bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II multi-center study of ruxolitinib phosphate for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL).
Authors: Kallam Avyakta , Witzig Thomas E. , Roschewski Mark J. , Lyden Elizabeth , Lunning Matthew Alexander , Bierman Philip Jay , Bociek Gregory , Armitage James O. , Vose Julie 
Published: March 2020

e19063 Background: Constitutive activation of the JAK-STAT pathway has been reported in lymphomas, suggesting that targeting this pathway could show clinical benefit. Ruxolitinib phosphate, an oral JAK inhibitor represents a potential therapeutic agent for high grade lymphomas. This study is designed to investigate benefits of ruxolitinib in patients with relapsed or refractory PTCL and DLBCL Methods: Patients with relapsed/refractory DLBCL and aggressive T cell lymphomas who were ineligible for, or relapsed after, stem cell transplantation were eligible. Patients received ruxolitinib, at a dose of 10mg or 5mg BID, with gradual escalation to 25mg BID. Weekly hematological assessments were done during the first cycle, CT scans were done after every two cycles. Descriptive statistics for response to therapy were collected. Progression free survival (PFS), Overall survival (OS) curves were plotted using Kaplan-Meier method, comparisons between groups were made using the log rank test. Primary outcome of the study was to assess the overall response rate (ORR). Secondary objectives were to determine PFS, OS, duration of response and safety. Relationship between responses to oral ruxolitnib and gene expression profiling was explored. Results: Of the 60 patients enrolled, 25 patients had PTCL, 32 DLBCL, 3 pending path review. Median age was 62 yrs., 56.6% had stage IV disease. Median number of cycles received was 2 (min 1, max 60). At the time of evaluation, 76% patients had progressed on therapy. The median follow-up of patients was 3.7 months (min 0.9; max 61.4). Data for 41 patients was available for evaluation of response. Complete response (CR) was noted in 1 patient with PTCL. Partial response (PR) was noted in 1, stable disease (SD) in 4 patients. Among the responders, a PTCL patient with SD had a sustained response for 60 months, a patient with PR had a response duration of 31 months. The median OS and PFS were 5.9 and 1.8 months. PFS was 2.2 months in patients with PTCL and 1.8 months in DLBCL. Median OS was 5 months in patients with DLBCL, 6.9 months in PTCL. The estimated 6 month PFS and OS were 17% (95%CI: 9%, 28%) , 49% (95%CI: 35%, 62%). There was no difference in PFS or OS between PTCL and DLBCL (p = 0.42, p = 0.94). Grade 3 or higher adverse events were seen in 62%. Anemia was seen in 20%, thrombocytopenia in 8%, infections in 6%. Conclusions: Ruxolitinib can produce responses in some patients with relapsed/refractory NHL, particularly in patients with PTCL. It may play a role in combination therapies in future. Clinical trial information: NCT01431209.
T-cell large granular lymphocytic leukemia evolution post-transplant: The Cleveland Clinic experience.
Authors: Awada Hassan , Durrani Jibran , Covut Fahrettin , Thapa Bicky , Mahfouz Reda Z. , Kerr Cassandra M. , Nagata Yasunobu , Adema Vera , Hamilton Betty Ky , Visconte Valeria , Majhail Navneet S. , Sekeres Mikkael A. , Sobecks Ronald M. , Maciejewski Jaroslaw P. 
Published: March 2020

e19072 Background: T-cell large granular lymphocytic leukemia (LGLL) has been reported after solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT); yet its underlying pathophysiological evolution has been poorly explained. Methods: We retrospectively screened a cohort of 243 LGLL patients at Cleveland Clinic for disease development post-transplantation and postulated several possible responsible pathophysiological mechanisms. Results: Five percent (n = 12) of the patients had a history of transplant. Of these, 67% (n = 8) had SOT (kidney, liver or heart) while 33% (n = 4) had HSCT. Twenty-five percent were females while 75% were males. The median age was 56 years (range: 15-65). The median time from transplant to diagnosis was 7 years. Conventional cytogenetic showed normal karyotype in 89% of the patients. TCR gene re-arrangement by PCR was detected in all tested individuals. Targeted deep sequencing identified somatic STAT3 mutations in 17% (n = 2) of the cases. Fifty percent (n = 6) had EBV DNA, IgM and/or IgG post-transplant. Forty-two percent (n = 5) had CMV DNA, IgM and/or IgG; of which 80% (n = 4) were post-transplant and 20% (n = 1) pre-transplant. The median survival from disease diagnosis was 64.3 months (8.37-232.9). Indeed, T-LGL clonal expansion resulted from long-term stimulation by viral antigens including EBV and CMV causing continuous cytotoxic T cell immune response or by “oncomodulation” as explained in 83% of patients. The latter theory suggests that CMV infects tumor cells and modulates their malignant properties, without direct transformation. Immunosuppression in setting of pre-transplant exposure to CMV, caused reactivation of the latent oncogenic viral genome as seen in 8% of patients. In 17% of cases that were seronegative for viral genome, graft allo-antigenic stimulation has triggered long-term recipient LGLL expansion from antigenic mismatch. Somatic STAT3 mutations, which are highly expressed in leukemic LGL, has led to aberrant signaling and transformation (17%). Conclusions: Our study highlights the complex nature of LGLL evolution post SOT and HSCT and points out confounding mechanisms. Certainly, investigating pre- vs. post-transplantation baseline, clinical and molecular characteristics is warranted to deeply understand this phenomenon.
Venous thromboembolism risk with contemporary lenalidomide-based regimes for multiple myeloma: A systematic review and meta-analysis.
Authors: Chakraborty Rajshekhar , Riaz Irbaz Bin , Malik Saad , Marneni Naimisha , Garcia Alex Mejia , Anwer Faiz , Khorana Alok A. , Rajkumar S. Vincent , Kumar Shaji , Murad M. Hassan , Wang Zhen , Khan Safi U. , Majhail Navneet S. 
Published: March 2020

e19503 Background: The risk of venous thromboembolic events (VTE) despite mandatory thromboprophylaxis (TPx) in patients with multiple myeloma (MM) receiving contemporary lenalidomide (Len)-based regimens is not well-defined. Methods: Medline, Embase, and CENTRAL databases were queried to identify phase 1-3 clinical trials of Len-based regimens with mandatory TPx published until April 2018. Random effects meta-analysis was performed using CMAv3 software to obtain crude, and per 100 patient-cycle incidence rate (IR). Prespecified subgroup analyses were performed to obtain IR for VTE by (1) line of treatment (newly diagnosed [ND], relapsed/refractory [RR] and maintenance [Mx] phase) and (2) different Len-based regimens. Results: We screened 1069 citations and analyzed data from 43 trials with 8696 patients, including 17 in ND, 23 in RR and 3 in Mx phase. 12 out of 43 were Phase 3 randomized controlled trials. The overall incidence of VTE in 8696 patients was 4.6% (95% CI, 3.7-5.8%), with 1.0 event (95% CI, 0.7-1.4%) per 100 patient cycles. In patients with NDMM (n = 3295), 193 (5.9%) experienced VTE with a pooled IR of 0.9 (95% CI, 0.3-2.3) per 100 patient-cycle. Among RRMM patients (n = 3981), 251 (6.3%) experienced VTE with a pooled IR of 1.0 (95% CI, 0.4-2.3) per 100 patient-cycle. The incidence of VTE was highest with the following triplet regimens: Rd + Proteasome inhibitor (PIs) and Rd + Anthracycline (Ac) [+/- Vincristine], with the latter having a high risk of VTE regardless of the treatment phase (table). With Len Mx (n = 1420), 38 (2.7%) patients had VTE, with a pooled IR of 0.2 (95% CI, 0-2.1) per 100 patient-cycle. Conclusions: Patients with MM undergoing treatment with Len-based regimens remain at risk of VTE despite current TPx strategies. The estimates of VTE IR provided by this analysis can guide clinicians in assessing treatment-related risk of VTE in this setting. [Table: see text]
Treatment patterns in patients with multiple myeloma (MM): A retrospective study using Medicare data.
Authors: Lin Peggy L. , Latremouille-Viau Dominick , Sasane Medha , Gagnon-Sanschagrin Patrick , Divan Hozefa A. , Drea Edward Joseph , Guerin Annie , Hari Parameswaran 
Published: March 2020

e19506 Background: MM is characterized by repeated relapses and refractoriness and is managed by successive lines of therapies (LT) each typically resulting in shorter response duration over prior LT. This study describes current MM treatment (tx) landscape in US clinical practice. Methods: Adult MM patients (pts) with continuous Medicare Part A, B, and D coverage initiated on 1st LT (1L), without stem cell transplant, were identified in the Medicare Research Identifiable Files (2012-2016). Claims for any MM tx within 60 days of the 1st tx constituted the tx regimen of an LT. End of LT was defined as a claim for a new MM tx > 60 days post LT initiation (tx augmentation or switch), discontinuation of all tx in a regimen for > 90 consecutive days, end of Medicare coverage/data or death. From 1L to 3L, overall survival (OS), LT duration (DoT), tx regimens and sequences were assessed. Results: 8374 MM pts with 1L (median [med] age = 76 years at 1L; 55% female) were analyzed. Over a med follow-up of 20 months (mos) from 1L (med 1L DoT = 5.6 mos), 2849 pts received a 2L (med 2L DoT = 5.6 mos) and 978 received a 3L (med 3L DoT = 4.7 mos). The most prominent tx regimens were bortezomib/corticosteroids (CS; VD) in 1L, and lenalidomide/CS (RD) in 2L and 3L. The most prevalent tx sequence was 1L VD, 2L RD and 3L VD. The 1- and 2-year OS rates were 81% [95% confidence interval: 81-82] and 68% [67-69] from 1L initiation, 80% [78-82] and 64% [61-66] from 2L, and 73% [69-76] and 55% [51-60] from 3L initiation, respectively. Conclusions: MM Medicare pts mainly cycle through bortezomib- or lenalidomide-based regimens in front LT; newer agents gain more usage in later LT. A better understanding of tx options and sequencing is warranted to prolong survival. [Table: see text]
Association between immunoglobulin isotypes and cytogenetic risk groups in multiple myeloma.
Authors: Muddasani Ramya , Ramdhanny Angela , Lutz Gabriel , Akerman Meredith , Ho Albert , Suarez Jaime Andres , Braunstein Marc Justin 
Published: March 2020

e19510 Background: Cytogenetic abnormalities (CA) carry prognostic significance in MM. Immunoglobulin isotypes also predict disease behavior, with non-IgG subtypes historically being associated with poorer outcomes. We hypothesized that MM non-IgG isotype and higher risk CA are associated with greater degree of marrow infiltration (BM%) and presence of end organ damage at presentation. Methods: 552 MM patients were retrospectively analyzed using a multi-institution repository of BM%, isotype, and CA risk groups stratified by mSMART criteria. A subset of 110 patients were used to assess clinical comparisons and associations between CA, isotype, and end organ damage using the chi-square or Fisher’s exact test for categorical variables and the Mann-Whitney test to compare between groups for continuous variables. Results: There was a higher BM% seen in the intermediate risk group compared to standard risk group (50% vs 20%, p < 0.04). A lower BM% was seen in the IgG subtype compared to other isotypes (27% vs 45%, p < 0.02). CA including del(13q), del(16q), dup(1p), dup(1q), t(4;14), t(11;14), and trisomy 11 were associated with a higher BM%. When comparing isotypes to CA risk groups, IgA isotype was associated with greater risk, including del(13q) and del(16q). IgG isotype was associated with trisomy 11, while light chain MM correlated with higher risk CA including del(17p), and dup(1q). Lytic lesions on presentation were more frequent in patients with trisomy 11 and less frequently in IgA MM. Anemia presented more in IgA MM, and renal failure in patients with t(14;16). Conclusions: Lower BM% was found in IgG isotype MM, which correlated with standard risk CA, whereas light chain MM was associated with higher risk CA; this risk group being more likely to present with renal failure. Unexpectedly, lytic lesions on presentation correlated with non-IgA isotype and better risk CA. Further studies are needed to confirm these findings prospectively to determine if they can predict end organ damage in patients with specific isotypes or CA groups.
Inching towards precision medicine for multiple myeloma with causal network models.
Authors: Zhu Jun , Liu Yu , Wang Li , Yu Haocheng , Yoo Seungyeul , Lee Eunjee , Schadt Eric E. 
Published: March 2020

e19526 Background: Multiple myeloma (MM) is the 2nd most prevalent blood cancer. For each molecular subtype of MM defined by molecular profiles, mechanisms underlying prognosis and drug response are largely unknown. Elucidating the mechanisms underlying differences in prognosis and drug response will enable a more personalized, precision medicine (PM) approach to treating patients. Methods: Big multiomics data are now widely available and contain the ingredients necessary to build causal models to uncover mechanisms of prognosis and drug response. However, data from resources like the MM Research Consortium (MMRC) dataset may contain errors (eg, sample mislabeling) that diminish modeling accuracy. We developed a probabilistic data matching method ( proMODMatcher) to correct such errors and applied it to the MMRC data. We identified labeling errors in 10 patients, including swaps in RNA and CNV profiles. Given the corrected MMRC data, we characterized recurrent genomic aberrations in MM. We found > 8000 genes significantly associated (FDR < 0.01) with CNVs spanning the gene locations. To distinguish expression correlations driven by causal biological relationships from those driven by coincident CNV influence, we constructed a causal MM network based on the MMRC dataset. Results: Overlaps among multiomic prognostic or drug response biomarkers are sparse. To identify common mechanisms of different biomarkers, we projected them onto our MM network to define the causal context in which they occur. Prognostic biomarkers were enriched in subnetworks associated with mitotic regulation and lipid metabolism, and predicted by our network to be regulated by ZWINT, BUB1B, DTL, TPX2 and NOP16. Proteasome inhibitor and immunomodulating drug responses were mediated by amino acid biosynthesis and cell surface protein complex subnetworks, respectively, with MTHFD2 and TMC8 inferred as the master regulators of these subnetworks, respectively. Regulators include genes (eg, BUB1B and MTHFD2) known to associate with tumor growth and drug response and novel therapeutic control points. Conclusions: Causal models can elucidate the molecular mechanisms underlying prognosis and drug response, enabling the design of more personalized MM treatments.
The unforeseen business and medical consequences of EHR data collection for a real-world data multiple myeloma registry.
Authors: Keogh Kevin M. , Belli Andrew J. , Matta Monica M. , Tanenbaum Kathryn A. , Farrish Kaeleigh , Mulcahy Michael , Mathura Shivam , Williams Christopher , Mehr Shaadi , Auclair Daniel , Norden Andrew David , Labkoff Steven E. 
Published: March 2020

e19528 Background: Record retrieval on behalf of a consenting patient within the context of real-world data is not well understood. As the need for real-world data continues to expand, methods for the efficient transfer of information across consenting parties will be critical to enable research collaborations. This need was highlighted through a partnership between COTA and the Multiple Myeloma Research Foundation (MMRF). As one component of the pilot study, COTA managed the record retrieval of consenting patients before going on to abstract the data for use in a registry. Methods: The pilot study identified 23 patients that consented to the release of medical records at 54 institutions across 20 states. COTA partnered with a retrieval vendor and employed its own outreach efforts for acquisition. Outreach and retrieval techniques were similar across COTA and the vendor, including targeted calls, delivery of IRB-approved consent materials, and on-site requests. The 30-day release parameter for a covered entity under 45 CFR 164.524(b)(2) of HIPAA’s Privacy Rule was used to evaluate the observed return rates. Results: A total of 56 medical records were requested, and 48 records were retrieved. The mean (±SD) retrieval time across all sites was 33 (±58) days. We found that 54% of records were released in < = 30 days, and 32% of records > 30 days. 14% of requested records were never released, despite a median of 19 outreach attempts (range 10 to 43). Cited issues for delay or non-release consisted of 22 institutions questioning the validity of the certified electronic patient signature, 6 requiring a physical signature, and 5 requiring their own authorization forms. In no cases did the records contain structured metadata, such as LOINC, MedDRA, and RxNorm. Conclusions: This pilot showed an unpredictable variance associated with the release of records in the context of real-world data. This variance contributed to barriers and delays in broader research efforts. The lack of accompanying metadata with released records resulted in additional required data processing. Future studies should be conducted to establish best practices in the release and retrieval of medical records used to support real-world data research.
Role of investigational monoclonal antibodies in the treatment of multiple myeloma: A systematic review.
Authors: Hassan Hamza , Iftikhar Ahmad , Iftikhar Nimra , Mushtaq Adeela , Rafae Abdul , Razzaq Faryal , Valent Jason Neil , Kanate Abraham Sebastian , Chakraborty Rajshekhar , Anwer Faiz 
Published: March 2020

e19533 Background: Immunotherapy for multiple myeloma (MM) has been of focus in recent years due to its myeloma-specific immune responses. We reviewed literature on non-FDA approved monoclonal antibodies (MoAbs) to highlight future perspectives. Methods: We searched PubMed, EMBASE, Web of Science, Cochrane and Clinicaltrilas.gov to include phase I/II clinical trials. Results: 40 studies (1917 patients) were included. Isatuximab (anti-CD38) and F50067 (anti-CXCR4) were the only MoAbs which produced encouraging results as monotherapy with ORR of 66.7% and 32% respectively. Isatuximab use in combination with Len-Dex produced CBR of 83%, and in combination with pomalidomide and dexamethasone CBR of 73%. Indatuximab Ravtansine, an antibody-drug conjugate, produced ORR 78% and 79% in combination with Len-Dex and pomalidomide + dexamethasone respectively. Conclusions: CD38 remains an important target for further clinical trials in combination therapy. Trials using indatuximab, pembrolizumab, lorvotuzumab, siltuximab, and dacetuzumab in combination therapy produced better outcomes as compared to monotherapies. [Table: see text]
Primary tumor location as an important predictor for survival in pulmonary adenocarcinoma.
Authors: Wang Zhe , Li Minghuan , Teng Feifei , Yu Jinming 
Published: March 2020

e20000 Background: The prognostic value of tumor location in pulmonary adenocarcinoma (ADC) is controversial. We compared the prognosis and relevant data between central-type (CT-ADC) and peripheral-type ADC (PT-ADC) in order to identify the reasons for the different outcomes between them and to improve the treatment strategy and prognosis of these two types. Methods: Data on 256 patients with pathologically diagnosed ADC were retrospectively reviewed. The prognostic factors for disease-free survival (DFS), progression-free survival (PFS) and overall survival (OS) were analyzed using univariate and multivariate analyses. Results: 124 and 132 patients had CT-ADC and PT-ADC respectively. CT-ADC was associated with an earlier age, poorer Karnofsky Performance Status (KPS), higher rates of advanced stage, bone metastasis, contralateral pulmonary metastasis and pleural effusion. Besides, CT-ADC showed a trend toward lower rate of epidermal growth factor receptor (EGFR) mutation. Patients with CT-ADC had a significantly shorter PFS/DFS and OS than did those with PT-ADC. Multivariate analysis revealed that advanced stage, central-type location, EGFR wild-type, no surgery, presence of chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) were independent poor prognostic factors for OS. The rate of surgery was significantly lower in patients with CT-ADC. Among patients with ILD or COPD, OS is shorter in patients with central- than peripheral-type tumors. Conclusions: CT-ADC is associated with poorer survival than PT-ADC and the lower rate of surgery in patients with CT-ADC is an important reason for this. Tumor location of pulmonary adenocarcinoma plays a critical role in predicting prognosis and choosing therapeutic strategies.
Comparison of preoperative and prechemotherapy lymphocyte counts to predict outcome of non-small cell lung cancer patients treated with adjuvant chemotherapy.
Authors: Lee Hyun Woo , Choi Yong Won , Ahn Mi Sun , Kang Seok Yun , Choi Jin-Hyuk 
Published: March 2020

e20002 Background: Several systemic inflammatory markers in blood have been suggested as prognostic factors in various cancers. We investigated the prognostic significance of neutrophil-to-lymphocyte ratio (NLR) and absolute lymphocyte count (ALC) in patients (pts) with non-small cell lung cancer (NSCLC) treated with adjuvant chemotherapy. Methods: A retrospective review was conducted on 108 pts who received adjuvant chemotherapy after surgical resection of NSCLC. Disease-free survival (DFS) and overall survival (OS) of pts with high NLR and ALC ( > median value) before surgery or chemotherapy were compared to those of pts with low NLR and ALC (≤median value). Results: The number of pts at AJCC stage IB, IIA, IIB, IIIA, and IIIB were 1, 38, 9, 58, and 2, respectively. Adenocarcinoma, squamous cell carcinoma, and other histologic types were present in 66 (61.1%), 32 (29.6%), and 10 (9.3%) pts, respectively. The most frequently used chemotherapy regimen was vinorelbine/cisplatin (81 pts), followed by paclitaxel/carboplatin (22 pts), and others (5 pts). A total of 61 (56.5%) pts received adjuvant radiotherapy (before adjuvant chemotherapy: 53 pts). Preoperative NLR and ALC were not associated with clinicopathologic characteristics including stage and histologic types. High prechemotherapy NLR and low ALC were more frequently observed in pts who underwent radiotherapy before chemotherapy (p < 0.0001). The median follow-up duration was 70 (38-162) months for survivors. Pts with stage III demonstrated poor DFS (p = 0.019) and OS (p = 0.028) compared to those with stage IB or II. The shorter median DFS was observed in pts with low prechemotherapy ALC (20 vs. 65 months, p = 0.021), without significant difference in OS (p = 0.088). On the other hand, NLR and preoperative ALC were not associated with outcome of pts. Conclusions: The present study suggests that high prechemotherapy ALC is associated with poor outcome in stage IB-III NSCLC pts who received adjuvant chemotherapy after surgical resection.