bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical impact of neutropenia and febrile neutropenia in mCRC pts treated with FOLFOXIRI/bevacizumab (bev): A pooled analysis of TRIBE and TRIBE2 studies.
Authors: Rossini Daniele , Sbrana Andrea , Bergamo Francesca , Manai Chiara , Santini Daniele , Ghidini Michele , Antoniotti Carlotta , Moretto Roberto , Marmorino Federica , Urbano Federica , Ronzoni Monica , Noventa Silvia , Randon Giovanni , Carlomagno Chiara , Latiano Tiziana Pia , Cordio Stefano Sergio , Granetto Cristina , Cremolini Chiara , Falcone Alfredo , Antonuzzo Andrea
Published: March 2020

11591

Background: FOLFOXIRI/bev is a valid option as first-line therapy for unresectable mCRC. TRIBE and TRIBE2 trials reported better activity and efficacy of the triplet/bev when compared with doublets/bev at the price of a higher incidence of chemo-related toxicities, including neutropenia (N). Here we aim at providing a detailed description of this adverse event, including the occurrence of febrile neutropenia (FN) and the use of granulocyte-colony stimulating factors (G-CSFs), in order to estimate the clinical relevance of N during FOLFOXIRI/bev. Methods: Safety data of 1175 pts enrolled in the TRIBE and TRIBE2 studies were reviewed. The incidence of N, the incidence and severity of FN, and the use of G-CSF in the triplet/bev and in the doublets/bev arms were compared using the Chi-square or the Fisher exact test as appropriate. Results: Out of 1175 pts included in the final analysis, 586 (49.8%) were treated with FOLFOXIRI/bev. Five pts (0.8%) in the doublets/bev arms and 29 (4.9%) in the triplet/bev arms received a primary prophylaxis with G-CSF. Among other pts, 118 (20.2%) in the doublets/bev arms and 276 (49.9%) in the triplet/bev arms experienced ≥ G3 N (p < 0.001). FN occurred in 25 (4.3%) and 41 (7.4%) cases respectively (p=0.041). Out of 78 FN episodes, 4 (13.3%) out of 30 in the doublets/bev arms and 13 out of 48 (27.1%) in the triplet/bev arms were associated with a poor MASCC score (<21) (p=0.17). G-CSF was used in 1069 (10.8%) cycles, 270 (5.3%) in doublets/bev and 799 (16.6%) in triplet/bev arms. In both arms, the majority of N and FN episodes were observed in the first two months (318 ≥ G3 N episodes out of 675 (47.1%), and 54 FN episodes out of 78 (69.2%)). Conclusions: FOLFOXIRI/bev was associated with a higher risk of N and FN than doublets/bev. However, the risk of FN was lower than 10%, thus not requiring a systematic use of primary G-CSF prophylaxis. The majority of FN episodes was associated with a good MASCC score, thus having a limited clinical impact. The vast majority of FN episodes occurred in the first two months of treatment, suggesting a closer monitoring of this adverse event during the first courses of therapy.
Predictors and trajectories of fatigue in ovarian and uterine cancer.
Authors: Poort Hanneke , de Rooij Belle Hadewijch , Weng Shicheng , Ezendam Nicole , van de Poll-Franse Lonneke V , Wright Alexi A.
Published: March 2020

11603

Background: Fatigue is one of the most common and distressing symptoms reported by patients with gynecological cancers, but few studies have empirically examined whether it resolves without intervention. The aims of this study were to identify: 1) clinically-distinct subgroups of patients with fatigue over time and 2) medical and psychological predictors of clinically-significant fatigue one-year post-diagnosis. Methods: Secondary analysis of a prospective cohort study. Symptoms of fatigue, depression, and anxiety were assessed at diagnosis, 6-months, and 12-months with the 10-item Fatigue Assessment Scale (FAS), and the Hospital Anxiety and Depression Scale (HADS), respectively. Group-based trajectory modeling was used to classify patients by their fatigue scores over time, and logistic regression models were fit to examine associations between clinically-significant fatigue and demographic, clinical, and psychosocial characteristics. Patients with recurrent or primary progressive cancers were excluded from the primary analysis. Results: Among 312 participants with newly diagnosed ovarian (n = 112) or endometrial (n = 200) cancers, the median age was 66 years (IQR = 60-72 years), 36% had ovarian cancer, and 79% had early stage disease. At baseline, 49% reported clinically significant fatigue and one year later, 42% had persistent fatigue. During the year after diagnosis, there were three distinct trajectories of fatigue that persisted: (1) severe fatigue (15%), (2) moderate fatigue (45%), and (3) no fatigue (41%). Patients with ≥2 comorbid conditions (odds ratio [OR] 2.52, 95% confidence interval [CI] = 1.21-5.27, P = 0.01), clinically significant fatigue at baseline (OR 5.47, 95% CI = 2.71-11.03, P < .0001), and those reporting depressive symptoms at baseline (OR 3.45, 95% CI = 1.13-10.55, P = 0.03) were more likely to report clinically-significant fatigue at 12 months. Conclusions: Half of women with gynecologic cancers have clinically-significant fatigue at diagnosis and 42% of survivors have persistent fatigue one year later, suggesting spontaneous regression of symptoms is rare. Importantly, depressive symptoms contribute to persistent fatigue and are modifiable with psychological interventions. Future studies should test scalable psychological interventions to address depressive symptoms, reduce fatigue, and improve quality of life in women with gynecologic cancers.
A phase II, double-blinded, randomized study using a proprietary amino acid mixture as diarrhea prevention in patients undergoing autologous stem cell transplantation (AST) for multiple myeloma (MM) and non-Hodgkin lymphoma (NHL).
Authors: Luque Laura , Soiffer Robert , Glotzbecker Brett , Kim Haesook , DeFilipp Zachariah Michael , Keefe Dorothy Mary Kate
Published: March 2020

11607

Background: Melphalan, remains the mainstay of conditioning for autologous hematopoietic stem cell transplantation (HSCT) in multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) patients. Gastrointestinal symptoms represent the most significant non-hematologic toxicities following high-dose melphalan conditioning, with approximately 40% of patients experiencing CTCAE grade 2 or higher diarrhea following conditioning regimens containing melphalan. Enterade is a proprietary blend of electrolytes and five amino-acids that can facilitate retention of the absorbing capacity of the small intestine by rebuilding the villi and reduce antigenic translocation by tightening the mucosal barrier. In a study of irradiated mice, enterade improved survival and improved body weight following irradiation. The goal was to investigate the effectiveness of enterade to reduce GI toxicities after high-dose melphalan chemotherapy. Methods: The trial was designed as a Phase 2, multi-center, double-blinded, 2-arm randomized study. 114 MM or NHL patients were enrolled between October 2016 and October 2017. Patients received either two 8oz bottles/day of enterade or placebo starting on the day of admission through Day +14. GI toxicity was scored by the CT-CAE 4.0 system from admission through Day + 14. Compliance was arbitrarily set at consumption of 2 bottles daily for 11+ days. Results: Of the 114 enrolled patients, 99 (61 MM, 38 NHL) attempted to consume at least 1 dose of enterade/placebo. Compliance overall was much lower than anticipated; with no MM patients achieving compliance compared to 34.2% in the NHL group. Compliance in NHL patients was 31.6% in the enterade group versus 36.8% in the placebo group. Analysis of primary endpoint in NHL patients showed a 16% incidence of diarrhea ≥ grade 2 in enterade compliant patients versus 86% in the placebo group (p= 0.02). Conclusions: Eleven days of two 8oz bottles of liquid is a difficult task during ASCT, especially for MM with nausea, altered taste and poor appetite. For those NHL patients, compliant per protocol (who consumed ≥11 days), enterade significantly reduced diarrhea. The use of enterade to prevent diarrhea following high-dose chemotherapy should be explored further in populations capable of reasonable oral intake. Clinical trial information: NCT02919670.
Therapy discontinuation processes in a gynecologic oncology population.
Authors: Watson Catherine H. , Puechl Allison , Truong Tracy , Lim Stephanie , Havrilesky Laura Jean , Davidson Brittany Anne
Published: March 2020

11611

Background: The decision to discontinue anti-cancer therapies in oncology patients is a complex one and may occur in several unique ways. We sought to understand the processes of therapy discontinuation in a gynecologic oncology population and to discern possible changes in the distribution of these processes after implementation of a palliative care (PC) quality improvement project. Methods: Women with incurable gynecologic malignancies seen in the outpatient setting at an academic center were identified with the recommendation for ‘goals of care’ discussion within 3 visits following identification. Processes of discontinuing chemotherapy for this population were assessed and categorized into 1 of 4 categories: definitive outpatient decision, definitive inpatient decision, interruption by hospitalization, treatment holiday, and “no decision.” Retrospective chart review identified a similar cohort of women prior to the implementation of our PC intervention. Univariate analyses were conducted to determine associations between characteristics and binary outcome of definitive outpatient decision versus all other decision processes. Results: 90/102 (88%) pre-intervention subjects and 83/157 (53%) post-intervention subjects had died at time of analysis. Of the total deceased cohort, 59/173 (34%) made a definitive decision to stop therapy in the outpatient setting. After implementation of the PC initiative, there was a trend towards fewer women identified as having made “no decision” (18.1% vs 30%). Those who made a definitive outpatient decision were less likely to die within 30 days of hospitalization than those who did not (OR 0.16 [95% CI 0.07,0.390], p < 0.0001). Conclusions: Discontinuation of therapy is a nuanced concept in gynecologic oncology patients that can be stratified into several processes. While our data demonstrates a possible increase in active decision-making with the PC initiative, a majority of patients near the end of life still did not make definitive therapy cessation decisions. This reveals an urgent need for the development of initiatives to enhance patient engagement and shared decision making for women near the end of life.
How far do laypersons believe in the cure of cancer? Results of the EDIFICE6 survey.
Authors: De La Motte Rouge Thibault , Couraud Sebastien , Roupret Morgan , Touboul Chantal , Lhomel Christine , Viguier Jerome , Eisinger Francois , Greillier Laurent , Morere Jean F.
Published: March 2020

11616

Background: Advances in therapy and early detection, by population-based screening in particular, have significantly increased the number of patients cured from cancer. However, cancer patients’ chances of being cured varies strongly from one cancer to another. We studied the understanding of the concept of cure in the lay population and the factors associated with believing that cancer can be cured. Methods: The French nationwide observational survey, EDIFICE 6, was conducted online (June 26-July 28, 2017) on a core sample of 12 046 individuals (age, 18-69y). Representativeness was ensured by quota sampling on age, sex, profession, and stratification by geographical area/type of urban district. This analysis focused on understanding of the meaning of cure in breast (BC), cervical (CC), colorectal (CRC), lung (LC) and bladder (BLC) cancer for individuals with no history of cancer. Results: The majority of respondents believed that cure exists (BC 95%; CC 91%; CRC 89%; BLC 87%, LC 71%). Some agreed with the definition that cure is the disappearance of the disease (BC 42%; CC 38%; CRC 35%; BLC 33%, LC 25%), while others preferred the definition that cure is several years without disease (BC, CC 53%; CRC, BLS 54%; LC 46%). More men than women (P < 0.05) believed that cure exists for CRC, BLC and LC. Socially non-vulnerable individuals were more likely to believe in cure than their vulnerable counterparts (P < 0.05), as were individuals aged 50-69y (P < 0.05) versus those of 18-50y, and for all cancer types except LC. In multivariate analysis, the variable “clinical research enables progress” was correlated with believing that cure exists (BC, OR = 2.93; CC, OR = 1.86; CRC, OR = 2.22; LC, OR = 1.57, BLC, OR = 2.06), as was “progress is rapid” (BC, OR = 1.61; CC, OR = 1.66; CRC, OR = 1.7; LC, OR = 1.84; BLC OR = 1.68), and also social non-vulnerability. However, the variables “prevention”, respectively screening/treatments, “are important for cancer control” had a low impact on the belief in cure (OR~1). Conclusions: The lay population is relatively optimistic about the cure for cancer. Confidence in the existence of cure relies on medical progress. However, factors related to individual behavior, e.g., prevention and screening, did not affect the perception of cure.
After cancer, what’s more important? The survivorship care plan or the survivorship care visit?
Authors: Saiganesh Harish , Duffy Christine M. , Higel-Mcgovern Camille , Lopresti Mary Lorraine , Fenton Mary Anne , Strenger Rochelle , Korber Susan F. , Szymanski Tara , Dizon Don S.
Published: March 2020

11618

Background: The Commission on Cancer has made the provision of survivorship care plans (SCPs) a prerequisite for accreditation of cancer programs. However, whether all patients desire or derive benefits from an SCP is not established. This study sought to characterize the provision of survivorship care at the Lifespan Cancer Institute (LCI) to (1) determine clinical and distress characteristics at first visit to the LCI among patients treated with curative intent for a solid tumor diagnosis; (2) characterize which factors are associated with receipt of an SCP with or without a survivorship care visit (SCV); and (3) determine referral patterns and outcomes among patients with an SCP with or without an SCV. Methods: We have retrospectively reviewed 650 patients at Lifespan Cancer Institute so far, all of whom were initially seen between the years 2014-2017. As part of routine practice, all new patients are screened with the NCCN Distress Thermometer (DT). Data related to demographics, treatment variables, and presenting distress score were gathered using our electronic medical records. Categorical data were analyzed using Fisher’s Exact Test or Chi-Square. Multinomial logistic regression was performed for multivariate analysis. All analyses were performed in STATA 15.0. Results: The median age was 63 (range 29 to 90), 74.8% were female, and 39.5% were married or partnered. The major cancers represented included breast (52.2%), lung (16.6%), and prostate (6%) cancers. Severe distress (DT≥4) was reported in 49.5% of patients at their first visit with top concerns being worry (54.3%), nervousness (46.6%) and fatigue (37.3%). An SCP was documented in 461 patients (71.1%) and of these, 267 (57.9%) were seen in an SCV as well. On multivariate analysis, gender, marital status, and stage were significantly associated with the receipt of an SCP. However, only disease site was significantly associated with being seen in an SCV. Compared to those with an SCP but not seen in an SCV, those who attended an SCV were significantly more likely (p < 0.005) to be referred for post-treatment evaluation, including psychological counseling (15.7 vs 6.7%), physical therapy (56.9 vs 22.7%), and nutrition (26.6 vs 8.2%). The majority of patients followed up with referrals, though it was significantly higher among those with an SCV (95.4 vs 87%, p = 0.015). Conclusions: Survivorship care varies by cancer type, with highest rates of visits for patients with gynecologic and GI cancers. Referral to other resources is significantly higher among those seen in visits, and those who are referred will follow up.
Depression and anxiety symptoms in bereaved caregivers of patients with advanced cancer.
Authors: Vanbenschoten Olivia , Greer Joseph , Jackson Vicki , Kamdar Mihir , Gallagher Emily R. , Anand Maya V. , Temel Jennifer S. , El-Jawahri Areej
Published: March 2020

11623

Background: Caregivers of patients with advanced cancer experience substantial caregiving burden and psychological distress during the illness course. However, data on depression and anxiety symptoms in bereaved caregivers and factors associated with their psychological distress are lacking. Methods: We conducted a secondary analysis of 168 caregivers enrolled in a randomized trial of early palliative care integrated with oncology care versus oncology care alone for patients newly-diagnosed with incurable lung and non-colorectal gastrointestinal cancers and their caregivers who completed bereavement assessments at 3 months after their loved one’s death. We used the Hospital Anxiety and Depression Scale (HADS) to assess patients’ and caregivers’ depression and anxiety symptoms at baseline within 8 weeks of diagnosis, and at 3-4 months after the patient’s death (for caregivers). We asked caregivers to rate patient’s physical and psychological distress in the last week of life on a 10-point scale. We used linear regression adjusting for randomization and cancer type to explore associations between patient and caregiver factors and bereaved caregivers’ depression and anxiety. Results: 30.4% (51/168) and 43.4% (73/168) of bereaved caregivers reported clinically significant depression and anxiety symptoms, respectively. Younger patient age (B = -0.06, P = 0.041), higher patient baseline anxiety (B = 0.28, P = 0.002), and caregiver rating of worse physical (B = 0.28, P = 0.035) and psychological (B = 0.41, P < 0.001) distress experienced by the patient at the end of life (EOL) were associated with worse depression symptoms in bereaved caregivers. Only caregiver factors, including age (B = -0.07, P = 0.004), female sex (B = 1.60, P = 0.024), and rating of worse psychological distress experienced by the patient at the EOL (B = 0.42, P < 0.001) were associated with worse bereaved caregivers’ anxiety symptoms. Conclusions: Bereaved caregivers of patients with advanced cancer experience substantial psychological distress which is associated with their perceptions of their loved one’s distress at the EOL. Interventions to optimize EOL care for patients and reduce bereaved caregivers’ psychological distress are needed.
The importance of altruism to biomarker development for pancreatic cancer.
Authors: Heo Danny HJ , DeCicco Corinne , Singer Tori , Vemulapalli Vijetha , Yee Christopher , Kiebish Michael A. , Grund Eric M. , Akmaev Viatcheslav R , Narain Niven R. , Kennedy Kevin F. , Moser A. James
Published: March 2020

11626

Background: Longitudinal donation of tissue and health information by patients with pancreatic ductal adenocarcinoma (PDAC) is critical to validating algorithms for precision treatment. Unlike therapeutic trials offering potential survival benefit, factors motivating long-term participation in biomarker studies are poorly understood. We hypothesized that long-term participation (PART) depends on identifiable factors motivating study volunteers in non-therapeutic biomarker studies. Methods: A prospective, single-institution biomarker study was screened to identify participants with, or at elevated risk for, PDAC and periampullary cancer (Jul 2015-Dec 2018). Study consent precluded individual receipt of value or research benefit. Detailed biospecimen and clinical data (n = 294) were analyzed using multivariable modeling and Bayesian AI (bAIcis) to characterize motivators of PART. Results: Of 294 participants, 185 had PDAC (63%); 89 had premalignant lesions (30%) or tumors (20; 7%) mimicking PDAC. Mean age was 68 years, 54% male, 26% with prior cancers, and 18% family PDAC history. Treatment was not indicated (37% no cancer), potentially curative (27%), non-curative (35%); or refused (1.4%). Bayesian AI showed PDAC diagnosis to be the leading predictor of PART. Using multivariable modeling and adjusting for the competing risk of death, none of the following domains predicted PART: demographics, perceived personal/family cancer risk, health insurance type, median income, housing price, travel time/distance or charitable expense, or primary institution providing clinical treatment. The following motivators were significant predictors of PART: worsening symptoms (McGill Brisbane > 9; HR 0.54; p = 0.045), non-curative treatment (HR 0.55; p = 0.042); and shorter AJCC predicted survival (HR 0.77, p = 0.042). Conclusions: Volunteers with symptomatic PDAC and shorter predicted survival who received non-curative treatment were more motivated to participate in biomarker discovery. Volunteers were undeterred by apparent self-interests such as travel time, insurance type, income, charitable expense, and personal life expectancy. We attribute these findings to altruistic behaviors among patients most likely to die of PDAC.
ENESTop 192-week results: Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) after stopping second-line (2L) nilotinib (NIL).
Authors: Hughes Timothy P. , Boquimpani Carla , Takahashi Naoto , Benyamini Noam , Clementino Nelma Cristina D. , Shuvaev Vasily , Lipton Jeffrey Howard , Turkina Anna G. , De Paz Arias Raquel , Moiraghi Beatriz , Nicolini Franck E. , Dengler Jolanta , Sacha Tomasz , Kim Dong-Wook , Fellague-Chebra Rafik , Acharya Sandip , Bouard Catherine , Mahon Francois-Xavier
Published: March 2020

7005

Background: In the ENESTop study (NCT01698905) of TFR in pts with CML-CP who achieved a sustained deep molecular response (MR) with 2L NIL, 57.9% remained in TFR 48 wks after stopping NIL (primary endpoint). Analyses at 144 wks showed durability of TFR. Data from longer follow-up (192 wks) evaluating the maintenance of TFR are reported. Methods: Pts treated with ≥2 y NIL after > 4 wks imatinib (≥3 y total) and achieving MR4.5 ( BCR-ABL1IS ≤0.0032%) on NIL were eligible. After a 1 y consolidation, pts with no confirmed loss of MR4.5 could attempt TFR. NIL was resumed upon loss of major MR ( BCR-ABL1IS ≤0.1%) or confirmed loss of MR4 ( BCR-ABL1IS ≤0.01%). At the data cut-off (Sep 24 2018), all pts had completed ≥192 wks of TFR, resumed NIL, or discontinued the study. Results: By the data cut-off, of 126 pts entering TFR, 56 were ongoing, 59 had resumed NIL, and 11 had discontinued. TFR rate at 192 wks was 46.0% (58/126; 95% CI, 37.1–55.1%); all but 1 of the 58 pts were in MR4.5. Only 1/61 pts in TFR at 144 wks lost response by 192 wks (confirmed loss of MR4); another 2 pts discontinued due to serious AE (polycythemia vera) and pt/guardian decision, respectively. Of 59 pts who resumed NIL, 56 (94.9%) and 55 (93.2%) regained MR4 and MR4.5, respectively. 40/56 pts (71.4%) who regained MR4 had stable MR4 at 96 wks (12 discontinued < 96 wks, and 4 remained on study with < 96 wks, after regaining MR4); 37/55 pts (67.3%) who regained MR4.5 had stable MR4.5 at 96 wks (12 discontinued < 96 wks, and 6 remained on study with < 96 wks, after regaining MR4.5). There were no disease progressions, deaths due to CML, or new deaths since the 144-wk analysis. The 192 wk treatment-free survival rate was 50.3% (95% CI, 41.2–58.7%). Of 62 pts who remained in TFR for > 144 wks, 11.3%, 53.2%, 21.0%, 14.5% and 3.2% had musculoskeletal pain AEs during consolidation and each subsequent 48 wk period of TFR. Among 59 pts who resumed NIL, most common AEs were hypertension (20.3%) and arthralgia (13.6%); the majority of AEs were grade 1/2. Conclusions: Results demonstrate long-term durability and safety of TFR following 2L NIL, with no disease progressions or CML-related deaths, and musculoskeletal pain AEs were transient. Clinical trial information: NCT01698905.
Post-transplant cyclophosphamide in matched and haploidentical transplant recipients receiving myeloablative timed sequential busulfan conditioning regimen: Results of a phase II study.
Authors: Popat Uday R. , Mehta Rohtesh S. , Bassett Roland , Olson Amanda Leigh , Alousi Amin Majid , Anderlini Paolo , Alatrash Gheath , Bashir Qaiser , Ciurea Stefan O. , Hosing Chitra , Kebriaei Partow , Khouri Issa F. , Marin David , Nieto Yago , Oran Betul , Rezvani Katayoun , Qazilbash Muzaffar H. , Shpall Elizabeth J. , Champlin Richard E. , Andersson Borje
Published: March 2020

7007

Background: Myeloablative stem cell transplants have a lower rate of relapse than reduced intensity regimens. Timed sequential busulfan (TSB) with fludarabine (Flu) is a promising myeloablative regimen for patients undergoing matched sibling (MSD) or unrelated (MUD) donor transplantation (HCT) with low non-relapse mortality (NRM) (Popat et al Lancet Haematology 2018), but was not tested in haploidentical (haplo). Also, whether this approach can be used with post-transplant cyclophosphamide (PTCy) in MSD, MUD and haplo HCT is unknown. To address these issues, we conducted a prospective phase II study. Methods: Patients with hematological malignancies with MSD, MUD or haplo donor were eligible. They received fixed doses of Busulfan(BU) 80mg/m2 either on day -13 and -12 (n=45) or on -20 and -13 (n=10). Then, Flu 40mg/m2 was given on day -6 to -2 followed by Bu dosed to achieve target area under the curve (AUC) of 20,000 umol/min for the whole course based on pharmacokinetic studies. Thiotepa 5mg/kg was given on day -7 to haplo group. GVHD prophylaxis was PTCy 50mg/kg on day 3 and 4 and tacrolimus. Haplo and later MUD recipients also received mycophenolate mofetil. Results: 55 patients with a median age of 47 (15-65) years were enrolled. 30 patients had AML or MDS, 9 CML or MPD, 5 lymphoma, 5 myeloma and 6 ALL. About half had haplo 26 (47%); others had MUD 18 (33%) or MSD 11(20%). Disease risk index was high in 18 (32%), intermediate in 32 (58%), and low in 5 (9%) patients. Comorbidity score was ≥3 in 22 (40%) patients. With a median follow up of 17 months (5-28), 1-year OS, PFS, NRM and relapse rates were 71% (60-84%), 63% (51-77%), 20% (9-31%), and 17% (7-27%), respectively [Table]. There were no graft failures. Day 100 grade II-IV and III-IV acute GVHD rates were 38% (25-51%) and 9% (95% CI 1-17%), respectively; 1-year chronic GVHD and extensive chronic GVHD rates were 10% (2-28%) and 8% (0-15%), respectively. 1-year OS in MSD, MUD and haplo groups were 91% (75-100%), 72% (54-96%), and 62% (45-83%) respectively (P=0.11). Conclusions: Myeloablative TSB with PTCy is feasible in MSD, MUD and haplo HCT. It lowers the incidence of severe acute and chronic GVHD without apparent increase in relapse. Clinical trial information: NCT02861417. [Table: see text]
The first-in-class anti-CD47 antibody Hu5F9-G4 is active and well tolerated alone or with azacitidine in AML and MDS patients: Initial phase 1b results.
Authors: Sallman David Andrew , Donnellan William Bruce , Asch Adam Steven , Lee Daniel Junseung , Al Malki Monzr , Marcucci Guido , Pollyea Daniel Aaron , Kambhampati Suman , Komrokji Rami S. , Van Elk Joanna , Lin Ming , Agoram Balaji , Chen James Y , Volkmer Jens-Peter , Takimoto Chris H.M. , Chao Mark , Vyas Paresh
Published: March 2020

7009

Background: Hu5F9-G4 (5F9) is an antibody targeting CD47, a macrophage immune checkpoint and “don’t eat me” signal on cancers. CD47 blockade induces tumor phagocytosis and eliminates leukemia stem cells (LSC) in AML models. Azacitidine (AZA) synergizes with 5F9 by inducing “eat me” signals on AML, enhancing phagocytosis. This trial explored the safety/efficacy of 5F9 alone or with AZA in AML/MDS patients (pts). Methods: This Phase 1b treated: r/r AML/MDS pts with 5F9; and untreated AML (induction chemo ineligible) and higher risk MDS pts with 5F9+AZA. A 5F9 priming/intrapatient dose escalation regimen (1-30 mg/kg weekly) was used to mitigate on target anemia. Results: 10 (6 AML, 4 MDS) r/r pts received 5F9 (median 2 prior therapies (range 1-6). 24 untreated pts (15 AML, 9 MDS) received 5F9+AZA. In total, median age was 73, 62% of AML pts were intermediate or poor cytogenetic risk (38% unknown), all MDS pts were intermediate or high risk by IPSS-R. 5F9 alone or with AZA was well-tolerated with no MTD reached. 5F9 did not potentiate AZA toxicities. Treatment-related AEs ( > 10% of pts) for 5F9+AZA were anemia (25%), thrombocytopenia (20%), and infusion reactions (15%). In 25 efficacy evaluable pts, 8/15 (53%) untreated AML/MDS pts had a CR/CRi to 5F9+AZA (5/10 (50%) in AML, 3/5 (60%) in MDS). 1/10 (10%) r/r AML/MDS pts had a response (MLFS) to 5F9 alone. LSC frequency was reduced/eliminated in most 5F9+aza responders; 50% of responders were MRD negative by flow cytometry. 4/10 (40%) AML pts became RBC transfusion independent and 4/5 (80%) MDS pts had hematologic improvement. Time to response was more rapid (median 1.9 mos) than expected for AZA alone. As of Jan 2019, no responder has relapsed (median follow-up of 3.4 mos (range 1.1 – 6.8 mos). 2 pts had successful allogeneic transplant. Conclusions: 5F9+AZA is a novel immunotherapy blocking a key macrophage checkpoint. It has been well tolerated with robust activity in AML/MDS pts with rapid CRs and MRD negativity. Adding 5F9 to cytotoxic agents may be a promising treatment strategy. An expansion cohort is ongoing. Funded by Forty Seven and the California Institute for Regenerative Medicine. Clinical trial information: NCT03248479.
Low-dose cytarabine with or without glasdegib in newly diagnosed patients with acute myeloid leukemia: Long-term analysis of a phase 2 randomized trial.
Authors: Smith B. Douglas , Papayannidis Cristina , Heuser Michael , Montesinos Pau , Sekeres Mikkael A. , Oriol Albert , Schiller Gary J. , Candoni Anna , Jamieson Catriona HM , Hoang Caroline J. , Ma Wendy , Zeremski Mirjana , O'Connell Ashleigh , Chan Geoffrey , Cortes Jorge E.
Published: March 2020

7010

Background: Glasdegib is a potent, selective, oral inhibitor of the Hedgehog signaling pathway, approved in the US – in combination with low-dose cytarabine (LDAC) – for treatment of newly diagnosed acute myeloid leukemia (AML) in patients (pts) unable to receive intensive chemotherapy due to comorbidities or age (≥75 y). Methods: In this follow-up analysis from the phase 2 BRIGHT AML trial (NCT01546038), newly diagnosed pts with AML ineligible for intensive chemotherapy were randomized 2:1 to glasdegib + LDAC or LDAC alone (study design: Cortes et al., Leukemia 2018). This long-term analysis evaluated efficacy and safety after ~20 mo of additional follow-up. Results: As of Oct 11, 2018, 116 pts were assigned to treatment with glasdegib + LDAC (n = 78) or LDAC alone (n = 38) (median follow-up: 43.4 and 42.0 mo, respectively). Median overall survival (OS) was higher with glasdegib + LDAC vs LDAC alone (Table). Improvement in OS was consistent across the prespecified subgroups. The main cause of death in both arms was disease progression (both during study and follow-up). The incidence of adverse events (AEs) and serious AEs on glasdegib was generally lower long term (after 90 days) than short term (during the first 90 days) (83.7% and 51.2% vs 98.7% and 65.3%, respectively). Clinical trial information: NCT01546038. Conclusions: Addition of glasdegib to LDAC vs LDAC alone continued to demonstrate improved OS in pts with AML in this analysis; improvement was consistent across groups stratified by cytogenic risk. Long-term follow-up confirmed treatment with glasdegib was associated with an acceptable safety profile.[Table: see text]
Pooled safety summary for patients treated with the CD22-directed cytotoxin moxetumomab pasudotox-tdfk.
Authors: Kreitman Robert J. , Coutre Steven , Elesinmogun Cynthia , Kuptsova-Clarkson Nataliya , Li Xia , Pastan Ira , Gladstone Douglas Edward
Published: March 2020

7014

Background: Moxetumomab pasudotox-tdfk was FDA-approved in 2018 for the treatment of adults with relapsed/refractory hairy cell leukemia (HCL) who have received ≥2 prior therapies, including a purine nucleoside analog. Methods: The pooled integrated safety summary included all adult patients (N=165) treated with ≥1 dose of moxetumomab across 5 open-label, single-arm clinical trials. Two trials included patients with HCL (N=129, with N=80 in the pivotal phase 3 trial) and 3 trials included patients with non-Hodgkin lymphoma (N=15) or chronic lymphocytic leukemia/small lymphocytic lymphoma (N=21). Overall, 81% were male, median age was 60 years (range 34–84) and 94% had an ECOG ≤1. Results: The most common adverse events (AEs) with moxetumomab were peripheral edema (41%), hypoalbuminemia (35%), and nausea (35%). Serious AEs occurred in 47 (28.5%) patients and were considered treatment-related in 21 (12.7%) patients. Treatment-related AEs were mainly grade 1/2; the most common were peripheral edema (32%), hypoalbuminemia (32%), increased ALT (29%), increased AST (28%), nausea (26%), headache (24%), pyrexia (23%), fatigue (22%), and myalgia (20%). In total, 19 deaths (11.5% of patients) occurred (including 3 in the pivotal trial), with most (13) due to underlying disease and 6 due to AEs (none were assessed as treatment-related by the investigators, however, 1 fatal AE in a non-HCL patient was re-assessed by the Sponsor as possibly related to moxetumomab). In 16 patients (9.7%), a treatment-related AE led to treatment discontinuation, with hemolytic uremic syndrome HUS; 3.6%) and capillary leak syndrome (CLS; 2.4%) the most common. Treatment-related AEs resulted in dose delay, omission or treatment interruption in 11 patients (6.7%). Conclusions: Moxetumomab had an acceptable safety profile based on pooled data from 165 adult patients with hematologic malignancies, with few treatment-related discontinuations. Proactive monitoring of patients is important to manage AEs. These results are consistent with results from the pivotal phase 3 trial in patients with HCL. Clinical trial information: NCT01829711, NCT00586924, NCT00587457, NCT00587015, NCT01030536.
Development and validation of a novel disease risk model for patients with AML receiving allogeneic hematopoietic cell transplantation.
Authors: Kongtim Piyanuch , Hasan Omar , Ramos Perez Jorge Miguel , Varma Ankur , Chen Julianne , Rondon Gabriela , Srour Samer , Bashir Qaiser , Qazilbash Muzaffar H. , Mehta Rohtesh , Shpall Elizabeth J. , Alousi Amin Majid , Khouri Issa F. , Kebriaei Partow , Popat Uday R. , Champlin Richard E. , Ciurea Stefan O.
Published: March 2020

7016

Background: Molecular data and minimal residual disease (MRD) have been shown to influence outcomes in AML patients undergoing allogeneic hematopoietic cell transplantation (AHCT). Here we developed and validated a novel AML-specific Disease Risk Group (AML-DRG) and revise our previously developed Hematopoietic Cell Transplant - Composite Risk (HCT-CR) model by incorporating molecular data and MRD status before transplant to predict post-transplant outcomes of patients with AML. Methods: The study included 1414 consecutively treated adult AML patients, who received first AHCT between 1/2005-8/2018 at our institution. Patients were randomly assigned into a training (N = 944) and validation set (N = 470). To develop the AML-DRG model, the coefficient of all significant AML-related variables in multivariable Cox’s regression analysis (MVA) in a training dataset was converted into scores.The AML-DRG was the sum of scores from all significant covariates, while the AML-HCT-CR was the sum of disease-related factors assessed by the AML-DRG model with the addition of weighted scores from patient-related factors. Results: Based on results of MVA, the following scores were assigned to each AML-related variable; 1 point to secondary AML; 1 point to the 2017 ELN adverse risk; 2 points to CR with MRD positive/unknown; and 4 points to active disease at transplant. These were used to generate the AML-DRG (low-risk score 0-2; intermediate-risk score 3-4; and high-risk score > 4) with significantly different OS with HR of 2.02 (P < 0.001), and 3.85 (P < 0.001) for intermediate and high risk group compared with low risk group. By adding 1 point for patients > / = 60 years or HCT-CI > 3 to the AML-DRG, we created 4 risk groups of AML-HCT-CR (low-risk: score 0-2; intermediate-risk: score 3; high-risk: score 4 and very high-risk: score ≥5) with distinct survival outcomes. The AML-DRG and AML-HCT-CR model had C-index of 0.672 and 0.715, respectively which were better compared with DRI, ELN2017 and cytogenetic risk model. Conclusions: Prognostic models incorporating molecular data and MRD status before transplant allow better stratification and improved survival estimates of AML patients post-transplant.
Adult Langerhans cell histiocytosis: A contemporary single-institution series of 186 patients.
Authors: Goyal Gaurav , Hu Marie , Young Jason R , Vassallo Robert , Ryu Jay H , Bennani Nabila Nora , Shah Mithun Vinod , Rech Karen , Go Ronald S. ,   Mayo Clinic Histiocytosis Working Group
Published: March 2020

7018

Background: Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm driven by MAPK-ERK mutations in majority of patients. Contemporary data on treatments and outcomes in adult LCH are lacking. Hence, we undertook this study to analyze a large cohort of adult LCH patients. Methods: This was a retrospective study of adult (≥18 years) LCH patients seen at our institution between 1998 and 2018. Results: We included 186 patients with adult LCH (median age 43; 19-88), and 54% were females. 70% of patients were diagnosed after 2007. Common presenting symptoms were cough/dyspnea (30%), rash (17%), pain/swelling in head (17%), and diabetes insipidus (10%). 70 (38%) patients had multisystem LCH, 62 (33%) had isolated pulmonary LCH, and 35 (19%) had unifocal LCH. Common sites of involvement included lung (59%), bone (37%), skin (21%), and nervous system (16%). 121 (65%) were smokers; 48% of these had lung disease, while 52% had multisystem disease. 18 of 31 tested (58%) patients had BRAF-V600E mutation. Most common first-line treatment was smoking cessation in 24 patients, and led to an overall response rate (ORR) of 83% in pulmonary lesions. Radiation therapy was used in 11 patients, and led to an ORR 82%. Surgical resection of lesion was done in 23 patients, with relapses in 24%. Systemic therapies were used in 78 (42%) patients (Table). Most common first-line systemic therapy was cladribine with ORR of 78%. Vemurafenib was used in 3 patients with BRAF-V600E, leading to an ORR of 67% . After a median follow-up of 23 months (0-261), 21 patients had died. Of these, 10 died of progressive LCH. Median OS was not reached, and mean OS was 196 months. Conclusions: This is the largest contemporary series of adult LCH. It shows that diverse clinical spectrum, ranging from benign course to a progressive multisystem disease. Although smoking cessation was an effective treatment for pulmonary LCH, a large subset required systemic chemotherapy. [Table: see text]
Inotuzumab ozogamicin (InO) treatment in patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL): Outcomes of patients treated in salvage one with a long duration of first remission.
Authors: Kantarjian Hagop M. , Stelljes Matthias , Advani Anjali S. , DeAngelo Daniel J. , Marks David I. , Stock Wendy , O'Brien Susan Mary , Cassaday Ryan Daniel , Wang Tao , Neuhof Alexander , Vandendries Erik , Jabbour Elias
Published: March 2020

7029

Background: In R/R ALL, data are limited supporting targeted therapies like InO as first salvage in patients (pts) who had a long first complete remission (CR1). InO, a calicheamicin-conjugated antibody, targets CD22 on ALL blasts. Here we report outcomes in pts with ALL in first salvage (S1) who had a long CR1 before receiving InO vs standard of care chemotherapy (SC). Methods: Adults with CD22+ R/R ALL, stratified by salvage and length of remission (CR1 ≥ or < 12 mos), were randomized to receive InO (n = 164) or SC (n = 162). Methods were previously described (Kantarjian et al, NEJM 2016), with data shown up to the last patient last visit (January 4, 2017). Outcomes including complete remission (CR)/CR with incomplete hematologic recovery (CRi) and overall survival (OS) were determined for S1 pts who achieved CR1 ≥ 12 mos and CR1 ≥ 18 mos. Results: For S1 pts with CR1 ≥ 12 mos or CR1 ≥ 18 mos, InO and SC arms had generally comparable baseline characteristics. For S1 pts with CR1 ≥ 12 mos and CR1 ≥ 18 mos, fewer pts had received a prior stem cell transplant in the InO vs SC arm (10.4% vs 25.0% and 9.7% vs 21.4%). For S1 pts with CR1 ≥ 12 mos and CR1 ≥ 18 mos respectively, InO vs SC treatment led to a higher CR/CRi rate (85.4% vs 27.5% [ P< 0.0001] and 83.9% vs 32.1% [ P< 0.0001]) and improved OS (HR = 0.547 [ P= 0.0086] and 0.504 [ P= 0.0163]), with veno-occlusive liver disease reported in 12.5% and 12.9% of InO pts Clinical trial information: NCT01564784. Conclusions: Improved outcomes were seen with InO vs SC among S1 pts who had a long first complete remission (CR1 ≥ 12 mos or CR1 ≥ 18 mos), supporting the benefit of InO vs SC in this population.[Table: see text]
A video decision aid to improve acute myeloid leukemia patients’ illness understanding: Results of a pilot trial.
Authors: LeBlanc Thomas William , Locke Susan C. , Herring Kris , Davis Debra M. , Troy Jesse D , Steinhauser Karen E. , Pollak Kathryn I. , Ubel Peter A.
Published: March 2020

7040

Background: Many acute myeloid leukemia (AML) patients harbor misunderstandings about their illness, overestimating both their likelihood of cure and risks of intensive therapies. Decision aids (DA) can improve illness understanding and reduce decisional conflict, but are not routinely used in AML. Methods: We developed an AML DA with input from patients, caregivers, clinicians, and laypersons, via the International Patient Decision Aids Standards (IPDAS) process. It includes 10 short animated videos with voiceovers, covering AML basics, etiology, outcomes, treatment paradigms, and risks/benefits of various treatment approaches. We enrolled 20 patients in a pilot feasibility and efficacy trial, with pre/post survey assessments of AML knowledge via an 18-item questionnaire, decisional conflict (Decisional Conflict Scale; DCS), anxiety (State Trait Anxiety Inventory, Short Form; STAI-6), and measures of DA usability and satisfaction. Results: Participants were a mean of 62.4 years old, 12 (60%) were male, 17 (85%) white, and 15 (75%) had newly-diagnosed disease. Mean time since AML diagnosis was 145 days (median 31; range 2-1092). 16 (80%) exhibited high-school-level understanding of medical terms per the REALM-SF, and participants on average exhibited moderate numeracy (mean score of 4.1 on the Subjective Numeracy Scale). All participants completed the study, exceeding our pre-determined feasibility threshold. AML knowledge scores generally improved, from a mean of 11.8 correct items on pre-test, to 15.2 on post-test assessment (p < 0.0001), with 80% of participants achieving improved scores. Struggles remained regarding patients’ understanding of the role that genetic tests play in AML care. There was no increase in anxiety after watching the videos, but decisional conflict was significantly reduced, from a mean of 28.5 at baseline to 22 in the post-test (p = .019). Participants reported high satisfaction and usability scores for the DA. Conclusions: Our AML decision aid exhibits favorable performance characteristics, with high satisfaction and usability, a marked increase in patient knowledge, and reduced decisional conflict. Further testing is warranted in a randomized trial. Clinical trial information: NCT03442452.
The Transplant Optimization Program (TOP): Implementing a geriatric assessment (GA)-guided interdisciplinary clinic (IDC) prior to allogeneic hematopoietic cell transplantation (HCT) in older adults.
Authors: Derman Benjamin Avi , Kordas Keriann , Ridgeway Jean , Chow Selina Lai-ming , Dale William , Hsiao Yung-Hsuan , Paloma Marc , Pisano Jennifer , Rosinski Thomas , Bishop Michael Russell , Artz Andrew S.
Published: March 2020

7045

Background: Limitations found on GA correlate with worse outcomes after HCT, but no data exists on prospectively utilizing GA prior to HCT. We established the TOP IDC in March 2013 to implement a cancer-specific GA and an IDC to risk-stratify HCT candidacy and create an individualized care plan for allograft candidates 60+ yrs. Methods: The IDC consisted of a HCT physician, advanced practice provider, dietician, PT/OT, social worker, ID physician, and a geriatric oncologist to devise a pt specific optimization strategy. We compared consecutive HCT pts ≥ 60 years undergoing GA prior to TOP implementation (pre-TOP) from 2005-2012 (n=75) to TOP pts from 2013-2018 (n=86). Results: 3/89 HCT pts 60+ yrs who did not attend TOP were excluded; all 3 died before 1 year post-HCT. Compared with controls, the TOP group was older (median age 67 vs. 64 yrs, p<0.001) but was similar in HCT-CI ≥ 3 (37% vs. 48%, p=0.2), use of myeloablative regimens (20% vs. 19%, p=0.8), and advanced ASBMT risk disease (46% for both). Relative to the pre-TOP group, TOP pts at baseline had fewer impairments in independent activities of daily living (30% vs. 48%, p=0.02) and fewer frail 4-meter walk tests (7% vs. 31%, p<0.001). Pts undergoing optimization in TOP fared better versus pre-TOP (Table). 1-yr non-relapse mortality (NRM) and 1-yr overall survival (OS) continued to improve including 11% NRM and 89% OS in 2017. Conclusions: A GA-guided interdisciplinary optimization clinic for allograft recipients age 60+ reduced transplant associated morbidity and mortality, with marked improvements in NRM and OS over time. A GA-based IDC can facilitate selection and optimization of older pts considering HCT.[Table: see text]
Allogeneic stem cell transplantation (AlloSCT) for patients (pts) with acute leukemia following venetoclax-based therapy.
Authors: Mukherjee Akash , Milton Denai R. , Jabbour Elias , Konopleva Marina , Dinardo Courtney Denton , Gulbis Alison , Ravandi Farhad , Daver Naval Guastad , Kadia Tapan M. , Oran Betul , Popat Uday R. , Ciurea Stefan O. , Im Jin , Kebriaei Partow , Mehta Rohtesh S. , Kantarjian Hagop M. , Champlin Richard E. , Khouri Issa F.
Published: March 2020

7047

Background: BCL-2 inhibitor Ven has shown a promising benefit in pts with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). There is paucity of information about the safety and efficacy of alloSCT post Ven. Methods: We conducted a retrospective analysis of 35 AML/ALL pts who received alloSCT following Ven-based therapies between 2013-2018 at MDA. Results: Median age at alloSCT was 60 years and 15 (43%) pts had an age-adjusted HCT-CI score ≥ 4. Disease diagnosis – AML (n = 31; 89%), ALL (n = 4; 11%). Disease status at transplant was CR1 (n = 17; 49%), CR2/CR3 (n = 9; 26%) or refractory (n = 9; 26%). 20/26 (77%) CR pts were MRD-negative. Median # of prior therapies was 2 (range 1-7) and 4 (11%) pts had failed a prior alloSCT. AML pts were classified by ELN 2017 criteria to have favorable, intermediate and adverse risks in 16%, 23% and 61% respectively. Ven was provided in combination of hypomethylating agents (HMA) or other chemotherapies in 26 (74%) and 9 (26%) pts, respectively. Among pts treated with Ven + HMA, some also received IDH1/2 inhibitors (n = 7, 20%), FLT3 inhibitors (n = 4; 11%) or anti-PD1 (n = 3, 9%). Median duration of Ven-based treatment was 2 months (range 0.5- 4.6). Ven was discontinued in 6 (17%) pts due to adverse events (n = 4) or progression (n = 2); the remaining pts (83%) continued their Ven-therapy as a bridge to alloSCT. The median time from last Ven dose and transplant was 26 days. Conditioning regimens were melphalan-based reduced intensity (n = 26, 74%), or busulfan-based myeloablative regimens (n = 9; 26%). Donor source was matched -unrelated (n = 14, 40%), -related (n = 9; 26%) or haplo- (n = 12; 34%). GVHD prophylaxis consisted of tacrolimus with either PT-Cy in 25 (71%) pts or methotrexate in 10 (29%) pts. All pts engrafted (median day 30 donor cells = 100%). Median days to ANC > 500 and platelets > 20K was 15.5 and 22.5, respectively. With a median follow up of 5.7 months (range 0.7-15.4), the 1-year rates of OS, PFS, and NRM were 71%, 63% and 3% respectively. CI of acute grade 2-4 and 3-4 GVHD were 26% and 3% respectively. Four pts died: 3 because of disease relapse and 1 of infection. Conclusions: AlloSCT is a safe and feasible consolidation treatment option in acute leukemia pts who were pre- treated with Ven, without excessive risk of NRM or acute GVHD. Larger prospective studies are required to validate our observations.