Eli Estey

NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation

Relapse is a major cause of treatment failure after allogeneic hematopoietic stem cell transplantation (alloHSCT). Treatment options for relapse have been inadequate, and the majority of patients ultimately die of their disease. There is no standard approach to treating relapse after alloHSCT. Withdrawal of immune suppression and donor lymphocyte infusions are commonly used for all diseases; although these interventions are remarkably effective for relapsed chronic myelogenous leukemia, they have limited efficacy in other hematologic malignancies. Conventional and novel chemotherapy, monoclonal antibody therapy, targeted therapies, and second transplants have been utilized in a variety of relapsed diseases, but reports on these therapies are generally anecdotal and retrospective. As such, there is an immediate need for well-designed, disease-specific trials for treatment of relapse after alloHSCT. This report summarizes current treatment options under investigation for relapse after alloHSCT in a disease-specific manner. In addition, recommendations are provided for specific areas of research necessary in the treatment of relapse after alloHSCT.

PR1 peptide vaccine induces specific immunity with clinical responses in myeloid malignancies

PR1, an HLA-A2-restricted peptide derived from both proteinase 3 and neutrophil elastase, is recognized on myeloid leukemia cells by cytotoxic T lymphocytes (CTLs) that preferentially kill leukemia and contribute to cytogenetic remission. To evaluate safety, immunogenicity and clinical activity of PR1 vaccination, a phase I/II trial was conducted. Sixty-six HLA-A2+ patients with acute myeloid leukemia (AML: 42), chronic myeloid leukemia (CML: 13) or myelodysplastic syndrome (MDS: 11) received three to six PR1 peptide vaccinations, administered subcutaneously every 3 weeks at dose levels of 0.25, 0.5 or 1.0u2009mg. Patients were randomized to the three dose levels after establishing the safety of the highest dose level. Primary end points were safety and immune response, assessed by doubling of PR1/HLA-A2 tetramer-specific CTL, and the secondary end point was clinical response. Immune responses were noted in 35 of 66 (53%) patients. Of the 53 evaluable patients with active disease, 12 (24%) had objective clinical responses (complete: 8; partial: 1 and hematological improvement: 3). PR1-specific immune response was seen in 9 of 25 clinical responders versus 3 of 28 clinical non-responders (P=0.03). In conclusion, PR1 peptide vaccine induces specific immunity that correlates with clinical responses, including molecular remission, in AML, CML and MDS patients.

Rapid rate of peripheral blood blast clearance accurately predicts complete remission in acute myeloid leukemia.

Rapid rate of peripheral blood blast clearance accurately predicts complete remission in acute myeloid leukemia

New drug approvals in acute myeloid leukemia: what's the best end point?

The US Food and Drug Administration requires proof of clinical benefit before granting approval to new drugs for treatment of neoplasms such as acute myeloid leukemia (AML). Clinical benefit, in this context, is defined as improvement in length and/or quality-of-life (QoL) or in validated surrogates for these end points. Although several drugs have been approved in the last 3 years for other leukemias including chronic myeloid leukemia, chronic lymphocytic leukemia and acute lymphoblastic leukemia, new drug approvals for AML have lagged. The overwhelming reason is failure to develop new, effective AML therapies. We cannot identify a drug whose Food and Drug Administration approval would have markedly changed the prognosis of most persons with AML. Nonetheless, some AML experts believe a greater emphasis on end points other than survival would facilitate drug development and approvals in AML. We discuss pros and cons of other potential end points for trials of new drugs for AML in light of distinctive disease characteristics, which complicate straightforward consideration of end points. An example is the demanding nature of AML therapy raising questions, particularly in older persons, about the magnitude of better survival and the proportion of persons benefitting needed to justify this demand. Other considerations include the efficacy of rescue (salvage) therapies after failure of initial therapy, especially allogeneic hematopoietic cell transplants and improvements in prevention and treatment of fungal and other infections, important causes of death in persons with AML. These rescue strategies and improvements in supportive care act to dissociate survival after AML therapy from surrogates such as event-free survival (EFS). Moreover, efficient access to blood and bone marrow samples allows identification of many cytogenetic and molecular subgroups of AML and provides sensitive, albeit imperfect ways to quantify residual leukemia cells in persons in histological complete remission. These developments raise the possibility of approving a new drug in only a subset of persons with AML and/or of using measurable residual disease (MRD) testing as a surrogate end point. However, despite these many advances and considerations we conclude no current end point for approving drugs in AML is entirely satisfactory.

The proportion of CD34 + CD38 low or neg myeloblasts, but not side population frequency, predicts initial response to induction therapy in patients with newly diagnosed acute myeloid leukemia

The proportion of CD34 + CD38 low or neg myeloblasts, but not side population frequency, predicts initial response to induction therapy in patients with newly diagnosed acute myeloid leukemia

Prediction of CR following a second course of '7+3' in patients with newly diagnosed acute myeloid leukemia not in CR after a first course.

Prediction of CR following a second course of ‘7+3’ in patients with newly diagnosed acute myeloid leukemia not in CR after a first course

The treatment-related mortality score is associated with non-fatal adverse events following intensive AML induction chemotherapy

The treatment-related mortality score is associated with non-fatal adverse events following intensive AML induction chemotherapy

Relative survival following response to 7 + 3 versus azacytidine is similar in acute myeloid leukemia and high-risk myelodysplastic syndromes: an analysis of four SWOG studies

Here we quantify and compare the absolute and relative overall survival (OS) benefits conveyed by complete remission (CR) in AML and high-risk MDS, and by CR with incomplete count recovery (CRi) in AML and by hematologic improvement (HI) in MDS, following treatment with 7u2009+u20093 versus azacytidine. We compared patients receiving 7u2009+u20093 in SWOG studies S0106 (nu2009=u2009301) and S1203 (nu2009=u2009261) enrolling adults ≤u200960 years, with patients receiving azacytidine therapies in S0703 (nu2009=u2009133 AML patients ≥u200960) and S1117 (nu2009=u2009277 MDS patients ≥u200918). Absolute survival benefit was evaluated with 1-year, 3-year, and median OS; relative benefit was evaluated with univariate and covariate-adjusted hazard ratios. CR conveyed a relative survival advantage in multivariable analysis, with a similar relative effect of CR across studies. CR also conferred an absolute survival benefit, but with a smaller magnitude of absolute benefit in the azacytidine trials. In AML, OS was similar for CRi and failure to achieve CR/CRi. In MDS, CR conferred a survival advantage versus HI and HI versus failure. The relative survival benefit of CR was similar regardless of initial therapy for AML or high-risk MDS. With both therapies, CR has a beneficial effect on survival compared with CRi or HI.

New drug approvals in acute myeloid leukemia: what|[rsquo]|s the best end point|[quest]|

The US Food and Drug Administration requires proof of clinical benefit before granting approval to new drugs for treatment of neoplasms such as acute myeloid leukemia (AML). Clinical benefit, in this context, is defined as improvement in length and/or quality-of-life (QoL) or in validated surrogates for these end points. Although several drugs have been approved in the last 3 years for other leukemias including chronic myeloid leukemia, chronic lymphocytic leukemia and acute lymphoblastic leukemia, new drug approvals for AML have lagged. The overwhelming reason is failure to develop new, effective AML therapies. We cannot identify a drug whose Food and Drug Administration approval would have markedly changed the prognosis of most persons with AML. Nonetheless, some AML experts believe a greater emphasis on end points other than survival would facilitate drug development and approvals in AML. We discuss pros and cons of other potential end points for trials of new drugs for AML in light of distinctive disease characteristics, which complicate straightforward consideration of end points. An example is the demanding nature of AML therapy raising questions, particularly in older persons, about the magnitude of better survival and the proportion of persons benefitting needed to justify this demand. Other considerations include the efficacy of rescue (salvage) therapies after failure of initial therapy, especially allogeneic hematopoietic cell transplants and improvements in prevention and treatment of fungal and other infections, important causes of death in persons with AML. These rescue strategies and improvements in supportive care act to dissociate survival after AML therapy from surrogates such as event-free survival (EFS). Moreover, efficient access to blood and bone marrow samples allows identification of many cytogenetic and molecular subgroups of AML and provides sensitive, albeit imperfect ways to quantify residual leukemia cells in persons in histological complete remission. These developments raise the possibility of approving a new drug in only a subset of persons with AML and/or of using measurable residual disease (MRD) testing as a surrogate end point. However, despite these many advances and considerations we conclude no current end point for approving drugs in AML is entirely satisfactory.