Lower Weight-Based Mycophenolate Mofetil Dosing is Associated with Superior Outcomes after Haploidentical Hematopoietic Cell Transplant with Post-transplant Cyclophosphamide.

Mycophenolate mofetil (MMF) is commonly included in post-transplant cyclophosphamide (PTCy) based graft-versus-host disease (GVHD) prophylaxis after haploidentical (haplo) hematopoietic cell transplant (HCT). In the non-PTCy setting, higher MMF dose/kg has been shown to reduce rates of acute graft-versus-host disease (GVHD). When used in conjunction with PTCy, MMF is dosed at 15 mg/kg three times daily up to a maximum dose of 3 g/day. Thus, patients who weigh ≥67 kg receive 3 g/day and a variable dose/kg of MMF. We investigated the impact of MMF dose/kg on clinical outcomes following haploidentical PBSCT with PTCy-based GVHD prophylaxis. All consecutive adult patients with hematologic malignancies receiving haploidentical T cell replete peripheral blood stem cell transplant (PBSCT) with PTCy/MMF and either tacrolimus or sirolimus at the Moffitt Cancer Center or City of Hope between April 2014-August 2020 were included. For analyses, MMF dose relative to patient actual body weight (mg/kg/day), was stratified into categories of low (<29 mg/kg/day), low intermediate (29-34 mg/kg/day), high intermediate (35-41 mg/kg/day), and high (>41 mg/kg/day). Three hundred eighty-six patients were included. Of these, 54 patients received low dose, 73 low intermediate, 137 high intermediate and 122 high dose MMF by relative weight exposure. In multivariate analysis, low MMF dose exposure was associated with reduced rates of relapse in comparison to the high dose group (HR = 0.45, 95% CI: 0.21 to 0.94, P = .03). This led to superior PFS among patients with low compared to high MMF dose exposure (HR = 0.58, 95% CI: 0.34 to 0.99, P = .045). MMF relative dose exposure was not associated with engraftment, GVHD, nonrelapse mortality, or OS. In this study of patients receiving haploidentical PBSCT with PTCy based GVHD prophylaxis, low MMF dose/kg was associated with improved rates of relapse and PFS. Future prospective studies should investigate optimal dosing strategies of MMF when given with the PTCy regimen.

Impact of extramedullary multiple myeloma on outcomes with idecabtagene vicleucel.

Idecabtagene vicleucel (Ide-cel) has demonstrated excellent efficacy and durable responses in patients with relapsed/refractory multiple myeloma (RRMM). However, the outcomes with ide-cel in patients with extramedullary disease (EMD) remain incompletely characterized. We included patients with RRMM treated with ide-cel between May 2021 and April 2023 across 11 US academic institutions. Visceral or soft tissue lesions non-contiguous from bone was classified as EMD. Time-to-event analyses were performed from date of ide-cel infusion. Among 351 patients, 84 (24%) had EMD prior to infusion. The median follow-up from ide-cel infusion was 18.2 months (95% CI: 17-19.3). The day 90 overall response rates (ORR) were 52% vs. 82% for the EMD and non-EMD cohorts, respectively (p < 0.001). The median progression-free survival (PFS) was 5.3 months (95% CI: 4.1-6.9) for the EMD cohort vs. 11.1 months (95% CI: 9.2-12.6; p < 0.0001) for the non-EMD cohort. In a multivariable analysis, EMD was an independent predictor of inferior PFS [hazard ratio 1.5 (1.1-2.2), p = 0.02]. The median overall survival was 14.8 months [95% CI: 9-Not reached (NR)] vs. 26.9 months (26.3 vs. NR, p = 0.006) for the EMD and non-EMD cohorts, respectively. Extramedullary disease represents an independent predictor of inferior day 90 ORR and PFS among patients treated with ide-cel.

Health Care Students' Perceptions of Bias During Their Clinical Training and Insights on Mitigating It.

PURPOSE: To understand health care students' perception of implicit bias and examine their insights to create a bias-free training environment. METHODS: Clinical phase students from one university's 4 health care programs participated in this study. Students were surveyed regarding their knowledge of implicit bias and perception of their experiences in the clinical learning environment. RESULTS: The response rate was 50.9%, N = 161. In total, 52.6% reported having prior training on implicit bias, and 55% self-reported that they had personally observed preceptors who exhibited an implicit bias toward patients based on race, ethnicity, or other qualities. There was no statistically significant relationship between those with prior training on implicit bias and being able to identify implicit bias exhibited by preceptors. Participants also expressed their unwillingness to report an incident unless it is confidential due to fear of retribution. CONCLUSION: This study found that health care students from one university's 4 health care programs perceived implicit bias in their clinical learning environment, which they believe could be improved by taking intentional steps. Some suggestions provided were "Safe space to report and openly discuss bias," "Education/training on implicit bias," "Time for self-reflection," and "Hiring process that evaluates/trains against implicit bias." The implication of our study is to create a bias-free training environment that will help interrupt the propagation of biases contributing to health disparity. Further research should examine a national population and identify interventional methods and outcomes in multiple health care disciplines.

Association between CYP3A4, CYP3A5 and ABCB1 genotype and tacrolimus treatment outcomes among allogeneic HSCT patients.

Aim: Successful treatment with tacrolimus to prevent graft versus host disease (GVHD) and minimize tacrolimus-related toxicities among allogeneic hematopoietic cell transplantation (alloHCT) recipients is contingent upon quickly achieving and maintaining concentrations within a narrow therapeutic range. The primary objective was to investigate associations between CYP3A4, CYP3A5 or ABCB1 genotype and the proportion of patients that attained an initial tacrolimus goal concentration following initiation of intravenous (iv.) and conversion to oral administration. Materials & methods: We retrospectively evaluated 86 patients who underwent HLA-matched (8/8) related donor alloHCT and were prescribed a tacrolimus-based regimen for GVHD prophylaxis. Results & conclusion: The findings of the present study suggests that CYP3A5 genotype may impact attainment of initial therapeutic tacrolimus concentrations with oral administration in alloHCT recipients.

Idecabtagene vicleucel chimeric antigen receptor T-cell therapy for relapsed/refractory multiple myeloma with renal impairment.

We evaluated patients with relapsed multiple myeloma with renal impairment (RI) treated with standard of care idecabtagene vicleucel (ide-cel), as outcomes with chimeric antigen receptor (CAR) T-cell therapy are unknown in this population. RI was defined as creatinine clearance (CrCl) <50 mL/min. CrCl of <30 mL/min or dialysis dependence were defined as severe RI. The study cohort included 214 patients, 28 (13%) patients with RI, including 11 patients severe RI (dialysis, N=1). Patients with RI were older, more likely to be female and had higher likelihood of having Revised International Staging System stage 3 disease. Rates and severity of cytokine release syndrome (89% vs. 84%, grade ≥3: 7% vs. 2%) and immune effector cell-associated neurotoxicity syndrome (23% vs. 20%) were similar in patients with and without RI, respectively. Patients with RI had higher incidence of short-term grade ≥3 cytopenias, although cytopenias were similar by 3 months following CAR T-cell therapy. Renal function did not worsen after CAR T-cell therapy in patients with RI. Response rates (93% vs. 82%) and survival outcomes (median progression-free survival: 9 vs. 8 months; P=0.26) were comparable in patients with and without RI, respectively. Treatment with ide-cel is feasible in patients with RI, with a comparable safety and efficacy profile as patients without RI, with notable exception of higher short-term high-grade cytopenias.

Belumosudil Impacts Immunosuppression Pharmacokinetics in Patients with Chronic Graft-versus-Host Disease.

Belumosudil (BEL) is a novel Rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor approved for the treatment of chronic graft-versus-host disease (cGVHD) in patients who have failed 2 or more prior lines of systemic therapy. Although the pharmacokinetic effects of BEL on other immunosuppressive (IS) agents have not been clinically evaluated, in vitro data indicate that BEL may have possible interactions with drugs with a narrow therapeutic index used to treat cGVHD, such as tacrolimus, sirolimus, and cyclosporine, through cytochrome P450 (CYP3A) and p-glycoprotein interactions. Further evaluation of these potential interactions is warranted to optimize the safety and effectiveness of these medications when combined with BEL. In this study, we investigated the potential effects of BEL on sirolimus and tacrolimus levels when used concurrently by assessing changes in IS levels after the addition of BEL. This retrospective single-center study of patients who started BEL while on tacrolimus and/or sirolimus between February 1, 2019, to February 1, 2023, included patients who had IS levels measured at baseline prior to starting BEL and at least 1 subsequent IS measurement to assess changes over time. The primary endpoint was the concentration-dose (C/D) ratio analyzed before and after the addition of BEL. Secondary endpoints included the incidence of IS levels outside of the therapeutic range (subtherapeutic or supratherapeutic) and mean dosage changes over time. Thirty-seven patients met our eligibility criteria and were included in this analysis. Patients taking sirolimus (n = 30) or tacrolimus (n = 16) concurrently with BEL had a statistically significant increase in the C/D ratio (sirolimus recipients, 160% [P < .001]; tacrolimus recipients, 113% [P = .013]) between the pre-BEL and final post-BEL assessments. The C/D ratios for both tacrolimus and sirolimus recipients continued to increase at several time points after initiation of BEL, indicating that multiple drug dosage adjustments may be required. After BEL initiation, 19% of tacrolimus levels and 57% of sirolimus levels were supratherapeutic. Despite dosage adjustments, 27% of tacrolimus levels were supratherapeutic at both the second and third assessments after starting BEL, and 28% and 30% of sirolimus levels were supratherapeutic at these 2 time points, respectively. All 12 of the patients who discontinued BEL during the study period (100%) showed a return to their baseline C/D ratio, confirming that the C/D ratio change can be attributed to BEL. The impact of BEL on IS levels is clinically significant, warranting dosage adjustments of concurrent medications. A significant number of patients taking sirolimus with BEL had levels >15 ng/mL during the study period, indicating a potential risk for toxicity if this interaction is unmonitored. We recommend empiric dose reductions of 25% for tacrolimus and 25% to 50% for sirolimus when adding BEL, as well as close monitoring of IS levels during the initial weeks of BEL therapy. Future studies are warranted to better describe the impact of BEL on patients taking CYP3A inhibitors.

Idecabtagene Vicleucel for Relapsed/Refractory Multiple Myeloma: Real-World Experience From the Myeloma CAR T Consortium.

PURPOSE: Idecabtagene vicleucel (ide-cel) is an autologous B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy approved for relapsed/refractory multiple myeloma (RRMM) on the basis of the phase II pivotal KarMMa trial, which demonstrated best overall and ≥ complete response rates of 73% and 33%, respectively. We report clinical outcomes with standard-of-care (SOC) ide-cel under the commercial Food and Drug Administration label. METHODS: Data were retrospectively collected from patients with RRMM who underwent leukapheresis as of February 28, 2022, at 11 US institutions with intent to receive SOC ide-cel. Toxicities were graded per American Society for Transplantation and Cellular Therapy guidelines and managed according to each institution's policies. Responses were graded on the basis of the International Myeloma Working Group response criteria. RESULTS: One hundred fifty-nine of 196 leukapheresed patients received ide-cel by data cutoff. One hundred twenty (75%) infused patients would have been ineligible for participation in the KarMMa clinical trial because of comorbidities at the time of leukapheresis. Any grade and grade ≥ 3 cytokine release syndrome and neurotoxicity occurred in 82/3% and 18/6%, respectively. Best overall and ≥ complete response rates were 84% and 42%, respectively. At a median follow-up of 6.1 months from chimeric antigen receptor T infusion, the median progression-free survival was 8.5 months (95% CI, 6.5 to not reached) and the median overall survival was 12.5 months (95% CI, 11.3 to not reached). Patients with previous exposure to B-cell maturation antigen-targeted therapy, high-risk cytogenetics, Eastern Cooperative Oncology Group performance status ≥ 2 at lymphodepletion, and younger age had inferior progression-free survival on multivariable analysis. CONCLUSION: The safety and efficacy of ide-cel in patients with RRMM in the SOC setting were comparable with those in the phase II pivotal KarMMa trial despite most patients (75%) not meeting trial eligibility criteria.

Early cytopenias and infections after standard of care idecabtagene vicleucel in relapsed or refractory multiple myeloma.

Idecabtagene vicleucel (ide-cel) was FDA-approved in March 2021 for the treatment of relapsed/refractory multiple myeloma after 4 lines of therapy. On the KarMMa trial, grade ≥ 3 cytopenias and infections were common. We sought to characterize cytopenias and infections within 100 days after ide-cel in the standard-of-care (SOC) setting. This multi-center retrospective study included 52 patients who received SOC ide-cel; 47 reached day-90 follow-up. Data were censored at day 100. Grade ≥ 3 cytopenia was present among 65% of patients at day 30 and 40% of patients at day 90. Granulocyte colony stimulating factor (G-CSF) was administered to 88%, packed red blood cell transfusions to 63%, platelet transfusions to 42%, thrombopoietin (TPO) agonists to 21%, intravenous immunoglobulin to 13%, and CD34+ stem cell boosts to 8%. At day 100, 19% and 13% of patients had ongoing use of TPO agonists and G-CSF, respectively. Infections occurred in 54% of patients and were grade ≥ 3 in 23%. Earlier infections in the first 30 days were typically bacterial (68%) and severe (50%). Later infections between days 31 and 100 were 50% bacterial and 42% viral; only 13% were grade ≥ 3. On univariate analysis, high pre-CAR-T marrow myeloma burden (≥ 50%), circulating plasma cells at pre-lymphodepletion (LD), and grade ≥ 3 anemia at pre-LD were associated with grade ≥ 3 cytopenia at both days 30 and 90. Longer time from last bridging treatment to LD was the only significant risk factor for infection.

Coping competence and hopelessness moderate the influence of perceived burdensomeness on suicidal ideation in undergraduate college students.

According to the interpersonal theory of suicide, the perception of imposing a burden on loved ones increases the risk for suicidal ideation. Little research, however, has examined the interaction of burdensomeness with cognitive variables in predicting suicidal ideation in college students even though the relationship between burdensomeness and ideation may be contingent on levels of cognitive risk factors. The present study thus examined the relationships between burdensomeness, hopelessness, coping competence, and suicidal ideation. Questionnaires were administered to 279 undergraduate students from a university in the Midwest United States. After controlling for depression, hopelessness, and coping competence, burdensomeness significantly predicted ideation and accounted for variance above and beyond the control variables. Moreover, the relationship between burdensomeness and suicidal ideation was significantly moderated by coping competence and hopelessness. The findings suggest that perceived burdensomeness plays a critical role in the risk for suicide in college students. More specifically, the findings suggest that coping competence and hopelessness can be ideal targets for interventions as changes in these variables may attenuate the association between perceived burdensomeness and suicidal ideation.

A phase 2 multicenter trial of ofatumumab and prednisone as initial therapy for chronic graft-versus-host disease.

Standard initial therapy of chronic graft vs. host disease (cGVHD) with glucocorticoids results in suboptimal response. Safety and feasibility of therapy with ofatumumab (1000 mg IV on days 0 and 14) and prednisone (1 mg/kg/day) was previously established in our phase I trial (n = 12). We now report the mature results of the phase II expansion of the trial (n = 38). The overall NIH severity of cGVHD was moderate (63%) or severe (37%) with 74% of all patients affected by the overlap subtype of cGVHD and 82% by prior acute cGVHD. The observed 6 month clinician-reported and 2014 NIH-defined overall response rates (ORR = complete + partial response [CR/PR]) of 62.5% (1-sided lower 90% confidence interval=51.5%) were not superior to pre-specified historic benchmark of 60%. Post-hoc comparison of 6 month NIH response suggested benefit compared to more contemporaneous NIH-based benchmark of 48.6% with frontline sirolimus/prednisone (CTN 0801 trial). Baseline cGVHD features (organ involvement, severity, initial immune suppression agents) were not significantly associated with 6-month ORR. The median time to initiation of second-line therapy was 5.4 months (range 0.9-15.1 months). Failure-free survival (FFS) was 64.2% (95% CI 46.5-77.4%) at 6 months and 53.1% (95% CI 35.8-67.7%) at 12 months, whereas FFS with CR/PR at 12 months of 33.5% exceeded a benchmark of 15% in post-hoc analysis, and was associated with greater success in steroid discontinuation by 24 months (odds ratio 8 (95% CI 1.21-52.7). This single-arm phase II trial demonstrated acceptable safety and potential efficacy of the upfront use of ofatumumab in combination with prednisone in cGVHD.  This trial was registered at www.clinicaltrials.gov as #NCT01680965.

Evolving Therapeutic Options for Chronic Graft-versus-Host Disease.

Despite improvements in prevention and treatment of acute graft-versus-host disease (GVHD), chronic GVHD (cGVHD) remains a significant contributor to morbidity and mortality of allogeneic transplant patients. Chronic GVHD remains a leading cause of late complications posttransplant and is impacted by donor-, patient-, and transplant-related (hematopoietic cell transplant [HCT]) factors. Advances in the biological understanding of cGVHD have provided opportunities to improve clinical interventions for prevention and treatment. Expansion of posttransplantation cyclophosphamide beyond haploidentical HCTs has transformed alternative donor, matched, and mismatch GVHD outcomes and is currently being investigated in two upcoming clinical trials network prophylaxis studies. Although corticosteroids remain the cornerstone therapy, several clinical trials are prospectively investigating the utility of using novel agents in combination with corticosteroids as upfront therapy to mitigate prolonged steroid exposure. Several treatment options for patients with steroid-refractory cGVHD are currently being investigated, and advances have resulted in ibrutinib becoming the first cGVHD agent approved by the U.S. Food and Drug Administration. We review recent advances in understanding of cGVHD pathophysiology and new approaches for the prevention and treatment of cGVHD.

Germline BRCA Mutation Rates in Latina Women Presenting for Gynecologic Oncology Care.

OBJECTIVE: Germline BRCA mutation rates in the Latina population are yet to be well described. We aimed to quantitate the rates of referral for genetic testing in qualifying women and testing completion rates in a population of women presenting for gynecologic oncology care. Results were then stratified by ethnic/racial background. METHODS: Charts of new patients evaluated at a comprehensive cancer center in Southern California were reviewed. Patients qualifying for genetic testing in accordance with NCCN Guidelines version 1.2017 for breast and/or ovarian cancer genetic assessment were identified. The actual rates of prescriptions for genetic testing placed, testing completion rates, test results, as well as patients' family history were abstracted. Data were analyzed with chi-square tests. RESULTS: Five hundred and seventy-two of 2,053 patients met testing criteria, and 256/572 (45%) were prescribed testing in accordance with the guidelines. By ethnicity, testing was prescribed in 44% of Non-Hispanic White (NHW), 44% of Latina, 46% of African-American, and 60% of Asian (p = 0.6) patients. Testing was completed in 65% of NHW, 66% of Latina, 65% of African-American, and 67% of Asian patients (p = 0.97). Completion rates were low overall: 28% of those who met testing criteria were tested (p = 0.85). Pathogenic BRCA mutations were found in 29% of NHW and 21% of Latina, 45% of African-American, and 20% of Asian patients (p = 0.4). CONCLUSIONS: There was no difference by ethnicity in rates of testing prescription, completion, or presence of BRCA mutations. Overall, testing rates were suboptimal. BRCA mutations were found in large percentage of Latinas (21%). Further studies are underway to identify barriers to testing prescriptions and completion for Latina women.

Surviving and thriving: Voices of Latina/o engineering students at a Hispanic serving institution.

This study examined factors that played a role in Latina/o undergraduate students' persistence in engineering at a Hispanic serving institution (HSI; N = 10) using the consensual qualitative research method (CQR; Hill, Thompson, & Williams, 1997). Data analyses resulted in five domains: institutional conditions, additive intersectional burdens, personal and cultural wealth, coping skills, and engineering identity. Participants described how they persisted in the face of stressors, citing specific coping skills they developed over time as well as general personal and cultural strengths they carried with them into their pursuit of engineering. Although the structures of the students' institution were generally described as supportive, Latina participants reported experiences with gendered racism that created added barriers to their persistence in engineering. Supportive institutional conditions, personal and cultural assets, and adaptive coping strategies appeared to facilitate the development of a strong engineering identity, which helped to solidify students' sense of belonging, pride, and commitment to complete their degree. Results highlight the need to address intersecting experiences of privilege and oppression to promote access and equity for Latinas/os in engineering. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Clotrimazole troches induce supratherapeutic blood levels of sirolimus and tacrolimus in an allogeneic hematopoietic cell-transplant recipient resulting in acute kidney injury.

Allogeneic hematopoietic cell transplantation is a potential curative treatment option for various malignant and nonmalignant hematologic disorders. Patients undergoing an allogeneic hematopoietic cell transplant are prescribed immune-suppressant therapies to facilitate hematopoietic donor-cell engraftment and prevent graft-versus-host disease. Drug-drug interactions may occur, owing to exposure to complex multidrug regimens with narrow therapeutic windows and high toxicity profiles. Here, we describe a unique case of a 65-year-old man with poor-risk acute myeloid leukemia who underwent a matched-sibling hematopoietic cell allograft. Sirolimus and tacrolimus were used for graft-versus-host disease prophylaxis. He developed oral thrush requiring treatment with clotrimazole troches, which subsequently resulted in serious renal toxicity attributed to supratherapeutic levels of sirolimus and tacrolimus. Patient renal function improved after temporarily holding both immune suppressants, and administering phenytoin to help induce sirolimus and tacrolimus metabolism. This case highlights sudden and serious toxicities that resulted from clotrimazole-sirolimus and clotrimazole-tacrolimus drug-drug interactions, even when administered topically.

Inferring the provenance of an alien species with DNA barcodes: the neotropical butterfly Dryas iulia in Thailand.

The Neotropical butterfly Dryas iulia has been collected from several locations in Thailand and Malaysia since 2007, and has been observed breeding in the wild, using introduced Passiflora foetida as a larval host plant. The butterfly is bred by a butterfly house in Phuket, Thailand, for release at weddings and Buddhist ceremonies, and we hypothesized that this butterfly house was the source of wild, Thai individuals. We compared wing patterns and COI barcodes from two, wild Thai populations with individuals obtained from this butterfly house. All Thai individuals resemble the subspecies D. iulia modesta, and barcodes from wild and captive Thai specimens were identical. This unique, Thai barcode was not found in any of the 30 specimens sampled from the wild in the species' native range, but is most similar to specimens from Costa Rica, where many exporting butterfly farms are located. These data implicate the butterfly house as the source of Thailand's wild D. iulia populations, which are currently so widespread that eradication efforts are unlikely to be successful.

Academic satisfaction among Latino/a and White men and women engineering students.

The current study tests a model of academic satisfaction in engineering based on Lent, Brown, and Hackett's (1994, 2000) social cognitive career theory among a sample of 527 engineering majors attending a Hispanic serving institution. The findings indicated that (a) an alternative bidirectional model fit the data for the full sample; (b) all of the hypothesized relations were significant for the full sample, except the path from engineering interests to goals; (c) social cognitive career theory predictors accounted for a significant amount of variance in engineering goals (26.6%) and academic satisfaction (45.1%); and (d) the model parameters did not vary across men and women or across Latino/a and White engineering undergraduate students. Implications for research and practice are discussed in relation to persistence in engineering among women and Latinos/as.