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Background: Despite improvements in prevention and treatment, severe coronavirus disease 2019 (COVID-19) is associated with high mortality. Phosphoinositide 3-kinase (PI3K) pathways contribute to cytokine and cell-mediated lung inflammation. We conducted a randomized, placebo-controlled, double-blind pilot trial to determine the feasibility, safety, and preliminary activity of duvelisib, a PI3Kδγ inhibitor, for the treatment of COVID-19 critical illness., Methods: We enrolled adults aged ≥18 years with a primary diagnosis of COVID-19 with hypoxic respiratory failure, shock, and/or new cardiac disease, without improvement after at least 48 hours of corticosteroid. Participants received duvelisib (25 mg) or placebo for up to 10 days. Participants had daily semi-quantitative viral load measurements performed. Dose modifications were protocol driven due to adverse events (AEs) or logarithmic change in viral load. The primary endpoint was 28-day overall survival (OS). Secondary endpoints included hospital and intensive care unit length of stay, 60-day OS, and duration of critical care interventions. Safety endpoints included viral kinetics and AEs. Exploratory endpoints included serial cytokine measurements and cytometric analysis., Results: Fifteen patients were treated in the duvelisib cohort, and 13 in the placebo cohort. OS at 28 days was 67% (95% confidence interval [CI], 38%-88%) compared to 62% (95% CI, 32%-86%) for placebo ( P = .544). Sixty-day OS was 60% versus 46%, respectively (hazard ratio, 0.66 [95% CI, .22-1.96]; P = .454). Other secondary outcomes were comparable. Duvelisib was associated with lower inflammatory cytokines., Conclusions: In this pilot study, duvelisib did not significantly improve 28-day OS compared to placebo for severe COVID-19. Duvelisib appeared safe in this critically ill population and was associated with reduction in cytokines implicated in COVID-19 and acute respiratory distress syndrome, supporting further investigation., Clinical Trials Registration: NCT04372602., Competing Interests: Potential conflicts of interest. J. P. reports employment with Verastem Oncology Inc. All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Patients with multiple myeloma (MM) have up to a 20-fold increased risk of venous thromboembolism (VTE) compared with the general population, with most events occurring within the first 6 months of diagnosis. Treatment with immunomodulatory drugs (IMiDs) is a strong risk factor for VTE in MM. In a meta-analysis of 2 large, randomized trials comparing anticoagulant thromboprophylaxis vs placebo in ambulatory patients with cancer at high risk of VTE based on a validated risk score, the risk of VTE decreased without increasing the risk of major bleeding. However, few patients with MM participated in these trials (1.1%). Initial guidance for risk-stratifying patients with MM resulted in persistent rates of VTE >10% and highlighted the need for improved VTE risk stratification in patients with MM. Three validated risk scores are now available to quantify risk of VTE in patients with MM: SAVED, IMPEDE VTE, and PRISM scores. Using best available data, thromboprophylaxis should be strongly considered in patients with MM assessed as high risk for VTE, especially newly diagnosed patients receiving IMiD-based combination therapies. However, prospective studies are needed to further validate available models and identify the optimal thromboprophylactic agent for each VTE risk category., (Copyright © 2022 by The American Society of Hematology.)

Purpose of Review: Advances in multiple myeloma therapies have greatly improved outcomes for patients living with the disease, although to date there is yet to be a cure. Cellular and immunotherapies, approved or in development, offer the promise of significantly advancing toward that possibility. The aim of this review is to provide a synopsis and commentary on the current and future states of bispecific agents aimed at harnessing the antineoplastic potential of T-cells in treating and eradicating myeloma., Recent Findings: Numerous bispecific agents are in clinical development with some on the precipice of regulatory approval. While BCMA remains the principal target, some agents are directed at novel targets such as GPRC5D and FcRH5. The constructs vary in design and pharmacokinetics which has dosing and administration implications. The toxicity profiles of these agents generally reflect that of other immune therapies, including cytokine release syndrome and rarely neurotoxicity, although immunosuppression has also led to elevated infection risks. However, the toxicities are generally manageable and offset by unprecedented efficacy seen in such heavily pretreated cohorts. Bispecific agents are poised to significantly alter the treatment paradigms for myeloma. They provide a convenient "off-the-shelf" platform with often deep and durable responses. Toxicities are often limited in duration and severity. In the early-phase trials, many patients have been able to remain on treatment for extended periods, even among those with high-risk features. Upcoming trials are likely to explore earlier implementation of these agents in order to offer this therapeutic opportunity to broader cohorts., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Immune checkpoint inhibitors (ICIs) are increasingly used to treat advanced malignancies. However, they are associated with the development of multiple gastrointestinal immune-related adverse events (GI-irAEs). We aimed to evaluate the types and severity of GI-irAEs associated with ICI therapy, to identify potential risk factors for developing GI-irAEs and to determine the relationship of GI-irAEs development to tumor responsiveness and overall survival., Methods: All patients who received ICIs for advanced malignancies at our center were included. Medical records were reviewed, and data extraction included: baseline demographic characteristics, immunotherapy regimens, development of GI-irAEs, response to treatment, and overall survival. Overall survival was calculated from the date of treatment initiation and estimated by the Kaplan-Meier method., Results: Five hundred sixty-seven patients received ICI therapy for stage IV malignancies. Forty-one (7%) patients experienced at least one GI-irAE. Among those experiencing GI-irAEs, 23 (56%) developed hepatitis, 17 (42%) developed colitis, four (10%) developed pancreatitis, and two (5%) developed gastritis. Patients who developed GI-irAEs experienced a better response to ICI therapy compared to patients who did not develop GI-irAEs (41% vs. 27%, P = 0.003). The 2-year overall survival rate of stage IV cancer patients who developed GI-irAEs was 62% (95% confidence interval (CI): 49 - 79) and 36% for those who did not develop GI-irAEs (95% CI: 32 - 41) (P = 0.002). The median follow-up time of surviving patients was 28 months. Twelve (29%) of the patients receiving dual ICI therapy developed GI-irAEs., Conclusion: Hepatitis, colitis, and pancreatitis were the most commonly encountered GI-irAEs with ICI therapy. Development of these GI-irAEs was associated with superior tumor responsiveness and better overall survival., Competing Interests: None to declare., (Copyright 2022, Alomari et al.)

Introduction: The American Society of Anesthesiologists (ASA) physical status classification system was developed as a simple categorization of patients' physiological status that predicts the operative risk. Peroral endoscopic myotomy (POEM) is a less invasive alternative to surgical myotomy in achalasia. As such, POEM seems to be an appealing option for high-risk patients with achalasia. However, there are no studies which systematically analyzed the outcomes of POEM among patients with different ASA classes. Hence, we aimed to compare the safety and efficacy of POEM in patients with lower and higher ASA classes., Methods: Medical records of all achalasia patients who underwent POEM at our institution between April 2014 and May 2019 were reviewed. Patients were categorized arbitrarily into two groups, lower ASA class (ASA I and II combined) and higher ASA class (ASA class III and IV combined). Demographic and procedural details, timed barium swallow (TBE), high-resolution esophageal manometry (HREM), pH study findings and Eckardt scores were compared between the two groups. Baseline characteristics were compared using Chi-square test and two-sample t-test for categorical and continuous variables, respectively., Results: A total of 144 patients met our study criteria (lower ASA class, n = 44; and higher ASA class, n = 100). Patients in higher ASA class were significantly more obese and older. More patients in lower ASA class had prior Heller myotomy and more patients in higher ASA Class had prior botulinum toxin injections. Procedural parameters were similar in both groups. Procedural complications were infrequent and were also similar in the two groups. The length of stay, 30-day readmission rate, reflux symptoms and esophageal pH study findings were also comparable between the two groups. Treatment success was similar in both groups, 97.7% in lower ASA class versus 92% in higher ASA class (p = 0.19). At 2-month follow-up, both groups had significant improvement in HREM and TBE parameters., Conclusion: POEM is a very safe and highly effective treatment option for achalasia patients with advanced ASA class similar to lower ASA class patients. POEM may be considered as the preferred choice for myotomy in these high-risk achalasia patients due to its low morbidity and high efficacy., (© 2021. The Japan Esophageal Society.)

The IMPEDE VTE score has recently emerged as a novel risk prediction tool for venous thromboembolism (VTE) in multiple myeloma (MM). We retrospectively reviewed 839 patients with newly diagnosed MM between 2010 and 2015 at Cleveland Clinic and included 575 patients in final analysis to validate this score. The c-statistic of the IMPEDE VTE score to predict VTE within 6 months of treatment start was 0·68 (95% CI: 0·61-0·75). The 6-month cumulative incidence of VTE was 5·0% (95% CI: 2·1-7·9) in the low risk group, compared to 12·6% (95% CI: 8·9-16·4%) and 24·1% (95% CI: 12·2-36·1) in the intermediate and high risk groups (P < 0·001 for both). In addition, a higher proportion of patients in the VTE cohort had ECOG performance status of ≥2 as compared to the no VTE cohort (33% vs. 16%, P = 0·001). Other MM characteristics such as stage, immunoglobulin subtype, and cytogenetics were not predictors of VTE. In summary, we have validated the IMPEDE VTE score in our patient cohort and our findings suggest that it can be utilized as a VTE risk stratification tool in prospective studies looking into investigating VTE prophylaxis strategies in MM patients., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Competing Interests: The authors have no conflicts of interest to declare.

Background: Tocilizumab was approved for chimeric antigen receptor T-cell therapy induced cytokine release syndrome and it may provide clinical benefit for selected COVID-19 patients., Methods: In this retrospective cohort study, we analyzed hypoxic COVID-19 patients who were consecutively admitted between March 13, 2020 and April 19, 2020. Patients with lung infiltrates and elevated inflammatory markers received a single dose of tocilizumab if no contraindication was present. Systemic steroid, hydroxychloroquine, and azithromycin were concomitantly used for majority of the patients., Findings: Of the 51 patients included for analysis, 28 (55%) received tocilizumab and 23 (45%) did not receive tocilizumab. Tocilizumab cohort required more invasive ventilation (68% vs. 22%) at baseline and during entire hospitalization (75% vs. 48%). The median time to clinical improvement in tocilizumab vs. no tocilizumab cohorts was 8 days (Interquartile range [IQR]: 6·25 - 9·75 days) vs. 13 days (IQR: 9·75 - 15·25 days) among patients who required mechanical ventilation at any time (Hazard ratio for clinical improvement: 1·83, 95% confidence interval [CI]: 0·57 - 5·84) and 6·5 days vs. 7 days among all patients (Hazard ratio for clinical improvement: 1·14, 95% CI: 0·55 - 2·38), respectively. The median duration of vasopressor support and invasive mechanical ventilation were 2 days (IQR: 1·75 - 4·25 days) vs. 5 days (IQR: 4 - 8 days), p  = 0.039, and 7 days (IQR: 4 - 14 days) vs. 10 days (IQR: 5 - 15 days) in tocilizumab vs. no tocilizumab cohorts, p  = 0.11, respectively. Similar rates of hospital-acquired infections occurred in both cohorts (18% in tocilizumab and 22% in no tocilizumab cohort)., Interpretation: In patients with severe COVID-19, tocilizumab was associated with significantly shorter duration of vasopressor support. Although not statistically significant, tocilizumab also resulted in shorter median time to clinical improvement and shorter duration of invasive ventilation. These findings require validation from ongoing clinical trials of Tocilizumab in COVID-19 patients., Competing Interests: The authors declare that they have no conflict of interest., (© 2020 The Author(s).)

Introduction Primary breast lymphoma (PBL) is a rare malignancy that accounts for less than 0.5% of all breast malignancies. Materials and Methods We retrospectively analyzed 36 PBL patients to report the clinical characteristics and outcomes of patients with indolent and aggressive histologic subtypes. Results Thirteen (36%) patients had aggressive and 23 (64%) had indolent PBL. Marginal zone lymphoma was the most common histologic subtype (33%). Stage IE, IIE, and IV disease were seen in 27 (75%), six (17%), and three (8%) patients, respectively. Patients with aggressive PBL more often presented with a breast lump and/or B symptoms (unexplained weight loss, fever, night sweats) (78% vs. 31%, p = 0.005). Commonly used treatment modalities for aggressive vs. indolent PBL were chemotherapy alone (23% vs. 26%, p = 0.8), chemoradiotherapy (46% vs. 9%, p = 0.009), radiotherapy alone (15% vs. 22%, p = 0.6), and observation (0% vs. 26%, p = 0.07), respectively. The five-year overall survival (OS) and progression-free survival (PFS) of PBL patients were 82% (95% CI: 67 - 100) and 63% (95% CI: 45 - 89), respectively. The five-year OS of patients with aggressive vs. indolent PBL were 92% (95% CI: 77 - 100) vs. 80% (95% CI: 63 - 100), respectively (p = 0.6). The five-year OS of patients who received > 1, 1, and 0 treatment modalities were 92% (95% CI: 77 - 100), 86% (95% CI: 63 - 100), and 53% (95% CI: 21 - 100), respectively. Conclusion In our cohort, the higher utilization of chemoradiotherapy in aggressive PBL was able to overcome the worse prognosis of these patients. At least one treatment modality should be considered in patients with indolent PBL, given that observation alone was associated with a poor prognosis., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Kewan et al.)

Background: It has been hypothesized that dysbiosis plays a significant role in the pathogenesis of intestinal failure-associated liver disease (IFALD). Therefore, we aimed to investigate the effect of probiotics on IFALD in patients receiving parenteral support, namely home parenteral nutrition (HPN) and home intravenous fluids (HIVFs)., Methods: We retrospectively reviewed charts of patients with intestinal failure who received HPN or HIVF for >2 weeks at our tertiary center between January 2005 and August 2016. We excluded patients <18 years of age, patients with other causes of liver disease, patients who used probiotics for <30 days, patients with <6 months' follow-up, and those who had long-term antibiotic use (>30 days). Bivariable and multivariable logistic regression analyses were used in this study., Results: A total of 282 patients who received parenteral support were included. Eighty-five percent of our sample received PN. A total of 78 (27.7%) patients used probiotics. The prevalence of IFALD in patients who used probiotics was 35.9% vs 54.4% in patients who did not use probiotics, P = .005. In multivariable analysis, only small-bowel length of 10-90 cm and HPN use showed a significant impact on IFALD, odds ratio (OR) = 4.394 (95% confidence interval [CI], 1.635-11.814; P = .003) and OR = 4.502 (95% CI 1.412-14.351; P = .011), respectively., Conclusion: Our study revealed that the prevalence of IFALD was comparable among the probiotic users and nonusers. Only small bowel length of 1090 cm and HPN use showed a significant impact on IFALD., (© 2019 American Society for Parenteral and Enteral Nutrition.)

Background & Aims: Chronic intestinal failure (CIF) has been long-recognized, however the underlying etiology and risk factors have not been historically well-studied. We aim to study the underlying etiologies of CIF and predictive factors for long-term parenteral support (PS)., Methods: We retrospectively identified patients with newly diagnosed CIF who received PS to maintain nutrition at the Cleveland Clinic between 2000 and 2017. Long-term PS was defined as a duration of more than 3 months. Univariable and multivariable logistic regression analyses were performed to identify the predictors of the need for long-term PS., Results: We identified 350 patients with CIF, 150 (43%) and 200 (57%) were diagnosed before and after 2010, respectively. The most common etiology was Crohn's disease (CD) in both cohorts (34.7% versus 30.5%, p = 0.41). Graft-versus-host-disease (GVHD) was a less frequent cause of CIF after 2010 (12.7% versus 2.5%, p = 0.0002). The type of PS was mostly total parenteral nutrition before and after 2010, 95% and 96%, respectively (p = 0.55). On univariable analysis, absence of ileocecal valve (p < 0.0001), ischemic bowel disease (p = 0.009), and whole colon resection (p = 0.033) were associated with the need for long-term PS. On multivariable analysis, absence of ileocecal valve (OR 2.19, p = 0.011) and ischemic bowel disease (OR 3.04, p = 0.003) remained statistically significant predictors of long-term PS., Conclusion: In our cohort of patients with CIF, CD remains the leading etiology over the last 20 years, whereas GVHD is less common after 2010. The absence of ileocecal valve and ischemic bowel disease were reliable predictive factors for requiring long-term PS., (Copyright © 2020 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: Clostridium difficile infection (CDI) is one of the leading causes of health-care-associated infections in the USA. There are limited data available regarding CDI in hospitalized patients with inflammatory bowel disease-related ileal pouch., Aims: This study aimed to evaluate the demographics, clinical features, risk factors, and admission outcomes among hospitalized patients with CDI-related pouchitis (CDP)., Methods: Retrospective chart review was performed for patients who were admitted to our institute for pouchitis between 2013 and 2016 to identify patients with CDP. Logistic regression analysis was performed to assess the risk factors associated with CDP., Results: A total of 160 subjects with pouchitis had a total of 218 admissions during the study period. Primary admission diagnosis was pouchitis or inflammatory bowel disease flare-up for 202 (93%) admissions. Clostridium difficile was tested at least once for 72 patients, and the diagnosis of CDP was established for 16 (10%) patients. All patients with CDP were symptomatic, 13 (81%) had diarrhea, 8 (50%) had abdominal pain, 7 (44%) had nausea/vomiting, and 2 (13%) had gastrointestinal bleeding. On multivariable analysis, only body mass index > 25 (OR 0.25, 95% CI 0.06-0.94, p = 0.048) was significantly associated with decreased risk of CDP. No patients in CDP cohort were admitted to ICU, died at the hospital, or readmitted in 30 days after the discharge., Conclusions: In our cohort, obesity was associated with low risk of CDP among hospitalized patients with pouchitis. This finding warrants further validation in prospective studies.

Introduction Ehlers-Danlos syndrome (EDS), specifically the hypermobility type (hEDS), is associated with a variety of gastrointestinal (GI) conditions. This study aims to evaluate the prevalence of and factors associated with gut dysmotility in patients with hEDS. Methods This is a retrospective study of hEDS patients conducted at the Cleveland Clinic's Center for Personalized Genetic Healthcare between January 2007 and December 2017. Demographics, GI motility testing, endoscopic, and imaging data were extracted from the patients' charts. Results A total of 218 patients with hEDS were identified. Among them, 136 (62.3%) patients had at least one GI symptom at the time of EDS diagnosis. Motility testing was performed and reported in 42 (19.2%) patients. Out of them, five (11.9%) had esophageal dysmotility, 18 (42.8%) had gastroparesis, five (11.9%) had small bowel/colon altered transit time, and four (9.5%) had global dysmotility. In univariable analysis, patients with postural orthostatic tachycardia syndrome (POTS) [odds ratio (OR): 8.88, 95% CI: 3.69-24.9, p<0.0001], fibromyalgia (OR: 4.43, 95% CI: 2.04-10.1, p=0.0002), history of irritable bowel syndrome (OR: 5.01, 95% CI: 2.31-11.2, p<0.0001), and gastroesophageal reflux disease (OR: 3.33, 95% CI: 1.55-7.44, p=0.002) were more likely to be diagnosed with GI dysmotility. On multivariable analysis, only POTS (OR: 5.74, 95% CI: 2.25-16.7, p=0.0005) was significantly associated with an increased likelihood of GI dysmotility. Conclusions This study suggests that GI symptoms are relatively common among patients with hEDS. Of the patients tested for dysmotility, 76.2% were found to have some form of dysmotility. POTS was found to be an independent predictive factor for GI dysmotility., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Alomari et al.)

Lenalidomide (LEN) is commonly used as part of induction therapy in transplant-eligible patients with multiple myeloma. However, LEN use is associated with increased chance of peripheral blood stem cell (PBSC) collection failure. This has led to early collection in patients receiving induction with LEN-containing regimens, and the use of mobilization agents such as plerixafor. Despite potential significant clinical implications, the impact of LEN on autograft composition is unclear. We examined the effect of LEN exposure on hematopoietic progenitors in collected grafts of 94 patients who underwent autologous stem cell transplantation (HSCT) at our institution. LEN exposure resulted in lower myeloid and erythroid progenitors in collected grafts, but this effect was not seen in patients who received plerixafor-based mobilization. Exposure to LEN did not affect PBSC collection, possibly due to high plerixafor use in our cohort (70%). LEN changes the composition of PBSC grafts; the clinical implication of this finding is unknown.

Background and Aim: The United Kingdom-primary biliary cholangitis (UK-PBC) and global primary biliary cholangitis group (GLOBE) prognostic models have been recently developed to predict long-term outcomes in primary biliary cholangitis (PBC). However, these predictive scores have not yet been well evaluated in the U.S. population., Methods: We retrospectively reviewed newly diagnosed PBC patients at the Cleveland Clinic between November 1998 and February 2017. Adverse events were defined as liver transplantation, liver-related mortality, and all-cause mortality. Transplant-free survival (TFS) was estimated using the Kaplan-Meier method. Predictive performances of all prognostic models were evaluated using the C-statistic., Results: We identified 352 patients who used ursodeoxycholic acid therapy. Of them, 311 (88.4%) only had PBC, while 41 (11.6%) were diagnosed with PBC-autoimmune hepatitis overlap. A total of 22 (6%), 47 (13%), and 55 (16%) patients had adverse events within 5, 10, and 15 years after diagnosis, respectively. In patients with PBC only, the C-statistic in predicting 15-year adverse events was 0.75 per GLOBE compared to 0.74 per UK-PBC ( P = 0.94), 0.73 per Rotterdam ( P = 0.44), 0.66 per Barcelona ( P = 0.004), 0.65 per Paris 1 ( P = 0.005), 0.62 per Paris 2 ( P < 0.0001), 0.60 per Toronto ( P < 0.0001), and 0.60 per Mayo ( P < 0.0001) scores. Median follow-up was 9.2 years. Ten-year TFS for patients who had optimal versus suboptimal treatment response was 92 versus 74% per Paris 1 ( P < 0.0001), 95 versus 79% per Paris 2 ( P = 0.0002), 93 versus 65% per Barcelona ( P < 0.0001), and 96 versus 68% per Rotterdam ( P < 0.0001) risk scores, respectively., Conclusion: In our cohort of PBC patients, the UK-PBC and GLOBE scores were both accurate and reasonably valid prognostic models in the U.S. population., (© 2019 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Introduction: Induction chemotherapy with cytarabine and an anthracycline (7+3) remains the standard of care for acute myeloid leukemia (AML)., Patients and Methods: We retrospectively analyzed 183 newly diagnosed AML patients to compare the utility of rapid peripheral blast clearance (PBC), day of peripheral blast disappearance, residual blasts, and cellularity at day 14 bone marrow biopsy (D14BM) in predicting clinical response to 7+3 induction, overall survival (OS), and relapse-free survival (RFS)., Results: In multivariable logistic regression analysis, day 2 PBC > 85% [P = .0016] was the only predictor of remission status, with sensitivity and specificity of 75%. Peripheral blast disappearance within 5 days after induction and < 10% cellularity in D14BM predicted superior OS and RFS in multivariate analysis. Median follow-up of patients was 28 months since diagnosis. Two-year OS and RFS for patients with ≤ 10% versus > 10% cellularity at D14BM was 60.6% [95% confidence interval (CI), 50.8%-72.2%] versus 32.5% [95% CI, 23.0%-45.8%], and 51.9% [95% CI, 41.9%-64.3%] versus 28.8% [95% CI, 19.1%-43.4%], respectively [P = .0003 for OS and .002 for RFS]., Conclusion: Rapid PBC after 7+3 induction showed a significant improvement in specificity compared with D14BM, with similar sensitivity. Neither of these methods were reliably specific tools for the decision of early reinduction, despite their prognostic value. Our findings indicate that morphological cellularity in D14BM is an independent prognostic factor for OS and RFS, regardless of blast percentage, and that ≤ 10% cellularity defines D14BM hypoplasia., (Copyright © 2018 Elsevier Inc. All rights reserved.)

High-dose melphalan (HDM) followed by autologous hematopoietic cell transplantation (auto-HCT) remains the standard-of-care therapy for multiple myeloma (MM) even with the availability of proteasome inhibitors and immunomodulatory drugs. Gastrointestinal (GI) toxicity is the main cause of morbidity after HDM. Amifostine, a cytoprotective agent, may reduce HDM-associated GI toxicity. We conducted a case control study comparing HDM + auto-HCT with or without amifostine for MM patients. One hundred and seven patients treated at University Hospitals Cleveland Medical Center who received pre-transplant amifostine were compared to 114 patients treated at MD Anderson Cancer Center without use of this agent. Amifostine 740 mg/m 2 was administered as a bolus infusion at 24 h and 15 min before HDM. Patients' characteristics were similar in both the groups. Amifostine therapy was well tolerated without any significant adverse effects. Grade II or greater oral mucositis (27.1% vs 47.4%; p = .002), nausea (31.8% vs. 86.0%; p = .0001), vomiting (18.7% vs. 52.6%; p = .0001) and diarrhea (56.1% vs. 72.7%; p = .006) occurred less frequently in the amifostine-treated group. There was no discernable effect of amifostine on engraftment, progression-free or overall survival. Our results indicate that amifostine decreases GI toxicity while preserving anti-myeloma efficacy of HDM and auto-HCT.

Anti-thymocyte globulin (ATG) is often added to hematopoietic stem cell transplant conditioning regimens to prevent graft rejection and reduce graft-versus-host disease (GVHD). Doses used in retrospective and prospective clinical trials have ranged from 2.5 to 20 mg/kg with rates of grade II-IV acute GVHD and chronic GVHD up to 40 and 60%, respectively. We retrospectively compared outcomes in recipients of matched unrelated donor (MUD) grafts given low dose rabbit ATG IV 3 mg/kg (n = 52) versus recipients of matched related donor (MRD) grafts (n = 48) without ATG. One year cumulative incidence of chronic GVHD was 25.2% in the MUD group versus 33.3% in the MRD group (p = .5). One-year cumulative incidence of extensive chronic GVHD was 9.6% in the MUD group versus 26.6% in the MRD group (p = .042). Our analysis supports the use of low dose ATG in MUD transplantation as an effective therapy to prevent chronic GVHD.

Purpose: Drug development in oncology is resource intensive, time consuming, and frequently unsuccessful. Here, we hypothesized that therapeutic benefit of published phase I studies of antimyeloma investigational agents was associated with advancement to phase II and future regulatory approval., Patients and Methods: Seventy four phase I trials that treated patients with multiple myeloma (n = 2,408) conducted from 2004 to 2015 were analyzed to assess drug safety, efficacy, phase advancement, and regulatory approval., Results: The median overall response rate (ORR) for all single-agent trials evaluated was 13.2%. However, the ORR in trials that advanced to phase II was 19%, whereas it was only 4% in trials that failed to advance. The median ORR was 23% for trials testing agents that were ultimately approved by the US Food and Drug Administration compared with only 8% for trials testing agents that were not approved (hazard ratio, 2.21; 95% CI, 2.01 to 2.61; P = .012). Importantly, the absolute number of phase I trials in multiple myeloma, but not the success rate, significantly increased over the period studied. The proportion of industry-sponsored trials also steadily increased over that same period. The ratio of initial dose to maximum tolerated dose was 0.29, suggesting that many patients were undertreated., Conclusion: Investigational agents with higher ORRs in phase I trials were more likely to advance to phase II trials and achieve US Food and Drug Administration approval. Our results suggest that designing phase I trials to maximize the antimyeloma efficacy of a given compound may lead to more successful and cost-effective drug development.