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Introduction/Aims: Expanded access protocols (EAPs) are a Food and Drug Administration (FDA)‐regulated pathway for granting access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. There is limited information about the use of EAPs in amyotrophic lateral sclerosis (ALS); the aim of this report is to share the design, operational features, and costs of an EAP program for ALS. Methods: The program was launched in 2018 at a single center. In alignment with FDA guidance, protocols were designed as individual (single participant) or intermediate size. Inclusion criteria were broad (e.g., no restrictions due to long disease duration or low vital capacity). Safety information was collected in all EAPs. Selected biomarkers were collected in nine of the EAPs. Results: From July 2018 through February 2022, 17 EAPs were submitted for FDA and institutional review board (IRB) approval. The mean time from submission to approval from the FDA and IRB were 24 days and 37 days, respectively. A total of 164 participants were enrolled and, of these, 77 participants were still receiving IP as of February 2022. The mean duration of participation in an EAP was 12.6 mo. No drug‐related serious adverse events were reported from any of the EAPs. Average site cost was $613.47 per participant per month, not including IP costs. Conclusion: EAPs provide a framework through which access to IP can be safely provided to people with ALS who do not qualify for clinical trials. Site resources are needed to launch and maintain these programs. See Editorial on pages 433–435 in this issue. [ABSTRACT FROM AUTHOR]

Introduction/aims: Lipid peroxidation is thought to play a biologically important role in motor neuron death in amyotrophic lateral sclerosis (ALS). 11,11 Di-deuterated linoleic ethyl ester (RT001) prevents lipid peroxidation in cellular and mitochondrial membranes. Herein we report on the use of RT001 under expanded access (EA).Methods: We provided RT001 to patients with ALS via EA at a single site. The starting dose was 2.88 g/day, which was increased to to 8.64 g/day as tolerated. Participants were not eligible for alternative clinical trials. Participants were followed for adverse events and pharmacokinetic (PK) parameters were measured approximately 3 months after RT001 initiation.Results: Sixteen participants received RT001 (5.6 ± 1.6 g/day; dose range, 1.92 to 8.64 g/day) for a mean period of 10.8 ± 7.1 months. After 3 months of treatment, PK studies showed that RT001 was absorbed, metabolized, and incorporated into red blood cell membranes at concentrations expected to be therapeutic based on in vitro models. The most common adverse events were gastrointestinal, including diarrhea, which occurred in 25% of the participants, and were considered possibly related to RT001. One participant (6%) discontinued due to an adverse event. Ten serious adverse events occurred: these events were recognized complications of ALS and none were attributed to treatment with RT001.Discussion: RT001 was administered safely to a small group of people living with ALS in the context of an EA protocol. Currently, there is an ongoing randomized, double-blind, controlled study of RT001 in ALS. [ABSTRACT FROM AUTHOR]

Pre-transplant PET/CT may be prognostic in diffuse large B-cell lymphoma (DLBCL) patients undergoing autologous stem cell transplantation (ASCT). We reviewed relapsed and pre-transplant PET/CT scans of 32 patients with DLBCL treated with ASCT to determine the Deauville score and the maximum standardized uptake value (SUVmax). Patients with a Deauville score of 4 had a significantly inferior prognosis. The 3-year progression-free survival (PFS) for patients with Deauville 1-3 score was 64%, compared to 0% for Deauville 4, while the 3-year overall survival (OS) was 84% and 25%, respectively (p < .001, p = .002). The change in the SUVmax (>66 versus ≤66%) was not predictive of PFS or OS, but a high pre-transplant SUVmax (>6) demonstrated a trend towards an inferior PFS. Pre-transplant PET/CT is a tool for identifying DLBCL patients at high risk for treatment failure with ASCT and could be used to risk-stratify patients in prospective clinical trials of novel transplant strategies. [ABSTRACT FROM AUTHOR]

Management of chronic lymphocytic leukemia has changed markedly over the last several years with the emergence of several novel oral agents targeting B-cell receptor and Bcl-2 signaling pathways. For patients requiring treatment, ibrutinib, idelalisib, and venetoclax offer unique clinical benefits with a different set of therapeutic considerations compared with traditional parenteral therapy. Despite the conveniences afforded by oral therapy, these agents also carry unique logistical obstacles. Drug interactions with agents that are metabolized via the cytochrome P450 3A4 pathway are possible with all three agents. Unique treatment-related adverse events including bleeding and atrial fibrillation with ibrutinib, hepatotoxicity with idelalisib, and tumor lysis syndrome with venetoclax can be severe and dose limiting. Furthermore, dose adjustments for organ dysfunction may also be warranted. Here, we review the available literature on the pharmacokinetic and pharmacodynamic properties of these novel agents to guide the reader in the appropriate use of ibrutinib, idelalisib, and venetoclax. [ABSTRACT FROM AUTHOR]

Data on real-world outcomes of axicabtagene ciloleucel (axi-cel) therapy for relapsed/refractory large B-cell lymphoma (R/R LBCL) are limited. In this intent to treat (ITT) analysis, we reviewed records of 38 consecutive patients with R/R LBCL for whom axi-cel was intended. Twenty-seven (71%) patients received axi-cel and 11 (29%) did not. Patients in the non-axi-cel group had a higher hematopoietic cell transplantation comorbidity index (HCT-CI) (median 4 vs. 2, p =.04). Median overall survival for the ITT, axi-cel and non-axi-cel group was 10 (95% CI, 3.7 to 13), 13 (95% CI, 7.7 to N.R.) and 1 (95% CI, 0.4 to 3.7) month(s) respectively. Factors limiting axi-cel use were disease progression, sepsis, manufacturing failure and socioeconomic barrier in 6 (55%), 3 (27%), 1 (9%) and 1 (9%) patient(s) respectively. Additional strategies are needed to ensure all LBCL patients for whom chimeric antigen receptor (CAR) T-cell therapy is prescribed can receive this treatment. [ABSTRACT FROM AUTHOR]

Summary: Bendamustine (B) with rituximab (R) is a standard frontline treatment for medically fit follicular lymphoma (FL) patients. The safety and efficacy of maintenance rituximab (MR) after BR induction has not been formally compared to observation for FL, resulting in disparate practice patterns. Prospective trials have shown benefit of MR after R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or R‐CVP (rituximab, cyclophosphamide, vincristine, prednisone), yet recent data from the GALLIUM study comparing outcomes of patients treated with chemotherapy with R or obinutuzumab (G) showed higher than anticipated fatal adverse events with BR/BG. In order to assess the efficacy and tolerability of MR after BR, we retrospectively collected data on 640 newly diagnosed patients treated with FL. We found that patients who achieved partial remission (PR) after ≥4 cycles of BR had improved duration of response (DOR) with MR vs. no maintenance, whereas those in complete remission did not. These findings were confirmed in a validation cohort. In the entire study population, the known fatal adverse event rate after BR was 2·5% and did not significantly differ in those receiving MR versus no maintenance. [Correction added on 14 January 2019, after online publication: The preceding sentence has been corrected in this current version.] Within the limitations inherent to retrospective analysis, these data suggest that FL patients with a PR to BR experience prolongation of remission with MR with an acceptable safety profile. [ABSTRACT FROM AUTHOR]

Patients with mantle cell lymphoma require treatment options following BTK inhibition, as evidenced by the 14.6 months median OS rate from initiation of BTK inhibitor in the recently published SCHOLAR-2 analysis [[11]]. Nine patients were refractory to prior therapy, 9 had previously received a BTK inhibitor (BTKi) including 7 who were refractory to BTKi and there were 3 who had progressive lymphoma following chimeric antigen receptor T-cell (CAR-T) therapy. Novel agents such as the Bruton's tyrosine kinase (BTK) inhibitors have improved outcomes for patients with mantle cell lymphoma (MCL) and continue to change treatment paradigms [[1]]. [Extracted from the article]

A total of 475 patients were included in our study, of which 46 patients had a DLCOc <= 60% and 429 had a DLCOc > 60% of the predicted value. Subgroup analysis confirmed that mOS was significantly shorter in the DLCOc <= 60% group irrespective of relapse, with mOS of 27.3 versus 77.2 months ( I p i = .0002) in relapsed patients with DLCOc <= 60% ( I n i = 22) and DLCOc > 60% ( I n i = 193), respectively. Patients with DLCOc <= 60% survived for a significantly shorter period with median overall survival (mOS) of 43 versus 91.7 months ( I p i < .0001) in patients with DLCOc > 60% (Figure 1A). [Extracted from the article]

Introduction/Aims: IC14 (atibuclimab) is a monoclonal anti‐CD14 antibody. A previous phase 1 trial of 10 participants with amyotrophic lateral sclerosis (ALS) demonstrated initial safety of IC14 in an acute treatment setting. We provided long‐term treatment with IC14 to individuals with ALS via an expanded access protocol (EAP) and documented target engagement, biomarker, safety, and disease endpoints. Methods: Participants received intravenous IC14 every 2 weeks. Consistent with United States Food and Drug Administration guidelines, participants were not eligible for clinical trials and the EAP was inclusive of a broad population. Whole blood and serum were collected to determine monocyte CD14 receptor occupancy (RO), IC14 levels, and antidrug antibodies. Ex vivo T‐regulatory functional assays were performed in a subset of participants. Results: Seventeen participants received IC14 for up to 103 weeks (average, 30.1 weeks; range, 1 to 103 weeks). Treatment‐emergent adverse events (TEAEs) were uncommon, mild, and self‐limiting. There were 18 serious adverse events (SAEs), which were related to disease progression and unrelated or likely unrelated to IC14. Three participants died due to disease progression. Monocyte CD14 RO increased for all participants after IC14 infusion. One individual required more frequent dosing (every 10 days) to achieve over 80% RO. Antidrug antibodies were detected in only one participant and were transient, low titer, and non‐neutralizing. Discussion: Administration of IC14 in ALS was safe and well‐tolerated in this intermediate‐size EAP. Measuring RO guided dosing frequency. Additional placebo‐controlled trials are required to determine the efficacy of IC14 in ALS. See Editorial on pages 337–338 in this issue. [ABSTRACT FROM AUTHOR]

Limited information is available on the efficacy of front‐line bendamustine and rituximab (BR) in chronic lymphocytic leukemia (CLL) with reduced renal function or coexisting conditions. We therefore analyzed a cohort of real‐world patients and performed a matched adjusted indirect comparison with a cohort of patients treated with ibrutinib. One hundred and fifty‐seven patients with creatinine clearance (CrCl) <70 mL/min and/or CIRS score >6 were treated with BR. The median age was 72 years; 69% of patients had ≥2 comorbidities and the median CrCl was 59.8 mL/min. 17.6% of patients carried TP53 disruption. The median progression‐free survival (PFS) was 45 months; TP53 disruption was associated with a shorter PFS (P = 0.05). The overall survival (OS) at 12, 24, and 36 months was 96.2%, 90.1%, and 79.5%, respectively. TP53 disruption was associated with an increased risk of death (P = 0.01). Data on 162 patients ≥65 years treated with ibrutinib were analyzed and compared with 165 patients ≥65 years treated with BR. Factors predicting for a longer PFS at multivariable analysis in the total patient population treated with BR and ibrutinib were age (HR 1.06, 95% CI 1.02‐1.10, P < 0.01) and treatment with ibrutinib (HR 0.55, 95% CI 0.33‐0.93, P = 0.03). In a post hoc analysis of patients in advanced stage, a significant PFS advantage was observed in patient who had received ibrutinib (P = 0.03), who showed a trend for OS advantage (P = 0.08). We arrived at the following conclusions: (a) BR is a relatively effective first‐line regimen in a real‐world population of unfit patients without TP53 disruption, (b) ibrutinib provided longer disease control than BR in patients with advanced disease stage. [ABSTRACT FROM AUTHOR]

• Augmentation of total body irradiation (TBI) dose from 2 to 4 Gy for patients with non-Hodgkin lymphoma undergoing reduced-intensity conditioning allogeneic hematopoietic cell transplantation is associated with higher nonrelapse mortality and inferior overall survival. • Higher dose of TBI does not result in improved disease control. Disease relapse is the most common cause of therapy failure in patients with non-Hodgkin lymphoma (NHL) undergoing reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (allo-HCT). It is not known whether or not increasing total body irradiation (TBI) dose from 2 to 4 Gy in a RIC platform can provide improved disease control without increasing nonrelapse mortality (NRM). Using the Center for International Blood & Marrow Transplant Research (CIBMTR) database, we evaluated the outcomes of patients with NHL receiving RIC allo-HCT with either fludarabine (Flu)/2-Gy TBI versus Flu/4-Gy TBI. In the CIBMTR registry, 413 adult patients with NHL underwent a first allo-HCT using either a matched related or unrelated donor between 2008 and 2017, using a RIC regimen with either Flu/2-Gy TBI (n = 349) or Flu/4-Gy TBI (n = 64). The primary endpoint was overall survival (OS). Secondary endpoints included acute (a) and chronic (c) graft-versus-host disease (GVHD), NRM, relapse/progression, and progression-free survival (PFS). At baseline, the Flu/2-Gy TBI cohort had significantly fewer patients with Karnofsky performance status ≥90 and significantly more patients had a higher HCT-comorbidity index. On multivariate analysis, the 2 conditioning cohorts were not significantly different in terms of risk of grade 3 to 4 aGVHD or cGVHD. Compared to Flu/2-Gy TBI, the Flu/4-Gy TBI conditioning was associated with a significantly higher risk of NRM (hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.11 to 2.89; P =.02) and inferior OS (HR, 1.51; 95% CI, 1.03 to 2.23, P =.03). No significant differences were seen in the risk of relapse/progression (HR, 0.78; 95% CI, 0.47 to 1.29, P =.33) or PFS (HR, 1.09; 95% CI, 0.78 to 1.54, P =.61) between the 2 regimens. Comparing Flu/2-Gy TBI versus Flu/4-Gy TBI cohorts, the 5-year adjusted outcomes were NRM (28% versus 47%; P =.005), relapse/progression (35% versus 29%; P =.28), PFS (37% versus 24%; P =.03), and OS (51% versus 31%; P =.001), respectively. Relapse was the most common cause of death in both cohorts. In patients with NHL undergoing Flu/TB I-based conditioning, augmenting TBI dose from 2 to 4 Gy is associated with higher NRM and inferior OS, without any significant benefit in terms of disease control. The optimal dose is 2-Gy in the RIC Flu/TBI platform for lymphomas. [ABSTRACT FROM AUTHOR]

Busulfan-based conditioning regimens are associated with serious toxicities and literature reports increased risk of toxicities when daily area under the curve concentrations exceed 6000 µM-minute. We implemented real time pharmacokinetic-guided therapeutic drug monitoring of busulfan for myeloablative conditioning regimens. The objective was to compare toxicity of intravenous busulfan before and after therapeutic drug monitoring implementation. The primary endpoint was incidence of hepatotoxicity. Medical records were retrospectively reviewed with weight-based dose Busulfan/Cyclophosphamide (BuCy) conditioning from August 2017 through March 2018 (N = 14) and therapeutic drug monitoring from April 2018 through December 2018 (N = 22). Recipients of busulfan therapeutic drug monitoring were younger than those receiving weight-based dose (median: 45 vs. 58 years, p = 0.008). No other baseline differences were observed. There was no difference in hepatotoxicity between therapeutic drug monitoring and weight-based dose (median 1 vs. 0 days, p = 0.40). In the therapeutic drug monitoring group, 45% of patients had increases and 41% had decreases in busulfan dose after Bu1. Repeat pharmacokinetic after Bu2 were required in 32% of patients. A pharmacokinetic dose monitoring program for myeloablative conditioning intravenous busulfan regimens may be considered a safe practice in stem cell transplant recipients. The majority of patients receiving pharmacokinetic-guided therapeutic drug monitoring required dose changes and therapeutic drug monitoring patients had no significant difference in toxicity compared to those receiving weight-based dose. [ABSTRACT FROM AUTHOR]

Fetal cells are widely considered a superior cell source for regenerative medicine; fetal cells show higher proliferative capacity and have undergone fewer replicative cycles that could generate spontaneous mutations. Fetal cells in amniotic fluid were among the first normal primary cells to be cultured ex vivo, but the undefined composition of amniotic fluid has hindered advance for regenerative applications.We first developed a highly efficient method to generate clonal populations by dilution of amniocentesis samples inmedia and direct plating without intervening refrigeration, centrifugation, or exposure of cells to the paracrine effects in mixed cell cultures.More than 40 clonal populations were recovered from 4 amniocentesis samples and representative clones were characterized by flow cytometry, conventional assays for differentiation potential, immunofluorescence imaging, and transcript analysis. The results revealed previously unreported diversity among stromal and epithelial cell types and identified unique cell types that could be lost or undetected in mixed cell populations. The differentiation potential of amniotic cells proved to be uncoupled from expression of definitive cell surface or cytoplasmic markers for stromal and epithelial cells. Evidence for diversity among stromal and epithelial cells in amniotic fluid bears on interpretations applied to molecular and functional tests of amniotic cell populations. [ABSTRACT FROM AUTHOR]

Busulfan (Bu) based conditioning regimens are associated with serious toxicities including myelosuppression, hepatotoxicity, and sinusoidal obstructive syndrome (SOS). Previous literature reports increased risk of toxicities when the daily AUC concentrations exceed 6000 uM-minute. Bu TDM has also been associated with improved overall and progression free survival in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. We implemented real time pharmacokinetic (PK)-guided therapeutic dose monitoring (TDM) of Bu for myeloablative conditioning (MAC) regimens. Compare toxicity of IV Bu before and after implementation of TDM. The primary endpoint was incidence of hepatotoxicity, defined as days of elevation of AST or ALT > 3 times the upper limit of normal (ULN) or total bilirubin >1.5 times ULN. Secondary outcomes included time to neutrophil and platelet engraftment, duration of IV opioid administration, breakthrough antiemetic use, incidence of SOS, hospital length of stay (LOS), incidence of Bu dose adjustment, and repeat Bu PK. A Bu PK-guided TDM program was implemented in April 2018 for patients receiving busulfan/ cyclophosphamide (BuCy) MAC regimens for allo-HSCT. Medical records were retrospectively reviewed with weight-based dose (WBD) BuCy conditioning from August 2017 through March 2018 (N=14) and TDM from April 2018 through December 2018 (N=22). Bu was given at a fixed dose of 0.8 mg/kg/dose every 6 hours for 16 doses on days -8 to -4 for WBD patients. For TDM patients, after a WBD of 3.2 mg/kg/dose on day -7 (Bu 1), serial plasma Bu concentrations were used to calculate Bu area under the curve (AUC) for subsequent dose adjustment on days -6 to -4 to target a daily AUC of 5000 μM-minute. If the AUC actual /AUC target exceeded 1.2 or was less than 0.8, the second dose of Bu (Bu 2) was changed by no more than ± 20%, repeat PK samples were drawn, and the process was repeated for TDM for the third dose of Bu. Recipients of Bu TDM were younger than those receiving WBD (median 45 vs. 58 years, p=0.008). No other baseline differences were observed. There was no difference in hepatotoxicity between TDM and WBD (median 1 vs. 0 days, p=0.40), time to neutrophil (median 17 vs. 17 days, P=0.18) or platelet engraftment (median 29 vs. 25 days, p=0.75), IV opioid administration (median 4 vs. 4 days, p=0.83), breakthrough antiemetic use (median 59 vs. 58 doses, p=0.99), SOS (4.5 vs. 7.1%, p=1.0), or LOS (median 28 vs. 27 days, p=0.95). In the TDM group, 45% of patients had increases and 41% had decreases in Bu dose after Bu 1. 32% of patients required repeat PK after Bu 2. A PK dose monitoring program for MAC IV Bu regimens may be considered a safe practice in allo-HSCT recipients. The majority of patients receiving PK-guided TDM required dose changes, and TDM patients had no significant difference in toxicity compared to those receiving WBD. [ABSTRACT FROM AUTHOR]

Introduction High-dose chemotherapy followed by autologous hematopoietic cell transplantation (AHCT) offers cure for appropriate patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) sensitive to chemotherapy. Post-AHCT consolidative radiation therapy (RT) has been associated with improved outcomes in R/R DLBCL patients with bulky [based on computed tomography (CT)] disease after AHCT. We and others have demonstrated that patients with a Deauville score 4-5 (high-risk) on pre-AHCT FDG positron emission tomography (PET) have significantly worse outcomes as compared to those with Deauville 1-3 (low risk). We here examined the impact of consolidative post-AHCT RT in R/R-DLBCL patients with high-risk functional imaging based on Deauville score) on pre-transplant FDG PET scan on AHCT outcomes. Therefore, we retrospectively studied the effect of post-ASCT RT within 6 months after ASCT on survival in patients with R/R-DLBCL with high-risk pre-ASCT PET scans. Methods We retrospectively studied 193 consecutive adult patients with R/R-DLBCL identified from the Cleveland Clinic and University of Minnesota who had available pre-transplant FDG PET scans and adequate clinical follow-up. PET scans were re-reviewed and scored Deauville 4-5 were considered high risk. Patients that died within 6 months of ASCT (n=20) were excluded from the final survival analyses. Univariate analysis was performed using the Kaplan-Meier method, and the log-rank test was used to compare the subgroups. Results The mean (SD) age of diagnosis was 54 (11) years and 61% patients were male. The mean follow-up for alive patients was 43 (32.6) months. We identified 69 patients with pre-transplant Deauville scores 4 (n=41) or 5 (n=28). Seventeen (25%) received RT at median 58 days post AHCT (IQR 39-79 days). Receiving post-ASCT RT did not impact overall survival in univariable (Figure 1) or multivariable analyses adjusted for age and gender. Conclusion Within the limits of the study design, we did not observe a benefit to RT on overall survival in patients with RR-DLBCL with high-risk pre-AHCT PET scans. Alternative treatment approaches for high risk patients based on pre-transplant PET should be investigated in prospective clinical trials. [ABSTRACT FROM AUTHOR]