Clint L. Divine

Wharton’s jelly-derived mesenchymal stromal cells as a promising cellular therapeutic strategy for the management of graft-versus-host disease

Allogeneic hematopoietic cell transplantation (allo-HCT), a treatment option in hematologic malignancies and bone marrow failure syndromes, is frequently complicated by Graft-versus-host disease (GVHD). The primary treatment for GVHD involves immune suppression by glucocorticoids. However, patients are often refractory to the steroid therapy, and this results in a poor prognosis. Therefore alternative therapies are needed to treat GVHD. Here, we review data supporting the clinical investigation of a novel cellular therapy using Wharton’s jelly (WJ)-derived mesenchymal stromal cells (MSCs) as a potentially safe and effective therapeutic strategy in the management of GVHD. Adult-derived sources of MSCs have demonstrated signals of efficacy in the management of GVHD. However, there are limitations, including: limited proliferation capacity; heterogeneity of cell sources; lengthy expansion time to clinical dose; expansion failure in vitro; and a painful, invasive, isolation procedure for the donor. Therefore, alternative MSC sources for cellular therapy are sought. The reviewed data suggests MSCs derived from WJ may be a safe and effective cellular therapy for GVHD. Laboratories investigated and defined the immune properties of WJ-MSCs for potential use in cellular therapy. These cells represent a more uniform cell population than bone marrow-derived MSCs, displaying robust immunosuppressive properties and lacking significant immunogenicity. They can be collected safely and painlessly from individuals at birth, rapidly expanded and stored cryogenically for later clinical use. Additionally, data we reviewed suggested licensing MSCs (activating MSCs by exposure to cytokines) to enhance effectiveness in treating GVHD. Therefore, WJCs should be tested as a second generation, relatively homogeneous allogeneic cell therapy for the treatment of GVHD.

Prophylactic use of zoledronic acid to prevent early bone loss is safe and feasible in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation

Ganguly S, Divine CL, Aljitawi OS, Abhyankar S, McGuirk JP, Graves L. Prophylactic use of zoledronic acid to prevent early bone loss is safe and feasible in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation. 
Clin Transplant 2011 DOI: 10.1111/j.1399‐0012.2011.01527.x. 
© 2011 John Wiley & Sons A/S.

BU, melphalan and thiotepa as a preparative regimen for auto-transplantation in Hodgkin’s disease

BU, melphalan and thiotepa as a preparative regimen for auto-transplantation in Hodgkin’s disease

Adequacy of peripheral blood stem cell mobilization in patients with relapsed B-cell non-Hodgkin lymphoma treated with bendamustine

Andrew Iliff, Clint Divine, Francisco Diaz, Omar Aljitawi, Sunil Abhayankar, Joseph McGuirk & Siddhartha Ganguly Department of Medicine, University of Kansas Medical Center, Kansas City, KS, USA, Division of Cellular Therapeutics and Hematologic Malignancies, University of Kansas Medical Center, Westwood, KS, USA, and Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA

Autologous transplantation in patients with relapsed or high-grade follicular lymphoma provides long term disease-free survival and best median duration of response

The best treatment option for patients with relapsed or high-grade follicular lymphoma (FL) is unknown. In spite of major advances in the therapy for FL, disease-free survival remains short, and median time to progression is just over a year. Autologous stem cell transplantation in patients with relapsed FL is safe and appears to improve disease-free survival. In an attempt to examine whether autologous stem cell transplantation provides long-term disease control in patients with relapsed or high-grade FL, we retrospectively evaluated our experience and analyzed the outcomes of autologous stem cell transplantation in patients with FL from 1991 to 2003. Seventeen men and seven women (n=24) of median age 47.5 years (range 28–64 years) were treated. Three patients with high-risk FL were in first remission. Twenty-one patients were salvaged after relapse with second-line chemotherapy. Of these, 14 were in CR at the time of transplantation, and seven patients were transplanted with active disease. Bone marrow was used in six patients as the source of stem cells prior to 1995 and peripheral blood stem cells were used in 18 patients. Twenty-three of 24 patients engrafted (96%). Median time for neutrophil recovery was 11.5 days (range 9–35 days) and 15 days (range 10–40 days) for platelets. Median duration of follow-up was 6 years (range 7 months–8 years). Of the 24 patients, six have died—with one patient death due to transplant-related pulmonary complications. Overall survival (OS) and disease-free survival (DFS) of all evaluable patients were 71.6 and 40%, respectively. Median duration of response was 4.3 years. OS and DFS in patients transplanted in CR were 80 and 57%, respectively. For those transplanted with disease, a complete response was achieved in 43% of patients, with the OS and DFS of 57 and 19%, respectively. Disease status at transplantation was not a significant variable for survival (p>0.3). Three patients developed moderate to severe treatment-related toxicity, two with grade III mucositis and one with life-threatening infection. When these results are compared with historical controls or patients treated with other modalities, autologous stem cell transplantation appears to be providing the longest disease-free survival and best duration of response.

Evaluation of Performance Status and Hematopoietic Cell Transplantation Specific Comorbidity Index on Unplanned Admission Rates in Patients with Multiple Myeloma Undergoing Outpatient Autologous Stem Cell Transplantation

Although outpatient autologous stem cell transplantation (ASCT) is safe and feasible in most instances, some patients undergoing planned outpatient transplantation for multiple myeloma (MM) will need inpatient admission for transplantation-related complications. We aim to evaluate the difference, if any, between outpatient and inpatient ASCT cohorts of MM patients in terms of admission rate, transplantation outcome, and overall survival. We also plan to assess whether the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) and Karnofsky Performance Status (KPS) can predict unplanned admissions after adjusting for confounding factors. Patients with MM (n = 448) who underwent transplantation at our institution between 2009 and 2014 were included in this retrospective analysis. Patients were grouped into 3 cohorts: cohort A, planned inpatient ASCT (n = 216); cohort B, unplanned inpatient admissions (n = 57); and cohort C, planned outpatient SCT (n = 175). The statistical approach included descriptive, bivariate, and survival analyses. There were no differences among the 3 cohorts in terms of type of myeloma, stage at diagnosis, time from diagnosis to transplantation, CD34 cell dose, engraftment kinetics, and 100-day response rates. Serum creatinine was higher and patients were relatively older in both the planned inpatient (median age, 62 years; range, 33 to 80 years) and unplanned (median age, 59 years; range, 44 to 69 years) admission cohorts compared with the outpatient-only cohort (median age, 57 years; range, 40 to 70 years) (P < .05). Performance status (cohort A: median, 90%; range, 60% to 100%; cohort B: 80%, 50% to 100%; cohort C: 80%, 60% to 100%) was lower (P < .05) and HCT-CI score (cohort A: median, 1.78; range, 0 to 8; cohort B: 2.67, 0 to 9; cohort C: 2.16, 0 to 7) was higher (P < .004) in both inpatient groups compared with the planned outpatient cohort. With a median follow up of 5 years, poor performance status (KPS <70%) appeared to be associated with worse survival (P < .002). HCT-CI >2 also appeared to be associated with worse outcomes compared with HCT-CI 0 to 1, the the difference did not reach statistical significance (hazard ratio, 1.41l 95% confidence interval, 0.72 to 2.76). Only 1 patient out of 448 died from a transplantation-related cause. Outpatient transplantation for myeloma is safe and feasible. In our experience, one-third of the patients undergoing outpatient transplantation needed to be admitted for transplantation-related toxicities. Patients in this group had lower preexisting KPS and higher HCT-CI scores. Whether planned admission for this group would have prevented unplanned admissions and undue stress on patients and the healthcare system should be tested in a prospective manner.

Routine radiographic screening after completion of initial chemotherapy and relapse-free survival after transplant in patients with relapsed lymphoma.

Th e role of radiological surveillance with positron emission tomography (PET) or computed tomography (CT) to detect early relapse after completion of chemotherapy in patients with lymphoma is controversial. PET/CT has an identifi ed role in the diagnosis and staging of lymphoma, but its benefi t in screening for relapse is less clear [1 – 3]. In a recent retrospective study conducted by Truong et al ., there was no diff erence in overall survival for patients whose fi rst relapse was detected clinically or with radiographic surveillance, including patients with indolent or aggressive lymphoma [4]. Patients with chemosensitive relapse with Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL), who subsequently undergo autologous stem cell transplant (auto-SCT), may represent a subset of patients with diff erent biology. We attempted to examine the role of surveillance after completion of initial chemotherapy in this group of patients who subsequently underwent auto-SCT for relapsed lymphoma.