Validity of Inclusion/Exclusion Criteria in Clinical Trials for Myelofibrosis and the Need for Expanded Access Programs [More Expanded Access Programs Are Needed to Assess the Impact of Comorbidity and Comedication in Patients with Myelofibrosis]

There are limited options in the treatment of myelofibrosis with currently no licensed pharmaceutical agent in Germany. In addition to off-label treatment with hydroxyurea and similar drugs, participation in a clinical trial or a compassionate use program remain an important alternative for many patients (pts). In order to participate in one of these trials, pts usually have to stand the test of a long list of inclusion/exclusion criteria which in many cases prevents participation.

The aim of our analysis was to investigate the reasons for which pts were not eligible for phase 2 and phase 3 clinical trials for myelofibrosis.

Clinical data of 21 pts presenting in our clinic during the past year were evaluated regarding six different clinical study protocols (phase II-III). Four of them were active and open for enrollment during this time (NCT01437787, NCT00949364, NCT01178281, NCT01493414) and two trials were screened retrospectively having had a major impact in this field (NCT00952289, NCT00934544). Inclusion/exclusion criteria as reported at http://www.clinicaltrials.gov were split into 6 different categories (specific disease criteria, non-hematologic laboratory abnormalities [serum chemistry/coagulation], hematologic laboratory abnormalities, patients« performance status, concomitant disease, and concomitant medication). Each patient was evaluated with respect to each trial. The Cumulative Illness Rating Scale (CIRS), a tool to measure comorbidity, measuring the chronic medical illness burden while taking into account the severity of chronic diseases, was used for quantification of pts comorbidities.

While a watch-and-wait strategy was indicated in two of 21 pts according to ELN Guidelines [Barbui et al JCO 2011], treatment was indicated in 19 of these 21 pts. Each of these 19 pts demonstrated a median of five (range: 0 – 16) criteria that prevented this patient from entering one of the trials, each patient being potentially eligible for a median of 2 trials (range 0–6). Only one patient could have been included in all of the trials, 14 pts. could have entered at least one trial. In table 1, the number of patients missing participation per protocol and category is listed. Summarizing all protocols, the most common reasons for ineligibility were specific disease criteria (not yet in need of transfusions, low Cervantes Score, etc) (37% of patients), concomitant diseases (23%), concomitant medication (10%), non-hematological laboratory abnormalities (17%), hematological abnormalities (12%) while a poor performance status prohibited enrollment only in one case (1%).

As most patients with myelofibrosis in need of treatment are older than 60 years and therefore are more likely to have concomitant diseases (the median CIRS Score of all patients was 7 (range 1–12) with an average of 4. 2 concomitant pharmaceuticals per person, some trials may miss the patient population in urgent need for improvement of therapeutic strategy. Surprisingly, only 2 pts were excluded for both reasons (concomitant disease and concomitant medication) from the same trial, implying that the concomitant medication itself seems to exclude candidates.

In our series, 74% of pts with myelofibrosis failed to meet the formal inclusion/exclusion criteria of six clinical trials evaluating JAK inhibitors or IMIDs. Since some drug combinations may raise concerns about patients' safety, more expanded access clinical trials are needed to provide specific data on drug interactions and the impact of specific disease comorbidities in order to allow a critical and quantifiable assessment of the risks and benefits of treatment in this patient population.

Brümmendorf:Bristol Myer Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Patent on the use of imatinib and hypusination: Patents & Royalties. Koschmieder:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel support, Grant support Other; Novartis Foundation: Support of Professorship at Aachen university, Support of Professorship at Aachen university Other; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel support, Grant support, Travel support, Grant support Other; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, Travel support, Travel support Other; Celgene: Honoraria, Speakers Bureau, Travel support Other; Shire: Honoraria, Speakers Bureau, Travel support, Travel support Other; Glaxo Smith Kline: Honoraria, Speakers Bureau, Travel support Other.