scholarly journals Single Centre, Retrospective Study to Evaluate Treatment Outcomes Following Tyrosine Kinase Inhibitor for Chronic Gvhd Treatment Including Ruxolitinib, Ibrutinib and Imatinib

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 17-18
Author(s):  
Swe Mar Linn ◽  
Omar Abduljalil ◽  
Igor Nicolas Novitzky-Basso ◽  
RAM V Nampoothiri ◽  
Ivan Pasic ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Dose Reduction ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Single Centre ◽  
Prednisone Dose ◽  
Steroid Dose ◽  
Heavily Pretreated

Background Chronic graft-versus-host-disease (cGVHD) is one of the main causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HCT). Tyrosine kinase inhibitor such as Ruxolitinib, Ibrutinib and Imatinib showed a promising efficacy in cGVHD treatment. Ruxolitinib is a JAK-STAT inhibitor, reducing inflammation and immune pathway. Ibrutinib is a BTK inhibitor, blocking B cell-activating factor (BAFF), while Imatinib inhibits the platelet-derived growth factor receptor pathway activated by cGvHD-induced antibodies. The present retrospective study evaluated the efficacy of 3 TKIs for cGVHD at a single-centre in terms of 1) overall response rate (ORR), 2) clinical benefit (CB), 3) dose reduction of steroid, 4) failure-free survival (FFS) and 5) overall survival (OS). Patients and Methods A total of 43 patients who developed cGVHD after HCT and treated with TKI therapy for cGVHD at Princess Margaret Cancer Centre, Canada from August 2014 to April 2020 were evaluated in this retrospective study. 16 patients were treated with more than one TKI drug. A total of 62 lines of TKI therapy was evaluated, including Ruxolinitib (n=18), Ibrutinib (n=13) and Imatinib (n=31). The ORRs and CBs were assessed at months 3, 6 and 12, retrospectively. Responses were evaluated according to NIH scoring/staging/response assessment as part of standard clinical practice. CB was assessed considering clinical response as well as steroid dose reduction. For systemic steroid dose reduction, prednisone dose per kg per day was captured prior to Ruxolitinib start, at months 3, 6 and 12. Treatment failure was defined as 1) resistance requiring treatment switch, 2) non-relapse mortality (NRM), 3) relapse, 4) intolerance requiring treatment discontinuation. FFS and OS were calculated from the day of starting TKI therapy for cGVHD treatment. Results The patients and disease characteristics are summarized as follow: median age was 54 years (range 16 -70); 33 patients (53%) presented with classical cGVHD, while 29 patients (47%) with overlap syndrome; 14 (23%) presented with moderate and 48 (77%) with severe grade cGVHD. There was no difference in cGVHD subtype among 3 TKI subgroups (p= 0.478). The median number of organ involvement was 3 (range 1-5), and number of previous lines of therapy was 5 (range 3-9), implying that most of the patients were heavily pretreated for cGVHD. The mean (±S.E.) dosage of TKI treatment was as follows: Ruxolitinib was started at 15±1.1mg as initial dose and 20±0.7, 19±1.5, 22±4.4 mg per day in two divided doses on months 3, 6 and 12, respectively. Ibrutinib dose was 226±37, 256±37, 308±40 and 370±33 mg per day, while Imatinib dose was 106±6, 189±18, 196±16 and 190±19 mg per day prior to TKI starts, at months 3, 6 and 12, respectively. With a median follow up duration of 12 months, 19 (31%), 20 (32%), and 17 patients (27%) responded to TKI therapy at 3, 6, and 12 months without any difference of ORR among the TKIs (p=0.126, 0.554, 0.721 at 3/6/12 months; Figure A). The CBs were achieved in 47 (76%), 34 (55%), and 23 patients (37%) at 3, 6 and 12 months without any difference of CBs among the TKIs (p=0.187, 0.499, 0.750 at 3/6/12 months; Figure B). Prednisone dose (mg/kg/day) was 0.238±0.03 prior to TKI initiation, 0.177±0.03, 0.173 ± 0.03 and 0.110 ± 0.02 at 3, 6, and 12 months, respectively. No difference was noted in steroid dose among the 3 TKIs at each time point. However, the Ibrutinib group tends to require higher prednisone dose over time than other 2 groups. The FFS at 12 months was higher in Imatinib (71%) or Ruxolitinib groups (67%) than Ibrutinib group (46%; Figure C). The OS rate at 12 months was similar: 100 % in Ruxolitinib and Ibrutinib, and 96% in Imatinib group (Figure D). With regard to those patients treated with TKI for sclerotic GVHD (n= 39), the ORR were 11 (28%), 15 (38%) and 13 (33%) for 3, 6 and 12 months, while CB was noted in 32 (82%), 25 (64%) and 16 patients (41%) at 3, 6 and 12 months respectively. Of interest, Ruxolitinib was as effective as Imatinib in improving PROM score of sclerotic GVHD, while no significant improvement of PROM score was observed in the patients treated with Ibrutinib. Conclusion This retrospective study evaluated the efficacy of TKI drugs for cGVHD treatment in heavily pretreated patients. Ruxolitinib seems as effective as Imatinib to treat sclerotic GVHD. No difference was observed in OS at 12 months; while FFS appears better with Ruxolitinib and Imatinib over Ibrutinib. Figure Disclosures Lipton: Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding.

scholarly journals Multicenter, Retrospective Evaluation of Therapeutic Efficacy of Ruxolitinib for Chronic Gvhd Treatment

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 45-47
Author(s):  
Jennifer White ◽  
Nada Hamad ◽  
Swe Mar Linn ◽  
Igor Nicolas Novitzky-Basso ◽  
Omar Abduljalil ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Dose Reduction ◽  
Clinical Benefit ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Median Number ◽  
Steroid Resistant ◽  
Prednisone Dose ◽  
Steroid Dose ◽  
Heavily Pretreated

Background Several agents have been investigated for beyond second-line treatment of chronic graft-versus-host disease (GVHD). Ruxolitinib has been recently approved for steroid-refractory acute GVHD, while a prospective randomized study is ongoing to examine its efficacy in steroid-resistant chronic GVHD (cGVHD). The present study evaluated the efficacy of Ruxolitinib in terms of 1) overall response rate (ORR), 2) clinical benefit (CB), 3) dose reduction of corticosteroid exposure, 4) failure-free survival (FFS) and 5) overall survival (OS), in patients heavily pretreated for steroid-resistant cGVHD. Patients and methods A total of 47 patients who developed cGVHD after HCT and treated with Ruxolitinib for cGVHD from March 2016 to April 2020, at three different sites (Princess Margaret Cancer Center, Canada; Vancouver General Hospital, Canada and Saint Vincent Hospital, Australia), were evaluated in the retrospective study. Patients and disease characteristics are as follows: median age 52 years; classical 35 (71%), overlap syndrome 14 (29%). Of note, 27 patients (57.4%) had a previous history of acute GVHD. The ORR and CB were assessed at months 3, 6 and 12, retrospectively. Responses were evaluated according to NIH scoring/staging/response assessment as part of standard clinical practice. CB was assessed considering clinical response as well as steroid dose reduction. For systemic steroid dose reduction, prednisone dose per kg per day was captured prior to Ruxolitinib start, at months 3, 6 and 12. Treatment failure was defined as 1) resistance requiring treatment switch, 2) non-relapse mortality (NRM), 3) relapse, 4) intolerance to treatment. FFS and OS were calculated from the day of starting Ruxolitinib therapy for cGVHD treatment. Results A total of 47 patients had moderate (11/47, 24.4%) to severe (33/47, 73.3%) cGVHD except one who had mild grade cGVHD with a high-risk feature (thrombocytopenia at the time of Ruxolitinib start). The median number of organ involvement was 3 (range 1-7). Over half of patients (63.8%) received Ruxolitinib as 4th line or beyond for cGVHD treatment, while median number of previous lines of therapy was 3 (range 1-9). All 47 patients (100%) had been previously treated with systemic steroids; other previous treatments included ECP therapy (53.2%), Imatinib (29.8%), Ibrutinib (23.4%), Rituximab (21.3%). Ruxolitinib was started at 10-15 mg daily as initial dose, then maintained at 20mg daily in two divided doses on months 3, 6 and 12.With a median follow-up duration of 12 months, ORR was attained in 35.7%, 36.0% and 35.0% at 3, 6 and 12 months, respectively (Figure A). Of note, ORR in patients with sclerotic changes was 56%, and 61.5% in those with lung involvement. Patients resistant to TKI (i.e. Imatinib or Ibrutinib) for cGVHD treatment showed similar ORR compared to those naïve to TKI therapy.The CB was observed in 53.5%, 66.7% and 72.2% at months 3, 6 and 12, respectively (Figure B). Patients resistant to TKI for cGVHD treatment did not show any difference in CB compared to those naïve to TKI therapy.In terms of prednisone dose reduction, by 12 months , half of patients (50.0%) could taper prednisone doses below 0.1mg/kg/day, while the proportion of patients on prednisone dose below 0.1mg/kg/day was 9.3%, 20.0%, 17.4%, and 50.0% at month 0, 3, 6 and 12, respectively (Figure C). The group who achieved CB at 3 months showed a significantly lower dose of prednisone at 12 months (0.078mg/kg/day) compared to those without clinical benefit at 3 months (0.197mg/kg/day; p=0.033; Figure D).Out of 37 patients evaluated, 11 failures (29.7%) were noted, including resistance requiring a switch to other therapy (n=7), NRM (n=2) and intolerance (n=2). The FFS rate at 1 year in the overall population was 68.5% (Figure E). The FFS at 1 year in those having CB at 3 months vs not was 86.5% vs 51.4% (p=0.025).The OS at 1 year was 90.9% (Figure F). The OS at 1 year in those having a CB at 3 months vs not was 100% vs 78.8% (p=0.053). Conclusion: This multicenter retrospective study revealed that Ruxolitinib is an effective treatment option for patients with cGVHD, with good ORR and CB. The achievement of CB in the first 3 months correlated well with steroid dose reduction. It suggests that Ruxolitinib is a feasible GVHD treatment option, even for patients who were heavily pretreated for cGVHD or failed previous TKI drug. Figure 1 Disclosures Hamad: Abbvie: Honoraria; Novartis: Honoraria. OffLabel Disclosure: Ruxolitinib treatment for steroid resistant chronic GVHD

A Phase 1 Study of DCC-2036, a Novel Oral Inhibitor of BCR-ABL Kinase, in Patients with Philadelphia Chromosome Positive (Ph+) Leukemias Including Patients with T315I Mutation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 601-601 ◽  
Author(s):  
Jorge E. Cortes ◽  
Moshe Talpaz ◽  
Hagop M Kantarjian ◽  
Hedy Smith ◽  
Dale Bixby ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Dose Level ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Cytogenetic Response ◽  
Lower Extremity Weakness ◽  
Hematologic Response ◽  
T315i Mutation ◽  
Dose Levels

Abstract Abstract 601 Background. DCC-2036 is a novel and potent tyrosine kinase inhibitor (TKI) which binds to a novel region called the switch pocket, thereby preventing BCR-ABL from adopting a conformationally active state. Efficacy against multiple imatinib-resistant BCR-ABL mutants has been demonstrated both in vitro and in vivo (Chan et al., Cancer Cell 2011;19:556). Importantly, DCC-2036 retains full potency against the T315I mutant in preclinical efficacy studies. Methods. This study was designed to find the maximal tolerated dose (MTD) of DCC-2036 when administered daily as a single-agent on a 28-day cycle. Eligible patients included adults with Ph+ CML/ALL who were refractory/intolerant to ≥2 TKI's or were T315I positive. Initially DCC-2036 capsules were administered orally once daily (QD) at increasing dose levels. Only 1 patient was enrolled in each of the lowest dose cohorts of 57mg QD and 114 mg QD. For higher doses, 3– 6 patients were enrolled into each ascending dose cohort with standard dose limiting toxicity (DLT) rules evaluating safety in cycle 1 to determine dose escalation. A transition from unformulated capsules (C) to formulated tablets (T) occurred after the 1200 mg QD dose level. Paired blood samples were obtained for PK and PD assessments. Results. 30 patients (16 males, 14 females; median age 59, range 31 – 80) with CML including 19 in Chronic (CP); 8 in Accelerated (AP) and 3 in Blast (BP) Phase were enrolled. Enrolled patients had received 1–6 prior CML treatments, and 11 patients had the T315I mutation. To date, a total of 212.5 (median 5.6; range 0.2 – 23.4) 28-day cycles were administered over 10 dose levels either as C (7 dose levels) or T (3 dose levels). The 7 C dose levels were studied first and included 57 mg QD through 1200 mg QD. Following transition to T, evaluation continued with 100 mg QD, 100 mg twice daily (BID), and 200 mg BID. Two reversible DLTs (Grade 3 peripheral neuropathy and Grade 4 lower extremity weakness) occurred during the initial treatment cycle at the 200 mg T BID dose level. Evaluation of 6 patients at the 150 mg T BID dose level determined that dose to be the MTD. Preliminary safety data show that other Grade (Gr) 3/4 adverse events (AEs) were Gr 3 slurred speech and Gr 3 eruptive nevi. Gr 1/2 AEs included dry mouth, constipation, diarrhea, paresthesias, and retinal vein occlusion. There was 1 case of Gr 2 pancreatitis that recurred on rechallenge in a patient with previous pancreatitis with nilotinib. Preliminary responses include one major molecular response in a CP patient with T315I mutation who started on capsules and transitioned to 100 mg T QD. There was one complete cytogenetic response in a CP patient at 100 mg T BID, and one partial cytogenetic response in a CP patient who started on capsules and transitioned to 100 mg T BID. One patient with AP CML and T315I mutation had a complete hematologic response at 450 mg C QD. Another patient with AP CML had a partial hematologic response after receiving 200 mg BID for 1 cycle and then downdosing to 100 mg T BID. Four out of 8 patients receiving 100 mg tablets and evaluable for efficacy (completed 3 cycles of treatment) had responses. PK results indicate dose-related, nonlinear increases in both peak plasma concentration (Cmax) and exposure (AUC). PD results reveal both acute and steady state post-treatment reductions in phospho-protein levels on Days 1 and 8. Marked reductions in pSTAT5 and pCRKL have been observed in subjects with both CP and AP and appear to be required for clinical response. Conclusion. The MTD of DCC-2036 tablets is 150 mg BID. Preliminary results suggest that DCC-2036 is well tolerated and has anti-leukemia activity in subjects with refractory CML and T315I positive disease. PD results are consistent with inhibition of BCR-ABL signaling in this first-in-man study of a switch pocket tyrosine kinase inhibitor. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Chemgenex: Consultancy, Research Funding; Deciphera Pharmaceuticals: Research Funding. Bixby:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; GlaxoSmithKline: Speakers Bureau. Rafferty:Deciphera Pharmaceuticals: Employment. Berger:Deciphera Pharmaceuticals: Employment. Wise:Deciphera Pharmaceuticals LLC: Employment. Rutkoski:Deciphera Pharmaceuticals: Employment. Smith:Deciphera Pharmaceuticals: Employment. Van Etten:Deciphera Pharmaceuticals: Consultancy, Research Funding.

Benefits of Early Switching From Imatinib to a Second-Generation Tyrosine Kinase Inhibitor Following 12 Month Complete Cytogenetic Response Failure: A Chart Review Analysis.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2792-2792
Author(s):  
Daniel J. DeAngelo ◽  
Lei Chen ◽  
Annie Guerin ◽  
Amy Styles ◽  
Clemence Aberki ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Disease Progression ◽  
Research Funding ◽  
Index Date ◽  
Second Generation ◽  
Kinase Inhibitor ◽  
Cytogenetic Response ◽  
Analysis Group

Abstract Abstract 2792 Background: The National Comprehensive Cancer Network (NCCN) guidelines (version 1.2013) recommend that patients with chronic myelogenous leukemia in chronic phase (CML-CP) should be tested for cytogenetic response 12 months following imatinib initiation. Failure to achieve complete cytogenetic response (CCyR) at 12 months should result in either an increased dose of imatinib (up to 800mg) or a change to a second-generation tyrosine kinase inhibitor (TKI). This study observed patients who failed to achieve CCyR at 12 months following the initiation of imatinib and compared treatment response rates and disease progression between patients who switched to a second-generation TKI early versus patients who did not. Methods: An online chart abstraction form was used to survey US oncologists and hematologists. Physicians submitted de-identified information on up to 10 adult patients with CML-CP who initiated imatinib as first line therapy (between 01/01/2007 and 26/07/2010) and failed to achieve CCyR at 12 months (between 10–14 months). Patients either switched to a second-generation TKI within 3 months following CCyR failure (early-switchers), or remained on imatinib for ≥3 months following CCyR failure (non-switchers). Non-switchers may have later switched to a second-generation TKI. The index date was defined as the date of the 12-month CCyR failure. Detailed patient information was collected, including demographics, comorbidities, imatinib dosage, and hematologic and cytogenetic response prior to the index date. Cytogenetic response and disease progression was also collected after the index date. CCyR was defined as 0% Philadelphia chromosome positive (Ph+) cells on cytogenetic testing. The proportion of patients achieving CCyR by 6, 12, and 24 months was reported among patients who had ≥1 cytogenetic test during these periods. Documented CCyR was defined as CCyR achievement analyzed among all patients, if patients were not tested for CCyR following the index date they were considered not to have achieved CCyR. Time to first documented CCyR achievement and time to disease progression were both estimated using multivariate Cox proportional hazard ratios (HR), where exposure was calculated from the index date to the first documented CCyR achievement, or to the date of progression, respectively. Multivariate regression analyses controlled for age, sex, race, index year, Charlson comorbidity index, imatinib dose and hematological response prior to index date, percentage of Ph+ cells and CML disease duration at index date, number of days between CML diagnosis and imatinib initiation, and rise in transcript level and chromosome abnormalities in Ph+ cells reported prior to the index date. Results: The majority of the 108 surveyed physicians were from a private practice (72.2%) and a small/intermediate practice size (61.1%). Physicians provided information on 593 patients who failed to achieve CCyR at 12 months; 306 were early-switchers and 287 were non-switchers. Among the non-switchers, 78 later switched to a second-generation TKI, and 104 increased imatinib dose after the index date. Patient demographics and comorbidities were similar among early-switchers and non-switchers, however, results of the 12-month cytogenetic test revealed that early-switchers had a greater number of Ph+ positive cells (51. 5 ± 16.6) compared to non-switchers (47.2 ± 13.1, p=.002). The median follow-up time was 612.5 days (range = 91–1625) and 591 days (range = 365–1623), respectively. Among patients tested for cytogenetic response during the follow-up period (274 early-switchers and 252 non-switchers), 35% of early-switchers subsequently achieved CCyR, compared to 24 % of non-switchers (p=.006). Within 6 months after the index date, 4.7% of the early-switchers achieved CCyR vs. 0.4% of non-switchers; by 12 months, 20.1% vs. 12.3% achieved CCyR; and by 24 months, 33.6% vs. 21.8% achieved CCyR, respectively (all p<.016). After adjusting for confounding factors, early-switchers had an 80% greater documented CCyR achievement rate compared to that of non-switchers (HR=1.80; p=.002) and a progression rate that was 81% lower (3.8% vs.1.5%, HR=0.19, p=.034). Conclusion: Early switching from imatinib to a second-generation TKI following 12-month CCyR failure was associated with better cytogenetic response and a lower risk of progression. Disclosures: DeAngelo: Novartis: Consultancy. Off Label Use: Everolimus in AML. Chen:Novartis Oncology: Employment, Own stock in Novartis Other. Guerin:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Styles:Analysis Group, Inc.: Consultancy, Employment, Research Funding. Aberki:Analysis Group, Inc.: Consultancy, Employment, Research Funding. Giguere-Duval:Analysis Group, Inc.: Consultancy, Employment, Research Funding. Wu:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding.

scholarly journals Propensity Score Matching Analysis Comparing Extracorporeal Photopheresis (ECP) Vs Best Available Therapy in Third Line or Later Treatment of Chronic Graft-Versus-Host Disease (cGVHD)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3896-3896
Author(s):  
Swe Mar Linn ◽  
Igor Novitzky-Basso ◽  
Elizabeth Shin ◽  
Christopher J. Patriquin ◽  
Ivan Pasic ◽  
...  
Keyword(s):  
Risk Factors ◽  
Propensity Score ◽  
Dose Reduction ◽  
Research Funding ◽  
Extracorporeal Photopheresis ◽  
Prednisone Dose ◽  
Steroid Dose ◽  
Previous Therapy ◽  
Third Line ◽  
Over Time

Abstract *DB and DK contributed to the work equally Background Prospective randomized controlled data comparing extracorporeal photopheresis (ECP) to other treatments for chronic graft vs host disease (cGvHD) as third-line or later therapy are limited, despite its clinical benefit observed in patients (pts) who failed ≥ 2 lines of previous therapy. Our single-center experience has reported promising results, including 68.3% failure-free survival (FFS) and 85.9% overall survival (OS) at 12 months in 75 heavily pre-treated cGvHD pts treated with ECP (ASH 2021 Abstract ID 152640). The present study compared outcomes, using propensity-score matching (PSM), between ECP ("ECP group", n=74) and a historical cohort treated with best available therapy (BAT) as third-line or later treatment from 2007 to 2021 ("BAT group", n=132). Statistical endpoints such as FFS and OS, as well as steroid dose reduction were evaluated instead of overall response due to limited response assessment data available from retrospective chart review. Patients and methods The BAT group received MMF (n=71, 53.8%), prednisone (n=37, 28.0%), prednisone/cyclosporine (n=7, 5.3%), rituximab (n=7, 5.3%), and others (n=10, 7.6%). There was an imbalance in characteristics between the two groups, as expected; the ECP group had more pts with severe cGVHD (91.1% vs 20.5%; p&lt;0.001), fewer with a previous history of acute GVHD (aGvHD: 60.8% vs 78.0%; p=0.008), and fewer on a prednisone dose ≥0.5mg/kg/day (37.8% vs. 90.5%; p&lt;0.001). PSM analysis was applied to adjust risk factors imbalanced between groups, including cGVHD grade (mild/moderate vs severe), aGVHD history, and baseline prednisone dose (&lt;0.5 vs. ≥ 0.5 mg/kg/day). A total of 54 pts (27 case-control pairs) were selected via PSM within 0.2 of a calliper difference, resulting in the balancing of risk factors between groups: cGVHD severity (p=0.941), aGVHD history (p=0.75) and prednisone dose ≥ 0.5 mg/kg/day (p=0.788). FFS and OS were calculated from the day of starting ECP or BAT, and were compared using Cox's hazard model. Daily prednisone dose at months 0, 3 and 6 were calculated divided by body weight (kg), and the proportions of pts on prednisone ≤ 0, 0.1, 0.2 and 0.5mg/kg/day were compared. Results In the overall cohort (n=206), with a median 29 months of follow-up, 114 treatment failures (55.3%) occurred. While the non-relapse mortality (NRM) was similar in both groups, the ECP group showed a lower rate of resistance requiring therapy switch. Failure was noted in 27 ECP pts (36.4%) due to causes including resistance/intolerance requiring a switch to other therapy (n=15; 20.3%), NRM (n=11, 14.8%), and relapse (n=1; 1.4%), while 87 failures (65.9%) were noted in BAT pts due to resistance requiring a switch to other therapy (n=63; 47.7%), NRM (n=7; 5.3%), and relapse (n=17; 12.9%). In the overall cohort, the 12-month FFS was 68.3% and 32.0% in ECP and BAT groups (p&lt;0.0001; Fig 1A), while OS was 86.2% and 82.2% in ECP and BAT groups, respectively (p=0.333; Fig 1B). In the PSM cohort (n=54), the ECP group showed a survival benefit at 12 months: FFS was 65.8% in the ECP group vs. 30.5% in the BAT group (p=0.00226; Fig 2A), and OS was 76.6% in the ECP group vs. 67.1% in the BAT group (p=0.0977; Fig 2B). Multivariate analysis in the PSM cohort confirmed that ECP was superior to BAT for FFS (p=0.024, HR 0.317 [0.117-0.859]) when adjusted for other risk factors including cGVHD severity, aGvHD history, age, HCT-CI score and prednisone dose ≤0.5mg/kg/day. Prednisone doses were gradually reduced over time; the median doses of prednisone at months 0, 3, and 6 were 0.35, 0.22 and 0.11 mg/kg/day, respectively, in the ECP group vs. 0.96, 0.24 and 0.19mg/kg/day in the BAT group. ECP also showed better kinetics of steroid dose reduction over time; the proportions of pts who discontinued prednisone at months 0, 3 and 6 were 16.2, 17.6% and 32.4% in ECP group vs. 0.8%, 0% and 2.5% in BAT group (Fig 3). The differences in the proportion of pts (delta) who discontinued prednisone in the ECP vs. BAT groups were 15.4%, 17.6% and 29.9% at 0, 3, and 6 months, respectively. Conclusion In the current study using PSM analysis, use of ECP was associated with a superior FFS to BAT when used as third-line or later therapy in cGVHD patients who failed at least 2 lines of previous therapy. Use of ECP also allowed for better steroid tapering in comparison to BAT. Figure 1 Figure 1. Disclosures Patriquin: Alexion: Consultancy, Honoraria, Speakers Bureau; BioCryst Pharmaceuticals: Honoraria; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria. Law: Novartis: Consultancy; Actinium Pharmaceuticals: Research Funding. Lipton: Bristol Myers Squibb, Ariad, Pfizer, Novartis: Consultancy, Research Funding. Mattsson: MattssonAB medical: Current Employment, Current holder of individual stocks in a privately-held company. Kim: Novartis: Consultancy, Honoraria, Research Funding; Paladin: Consultancy, Honoraria, Research Funding; Bristol-Meier Squibb: Research Funding; Pfizer: Honoraria.

scholarly journals For Patients with Sustained MR4-MR4.5, Less Frequent Molecular Monitoring during the First 12 Months after Tyrosine Kinase Inhibitor Cessation Is Viable for Timely Detection of Loss of MMR

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1890-1890
Author(s):  
Naranie Shanmuganathan ◽  
Susan Branford ◽  
Jodi Braley ◽  
Devendra Hiwase ◽  
David T. Yeung ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Molecular Response ◽  
Monitoring Strategy ◽  
Molecular Monitoring ◽  
Advisory Committees

Abstract Background: Discontinuation of tyrosine kinase inhibitor (TKI) treatment for chronic myeloid leukaemia (CML) patients in stable deep molecular response leads to treatment-free remission (TFR) in approximately 50% of cases. In most studies, monthly PCRs was performed for 12 months followed by 2-3 monthly testing thereafter. Around 80% of molecular relapses occur within the first 6 months after TKI cessation. The current recommendation for TKI recommencement is a single BCR-ABL1 value ≥0.1% IS (International scale), indicating loss of major molecular response (MMR). Not all institutions can offer monthly PCR monitoring due to financial constraints, particularly relevant in developing countries. For some patients, remaining on TKI is a cheaper alternative. Aim: To assess the safety of less frequent BCR-ABL1 monitoring for detection of loss of MMR for CML patients attempting TFR. Methods: We monitored 85 patients who ceased TKI with the aim of achieving TFR. Patients had a minimum of 24 months of sustained MR4 (n=3) or MR4.5 (n=82) prior to TKI cessation. At the time of TKI cessation, 64 patients were on imatinib (75%), 17 on nilotinib (20%) and 4 on dasatinib (5%). Forty of the patients were enrolled in the TWISTER study where the criteria for TKI recommencement was loss of MMR or 2 consecutively rising BCR-ABL1 positive values. The remaining patients were on a registry study and the trigger for TKI recommencement was loss of MMR. Results: TKI recommencement occurred in 49 of 85 patients. Median time to TKI recommencement was 4 months (range 2-28 months) at a median BCR-ABL1 value of 0.27% on the International Scale (IS), range 0.002-24% IS. Thirty-six of the 49 patients (73%) lost MMR prior to TKI recommencement; the median time to loss of MMR was 3 months (range 1 to 10 months). One patient lost MMR within the first month. Figure A demonstrates the time to loss of MMR in the 36 patients with PCR values ≥ 0.1%. Eighteen of the 36 patients (50%) lost MMR by the 3 month BCR-ABL1 assessment and 35 of 36 patients (97%) lost MMR by 6 months. The latest loss of MMR was at 10 months. Fourteen patients recommenced TKI at a BCR-ABL1 value of >1% and 1 recommenced at a value >10%. Clinician delay in TKI recommencement of 1 month resulted in a BCR-ABL1 rise from 0.84% to 24% with associated loss of complete hematological response. We propose monthly BCR-ABL1 testing between 2 and 6 months post TKI cessation followed by 2 monthly testing. Detection of a BCR-ABL1 value of ≥0.1% would trigger TKI recommencement. In the presence of a rising BCR-ABL1, which remains ≤0.1%, monthly monitoring should ensue in order to avoid hematological relapse. If this strategy were employed in this cohort of patients, only 1 patient would have had the trigger for TKI recommencement delayed by 1 month (estimated BCR-ABL1 at recommencement ~2.5%). This patient had loss of MMR in the first month post TKI cessation. If this molecular monitoring strategy was applied to patients in our cohort who had not lost MMR at TKI recommencement, we estimate that 1 other patient would have had TKI recommencement delayed by 1 month based on the average BCR-ABL1 doubling time of 1 log per month. A proportion of patients maintain low levels of BCR-ABL1 after TKI cessation and do not lose MMR. There were 2 such patients in our cohort. Conclusion: The critical time for molecular monitoring to trigger TKI recommencement is the first 6 months. A monthly monitoring strategy beginning 2 months after cessation would capture the majority of patients at loss of MMR. The data suggest that after 6 months, 2-monthly monitoring could follow. Monthly BCR-ABL1 testing can be re-introduced in the event of a positive result in those that ceased TKI with undetectable BCR-ABL1 or if there is a BCR-ABL1 result higher than the cessation value. This approach would reduce BCR-ABL1 testing by approximately 33% in the majority of cases while minimizing hematological relapse. Therefore this strategy would reduce the cost and inconvenience of molecular monitoring for a trial of TKI cessation, making the option of TFR available to some patients for whom it is otherwise not feasible. Disclosures Branford: Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cepheid: Consultancy; Ariad: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yeung:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Research Funding. Ross:Novartis Pharmaceuticals: Honoraria, Research Funding; BMS: Honoraria. Hughes:Bristol-Myers Squibb: 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; Novartis Pharmaceuticals: 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.

Impact of Treatment Strategies on Clinical Outcomes In Chronic Phase Chronic Myeloid Leukemia (CP-CML) Patients In Canada

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2569-2569
Author(s):  
Nancy Cribb ◽  
Tazmin Merali ◽  
Bonnie MK Donato
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Clinical Outcomes ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Second Generation ◽  
Kinase Inhibitor ◽  
Response Times ◽  
Line Treatment

Abstract Abstract 2569 Background: New treatment options in chronic myeloid leukemia (CML) have become available in the past years. However, there is a scarcity of published data documenting how patients are treated as well as the impact of the treatment of CP-CML in Canada. Objective: To describe current treatment patterns and clinical outcomes of CP-CML patients receiving treatment in Canada. Methods: Treatment data on CP-CML patients was extracted from a cancer patient treatment summary database, ONCO-CAPPS. The database is comprised of treatment summaries of over 12,000 Canadian cancer patients from across the country. For the study, CP-CML patients aged 18 years or older, who received 400mg of imatinib as 1st-line treatment, and who completed at least 4 continuous weeks of this treatment between October 1, 2008 and December 31, 2009, were eligible for study inclusion. Results: A total of 301 patients met the selection criteria. At the time of review, 62% of patients had a confirmed diagnosis of CP-CML for 2 years or more. Of the CP-CML patients in the study who were prescribed 400mg of imatinib as their initial CP-CML treatment, 51% (155/301) received a 2nd line treatment option, either a dose modification or a change of therapy. Of those requiring 2nd line treatment, 32% (50/155) of patients received an increase in their imatinib dose, resulting in an average daily dose of 664 mg, and representing a 66% increase in the dose of imatinib. Average response times for patients who received an increase in imatinib dose for Complete Hematological Response (CHR) was 183 days, for Complete Cytogenetic Response (CCyR) was 671 days, and for Major Molecular Response (MMR) was 971 days. These response times exceed both Canadian Consensus Guidelines as well as the 2009 ELN (European Leukemia Network) recommendations. Furthermore, 45% (69/155) of patients receiving a 2nd line CML treatment experienced intolerance to imatinib 400 mg resulting in dose decrease or treatment interruption. Switching to second generation tyrosine kinase inhibitor agents (dasatinib or nilotinib) due to inadequate response, loss of response or intolerance to imatinib occurred in 20% of the population. Conclusions: Analysis of Canadian patients over time revealed that 51% of CP-CML patients initiated on 400mg imatinib received 2nd line treatment. The most frequent modification was due to intolerance. Of note, 32% received a dose escalation, which was more common than switching to a second generation tyrosine kinase inhibitor. Furthermore, response times observed amongst patients in this study whose imatinib dose was escalated exceeded timelines for treatment response determination as noted in both internationally and locally recognized treatment guidelines. Published research demonstrates that delays in achieving response are associated with increased risk of progression among patients with CML. Disclosures: Cribb: Drug Intelligence Inc.: Research Funding. Merali:Bristol-Myers Squibb Canada: Research Funding. Donato:Drug Intelligence Inc.: Research Funding.

A New Computational Method to Predict Long-Term Minimal Residual Disease and Molecular Relapse after TKI-Cessation in CML

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3099-3099 ◽  
Author(s):  
Ingmar Glauche ◽  
Hendrik Liebscher ◽  
Christoph Baldow ◽  
Matthias Kuhn ◽  
Philipp Schulze ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Molecular Response ◽  
Tki Treatment

Abstract Predicting minimal residual disease (MRD) levels in tyrosine kinase inhibitor (TKI)-treated chronic myeloid leukemia (CML) patients is of major clinical relevance. The reason is that residual leukemic (stem) cells are the source for both, potential relapses of the leukemicclone but also for its clonal evolution and, therefore, for the occurrence of resistance. The state-of-the art method for monitoring MRD in TKI-treated CML is the quantification of BCR-ABL levels in the peripheral blood (PB) by PCR. However, the question is whether BCR-ABL levels in the PB can be used as a reliable estimate for residual leukemic cells at the level of hematopoietic stem cells in the bone marrow (BM). Moreover, once the BCR-ABL levels have been reduced to undetectable levels, information on treatment kinetics is censored by the PCR detection limit. Clearly, BCR-ABL negativity in the PB suggests very low levels of residual disease also in the BM, but whether the MRD level remains at a constant level or decreases further cannot be read from the BCR-ABL negativity itself. Thus, also the prediction of a suitable time point for treatment cessation based on residual disease levels cannot be obtained from PCR monitoring in the PB and currently remains a heuristic decision. To overcome the current lack of a suitable biomarker for residual disease levels in the BM, we propose the application of a computational approach to quantitatively describe and predict long-term BCR-ABL levels. The underlying mathematical model has previously been validated by the comparison to more than 500 long-term BCR-ABL kinetics in the PB from different clinical trials under continuous TKI-treatment [1,2,3]. Here, we present results that show how this computational approach can be used to estimate MRD levels in the BM based on the measurements in the PB. Our results demonstrate that the mathematical model can quantitatively reproduce the cumulative incidence of the loss of deep and major molecular response in a population of patients, as published by Mahon et al. [4] and Rousselot et al. [5]. Furthermore, to demonstrate how the model can be used to predict the BCR-ABL levels and to estimate the molecular relapse probability of individual patients, we compare simulation results with more than 70 individual BCR-ABL-kinetics. For this analysis we use patient data from different clinical studies (e.g. EURO-SKI: NCT01596114, STIM(s): NCT00478985, NCT01343173) where TKI-treatment had been stopped after prolonged deep molecular response periods. Specifically, we propose to combine statistical (non-linear regression) and mechanistic (agent-based) modelling techniques, which allows us to quantify the reliability of model predictions by confidence regions based on the quality (i.e. number and variance) of the clinical measurements and on the particular kinetic response characteristics of individual patients. The proposed approach has the potential to support clinical decision making because it provides quantitative, patient-specific predictions of the treatment response together with a confidence measure, which allows to judge the amount of information that is provided by the theoretical prediction. References [1] Roeder et al. (2006) Dynamic modeling of imatinib-treated chronic myeloid leukemia: functional insights and clinical implications, Nat Med 12(10):1181-4 [2] Horn et al. (2013) Model-based decision rules reduce the risk of molecular relapse after cessation of tyrosine kinase inhibitor therapy in chronic myeloid leukemia, Blood 121(2):378-84. [3] Glauche et al. (2014) Model-Based Characterization of the Molecular Response Dynamics of Tyrosine Kinase Inhibitor (TKI)-Treated CML Patients a Comparison of Imatinib and Dasatinib First-Line Therapy, Blood 124:4562 [4] Mahon et al. (2010) Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 11(11):1029-35 [5] Rousselot 
et al. (2014) Loss of major molecular response as a trigger for restarting TKI therapy in patients with CP- CML who have stopped Imatinib after durable undetectable disease, JCO 32(5):424-431 Disclosures Glauche: Bristol Meyer Squib: Research Funding. von Bubnoff:Amgen: Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria. Saussele:ARIAD: Honoraria; Novartis: Honoraria, Other: Travel grants, Research Funding; Pfizer: Honoraria, Other: Travel grants; BMS: Honoraria, Other: Travel grants, Research Funding. Mustjoki:Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Novartis: Honoraria, Research Funding. Guilhot:CELEGENE: Consultancy. Mahon:NOVARTIS PHARMA: Honoraria, Research Funding; BMS: Honoraria; PFIZER: Honoraria; ARIAD: Honoraria. Roeder:Bristol-Myers Squibb: Honoraria, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document