scholarly journals Trial in Progress: Asciminib in Monotherapy 4 CML (AIM4CML), a Phase IIIb Study of Asciminib Monotherapy in Patients with Chronic Myeloid Leukemia in Chronic Phase without or with T315I Mutations

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3599-3599
Author(s):  
David Andorsky ◽  
Sarah Tomassetti ◽  
Yehuda E. Deutsch ◽  
E Randolph Broun ◽  
Ghayas C. Issa ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Activity ◽  
Treatment Options ◽  
Chronic Phase ◽  
Advisory Committees ◽  
Phase Iiib ◽  
T315i Mutation ◽  
Previously Treated

Abstract BACKGROUND: Chronic myeloid leukemia (CML) is driven by the constitutively active BCR-ABL1 tyrosine kinase. Several adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitors (TKIs) are approved that inhibit BCR-ABL1 activity, and these have transformed CML from a fatal disease to a chronic one with near-normal life expectancy. However, many patients (pts) experience resistance to or intolerance of successive lines of TKI therapy. These pts have poor outcomes and few remaining treatment options. Moreover, pts with CML harboring the T315I mutation have limited treatment options as they are resistant to all approved TKIs except for ponatinib. Hence, there is a need for new CML therapies that are effective and well tolerated. Asciminib is an investigational agent with a novel mechanism of action. It is the first BCR-ABL1 inhibitor that inhibits BCR-ABL1 kinase activity by Specifically Targeting the ABL Myristoyl Pocket (STAMP). This contrasts with approved TKIs that target the ATP site of BCR-ABL1 to inhibit its kinase activity but are not entirely BCR-ABL1-specific and may target other kinases. In the phase III ASCEMBL trial in pts with CML in chronic phase (CP) after prior treatment with ≥2 ATP-competitive TKIs, asciminib showed superior efficacy vs bosutinib: major molecular response (MMR; BCR-ABL1 on the International Scale ≤0.1%) rate at week 24 was 25.5% vs 13.2%, respectively. In a large phase I trial, asciminib demonstrated promising efficacy and safety in pts with CML-CP without the T315I mutation previously treated with ≥2 TKIs and in those with the T315I mutation previously treated with ≥1 TKI: by 6 months, 37% and 25% of pts, respectively, achieved or maintained an MMR. Here, we describe the AIM4CML trial that was initiated to further assess the efficacy and safety of asciminib and explore a once-daily (QD) dosing regimen in pts with CML-CP (ClinicalTrials.gov, NCT04666259). DESIGN: This is a multicenter, phase IIIb, open-label, 3-cohort study of asciminib in pts with CML-CP without T315I after ≥2 prior TKIs and pts with T315I after ≥1 prior TKI (Figure 1). Adults aged ≥18 years with a diagnosis of CML-CP are eligible. Pts must have treatment failure with (as per 2020 European LeukemiaNet recommendations) or intolerance of the most recent TKI at screening. Key eligibility criteria are described in Table 1. Pts without the T315I mutation will undergo random selection to receive either asciminib 40 mg twice daily (BID; cohort A) or 80 mg QD (cohort B); those with the T315I mutation will receive asciminib 200 mg BID (cohort C). OBJECTIVES AND ENDPOINTS: The primary objective is to evaluate the safety profile of asciminib 40 mg BID and 80 mg QD in pts with CML-CP without T315I after ≥2 prior TKIs and of asciminib 200 mg BID in pts with T315I after ≥1 prior TKI. Primary endpoint analyses include incidence and severity of adverse events (AEs), serious AEs, changes in laboratory values and vital signs, and incidence of notable electrocardiogram abnormalities for 24 weeks. Primary and secondary study objectives/endpoints are summarized in Table 2. CONCLUSIONS: The AIM4CML study is currently enrolling pts across multiple sites in the United States, with an anticipated enrollment of approximately 115 heavily pretreated pts with CML-CP. Asciminib has the potential to transform the standard of care in this pt population through its novel mechanism of action as a BCR-ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP). This study is sponsored by Novartis. Figure 1 Figure 1. Disclosures Andorsky: AbbVie: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; AbbVie: Research Funding; AstraZeneca: Other: served on steering committees; Celgene/Bristol Myers Squibb: Research Funding; Epizyme: Research Funding. Tomassetti: Seagene: Research Funding; Rigel: Research Funding; Beigene: Research Funding; Natera: Research Funding; Novartis: Research Funding; Parexel: Research Funding. Deutsch: Astellas: Membership on an entity's Board of Directors or advisory committees. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Levy: Dova: Consultancy, Other: Promotional speaker; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Novartis: Consultancy, Other: Promotional speaker; Epizyme: Consultancy, Other: Promotional speaker; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau. Deininger: Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Fusion Pharma, Medscape, DisperSol: Consultancy. Maegawa: Novartis Pharmaceuticals Corporation: Current Employment, Current equity holder in publicly-traded company. Shrestha: Novartis: Current Employment. Mauro: Bristol Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Sun Pharma / SPARC: Research Funding.

scholarly journals A Novel Approach to Identify a Putative Leukemia Stem Cell Population in Acute Lymphocytic Leukemia (ALL) and Distinguish Philadelphia Chromosome-Positive ALL from Lymphoid Blast Crisis Chronic Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2912-2912
Author(s):  
Jonathan M. Gerber ◽  
Lawrence J. Druhan ◽  
David Foureau ◽  
Elizabeth Jandrisevits ◽  
Amanda Lance ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Lymphocytic Leukemia ◽  
Aldh Activity ◽  
Advisory Committees

Abstract Introduction: Recent evidence supports the clinical significance of leukemia stem cells (LSCs) in acute myeloid leukemia (AML). However, the identification of LSCs in acute lymphocytic leukemia (ALL) has proved challenging, as transplantation studies in immunocompromised mice have yielded conflicting results. The distinction between Philadelphia chromosome-positive (Ph+) ALL and lymphoid blast crisis (LBC) chronic myeloid leukemia (CML) is also controversial. We previously identified a clinically relevant CD34+CD38- population of LSCs with intermediate (int) levels of aldehyde dehydrogenase (ALDH) activity (CD34+CD38-ALDHint) in AML [Gerber, et al. Blood, 2012]. This population was not present in healthy controls and could be distinguished from normal hematopoietic stem cells (HSCs), which had higher levels of ALDH activity (CD34+CD38-ALDHhigh). We hypothesized that the same approach could be used to identify a putative LSC population in ALL. Furthermore, in contrast to most cases of AML, the chronic phase CML stem cell was found to reside in the same CD34+CD38-ALDHhigh population as normal HSCs [Gerber, et al. Am J Hematol, 2011]. We therefore also hypothesized that the presence of BCR/ABL mutations in the CD34+CD38-ALDHhigh population might help distinguish LBC CML from Ph+ ALL. Methods: Bone marrow and/or peripheral blood specimens were collected at diagnosis from patients with B cell ALL or LBC CML on an IRB-approved protocol. A total of 7 patients were evaluated: 2 Ph- ALL, 2 Ph+ ALL, and 3 LBC CML patients. CD34+ cells were isolated by magnetic bead and column selection, then analyzed by flow cytometry with respect to CD38 expression and ALDH activity. Sorted cell populations were analyzed by fluorescence in situ hybridization (FISH) for leukemia-specific abnormalities. Polymerase chain reaction was performed on clinical samples to determine the presence of a p190 vs. p210 transcript. Results: All patients harbored an aberrant CD34+CD38-ALDHint population, similar to that previously seen in AML. This population was ≥95% positive for BCR/ABL by FISH in all Ph+ ALL and LBC CML cases. It was similarly positive (≥75%) for other leukemia-specific FISH abnormalities (including trisomy 4, 8, 10, 12, and/or 21) in all four ALL cases, as well as one LBC CML case. Conversely, the CD34+CD38-ALDHhigh population (which typically contains the normal HSCs) lacked any of the other cytogenetic abnormalities in all of the cases, irrespective of Ph status or a diagnosis of ALL vs. CML. Notably, the CD34+CD38-ALDHhigh population was negative for BCR/ABL in the Ph+ ALL cases but was >95% positive for BCR/ABL by FISH in the LBC CML cases. The B cell differentiation marker, CD19, was expressed on the CD34+CD38-ALDHint but not the CD34+CD38-ALDHhigh population in all ALL cases, both Ph- and Ph+. In contrast, CD19 expression was variable in the LBC CML cases. Both Ph+ ALL cases possessed a p190 BCR/ABL transcript, whereas all of the LBC CML cases contained a p210 transcript. Also of note, the CD34+CD38-ALDHint population was persistently detectable in one of the LBC CML patients while in complete remission after induction therapy; that patient subsequently relapsed. Conclusions: An abnormal CD34+CD38-ALDHint population was identified in all cases of B cell ALL and LBC CML. This population is analogous to a previously identified, clinically relevant LSC population in AML and may represent a putative LSC population in ALL. The CD34+CD38-ALDHhigh population was normal by FISH in the ALL cases but contained the BCR/ABL mutation in the LBC CML cases, thus permitting distinction between Ph+ ALL and LBC CML (which also differed based on the presence of p190 vs. p210 transcripts, respectively). Additionally, clonal evolution from chronic phase to lymphoid blast crisis CML was apparent, based on the acquisition of additional cytogenetic abnormalities unique to the CD34+CD38-ALDHint population as compared to the CD34+CD38-ALDHhigh population. The presence of CD19 on the putative LSCs in the four cases of ALL suggest that CD19-directed therapies may target the LSCs and thus may have curative potential in those cases. This assay may serve as a means to evaluate other possible therapeutic targets. Lastly, the detection of the abnormal CD34+CD38-ALDHint population may have utility as a minimal residual disease assay for monitoring response to treatment. These findings warrant validation in a larger patient cohort. Disclosures Gerber: Janssen: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Grunwald:Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medtronic: Equity Ownership; Janssen: Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding. Avalos:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Survey of the Frontline Treatment and Management of Chronic Myeloid Leukemia (CML) in a Real-Word Setting: The 3rd Annual Update of the Worldwide Observational Registry Collecting Longitudinal Data on Management of Chronic Myeloid Leukemia Patients (The WORLD CML Registry)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1695-1695
Author(s):  
Ricardo Pasquini ◽  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
David Joske ◽  
Luis A Meillon ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Disease Status ◽  
Asia Pacific ◽  
Primary Therapy ◽  
Molecular Monitoring ◽  
Advisory Committees

Abstract Abstract 1695 Background: A global, prospective registry was established to document the frequency of diagnostic testing, management (mgmt) strategies, and outcomes of patients (pts) with CML. Here, we summarize the reported deviations from published disease mgmt recommendations and the overall efficacy achieved by pts. Methods: 1853 pts (≥ 16 years of age) within 6 months (mo) + 2 weeks of CML diagnosis were enrolled from Latin America (LA; n = 497), United States (US; n = 379), Asia Pacific (AP; n = 465), Middle East and Africa (MEA; n = 209), and Russia and Turkey (RT; n = 303). Baseline demographics and medical history were collected at enrollment; current disease status and mgmt information were collected at approximately 6-mo intervals or with a change in disease status or mgmt. Results: From February 2008 to June 2011, data were available for 1831 (99%) pts. Across all regions, nearly all (93.8%) screened pts were in chronic phase CML. Regardless of the time of evaluation (eval), disease burden was mostly assessed through the use of hematologic counts (Table 1). Cytogenetic testing and molecular monitoring were used in a minority of pts at any timepoint. Hydroxyurea (HU) and imatinib were the first agents used in 61.9% and 29.5% of pts, respectively (Table 2). Overall, 81.1% of pts received imatinib therapy at some time and it was the most common second agent (48.1%) pts received. Among the 49% of pts who had response assessments, subsequent treatment changes occurred most frequently (23.9% of pts) at the 3-mo timepoint (Table 1). The median time from disease eval to dose/regimen modification was 3 days. Of those who received imatinib, 32% had dose modifications primarily for: lack of efficacy (20%), physician request (20%), and adverse events (19%). Of the pts with a corresponding eval at 12 mo after diagnosis, 88% had a CHR, 65.4% had a CCyR, and 42.5% had a MMR (BCR-ABLIS ≤.1%). These data are preliminary; response assessments by treatment, as well as further efficacy analyses, are ongoing. Conclusions: Overall, the majority of pts did not have cytogenetic or BCR-ABL transcript level testing performed per the European LeukemiaNet recommendations. Furthermore, despite availability of more effective therapies for the treatment of CML, HU is still used as a primary therapy in a substantial proportion of pts. Based on this analysis, pts outside the US primarily receive HU as initial therapy rather than tyrosine kinase inhibitors (TKIs). Overall, second-generation TKIs, such as nilotinib and dasatinib, are infrequently used. These results illustrate the need for continuing education on the mgmt of CML in order to improve outcomes for all pts. Disclosures: Pasquini: Bristol Myers Squibb: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cortes:Bristol Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuitcals: Consultancy, Research Funding. Kantarjian:Pfizer: Research Funding; Novartis: Research Funding; Novartis: Consultancy; BMS: Research Funding. Zernovak:Novartis: Employment, Equity Ownership. Sivarathinasami:Novartis: Employment. Collins:Novartis: Employment. Hughes:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Antibody-Targeting of IL-3 Receptor-α Increases the Susceptibility of CD34+ CML Progenitors to Dasatinib-Induced Cell Death,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3745-3745
Author(s):  
Eva Nievergall ◽  
Deborah L. White ◽  
Hayley Ramshaw ◽  
Angel F. Lopez ◽  
Timothy P. Hughes ◽  
...  
Keyword(s):  
Stem Cells ◽  
Flow Cytometry ◽  
Progenitor Cells ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Advisory Committees ◽  
Cd34 Cells

Abstract Abstract 3745 Despite the remarkable efficacy of tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML), Ph+ CD34+ progenitor cells remain detectable even in patients with stable complete cytogenetic response. Over 40% of patients in stable complete molecular remission will develop molecular relapse within 6 months of stopping imatinib. While the exact causes are largely unknown, one of the proposed mechanisms is the protection of leukemic stem and early progenitor cells by the paracrine or autocrine production of cytokines, such as IL-3, GM-CSF and G-CSF, which activate survival pathways that bypass TKI-induced cytocidal effects. In acute myeloid leukemia (AML), the IL-3 receptor α chain (CD123) is recognized as a specific marker for CD34+/CD38− stem cells and therefore is attracting increasing interest as a therapeutic target. However, the function of CD123 in CML remains to date mostly unexplored. The aim of this study is to investigate potential synergy between TKIs and CSL362 (a humanized antibody version of 7G3 against CD123) in targeting CML progenitor and stem cells. CD34+ and CD34+/CD38− cells were isolated from mononuclear cells of newly diagnosed CML chronic phase and blast crisis patients. Flow cytometry studies indicated significantly increased CD123 expression on CD34+/CD38− cells of CML patients in both chronic phase and blast crisis when compared to normal hematopoietic stem cells (p<0.01 and p<0.001 for chronic phase and blast crisis, respectively; Figure A). A functional relevance of increased CD123 expression was demonstrated by IL-3-dependent increase in STAT5 phosphorylation (260.5% of baseline with 20 ng/ml IL-3; n=12; p<0.001) in CML CD34+ cells. Dasatinib inhibits STAT5 phosphorylation by blocking BCR-ABL signaling but only in the absence of IL-3 (62.5% of baseline for dasatinib alone vs. 130.8% for dasatinib + IL-3; n=3; p<0.01). In agreement, IL-3 effectively rescues dasatinib-induced cell death, as evaluated by AnnexinV/7-AAD staining (103.3% vs. 72.45%, n=5; p<0.01) and CFU-GM colony forming assays (69.39% vs. 46.13% relative to no treatment control; n=4; p<0.05). CSL362, in turn, revokes IL-3-mediated STAT5 phosphorylation (37.12% vs. 130.8%; n=3; p<0.001) and cytoprotection (45.05% vs. 69.39% CFC; n=4; p<0.01). In order to further elucidate the role of CSL362, CML CD34+ cells were cultured with increasing concentrations of dasatinib in the presence of IL-3 and CSL362 or BM4 isotype-matched control antibody. Even at very low dasatinib concentrations, CSL362 significantly reduces CML CD34+ colony forming cells (p<0.05; Figure B). Together these results substantiate a relevant role for IL-3-mediated resistance in CML progenitor cells and additionally confirming the ability of CSL362 to effectively bind to CD123 and impede IL-3 function. CSL362 furthermore has been optimized to mediate antibody dependent cell cytotoxicity (ADCC). CSL362 causes specific cell lysis of CML CD34+ progenitor cells in co-culture with allogeneic Natural killer cells as determined by increased lactate dehydrogenase release (ADCC activity of 42.4% ± 8.1%; n=3) and a decrease in the number of CFU-GM colonies by 74.1 % ± 12.2% (n=3). Collectively, our results indicate that a combination of dasatinib and CSL362 inhibits CML progenitor cell survival more effectively in vitro. Therefore, targeting IL-3 receptor α with CSL362 in chronic phase and blast crisis CML patients might provide a novel specific treatment approach aiding the elimination of refractory chronic myeloid leukemic stem and progenitor cells. A: Flow cytometry analysis reveals that CD123 expression is significantly higher in CD34+/CD38− cells of CML patients in chronic phase (CML-CP) and blast crisis (BC-CML) as compared to normal patients (NP), as previously documented for AML patients. ** p<0.01, *** p<0.001 by unpaired, two-tailed Student's t-test. B: In the presence of IL-3, CSL362 significantly reduces the number of colony forming cells. CD34+ cells of de novo CML-CP patients were cultured with dasatinib (0 to 10 nM) +IL-3 (1 ng/ml) ± CSL362 or BM4 (isotype control for CSL362). After 72 hours of culture live cells were plated for CFU-GM assay and colonies were counted after 2 weeks. Mean ± SE of three independent experiments is shown, n=4, p<0.05 by two-way ANOVA. Disclosures: Nievergall: CSL: Research Funding. White:CSL: Research Funding. Lopez:CSL: Research Funding. Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hiwase:CSL: Research Funding.

Gemtuzumab in Children with Relapsed and Refractory Acute Myeloid Leukemia Treated on Compassionate-Use Basis: A Report of the AML-BFM Study Group

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1637-1637 ◽  
Author(s):  
Mareike Rasche ◽  
Beate Lerius ◽  
Ursula Creutzig ◽  
Martin Zimmermann ◽  
C. Michel Zwaan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Treatment Options ◽  
Refractory Disease ◽  
Compassionate Use ◽  
Advisory Committees ◽  
Acute Myeloid ◽  
Refractory Aml

Abstract BACKGROUND: Long-term survival in pediatric acute myeloid leukemia (AML) improved remarkably during the last decades. However, children with refractory disease or relapsed AML still suffer from exceedingly poor outcome, especially those who relapse within one year of diagnosis with very limited treatment options. Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody linked to calicheamicin, a potent cytotoxic agent. Developed for targeted treatment of CD33-positive AML, studies in adults showed its efficacy in relapsed and refractory AML. We performed this retrospective analysis of patients with highly advanced pediatric AML, receiving GO as compassionate use. PATIENTS AND METHOD: In total, 96 children <18 years diagnosed from 1995 to 2014 with multiple relapsed or refractory AML received GO as compassionate use. Eighty-eight patients had sufficient data available for this retrospective analysis, evaluation of adverse effects during first cycle of GO was based on medical reports of 83 patients. Sixty-one patients were treated in refractory disease or early first relapse, but also including 7 patients with 2 relapses within the first year after diagnosis. Nine patients were in 2nd relapse (>1year from diagnosis) and one patient in 3rdrelapse, four children had AML as secondary malignancy. Fourteen children have been already transplanted once, one child twice before GO therapy. Fourty-seven children received monotherapy with GO, 35 children were treated combined with cytarabine and 3 children received other combinations with other agents (3 unknown). Fifty-three patients received one cycle, 34 received 2 cycles of GO, however one patient received 4 cycles of monotherapy. Of note, eight patients have been previously reported elsewhere (Zwaan et al., Br J Haematol. 2010). Time of database lock was 07/2016 with a median follow-up of 9.8 years for the surviving patients. RESULTS: Safety profile was comparable to other pediatric studies. Adverse effects during first cycle of treatment consisted mostly of fever in neutropenia (n=49), less frequently infections (n=9) or allergic reactions (n=18). A few patients reported about mild gastrointestinal symptoms, which was not clearly related to GO due to combination therapy. Two patients suffered from sepsis. Veno-occlusive disease (VOD) of the liver occurred in three patients, one of those had a previous VOD, but all of them have been treated successfully with defibrotide. No lethal event was observed during treatment with GO. One patient developed a VOD during subsequent transplantation despite of prophylactic use of defibrotide. Sixty patients were evaluable for response assessment of the bone marrow. Twenty-eight children showed a response with a blast reduction to 5% or less in the bone marrow samples after treatment (46%). Fourteen out of these patients, received GO combined with cytarabine, 12 patients had monotherapy, and two other combinations. Subsequently, 53 children proceeded to stem cell transplantation (SCT) (one patient unknown). Of note, 13 out of those, received further chemotherapy before HSCT was performed. In details, 47 patients proceeded to first SCT, whereas 5 patients received 2ndSCT (one unknown). Time to transplantation varied (<3 weeks, n=14; 3 to 6 weeks, n=28; >6 weeks, n=11 patients [median time to transplantation after GO: 30 days]). The probability of 4-year overall survival after treatment with GO of all patients (n=88) was 21±4%. In patients treated with monotherapy it was 18±6%. Eighteen patients of this cohort are still alive at time of database lock. CONCLUSION: To our knowledge, this analysis is the largest pediatric cohort of patients, treated with GO in a very advanced disease. The results of this retrospective trial indicate efficacy of GO, while having an acceptable toxicity profile, even in heavily pretreated patients. It can induce blast reduction and even survival in patients, who have no further conventional treatment options. Further randomized studies are necessary to learn more about efficacy and side effects in a relapse setting, especially for therapeutic implications in future. Disclosures Rasche: Jazz Pharma: Other: Travel accomodation. Zwaan:Pfizer: Research Funding; Pfizer: Consultancy. Reinhardt:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Jazz Pharma: Other: Travel Accomodation.

scholarly journals The Predictive Value of Intracellular Imatinib Levels in Chronic Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4250-4250 ◽  
Author(s):  
Nicholas L Jackson Chornenki ◽  
Christopher M. Hillis ◽  
Isabelle Bence-Bruckler ◽  
Lambert Busque ◽  
Caroline Hamm ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Plasma Levels ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Transcript Levels ◽  
Disease Response ◽  
Log Reduction

Abstract Background: Plasma levels of imatinib have been shown to be predictive of disease response in chronic phase chronic myeloid leukemia (CML). However, the ultimate site of action of imatinib is intracellular. While intracellular imatinib has been reported to be correlated with plasma imatinib, the use of intracellular imatinib for the prediction of clinical outcomes is unclear. The concentration of intracellular imatinib depends on many factors including the level of alpha-1-acid glycoprotein, which binds to imatinib and prevents intracellular uptake, and the OCT-1 transporter, which mediates the influx of imatinib across the plasma membrane of leukemic cells. We conducted the present study of newly diagnosed CML patients with the primary objective of determining if intracellular levels of imatinib two weeks after treatment initiation predicted major molecular response. The secondary objectives were to elucidate the relationships between the levels of OCT-1 and plasma imatinib with intracellular imatinib. Methods: We prospectively studied newly diagnosed chronic phase CML patients in Canada who were treated with standard dose imatinib (400 mg). We measured both intracellular and extracellular (plasma) levels of imatinib by tandem mass spectrometry at two weeks, four weeks, and twelve months after enrollment. Additionally, we measured transcript levels of OCT-1 and BCR-Abl by q-rt-PCR before treatment, at six months, and at twelve months to determine therapeutic response. Results: Eighty-one patients were screened. A total of 76 patients entered the study, and 55 completed the study per protocol. Patient information is shown in Table 1. There was a significant correlation between intracellular imatinib levels at two weeks and a 2-log reduction of BCR-Abl transcript at six months (r=0.390; 95% CI = 0.136 - 0.595; p = 0.004) (Figure 1), but not at twelve months (r=0.183; 95% CI = -0.094 - 0.434; p = 0.194). Notably, intracellular imatinib levels and plasma levels of imatinib were highly correlated at two weeks (r=0.698; 95% CI = 0.559-0.799; p <0.001) and four weeks (0.699; 95% CI = 0.555 - 0.802; p < 0.001) but not between four weeks and twelve months (r= 0.230; 95% CI = -0.040 - 0.469; p = 0.094). There was no correlation between intracellular imatinib levels at two weeks and the pre-treatment OCT-1 transcript level (r=0.072; 95% CI = -0.166 to 0.301; p =0.556). Conclusions: Intracellular imatinib levels at two weeks was moderately predictive of a disease response at six months as indicated by a 2-log reduction in BCR-Abl transcript. OCT-1 transcript levels did not have utility for predicting intracellular imatinib levels. Measurement of intracellular Imatinib levels may prove to have utility in identifying patients who would benefit from adjustments to therapy. Disclosures Hillis: Bristol-Myers Squibb: Honoraria; Novartis: Honoraria. Busque:Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy; BMS: Consultancy. Lipton:Bristol-Myers Squibb: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Savoie:Pfizer: Consultancy; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Leber:Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Absolute Quantification of Mutant T315I BCR-ABL Transcripts At 6 Months Identifies Imatinib Resistant CML Patients with a Low Probability to Achieve MMR After 12 Months on Second Line Tyrosine Kinase Therapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1679-1679
Author(s):  
Thoralf Lange ◽  
Thomas Ernst ◽  
Markus Pfirrmann ◽  
Jacqueline Maier ◽  
Martin C. Müller ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Prognostic Significance ◽  
Chronic Phase ◽  
Absolute Quantification ◽  
Molecular Response ◽  
Second Line ◽  
Advisory Committees ◽  
Detection Range ◽  
T315i Mutation

Abstract Abstract 1679 The BCR-ABL T315I mutation is associated with resistance against imatinib (IM), nilotinib (NI) and dasatinib (DA) in patients with chronic myeloid leukemia (CML). Although this mutation can be detected by different techniques and at different levels of the mutated clone, the prognostic significance of the absolute amount of the mutated allele is widely unknown. We therefore sought to determine absolute T315I allele levels after 6 months on second line NI or DA therapy to identify a cut off value for predicting the achievement of major molecular response after 12 months (MMR12; ≤0.1% BCR-ABL transcripts at international scale). Forty randomly selected BCR-ABL positive CML patients (n=24 male, median age 64, range 39–78 years) in chronic (n=31), accelerated (n=7), or blastic phase (n=2) with failure to IM were treated with DA 140 mg/day (n=20) or NI 800 mg/day (n=20) and analyzed by denaturing high-performance liquid chromatography (D-HPLC) and high-sensitive allele-specific ligation PCR (L-PCR) for quantification of mutated T315I BCR-ABL allele normalized by beta-glucuronidase (GUS) expression. This method was previously shown to obtain a dynamical detection range of 100% to <0.1% mutant T315I allele (3–3.5 log). The levels of the BCR-ABL T315I alleles at 6 months were correlated with the achievement of a MMR12 on second line treatment. The L-PCR investigator was blinded for the MMR12 results. On second line therapy, MMR12 was achieved by 12 (20%) patients. After 6 months, 37 (10 with MMR12) patients were available for D-HPLC assessment and showed a T315I mutation in 3 (8%) patients. None of these patients achieved MMR12. In comparison, 35 evaluable patients (8 with MMR12) showed >10−5 BCR-ABLT315I/GUS (n=10, 20%), <10−5 (n=8, 22%) or no (n=17, 48%) T315I mutation by L-PCR. All patients with >10−5 BCR-ABLT315I/GUS did not achieve MMR12, all patients with <10−5 developed MMR12 (p<0.0001). This pre-defined value of >10−5 BCR-ABLT315I/GUS as a negative predictor for MMR12 was applied to a new second independent group of 40 IM resistant patients (n=17 male, median age 60, range 32–79 years) all in first chronic phase, MMR12 n=9, 22.5%) equally distributed to NI and DA. In this group 12 (30%) patients showed >10−5 BCR-ABLT315I/GUS after 6 months and all but one did not achieve MMR12. In contrast, 5 patients with <10−5 showed MMR12, 3 patients did not (p=0.0181). In conclusion, absolute quantification of the mutant T315I allele is helpful to identify patients with a low chance of MMR12 on second line nilotinib or dasatinib treatment. Therefore, relevant mutations should be quantified into clinical trial protocols to identify certain amounts with prognostic significance of the mutated clones for a specific mutations on a given TKI treatment in CML. Disclosures: Lange: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hochhaus:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Nilotinib Shows Safety and Efficacy in Older Patients (≥ 65 years) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase Comparable with That in Younger Patients with Chronic Myeloid Leukemia in Chronic Phase: Results From ENESTnd,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3768-3768 ◽  
Author(s):  
Richard A. Larson ◽  
Udomsak Bunworasate ◽  
Anna G. Turkina ◽  
Stuart L. Goldberg ◽  
Pedro Dorlhiac-Llacer ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 3768 Background: Data from the phase 3, randomized multicenter ENESTnd trial have demonstrated the superiority of nilotinib over imatinib after 24 months (mo) of follow-up, with significantly higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR), and significantly lower rates of progression to accelerated phase/blast crisis (AP/BC). The current subanalysis evaluated the efficacy and safety of nilotinib 300 mg twice daily (Nil300) and nilotinib 400 mg twice daily (Nil400) in older (≥ 65 years [yrs] at study entry) patients (pts) with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) with a minimum follow-up of 24 mo. Methods: In ENESTnd, 846 pts stratified by Sokal risk score were randomized 1:1:1 to Nil300 (n = 282), Nil400 (n = 281), or imatinib 400 mg once daily (n = 283). Pts with impaired cardiac function or ECOG performance status > 2 were excluded. Rates of CCyR and MMR by 24 mo, progression to AP/BC on treatment, and safety were evaluated according to age group (< 65 vs ≥ 65 yrs) in the 2 nilotinib arms. Safety data are reported for any pt who received ≥ 1 dose of nilotinib (n = 279, Nil300; n = 277, Nil400). Results: 36 pts (13%) and 28 pts (10%) were ≥ 65 yrs old in the Nil300 and Nil400 arms, respectively. Of the pts aged ≥ 65 yrs, 51/64 (80%) had an ECOG performance status of 0 at baseline and 60/64 (94%) had intermediate or high Sokal risk scores. Of the older pts, 8 (22%) on Nil300 and 6 (21%) on Nil400 had type 2 diabetes at baseline. CCyR rates by 24 mo were 83% and 68% among older pts treated with Nil300 and Nil400, respectively, and 87% for pts aged < 65 yrs in each nilotinib arm. By 24 mo, MMR was achieved by 72% and 61% of older pts on Nil300 and Nil400, respectively; in pts aged < 65 yrs, the respective rates were 71% and 67%. All 5 pts who progressed to AP/BC on treatment (2 on Nil300 and 3 on Nil400) were aged < 65 yrs. The frequency of grade 3/4 hematologic adverse events (AEs) was low in older pts; no pts had grade 3/4 neutropenia and only 1 older pt reported grade 3/4 thrombocytopenia in each nilotinib arm (Table). Transient, asymptomatic lipase elevations were reported in 11% and 16% of older pts treated with Nil300 and Nil400, and 7% of younger pts in each arm. Hyperglycemia occurred in 23% and 16% of older pts on Nil300 and Nil400, respectively, and 4% of younger pts in each arm; regardless of age, no pt discontinued study due to hyperglycemia. Among the 12 older pts with grade 3/4 hyperglycemia (8 on Nil300; 4 on Nil400), 9 pts had type 2 diabetes at baseline. There were no QTcF increases of > 60 msec from baseline in older pts and 3 in nilotinib-treated pts < 65 yrs old (1 on Nil300; 2 on Nil400). QTcF prolongation of > 500 msec did not occur in any pt treated with nilotinib on study. Periodic echocardiograms were done, and there were no decreases of > 15% in left ventricular ejection fraction from baseline in any pt treated with nilotinib on study. There were 4 cases of ischemic heart disease reported in older pts (1/35 [3%] on Nil300; 3/25 [12%] on Nil400) and 7 cases in pts < 65 yrs of age (4/244 [2%] on Nil300; 3/252 [1%] on Nil400). No sudden deaths occurred on study. Discontinuation occurred in approximately 25% of older and younger pts with Nil300, of which, 6% and 9%, respectively, were due to AEs/lab abnormalities. Discontinuation from study with Nil400 was 46% in older pts and 19% in younger pts; of which, 36% and 10% were due to AEs/lab abnormalities. Conclusions: Older pts treated with nilotinib demonstrated high rates of cytogenetic and molecular responses and low rates of progression. Nilotinib was generally well tolerated by older pts. In older pts, Nil300 had numerically higher rates of CCyR and MMR and was generally better tolerated (as evidenced by fewer AEs and discontinuations) vs Nil400. These data support the use of Nil300 in older pts with newly diagnosed CML-CP. Disclosures: Larson: Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Bunworasate:Novartis Pharmaceutical: Research Funding. Turkina:Novartis: Consultancy, Honoraria; BMS: Honoraria. Goldberg:Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding. Dorlhiac-Llacer:Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding. Saglio:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis Pharmaceutical: Consultancy, Speakers Bureau; Pfizer: Consultancy. Hochhaus:Ariad: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Yu:Novartis: Employment, Equity Ownership. Gallagher:Novartis: Employment, Equity Ownership. Clark:Bristol Myers Squibb: Honoraria, Research Funding; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau. Hughes:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Treatment-Free Remission in Patients with Chronic Myeloid Leukemia in Chronic Phase According to Reasons for Switching from Imatinib to Nilotinib: Subgroup Analysis from ENESTop

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 792-792 ◽  
Author(s):  
Timothy P. Hughes ◽  
Carla Maria Boquimpani ◽  
Naoto Takahashi ◽  
Noam Benyamini ◽  
Nelma Cristina D Clementino ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Molecular Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Loss Of Response ◽  
Equity Ownership ◽  
Treatment Free Remission

Abstract Background: ENESTop, an ongoing, single-arm, phase 2 study (ClinicalTrials.gov, NCT01698905), is the first trial specifically evaluating treatment-free remission (TFR; ie, stopping tyrosine kinase inhibitor [TKI] treatment without a loss of response) in patients with chronic myeloid leukemia in chronic phase (CML-CP) who achieved a sustained deep molecular response after switching from imatinib (IM) to nilotinib (NIL). Of 126 patients in ENESTop who were eligible to stop NIL, 57.9% (95% CI, 48.8%-66.7%) maintained TFR at 48 weeks. Here we present results from a subgroup analysis based on reasons for switching from IM to NIL, categorized as intolerance, resistance, and physician preference. Methods:Eligible patients were adults with CML-CP who received ≥ 3 years of total TKI therapy (> 4 weeks of IM, followed by ≥ 2 years of NIL) and achieved a sustained MR4.5 (BCR-ABL1 ≤ 0.0032% on the International Scale [BCR-ABL1IS]) on NIL therapy; patients with a documented MR4.5 at the time of switch from IM to NIL were not eligible. Enrolled patients continued NIL treatment in a 1-year consolidation phase, and those without confirmed loss of MR4.5 (ie, consecutive BCR-ABL1IS > 0.0032%) were eligible to stop NIL in the TFR phase. Patients with loss of major molecular response (MMR; ie, BCR-ABL1IS > 0.1%) or confirmed loss of MR4 (ie, consecutive BCR-ABL1IS > 0.01%) during the TFR phase reinitiated NIL treatment. The primary endpoint was the proportion of patients who maintained TFR (ie, no loss of MMR, confirmed loss of MR4, or treatment reinitiation) at 48 weeks after stopping NIL. In this post hoc analysis, rates of TFR at 48 weeks after stopping NIL and a Kaplan-Meier (KM) analysis of treatment-free survival (TFS; defined as the time from the start of TFR to the earliest occurrence of any of the following: loss of MMR, confirmed loss of MR4, reinitiation of NIL due to any cause, progression to accelerated phase/blast crisis, death due to any cause) were evaluated in subgroups of patients who switched from IM to NIL due to intolerance, resistance, or physician preference. These categories were determined by grouping the reasons for switching from IM to NIL, as reported by the investigators, based on relatedness to safety (intolerance), loss of response/treatment failure (resistance), and the physician's clinical judgment (physician preference); individual reasons included within each category are presented in the Figure. Results:A total of 125 patients who entered the TFR phase were included in this analysis; 1 patient who was found to have had atypical transcripts was excluded. Among these 125 patients, the reasons for switching to NIL were categorized as intolerance in 51 patients (40.8%), resistance in 30 patients (24.0%), and physician preference in 44 patients (35.2%). The proportion of patients who maintained TFR at 48 weeks after stopping NIL was generally similar across the 3 subgroups: 30 of 51 (58.8%; 95% CI, 44.2%-72.4%) in the intolerance subgroup, 16 of 30 (53.3%; 95% CI, 34.3%-71.7%) in the resistance subgroup, and 27 of 44 (61.4%; 95% CI, 45.5%-75.6%) in the physician preference subgroup. KM analysis of TFS showed that in all 3 subgroups, the majority of TFS events occurred within the first 24 weeks after stopping NIL (Figure). There were no notable differences in the kinetics of TFS events among subgroups. The KM-estimated median duration of TFS was not reached by the data cutoff date in all 3 subgroups. Conclusion: Primary analysis from ENESTop showed that among patients with CML-CP who achieved a sustained MR4.5after switching from IM to NIL, 57.9% of those who stopped NIL maintained TFR at 48 weeks. In the present analysis, TFR was maintained at 48 weeks after stopping NIL by > 50% of patients in the intolerance, resistance, and physician preference subgroups, with generally similar results across subgroups. These findings suggest that the rate of successful TFR following second-line NIL does not differ based on the reasons for switching from IM to NIL. Figure. Figure. Disclosures Hughes: Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Australasian Leukaemia and Lymphoma Group (ALLG): Other: Chair of the CML/MPN Disease Group. Boquimpani:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau. Takahashi:Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria. Shuvaev:Pfizer: Honoraria; BMS: Honoraria; Novartis pharma: Honoraria. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Lipton:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Turkina:Pfizer: Honoraria; Novartis Pharma: Honoraria; BMS: Honoraria. Moiraghi:BMS: Speakers Bureau; NOVARTIS: Speakers Bureau. Nicolini:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; Ariad pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sacha:BMS: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria. Kim:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding. Fellague-Chebra:Novartis: Employment. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Krunic:Novartis: Employment, Equity Ownership. Jin:Novartis: Employment, Equity Ownership. Mahon:BMS: Honoraria; PFIZER: Honoraria; NOVARTIS PHARMA: Honoraria, Research Funding; ARIAD: Honoraria.

scholarly journals Second Treatment Free Remission after Combination Therapy with Ruxolitinib Plus Tyrosine Kinase Inhibitors in Chronic Phase Chronic Myeloid Leukemia (CML)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2555-2555
Author(s):  
Kendra Sweet ◽  
Ehab L. Atallah ◽  
Jerry P. Radich ◽  
Mei-Jie Zhang ◽  
Eva Sahakian ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Molecular Response ◽  
Advisory Committees ◽  
Treatment Free Remission ◽  
One Year

Abstract Background: Discontinuation of tyrosine kinase inhibitors (TKIs) is feasible in a subset of CML patients who have maintained a deep molecular response for at least two years. Numerous discontinuation trials have been performed and consistently show approximately 50% of patients relapse after stopping TKIs. A recent study examining rates of treatment free remission (TFR) after a second attempt at stopping TKIs found, with a median follow up time of 38.3 months, 64.3% of patients had a molecular relapse (defined as a loss of major molecular response (MMR)). At 12, 24 and 36 months, TFR rates were 48%, 42% and 35%, respectively. These data suggest some patients with a history of molecular relapse upon TKI cessation could successfully stop treatment on a subsequent attempt, yet the majority will relapse a second time. 'Complete eradication' of CML remains elusive in most patients likely as a result of minimal residual disease (MRD), which is the result of BCR-ABL independent drug resistance. More specifically, CML cells that reside in sanctuary sites such as the bone marrow adhere to fibronectin and demonstrate cell adhesion mediated drug resistance (CAM-DR). The bone marrow microenvironment contains many cytokines and growth factors capable of inducing STAT3-Y705 phosphorylation via the JAK-STAT pathway leading to protection against TKI-induced cell death. Inhibiting JAK2 and TYK2 leads to complete inhibition of pSTAT3-Y705, thereby implicating the role of activation of JAK2 and TYK2 in STAT3-Y705 phosphorylation and resistance towards BCR-ABL TKI-induced cell death. A phase I clinical trial combined ruxolitinib, which inhibits JAK2 and TYK2, plus nilotinib in chronic phase (CP) CML patients and found that ruxolitinib 15mg PO BID was safe and well tolerated with 4/10 patients achieving undetectable BCR-ABL1 transcripts by PCR. Study Design and Methods: This single arm phase II study (NCT03610971) will enroll 41 subjects from the H Jean Khoury Cure CML Consortium. Eligible subjects must have a confirmed diagnosis of CP-CML and have previously attempted to discontinue TKI therapy per NCCN guidelines and had molecular recurrence, defined as loss of MMR, and were restarted on TKI. This trial combines ruxolitinib 15mg BID plus BCR-ABL TKI (imatinib, dasatinib, nilotinib or bosutinib) for 12 28-day cycles in the combination treatment phase (CTP). RQ-PCR to measure BCR-ABL transcripts will be checked at screening and every three months during the CTP. In the event that a subject experiences intolerance to a TKI, has confirmed loss of MMR, or loss of MR4.5 (&gt;0.0032% IS) on two central PCR results, or discontinues ruxolitinib, the subject will be removed from CTP and enter into long term follow-up (LTFU). CTP phase will be followed by further RQ-PCR screening for the concurrent TFR phase. At this time ruxolitinib will be discontinued and any subject who has met the criteria for the TFR phase will be enrolled. During the TFR phase, subjects will discontinue their TKI and be monitored off treatment with RQ-PCR checked monthly for the first year, every six weeks for year two, and every 12 weeks during year three. Upon molecular recurrence, defined as loss of MMR, TKIs will be restarted. The primary endpoint is the 12-month TFR rate subsequent to completion of 12 cycles of combination therapy; however, subjects will remain in the TFR phase for three years. Therefore, the total duration of the trial will be approximately five years (one year on CTP + three years in the TFR phase + one-year LTFU). Study statistical design was calculated to yield a one-sided type I error rate of 0.025 and power of 65% when the true one-year relapse rate is 35%. This study will additionally assess patient-reported outcomes in conjunction with RQ-PCR testing. PROMIS and other measures will be self-administered through REDCap. Correlative studies will include comparing changes in pSTAT3 in K562 and KU812 cell lines using plasma from CML patients being treated with TKIs plus ruxolitinib, using the plasma inhibitory assay technique. Changes in pSTAT3 and pSTAT5 will be correlated with clinical response and rate of TFR. Additional correlatives include multiparameter flow-based assessment of the T-cell compartment (activity/polarization) as well as natural killer cell fractions in CML patients at various time points (TKIs alone, TKIs plus ruxolitinib and during TFR). Thus far, 14 patients have been enrolled. Disclosures Sweet: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Atallah: Amgen: Consultancy; BMS: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Abbvie: Consultancy, Speakers Bureau. Radich: Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Thompson: Novartis/ Bristol-Myers Squibb: Research Funding. Mauro: Pfizer: Consultancy; Takeda: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Sun Pharma / SPARC: Research Funding. Pinilla Ibarz: AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory; Sellas: Other: ), patents/royalties/other intellectual property; MEI, Sunesis: Research Funding; AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau. OffLabel Disclosure: Ruxolitinib is being used off-label in chronic myeloid leukemia

scholarly journals Interim Analysis of a Pan European Stop Tyrosine Kinase Inhibitor Trial in Chronic Myeloid Leukemia : The EURO-SKI study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 151-151 ◽  
Author(s):  
Francois-Xavier Mahon ◽  
Johan Richter ◽  
Joelle Guilhot ◽  
Martin C Muller ◽  
Christian Dietz ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Board Of Directors ◽  
Interim Analysis ◽  
Null Hypothesis ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Molecular Response ◽  
Advisory Committees ◽  
Tki Treatment

Abstract Background: The tyrosine kinase inhibitors (TKIs) have dramatically changed the natural history of chronic myeloid leukemia (CML) leading to significant improvement in clinical outcome and survival rates. The option of treatment cessation has recently become of utmost importance. Indeed, prospective trials suggest that imatinib therapy may be safely and successfully discontinued in CML pts with deep and sustained molecular responses (Mahon Lancet Oncol 2010, Ross Blood 2013). The major aim of the EURO-SKI study (European Leukemia Net Stop TKI study) was to define prognostic markers to increase the rate of patients in durable deep MR after stopping TKI. Further aims were the evaluation of harmonized methods of molecular monitoring, assessment of quality of life, and calculation of saved treatment costs per country. Methods: Adult CML patients in chronic phase CML on TKI treatment in confirmed deep molecular response (MR4, BCR-ABL <0.01%) for at least one year (>4 log reduction on TKI therapy for >12 months confirmed by three consecutive PCR tests) and under TKI treatment for at least 3 years were eligible. MR4confirmation was performed in a standardized laboratory (n=6). Primary endpoint was the assessment of the duration of MR (defined by continuous MMR) after stopping TKI. Patients (pts) after a prior TKI failure were excluded. According to protocol, an interim analysis was planned after 200 patients with eligible molecular results at month (mo) 6 were available to test the null hypothesis that relapse-free survival at 6 mo is less or equal 40%. Results: From June 2012 to June 2014, 498 CML pts in chronic phase from 10 countries were enrolled and included in the trial. From June 2012 to July 2013, 254 pts from 8 countries were registered; 54 were excluded (consent withdrawal n=1, protocol violation n=1, not eligible n=34, restart of TKI without relapse n=4, atypical or unknown transcript n=6, missing data n=8). Of the eligible 200 pts, 41.5% were female. Median age at diagnosis was 53.3 years (range, 13.8 to 85.5). In assessable pts 8.7% and 18.2 % were high-risk according to EUTOS and Sokal Scores. 103 pts were treated prior to the start TKI therapy, mostly with hydroxyurea or interferon. 1st-line TKI was imatinib in 97%, dasatinib in 1.5%, and nilotinib in 1.5% of pts. Twenty-four pts switched to second-line TKI therapy due to intolerance, 16 to dasatinib, 2 to imatinib, and 6 to nilotinib. The median time from diagnosis of CML to TKI cessation was 8 years (range, 3-19 years). TKI treatment duration was less than 5 years in 16%, 5-8 years in 36% and > 8 years in 48% of pts. Median duration of TKI treatment was 8 years (range, 3-12.6 years) and median duration of MR4 before TKI cessation was 5.4 years (range, 1-11.7 years). MR4duration was less than 2 years in 8%, 2-5 years in 37%, 5-8 years in 39% and >8 years in 16% of pts. For all eligible pts, a standardized European laboratory confirmed MR4 assessment. Since 123 of the 200 pts (61.5%, 95% CI: [54.4%; 68.3%]) remained without relapse the first 6 mo, the null hypothesis could be discarded (p<0.0001). Recurrence of CML, defined as loss of MMR, was observed in 43/92 pts (47%) treated <8 years, as compared to 23/87 pts (26%) treated for >8 years (p= 0.005). So far, there was a trend for prognostic significance of MR4 duration: 33/71 pts with MR4 <5 years (46%) lost MMR within 6 mo as compared to 28/87 pts (32%) with MR4duration >5 years (p=0.07). No significant difference was observed for relapse within 6 mo according to depth of molecular response at discontinuation (MR4 vs MR4.5 vs MR5). TKI cessation was a safe procedure but a substantial proportion of pts reported transitory musculoskeletal pain starting within weeks after imatinib discontinuation. The phenomenon was described in 30% of Swedish patients as a “TKI withdrawal syndrome” (Richter JCO 2014). Taking into account the cost of imatinib in Europe and time without treatment in the total study population at the most recent analysis, total savings for the community within the EURO-SKI trial were estimated at 7 million Euros. Conclusion: Employing a standardized molecular testing for patient selection within a TKI cessation trial in CML the chance to stay in treatment-free remission could be higher than previously reported. The EURO-SKI trial will further elucidate the prognostic factors but the preliminary results confirm (as reported in the STIM Study) the prognostic impact of the duration of TKI therapy before stopping. Disclosures Mahon: NOVARTIS PHARMA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BRISTOL MYERS SQUIBB: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ARIAD: Honoraria; PFIZER: Honoraria. Porkka:BMS: Honoraria; BMS: Research Funding; Novartis: Honoraria; Novartis: Research Funding; Pfizer: Research Funding. Hjorth-Hansen:Novartis: Honoraria; Bristol-myers Squibb: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Mayer:Janssen Research & Development: Research Funding; Roche: Research Funding; GlaxoSmithKline: Research Funding; Celgene: Research Funding. Almeida:Celgene: Consultancy; Novartis: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Bristol-Meyer Squibb: Membership on an entity's Board of Directors or advisory committees. Berger:Genzyme/Sanofi and Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mustjoki:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Saussele:Novartis: Honoraria, Research Funding, Travel Other; Bristol-Myers Squibb: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria, Travel, Travel Other.

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