Shernan G. Holtan

Composite end point of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation

The success of allogeneic hematopoietic cell transplantation (HCT) is typically assessed as individual complications, including graft-versus-host disease (GVHD), relapse, or death, yet no one factor can completely characterize cure without ongoing morbidity. We examined a novel composite end point of GVHD-free/relapse-free survival (GRFS) in which events include grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death in the first post-HCT year. In 907 consecutive University of Minnesota allogeneic HCT recipients (2000-2012), 1-year GRFS was 31% (95% confidence interval [CI] 28-34). Regression analyses showed age, disease risk, and donor type significantly influencing GRFS. Adults age 21+ had 2-fold worse GRFS vs children; GRFS did not differ beyond age 21. Adjusted for conditioning intensity, stem cell source, disease risk, age, and transplant year, HLA-matched sibling donor marrow resulted in the best GRFS (51%, 95% CI 46-66), whereas HLA-matched sibling donor peripheral blood stem cells were significantly worse (25%, 95% CI 20-30, P = .01). GRFS after umbilical cord blood transplants and marrow from matched unrelated donors were similar (31%, 95% CI 27-35 and 32%, 95% CI 22-42, respectively). Because GRFS measures freedom from ongoing morbidity and represents ideal HCT recovery, GRFS has value as a novel end point for benchmarking new therapies.

Cancer and Pregnancy: Parallels in Growth, Invasion, and Immune Modulation and Implications for Cancer Therapeutic Agents

Many proliferative, invasive, and immune tolerance mechanisms that support normal human pregnancy are also exploited by malignancies to establish a nutrient supply and evade or edit the host immune response. In addition to the shared capacity for invading through normal tissues, both cancer cells and cells of the developing placenta create a microenvironment supportive of both immunologic privilege and angiogenesis. Systemic alterations in immunity are also detectable, particularly with respect to a helper T cell type 2 polarization evident in advanced cancers and midtrimester pregnancy. This review summarizes the similarities between growth and immune privilege in cancer and pregnancy and identifies areas for further investigation. Our PubMed search strategy included combinations of terms such as immune tolerance, pregnancy, cancer, cytokines, angiogenesis, and invasion. We did not place any restrictions on publication dates. The knowledge gained from analyzing similarities and differences between the physiologic state of pregnancy and the pathologic state of cancer could lead to identification of new potential targets for cancer therapeutic agents.

Diagnosis of Obesity by Primary Care Physicians and Impact on Obesity Management

OBJECTIVE To evaluate whether primary care physicians document obesity as a diagnosis and formulate a management plan. PATIENTS AND METHODS The Mayo Clinic primary care database was used to identify general medical examinations performed from November 1, 2004, to October 31, 2005, in a primary care clinic for obese patients (body mass index [BMI] equals 30). Data on demographic variables, BMI, comorbidities, documentation of obesity, and obesity management strategy were obtained through the database. Multivariate logistic regression analyses were conducted to estimate multivariate odds ratios (ORs) and 95 percent confidence intervals (CIs). RESULTS A total of 9827 patients were seen for a general medical examination. Of the 2543 obese patients, 505 (19.9 percent) had a diagnosis of obesity documented, and 574 (22.6 percent) had an obesity management plan documented. Older patients (OR, 0.97 per year; 95 percent CI, 0.96-0.98) and men (OR, 0.60; 95% CI, 0.47-0.76) were significantly less likely to be diagnosed as having obesity, whereas those with a BMI greater than 35 (OR, 2.54; 95 percent CI, 2.10-3.16), diabetes mellitus (OR, 1.40; 95 percent CI, 1.09-1.78), and obstructive sleep apnea (OR, 2.34; 95 percent CI, 1.79 to 3.07) were significantly more likely to have the diagnosis made. Staff physicians were less likely than residents to document obesity as a diagnosis (OR, 0.55; 95 percent CI, 0.44 to 0.69). Diagnosis of obesity was the strongest predictor of formulation of an obesity plan (OR, 2.39; 95 percent CI, 1.90 to 3.02). CONCLUSION Most obese patients did not have a diagnosis of obesity or an obesity management plan made by their primary care physician. Diagnosis of obesity results in a higher chance of formulation of an obesity plan.

Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma†‡

Patients with metastatic melanoma (MM) have very few therapy options. Based on reports of responses to paclitaxel and carboplatin (PC), 31 patients with MM were treated with PC.

Acute graft-versus-host disease: A bench-to-bedside update

Over the past 5 years, many novel approaches to early diagnosis, prevention, and treatment of acute graft-versus-host disease (aGVHD) have been translated from the bench to the bedside. In this review, we highlight recent discoveries in the context of current aGVHD care. The most significant innovations that have already reached the clinic are prophylaxis strategies based upon a refinement of our understanding of key sensors, effectors, suppressors of the immune alloreactive response, and the resultant tissue damage from the aGVHD inflammatory cascade. In the near future, aGVHD prevention and treatment will likely involve multiple modalities, including small molecules regulating immunologic checkpoints, enhancement of suppressor cytokines and cellular subsets, modulation of the microbiota, graft manipulation, and other donor-based prophylaxis strategies. Despite long-term efforts, major challenges in treatment of established aGVHD still remain. Resolution of inflammation and facilitation of rapid immune reconstitution in those with only a limited response to corticosteroids is a research arena that remains rife with opportunity and urgent clinical need.

WHO-defined ‘myelodysplastic syndrome with isolated del(5q)’ in 88 consecutive patients: survival data, leukemic transformation rates and prevalence of JAK2 , MPL and IDH mutations

The 2008 World Health Organization (WHO) criteria were used to identify 88 consecutive Mayo Clinic patients with ‘myelodysplastic syndrome with isolated del(5q)’ (median age 74 years; 60 females). In all, 60 (68%) patients were followed up to the time of their death. Overall median survival was 66 months; leukemic transformation was documented in five (5.7%) cases. Multivariable analysis identified age ⩾70 years (P=0.01), transfusion need at diagnosis (P=0.04) and dysgranulopoiesis (P=0.02) as independent predictors of shortened survival; the presence of zero (low risk), one (intermediate risk) or ⩾2 (high risk) risk factors corresponded to median survivals of 102, 52 and 27 months, respectively. Janus kinase 2 (JAK2), thrombopoietin receptor (MPL), isocitrate dehydrogenase 1 (IDH1) and IDH2 mutational analysis was performed on archived bone marrows in 78 patients; JAK2V617F and MPLW515L mutations were shown in five (6.4%) and three (3.8%) patients, respectively, and did not seem to affect phenotype or prognosis. IDH mutations were not detected. Survival was not affected by serum ferritin and there were no instances of death directly related to iron overload. The current study is unique in its strict adherence to WHO criteria for selecting study patients and providing information on long-term survival, practical prognostic factors, baseline risk of leukemic transformation and the prevalence of JAK2, MPL and IDH mutations.

A Refined Risk Score for Acute Graft-versus-Host Disease that Predicts Response to Initial Therapy, Survival, and Transplant-Related Mortality

To develop a novel acute graft-versus-host disease (GVHD) risk score, we examined the GVHD clinical stage and grade of 1723 patients at the onset of treatment with systemic steroids. Using clinical grouping, descriptive statistics and recursive partitioning, we identified poorly responsive, high-risk (HR) acute GVHD by the number of involved organs and severity of GVHD at onset. The overall response (complete response/partial response) rate 28 days after initiation of steroid therapy for acute GVHD was lower in the 269 patients with HR-GVHD than in the 1454 patients with standard risk (SR)-GVHD (44% [95% confidence interval (CI) 38% to 50%] versus 68% [95% CI, 66% to 70%], P < .001). Patients with HR-GVHD were less likely to respond at day 28 (odds ratio [OR], .3; 95% CI, .2 to .4; P < .001) and had higher risks of mortality (relative risk, 2.1; 95% CI, 1.7 to 2.6; P < .001) and transplant-related mortality (relative risk, 2.5; 95% CI, 2.0% to 3.2%, P < .001) than patients with SR-GVHD. This refined definition of acute GVHD risk is a better predictor of response, survival, and transplant-related mortality than other published acute GVHD risk scores. Patients with HR-GVHD are candidates for studies investigating new treatment approaches. Likewise, patients with SR-GVHD are candidates for studies investigating less toxic therapy.

Regional immunity in melanoma: immunosuppressive changes precede nodal metastasis

In order to characterize the degree of immunosuppression in regional immunity in patients with melanoma, we used immunohistochemistry to analyze markers of T-cell subtype and polarity, costimulation, dendritic cell maturation, monocytes, lymphatic vasculature, and angiogenesis. Specifically, we analyzed expression of CD4, CD8, CD14, CD40, CD86, CD123, HLA-DR, IL-10, LYVE, VEGFR3, and VEGF-C in lymph nodes. We compared sentinel lymph nodes with and without metastasis from patients with melanoma with both infection inflamed (reactive) and dormant human lymph nodes. There were no differences demonstrated between sentinel lymph nodes with or without metastasis from patients with melanoma in any of the markers that were tested. Both groups of sentinel lymph nodes had fewer CD8+ T cells than either set of control nodes. Whereas the infection inflamed lymph nodes demonstrated Th2 polarity, the dormant lymph nodes demonstrated Th1 polarity. In conclusion, changes in regional immunity appeared to precede metastasis in melanoma. Whether there was tumor present in sentinel lymph nodes or not, these nodes demonstrated a marked decrease in cytotoxic T cells compared with both sets of controls. Furthermore, the control lymph nodes used for comparison can significantly impact interpretation, as the dormant and reactive lymph nodes markedly varied in their immune profiles. These immunologic changes may explain the successful metastasis of melanoma in the midst of the immune environment of the sentinel lymph node, and lend insights into the mechanisms of lymphatic metastases in other solid malignancies.

Peripheral Blood Lymphocyte and Monocyte Recovery and Survival in Acute Leukemia Postmyeloablative Allogeneic Hematopoietic Stem Cell Transplant

Many previous studies of immune reconstitution (IR) postallogeneic hematopoietic stem cell transplantation (HSCT) have focused on lymphocyte recovery. Recognizing that IR involves complex interactions between innate and adaptive immune networks, we hypothesized that patterns of both monocyte and lymphocyte recovery could provide additional prognostic information. To test our hypothesis, we analyzed data from 135 consecutive patients undergoing myeloablative allogeneic HSCT for acute myeloid (AML) and lymphoblastic leukemia (ALL) from 2001 to 2010. The absolute lymphocyte and monocyte counts (ALC and AMC, respectively) were determined longitudinally at days +15, +30, +60, and +100, and correlated with clinical outcomes. At the day +30 time point, both ALC and AMC >0.3 × 10(9) cells/L were strongly associated with improved survival (overall survival [OS] 29.6 months versus 5.4 months, P = .006 and 25.3 months versus 5.1 months, P = .01 respectively), a pattern that generally continued through the day +100 evaluation. Multivariate analysis revealed the following independent prognostic factors: early disease status at transplantation, the development of chronic GVHD, the day +30 AMC, day +100 AMC, and day +100 ALC. To further explore whether any inherent patterns in the timing of lymphocyte and monocyte recovery had prognostic value post-HSCT, we performed unsupervised hierarchical clustering on the longitudinal hematopoietic parameters studied in this cohort. Four clusters of patients were identified: clusters A-D. Patient clusters B and D both demonstrated improved ALC and AMC recovery at the day +60 and day +100 time points and had significantly improved OS compared with clusters A and C (57.8 months versus 19.7 and 4.4 months, respectively, P < .001). Our data suggest that patients with poor lymphocyte and monocyte recovery beyond the day +60 time points may be at risk for poorer outcomes, and that further investigation into lymphoid/myeloid interactions in developing individualized immunotherapy is warranted.

Myelodysplastic syndromes associated with interstitial deletion of chromosome 5q: Clinicopathologic correlations and new insights from the prelenalidomide era

To better estimate prognosis for patients with myelodysplastic syndromes (MDS) associated with clonal interstitial deletions of the long arm of chromosome 5 (del(5q)), we reviewed the medical records of 130 adults with del(5q) MDS seen at our institution over a 15‐year period. Overall median survival of this cohort was 9.5 months, shorter than reported in earlier series. The least favorable outcomes are associated with complex cytogenetics, lack of any normal metaphases, normocytic rather than macrocytic erythrocyte indices, and low baseline lymphocyte counts. Lymphopenia but not neutropenia at the time of diagnosis appears to be a new adverse prognostic indicator. Cytogenetic breakpoints defined by G‐banded karyotyping correlate poorly with particular disease features. Surprisingly, survival of patients with treatment‐related MDS was equivalent to that of de novo MDS with del(5q) in this series. Morphologic features associated with del(5q) are diverse. Most patients with del(5q) MDS do not meet criteria for WHO‐defined 5q‐syndrome, and the presence of del(5q) does not appear to modify the clinical phenotype otherwise risk‐stratified by the International Prognostic Scoring System (IPSS). Additional important prognostic factors not taken into account by the IPSS include the baseline erythrocyte indices, lymphocyte count, and clonal burden. Am. J. Hematol., 2008.