Neuromuscular electrical stimulation for physical function maintenance during hematopoietic stem cell transplantation: Study protocol.

Hematopoietic stem cell transplantation is a common life-saving treatment for hematologic malignancies, though can lead to long-term functional impairment, fatigue, muscle atrophy, with decreased quality of life. Although traditional exercise has helped reduce these effects, it is inconsistently recommended and infrequently maintained, and most patients remain sedentary during and after treatment. There is need for alternative rehabilitation strategies, like neuromuscular electrical stimulation, that may be more amenable to the capabilities of hematopoietic stem cell transplant recipients. Patients receiving autologous HCT are being enroled in a randomized controlled trial with 1:1 (neuromuscular electrical stimulation:sham) design stratified by diagnosis and sex. Physical function, body composition, quality of life, and fatigue are assessed prior to hematopoietic stem cell transplant (prior to initiating preparatory treatment) and 24±5 days post hematopoietic stem cell transplant (Follow-up 1); physical function and quality of life are also assessed 6-months post hematopoietic stem cell transplant (Follow-up 2). The primary outcome is between-group difference in the 6-minute walk test change scores (Follow-up 1-Pre-transplant; final enrolment goal N = 23/group). We hypothesize that 1) neuromuscular electrical stimulation will attenuate hematopoietic stem cell transplant-induced adverse effects on physical function, muscle mass, quality of life, and fatigue compared to sham at Follow-up 1, and 2) Pre-transplant physical function will significantly predict fatigue and quality of life at Follow-up 2. We will also describe feasibility and acceptability of neuromuscular electrical stimulation during hematopoietic stem cell transplant. This proposal will improve rehabilitative patient care and quality of life by determining efficacy and feasibility of a currently underutilized therapeutic strategy aimed at maintaining daily function and reducing the impact of a potent and widely used cancer treatment. This trial is registered with clinicaltrials.gov (NCT04364256).

Pilot clinical trial of macimorelin to assess safety and efficacy in patients with cancer cachexia.

BACKGROUND: Cancer cachexia is associated with reduced body weight, appetite and quality of life (QOL) with no approved treatments. Growth hormone secretagogues like macimorelin have potential to mitigate these effects. METHODS: This pilot study assessed the safety and efficacy of macimorelin for 1 week. Efficacy was defined a priori as 1-week change in body weight (≥0.8 kg), plasma insulin-like growth factor (IGF)-1 (≥50 ng/mL) or QOL (≥15%). Secondary outcomes included food intake, appetite, functional performance, energy expenditure and safety laboratory parameters. Patients with cancer cachexia were randomized to 0.5 or 1.0 mg/kg macimorelin or placebo; outcomes were assessed non-parametrically. RESULTS: Participants receiving at least one of either macimorelin dose were combined (N = 10; 100% male; median age = 65.50 ± 2.12) and compared with placebo (N = 5; 80% male; median age = 68.00 ± 6.19). Efficacy criteria achieved: body weight (macimorelin N = 2; placebo N = 0; P = 0.92); IGF-1 (macimorelin N = 0; placebo N = 0); QOL by Anderson Symptom Assessment Scale (macimorelin N = 4; placebo N = 1; P = 1.00) or Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F; macimorelin N = 3; placebo N = 0; P = 0.50). No related serious or non-serious adverse events were reported. In macimorelin recipients, change in FACIT-F was directly associated with change in body weight (r = 0.92, P = 0.001), IGF-1 (r = 0.80, P = 0.01), and caloric intake (r = 0.83, P = 0.005), and inversely associated with change in energy expenditure (r = -0.67, P = 0.05). CONCLUSIONS: Daily oral macimorelin for 1 week was safe and numerically improved body weight and QOL in patients with cancer cachexia compared with placebo. Longer term administration should be evaluated for mitigation of cancer-induced reductions in body weight, appetite and QOL in larger studies.

Efficacy, safety, and molecular response predictors of oral ixazomib and short-course rituximab in untreated iNHL.

Patients with indolent B-cell non-Hodgkin lymphoma (iNHL) generally require treatment but experience normal survival, emphasizing the need for simpler, safer therapies. Proteasome inhibitors target aberrant signaling pathways within iNHL and have manageable toxicities. We evaluated the oral proteasome inhibitor ixazomib as initial monotherapy, and combined with rituximab, for first-line treatment of iNHL. Treatment-naïve patients with iNHL needing therapy received oral ixazomib 4 mg weekly until progressive disease or unacceptable adverse events. A 4-week course of rituximab was added during month 7. The primary end point was overall response rate (ORR) during the ixazomib monotherapy window. Correlations included gene expression profiling and response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Thirty-three patients with follicular lymphoma (FL) (n = 20), marginal zone lymphoma (n = 7), and other iNHL were treated with a median follow-up of 30.3 months. During the 6-month ixazomib window, the ORR was 24%, including 35% in FL. The best ORR over the entire study period was 52% overall and 65% in FL; complete response was achieved in 33% and 45%, respectively. The median duration of response was 25.8 months (range, 0-49.7), and the 24-month progression-free and overall survival rates were 51% (95% confidence interval [CI], 32-67) and 91% (95% CI, 74-97), respectively. Ixazomib was well tolerated. Baseline downregulation of proteasome genes, PSMB9 (P = .03) and PSMB8 (P = .007), were associated with response. All evaluated patients generated anti-S antibodies to SARS-CoV-2 vaccination, with a median of 254.9 binding arbitrary unit per mL. Ixazomib demonstrated efficacy alone and with short-course rituximab in untreated iNHL while exhibiting favorable toxicity, convenience, and retention of the B-cell immune response. This trial is registered at www.clinicaltrials.gov as NCT02339922.

The evidence to date on umbralisib for the treatment of refractory marginal zone lymphoma and follicular lymphoma.

INTRODUCTION: Between 2014 and 2018 The United States Food and Drug Administration granted approvals for three small molecule inhibitors of phosphoinositide 3-kinases (PI3Ks) as monotherapy for follicular lymphoma relapsed after at least 2 prior therapies. Idelalisib, copanlisib, and duvelisib each showed similar overall response rate and progression-free survival efficacy along with significant toxicity in separate phase II single-arm studies. Umbralisib, as the 4th iteration in this PI3K-inhibitor class for relapsed/refractory indolent B-cell lymphoma (iB-NHL), appears comparably active but may have improved tolerability. AREAS COVERED: We review the use and limitations of PI3K-inhibitors for iB-NHL and discuss the development of and clinical results for umbralisib. Efficacy data are contextualized alongside other PI3K-inihibitors within the limitations of published single-arm studies. We compare and contrast available safety data, covering the off-target inhibition by umbralisib of casein kinase 1ε that is thought to contribute to a more favorable immune-mediated toxicity profile. EXPERT OPINION: Though a late-comer to the PI3K-inihibitor party in iB-NHL, umbralisib may carve out an important role in treatment algorithms. Umbralisib's apparently superior safety needs to be confirmed in real-world and, ideally, comparative studies but stands to make it an attractive option in patients who are frail and/or seek treatments more compatible with remote management.

Androgens and estrogens predict sexual function after autologous hematopoietic stem cell transplant in men.

BACKGROUND: Autologous hematopoietic stem cell transplantation (AHSCT) is associated with sexual dysfunction and hypogonadism. Androgens are associated with sexual function in healthy men, but the role of estrogens is less well-known, and the association of these sex steroids with sexual function during AHSCT has not been characterized. OBJECTIVES: The purpose of this study was to determine the predictive value of sex hormones before and acutely after AHSCT on sexual function recovery. MATERIALS AND METHODS: We examined sex hormones and self-reported sexual function before (PRE) and 1-month post-AHSCT (MONTH1; n = 19), and sexual function again 1-year post-AHSCT in men (YEAR1; n = 15). RESULTS: Sexual function decreased from PRE to MONTH1 (p ≤ 0.05) with no differences between PRE and YEAR1. Erectile dysfunction was prevalent at PRE (68.4%) and increased at MONTH1 (100%; p ≤ 0.05) but was not different between PRE and YEAR1 (60.0%). From PRE to MONTH1, total testosterone (TT), dihydrotestosterone (DHT), follicle-stimulating hormone, and sex-hormone-binding globulin (SHBG) increased (p ≤ 0.02) while estradiol (p ≤ 0.026) and estrone decreased (p ≤ 0.001). MONTH1 TT and DHT were associated with sexual function at MONTH1, while PRE SHBG, MONTH1 estradiol, and change in estrone predicted sexual function at YEAR1. DISCUSSION: Sexual dysfunction is very prevalent prior to AHSCT and is transiently and severely worsened acutely after. AHSCT induces acute decreases in total and free estrogens, with SHBG increases leading to increases in total androgens, without changes in free androgens. CONCLUSION: Androgens and estrogens are both adversely affected by AHSCT but may predict sexual dysfunction in this population. This supports the premise that estrogen impacts sexual function independent from androgens and that steroid hormones are associated with acute changes in sexual function in this setting. Larger, controlled trials with long-term sex hormone assessment will need to confirm the association between early changes in estrogens and long-term sexual function recovery.

Weight Loss in Cancer Patients Correlates With p38ß MAPK Activation in Skeletal Muscle.

Unintentional weight loss, a first clinical sign of muscle wasting, is a major threat to cancer survival without a defined etiology. We previously identified in mice that p38ß MAPK mediates cancer-induced muscle wasting by stimulating protein catabolism. However, whether this mechanism is relevant to humans is unknown. In this study, we recruited men with cancer and weight loss (CWL) or weight stable (CWS), and non-cancer controls (NCC), who were consented to rectus abdominis (RA) biopsy and blood sampling (n = 20/group). In the RA of both CWS and CWL, levels of activated p38ß MAPK and its effectors in the catabolic pathways were higher than in NCC, with progressively higher active p38ß MAPK detected in CWL. Remarkably, levels of active p38ß MAPK correlated with weight loss. Plasma analysis for factors that activate p38ß MAPK revealed higher levels in some cytokines as well as Hsp70 and Hsp90 in CWS and/or CWL. Thus, p38ß MAPK appears a biomarker of weight loss in cancer patients.

Ibrutinib Monotherapy in Relapsed or Refractory, Transformed Diffuse Large B-cell Lymphoma.

BACKGROUND: Histologic transformation to diffuse large B-cell lymphoma (tDLBCL) occurs in a significant proportion of indolent lymphomas. However, few studies of novel agents inform its management, particularly when relapsed after or refractory (R/R) to prior treatment. PATIENTS AND METHODS: We prospectively evaluated ibrutinib monotherapy in pathologically documented patients with R/R tDLBCL in a single-arm study. The primary endpoint was overall response rate. RESULTS: Twenty patients who had received a median of 4 (range, 2-9) prior lines of therapy overall (median, 2.5; range, 1-9 for tDLBCL) were treated. The overall response rate was 35%, including complete responses in 15%. The median progression-free survival and overall survival were 4.1 months (95% confidence interval, 2.4-6.2 months) and 22.4 months (95% confidence interval, 7.5 months to not reached), respectively. Disease control > 2 months was seen in 75% and > 1 year in 15%. Response was associated with either low tumor bulk or low metabolic tumor volume (P = .05) but not with antecedent lymphoma histology (P = 1.0). Treatment-related adverse events were consistent with prior studies of ibrutinib. CONCLUSIONS: Ibrutinib showed low toxicity and meaningful efficacy in R/R tDLBCL, including short-term disease control in most cases. Results demonstrate the potential utility of ibrutinib in this challenging clinical setting, including as a potential bridge to more definitive treatments.

Venetoclax and Decitabine for T/Myeloid Mixed-Phenotype Acute Leukemia Not Otherwise Specified (MPAL NOS).

T/myeloid mixed-phenotype acute leukemia not otherwise specified (MPAL NOS) is an uncommon and aggressive leukemia without well-established treatment guidelines, particularly when relapsed. Venetoclax plus a hypomethylating agent offers a promising option in this situation since studies support its use in both acute myeloid and, albeit with fewer data to date, acute T-cell-lymphoblastic leukemias. We report the successful eradication of T/myeloid MPAL NOS relapsed after allogeneic stem cell transplant with venetoclax plus decitabine. A consolidative allogeneic stem cell transplant from a second donor was subsequently performed, and the patient remained without evidence of disease more than one year later. Further investigation is indicated to evaluate venetoclax combined with hypomethylating agents and/or other therapies for the management of T/myeloid MPAL NOS.

Clinical research in older adults with hematologic malignancies: Opportunities for alignment in the Veterans Affairs.

Management of hematologic malignancies in older patients is complex and, with recent and anticipated trends in demographics, increasingly common. As a large, nationally integrated medical system the Veterans Affairs has the potential to lead in research to benefit these patients. In this review we describe the evolving treatment paradigms of hematologic malignancies and how they are best fit with older patients through comprehensive evaluation of key vulnerabilities. We also discuss optimization of supportive care and navigation services to target identified risks and challenges aimed at ameliorating the patient's burden of cancer and treatment. Lastly, we discuss opportunities in design of prospective clinical trials to better align with real-world cases, thereby expanding enrollment of and applicability to older patients with hematologic malignancies.

Mantle cell lymphoma relapsed after autologous stem cell transplantation: a single-center experience.

BACKGROUND: Autologous stem cell transplantation (autoSCT) can extend remission of mantle cell lymphoma (MCL), but the management of subsequent relapse is challenging. METHODS: We examined consecutive patients with MCL who underwent autoSCT at Veterans Affairs Puget Sound Health Care System between 2009 and 2017 (N=37). RESULTS: Ten patients experienced disease progression after autoSCT and were included in this analysis. Median progression free survival after autoSCT was 1.8 years (range, 0.3-7.1) and median overall survival after progression was only 0.7 years (range, 0.1 to not reached). The 3 patients who survived more than 1 year after progression were treated with ibrutinib. CONCLUSION: Our findings suggest that ibrutinib can achieve relatively prolonged control of MCL progressing after autoSCT.

Clinical research in older adults with hematologic malignancies: Opportunities for alignment in the Veterans Affairs.

Management of hematologic malignancies in older patients is complex and, with recent and anticipated trends in demographics, increasingly common. As a large, nationally integrated medical system the Veterans Affairs has the potential to lead in research to benefit these patients. In this review we describe the evolving treatment paradigms of hematologic malignancies and how they are best fit with older patients through comprehensive evaluation of key vulnerabilities. We also discuss optimization of supportive care and navigation services to target identified risks and challenges aimed at ameliorating the patient's burden of cancer and treatment. Lastly, we discuss opportunities in design of prospective clinical trials to better align with real-world cases, thereby expanding enrollment of and applicability to older patients with hematologic malignancies.

Assessing Cachexia Acutely after Autologous Stem Cell Transplant.

Autologous hematopoietic stem cell transplantation (AHCT) is an accepted strategy for various hematologic malignancies that can lead to functional impairment, fatigue, muscle wasting, and reduced quality of life (QOL). In cancer cachexia, these symptoms are associated with inflammation, hypermetabolism, and decreased anabolic hormones. The relative significance of these factors soon after AHCT setting is unclear. The purpose of this study was to characterize the acute effects of AHCT on physical function, body composition, QOL, energy expenditure, cytokines, and testosterone. Outcomes were assessed before (PRE) and 30 ± 10 days after (FU) AHCT in patients with multiple myeloma (n = 15) and non-Hodgkin lymphoma (n = 6). Six-minute walk test (6MWT; p = 0.014), lean mass (p = 0.002), and fat mass (p = 0.02) decreased; nausea and fatigue increased at FU (both p = 0.039). Recent weight change and steroid exposure were predictors of reduced aerobic capacity (p < 0.001). There were no significant changes in interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF), energy expenditure, or bioavailable testosterone. Alterations in cytokines, energy expenditure, and testosterone were not associated with functional impairment acutely following AHCT. Recent history of weight loss and steroid exposure were predictors of worse physical function after AHCT, suggesting that targeting nutritional status and myopathy may be viable strategies to mitigate these effects.

Eradication of Hepatitis C Virus Is Associated With Reduction in Hematologic Malignancies: Major Differences Between Interferon and Direct-Acting Antivirals.

It is unclear whether eradication of hepatitis C virus (HCV) leads to a reduction in the risk of hematologic malignancies. We aimed to determine the impact of sustained virologic response (SVR) induced by either direct-acting antivirals (DAAs) or interferon (IFN) on the risk of hematologic malignancies. We identified 69,581 patients who initiated antiviral treatment in the Veterans Affairs national health care system from January 1, 1999, to December 31, 2015, including 40,410 (58%) IFN-only regimens, 4,546 (6.5%) DAA + IFN regimens, and 24,625 (35%) DAA-only regimens. We retrospectively followed patients to identify incident cases of hematologic malignancies or monoclonal gammopathy of unknown significance (MGUS), a premalignant precursor of multiple myeloma. Among patients treated with IFN, SVR was significantly associated with a reduction in the risk of lymphoma (adjusted hazard ratio [AHR], 0.70; 95% confidence interval [CI], 0.51-0.97), multiple myeloma (AHR, 0.40; 95% CI, 0.20-0.77), MGUS (AHR, 0.65; 95% CI, 0.42-0.99), or all hematologic malignancies and MGUS combined (AHR, 0.67; 95% CI, 0.53-0.84) over a mean follow-up of 10.6 years. In contrast, among patients treated with DAA, SVR was not associated with the risk of lymphoma, multiple myeloma, MGUS, or all hematologic malignancies and MGUS combined (AHR, 1.08; 95% CI, 0.66-1.78) during a mean follow-up of 2.9 years. Neither IFN-induced SVR nor DAA-induced SVR was associated with risk of colon cancer or prostate cancer, which were chosen a priori as comparison/control malignancies. Conclusion: We describe novel strong associations between IFN-induced SVR and lymphoma, multiple myeloma, MGUS, and all hematologic malignancies combined. Surprisingly, these associations were not observed with DAA-induced SVR.

On the front line: first choice pharmacotherapeutics for chronic lymphocytic leukemia.

INTRODUCTION: Chronic lymphocytic leukemia (CLL) is a common hematologic malignancy with a highly variable clinical course. Frontline treatments include cytotoxic chemotherapies, immunotherapies, and small molecule inhibitors. Clinical and molecular factors guide treatment initiation and selection. Over the last decade, refinement of CLL risk stratification tools and growth of the arsenal of effective therapeutics have profoundly improved outcomes. These advances have concurrently increased the complexity of managing the early phases of treatment. AREAS COVERED: This review describes the factors considered in the determination of first-line treatment of CLL. Areas of emphasis include assessment of patient fitness, disease classification and risk stratification, and the mechanisms, efficacy, and toxicities associated with available pharmacotherapeutics. EXPERT OPINION: Multiple different treatments may be appropriate for a specific clinical scenario, and selection among them requires discussion of relative risks and benefits. Advances in frontline CLL treatment will continue to shift the treatment paradigm toward prioritizing quality of life alongside survival, limiting treatment and toxicity, and the development of biologically rational synergistic drug combinations and sequences.

Unhealthy alcohol use is associated with postoperative complications in veterans undergoing lung resection.

BACKGROUND: Lung resections carry a significant risk of complications necessitating the characterization of peri-operative risk factors. Unhealthy alcohol use represents one potentially modifiable factor. In this retrospective cohort study, the largest to date of lung resections in the Veterans Health Administration (VHA), we examined the association between unhealthy alcohol use and postoperative complications and mortality. METHODS: Veterans Affairs Surgical Quality Improvement Program data recorded at 86 medical centers between 2007 and 2011 were used to identify 4,715 patients that underwent lung resection. Logistic regression models, adjusted for demographics and comorbidities, were fit to assess the association between unhealthy alcohol use (report of >2 drinks per day in the 2 weeks preceding surgery) and 30-day outcomes. RESULTS: Among 4,715 patients that underwent pulmonary resection, 630 (13.4%) reported unhealthy alcohol use (>2 drinks/day). Overall, postoperative complications occurred in 896 (19.0%) patients, including pneumonia in 524 (11.1%). The rate of mortality was 2.6%. In adjusted analyses, complications were significantly more common among patients with unhealthy alcohol use [odds ratio (OR), 1.42; 95% confidence interval (CI), 1.15-1.74] including, specifically, pneumonia (OR, 1.69; 95% CI, 1.32-2.15). No statistically significant association was identified between unhealthy alcohol use and mortality (OR, 1.27; 95% CI, 0.75-2.02). In secondary analyses that stratified by smoking status at the time of surgery, drinking more than 2 drinks per day was associated with post-operative complications in patients reporting current smoking (OR, 1.51; 95% CI, 1.18-1.91) and was not identified in those reporting no current smoking at the time of surgery (OR, 1.23; 95% CI, 0.79-1.85). CONCLUSIONS: In this large VHA study, 13% of patients undergoing lung resection reported drinking more than 2 drinks per day in the preoperative period, which was associated with increased risk of post-operative complications. Unhealthy alcohol use may be an important target for perioperative risk-mitigation interventions, particularly in patients who report current smoking.

Total Body Irradiation Is Safe and Similarly Effective as Chemotherapy-Only Conditioning in Autologous Stem Cell Transplantation for Mantle Cell Lymphoma.

Autologous stem cell transplant (ASCT) consolidation has become a standard approach for patients with mantle cell lymphoma (MCL), yet there is little consensus on the role of total body irradiation (TBI) as part of high-dose transplantation conditioning. We analyzed 75 consecutive patients with MCL who underwent ASCT at our institution between 2001 and 2011 with either TBI-based (n = 43) or carmustine, etoposide, cytarabine, melphalan (BEAM; n = 32) high-dose conditioning. Most patients (97%) had chemosensitive disease and underwent transplantation in first remission (89%). On univariate analysis, TBI conditioning was associated with a trend toward improved PFS (hazard ratio [HR], .53; 95% confidence interval [CI], .28-1.00; P = .052) and similar OS (HR, .59; 95% CI, .26-1.35; P = .21), with a median follow-up of 6.3 years in the TBI group and 6.6 years in the BEAM group. The 5-year PFS was 66% in the TBI group versus 52% in the BEAM group; OS was 82% versus 68%, respectively. However, on multivariate analysis, TBI-based conditioning was not significantly associated with PFS (HR, .57; 95% CI .24-1.34; P = .20), after controlling for age, disease status at ASCT, and receipt of post-transplantation rituximab maintenance. Likewise, early toxicity, nonrelapse mortality, and secondary malignancies were similar in the 2 groups. Our data suggest that both TBI and BEAM-based conditioning regimens remain viable conditioning options for patients with MCL undergoing ASCT.

Anamorelin hydrochloride in the treatment of cancer anorexia-cachexia syndrome: design, development, and potential place in therapy.

Cancer anorexia-cachexia syndrome (CACS) is a complex and largely untreatable paraneoplastic complication common in advanced cancer. It is associated with profoundly deleterious effects on quality of life and survival. Since its discovery over a decade ago, anamorelin hydrochloride (anamorelin), a mimetic of the growth hormone secretagogue ghrelin, has shown considerable promise in ameliorating components of CACS when administered to patients with advanced cancer, including loss of lean body mass and reversal of anorexia. This review summarizes the development of anamorelin and its safety and efficacy in clinical investigations. The potential future role of anamorelin in treating CACS is also discussed.

Targeted Drugs as Maintenance Therapy after Autologous Stem Cell Transplantation in Patients with Mantle Cell Lymphoma.

The treatment landscape for mantle cell lymphoma (MCL) is rapidly evolving toward the incorporation of novel and biologically targeted pharmaceuticals with improved disease activity and gentler toxicity profiles compared with conventional chemotherapeutics. Upfront intensive treatment of MCL includes autologous stem cell transplantation (SCT) consolidation aimed at deepening and lengthening disease remission, but subsequent relapse occurs. Maintenance therapy after autologous SCT in patients with MCL in remission features lower-intensity treatments given over extended periods to improve disease outcomes. Targeted drugs are a natural fit for this space, and are the focus of considerable clinical investigation. This review summarizes recent advances in the field and their potential impact on treatment practices for MCL.