Trials In Chronic Myeloid Leukemia Research Articles

Spotlight on the real-world treatment of CML pts in Germany: a retrospective survey in private oncology practices

Clinical trials in chronic myeloid leukemia (CML) are usually carried out in specialized centers whereas primary care for patients (pts) with CML is mainly provided by local oncology practices. The aim of this study was to assess treatment practices in pts with CML in the setting of private oncology practices in Germany. We collected data of 819 pts with a confirmed diagnosis (dx) of CML in 2013 or later from 43 practices. At dx, 84.2% (n=690) and 9.4% (n=77) of pts were in chronic or accelerated phase, 0.7% (n=6) had a blast crisis. Molecular monitoring was provided by EUTOS certified laboratories in 87.7% of pts. Typical BCR::ABL1 transcripts were detected in 86.6% (n=709). Molecular response was assessed after 2.8, 6.0, 9.4 and 12.9 m (mean) after start of treatment. Of the pts with available data, 11.1% did not achieve early molecular response and at 18 m, 83.7% had at least a major molecular response. 288 (35.2%) of pts switched to 2nd line (2L) treatment after a mean of 21.0 months. Reasons for 2L treatment were side effects in 43.4% and suboptimal response or failure in 31.4% of pts. 106 pts went on to third line (3L) treatment. 36.8 % of pts switched to and 92.8 % of pts still on 3L treatment achieved BCR::ABL1IS ≤1% at 12 m. In conclusion, in Germany pts with CML are routinely monitored by qPCR and good responses are achieved in the majority. Treatment changes are mainly due to adverse events rather than suboptimal responses.

The Contemporary Role of Hematopoietic Stem Cell Transplantation in the Management of Chronic Myeloid Leukemia: Is It the Same in All Settings?

Hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) patients has transitioned from the standard of care to a treatment option limited to those with unsatisfactory tyrosine kinase inhibitor (TKI) responses and advanced disease stages. In recent years, the threshold for undergoing HSCT has increased. Most CML patients now have life expectancies comparable to the general population, and therefore, the goal of therapy is shifting toward achieving treatment-free remission (TFR). While TKI discontinuation trials in CML show potential for achieving TFR, relapse risk is high, affirming allogeneic HSCT as the sole curative treatment. HSCT should be incorporated into treatment algorithms from the time of diagnosis and, in some patients, evaluated as soon as possible. In this review, we will look at some of the recent advances in HSCT, as well as its indication in the era of aiming for TFR in the presence of TKIs in CML.

An evaluation of ponatinib as a therapy in adult patients with resistant/intolerant chronic-phase chronic myeloid leukemia

Introduction: Chronic myeloid leukemia is now a highly treatable leukemia due to the availability of multiple tyrosine kinase inhibitors (TKIs) inhibiting the BCR-ABL1 oncogene. Some patients with CML can display resistance or intolerance to multiple TKIs, oftentimes due to the presence of mutations in BCR-ABL1, such as T315I, which limits effective treatment options. Ponatinib is a third-generation, rationally-designed TKI with clinically meaningful activity in this difficult-to-treat population. Ponatinib is associated with an increased risk of arterial occlusive events (AOEs) which has required a re-examination of its dosing in order to limit the risk of these events. Areas covered: This review will provide an overview of the mechanism of action of ponatinib and the safety and efficacy data from clinical trials in chronic myeloid leukemia Expert opinion: Ponatinib is a potent pan-BCR-ABL1 TKI with substantial activity in patients with more resistant or advanced CML. Its efficacy needs to be balanced with the increased risk of vascular events, which seems to be at least partially diminished by the implementation of mitigation strategies aimed at modifying cardiovascular risk factors and adaptive dosing of the drug.

Disovery of Novel Mutations Exclusively Shared By Accelerated and Blast Crisis Phase CML Patients Using Whole Exome Sequencing:Implication in Hunt for Common Biomarker /Drug Target of CML Progression

Introduction:Chronic Myeloid Leukemia (CML) is resulted due t (9;22) which leads to fusion oncogene BCR-ABL. Although chronic phase (CP) CML is treatable, accelerated (AP) and blast phases (BP) have high degrees of drug resistance and subsequent treat failures 1. Mechanism of this disease progression in CML is poorly understood and few markers studied in this regard are found only in a subset of advanced phase CML patients 2,3. Therefore, this study was designed to find out common gene mutations (trunk mutations) associated with all advanced phase CML patients.Material and Methods:We investigated imatinib responder AP (N=13), BC (10) and CP (5) CML patients along with age-sex matched healthy controls using whole exome sequencing (WES). Illumina NGS instrument (HiSeq) generated bcl files which were converted to fastq files by using bcl2fastqtool 4. Raw reads were aligned to genome using BWA tools while whole exome variants were annotated using Illumina Variant Studio 4. R package was employed to align specific gene mutants to disease phases 5. In order find a common CML progression biomarkers, gene mutations shared by all patients at a CML phase (so called trunk mutations) were selected and confirmed using Sanger sequencing.Results:Whole exome sequencing revealed novel gene mutations associated with different disease phases in CML. CP CML patients with long term CML response harbored mutations in TTN, PDLIM4, CELF2, ANO5, DOK2, MYO16, RAI1, LTBP3, CNNM3. On the other hand, specific genes were found mutated in AP (EV15L, FAM120B, ZNF208, PML, TMEM145, ASXL1, ABL1) and BC (ATXN3)CML patients.Discussion & Conclusions:All the genes mutated in AP and BC CML were either involved in other cancers or cellular processes like DNA repair, regulation of gene expression (for instance ATXN3 gene mutated in all BC-CML is involved in DNA repair and in repressing expression of some other genes6 which indicates role of damaged DNA repair in CML blast crisis). Mutations in long term CML responders indicate role of all are some of these genes in relation to sensitivity to tyrosine kinase inhibitors (TKIs). Very recently, it has been reported that CML patients with rs460089-GC (SLC22A4) genotype had stable major molecular response 7. Biomarkers of stable response can help identify patients who can be the candidates of cessation of TKIs which is one of the major focus of many CML trials. Identification of biomarkers of early CML progression can help identify and clinically intervene patients at high risk of transformation to advanced and blast phases of CML which can considerably minimize morbidities and mortalities associated with CML patients 2,3.

Horn of plenty: Value of the international registry for pediatric chronic myeloid leukemia.

Chronic myeloid leukemia (CML) in minors is a rare disease which can be effectively treated by tyrosine kinase inhibitors (TKIs) since the year 2000. A majority of pediatricians will encounter one or two CML patients in the course of their careers and will typically have to rely on written information along with their own intuition to provide care. Knowledge of response to TKIs and of age-specific side effects has an impact on the design of pediatric CML trials in many ways aiming to contribute toward greater predictability of clinical improvements. Information from a registry on a rare disease like CML offers the enormous benefit of enabling treating physicians to interact and share their collective experience. The International Registry on Pediatric CML (IR-PCML) was founded at Poitiers/France almost 10 years ago. Since then, the number of collaboration centers and in parallel of registered patients continuously increased (> 550 patients as of December 2019). Ideally, from a given treatment center in a country data are transferred to a national coordinator who interacts with the IR-PCML. In the sense of quality assurance, the registry can offer dissemination of knowledge on state-of-the-art diagnostics (including reference appraisal), optimal treatment approaches, and follow-up procedures within a network that is exerting its strength via participation. With continuous growth during the recent years, very rare subgroups of patients could be identified (e.g., CML diagnosed at age < 3 years, children presenting with specific problems at diagnosis or during course of treatment) which had not been described before. Publications coming from the IR-PCML disseminated this useful information derived from patients who robustly participate and share information about their disease, among themselves and with their caregivers and clinicians. Patient input driving the collection of data on this rare leukemia is the basis for the considerable success of bringing new therapeutics into clinical use.

Cardiovascular events in chronic myeloid leukemia clinical trials. Is it time to reassess and report the events according to cardiology guidelines?

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML). Although these treatments have changed the natural course of CML and many other cancers, they may cause cardiovascular and/or metabolic complications. In this review, we discuss how overlooking the main drivers of cardiovascular events (CVEs) and lack of standard definitions for cardiovascular adverse events might have affected these event rates in CML trials. Methodological limitations that affect the available data are discussed, with an emphasis on the future direction of cardiovascular safety research in trials of investigational drugs in cancer treatment.

Tyrosine Kinase Inhibitors in the Treatment of Chronic-Phase CML: Strategies for Frontline Decision-making.

Over the past two decades, the introduction of tyrosine kinase inhibitors (TKIs) has transformed the treatment of chronic myeloid leukemia (CML). With four agents currently approved for frontline use in chronic-phase (CP) disease, it follows that treatment decision-making has been rendered more challenging. Here we will review recent advances that help inform the selection of a first-line TKI. Extended follow-up of the seminal CML trials has demonstrated the long-term efficacy of TKIs, while also highlighting significant differences in their respective toxicity profiles and potency. Dasatinib and nilotinib generate deeper molecular responses than imatinib, particularly among patients with higher risk disease, but this has not translated into a significant survival advantage. Similar results have been obtained at 1year with bosutinib; its efficacy and toxicity were well balanced at a dose of 400mg daily, prompting its recent approval for this indication. Lastly, multiple studies have demonstrated that TKIs can be safely discontinued in select individuals who have maintained deep responses for extended periods, establishing treatment-free remission as a novel goal in CP CML. The careful consideration of parameters such as disease risk, the potency, and toxicity profile of each TKI, as well as each patient's unique comorbidities and preferences, enables truly individualized therapeutic decision-making in CP CML, with the goal of ensuring that a high quality of life accompanies the survival advantage conferred by these agents.

Enrollment of Older Adults in Clinical Trials Evaluating Patients with Hematologic Malignancies - the Food and Drug Administration (FDA) Experience

▪Background: The majority of hematologic malignancies are most frequently diagnosed in patients over 65 years of age (1). However, older adults are underrepresented in clinical trials evaluating new cancer therapies (2). This analysis quantifies age related enrollment in trials evaluating patients with hematologic malignancies submitted to FDA in support of drug approval.Methods: We retrospectively analyzed demographic datasets of patients enrolled to trials submitted to FDA in support of approval of new or supplemental indications for hematologic cancer therapies from 2005-2015. Patients enrolled in trials for hematologic malignancies were grouped into disease categories based on the diagnosis specified for trial entry and analyzed according to age distributions of <65, 65-74 and ≥ 75 years. The rates of enrollment for patients with chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), multiple myeloma (MM) and lymphomas (Hodgkin's and non-Hodgkin's lymphoma excluding CLL) were compared with the age distribution of incidence cases by site derived from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute 2010-2014 (1).Results: We identified a total of 44,144 patients enrolled in clinical trials evaluating hematologic malignancies. Forty five percent (19908) of the patients were enrolled in lymphoma trials, 24% (10465) in chronic myeloid leukemia (CML) trials, 22% (9605) in multiple myeloma (MM) trials, 2% (1052) in acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) trials and 6% were enrolled in trials classified as “other” (includes myeloproliferative neoplasms and trials enrolling multiple malignancies). Less than 1% (403) of patients were enrolled in acute lymphoblastic leukemia (ALL) trials. Greater than 50% of the patients with the exception of those enrolled in CLL and AML/MDS trials were <65 years of age. Greater than 85% of the participants in ALL trials were < 65 years of age.Compared to the U.S cancer population, clinical trials for lymphomas, CLL, CML and MM enrolled a disproportionately higher percentage of patients <65 years of age (Table 2). For participants ≥65 years in the lymphoma and CML trials, enrollment in the 65-74 year old age group was lower than the SEER incidence cases (24.6% versus 23.1% for lymphoma and 16.5% versus 20.7% for CML respectively); but the difference was less than 5%. CLL and MM trials enrolled a higher percentage of patients in the 65-74 year old age group compared with the SEER data. Patients ≥75 years of age were consistently underrepresented in lymphoma, CLL, CML and MM trials compared to the SEER incidence cases in the same age group. The greatest difference was seen for patients in CML trials: only 3.8% were ≥75 years of age compared with SEER incidence of 28.6%.Conclusion: Older adults 65-74 years of age were adequately represented in hematologic malignancy trials submitted to support approval of new or supplemental indications of cancer therapies. Despite a high number of incident cases diagnosed in this age group, adults ≥ 75 years of age were disproportionately underrepresented in malignant hematology clinical trials. The FDA has encouraged sponsors to design trials to enroll patients who are representative of their intended population. Additional strategies to increase clinical trial participation may be needed to enhance the quantity and quality of information needed to treat adults ≥75 years of age and provide an appropriate benefit-risk profile in the population that is likely to receive the treatment. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Nationwide Observational Study of the Israeli Experience with Ponatinib Outside Clinical Trials in Chronic Myeloid Leukemia

Ponatinib is an oral tyrosine kinase inhibitor (TKI) that has been designed to be effective also in patients who harbor the TKI-refractory threonine to isoleucine mutation at position 315 (T315I). In December 2014 the drug was granted an accelerated approval by the FDA, based on the promising results from the phase II PACE (Ponatinib Ph ALL and CML evaluation) trial. In this trial, 56% of previously treated patients who had resistance to or unacceptable side effects from dasatinib or nilotinib achieved a major cytogenetic response, including 70% of patients with the T315I mutation. Albeit the PACE trial convincingly demonstrated the efficacy of ponatinib, the wide use of the drug has been limited due to safety matters and in particular arterial thrombotic complications, reported in up to 17% of patients. Currently, there is very little real-life information regarding the use of ponatinib outside of clinical trials. The purpose of this study is to characterize patients with chronic myeloid leukemia (CML) who received ponatinib and to assess the effectiveness and safety profile of ponatinib outside of clinical trials.Between 4.2011 and 7.2015 (51 months) 24 patients with CML received ponatinib in 7 medical centers in Israel. We reviewed the medical records of these patients and asked their physicians to rank the quality of life of their patients on a 1 to 5 scale.Prior to ponatinib therapy, patients were treated for a median of 55 months (range: 1 to 215) with 1 to 3 different TKIs (median: 3). In addition 13 patients received at least one course of chemotherapy or interferon and 2 underwent allogeneic bone marrow transplantation.Screening for mutations at the DNA binding domain was performed at least once during the pre-ponatinib follow-up time in most patients (67%, N=16). Mutations were detected in 11 patients (69%) and the T315I mutation was detected in 8 of those.The median age when starting ponatinib was 44 years (rang: 23 to 79). Most patients had advanced disease and their disease was classified as either accelerated (21%, N=5) or blast crisis (41%, N=10) when they started ponatinib. Based on the medical history, 48% were at-risk to develop vascular complications either because of prior cerebrovascular event or myocardial infarction (18%) or because of vascular risk factors (30%). Baseline ECG and cardiac ECHO studies were available in 11 patients. Only two had signs of prior MI in ECG and none had significant structural or functional pathology.At time of analysis the median duration of follow up was 6 months (range <1 to 34 months), 4 patients died and 14 were still receiving ponatinib. Patients discontinued the treatment either because of major cardiovascular events (N=3), severe pancytopenia (N=1), planned bone-marrow transplantation (N=1) or because they were lost to follow-up (N=1). Seventeen patients were available for response assessment at time of analysis and the overall response rate was 77% (N=13). Five of six patients at chronic phase achieved either complete or major molecular response. Eight patients at accelerated phase or at blast crisis (8/11, 72%) achieved either hematological (5/11, 45%) or molecular response (3/11, 27%). Two of those, with hematological response, underwent allogeneic bone marrow transplantation. The median subjective scoring of ponatinib contribution to the quality of life of patients was 2.4 (range 1 to 5). Physicians that gave low scoring mentioned severe weakness, myalgia and cytopenias as a major concern.Conclusions: In real- life setting ponatinib is generally used as a last resort. In our cohort, it was almost exclusively given to patients who experienced failure to previous TKIs. The only exceptions were 2 patients who received ponatinib for suboptimal molecular response and achieved MMR when switched to ponatinib. Only one third of patients tolerated the recommended dose of 45mg. Yet, response rate was still relatively high, suggesting that a daily dose of 30mg might be appropriate.With only 6 months of follow-up we documented 3 cardiovascular events (12%) that prompted discontinuation of the drug and only one patient had a significant prior vascular risk.The high response rate and overall contribution to quality of life in patients with very few alternatives, who already experienced failure of other TKIs, support the use of this treatment for patients with advanced disease. DisclosuresRaanani:Novartis: Other: Advisory Board, Research Funding; BMS: Other: Advisory Board; Ariad: Other: Advisory Board; Pfizer: Other: Advisory Board. Lavie:Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Rozovski:Novartis: Other: Advisory board.

Post hoc analysis of sustained efficacy/tolerability of ≥12 cycles of omacetaxine mepesuccinate in chronic myeloid leukemia (CML).

7066 Background: Subcutaneous omacetaxine mepesuccinate (OMA), a first-in-class cephalotaxine, inhibits protein synthesis independent of Bcr-Abl signaling. It showed clinical activity in 2 phase II, open-label CML trials, 1 in patients with a T315I Bcr-Abl mutation failing imatinib, and 1 in patients failing ≥2 tyrosine kinase inhibitors (TKIs). Methods: This post hoc analysis pooled patients with chronic phase (CP) or accelerated phase (AP) from the 2 trials. 28-day cycles of OMA 1.25 mg/m2BID were given ≤14 days for induction, ≤7 days as maintenance with dose delay/change as needed. Primary endpoints were major cytogenetic response (MCyR) for CP and complete hematologic response (CHR) for AP. Adverse events (AEs) were assessed. Results: Of 108 CP and 51 AP patients from the 2 trials, 31 (29%) CP and 7 (14%) AP patients received ≥12 cycles (Table). At baseline in the ≥12-cycle groups, most CP (median age 59 y) and AP patients (median age 67 y) had received hydroxyurea (17/31, 4/7) and ≥2 TKIs (22/31, 5/7), were not in CHR (22/31, 5/7), and were T315I positive (23/31, 3/7). As of March 31, 2012, 9 CP and 2 AP patients continued OMA treatment. Overall, mean days dosed per cycle were 6.1 for CP, 9.7 for AP; 5.3 and 8.9 at cycle 12. Grade 3/4 AEs occurred in 35/38 patients in this post hoc analysis, most in early cycles; 15/31 CP, 2/7 AP had grade ≥3 AEs first occurring at ≥12 cycles. Across all cycles, most common grade ≥3 AEs were thrombocytopenia (24/31 CP, 5/7 AP), anemia (16/31, 7/7), and neutropenia (17/31, 3/7).Nine patients receiving ≥12 cycles (5/31, 4/7) discontinued, most commonly due to disease progression (n=2). Conclusions: In this post hoc analysis of heavily pretreated CML-CP and CML-AP patients who had failed prior TKI therapy, efficacy was often durable for those who received OMA for ≥12 cycles. Most grade 3/4 AEs were hematologic and declined with time. Support: Teva BPP R and D, Inc. Clinical trial information: NCT00375219, NCT00462943.

Definitions, methodological and statistical issues for phase 3 clinical trials in chronic myeloid leukemia: a proposal by the European LeukemiaNet

AbstractThe treatment policy of chronic myeloid leukemia (CML), particularly with tyrosine kinase inhibitors, has been influenced by several recent studies that were well designed and rapidly performed, but their interpretation is of some concern because different end points and methodologies were used. To understand and compare the results of the previous and future studies and to translate their conclusion into clinical practice, there is a need for common definitions and methods for analyses of CML studies. A panel of experts was appointed by the European LeukemiaNet with the aim of developing a set of definitions and recommendations to be used in design, analyses, and reporting of phase 3 clinical trials in this disease. This paper summarizes the consensus of the panel on events and major end points of interest in CML. It also focuses on specific issues concerning the intention-to-treat principle and longitudinal data analyses in the context of long-term follow-up. The panel proposes that future clinical trials follow these recommendations.

Clinical Trials in Chronic Myeloid Leukemia

The introduction of the tyrosine kinase inhibitor (TKI) imatinib in the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) has substantially improved the outcome of CML patients. Despite the positive results, problems and questions remained. This was the rationale to setup trials for treatment optimization, where imatinib was administered in higher dose and/or in combination with other therapy but where also new and potentially more efficacious second-generation TKI, nilotinib and dasatinib, were investigated. This review summarizes data of recently published first-line studies with the standard treatment imatinib 400 mg as one study arm. Results of randomized comparisons to higher-dose imatinib treatment, nilotinib or dasatinib are discussed. With regard to outcome interpretation, general aspects on statistical issues and endpoint definitions are put into focus. Considering decidedly increased longevity thanks to TKI treatment, future research should include the evaluation of the quality of life (QoL). Relating also to QoL, safe ways of drug discontinuation need to be investigated.

Different Definitions of Progression-Free Survival (PFS) and Event-Free Survival (EFS) May Result In Perceived but Not Real Differences In Long-Term Outcome When Comparing Trials In Chronic Myeloid Leukemia (CML)

AbstractAbstract 672 BackgroundThe favorable results of second generation tyrosine kinase inhibitors (TKIs; nilotinib, dasatinib) in frontline therapy of Philadelphia chromosome (Ph) positive-CML may establish them as new standards in frontline therapy. This depends on the maturing data with the long-term endpoints of PFS and EFS. Different definitions are used to define “progression” and “event” in different studies. This may result in perceived but not real differences in outcomes with various TKIs when comparing trials. In addition, multi-institutional sponsored trial designs may compound the variable definitions: 1) patients taken off study for occurrences other than the defined “progression” or “event” (eg toxicity, intolerance, other) are censored at the time they are off therapy and not coded for progression/event/death once they are off TKI; and 2) such studies have limited capacities to follow up patients for progression/event after they are off drug therapy for more than 30–60 days. Single institutional studies have a potential advantage of continuing to monitor patients for progression/events after they are off the particular protocol TKI. Study AimTo analyze the impact of differences in the definitions of PFS and EFS used in the IRIS, ENEST-nd, DASISION, and M.D. Anderson (MDACC) trials on outcome, when these definitions are applied to patients with newly diagnosed CML treated with TKIs on MDACC studies. Patients and Methods435 patients (July 2000-April 2010) with early chronic phase Ph-positive CML treated with imatinib (n=281), nilotinib (n=78), and dasatinib (n=76)were analyzed for outcome using different definitions. Definitions were: 1) PFS- ENEST: progression = accelerated or blastic phase (AP-BP) on nilotinib/imatinib therapy + CML related death on nilotinib/imatinib therapy or within 30 days off therapy; 2) EFS-IRIS: event = progression to AP-BP on imatinib + death of any cause on imatinib + loss of CHR or major CG response; 3) PFS-DASISION: progression = EFS-IRIS definition + WBC increase to more than 20; deaths are coded on dasatinib and within 60 days off dasatinib; 4) EFS MDACC: event = progression to AP-BP + loss of major CG response +resistance/loss of CHR/lack of achievement of response by ELN criteria + off for toxicity + death from any cause on or off therapy (if not counted prior to death as progression/event). ResultsThe median follow-up is 67 months (2-116). Of the 435 patients treated, 312 (72%) remain on TKI therapy; 123 (28%) were taken off for the following reasons: resistance/loss of response n = 33; blastic phase on TKI therapy n=6; intolerance/toxicity n= 29; other causes n = 55. Reasons off for the latter 55 patients are: lost to follow – up (n=14); non-compliance (n=11); financial issues (n=8): intercurrent illness (n=7); patient choice (n=5); referral to SCT in chronic phase (n=2); and death from non-CML cause (n=8: 1 complications of surgery, 2 old age, 1 CHF, 1 pneumonia, 2 car accident/suicide, 1 cardiac infarction). So far, 33 patients (7.6%) have died; 8 while on TKI therapy (none from CML; detailed earlier); 2 within 60 days off TKIs (1 AML, 1 renal cancer); and 23 off TKIs for > 60 days. Deaths in the latter 23 were from: 10 post resistance/relapse/BP (accounted for as event/resistance at time off TKI); 10 taken off for toxicity/intolerance (censored at time off; 8 deaths later from CML, 1 post SCT, 1 unknown); 4 off for other illness/non-compliance/lost to FU/pt choice (3 deaths later from CML; 1 from other). Thus, of the 33 deaths, only 19 (8 deaths on TKI + 2 deaths within 60 days + 9 off for resistance/relapse/BP) would be counted as progression/events on the IRIS/ENEST/DASISION studies while 14 would be censored at time off TKI. Based on these 4 definitions, the number of progression/events were: PFS-ENEST 26 progressions; EFS-IRIS 40 events; PFS-DASISION 43 progression/events; EFS-MDACC 76 events. The corresponding 5-year PFS EFS rates were 93%, 90%, 89%, and 81%. (Figure) [Display omitted] ConclusionsWith the importance of EFS and PFS in determining whether new TKIs are better than imatinib in frontline therapy, precise and common definitions of these endpoints across randomized clinical trials and single institutional trials are needed. Randomized multi-institutional trials may not collect accurately all events after patients are off TKI therapy for 30–60 days. Disclosures:Kantarjian:Novartis Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding. O'Brien:Novartis: Research Funding; BMS: Research Funding. Kadia:Novartis: Membership on an entity's Board of Directors or advisory committees. Cortes:Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Pfizer: Consultancy.

Dose Changing and Discontinuation of Imatinib In Patients Affected by Philadelphia Positive Chronic Myeloid Leukemia: a Longitudinal Analysis, a Single Centre Experience.

AbstractAbstract 4478 Introduction:Imatinib mesylate (IM) therapy is effective in patients with chronic myeloid leukemia (CML). However, its discontinuation or dose variation in patients who experience sustained molecular response is debated. The possibility of treating patients with an intermittent therapy could also be applied to the second-generation TK-inhibitors. We describe our single institute experience in patients with undetectable levels or in major molecular response of BCR-ABL transcript who reduced or were discontinued from IM therapy. We applied a model for the analysis of longitudinal data to study the BCR/ABL variation according to dose change or discontinuation. Methods:One hundred forty CML patients came to our observation between 1985 and 2009. Among these, 89 patients in chronic phase were eventually treated with IM. Fifty-five patients were treated with IM as naive patients. Each patient's treatment history was subdivided into time periods at constant dosage. Fifty-nine patients were followed-up for a total of 288 periods at constant dosage. At the end of each period, cytogenetic and/or molecular responses were evaluated. Thirty-eight progressions were recorded: 22 molecular, 6 cytogenetic and 10 of both types. The association between progression (molecular, cytogenetic or either) and treatment dose was assessed with the aid of generalized estimating equations (GEE) models, i.e. regression models designed to account for correlation due to repeated measurements over time on the same subject. Ten patients discontinued IM therapy for a period which ranged from three to 60 months, after the patient's individual request and informed consent. Results:We found no association between dose and progression, not even after accounting for period length. Discontinuation of treatment was not associated to an increased risk of progression. No association with a higher risk of progression was found for periods at reduced dosage (<400mg). Four of the 10 patients who discontinued IM are still in complete molecular response and off treatment. Conclusions:It is unclear whether IM can “cure” chronic myeloid leukemia but according to our data this therapy can be safely stopped or its dose varied in patients with complete cytogenetic and major molecular response of up to 18 months. Our experience suggests that withdrawal of IM therapy in CP-CML patients after achievement of a complete molecular response may result in divergent molecular outcomes. The prompt improvement seen after the restart of therapy argues against the development of resistance. The selection of resistant clones after IM exposure, and the emergence of Ph negative clones with secondary cytogenetic abnormalities, are matters of concern, particularly in patients receiving long-term IM. The improved quality of life while off therapy, and the prompt response to restart of IM therapy, suggest that the subset of patients who have sustained complete molecular response may be candidates for a tailored approach to intermittent therapy. We suggest that the same statistical analysis can also be used for other TK-inhibitors that are under study for both retrospective or prospective trials in CML. Disclosures:No relevant conflicts of interest to declare.

Development of Standardized Approaches to Reporting of Minimal Residual Disease Data Using a Reporting Software Package Designed within the European LeukemiaNet (ELN).

Abstract 1619Poster Board I-645 BackgroundQuantitative PCR (qPCR) for fusion transcripts and overexpressed genes is a promising tool for following minimal residual disease (MRD) and detecting early relapse in patients with acute leukemia, and for identifying treatment failure in patients with chronic myeloid leukemia (CML). Its widespread use has, however, to some extent been hampered by differences in data analysis and in presentation. These issues constitute major challenges in the translation of these thoroughly pre-clinically validated assays into multicenter clinical trials. To address these problems we have designed an MRD reporting software package, in which data from the qPCR equipment can be imported, processed, and presented in a standardized fashion to generate a readily comprehensible report. SoftwareThe software builds upon a database with basic patient information and data imported from qPCR runs. The software is highly flexible, and data from a variety of qPCR platforms can be accommodated (Figure 1) when exported from the equipment as tab- or comma-separated files. MRD calculations may be based on both “relative” quantification, i.e. where a diagnostic sample or a cell line is used as reference, as well as “absolute” quantification, where plasmid standards are included as controls (Figure 2). Moreover, while a series of premade report types are available, individualized report generation is also possible. Report types include graphs detailing blood and bone marrow MRD either separately or simultaneously. Moreover, two or three target genes can be displayed within the same graph. QC StudyTo validate the software and provide proof of principle for applicability in multicenter studies we performed a quality control study involving analysis and reporting of multiple blinded leukemic samples by 8 laboratories. cDNA samples representing five consecutive samples from the same CML patient (BCR/ABL+), five from the same AML patient (MYH11/CBFá+, WT1+), as well as a K562 cell line sample were centrally prepared by the Aarhus laboratory. Samples were distributed to the test laboratories together with primer/probe kits from Ipsogen (Ipsogen, Marseilles, France) for the three target genes and the ABL control gene. Each laboratory performed qPCR using their in-house qPCR equipment (including ABI7500, ABI7900 (Applied Biosystems), Mx3000P (Stratagene), or LightCycler 480 (Roche)) and submitted 16 different reports as pdf files for comparison. The reports included relative quantification using the diagnostic sample as reference, relative quantification using cell line as reference, absolute quantification using plasmid standard curves, and lists of calculated MRD values and sensitivities. Excellent concordance in the quality of the reports was observed for all report types. PerspectivesThis software package, which has been distributed to members of the ELN MRD Workpackage, will shortly be made more widely available. The validation procedures outlined above should make this package suitable for general use in translational hematology allowing standardized reporting of MRD results (e.g. use of International Scale in CML trials) and facilitating comparison of results obtained between trial groups. AcknowledgmentWe thank Nicolas Maroc from Ipsogen for providing reagents for the QC Study and Karin Braendstrup and Lone Siig Mikkelsen for excellent technical assistance. [Display omitted] [Display omitted] DisclosuresGrimwade:Ipsogen, Marseille, France: Membership on an entity's Board of Directors or advisory committees.

Prognosis, Imatinib Dose, and Benefit of Sunitinib in GIST: Knowing the Genotype

Prognosis, Imatinib Dose, and Benefit of Sunitinib in GIST: Knowing the Genotype

Chronic Myeloid Leukemia (CML): A Model Disease for Utilizing Evidence Based Guidelines in a Decade of Progress.

The importance of evidence-based guidelines (EBG), including CML, has been long recognized and supported by the American Society of Hematology (ASH). The extraordinary progress in treating CML with imatinib is well known, yet there remains need for alternative treatment for imatinib (IM) resistant disease. This mandated an up-to-date evaluation of current treatment results and methods for quantifying treatment effects. The European LeukemiaNet therefore assembled 19 experts from 9 countries in Europe, the USA, and Australia to recommend new guidelines for evaluating the treatment of CML. Eight members of the current committee were also members of the prior ASH committee of 1998. We also examined progress in evidence-based CML trials since the last (1998) ASH guidelines publication. A computerized Medline search of relevant literature since 1998 was conducted together with pertinent abstracts presented in 2004 and 2005 at ASH, ASCO, and European and International Society meetings. The new major conclusions are: the initial treatment recommended for nearly all CML patients is IM 400mg/d (for very young patients with an appropriate HLA match, allo HSCT may be considered). Failure is defined as no hematologic response (HR) at 3 mos, incomplete HR, or no cytogenetic response (CgR) at 6 mos, less than partial CgR at 12 mos (Ph>35%), less than complete CgR at 18 mos, and loss of HR or CgR or the appearance of IM resistant BCR-ABL mutations with a major increase of the IC50 to IM. Suboptimal response is defined as incomplete HR at 3 mos, less than partial CgR at 6 mos, less than complete CgR at 12 mos, less than major molecular response (MMolR) at 18 mos, loss of MMolR, BCR-ABL mutations with a minor increase of IC50 to IM, or additional chromosome abnormalities. In this event, a dose increase of IM, allo HSCT, dasatinib, or investigational agents are recommended. The importance of regular molecular monitoring for BCR-ABL transcripts is stressed. We compared the data of the EBG of 1998 with those of 2006. Older data (1998) often did not include relevant information such as age, physical findings, duration of follow up, and long-term survival. In general, sample sizes were small, and treatment protocols were not adhered to systematically. External review committees did not exist and committee members felt personally challenged if their opinions, not evidence-based, disagreed with the majority. Based on evidence, an overall superiority of allo HSCT compared to interferon-based regimens could not be demonstrated. Studies of the past 8 years have substantially corrected the deficiencies of the past. Shared decision-making between patient and physician remains critical. The current guidelines represent an important achievement of the European LeukemiaNet, reflect improved scientific quality of CML trials, and are a splendid example of international cooperation.

A Prospective Analysis of Adverse Events in a Phase 2 Trial of Imatinib in the Treatment of Polycythemia Vera.

Imatinib has recently been demonstrated to be an effective treatment in Polycythemia Vera. Initial response rates are high, approaching 80%. Patients enrolled in our trial, Novartis CST 1571B (US 144), were asked to complete a questionnaire identifying side effects of imatinib known from previous trials in chronic myeloid leukemia and GIST. Questionnaires were completed weekly for the first month, biweekly for the second month, and monthly for the remainder of the study. Mean time on study is now 1.1 years. Target enrollment was 20 patients. Mean age was 54 years; male to female ratio was 1.3: 1. Fourteen patients were Caucasian and 2 African American. Twelve patients were naïve to treatment and 4 patients were previously treated with hydroxyurea. Two dose escalations were allowed sequentially to 600mg and 800mg daily based on response using the Polycythemia Vera Study Group Criteria. Toxicity was graded according to the NCI Common Toxicity Criteria, version 2.0. Patient reported toxicities are expressed as the total number of events reported during the 120 week study period. Diarrhea was the most common reported toxicity at 53 events. Periorbital edema (33), pruritis (39), fatigue (29), arthralgias (20), headache (18), nausea (19), reflux (38), and dry mouth (15) were the next most commonly reported events on study. Other toxicities reported less commonly were chest pain (3), depression (4), cough (5), insomnia (6), weight gain (3), taste changes (7), and depigmentation (3). Most toxicities were mild at grade 1 and resolved spontaneously within 30 to 40 weeks from the time of treatment initiation. The exceptions to this were diarrhea, periorbital edema, and reflux esophagitis, which persisted in a number of patients throughout the study. The severity of gastrointestinal side effects was dose dependent. Previous studies of imatinib induced toxicity in patients with chronic myeloid leukemia have reported cutaneous manifestations as the most common event. Our study demonstrates the toxicities of imatinib in patients with polycythemia vera are generally mild and self limited, although resolution may take up to 35 weeks. In contrast with studies of imatinib and chronic myeloid leukemia, gastrointestinal toxicity was more common and tended to persist, but did not result in patient withdrawal from study. These differences from our findings may be the result of several factors: the use of a patient reported adverse events scale, small trial size, or differences in drug metabolism in a related myeloproliferative disorder.

Signal transduction inhibition: Results from phase I clinical trials in chronic myeloid leukemia

The tyrosine kinase inhibitor, imatinib mesylate (Gleevec ™, Novartis Pharmaceuticals Corp, East Hanover, NJ) (formerly STI571) showed significant antileukemic activity with minimal toxicity in preclinical studies. Based on these data, a phase I clinical trial was conducted in patients with chronic myeloid leukemia (CML) who failed other treatment options. Once therapeutic doses were attained, 53 of 54 patients (98%) in the chronic phase achieved hematologic remissions. With prolonged therapy of 2 to 5 months duration, a growing percentage of patients achieved cytogenetic responses. Imatinib mesylate also has activity as a single agent in CML blast crisis and in patients with Ph + acute lymphocytic leukemia (ALL). Although responses tend not to be durable, 20% of patients with myeloid blast crisis are in continuous remission for periods up to 1 year. Ongoing clinical studies are directed at optimizing the use of imatinib mesylate.

Signal transduction inhibition: Results from phase I clinical trials in chronic myeloid leukemia

Signal transduction inhibition: Results from phase I clinical trials in chronic myeloid leukemia