William B. Clark

Extramedullary relapses after allogeneic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndrome.

Allogeneic stem cell transplant is a potentially curative treatment for patients with acute myeloblastic leukemia and myelodysplastic syndrome. In this issue of the journal, Craddock et al. [1][1] report the largest reported series of T-cell depleted reduced intensity stem cell transplant for acute

Epigenetic induction of adaptive immune response in multiple myeloma: sequential azacitidine and lenalidomide generate cancer testis antigen‐specific cellular immunity

Patients with multiple myeloma (MM) undergoing high dose therapy and autologous stem cell transplantation (SCT) remain at risk for disease progression. Induction of the expression of highly immunogenic cancer testis antigens (CTA) in malignant plasma cells in MM patients may trigger a protective immune response following SCT. We initiated a phase II clinical trial of the DNA hypomethylating agent, azacitidine (Aza) administered sequentially with lenalidomide (Rev) in patients with MM. Three cycles of Aza and Rev were administered and autologous lymphocytes were collected following the 2nd and 3rd cycles of Aza‐Rev and cryopreserved. Subsequent stem cell mobilization was followed by high‐dose melphalan and SCT. Autologous lymphocyte infusion (ALI) was performed in the second month following transplantation. Fourteen patients have completed the investigational therapy; autologous lymphocytes were collected from all of the patients. Thirteen patients have successfully completed SCT and 11 have undergone ALI. Six patients tested have demonstrated CTA up‐regulation in either unfractionated bone marrow (n = 4) or CD138+ cells (n = 2). CTA (CTAG1B)‐specific T cell response has been observed in all three patients tested and persists following SCT. Epigenetic induction of an adaptive immune response to cancer testis antigens is safe and feasible in MM patients undergoing SCT.

Genetic variation in recipient B-cell activating factor modulates phenotype of GVHD

B-cell activating factor (BAFF) single nucleotide polymorphisms (SNPs) are associated with autoimmune diseases. Because patients with classic and overlap chronic GVHD (cGVHD) have features of autoimmune diseases, we studied the association of recipient and/or donor BAFF SNPs with the phenotype of GVHD after allogeneic stem cell transplantation. Twenty tagSNPs of the BAFF gene were genotyped in 164 recipient/donor pairs. GVHD after day 100 occurred in 124 (76%) patients: acute GVHD (aGVHD) subtypes (n = 23), overlap GVHD (n = 29), and classic cGVHD (n = 72). In SNP analyses, 9 of the 20 tag SNPs were significant comparing classic/overlap cGVHD versus aGVHD subtypes/no GVHD. In multivariate analyses, 4 recipient BAFF SNPs (rs16972217 [odds ratio = 2.72, P = .004], rs7993590 [odds ratio = 2.35, P = .011], rs12428930 [odds ratio2.53, P = .008], and rs2893321 [odds ratio = 2.48, P = .009]) were independent predictors of GVHD subtypes, adjusted for conventional predictors of cGVHD. This study shows that genetic variation of BAFF modulates GVHD phenotype after allogeneic stem cell transplantation.

Favorable Outcomes in Patients with High Donor-Derived T Cell Count after In Vivo T Cell–Depleted Reduced-Intensity Allogeneic Stem Cell Transplantation

Patients with hematologic malignancies were conditioned using a rabbit antithymocyte globulin-based reduced-intensity conditioning regimen for allogeneic stem cell transplantation. Donor-derived CD3(+) cell count (ddCD3), a product of CD3(+) cell chimerism and absolute CD3(+) cell count, when <110/μL at 8 weeks post-stem cell transplantation predicted a high risk of sustained mixed chimerism and relapse. Alternatively, patients with a higher ddCD3 developed graft-versus-host disease more frequently, and when partially chimeric, had higher rates of conversion to full donor chimerism after withdrawal of immunosuppression. Early data from our small cohort of patients indicate that ddCD3 at 8 weeks may be used to guide decisions regarding withdrawal of immunosuppression and administration of donor lymphocyte infusion in partially T cell-depleted reduced-intensity regimens.

Stem cell transplantation as a dynamical system: are clinical outcomes deterministic?

Outcomes in stem cell transplantation (SCT) are modeled using probability theory. However, the clinical course following SCT appears to demonstrate many characteristics of dynamical systems, especially when outcomes are considered in the context of immune reconstitution. Dynamical systems tend to evolve over time according to mathematically determined rules. Characteristically, the future states of the system are predicated on the states preceding them, and there is sensitivity to initial conditions. In SCT, the interaction between donor T cells and the recipient may be considered as such a system in which, graft source, conditioning, and early immunosuppression profoundly influence immune reconstitution over time. This eventually determines clinical outcomes, either the emergence of tolerance or the development of graft versus host disease. In this paper, parallels between SCT and dynamical systems are explored and a conceptual framework for developing mathematical models to understand disparate transplant outcomes is proposed.

Microbiome-Host Interactions in Hematopoietic Stem-Cell Transplant Recipients

Author: Tessa Andermann, Jonathan Peled, Christine Ho, Pavan Reddy, Marcie Riches, Rainer Storb, Takanori Teshima, Marcel van den Brink, Amin Alousi, Sophia Balderman, Patrizia Chiusolo, William Clark, Ernst Holler, Alan Howard, Leslie Kean, Andrew Koh, Philip McCarthy, John McCarty, Mohamad Mohty, Ryotaro Nakamura, Katy Rezvani, Brahm Segal, Bronwen Shaw, Elizabeth Shpall, Anthony Sung, Daniela Weber, Jennifer Whangbo, John Wingard, William Wood, Miguel-Angel Perales, Robert Jenq, Ami Bhatt

Low-dose splenic irradiation prior to hematopoietic cell transplantation in hypersplenic patients with myelofibrosis

For patients with myelofibrosis undergoing hematopoietic cell transplantation (HCT), splenomegaly can lead to a protracted post-transplant course and is associated with lower survival in some series [1–3]. Splenectomy has been used in some patients prior to HCT, and studies have demonstrated that splenectomy prior to HCT reduced engraftment time (13 versus 20 d [2]). However, at many centers, splenectomy has fallen out of favor due to high complication rates (5% peri-operative mortality and 30–45% peri-operative morbidity [4]) and acceptable engraftment rates with HCT even in patients with significant splenomegaly [5]. Splenic irradiation has a long history in treating myelofibrosis, with low-dose treatment effective in alleviating painful splenomegaly [6,7]. In patients undergoing HCT for chronic myeloid leukemia, splenic irradiation has been used prior to transplant to reduce tumor burden and improve post-transplant kinetics [8], with a randomized study showing a survival benefit to splenic irradiation in a subset of patients [9]. Immunomodulatory drugs, JAK inhibitors, and mTOR inhibitors have also demonstrated efficacy in improving splenomegaly but have not been evaluated in the pre-transplant setting [10]. Starting in 2011, it has been standard practice at our institution to refer myelofibrosis patients with splenomegaly for low-dose splenic irradiation (LDSI) prior to HCT to attempt to reduce spleen size and improve posttransplant count recovery without the morbidity of splenectomy. Herein we report the outcomes of these patients. Medical records were examined after approval was obtained from our institution’s institutional review board. Between 2011 and 2015, eight patients received LDSI prior to HCT for myelofibrosis. Radiographic documentation of spleen size preand post-transplantation was available for seven patients. Spleen length is reported as the maximum cranio-caudal dimension on abdominal ultrasound. Regarding HCT, five patients had HLA matched related donors. All patients underwent reduced intensity conditioning regimens with busulfan plus fludarabine or melphalan. Anti-thymocyte globulin was given to one of five related donor patients and to all three unrelated donor patients. No patient received total body irradiation. Graft versus host disease (GVHD) prophylaxis was evenly split between cyclosporine and tacrolimus: one patient, whose donor was an identical twin, did not require GVHD prophylaxis. Median LDSI prescription dose was 4.5 Gray (range 3.0–6.0 Gray), delivered in 3 fractions (range 3–6 fractions) over 6 d (range 3–9 d). Patients finished treatment a median of 14 d prior to HCT (range 7–24 d). The date of graft infusion was defined as day 0 of transplant. Patients achieved neutrophil and platelet engraftment on the first of three consecutive days with an absolute neutrophil count of 0.5 10/L and an absolute platelet count of 50,000 10/L, respectively. At our institution, patients received red blood cell and platelet transfusions if their hemoglobin level fell below 8 g/dL and their platelet level fell below 30,000 10/L, respectively. Change in spleen length was evaluated by the Wilcoxon rank sum test, with continuity correction for continuous variables. Median age and Karnofsky performance score were 60 years and 80, respectively (Table 1). Median pre-transplant spleen length was 27 cm. All patients had a spleen size greater than 20 cm. Median time after HCT to repeat splenic imaging was 5 months (range 2–8 months). The patient cohort experienced a significant reduction in spleen size (median decrease 10cm (36%), p< .01). Acute LDSI treatment toxicity was mild (two patients with grade 1 and two patients with grade 2 nausea); no grade 3 toxicities were observed. Median times to neutrophil and platelet engraftment were 13 and 26 d, respectively. At 2 years post-HCT, 75%

The influence of lymphoid reconstitution kinetics on clinical outcomes in allogeneic stem cell transplantation.

Abstract Lymphoid recovery following myeloablative stem cell transplantation (SCT) displays a logistic pattern of exponential growth followed by a plateau. Within this logistic framework, lymphoid recovery is characterized by the parameters R (slope of ascent), a (time of maximal rate of ascent) and K (plateau), the ‘steady-state’ lymphocyte count. A retrospective analysis of allogeneic SCT performed from 2008 to 2013 was undertaken to compare lymphoid recovery and clinical outcomes in 131 patients with acute myelogenous leukemia, acute lymphocytic leukemia, and myelodysplastic syndromes. Using Prism software, a logistic curve was successfully fit to the absolute lymphocyte count recovery in all patients. Patients were classified according to the magnitude and rate of lymphoid recovery; pattern A achieved an absolute lymphocyte counts (ALC) of >1000/μL by day 45, pattern B an ALC 500 < x < 1000/μL, and pattern C an ALC <500/μL. Pattern A was characterized by a higher mean K (p < .0001) compared with patterns B and C. Patients with patterns B and C were more likely to have mixed T cell chimerism at 90 d following SCT (p = .01). There was a trend towards improved survival (and relapse-free survival) in those with pattern A and B at 1 year compared to pattern C (p = .073). There was no difference in cGVHD (p = .42) or relapse (p = .45) between pattern types. Cytomegalovirus (CMV), aGVHD, and all relapse were heralded by deviation from logistic behavior. Pattern C patients were more likely to require donor lymphocyte infusion (DLI) (p = .017). Weaning of tacrolimus post-transplant was associated with a second, separate logistic expansion in some patients. This study demonstrated that lymphoid reconstitution follows a prototypical logistic recovery and that pattern observed correlates with T cell chimerism and need for DLI, and may influence survival.

A Prospective Trial of Extracorporeal Photopheresis for Chronic Graft-versus-Host Disease Reveals Significant Disease Response and No Association with Frequency of Regulatory T Cells

Extracorporeal photopheresis (ECP) is an accepted treatment for chronic graft-versus-host disease (cGVHD); however, the mechanism of action is unclear. We conducted a prospective multicenter clinical trial to assess ECP response rates using the 2005 National Institutes of Health (NIH) consensus criteria and to assess the relationship between regulatory T cells (Tregs) and treatment response (NCT01324908). Eighty-three patients with any NIH subtype of cGVHD were enrolled, irrespective of number of prior lines of treatment, and 6 were subsequently excluded because of the absence of follow-up from cancer relapse, infection, or study withdrawal. Study outcomes were provider-assessed response and formal response by 2005 NIH criteria. Peripheral blood samples were collected at prespecified study visits and were analyzed by flow cytometry for Tregs. In a heavily pretreated cohort of patients, with a median of 2 prior lines of therapy, 62.3% of patients had a provider-assessed response to ECP and 43.5% had response by NIH criteria. These assessments showed only a slight agreement (kappa statistic, .09). In a logistic regression model that included previously identified risk factors such as bilirubin, platelet count, and time from transplant to study entry, no clinical factors were associated with the providers response assessment. Furthermore, there was no significant difference in percentage of Tregs in blood leukocytes at study entry and completion or in overall change in Treg frequency between ECP responders and nonresponders. ECP was associated with a clinically significant decrease in median prednisone dose (.36 to .14 mg/kg, P < .001) from study entry to last visit and a significant decrease in global severity of cGVHD and total body surface area with erythematous rash. Overall, ECP was able to deliver response using NIH response criteria in a highly pretreated cohort with moderate and severe cGVHD independent of most previous risk factors for adverse outcomes of cGVHD.