated proportion of patients progression free at 3 months is 0.24 (95% CI, 0.09 to 0.45). Median PFS and OS were 12.0 weeks (95% CI,11.6 to 14.3) and 29.6 weeks (95% CI, 19.3 to 61.0) respectively. Two patients had confirmed PR with response duration of 93 and 112 weeks, respectively, despite the absence of mutations in exons 11, 13, and 17 of the c-KIT gene. Conclusions: The trial successfully recruited to target in this rare disease area failing to convincingly show improved PFS in a selected cohort of c-kit immunopositive patients. Both patients with PR experienced long periods of disease control. Response was not dependent upon the presence of activating mutations in KIT. Further translational studies are ongoing to determine putative biomarkers of response.
Activity of cabozantinib (XL184) in metastatic melanoma: Results from a phase II randomized discontinuation trial (RDT).
Authors: Gordon Michael S. , Kluger Harriet M. , Shapiro Geoffrey , Kurzrock Razelle , Edelman Gerald , Samuel Thomas A. , Moussa Ali H. , Ramies David A. , Laird A. Douglas , Schimmoller Frauke , Shen Xiaodong , Daud Adil
Published: March 2020

8531

Background: MET and VEGF signaling are implicated in angiogenesis, invasion, and metastasis. Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2. A RDT evaluated activity and safety in 9 tumor types. Here we report on the metastatic melanoma cohort, including the ocular subtype. Methods: Eligible patients (pts) were required to have progressive measurable disease per RECIST. Pts received cabo at 100 mg qd over a 12 wk Lead-in stage. Tumor response (mRECIST) was assessed q6 wks. Treatment ≥ wk 12 was based on response: pts with PR continued open-label cabo, pts with SD were randomized to cabo vs placebo, and pts with PD discontinued. Primary endpoint in the randomized phase was progression free survival (PFS). Results: Enrollment to this cohort is complete (n = 77); all pts are unblinded. Baseline characteristics: median age 66 years; melanoma subtype: cutaneous/mucosal 70% and ocular 30%; known BRAF mutation 32%; LDH ≥ 1.1 x upper limit normal 35%; bone metastases 19%; median prior lines of therapy 1 (range 0-5). Median follow-up was 2.8 months (range 0.3 - 25). 35 pts (45%) completed the open-label Lead-in stage with 25 pts randomized to continue cabo (n=12) or to placebo (n=13). Median PFS from randomization was 5.7 months for cabo vs. 3 months for placebo (HR=0.3, p =0.055). Median PFS from Study Day 1 was 4.4 months. The estimate of PFS at month 6 (PFS6) is 44%. Evidence of objective tumor regression was observed in 39/65 pts (60%) with ≥ 1 post-baseline tumor assessment including 11/23 pts (48%) with ocular melanoma. Two bone scan evaluable pts demonstrated partial resolution of bone lesions at wk 6 accompanied by pain relief. Most common Grade 3/4 AEs were fatigue (14%), HTN (9%), constipation (4%), and diarrhea (3%); one related Grade 5 AE of diverticular perforation and peritonitis reported during Lead-in stage. Conclusions: Cabo demonstrates activity in metastatic melanoma pts, regardless of subtypes or BRAF mutation status, with improvement in PFS relative to placebo, and high rates of PFS6 and objective tumor regression. The safety profile of cabo was comparable to that of other VEGFR TKIs.
Randomized phase III trial of intravenous (IV) versus hepatic intra-arterial (HIA) fotemustine in patients with liver metastases from uveal melanoma: Final results of the EORTC 18021 study.
Authors: Leyvraz Serge , Suciu Stefan , Piperno-Neumann Sophie , Baurain Jean-Francois , Zdzienicki Marcin , Testori Alessandro , Marshall Ernest , Scheulen Max E. , Jouary Thomas , Negrier Sylvie , Vermorken Jan Baptist , Kaempgen Eckhart , Durando Xavier , Schadendorf Dirk , Karra Gurunath Ravichandra , Polders Larissa , De Schaetzen Gaetan , Vanderschaeghe Simon , Gauthier Marie-Pierre , Keilholz Ulrich
Published: March 2020

8532

Background: HIA fotemustine has shown promising results in Phase II studies that led to the EORTC randomized phase III trial (18021) in unpretreated patients (pts) with liver metastases from uveal melanoma. Methods: The treatment consisted in an induction cycle of either HIA (fotemustine 100 mg/m² over 4 hours, day 1, 8, 15, 22) vs IV control arm (fotemustine 100 mg/m² over 1 hour, day 1, 8, 15). After a 5-week break, maintenance cycles were given every 3 weeks. Randomization was stratified by PS (0 vs 1), LDH (normal vs abnormal) and center. Main endpoint was overall survival (OS). Required accrual per protocol was set to 262 pts, with final analysis planned after 220 deaths (hazard ratio (HR) =0.67, power=85%, 1-sided α=2.5%). Due to poor accrual an interim analysis was done after 134 deaths, in order to test futility (power=79%). Results: Between Feb-2005- Feb-2011, 171 pts were randomized (HIA: 86, IV: 85). Characteristics: PS 1: 20%, abnormal LDH: 42%, male: 50%, median age: 59 y.; balanced between arms. In the HIA arm 20 (23%) pts never started treatment mainly due to catheter problems and 2 pts in the IV arm. In those who started the treatment, leucopenia grade 3-4 was 18% and thrombopenia grade 3-4: 21% in the HIA arm compared to 32% and 42% in the IV arm. Non-hematological grade 3-4 toxicities were minimal (GI toxicity, catheter complications). In May 2011, as the OS HR=1.097 was > critical value 0.87, the IDMC recommended stopping accrual for futility. The final results from Jan-2012 are presented in the table below. Treatment comparison adjusted by PS and LDH provided similar results. Conclusions: Even if HIA fotemustine administration could not start in 23% of pts, it led to a higher ORR and longer PFS compared to IV administration. HIA did not translate into an improvement in OS. [Table: see text]