bluuebunny/crossref_metadata_2025 huggingface dataset:
Achieving quality: Comparing recommendations for cancer care between NCCN and ESMO.
Authors: Gao Jennifer , Calkins Geoffrey , Birrer Michael J. , Dizon Don S.
Published: March 2020

6579

Background: Guidelines for the treatment of cancer are in place in both the United States and Europe. However, specific recommendations that can be utilized as measures of quality care have not been evaluated in either guideline set, nor have they have been compared against one another. Our aim was to delineate the number of concrete treatment recommendations made using the PICO model for evidence-based medicine. Methods: Three authors (JG, GC, DD) independently reviewed treatment guidelines of the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) for three common cancers: 1) breast cancer; 2) colon cancer; 3) non-Hodgkin lymphoma (specifically diffuse large B-cell lymphoma and follicular lymphoma). The primary objective was to differentiate the concordant versus discordant recommendations. Recommendations were identified by first identifying all category 1 and 2 guidelines in ESMO, then finding the equivalent NCCN recommendations, and finally assessing their fulfillment of the PICO model (Patient/Problem – Intervention – Comparison – Outcome). Each recommendation was separately analyzed by the three aforementioned authors of this abstract. The results reflect the unanimous agreement of all three reporters. Results: Using PICO criteria, we identified a total of 46 recommendations (10 colon cancer, 22 breast cancer, and 14 in NHL). Concordance between NCCN and ESMO was 80, 86, and 100 percent, respectively. Discordance between NCCN and ESMO were noted in first line chemotherapy regimens in localized colon cancer and fluoropyridine as maintenance therapy in unresectable colon cancer; patients who should receive partial breast irradiation and chemotherapy regimens in the elderly with breast cancer. Conclusions: The number of actual recommendations that meet the PICO evidence-based medicine criteria is relatively small. However, comparing NCCN and ESMO, there is a high rate of agreement between guidelines reviewed regarding treatment recommendations. Our data suggest that it may be possible to identify specific measures of quality treatment as defined by evidence based medicine criteria.
A pilot study of the patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) in a phase I clinical trial.
Authors: Qin Rui , Dueck Amylou C. , Satele Daniel , Molina Julian R. , Erlichman Charles , Basch Ethan M. , Sloan Jeff A.
Published: March 2020

6587

Background: Recently the Patient-Reported Outcomes version of the CTCAE was developed to augment clinically graded adverse events with information reported directly by patients on clinical trials (Basch, 2009). The validation and potential application of PRO-CTCAE in phase I clinical trials are of great interest as toxicity is the primary endpoint. Methods: Selected PRO-CTCAE items (21 items measuring 12 symptomatic adverse events) corresponding to the major adverse events required to be graded clinically were collected in an ongoing phase I clinical trial of weekly cilengitide and paclitaxel in patients with advanced solid malignancies (NCT01276496). PRO-CTCAE was administered in a paper booklet by a clinical research associate prior to treatment on days 1, 8 and 15 of their regular visits. These PRO-CTCAE items were summarized descriptively in comparison to clinician-assessed CTCAE ver 4.0 (NCI, 2009) during the first cycle. As a pilot study to assess feasibility of PRO-CTCAE in phase I trials, PRO-CTCAE was not intended for determination of dose-limiting toxicity. Results: Twelve patients were accrued to two separate doses of cilengitide and paclitaxel. The median age was 56 (range 36—67) and half of patients were female. All patients had an ECOG performance score <= 1. Over 90% of patients had received prior surgery and chemotherapy. All but one patient completed weekly PRO-CTCAE during the first cycle, the only patient refused to complete weeks 2 and 3 did not give a reason. PRO-CTCAE captured most of the symptomatic adverse events reflected in clinician-assessed CTCAE. Some symptomatic adverse events were not reported clinically by CTCAE but were reported by patients by PRO-CTCAE. Overall, PRO-CTCAE items indicated slightly more severe degree of symptoms experienced by patients than those reported in CTCAE. Conclusions: This is the first study that PRO-CTCAE items were integrated within regular study visits in a phase I trial. The administration of PRO-CTCAE has been proved feasible and fruitful, providing consistent and enhanced symptomatic toxicity from the patient point of view. The addition of PRO-CTCAE did not significantly increase patient burden. Clinical trial information: NCT01276496.
How oncologists adhere to evidence-based G-CSF-guidelines to prevent febrile neutropenia: A sample survey in hospitals and practices in Germany.
Authors: Link Hartmut , Nietsch Josef , Kerkmann Markus , Ortner Petra Angelika ,   Supportive Care Working Group (ASORS) of the German Cancer Society (DKG)
Published: March 2020

6591

Background: Primary G-CSF prophylaxis after chemotherapy is recommended in evidence based guidelines (GL), if the risk of febrile neutropenia (FN) is high (≥20%), or intermediate (≥ 10% - 20%) in case of risk factors. The aim was to evaluate, if G-CSF is used as proposed by GL, to identify determinants of GL implementation and adherence. Methods: The sample size was calculated at 2% of the incidence of malignant lymphoma, breast and lung cancer in Germany. Pts who had received 3-9 cycles of chemotherapy with a FN risk ≥10% between 5/2011 to 4/2012 were documented retrospectively. Results: 286 lymphoma, 666 lung cancer and 976 breast cancer pts were collected from 87 hospitals and 59 oncology practices with 195 physicians participating. Adherence to GL was higher in physicians up to 10 than over 10 years of experience. Conclusions: The adherence to and acceptance of GL for G-CSF may not be sufficient. Patient risk factors are underestimated therefore resulting in a possible underuse of G-CSF. Physicians may underestimate FN risk in pts who have an intermediate risk of FN and they overestimate their adherence to the GL. [Table: see text]
Impact of cetuximab on chemoradiation use in older patients with locally advanced head and neck cancer.
Authors: Baxi Shrujal S. , Sherman Eric Jeffrey , Atoria Coral L , Lee Nancy Y. , Pfister David G. , Elkin Elena B.
Published: March 2020

6594

Background: The benefit of chemoradiation (CTRT) in the treatment of locally advanced head and neck cancer (LAHNC) declines in older and sicker patients. In 2006, the FDA approved cetuximab in LAHNC. Cetuximab with radiation has a perceived lower side effect profile compared to standard chemotherapies used in CTRT. Our objective was to examine the impact of cetuximab on the use of CTRT in elderly patients with LAHNC. Methods: We identified adults aged 66 and older diagnosed with LAHNC between 1999 and 2007 in the Surveillance Epidemiology and End Results (SEER)-Medicare linked database. Treatment was categorized as CTRT or other based on Medicare claims within 6 months of diagnosis. We excluded patients who did not receive definitive treatment. In patients who had CTRT, we identified use of cetuximab based on drug-specific billing codes. We assessed trends in the use of CTRT over the entire study period and in the use of cetuximab since 2006. We examined the influence of age and comorbidity on the likelihood of receiving CTRT before and after 2006 adjusting for clinical and demographic factors. Results: We identified 4,809 patients with LAHNC. One-fourth were ≥80 years and almost a fifth had a Charlson comorbidity score (CCS) of ≥2. Overall more than 20% of patients received CTRT. The use of CTRT more than tripled over time, from 10% of patients diagnosed in 1999 to 38% in 2007 (p<0.0001 for trend). Of the 336 patients who had CTRT since 2006, 45% received cetuximab. Prior to 2006, patients ≥80 years or those with a CCS of ≥2 were significantly less likely to be treated with CTRT compared to younger patients or those with a CCS of 0. In patients diagnosed in 2006 or later, age and comorbidity no longer predicted the likelihood of receiving CTRT. Conclusions: In this population-based cohort of older adults, the use of CTRT increased substantially over time. The availability of cetuximab, with a perceived gentler side effect profile, may have increased the use of CTRT, especially in older and sicker patients. [Table: see text]
Survival of non-small cell lung cancer (NSCLC) patients with and without diabetes mellitus (DM): Findings from the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS).
Authors: Abu Hejleh Taher , Chrischilles Elizabeth A. , Pendergast Jane F , Porter Aaron T , Wallace Robert B ,   Cancer Care Outcomes Research and Surveillance Consortium (CanCORS)
Published: March 2020

6602

Background: DM increases all-cause mortality in the general population. It is also associated with more complications from chemotherapy, increased risk of radiation pneumonitis and worse surgical-wound healing. In this study, we explored the effect of DM on NSCLC overall survival. Methods: This study utilized the surveys and abstracted medical record resources of NSCLC patients studied by CanCORS, an inception cohort of newly diagnosed lung and colon cancer patients from the United States. Patients with NSCLC stage I-IV were included. The log-rank test was used to compare the survival curves of patients with and without DM. Cox proportional hazard models were used to adjust for other variables in the survival model. Results: Of the 2243 NSCLC patients, 359 (16%) had DM. Survival for patients diagnosed with DM was significantly worse than patients without DM [hazard ratio (HR) 1.28; 95% confidence interval (CI) 1.13-1.45]. The median overall survival for patients with and without DM was 561 and 833 days, respectively. DM was also associated with poorer survival (HR 1.20; 95% CI 1.05, 1.36) after adjusting for age, smoking status, stage, treatment (radiation, chemotherapy), brain metastasis, severity of respiratory symptoms at diagnosis, and comorbidities. While a significant interaction between stage and DM was not detectable after adjusting for the above, the estimated Kaplan-Meier plots present more prominent differences in stages I-III, with virtually overlapping plots in stage IV. Conclusions: DM was associated with worse survival in NSCLC patients. Although this finding can be utilized when counseling diabetic NSCLC patients, it is unknown if improving DM care will result in a better survival. The effect of DM on survival in the various stages of NSCLC needs further study.
Updated use of first-line chemotherapy for advanced pancreatic cancer: FOLFIRINOX versus gemcitabine.
Authors: Cartwright Thomas H. , Arlen Aimee Ginsburg , Wilfong Lalan S. , Harrell Robyn K. , Hoverman J. Russell , Beveridge Roy A.
Published: March 2020

6607

Background: Pancreatic cancer (PC) is the fourth leading cause of death in the United States. It is estimated that 45,220 patients will be diagnosed in 2013 and 38,460 will die (Siegel, CA Cancer J Clin 2013). Gemcitabine has long been the standard of care chemotherapy. Recent advances in treatment created a combination regimen (oxaliplatin, irinotecan, leucovorin, fluorouracil [FOLFIRINOX]) for patients with good Karnofsky performance status (PS) (Conroy, NEJM 2011). This retrospective analysis was conducted as an update to results reported at ASCO 2012 (Ginsburg Arlen, JCO 2012) to evaluate characteristics and overall survival (OS) of patients receiving FOLFIRINOX and gemcitabine-based treatments in a large outpatient community setting. This is the largest study describing FOLFIRINOX patients to date. Methods: Patients with advanced PC treated within The US Oncology Network entered into the iKnowMed (iKM) database between June 2010 and November 2012 were included. Patterns of treatment were characterized by the median age at diagnosis, sex, PS, and first-line metastatic chemotherapy prescribed. The primary endpoints of the analysis were OS and uptake of FOLFIRINOX within the network. Results: Compared to ASCO 2012 results, 1,000 additional patients were identified in iKM. Of the 1,714 total patients, 24% received FOLFIRINOX (up from 13% in 2012) and 76% gemcitabine-based therapy (87% in 2012). Increased utilization of FOLFIRINOX for patients with good PS began in June 2010. For all patients (55% male), the median age at diagnosis was 67 years and the majority (85%) had a PS of 70% or greater. The OS was significantly longer for FOLFIRINOX (9.6 mos) versus gemcitabine (6.3 mos) (p<0.0001). This held true for PS of 70% or greater patient given FOLFIRINOX (9.6 mos) versus gemcitabine (7 mos) (p<0.0001). Conclusions: Utilization of FOLFIRINOX has continued to expand after the publication of phase III trials. Our data in a community setting supports a survival advantage for FOLFIRINOX. Although the magnitude of benefit may be smaller in the community, we agree that FOLFIRINOX should become a standard of care for good PS patients.
Impact of center case volume on cardiotoxicity during adjuvant trastuzumab in breast cancer.
Authors: Chin-Yee Nicolas J. , Yan Andrew , Tomlinson George A. , Earle Craig , Trudeau Maureen E. , Krahn Murray , Ko Dennis , Krzyzanowska Monika , Pal Raveen , Brezden Christine B. , Chan Kelvin K.
Published: March 2020

6625

Background: A recent study suggested that cardiotoxicity from trastuzumab (T) was associated with regional variation and insufficient cardiac monitoring (Ng et al.SABCS 2012). Few studies have examined the impact of centre or physician (MD) case volume (vol) on outcomes in systemic therapy. Methods: All breast cancer patients who were diagnosed in 2003-2009 in Ontario and treated with adjuvant T were identified through a provincial drug funding program, and linked to administrative databases to ascertain patient demographics, hospitalizations, cardiac risk factors, cardiac imaging, comorbidities, and treating centre and MD. For each year, we calculated case vol as the number of patients treated with adjuvant T by each MD and by each centre. Cardiotoxicity was defined as receiving less than 16 out of 18 doses of T because of heart failure (HF) admission, HF diagnosis by physician claims, or discontinuation after cardiac imaging. Insufficient cardiac monitoring was defined as per recent guideline and per Ng et al. Logistic regression and mixed models were constructed to examine factors associated with cardiotoxicity. Results: Our cohort consisted of 3,777 patients, 214 MDs and 68 centres. For patients, 16.5% were over age 65; 30.3%, 9.4%, and 1.2% had previous diagnoses of hypertension, diabetes, and HF, respectively; 16.9% had cardiotoxicity. Univariate analyses found that high centre vol, but not MD vol, was associated with lower cardiotoxicity. Cardiotoxicity rates by centre vol quintiles (Q) were 23.4% (Q1-3), 18.2% (Q4), and 15.2% (Q5). Multivariable analyses found that lower cardiotoxicity was associated with higher centre vol (OR=0.85 per Q, p=0.02) and diagnosis in recent years (2008-2009 vs. before 2008; OR=0.50, p<0.001), after adjusting for age, previous HF, comorbidities, regional variation, and cardiac monitoring. Accounting for clustering within centres, there remained a strong trend of lower cardiotoxicity with higher centre vol (OR=0.77 per Q, p=0.06) and recent diagnosis (OR=0.50, p<0.001). Conclusions: Our findings suggest a reduction in cardiotoxicity with experience and over time, and support the notion of centralization of systemic therapy in high vol centres to optimize outcomes.
Effect of breakthrough pain on functional status, pain interference, and disability in cancer patients: Findings from the national breakthrough pain survey.
Authors: Narayana Arvind , Katz Nathaniel , Shillington Alicia , Stephenson Judith J , Frye Carla B , Portenoy Russell
Published: March 2020

6627

Background: Few studies have evaluated the epidemiology of breakthrough pain (BTP) in community-dwelling populations with cancer and chronic pain. The National Breakthrough Pain Survey (NBTPS) assessed the prevalence, characteristics, and impact of BTP in a large commercially-insured population and determined the BTP-associated functional impairments and disability in cancer patients with controlled, persistent pain. Methods: Administrative claims from the HealthCore Integrated Research Database were utilized to identify commercially-insured adult patients with ≥2 medical claims at an interval ≥3 months with an ICD-9-CM code indicating a chronic pain condition (cancer or noncancer) and ≥3 opioid prescription claims. Patients were called and, after consent, completed the Brief Pain Inventory (BPI), Sheehan Disability Scale (SDS), and 12-Item Short-Form Health Survey (SF-12) by interview. Data from patients with cancer and controlled, persistent pain were included in this subanalysis. Results: Of 2198 patients surveyed, 1279 had controlled, persistent pain. Of these, 145 had cancer pain, 77.2% of whom reported BTP (BTP, 112; no BTP, 33). Compared to those without BTP, cancer patients with BTP had significantly higher total BPI pain interference scores (mean±SD 34.7±14.5 vs 23.4±16.7, P=.001) and significantly greater global functional impairment on the SDS (mean±SD 16.8±8.3 vs 12.4±8.3, P=.028). There also was a non-significant finding of decreased quality of life, as assessed by SF-12 physical and mental component scale scores, among cancer patients with BTP vs no BTP (mean±SD 27.8±9.1 vs 32.2±10.1, P=.11, and 47.0±11.9 vs 49.4±11.6, P=1.0, respectively). Conclusions: In a sample of commercially-insured patients, cancer patients with controlled, persistent pain and BTP had greater pain-related functional impairments and disability than those with controlled, persistent pain and no BTP. These data suggest that BTP is clinically important among populations receiving cancer care in the community.
Unplanned hospitalizations among gastrointestinal cancer patients in the state of Texas.
Authors: Manzano Joanna-Grace , Luo Ruili , Elting Linda S. , Suarez-Almazor Maria
Published: March 2020

6634

Background: Hospitalization rates and cost of care for patients with Gastrointestinal (GI) malignancies are among the highest in the spectrum of cancers. It is poorly understood if these are driven by planned or unplanned hospitalizations. Methods: We conducted a retrospective cohort study using linked Texas Cancer Registry and Medicare claims data to describe the patterns of unplanned hospitalization among GI cancer patients in Texas. Our outcome, unplanned hospitalization, was defined as any emergent or urgent admission. Prior comorbidities were assessed using a modified Charlson score. Data were collected for 2 years from date of cancer diagnosis. Modified Poisson regression model was used to identify factors associated with the outcome. Results: 30,199 patients aged >66 years were included in the study. 25,096 patients had 70,256 in-patient claims. 53.6% of these claims were unplanned hospitalizations. The top 3 reasons for unplanned hospitalization were pneumonia, congestive heart failure and volume depletion. Unplanned hospitalization rates ranged from 57.9% (colon) to 67.4% (esophageal) among the different cancer types. After multivariate analysis, unplanned hospitalization was more likely among those with esophageal cancer (RR=1.15, CI 1.1-1.2), gastric cancer (RR=1.07, CI 1.04-1.11), pancreatic cancer (RR=1.04, CI 1.01-1.07) and rectal cancer (RR= 1.03, CI 1.00-1.06). Patients with regional and distant disease were at higher risk for unplanned hospitalization (RR=1.14, CI 1.11-1.16 and RR=1.13 CI 1.1-1.16 respectively), as well as those aged >80 (RR=1.04 CI 1.01-1.06), of black race (RR=1.06, CI 1.02-1.09), and living in census tract with >21% poverty level (RR=1.06 CI 1.03-1.09). Risk of unplanned hospitalization also increased with Charlson scores (p<.0001). Conclusions: The majority of hospitalizations were unplanned. Top reasons for unplanned hospitalization were diagnoses that are considered potentially preventable, and should be a focus for intervention. The disparity in unplanned hospitalizations among blacks and those living in poverty-stricken areas warrants further investigation as to whether this finding correlates with timely access to outpatient care in this population.
Response rate and bridging to hematopoietic stem cell transplantation (HSCT) with quizartinib (AC220) in patients with FLT3-ITD positive or negative relapsed/refractory AML after second-line chemotherapy or previous bone marrow transplant.
Authors: Cortes Jorge E. , Perl Alexander E. , Dombret Hervé , Dohner Hartmut , Steffen Bjoern , Rousselot Philippe H. , Martinelli Giovanni , Estey Elihu , Shah Neil P. , Burnett Alan K. , Gammon Guy , Trone Denise , Levis Mark J.
Published: March 2020

7012

Background: FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) in acute myeloid leukemia (AML) is associated with early relapse after chemotherapy and poor survival. Relapse after HSCT or failure of salvage chemotherapy in FLT3-ITD AML is rarely associated with subsequent HSCT or durable survival. Quizartinib, an oral FLT3 inhibitor, shows promising activity; a Ph 2 study (n=333) of quizartinib monotherapy (Levis et al, ASH 2012) reported that quizartinib often bridged patients (pts) to HSCT. Methods: 136 FLT3-ITD(+) and 40 FLT3-ITD(-) pts, relapsed/refractory after HSCT or 1-second line regimen, were included. The response category of composite complete remission (CRc) comprised complete remission [CR] + complete remission with incomplete platelet recovery [CRp] + complete remission with incomplete hematologic recovery [CRi]. Results: Quizartinib was discontinued for HSCT in 47/136 FLT3-ITD(+) pts (35%), with 44/47 having at least a PR (2 CRp, 24 CRi, 18 PR). Median overall survival (OS) was 41.5 wks for pts with CRc prior to HSCT and 29 wks for pts with PR. The 1y survival rate was 39% for both response groups. Pts with a CRc (n=36) or PR (n=20) but no HSCT, respectively, had a median OS of 24.5 and 20.9 wks and 1y survival rates of 25% and 5%. Of 27 pts with OS >52 wks, 17 (63%) had HSCT. Quizartinib was discontinued for HSCT in 14/40 FLT3-ITD(-) pts (35%), with 13/14 having at least a PR (1 CR, 1 CRp, 7 CRi, 4 PR). Median OS was not yet reached for pts with CRc, and was 40.7 wks for pts with PR. The 1y survival rate was 78% for pts with CRc and 50% for pts with PR. 8 of these 14 pts had detectable ITD mutation but the level was below the prespecified 10% cutoff. Conclusions: Of clinical significance in these heavily pretreated pts who had failed salvage chemotherapy or HSCT, approximately 1/3 were successfully bridged to potentially curative HSCT, with encouraging 1y survival rates. To extend the potential benefits of FLT3 inhibitor therapy in combination with allogeneic HSCT, studies of maintenance quizartinib to prevent relapse post HSCT are ongoing. Clinical trial information: NCT00989261.
BH3 profiling as a predictive biomarker for response to cytarabine-based treatment of acute myelogenous leukemia.
Authors: Pierceall William E. , Carlson Nicole E. , Richard David J. , Huang Xuelin , Elaschoff Michael , Konopleva Marina , Kornblau Steven Mitchell , Cardone Michael H. , Andreeff Michael
Published: March 2020

7022

Background: Acute myelogenous leukemia (AML) is the most frequently diagnosed of the leukemias with approximately 13,000 new cases per year in the U.S. Although intense therapeutic discovery efforts have been directed towards AML, cytarabine-based treatment remains unchanged as the standard-of-care (SOC). As patient response to SOC is variable, segregating patients based on biomarker-driven predicted response may lead to improved clinical outcomes. One personalized diagnostic approach that may provide actionable information in patient management is BH3 profiling, a surrogate functional biomarker assay that assesses cell mitochondrial response to pro-apoptotic signaling. Methods: Blinded to outcomes, we profiled an AML cohort (n=63) treated with cytarabine-based therapy using a panel of BH3 peptides with response as a primary endpoint. Peripheral blood mononuclear cell (PBMC) or bone marrow aspirate (BM) specimens were obtained from newly diagnosed AML patients and viably preserved. Specimens were assayed by flow cytometry following cell permeabilization and incubation with potentiometric JC-1 mitochondrial dye and individual BH3 peptides. Results: Mann-Whitney analysis indicates BH3 profiling biomarkers are correlated with response to induction therapy. Among BH3 peptides, BIM was highly significant (p=2X10-6; CI[0.73,0.94]) with a notable sensitivity/specificity profile (AUC=0.84; p=2X10-10). Multivariate analysis indicates improved profiles for BIM + patient age (AUC=0.89; CI[0.81,0.97])and BIM + patient age +cytogenetic status (AUC=0.91; CI[0.83,0.98]). When patients were stratified by cytogenetic status, BIM was significant for both intermediate (p=0.0017; AUC=0.88; CI[0.71,1.04]) and unfavorable (p=0.016; AUC=0.80; CI[0.60,1.00]), demonstrating that the predictive power of the assay is independent of cytogenetics. Conclusions: Here, BH3 profiling predicts patient response to cytarabine-based treatment regimens with accuracies of 90%. Thus, patients may potentially benefit from being given alternate therapies while at the same time spared the toxicities, cost, and time lost associated with a therapy less likely to exhibit response.
Rate of complete hematological response of elderly Ph+ acute lymphoblastic leukemia (ALL) patients by sequential use of nilotinib and imatinib: A GIMEMA protocol LAL 1408.
Authors: Papayannidis Cristina , Piciocchi Alfonso , Vitale Antonella , Iacobucci Ilaria , Soverini Simona , Di Raimondo Francesco , Paolini Stefania , Pizzolo Giovanni , Carella Angelo Michele , Cazzola Mario , Cuneo Antonio , Leoni Pietro , Luppi Mario , Morra Enrica , Specchia Giorgina , Elia Loredana , Foa Robin , Baccarani Michele , Martinelli Giovanni
Published: March 2020

7025

Background: We have explored if the administration of two TKIs, Nilotinib (NIL) and Imatinib (IM) can improve the results without increasing the toxicity in the elderly Ph+ Acute Lymphoblastic Leukemia (ALL) patients. We investigate the type and number of BCR-ABL kinase domain mutations developing during and after the study. Methods: We have designed a study (ClinicalTrials.gov. NCT01025505) in which patients more than 60 years old or unfit for intensive chemotherapy and SCT where treated with two TKIs, NIL 400 mg twice daily, and IM 300 mg twice daily, alternating for 6 weeks for a minimum of 24 weeks (study core) and indefinitely in case of response. The 6-weeks rotation schedule was respected, irrespectively of temporary discontinuations. The primary end-point was the rate of Disease Free Survival (DFS) at 24 weeks (4 courses of treatment); the secondary end points included the evaluation of CHR, CCgR and CMR rates. Results: 39 patients have been enrolled in 15 Italian hematologic Centers (median age 66 years, range 28-84). Among these, 8 patients were unfit for standard chemotherapy or SCT (median age 50 years, range 28-59). 27 patients were p190, 5 were p210 and 7 were p190/p210. After 6 weeks of treatment, 36 patients were evaluable for response: 34 were in CHR (94%) and 2 in PHR (6%). 23 patients have already completed the study core (24 weeks), 87% were in CHR and 17 are currently continuing therapy in the protocol extension phase. Thus, the OS at 1 year is 79%, and 64% at 2 years. Overall, 1 patient was primarily resistant and 13 patients have relapsed, with a median time to relapse of 7.6 months (range 0.8-16.1 months), for a DFS of 51.3% at 12 months. Conclusions: In this small cohort of Ph+ ALL elderly/unfit patients, the rates of relapse and progression were not likely to be different from the rates observed with Imatinib alone. Acknowledgements: ELN, AIL, AIRC, PRIN. Clinical trial information: NCT01025505.
Use of Axl, a therapeutic target in AML, to mediate stroma-induced chemoresistance.
Authors: Ben Batalla Isabel , Schultze Alexander , Wroblewski Mark , Erdmann Robert , Heuser Michael , Riecken Kristoffer , Binder Mascha , Cubas-Cordova Miguel , Melanie Janning , Wellbrock Jasmin , Fehse Boris , Hagel Christian , Krauter Jürgen , Lorens James B. , Ganser Arnold , Fiedler Walter M. , Carmeliet Peter , Pantel Klaus , Bokemeyer Carsten , Loges Sonja
Published: March 2020

7027

Background: Axl, the receptor for Growth Arrest-specific protein 6 (Gas6) plays a role in AML pathobiology (Blood Suppl. Nov 2011; 118: 940). Here, we investigated whether Axl represents a therapeutic target in AML. Methods: Gas6 levels were measured by ELISA and immunohistochemistry. Axl expression was detected by flow cytometry. Co-cultures of (murine) BM stroma cells (primary, OP9, S17) with Mv4-11 and OCI-AML5 cell lines were performed. Results: We found (i) higher expression of Axl in AML BM compared to healthy BM donors (66.20 ± 10.87 vs. 0.65 ± 0.10 %; n=8/6; p<0.05); (ii) Axl expression by 68 ± 31% of AML blasts and (iv) higher expression of Axl by CD34+CD38- AML stem cells compared to healthy CD34+CD38- BM stem cells (58.43 ± 4.63 % vs. 6.00 ± 2.01 %; n=7/6; p<0.05). The Axl inhibitor BGB324 dose-dependently inhibited proliferation of primary AML cells with a mean IC50 of 1.8 µM. Sensitivity to BGB324 (i.e. a lower IC50) correlated with Axl expression on leukemia cells (Pearson’s r = -0.9656, p<0.05). Combination therapy with BGB324 and cytarabine exerted an additive therapeutic effect and BGB324 could chemosensitize cytarabine-resistant AML cells. Analyses of BM sections revealed that Gas6 expression was low in AML cells, similar to healthy hematopoietic cells while it was abundantly expressed in AML BM stromal cells with fibroblastic/mesenchymal morphology (BMDSCs). Gas6 expression was considerably lower in control BMDSCs (86 ± 14 % vs. 20 ± 20 %; n=5/7; p<0.05) thus suggesting a possible paracrine interaction between AML cells and BMDSCs leading to Gas6 upregulation in the stroma compartment. Co-culture experiments indicated specific upregulation of murine (m)Gas6 in BMDSCs via leukemia-cell derived IL-10 and M-CSF. This stroma-derived Gas6 could mediate chemoresistance of AML cells in co-culture, which was abrogated by sAxl or by BGB324. Thus, interaction between stroma-derived Gas6 and Axl+leukemia cells forms a chemoprotective niche for leukemia cells. In line with these findings Axl blockade chemosensitizes Mv4-11 cells for treatment with doxorubicine in vivo. Conclusions: Axl represents a therapeutic target in AML and Axl inhibition by BGB324 holds potential to treat chemosensitive and chemoresistant AML.
Activity and tolerability of SL-401, a targeted therapy directed to the interleukin-3 receptor on cancer stem cells and tumor bulk, as a single agent in patients with advanced hematologic malignancies.
Authors: Frankel Arthur E. , Konopleva Marina , Hogge Donna , Rizzieri David , Brooks Christopher , Cirrito Thomas , Kornblau Steven Mitchell , Borthakur Gautam , Bivins Carol , Garcia-Manero Guillermo , Ravandi Farhad , Kadia Tapan M. , Andreeff Michael , Cortes Jorge E. , Hoberman Kenneth , Szarek Michael , Bergstein Ivan , Kantarjian Hagop M. , Rowinsky Eric K.
Published: March 2020

7029^

Background: SL-401 is a novel biologic targeted therapy directed to the interleukin-3 receptor (IL-3R). IL-3R is overexpressed on cancer stem cells (CSCs) and tumor bulk relative to normal hematopoietic cells in a wide range of hematologic malignancies including AML and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Since SL-401 targets both leukemia blasts and CSCs, tumor regression and improvement in long-term outcome is expected. The clinical activity and side effect profile of SL-401 were evaluated in a multicenter Phase I/II trial of patients with advanced hematologic cancers. Methods: Eighty-one patients with advanced hematologic cancers, including relapsed or refractory AML (n = 59) and heavily pretreated BPDCN (n = 4), have been enrolled. Patients received a single cycle of SL-401 via 15-minute IV infusion to determine the maximum tolerated dose (MTD) and assess antitumor activity. Results: A single cycle of SL-401 demonstrated single agent activity in relapsed or refractory AML patients, including 2 durable CRs of 8 and 25+ months duration and multiple cases of blast reductions. SL-401, when delivered at therapeutically relevant doses, was associated with > 3-fold greater median overall survival (OS) in AML patients who received 2+ prior lines of treatment relative to historical results. In addition, 3 heavily pre-treated patients with BPDCN, an uncommon malignancy that expresses high levels of IL-3R and is ultrasensitive to SL-401 (IC50 values in the femtomolar [10-15 M] range), had CRs, with durations of 5, 3+ and 1+ months. The MTD was 16.6 µg/kg/day; the dose-limiting toxicities of hypoalbuminemia and edema, which are manifestations of capillary leak, occurred at 22.1 µg/kg/day. Other ≥ Grade 3 adverse events included transient transaminase elevations. There was no treatment-related myelosuppression. Conclusions: SL-401 was well tolerated and demonstrated single agent activity in patients with relapsed or refractory AML and BPDCN. Based on these findings, single agent SL-401 given in multiple cycles will be advanced into pivotal studies of AML (3rd-line) and BPDCN. Clinical trial information: NCT00397579.
Phase II study of orally administered rigosertib (ON 01910.Na) in transfusion-dependent lower-risk myelodysplastic syndrome (MDS) patients.
Authors: Raza Azra , Mukherjee Siddhartha , Eisenberger Andrew , Mears J. Gregory , Wilhelm Francois
Published: March 2020

7031

Background: Rigosertib, a novel small molecule inhibitor of PI3-Kinase and PLK pathways is currently evaluated (IV infusions) in a phase III trial in higher risk MDS patients who have failed hypomethylating agents. A previous phase I study found good bioavailability and activity of orally administered rigosertib in transfusion-dependent MDS patients (ASH 2011). Here we report preliminary results from an ongoing phase II study. Methods: This is a randomized, two-arm study of oral rigosertib (560 mg bid) administered either intermittently (2 out of 3 weeks) or continuously. Transfusion-dependent patients must have received at least 4 units RBC transfusions over 8 weeks before randomization, and can receive transfusions and erythrocyte stimulating agents (ESAs) while on study. Results: Twenty nine MDS patients (25 intermediate-1 and 4 low risk per IPSS classification) have been randomized as of December 17, 2012. Overall oral rigosertib was well tolerated except for a high incidence (5 of 9 patients) of grade 2+ urinary side effects (dysuria, hematuria, cystitis, and urinary urgency), in the continuous dosing arm. Accordingly, the protocol was amended to allow all patients to be treated with intermittent dosing, with option of dose interruption/reduction resulting in a much lower frequency of urinary side effects (4/20 patients with urinary grade 2+ toxicity). Fifteen patients (none of them with del5q cytogenetic) have been treated with intermittent dosing for at least 8 weeks. Seven (47%) patients achieved transfusion independence (no RBC transfusion for at least 8 consecutive weeks), which lasted 8 to 27 + weeks. Six of 7 responding patients were refractory to prior treatment with ESAs and 5 of these 7 patients received concomitant ESAs, suggesting an effect of rigosertib on ESA resistance. Conclusions: Preliminary results of this phase II study indicate that intermittent dosing of rigosertib administered orally is well tolerated and active in producing transfusion independence in approximately 50% transfusion dependent, lower risk MDS patients. The contributing role of rigosertib and ESAs in these transfusion responses is being investigated. Clinical trial information: NCT01584531.
Cutaneous complications in hematopoietic cell transplant recipients: Impact of biopsy on patient management.
Authors: Paun Oana Valeria , Phillips Tycel Jovelle , Fu PingFu , Novoa Robert , Honda Kord , Lu Kurt Quoc , Lazarus Hillard M.
Published: March 2020

7036

Background: Although skin biopsies are recommended for diagnostic purposes in hematopoietic cell transplant (HCT) recipients, their utility in directing management of post transplant cutaneous eruptions remains uncertain. Little evidence was found in support of this procedure either from a diagnostic or prognostic perspective. Methods: We retrospectively evaluated 351 consecutive HCT recipients transplanted at our institution between January 2005 and December 2011; 156 patients underwent 388 cutaneous biopsies. Results: The group that underwent cutaneous biopsy after transplantation and the group that was spared the procedure were homogenous with regards to age and gender. The pre-biopsy diagnosis and final diagnosis differed in 213 episodes (55%) as determined by histologic evaluation. Biopsy results led to a change in therapy in 61 of 388 (16%) biopsied rashes. With regards to therapy changes, 24 of 61 (39%) occurred in response to a clinical diagnosis of GVHD. In this situation the most frequently noted change was augmentation or addition of systemic immuno-suppression (19 of 24). Changes in systemic therapy occurred with similar frequencies with respect to concordance or discordance between clinical and histopathologic diagnosis (p = 0.12). We used classification and regression tree analysis to develop an algorithm to predict the biopsy yield as expressed by change of management. This is a non-parametric decision tree learning technique that produces a classification tree based on a categorical dependent variable, formed by a collection of rules based on variables in the modeling data set. Conclusions: Cutaneous biopsy findings often changed the clinical dermatologic diagnoses of HCT recipients; however, the impact of biopsy results on treatment decisions was less profound; altered diagnoses in patients who underwent biopsy often did not lead to therapy changes. Skin biopsies of post-transplant patients may not be mandatory for either diagnostic or therapeutic reasons, but in carefully chosen circumstances can yield extremely important data. A prospective study should be undertaken in order to evaluate current practice data and to validate our decision making analysis tree.
Impact of oral mucositis on outcomes of multiple myeloma patients treated with high-dose melphalan conditioning and autologous stem cell transplantation (ASCT).
Authors: Jaguar Graziella Chagas , Rodrigues Gustavo Henrique , Guollo Andre , Camandoni Vanessa Oliveira , Melo Leila Maria Magalhães Pessoa , Alves Fabio Abreu , Lima Vladmir Claudio Cordeiro
Published: March 2020

7037

Background: High-dose melphalan is the standard conditioning regimen for patients with multiple myeloma (MM) undergoing ASCT. However, this therapy is commonly associated with severe oral mucositis (OM). Low-level laser therapy (LLLT) has been reported as an effective method in preventing this complication. The aim of this study was to define the potential impact of OM on outcomes in patients with MM undergoing ASCT and receiving preventive LLLT. Methods: We describe a retrospective cohort of 79 consecutive patients with MM who received high-dose melphalan conditioning. All patients received prophylactic LLLT application performed daily from the beginning of the conditioning regimen up to day +2. The patients continued receiving LLLT in case of OM grade ≥ 2 until complete remission of the lesions. OM severity was assessed daily using WHO scale from the beginning of conditioning until hospital discharge. We examined the relationship between worst OM grade and clinical outcomes, including days with oral pain, days of total parenteral nutrition, days of LLLT and days with neutropenic fever. Results: Of 79 patients, 55 (69.62%) experienced OM grade 0-1, 16 (20.25%) experienced OM grade 2, 7 (8.86%) grade 3 and 1 (1.26%) grade 4. Patients with OM grade 0-2 had statistically fewer days of oral pain compared with grade 3-4 (0.88 and 6.25 days, respectively, p = 0.0001). The worst OM grade was also significantly (p < 0.05) associated with days of narcotic therapy and length of LLLT. Severe OM was not associated with febrile days or the use of parenteral nutrition. Conclusions: Severe OM is associated with worse clinical outcomes. In this transplantation setting, severe OM was not common as previously reported in literature, probably due to LLLT. Controlled randomized trials should be performed to confirm the real benefit of LLLT in this scenario as well as the pharmacogenomics and pharmacokinetic studies to better understand interpatient variability of melphalan exposure and toxicity.
Primary payer status and outcomes after autologous hematopoietic stem cell transplant: A national perspective.
Authors: Rahman Abu Ahmed Zahidur , Mujib Nusrat , Mujib Marjan , Nazir Tariq
Published: March 2020

7042

Background: With healthcare cost in rise, it is of interest to explore variation in healthcare delivery outcome with different payment source. This study was aimed to analyze relationship between payment source and outcome following autologous hematopoietic stem cell transplant (AutoHSCT) in a national database. Methods: We identified all hospitalizations with AutoHSCT (n=1,673) from Nationwide Inpatient Sample (NIS), Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality 2010 database using the ICD 9 procedure codes 41.04 and 41.07. Based on sample weights an estimated 8,444 AutoHSCT procedures were performed nationwide in 2010. Patients were stratified on the basis of payer status: Medicare (27%), Medicaid (12%), private insurance (60%), and uninsured (0.8%). Multivariable logistic regression models were used to determine the association of primary payer status and outcomes. Results: Patients had a mean age of 54 (±13) years, 39% were women and 69% were whites. In-hospital mortality occurred in 1.1%, 2.9% and 3.3% of AutoHSCT patients with primary payer status of private insurance, Medicaid and Medicare respectively. AutoHSCT patients with primary payer status of Medicaid and Medicare had a statistically significant higher chance of in-hospital mortality compared to patients with private insurance (adjusted odds ratios and 95% confidence intervals, 2.68; 1.54-4.65; P <0.001 and 1.90; 1.21-2.99; P=0.005 respectively). Length of stay was longer for Medicare patients (20 ± 11 days) and Medicaid patients (20 ± 12 days) compared to private insurance (18 ± 8 days; P <0.001). Medicare and Medicaid patients also accrued higher hospital charges (USD 175,221 and USD 166,453), compared to private insurance patients (USD 157,120; P <0.001). Conclusions: In this national study Medicaid and Medicare patients had an independent risk for in-hospital mortality compared to private insurance patients. Medicaid and Medicare patients also had longer length of hospital stays and accrued higher hospital charges. This may mandate a closer look into the current resource utilization strategies to reduce such disparities among patients undergoing AutoHSCT.
Arsenic trioxide: Pharmacokinetics in acute promyelocytic leukemia (APL) patients.
Authors: Ghiuzeli Cristina Maria , Calabro Anthony , Saunders Randall Jesse , Budman Daniel R. , Styblo Miroslav , Devoe Craig E. , Allen Steven L.
Published: March 2020

7055

Background: Arsenic (As) has significantly increased survival for APL patients. As and its metabolites’ effects on cell proliferation, apoptosis, and methylation, especially long term, remain largely unknown. It is imperative to study the pharmacokinetics of As at therapeutic doses in order to limit untoward effects resulting from treatment. Arsenic trioxide (ATO), available as arsenous acid (iAsIII), is readily metabolized through sequential methyl group additions and electron reduction steps: iAsIII →MAsV →MAsIII →DMAsV →DMAsIII →TMAsVO →TMAsIII. iAsIII, MAsIII and DMAsIII are more biologically active and more toxic than pentavalent forms. The key enzyme involved is arsenic methyltransferase, and polymorphisms contribute to metabolic differences between individuals. Methods: Cancer patients not treated with ATO (controls) had one collection of blood and urine samples, while APL patients receiving therapeutic doses of ATO had collections immediately prior to and at 1, 2, 4, 6, and 24 hours, days 4, 8, 15, and 4 weeks after ATO-free interval. Total iAs (iAsIII+iAsV), MAs (MAsIII+MAsV) and DMAs (DMAsIII+DMAsV) were measured in plasma using hydride generation cryotrapping atomic absorption spectrometry, a sensitive automated method of arsine detection. The same As species were measured in urine and in exfoliated bladder cells isolated from urine. Results: We report data on ten control patients and six treated patients (ATO 0.15 mg/kg/day). Initial average As concentrations in treated patients (0.051 ng/ml) were similar at baseline to the controls (0.046 ng/ml). We observed that iAs is quickly metabolized from a peak average plasma concentration of 32 ng As/ml to a trough of 10 ng As/ml within six hours from infusion, remaining unchanged for at least 24 hours. MAs and DMAs concentrations begin to increase at six hours, and continue to rise by day 4 to an average concentration of 8.5 and 10.4 ng As/ml respectively, followed by decline to baseline 4 weeks after final ATO infusion. Conclusions: Treatment with ATO leads to the formation of MAs and DMAs whose long term toxicity in APL patients is poorly understood. Studies involving analysis of As metabolites are needed to assess possible long term toxicities on non-targeted organs.
The role of salvage induction chemotherapy after azacitidine (AZA) treatment failure.
Authors: Yee Karen W. L. , Brandwein Joseph , Schimmer Aaron D. , Gupta Vikas , Minden Mark D. , Schuh Andre C.
Published: March 2020

7078

Background: Hypomethylating agents (HMA) such as AZA, are considered standard of care for patients (pts) with IPSS Int-2 or High-risk MDS. These agents are not curative. Many centers have used HMAs as a bridge to alloSCT in pts with MDS in an attempt to reduce tumor burden and prolong time to progression to AML. However, pts are at risk of AZA treatment failure, which may delay or prevent subsequent alloSCT. Recent data have demonstrated poor responses to intensive chemotherapy after AZA failure [ORR of 0% (0 of 4 pts) to 14% (3 of 22 pts) (J Clin Oncol 2011; Br J Haematol 2012)]. Methods: This retrospective analysis evaluates the outcomes of 18 pts with MDS, CMML and AML, who failed AZA therapy, and subsequently received induction chemotherapy at the Princess Margaret between July 2009 and December 2012. Results: Median age was 57.7 y (range, 19 - 75 y); only 1 pt was > 70 y. 56% were male. Of the 18 pts, 83% were treated for MDS, 6% CMML-2, and 11% AML. IPSS was Int-2/High-risk in 16 pts and Int-1 risk in 2 pts. 83% of pts had been treated with AZA as first-line therapy. Two pts had received growth factors & 1 pt hydroxyurea prior to AZA. Median number of AZA cycles administered was 5.5 (range, 1 - 18) with 72% of pts receiving < 6 cycles. Eleven (61%) pts had primary AZA failure, 5 (28%) secondary AZA failure, and 2 (11%) were taken off AZA to receive induction chemotherapy as an HLA-identical donor was found. At the time of induction chemotherapy, 15 pts had s/tAML, 2 RAEB-2 and 1 CMML-2. Cytogenetic risk was intermediate in 4 and poor in 11 pts, respectively. Karyotype analysis was not done or inconclusive in 3 pts. ORR was 44% and 37.5% in all pts and in AZA failures only, respectively. CR rate was 22% and 25%, CRi 27% and 12.5%, and MLFS 6% and 0% in all pts and in AZA failures only, respectively. Four pts died during induction. Four of 8 responders received an alloSCT, with the remaining 4 pts relapsing (3 while awaiting an alloSCT). Median F/U of all pts was 12.6 mos, with a median OS of 8.3 mos. Conclusions: Contrary to prior reports, salvage induction chemotherapy can yield responses in a significant number of pts who have failed AZA therapy. However, response duration and OS remain poor for AZA treatment failures. There is an unmet need for novel therapeutic agents in this group of patients.