Teresa Zyczynski

The role of observational studies in optimizing the clinical management of chronic myeloid leukemia

Survival has increased dramatically for patients with chronic phase chronic myeloid leukemia (CP-CML) using BCR-ABL targeted tyrosine kinase inhibitors, such that life expectancy is expected to approximate that of patients without CP-CML. Randomized controlled trials (RCTs) and observational studies provide valuable insights into the management of chronic diseases such as CP-CML. RCTs are undoubtedly the backbone of clinical research, and the ‘gold standard’ for evaluating the efficacy and safety of new therapies. However, many questions surrounding the optimal management of patients with CML remain unanswered, and it is widely accepted that these questions will be best answered by evaluating the use of available therapies in clinical practice. Observational studies can extend the knowledge base beyond the clinical trial setting and thus capture a more accurate picture of everyday clinical practice, particularly patients’ experiences of long-term CML treatment. There is therefore growing interest in and appreciation of the value of observational research. This review article will examine the relative merits of RCTs and observational studies in the setting of CML, highlighting those factors – such as the advancing age of the CML patient population and growing importance of patient-reported outcomes – that mean that observational studies should play an important role in shaping clinical practice. This article also provides an overview of what observational studies have told us thus far about the optimal management of patients with CML, outlines some of the key remaining unanswered clinical questions in CML, and summarizes ongoing observational studies designed to provide answers to these key questions.

First-line treatment selection and early monitoring patterns in chronic phase-chronic myeloid leukemia in routine clinical practice : SIMPLICITY

Achieving successful outcomes in chronic phase‐chronic myeloid leukemia (CP‐CML) requires careful monitoring of cytogenetic/molecular responses (CyR/MR). SIMPLICITY (NCT01244750) is an observational study exploring tyrosine kinase inhibitor use and management patterns in patients with CP‐CML receiving first‐line imatinib (n = 416), dasatinib (n = 418) or nilotinib (n = 408) in the US and 6 European countries in routine clinical practice. Twelve‐month follow‐up data of 1242 prospective patients (enrolled October 01 2010‐September 02 2015) are reported. 81% of patients had baseline comorbidities. Treatment selection was based on perceived efficacy over patient comorbidity profile. There was a predominance of imatinib‐treated patients enrolled earlier in the study, with subsequent shift toward dasatinib‐ and nilotinib‐treated patients by 2013/2014. Monitoring for either CyR/MR improved over time and was documented for 36%, 82%, and 95% of patients by 3, 6, and 12 months, respectively; 5% had no documentation of CyR/MR monitoring during the first year of therapy. Documentation of MR/CyR testing was higher in Europe than the US (P < .001) and at academic versus community practices (P = .001). Age <65 years, patients being followed at sites within Europe, those followed at academic centers and patients no longer on first‐line therapy were more likely to be monitored by 12 months. SIMPLICITY demonstrates that the NCCN and ELN recommendations on response monitoring have not been consistently translated into routine clinical practice. In the absence of appropriate monitoring practices, clinical response to TKI therapy cannot be established, any needed changes to treatment strategy will thus not be implemented, and long‐term patient outcomes are likely to be impacted.

Predictors of performing response monitoring in patients with chronic-phase chronic myeloid leukemia (CP-CML) in a prospective observational study (SIMPLICITY).

116 Background: Previous SIMPLICITY data (ASCO 2014) have shown, in CP-CML patients (pts) with at least 12 months (mths) follow-up, monitoring for cytogenetic response (CyR) and molecular response (MR) differs from NCCN/ ELN recommendations and shows regional and practice-type variation. Few data describe predictors of monitoring. METHODS SIMPLICITY is an ongoing observational study of CP-CML pts receiving first-line (1L) imatinib (IM), dasatinib (DAS) or nilotinib (NIL) in the United States (US) and Europe (Eu); its primary objective is to understand tyrosine kinase inhibitor (TKI) management patterns in clinical practice (NCT01244750). Frequency of testing for CyR, by FISH or karyotype, and MR, by PCR, were analyzed in 3, 6 and 12 mth increments from TKI start. Stepwise multivariable logistic regression was performed to assess predictors of monitoring (including: age, sex at birth, region, practice type, 1L TKI, ECOG performance status, still on 1L TKI). RESULTS 1,083 pts (US: 66%; Eu: 34%) were enrolled prospectively through 1Apr2014, receiving IM (n=415), DAS (n=343) or NIL (n=325). 1,050, 985 and 862 pts were followed for at least 3, 6 and 12 mths, respectively. Of these, 15%, 34% and 49% were tested for CyR, and 27%, 65% and 83% were tested for MR, between 0-3 mths, 0-6 mths and 0-12 mths. By 3 mths, 33% had either CyR and/or MR testing and 88% of pts underwent testing by 12 mths. None of the candidate predictors distinguished between pts who were monitored vs. those that were not by 3 mths after start of 1L TKI. Pts <65 years (yrs) at start of 1L TKI (odds ratio [OR]=1.41) and those in Eu vs. US (OR=1.45) were more likely to be monitored by 6 mths. By 12 mths, pts <65 yrs (OR=2.27), those no longer on 1L TKI (OR=1.96), and those seen in academic centers (OR=1.59) were more likely to be monitored (all p<.05). A comparison of monitoring patterns with ELN/NCCN recommendations will also be presented. CONCLUSIONS Two-thirds of pts were not monitored for CyR or MR within 3 mths of TKI start.Although there were no predictors of monitoring for CyR or MR by 3 mths, age <65 yrs at initiation of 1L TKI was a consistent predictor of monitoring by 6 and 12 mths. CLINICAL TRIAL INFORMATION NCT01244750.

Impact of elotuzumab treatment on pain and health-related quality of life in patients with relapsed or refractory multiple myeloma: results from the ELOQUENT-2 study

Treatment of relapsed/refractory multiple myeloma (RRMM) aims to prolong survival while maintaining health-related quality of life (HRQoL) by managing disease-related symptoms and complications—one of the most frequent and debilitating being bone pain. In the ELOQUENT-2 study (NCT01239797), which evaluated the addition of elotuzumab to lenalidomide plus dexamethasone versus lenalidomide plus dexamethasone, pain and HRQoL were assessed in patients with relapsed/refractory disease using the Brief Pain Inventory–Short Form (BPI-SF) and the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–Core 30 module (QLQ-C30) and myeloma-specific module (QLQ-MY20). Mean baseline pain scores were low and remained so throughout treatment with both regimens; mean HRQoL scores did not change substantially from baseline. A significantly higher proportion of patients with objective response than without had clinically meaningful improvements in worst pain over two consecutive treatment cycles (29 versus 12%; p < 0.001). Patients with very good partial response (VGPR) or better reported reduced scores for pain severity and worst pain; those with progressive disease reported increased scores for these domains and pain interference. These findings show that previously reported improvements in progression-free survival and response rate with elotuzumab are achieved without detriment to HRQoL, which is maintained over time.

Cell-type-specific transcriptional regulation of PIGM underpins the divergent hematologic phenotype in inherited GPl deficiency.

A rare point mutation in the core promoter -270GC-rich box of PIGM, a housekeeping gene, disrupts binding of the generic transcription factor (TF) Sp1 and causes inherited glycosylphosphatidylinositol (GPI) deficiency (IGD). We show that whereas PIGM messenger RNA levels and surface GPI expression in IGD B cells are low, GPI expression is near normal in IGD erythroid cells. This divergent phenotype results from differential promoter chromatin accessibility and binding of Sp1. Specifically, whereas PIGM transcription in B cells is dependent on Sp1 binding to the -270GC-rich box and is associated with lower promoter accessibility, in erythroid cells, Sp1 activates PIGM transcription by binding upstream of (but not to) the -270GC-rich box. These findings explain intact PIGM transcription in IGD erythroid cells and the lack of clinically significant intravascular hemolysis in patients with IGD. Furthermore, they provide novel insights into tissue-specific transcriptional control of a housekeeping gene by a generic TF.

Tyrosine Kinase Inhibitor Interruptions, Discontinuations and Switching in Patients with Chronic-Phase Chronic Myeloid Leukemia in Routine Clinical Practice: SIMPLICITY

SIMPLICITY (NCT01244750) is an observational study exploring tyrosine kinase inhibitor (TKI) use and management patterns in patients with chronic phase‐chronic myeloid leukemia in the US and Europe in routine clinical practice. Herein we describe interruptions, discontinuations and switching of TKI therapy during the initial 2 years of treatment among 1121 patients prospectively enrolled between October 1, 2010 and March 7, 2017. Patient characteristics were broadly similar between the imatinib (n = 370), dasatinib (n = 376), and nilotinib (n = 375) cohorts. Treatment interruptions occurred in 16.4% (year 1) and 4.0% (year 2) of patients, mainly attributed to hematologic intolerances. Treatment discontinuations occurred in 21.8% (year 1) and 10.2% (year 2) of patients, with the highest rate within the first 3 months for intolerance. Switching of TKI was seen in 17.8% (year 1) and 9.5% (year 2) of patients. Significant associations were found between TKI switching and female gender (year 1), age ≥65 years at diagnosis (year 2) and treatment with imatinib (year 2). Intolerance was the most common reason given for patients discontinuing and for switching TKI therapy; however resistance was also cited. Lack of response monitoring in routine clinical practice may have resulted in lower identification of resistance in this dataset. Data from SIMPLICITY suggest that, in routine clinical practice, intolerance and resistance to TKIs influence decisions to change treatment. Changes in TKI therapy are frequent, with nearly a third of patients discontinuing their first‐line TKI.