Survival Impact of Patients (Pts) with Chronic Myeloid Leukemia (CML) Due to Failure from the Use of One or More Tyrosine Kinase Inhibitors (TKI)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1587-1587 ◽  
Author(s):  
Mary Akosile ◽  
Sherry Pierce ◽  
Mark Brandt ◽  
Srdan Verstovsek ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Overall Survival ◽  
Median Survival ◽  
Survival Probability ◽  
Research Funding ◽  
Treatment Options ◽  
Chronic Phase ◽  
Response To Therapy ◽  
Free Survival ◽  
The Impact

Abstract Background: Imatinib induces durable complete cytogenetic remissions (CCyR) in at least two thirds of pts with chronic phase (CP) CML, most of them also achieving a major molecular response (MMR). However, some pts become intolerant or resistant to imatinib and require change of therapy to a 2nd or 3rd generation TKIs (dasatinib, nilotinib, bosutinib, and/or ponatinib). The projected 3-year survival for these pts was reported as 72% (Kantarjian et al. Cancer 2007) at a time when treatment options for such pts was limited. A smaller subset of pts may require additional changes to a third or fourth TKI. The impact of sequential TKI therapy, although standard practice, has not been well studied. We analyzed the long term outcome of pts receiving multiple TKIs. Method: We analyzed the medical records of 1775 pts with CML-CP treated at a single institution between 02/2000 and 07/2015. Among them 582 (33%) received more than one TKI as follows: 2TKIs (n=370), 3TKIs (n=130), and 4+TKIs (n=82; 4 TKI n=59, 5 TKI n=20, 6 TKI n=1, 7 TKI n=2). For the purpose of this analysis, a TKI used more than once was counted as 2 TKI provided there was a different TKI used between the two periods when the TKI in question was used. We analyzed pt's characteristics, response to therapy, transformation to accelerated and blast phase, and long term outcomes. Overall Survival (OS) and Transformation-Free Survival (TFS) probabilities were measured using Kaplan-Meier method starting from the date they began to use the their 2nd TKI and grouped by the number of TKI used. Results: The number of CML pts in early CP (diagnosis to start of therapy, ≤ 12 months) that used 2, 3, and 4+TKIs was 229, 54, and 34, respectively. The number of pts in late CP (diagnosis to start of therapy >12 months) that used 2, 3, and 4+TKIs was 141, 76 and 48 respectively. The median age (range) for pts that used 2, 3, and 4+ TKIs were 48 yrs (15-81), 52 yrs (18-87), and 53 yrs (18-80), respectively. The ratio of males to females in each cohort was 187:183, 58:72, and 37:45, respectively. The median time from diagnosis to 2nd, 3rd and 4th TKI was 2, 4, and 6 years respectively. For the 3 cohorts (2, 3, 4+TKIs), TKIs used included imatinib (n=322, n=130, n=79), dasatinib (n=227, n=112, n=77), nilotinib (n=119, n=109, n=70), ponatinib (n=44, n=27, n=37) and bosutinib (n=26, n=13, n=29), respectively. The 3-year overall survival probability for pts treated with 2 TKI was 88% (median survival not reached); for those that used 3 TKI 72% (median survival not reached), and for those that used 4+ TKI 48% (median survival 34 months) (Fig. 1). Corresponding 5-year figures are 80%, 53% and 38%. The 3-year transformation-free survival probability for pts treated with 2 TKI was 93%; for those treated with 3 TKI 88%; and for pts treated with 4 TKI 80% (median not reached in any cohort ) (Fig. 2). Corresponding figures for 5-years are 90%, 84%, and 75%. Conclusion: With more and improved treatment options, pts with resistance or intolerance to multiple TKI have the potential for long-term survival. Nearly 80% of pts who receive 2 TKI are alive at 5 years and more than 90% remain in chronic phase. As pts experience subsequent failure, the outcome worsens. These results provide information that may help with treatment planning and set the expectations against which treatment options used in such pts should be measured. Figure 1. Overall Survival Probability Figure 1. Overall Survival Probability Figure 2. Transformation-Free Survival Probability Figure 2. Transformation-Free Survival Probability Disclosures Wierda: Glaxo-Smith-Kline Inc.: Research Funding; Celgene Corp.: Consultancy. Daver:ImmunoGen: Other: clinical trial, Research Funding. Burger:Pharmacyclics LLC, an AbbVie Company: Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BerGenBio AS: Research Funding; BMS: Consultancy, Research Funding; Teva: Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

Seven-Year Follow-up Data on Sequential Prospective Trials of Imatinib 400mg Vs 800mg Daily Schedule for Front-Line Treatment of Chronic Myeloid Leukemia (CML).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3438-3438
Author(s):  
Naveen Pemmaraju ◽  
Hagop Kantarjian ◽  
Susan O'Brien ◽  
Srdan Verstovsek ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Chronic Phase ◽  
Annual Rate ◽  
Molecular Response ◽  
Free Survival ◽  
Cumulative Rate ◽  
Prospective Trials

Abstract Abstract 3438 Background: The standard of care for most patients (pts) with CML has been imatinib mesylate at a dose of 400mg by mouth daily. Earlier studies have suggested that there may be a benefit to pts to start treatment at a higher dose as this may result in faster and more durable responses to imatinib. It is not yet known whether long-term event-free survival (EFS), transformation-free survival (TFS), and overall survival (OS) will be impacted by the higher dosing schedule. Objectives: To determine the long term responses and clinical benefit of imatinib 800mg daily versus 400mg daily dosing when used as upfront treatment strategy in CML. Methods: We conducted sequential prospective trials using imatinib 400mg or 800mg daily as initial therapy for patients with previously untreated chronic phase CML. Results: A total of 281 pts were included in these trials: 208 treated with 800mg and 73 with 400mg. The median follow-up for each group was 79 months (range: 3–107) and 110 months (range: 2–116). The overall, cumulative rate of complete cytogenetic response (CCyR) was 91% and 87%, respectively (p=0.49) for those treated with high- and standard-dose, and the cumulative rate of major molecular response (MMR) was 87% and 78%, respectively (p=0.06). Rates of CCyR at 12 months were 90% and 66%, respectively (p < 0.001), and MMR at 18 months 82% and 68%, respectively (p=0.04). A significantly better EFS (definition per IRIS criteria) was observed for the 800 mg group compared to that in the 400mg group (log-rank test, p=0.049; estimated 7-year EFS 86% vs 76% by Kaplan-Meier method). No significant differences were seen for survival free from transformation to accelerated and blast phase (p = 0.46) and overall survival (p = 0.27). For OS, thus far 19 pts in the 800mg group have died (2 probable CML-related, 3 unknown causes, 14 non CML related) compared to 13 pts (10 probable CML-related, 3 non CML-related) in the 400mg group. The table below shows the annual rate of events and transformation for each dose group. Treatment discontinuation for toxicity occurred in 16 (8%) pts treated with 800mg and 6 (8%) pts treated with 400mg. Conclusions: At 7-year follow up, pts treated with 800mg demonstrated a significantly better EFS (by IRIS criteria) compared to those treated with 400mg. There is a trend for a lower annual rate of events and transformation with the higher dose, particualry in the earlier years, but no difference in OS. These results suggest a modest benefit for patients treated with higher dose imatinib. Disclosures: Off Label Use: imatinib at dose of 800mg po daily for CML. Kantarjian:BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Verstovsek:Incyte Corporation: Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau. Cortes:Pfizer: Consultancy, Research Funding; BMS: Honoraria, Research Funding; Novarits: Honoraria, Research Funding.

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

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 672-672
Author(s):  
Hagop Kantarjian ◽  
Susan O'Brien ◽  
Elias Jabbour ◽  
Jianqin Shan ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Research Funding ◽  
Chronic Phase ◽  
Patient Choice ◽  
Imatinib Therapy ◽  
Free Survival ◽  
Blastic Phase ◽  
Resistance Loss ◽  
Frontline Therapy

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

Improved Survival in Chronic Myeloid Leukemia (CML) Since the Introductin of Imatinib Therapy - A Single Institution Historical Experience

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2750-2750
Author(s):  
Hun Lee ◽  
Jorge E. Cortes ◽  
Susan O'Brien ◽  
Elias Jabbour ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Median Survival ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Imatinib Therapy ◽  
Blastic Phase ◽  
Group A ◽  
The Impact ◽  
Over Time

Abstract Abstract 2750 Background: Outcome of CML since introduction of imatinib therapy has improved. Aims: analyze improvement of CML outcome in different phases. Study Group: A total of 1,569 patients with CML referred since 1965, within 1 month from diagnosis, were reviewed and used to identify phase-specific prognostic factors: 1,148 chronic, 175 accelerated, 246 blastic. Results: The median survival was 8.9 years in chronic, 4.8 years in accelerated, and 6 months in blastic phase. In chronic phase, the 8-year survival was ≤ 15% before 1983, 42–65% from 1983 to 2000, and 87% since 2001 (Figure 1). Survival was worse in older patients (p=0.004), but less significant since 2001 (p=0.07). Survival by Sokal risk was significantly different before 2001 (p<0.001), but not since 2001 (p=0.4). In accelerated phase, survival improved over time (p<0.001); the 8-year survival in patients treated since 2001 was 75% (Figure 2). Survival by age was not different in years < 2001 (p=0.09), but was better since 2001 in patients ≤ 70 years (p=0.004). Multivariate analysis derived adverse factors since 2001: older age (p=0.049), increased marrow blasts (p=0.03). In blastic phase, the median survival improved over time (p<0.001), although it is only 7 months since 2001. Conclusions: Survival in CML significantly improved significantly since 2001, particularly so in chronic and accelerated phases. Imatinib therapy minimized the impact of known prognostic factors and Sokal risk in chronic phase, and accentuated the impact of age in accelerated and blastic phases. Disclosures: Cortes: Novartis: Consultancy; Novartis: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

Results of Second Generation Tyrosine Kinase Inhibitor Frontline Therapy in Chronic Myeloid Leukemia with Variant Philadelphia Chromosome

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3774-3774
Author(s):  
Carlos G. Romo ◽  
Hagop M Kantarjian ◽  
Susan O'Brien ◽  
Alfonso Quintas-Cardama ◽  
Steven M. Kornblau ◽  
...  
Keyword(s):  
Research Funding ◽  
Second Generation ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Initial Therapy ◽  
Response To Therapy ◽  
Chromosome 9 ◽  
Derivative Chromosome ◽  
Free Survival ◽  
Ph Chromosome

Abstract Abstract 3774 Background: Variant Philadelphia (Ph) chromosomes are observed in 5–10% of patients (pts) with CML, involving one or more additional chromosomes besides 9 and 22. Deletions of derivative chromosome 9 (del der (9)) occur in 10–15% of pts, and frequently these abnormalities coexist. Prior to the advent of TKIs pts with variant Ph or del der (9) had a worse outcome. With imatinib the adverse prognosis conferred by these abnormalities has been minimized. To our knowledge there are no published reports regarding the outcomes of pts with variant Ph or del der(9) while on treatment with a 2nd generation TKI as initial therapy for CML. We analyzed the significance of these abnormalities among patients with CML in chronic phase (CP) enrolled in 2 parallel trials of dasatinib or nilotinib as initial therapy. Patients and Methods: A total of 205 pts with CML in CP treated between 2005 and 2012 at our institution with frontline dasatinib or nilotinib based protocols were included in this analysis. Among them 193 (94%) had classic Ph chromosome, and 12 (6%) had a variant Ph chromosome. Nineteen of the 205 pts (9%) had del der (9). Their characteristics and outcomes were compared. Results: Only one additional chromosome was present in the Ph rearrangement in each of the variant Ph-positive cases. The additional chromosomes found were 17 in three patients and chromosomes 1, 3, 4, 5, 9, 11, 14, 19, 21 in one patient each. Del der (9) was found in 2 of 12 pts with variant Ph and in 17 with classic Ph. Five (50%) of the pts with variant Ph were treated with dasatinib and 5 (50%) with nilotinib. Of those with classical Ph 93 (48%) were treated with dasatinib and 100 (52%) with nilotinib. The median age was 48 yrs (range 17 to 86) for those with classic Ph, and 53 yrs (24 to 79) for those with variant Ph. The Sokal risk group for those with classic Ph was high in 16 (8%), intermediate in 53 (28%), and low in 124 (64%). For the patients with variant Ph risk classification was 10%, 50% and 40%. No significant differences were observed in response to therapy between pts with variant Ph and those with classic Ph (CCyR 100% vs. 93%; MMR 100% vs. 85%, respectively), or between those with del der (9) and those without it (CCyR 100% vs. 93%; MMR 100% vs. 84%). The 3-year probability of overall survival (OS) was 99% for pts with classic Ph and 89% for those with variant Ph. Corresponding values for 3-year event-free survival (EFS) were 96% and 89%, and transformation-free survival (TFS) 99% and 100% respectively. 3-year OS, EFS and TFS were also similar between pts with del derv (9) and those without it (Table 1). Among the 2 pts with concomitant variant Ph and del der (9), one achieved CCyR at 3 months and has maintained it with 12 months of follow up. The second one achieved CCyR but became pregnant during the course of treatment; the TKI was temporarily discontinued and she lost cytogenetic response, but regained response after 3 months of reinitiating TKI therapy and delivering a healthy baby. Conclusion: The presence of variant Ph chromosome or del der (9) does not affect the clinical characteristics or outcome of pts with CML CP treated with second generation TKI as initial therapy. Disclosures: Kantarjian: Pfizer: Research Funding; Ariad: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Jabbour:Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Cortes:Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding.

scholarly journals Depth of Response in Waldenstrom Macroglobulinemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4141-4141
Author(s):  
Jonas Paludo ◽  
Jithma Prasad Abeykoon ◽  
Morie A. Gertz ◽  
Prashant Kapoor ◽  
Aneel Paulus ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response To Therapy ◽  
Response Criteria ◽  
Advisory Committees ◽  
Free Survival ◽  
Depth Of Response ◽  
Best Response ◽  
The Impact ◽  
Disease Free

Abstract Introduction Recent advances in the understanding of the WM pathobiology led to the expansion of our therapeutic options in this disease. A number of targeted drugs are either available or under investigation and are poised to change the chemo-immunotherapy paradigm in the treatment of WM. Now more than ever, an individualized treatment approach for patients with WM is possible, where patient characteristics and preferences can be matched by different treatment goals and side effect profiles. While deep responses have been associated with longer disease-free survival in other hematologic malignancies, data on patients with WM are sparse. We report the impact of depth of response in disease-free and overall survival (OS) in WM. Methods WM patients consecutively seen at Mayo Clinic between 01/1998 and 12/2016 were reviewed for response to therapy and disease burden. The best response achieved after the treatment of interest (TOI) was classified using the IWWM-7 Response Criteria. The included TOI were: BR, DRC, BDR and high-dose chemotherapy followed by ASCT. All time-to-event analyses were performed from the TOI initiation date using the Kaplan-Meier method and the log-rank test. A landmark analysis from the date-of-best response was also performed for OS to prevent immortal-time bias. Univariate and multivariate analyses of progression-free survival (PFS) and time-to-next therapy (TTNT) were performed using the Cox regression method. Results A total of 181 patients had disease response assessed after the TOI. Baseline characteristics at time of diagnosis are summarized in table 1. The median follow up from TOI was 3.8 years (95% CI: 3-4), the majority of patients received TOI as salvage therapy [n=112 (63%); median 2nd line (rage 1-11)]. Best response rates with the corresponding 5-year PFS and TTNT are summarized in table 2. The median OS from TOI was longer in patients who achieved at least a PR [median 7.2 years (95% CI: 5-NR) vs 3.7 years (95% CI: 1.6-NR), p=0.01]. A trend towards a longer OS was also seen with deeper responses (PR or better) achieved with frontline therapy [median 5.8 years (95% CI: 5.8-NR) vs 3.4 years (95% CI: 1.6-NR), p=0.24]. Figure 1 shows the correlation between deeper responses with PFS and TTNT. Among patients achieving a PR or VGPR, those with a normal FLC ratio post TOI demonstrated a longer PFS and TTNT [PFS: median NR (95% CI: 3.4-NR) vs 4.9 years (95% CI: 2.8-8.7), p=0.01; TTNT: median NR (95% CI: 3.5-NR) vs 5.2 years (95% CI: 4.2-9.4), p=0.04], figure 2. In a multivariate analysis including normal FLC ratio, normal IgM level and minimal BM involvement (<5%) post TOI, normal FLC ratio remained an independent prognostic factor for longer PFS and TTNT. Similar trends were seen when considering treatment naïve and relapsed/refractory patients independently (data not shown). Discussion Our results not only suggest an association between depth of response with PFS and TTNT, but also with OS in patients with WM. A normal FLC ratio (not part of the IWWM-7 response criteria) seems to predict a longer disease-free interval in patients achieving a PR or VGPR. Disclosures Gertz: Ionis: Honoraria; Apellis: Consultancy; annexon: Consultancy; Prothena: Honoraria; janssen: Consultancy; Physicians Education Resource: Consultancy; Alnylam: Honoraria; Teva: Consultancy; spectrum: Consultancy, Honoraria; Medscape: Consultancy; celgene: Consultancy; Research to Practice: Consultancy; Amgen: Consultancy; Abbvie: Consultancy. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Ailawadhi:Amgen: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Pharmacyclics: Research Funding; Celgene: Consultancy. Reeder:Affimed: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Kumar:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:Seattle Genetics: Research Funding; Celldex: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Regeneron: Research Funding.

scholarly journals Ponatinib in Combination with FLAG-IDA Chemotherapy for Blast-Phase Chronic Myeloid Leukemia: Final Results of the Seamless Phase I/II Dose-Finding UK Trials Acceleration Programme (TAP) Matchpoint Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 312-312
Author(s):  
Mhairi Copland ◽  
Daniel Slade ◽  
Graham McIlroy ◽  
Gillian Horne ◽  
Jennifer Byrne ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Chronic Phase ◽  
Optimal Dose ◽  
High Dose Chemotherapy ◽  
Dose Finding ◽  
High Dose ◽  
Blast Phase

Abstract Background Outcomes for patients with blast-phase chronic myeloid leukaemia (BP-CML) are extremely poor, and allogeneic stem cell transplantation (alloSCT) represents the only opportunity for cure. Crucially, long-term survival post-transplant depends on first attaining a return to chronic phase though salvage treatment. Novel strategies that improve response and can optimise transplant outcomes are therefore required. In the era of tyrosine kinase inhibitors (TKIs), BP-CML has become an orphan disease. Consequently, the prospective trials needed to guide clinical practice are rarely attempted. We now report the final results of the prospective MATCHPOINT trial which uses an innovative EffTox design to investigate the activity and tolerability of the TKI ponatinib in combination with high-dose chemotherapy, to improve remission status and transplant outcomes in BP-CML. Methods and patients Between March 2015 and April 2018, 17 patients were recruited through the UK Trials Acceleration Programme to this dose-finding, seamless phase I/II trial of daily ponatinib combined with fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin (PON-FLAG-IDA) salvage therapy. We employed EffTox, an advanced Bayesian method to simultaneously consider response to treatment (efficacy) and dose-limiting toxicity (DLT) in all treated patients, providing a single measure of clinical utility, which then informed the subsequent dose level recommendation. The primary objective was to determine the optimal dose of ponatinib, in combination with chemotherapy, as determined by the EffTox model. The primary outcomes were attainment of a second chronic phase and occurrence of a DLT. Secondary outcomes investigated the toxicity of combination therapy, alloSCT outcomes, and survival. The median follow-up of trial patients is 41 months. Results Nine patients completed one cycle of PON-FLAG-IDA, a further eight patients completed both planned cycles. Using an EffTox analysis, the optimal dose of ponatinib was determined as 30mg once daily. Eleven patients achieved a return to chronic phase and four experienced a DLT, fulfilling the pre-specified criteria for clinically relevant efficacy and toxicity. After PON-FLAG-IDA salvage, eight patients attained complete cytogenetic response and five major molecular response (MMR). The most common grade 3-4 non-hematologic toxicities were febrile neutropenia (29% of patients), lung infection (24%), fever (18%) and hypocalcaemia (18%). Three patients experienced treatment-related mortality. Twelve patients proceeded to alloSCT, of whom seven are alive after median 36 months post-transplant follow-up. Only one of the five patients achieving MMR relapsed post-alloSCT, neither of the other relapsing patients achieved a second chronic phase pre-transplant. Median overall survival (OS) of the whole cohort was 12 months (95% confidence interval 6 months to non-calculable), median OS of patients undergoing alloSCT has not been reached. Conclusions Ponatinib has shown that it can be safely combined with high-dose chemotherapy to achieve a return to chronic phase in patients with BP-CML, and represents an effective novel treatment strategy in this high-risk population. Responding patients subsequently undergoing alloSCT can benefit from long-term disease-free survival. The EffTox method enabled very efficient data usage from this high-risk patient population, and is a model for investigating novel therapies in other ultra-orphan cancers. Figure: Overall survival of the MATCHPOINT cohort Figure 1 Figure 1. Disclosures Copland: Incyte: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Jazz: Honoraria, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; Cyclacel Ltd: Research Funding. Byrne: Incyte: Honoraria. Rothwell: Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Honoraria. Brock: Eli Lily: Honoraria; Invex Therapeutics: Honoraria; Merck: Honoraria; Roche: Honoraria; AstraZeneca: Current holder of individual stocks in a privately-held company; GSK: Current holder of individual stocks in a privately-held company. De Lavallade: Pfizer, Novartis.: Honoraria; Bristol Myers Squibb, Incyte: Honoraria, Research Funding. Craddock: Novartis Pharmaceuticals: Other: Advisory Board ; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Clark: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria. Smith: Daiichi Sankyo: Speakers Bureau; Pfizer: Speakers Bureau; ARIAD: Honoraria. Milojkovic: Novartis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau. Yap: Faron Pharmaceuticals: Honoraria; Celgene: Honoraria. OffLabel Disclosure: Ponatinib for the treatment of blast-phase CML

Long-Term Prognostic Impact of the Use of Erythropoiesis-Stimulating Agents (ESA) in Patients (pts) with Chronic Myeloid Leukemia (CML) Treated with Imatinib.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2959-2959
Author(s):  
Yesid Alvarado ◽  
Hagop Kantarjian ◽  
Dushyant Verma ◽  
Gloria Mattiuzzi ◽  
Ahmed Aribi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Phase ◽  
Metastatic Breast ◽  
Prognostic Impact ◽  
Event Free Survival ◽  
Long Term Outcome ◽  
Free Survival ◽  
Erythropoiesis Stimulating Agents ◽  
Grade 3

Abstract Background: ESA have been reported to effectively improve the hemoglobin (Hb) in pts with CML who develop anemia during the course of therapy with imatinib and other tyrosine kinase inhibitors. Recently, it has been suggested that when ESA were administered to target a Hb ≥12 g/dL, they may promote tumor growth and decreased survival among pts with advanced head and neck cancer receiving radiation therapy, pts with non-small cell lung cancer, and pts with metastatic breast cancer receiving chemotherapy. We thus investigated whether pts with CML who had received ESA during the course of therapy with imatinib had an inferior long-term outcome. Methods: We analyzed the outcome of 565 pts with CML in chronic phase treated with imatinib in our institution (306 previously untreated, 259 post imatinib failure). Results: Based on the Common Terminology Criteria for Adverse Events (CTCAE) V. 3.0 of the National Cancer Institute (NCI), grade 1 anemia occurred in 235 (42%) pts, grade 2 in 180 (32%), grade 3 in 47 (8%), and grade 4 in 12 (2%) pts. A total of 245 (43%) pts received ESA at some point during the course of therapy. The median nadir Hb among pts treated with ESA was 9.4 g/dL [45 (18%) with grade 3–4 anemia] vs 11.2 g/dL [14 (4%) with grade 3–4 anemia] in those not treated with ESA. Treated patients received therapy with variable intermittent doses during a median time of 14 months (mo) range (1–96 mo). The observed increase in Hb with ESA therapy was >3 g/dL in 132 (54%) pts, 2–3 g/dL in 64 (26%), 1-<2 g/dL in 35 (14%), and <1 g/dL in 14 (6%) pts. The median Hb level achieved with ESA was 12.6 g/dL. The table summarizes the 5-year overall survival and event free survival (EFS) among pts treated with ESA and those not treated with ESA: As previously reported (Cortes et al. Cancer2004; 100:2396–402), the presence of anemia itself has a significant adverse effect on outcome in this patient population. The 5-year EFS for pts with anemia grade 3–4 was 56% vs. 79% for those with grade 0–2 (p=0.002). Corresponding figures for 5-yr OS were 82% and 88% (p=0.006). Conclusion: There is no evidence that the use of ESA to manage anemia associated with imatinib therapy in pts with CML in chronic phase adversely affects long term overall survival or event-free survival. INF- failure (%) Frontline Imatinib (%) OS: overall survival, EFS: event free survival (event = loss of complete hematologic response, loss of major cytogenetic response, transformation to accelerated or blast phase or death from any cause), INF: interferon, ESA: erythropoiesis-stimulating agents. ESA use OS EFS OS EFS No 84 75 92 84 Yes 82 68 89 85 P Value 0.59 0.12 0.58 0.68

Significance of ELN Provisional Response Definitions In Predicting Long-Term Outcomes of Patients with CP-CML Treated with Dasatinib After Imatinib Failure.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3439-3439
Author(s):  
Jorge E. Cortes ◽  
Neil P. Shah ◽  
Charles A. Schiffer ◽  
Philipp D. LeCoutre ◽  
Giuseppe Saglio ◽  
...  
Keyword(s):  
Research Funding ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Long Term Outcomes ◽  
Free Survival ◽  
Optimal Response ◽  
Response Table ◽  
Starting Dose

Abstract Abstract 3439 Introduction: The European LeukemiaNet (ELN) recommendations for the management of chronic phase chronic myeloid leukemia (CP-CML) have provisionally defined criteria for suboptimal and failure to second-generation tyrosine kinase inhibitors (TKIs) (Baccarani et al., J Clin Oncol. 27 (35):6041-51, 2009). We tested the significance of these definitions in 3 studies of dasatinib after imatinib failure. Methods: Data from 1150 treated patients (pts) included in the 3 studies [CA180-013 (n=387); dasatinib only arm of CA180-017 (n=101); CA180-034 (n=662)] were analyzed. For the purpose of this analysis, we modified the 2009 ELN recommendations to add an optimal response category as shown in Table 1. Background: The median age of the pts included in this analysis was 56 yrs (range, 18–85) and the median duration of CML in these pts was 58 months (range, 0.9–250.8). Thirty-eight percent of the pts had received imatinib at a dose > 600mg/day and 45% had been on imatinib therapy >3 yrs. Twenty-four percent of pts included in this analysis had demonstrated imatinib-intolerance. Thirty-five percent of pts had mutations before the start of dasatinib therapy (5% had T315l). Results: Rates of optimal response at 3, 6 and 12 months were 51%, 44% and 36%. Rates of suboptimal response at 3, 6 and 12 months were 7%, 16% and 27%. Rates of failure response at 3, 6 and 12 months were 29%, 34% and 37%. Rates of warning response at 3 and 6 months were 12% and 6%. The starting dose of dasatinib did not influence these response rates. The group defined as suboptimal at 12 months (of whom 52% had already achieved CCyR) had a higher probability of achieving CCyR within 2 yr (83%) compared to the groups defined as suboptimal at 6 months (69%) or 3 months (51%). This suboptimal group at 12 months also had a higher 2 yr progression-free survival (PFS) (92%) compared to the suboptimal groups at 6 months (82%) and 3 months (80%). The probability of achieving an MMR within 2 yr was slightly higher in pts defined as optimal at 6 months (80%) vs. those at 3 months (71%). However, the probability of achieving an MMR within 2 yr showed minimal change for the suboptimal (31-35%) or the failure (5%) response groups defined at 3, 6 and 12 months. The pts with a warnings response had a profile that was intermediate between suboptimal and failure response. Table 2 summarizes 2 yr outcomes based on response. Conclusions: These results suggest that the 2009 ELN provisional response definitions may be helpful in predicting long term outcomes in pts receiving second-line dasatinib therapy. In this cohort of pts, optimal responders identified themselves rapidly as did pts with failure. However, the outcome of pts defined as suboptimal at 12 months appeared more favorable than that of pts defined as suboptimal at 3 and 6 months. This, in addition to the higher proportion of pts classified as suboptimal at 12 months, compared to those classified as suboptimal at 3 and 6 months, may suggest that the ELN defined cut-off between optimal vs. suboptimal at 12 months (i.e. MMR) may need to be modified in order to make the prognosis for suboptimal response more consistent across different time points. Pts classified in the warnings category at 3 and 6 months had an outcome intermediate between those with suboptimal and failure response. Disclosures: Cortes: Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Shah:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Ariad: Consultancy. LeCoutre:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Kantarjian:Novartis Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding. Jabbour:GlaxoSmithKline: Research Funding. Bahceci:Bristol-Myers Squibb: Employment. Chen:Bristol-Myers Squibb: Employment. Lambert:Bristol-Myers Squibb: Employment. Guilhot:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy.

Disease Patterns for Patients (pts) with Chronic Myeloid Leukemia (CML) That Have BCR-ABL Transcript Levels > 10% At 3 Month of Therapy with Tyrosine Kinase Inhibitors (TKIs)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3757-3757
Author(s):  
Aziz Nazha ◽  
Hagop M. Kantarjian ◽  
Preetesh Jain ◽  
Elias J. Jabbour ◽  
Alfonso Quintás-Cardama ◽  
...  
Keyword(s):  
Research Funding ◽  
Strong Predictor ◽  
Chronic Phase ◽  
Transcript Level ◽  
Initial Therapy ◽  
Molecular Response ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Free Survival

Abstract Abstract 3757 Background: Response to TKIs in CML at 3 month is a strong predictor for long term outcome in CML patients treated with TKIs. Pts who do not achieve a BCR-ABL transcript level < 10% or a MCyR at 3 months have lower event-free survival (EFS) and perhaps overall survival (OS). However, pts have rarely changed therapy based on response at this early time points. The purpose of this analysis is to understand the patterns of disease progression and management in this group of patients. Patients and Methods: A total of 489 newly diagnosed CML pts that received initial treatment with TKIs: imatinib 400 mg daily (83) imatinib 800 mg daily (199), and second generation TKIs (2GTKIs) (207) in consecutive or parallel trials between 7/2000 and 6/2011 were included in this analysis. Cytogentic and molecular responses were evaluated every 3 month for the first year and then every 6 month. Event was defined as transformation to accelerated phase (AP) or blast phase (BP), loss of complete hematologic response (CHR), or loss of MCyR. Results: Among the 489 treated pts, 58 (12%) did not achieve a MCyR or BCR-ABL transcript level < 10 % at 3 months (26 pts (31%) received IM400, 19 (10%) IM800, and 13 (6%) 2GTKIs. Eleven of these pts (19%) had high sokal score at diagnosis (1 pt treated with imatinib 400, 7 with imatinib 800, 3 with 2GTKIs). By 6 months, 52/58 pts (90%) continued on their original therapy: 39 (67%) at the same dose and 19 (33%) with a decreased dose because of adverse events. No pt had a dose increase. Six pts had discontinued therapy by 6 month: 4 due to intolerance, 1 loss of CHR and 1 for progression to BP. At 6 month, 27 pts (47%) achieved MCyR or BCR-ABL transcript level < 10 %. At 12 months, 47 pts (81%) were still receiving their initial therapy, 11 pts (19%) had discontinued their initial TKI: 6 due to intolerance, 1 loss of CHR, 2 for progression to BP, and 2 for resistant disease. After a median follow up of 95 months, 17 pts (29%) continue to receive their initial therapy and their current disease status are: complete cytogenetic response (CCyR) in 14 (82%), 2 (12%) lost their CCyR, and 1(6%) pt who never achieve any cytogenetic or molecular response and remains in chronic phase on the same dose of imatinib for over 8 years. Among these 17 pts, 11 (65%) have MMR, 2 (12%) with MR4.5, and 4 (24%) have lost MMR (2 of them with loss of CCyR). The 5 years OS, EFS and transformation-free survival (TFS) for the patients who did not achieve any response at 3 month was 88%, 77%, and 94%, respectively. The OS, EFS, and TFS for the patients who subsequently achieved a response (MCyR or BCR-ABL transcript level < 10 %) at 6 month was 100%, 66%, and 95%, respectively vs those who continued to have no response 79%, 95%, and 100%, respectively (P = 0.17, 0.07, 0.99, respectively). Conclusions: Although BCR-ABL transcript level at 3 month may predict long-term outcome of pts with CML treated with TKIs, this represents a static, one-time measure. Assessing the response at 6 months of pts with poor response at 3 months may provide a better predictor of long term outcome. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

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