Michael Krumlauf

Phase I Study of Recombinant Human Interleukin-7 Administration in Subjects with Refractory Malignancy

Purpose: Interleukin-7 (IL-7) has critical and nonredundant roles in T-cell development, hematopoiesis, and postdevelopmental immune functions as a prototypic homeostatic cytokine. Based on a large body of preclinical evidence, it may have multiple therapeutic applications in immunodeficiency states, either physiologic (immunosenescence), pathologic (HIV), or iatrogenic (postchemotherapy and posthematopoietic stem cell transplant), and may have roles in immune reconstitution or enhancement of immunotherapy. We report here on the toxicity and biological activity of recombinant human IL-7 (rhIL-7) in humans. Design: Subjects with incurable malignancy received rhIL-7 subcutaneously every other day for 2 weeks in a phase I interpatient dose escalation study (3, 10, 30, and 60 μg/kg/dose). The objectives were safety and dose-limiting toxicity determination, identification of a range of biologically active doses, and characterization of biological and, possibly, antitumor effects. Results: Mild to moderate constitutional symptoms, reversible spleen and lymph node enlargement, and marked increase in peripheral CD3+, CD4+, and CD8+ lymphocytes were seen in a dose-dependent and age-independent manner in all subjects receiving ≥10 μg/kg/dose, resulting in a rejuvenated circulating T-cell profile, resembling that seen earlier in life. In some subjects, rhIL-7 induced in the bone marrow a marked, transient polyclonal proliferation of pre-B cells showing a spectrum of maturation as well as an increase in circulating transitional B cells. Conclusion: This study shows the potent biological activity of rhIL-7 in humans over a well-tolerated dose range and allows further exploration of its possible therapeutic applications. Clin Cancer Res; 16(2); 727–35

Salivary Gland Involvement in Chronic Graft-Versus-Host Disease: Prevalence, Clinical Significance, and Recommendations for Evaluation

Although xerostomia is a commonly reported complaint in patients with chronic graft-versus-host disease (cGVHD), criteria for evaluating the prevalence and characteristics of salivary gland involvement have not been well defined in this patient population. Previous studies also have made no distinction between salivary and mucosal oral cGVHD. We systematically evaluated signs and symptoms of sicca in a large cohort of patients with cGVHD (n = 101) using instruments widely used to study Sjogrens syndrome. Xerostomia was reported in 60 (77%) patients reporting ocular and 52 (67%) patients reporting oral complaints [corrected]. The salivary flow rate was < or =0.2 mL/min in 27%, and < or =0.1 mL/min in 16%. Histopathological changes, consisting of mononuclear infiltration and/or fibrosis/atrophy, were present in all patients with salivary dysfunction. Importantly, there was no correlation of salivary and oral mucosal involvement in cGVHD. Patients with cGVHD-associated salivary gland involvement had diminished oral cavity-specific quality of life and lower body mass index. Salivary gland involvement is a common and clinically distinct manifestation of cGVHD. Formal evaluation of salivary function using standardized criteria is needed, and this could be incorporated as an outcome measure in clinical trials of cGVHD.

Symptom Distress Predicts Long-Term Health and Well-Being in Allogeneic Stem Cell Transplantation Survivors

The number of survivors after allogeneic hematopoietic stem cell transplantation (HSCT) continues to increase, yet their survivorship experience has not been fully characterized. This study examines the health status and health-related quality of life (HRQL) of HSCT survivors. The aims of the study were to: (1) explore the baseline and change over time in these health outcomes, and (2) characterize subgroups experiencing adverse outcomes. In this longitudinal study, adults who survived >3 years from date of allogeneic HSCT completed a series of patient-reported outcome measures annually, including measures of health status, HRQL, and symptoms. Data were analyzed using hierarchical linear modeling. Subjects (N = 171) were on average 44 (±13.5) years of age and primarily male (62.6%); 40% were Hispanic. Mean scores for physical and mental health and HRQL were preserved relative to population norms. Hierarchical linear modeling revealed no significant change in the mean trajectories of these outcomes, although significant between-individual variability was observed. When controlling for demographic and clinical factors, physical symptom distress negatively affected all outcomes. The impact of symptom distress on physical health varied based on time since HSCT; impairment in physical health was greatest in survivors experiencing high symptom distress and who were within the first decade post transplantation. Extended treatment with systemic immunosuppressive therapy also predicted inferior physical health. These findings suggest that patient-centered outcomes are preserved relative to normative values and are generally stable after allogeneic HSCT, although survivors with persistent symptoms and those receiving systemic immunosuppression experience impairments in health status and HRQL.

Function, Adjustment, Quality of Life and Symptoms (FAQS) in Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Survivors: A Study Protocol

BackgroundThe population of survivors following allogeneic HSCT continues to increase, and yet their experiences of recovery and long-term survivorship have not been fully characterized. This paper presents a study protocol examining over time the functional status, psychosocial adjustment, health-related quality of life, and symptom experience of survivors who have undergone allogeneic transplantation. The aims of the study are to: 1) explore the patterns of change in these health outcomes during the survivorship phase; 2) characterize subgroups of survivors experiencing adverse outcomes; and 3) examine relationships among outcomes and demographic and clinical factors (such as age, graft-versus-host disease (GVHD), and disease relapse).MethodsIn this longitudinal observational study, adults who survive a minimum of 3 years from date of allogeneic transplantation complete a series of questionnaires annually. Demographic and clinical data are collected along with a series of patient-reported outcome measures, specifically: 1) Medical Outcomes Study SF- 36; 2) Functional Assessment of Chronic Illness Therapy (FACIT) - General, 3) FACIT-Fatigue; 4) FACIT- Spiritual; 5) Psychosocial Adjustment to Illness Scale; 6) Rotterdam Symptom Checklist-Revised; and 7) Pittsburgh Sleep Quality Index.ConclusionsThis study will provide multidimensional patient-reported outcomes data to expand the understanding of the survivorship experience across the trajectory of allogeneic transplantation recovery. There are a number of inherent challenges in recruiting and retaining a diverse and representative sample of long-term transplant survivors. Study results will contribute to an understanding of outcomes experienced by transplant survivors, including those with chronic GVHD, malignant disease relapse, and other late effects following allogeneic transplantation.Trial RegistrationClinicalTrials.gov: NCT00128960

Targeted pretransplant host lymphocyte depletion prior to T-cell depleted reduced-intensity allogeneic stem cell transplantation

Mixed chimaerism and graft rejection are higher after reduced‐intensity allogeneic stem cell transplantation (RIST) with T‐cell depleted (TCD) allografts. As host immune status before RIST affects engraftment, we hypothesized that targeted depletion of host lymphocytes prior to RIST would abrogate graft rejection and promote donor chimaerism. Lymphocyte‐depleting chemotherapy was administered at conventional doses to subjects prior to RIST with the intent of decreasing CD4+ counts to <0·05 × 109cells/l. Subjects (n = 18) then received reduced‐intensity conditioning followed by ex vivo TCD human leucocyte antigen‐matched sibling allografts. All evaluable patients (n = 17) were engrafted; there were no late graft failures. At day +28 post‐RIST, 12 patients showed complete donor chimaerism. Mixed chimaerism in the remaining five patients was associated with higher numbers of circulating host CD3+ cells (P = 0·0032) after lymphocyte‐depleting chemotherapy and was preferentially observed in T lymphoid rather than myeloid cells. Full donor chimaerism was achieved in all patients after planned donor lymphocyte infusions. These data reflect the importance of host immune status prior to RIST and suggest that targeted host lymphocyte depletion facilitates the engraftment of TCD allografts. Targeted lymphocyte depletion may permit an individualized approach to conditioning based on host immune status prior to RIST.

The prevalence of sleep disturbance in alcoholics admitted for treatment: a target for chronic disease management.

Prolonged and heavy use of alcohol is associated with persistent sleep disturbances. Objective and subjective measures of sleep quantity and quality were collected on 164 individuals undergoing detoxification. A high prevalence of sleep disturbance was found in this sample. Sleep quality improved by week 4 but continued to be altered, signaling a target area for recovery management. This study supports the high prevalence of sleep disturbance in individuals undergoing alcohol treatment. Health promotion strategies in an addiction recovery model should address quality-of-life enhancements for individuals and their families including optimizing sleep quality and duration through sustained recovery.

Phase I Trial of Adoptive Cell Transfer with Mixed-Profile Type-I/Type-II Allogeneic T Cells for Metastatic Breast Cancer

Purpose: Metastatic breast cancer (MBC) response to allogeneic lymphocytes requires donor T-cell engraftment and is limited by graft-versus-host disease (GVHD). In mice, type-II–polarized T cells promote engraftment and modulate GVHD, whereas type-I–polarized T cells mediate more potent graft-versus-tumor (GVT) effects. This phase I translational study evaluated adoptive transfer of ex vivo costimulated type-I/type-II (T1/T2) donor T cells with T-cell–depleted (TCD) allogeneic stem cell transplantation (AlloSCT) for MBC. Experimental Design: Patients had received anthracycline, taxane, and antibody therapies, and been treated for metastatic disease and a human leukocyte antigen (HLA)-identical–sibling donor. Donor lymphocytes were costimulated ex vivo with anti-CD3/anti-CD28 antibody–coated magnetic beads in interleukin (IL)-2/IL-4–supplemented media. Patients received reduced intensity conditioning, donor stem cells and T1/T2 cells, and monitoring for toxicity, engraftment, GVHD, and tumor response; results were compared with historical controls, identically treated except for T1/T2 product infusions. Results: Mixed type-I/type-II CD4+ T cells predominated in T1/T2 products. Nine patients received T1/T2 cells at dose level 1 (5 × 106 cells/kg). T-cell donor chimerism reached 100% by a median of 28 days. Seven (78%) developed acute GVHD. At day +28, five patients had partial responses (56%) and none had MBC progression; thereafter, two patients had continued responses. Donor T-cell engraftment and tumor responses appeared faster than in historical controls, but GVHD rates were similar and responders progressed early, often following treatment of acute GVHD. Conclusion: Allogeneic T1/T2 cells were safely infused with TCD-AlloSCT, appeared to promote donor engraftment, and may have contributed to transient early tumor responses. Clin Cancer Res; 17(21); 6878–87. ©2011 AACR.

Magnetic Resonance Imaging in Sclerotic-Type Chronic Graft-vs-Host Disease

BACKGROUND Sclerotic-type chronic graft-vs-host disease (cGVHD) of the skin is an uncommon but potentially debilitating sequela of allogeneic hematopoietic stem cell transplantation. There is no standardized assessment measure for this form of cGVHD. Because a full-thickness incisional biopsy specimen to the level of the fascia may be needed to make a definitive histologic diagnosis of cGVHD-related fasciitis, a noninvasive technique for the assessment and monitoring of sclerotic-type cGVHD, particularly cGVHD-related fasciitis, would be of potential value. OBSERVATIONS Sixty-two consecutive patients with cGVHD following allogeneic hematopoietic stem cell transplantation were evaluated for sclerotic skin disease. Forty-four patients (71%) had cutaneous cGVHD, and 28 patients (45%) had evidence of sclerotic involvement based on physical examination findings. Fifteen patients agreed to undergo research magnetic resonance imaging to evaluate quantifiable changes in the dermis, subcutaneous tissue, and muscle. Among 15 patients, magnetic resonance imaging identified abnormalities in the skin in 7 (47%), subcutaneous fibrous septa in 13 (87%), deep fascia in 12 (80%), epimysium in 9 (60%), and muscle in 3 (20%). CONCLUSIONS Magnetic resonance imaging should be considered in the evaluation of patients with cGVHD suspected of having subcutaneous or fascial involvement. Additional studies are needed to validate this noninvasive modality for serial monitoring of disease activity and response to therapy. Trial Registration clinicaltrials.gov Identifier: NCT00331968.

Documenting stress in caregivers of transplantation patients: initial evidence of HPA dysregulation.

Abstract There is growing evidence linking caregiver stress with an increased risk for morbidity and mortality. While the emotional and practical burden experienced by caregivers is well established, the physiological changes that may affect the caregiver’s health are less understood. This study sought to compare self-reported stress, anxiety and depression along with neuroendocrine and immune markers of stress among adult caregivers of allogeneic hematopoietic stem cell transplantation patients during the acute transplant recovery period to matched non-caregivers controls. Biomarkers and self-reported data were collected at three points during the patient’s HSCT: (1) before transplant, (2) after initial transplantation discharge (±7 days) and (3) 6 weeks after initial transplantation discharge. Mixed linear modeling was used to examine differences by group and time. Twenty-one caregivers and 20 controls completed all study procedures. The majority of caregivers were female (57% or 57.1%) and married (95.2%), with a mean age of 52 ± 11.4 years. Caregiver perceived stress, anxiety and depression scores were significantly higher than controls (p < 0.001) with effect sizes (ES) ranging from 1.37 to 1.80 and they did not change over time (p > 0.05) for either group. Caregivers had significantly lower serum cortisol levels than controls at both discharge (p = 0.013; ES = 0.81) and 6 weeks after discharge (p = 0.028; ES = 0.72) but exhibited no significant relationship between self-reported stress and serum cortisol. In addition, caregivers showed a significant inverse relationship between stress and epinephrine levels (rs=−0.654, p = 0.021). These findings support the evidence of the caregiving experience being stressful. The counter-intuitive relationship between cortisol and epinephrine might suggest dysregulation of the HPA axis and central nervous system but additional research on the physiological impact of caregiving is warranted.

Are you Sleeping? Pilot Comparison of Self-Reported and Objective Measures of Sleep Quality and Duration in an Inpatient Alcoholism Treatment Program

Sleep disturbances are common among alcohol-dependent individuals and can increase risk of relapse. The current study compares subjective and objective measures of sleep quality and duration and describes the prevalence of baseline sleep disturbances in an inpatient population of alcoholics undergoing their first week of detoxification. At baseline, the PSQI revealed that 79% of participants were above the cutoff score (≥5) for clinically meaningful sleep disturbances (mean = 12.57, SD = 4.38). Actigraphy results revealed that average sleep efficiency was 75.89%. Sleep efficiency scores were significantly correlated with self-reported sleep efficiency (P = 0.04, r = 0.47). Sleep duration measured by the actigraphy watches was not significantly correlated with self-reported sleep duration (P = 0.65, r = 0.10). Ongoing assessment of sleep disturbances may be a valuable tool for informing the development of customized sleep interventions in a similar inpatient alcohol treatment sample.