Bipin N. Savani

First and Second-Line Systemic Treatment of Acute Graft-versus-host Disease: Recommendations of the American Society of Blood and Marrow Transplantation

Despite prophylaxis with immunosuppressive agents or a variety of other approaches, many patients suffer from acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation. Although consensus has emerged supporting the use of high-dose methylprednisolone or prednisone for initial treatment of aGVHD, practices differ among centers with respect to the initial glucocorticoid dose, the use of additional immunosuppressive agents, and the approach to withdrawal of treatment after initial improvement. Despite many studies, practices vary considerably with respect to the selection of agents for treatment of glucocorticoid-resistant or refractory GVHD. Investigators and clinicians have recognized the lack of progress and lamented the absence of an accepted standard of care for secondary treatment of aGVHD. The American Society of Blood and Marrow Transplantation has developed recommendations for treatment of aGVHD to be considered by care providers, based on a comprehensive and critical review of published reports. Because the literature provides little basis for a definitive guideline, this review also provides a framework for the interpretation of previous results and the design of future studies.

Rapid natural killer cell recovery determines outcome after T-cell-depleted HLA-identical stem cell transplantation in patients with myeloid leukemias but not with acute lymphoblastic leukemia

Natural killer (NK) cells are the first lymphocytes to recover after allogeneic stem cell transplantation (SCT) and can exert powerful graft-versus-leukemia (GVL) effects determining transplant outcome. Conditions governing NK cell alloreactivity and the role of NK recovery in sibling SCT are not well defined. NK cells on day 30 post-transplant (NK30) were measured in 54 SCT recipients with leukemia and donor and recipient killer immunoglobulin-like receptor (KIR) genotype determined. In univariate analysis, donor KIR genes 2DL5A, 2DS1, 3DS1 (positive in 46%) and higher numbers of inhibitory donor KIR correlated with higher NK30 counts and were associated with improved transplant outcome. NK30 counts also correlated directly with the transplant CD34 cell dose and inversely with the CD3+ cell dose. In multivariate analysis, the NK30 emerged as the single independent determinant of transplant outcome. Patients with NK30 >150/μl had less relapse (HR 18.3, P=0.039), acute graft-versus-host disease (HR 3.2, P=0.03), non-relapse mortality (HR 10.7, P=0.028) and improved survival (HR 11.4, P=0.03). Results suggest that T cell-depleted SCT might be improved and the GVL effect enhanced by selecting donors with favorable KIR genotype, and by optimizing CD34 and CD3 doses.

Stem cell transplantation with reduced-intensity conditioning regimens : a review of ten years experience with new transplant concepts and new therapeutic agents

The realization in the 1990s that allogeneic stem cell transplants (SCT) have a potentially curative graft-versus-leukemia (GVL) effect in addition to the antileukemic action of myeloablative conditioning regimens was a major stimulus for the development of reduced-intensity conditioning (RIC) regimens, aimed primarily at securing engraftment to provide the GVL effect, while minimizing regimen-related toxicity. It is now over 10 years since RIC regimens were heralded as a new direction in the field of SCT. Over the last decade much has been learned about the ways in which the conditioning regimen can be tailored to provide adequate immunosuppression, and modulated to deliver a chosen degree of antimalignant treatment. The huge literature of clinical data with RIC transplantation now permits us to more clearly define the success and limitations of the approach. This review examines the origins of RIC SCT, explores the degree to which the initial expectations and purpose of the approach have been realized, and outlines some ways forward for the field.

Ex vivo characterization of polyclonal memory CD8 + T-cell responses to PRAME-specific peptides in patients with acute lymphoblastic leukemia and acute and chronic myeloid leukemia

Preferentially expressed antigen of melanoma (PRAME) is aberrantly expressed in hematologic malignancies and may be a useful target for immunotherapy in leukemia. To determine whether PRAME is naturally immunogenic, we studied CD8(+) T-cell responses to 4 HLA-A*0201-restricted PRAME-derived epitopes (PRA100, PRA142, PRA300, PRA425) in HLA-A*0201-positive patients with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and healthy donors. CD8(+) T cells recognizing PRAME peptides could be detected ex vivo in 4 of 10 ALL, 6 of 10 AML, 3 of 10 CML patients, and 3 of 10 donors by HLA-A2 tetramer analysis and flow cytometry for intracellular interferon-gamma. The frequency of PRAME-specific CD8(+) T cells was greater in patients with AML, CML, and ALL than healthy controls. All peptides were immunogenic in patients, while responses were only detected to PRA300 in donors. High PRAME expression in patient peripheral blood mononuclear cells was associated with responses to greater than or equal to 2 PRAME epitopes compared with low PRAME expression levels (4/7 vs 0/23, P = .001), suggesting a PRAME-driven T-cell response. PRAME-specific T cells were readily expanded in short-term cultures in donors and patients. These results provide evidence for spontaneous T cell reactivity against multiple epitopes of PRAME in ALL, AML, and CML. The potential for developing PRAME as a target for immunotherapy in leukemia deserves further exploration.

Imatinib synergizes with donor lymphocyte infusions to achieve rapid molecular remission of CML relapsing after allogeneic stem cell transplantation

Summary:Donor lymphocyte infusions (DLI) have been the mainstay of treatment for chronic myeloid leukemia (CML) relapsing after allogeneic stem cell transplantation (allo-SCT). Imatinib mesylate (IM) is also effective in these patients. However, advanced phase relapse (APRel) responds poorly with either treatment. To test the possibility that combinations of DLI and IM might be more effective, 37 patients with CML relapsing after allo-SCT between August 1994 and May 2004 were studied. Ten had molecular relapse (MRel), 14 hematological relapse (HRel) and 13 APRel. Thirteen received DLI, 9 IM and 11 DLI+IM. Four patients received DLI+IM but not concurrently. Thirty (81%) patients responded (actuarial survival and current leukemia-free survival of 80.6±6.7% and 69.1±7.7%). Of 30 patients, 26 are in molecular remission (MR), median follow-up of 1226 days (range 249–3257) since relapse. Ten of 11 patients (including four with APRel) treated with DLI+IM achieved MR in 3 months and all are alive in MR. In contrast, only two of 22 treated with either modality (1/13 DLI and 1/9 IM) achieved MR at 3 months, 15 are alive, 11 in MR. Four patients receiving nonconcurrent DLI+IM are also alive in MR. In conclusion, DLI appears to synergize with IM to induce rapid and durable MR.

Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI

Cyclophosphamide combined with total body irradiation (Cy/TBI) or busulfan (BuCy) are the most widely used myeloablative conditioning regimens for allotransplants. Recent data regarding their comparative effectiveness are lacking. We analyzed data from the Center for International Blood and Marrow Transplant Research for 1230 subjects receiving a first hematopoietic cell transplant from a human leukocyte antigen-matched sibling or from an unrelated donor during the years 2000 to 2006 for acute myeloid leukemia (AML) in first complete remission (CR) after conditioning with Cy/TBI or oral or intravenous (IV) BuCy. Multivariate analysis showed significantly less nonrelapse mortality (relative risk [RR] = 0.58; 95% confidence interval [CI]: 0.39-0.86; P = .007), and relapse after, but not before, 1 year posttransplant (RR = 0.23; 95% CI: 0.08-0.65; P = .006), and better leukemia-free survival (RR = 0.70; 95% CI: 0.55-0.88; P = .003) and survival (RR = 0.68; 95% CI: 0.52-0.88; P = .003) in persons receiving IV, but not oral, Bu compared with TBI. In combination with Cy, IV Bu is associated with superior outcomes compared with TBI in patients with AML in first CR.

Increasing Incidence of Chronic Graft-versus-Host Disease in Allogeneic Transplantation: A Report from the Center for International Blood and Marrow Transplant Research

Although transplant practices have changed over the last decades, no information is available on trends in incidence and outcome of chronic graft-versus-host disease (cGVHD) over time. This study used the central database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to describe time trends for cGVHD incidence, nonrelapse mortality, and risk factors for cGVHD. The 12-year period was divided into 3 intervals, 1995 to 1999, 2000 to 2003, and 2004 to 2007, and included 26,563 patients with acute leukemia, chronic myeloid leukemia, and myelodysplastic syndrome. Multivariate analysis showed an increased incidence of cGVHD in more recent years (odds ratio = 1.19, P < .0001), and this trend was still seen when adjusting for donor type, graft type, or conditioning intensity. In patients with cGVHD, nonrelapse mortality has decreased over time, but at 5 years there were no significant differences among different time periods. Risk factors for cGVHD were in line with previous studies. This is the first comprehensive characterization of the trends in cGVHD incidence and underscores the mounting need for addressing this major late complication of transplantation in future research.

Repeated PR1 and WT1 peptide vaccination in Montanide-adjuvant fails to induce sustained high-avidity, epitope-specific CD8+ T cells in myeloid malignancies

Background We previously showed that vaccination with one dose of PR1 and WT1 peptides induces transient anti-leukemia immunity. We hypothesized that maintenance of a sustained anti-leukemia response may require frequent boost injections. Design and Methods Eight patients with myeloid malignancies were enrolled in this phase II study, and 6 completed 6 injections of PR1 and WT1 peptides in Montanide-adjuvant with GM-CSF, every two weeks. Results Both high- and low-avidity PR1 or WT1-specific CD8+ T cells were detected in all evaluable patients after the first vaccine dose. Repeated vaccination led to selective deletion of high avidity PR1- and WT1-specific CD8+ T cells and was not associated with significant reduction in WT1-expression. Additional boosting failed to increase vaccine-induced CD8+ T-cell frequencies further and in all patients the response was lost before the 6th dose. PR1- or WT1-specific CD8+ T cells were not detected in bone marrow samples, excluding their preferential localization to this site. Following a booster injection three months after the 6th vaccine dose, no high-avidity PR1 or WT1-specific CD8+ T cells could be detected, whereas low-avidity T cells were readily expanded. Conclusions These data support the immunogenicity of PR1 and WT1 peptide vaccines. However, repeated delivery of peptides with Montanide-adjuvant and GM-CSF leads to rapid loss of high-avidity peptide-specific CD8+ T cells. These results may offer an explanation for the lack of correlation between immune and clinical responses observed in a number of clinical trials of peptide vaccination. New approaches are needed to induce long-term high-avidity memory responses against leukemia antigens. (ClinicalTrials.gov Identifier: NCT00499772)

How I treat late effects in adults after allogeneic stem cell transplantation

More than 25,000 allogeneic hematopoietic stem cell transplantations (allo-HCTs) are expected to be performed worldwide in 2010, a number that has been increasing yearly. With broadening indications, more options for allo-HCT, and improvement in survival, by 2020 there may be up to half a million long-term survivors after allo-HCT worldwide. These patients have increased risks for various late complications, which can cause morbidity and mortality. Most long-term survivors return to the care of their local hematologists/oncologists or primary care physicians, who may not be familiar with specialized monitoring recommendations for this patient population. The purpose of this article is to describe practical approaches to screening for and managing these late effects, with the goal of reducing preventable morbidity and mortality associated with allo-HCT.

Donor KIR Genes 2DL5A, 2DS1 and 3DS1 Are Associated with a Reduced Rate of Leukemia Relapse After HLA-Identical Sibling Stem Cell Transplantation for Acute Myeloid Leukemia but Not Other Hematologic Malignancies

Stem cell transplantation (SCT) from a healthy donor can be curative for patients with hematologic malignancies resistant to other treatments. Elimination of malignant cells through a graft-versus-leukemia (GVL) effect involves donor T and natural killer (NK) cells, but their relative contribution to this process is poorly defined. NK cell alloreactivity and GVL effects are controlled by the nature of the interaction of NK activation receptors and killer-immunoglobulin-like-receptors (KIR) with major histocompatibility locus class I antigens on the target cell. We performed KIR-genotyping of HLA-identical sibling donors in 246 T cell-depleted SCTs to identify genetic factors affecting transplant outcome (treatment-related mortality [TRM], leukemic relapse, and survival). Univariate and multivariate analysis of transplant-related risk factors and KIR genotyping was performed to identify independent variables predictive of outcome for different forms of leukemia. Further to confirming known predictive factors for TRM and survival (CD34 cell dose, patient age, disease stage), statistical analysis revealed that 3 donor B haplotype KIR genes, 2DL5A, 2DS1, and 3DS1, were associated with significantly less relapse in patients with acute myelogenous leukemia (AML) (13% versus 57%) but not in patients with other myelogenous or lymphoid malignancies. AML patients receiving SCT from donors with these KIR genes relapsed 4 times less frequently than patients transplanted from donors with other KIR genotypes. These findings suggest specific, genetically determined, interactions between NK cells and AML cells that facilitate the GVL effect, and have implications for donor selection for AML patients.