Tobias Polak

The clinical value of drugs under development in hematological malignancies 51 3♣ Although provision of drugs in phase II through expanded access is less common than drugs that are under investigation in phase III,3 the positive presentation of early-phase drugs may prompt physicians to consider requesting expanded access to phase II drugs as well. Based on our findings, we recommend physicians to exercise caution when requesting expanded access on the basis of positive poster presentations in phase II. The initial enthusiasm surrounding these therapies may be overstated, as they do not always result in consistent positive outcomes in peer-reviewed research,4 and frequently are not associated with initiation of a phase III trials. Although there may be other reasons than lack of clinical benefit to dismiss a phase III trial, the absence of progression can be viewed as an indirect measure of the new drug’s potential and, consequently, its suitability for expanded access. On the other hand, we will see in the next chapter that drugs that initially fail a first phase II trial are not by definition ‘ineffective’. They may subsequently successfully complete a different phase II trial aimed at a different line of therapy or a different patient population. THE CLINICAL BENEFITS OF DRUGS DEVELOPED FOR ACUTE MYELOID LEUKEMIA Next, we focused on a single disease in hematology, to better be able to compare novel drugs under development. In line with evaluating the predictive value of ‘positive’ conclusions for progression of a drug through phase II to phase III, we here evaluated if and how novel agents progressed from phase II to phase III to FDA approval, and in addition evaluated the clinical benefit these drugs using specialized disease benefit scales. We focused on the hematological malignancy of acute myeloid leukemia (AML). Research – and expanded access - in hematology is primarily devoted to studying treatments for hematological malignancies, rather than benign conditions (e.g., anemia, sickle cell disease), and AML is a hematological malignancy with a high disease burden: the 5-year overall survival rate is 28%.5 This percentage is even lower for elderly patients, who are unable to qualify for stem cell therapy, the only curative treatment. Until 2016, the only approved treatment options for AML were chemotherapy and stem cell transplantation, which consistently induce serious and sometimes life-threatening toxicities.6 Moreover, despite intensive therapy, most patients eventually relapse, and subsequently have very dismal survival rates.7 Since the remarkable discovery of imatinib for chronic myeloid leukemia,8 hopes for more successful targeted therapies to treat other hematological malignancies have skyrocketed. Although AML is not characterized by a single genetic aberration such as chronic myeloid leukemia, myeloid cells express various targetable proteins which has led to a surge in development of targeted

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