Six Year Follow-Up Results of a Phase II Study of Imatinib in Late Chronic Phase (L-CP) Chronic Myeloid Leukemia (CML) Post Interferon-A (IFN) Refractoriness/Intolerance.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 428-428 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Charles Sawyers ◽  
Andreas Hochhaus ◽  
Charles A. Schiffer ◽  
Francois Guilhot ◽  
...  
Keyword(s):  
Overall Survival ◽  
Blast Crisis ◽  
Survival Rates ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Long Term Outcomes ◽  
Duration Of Treatment ◽  
Laboratory Values

Abstract Background: Imatinib is a selective inhibitor of the Bcr-Abl tyrosine kinase indicated for the treatment of all phases of Ph+ CML. This study updates the results up to more than 60 months (mos) after last patient (pt) started treatment. Methods: Imatinib 400 mg/d was first administered to 454 patients with L-CP CML between December 1999 and May 2000. Median time since diagnosis was 34 months (mos). Pts had received a median of 14 mos of prior IFN treatment before entering the study but were hematologically (n=133) or cytogenetically resistant/refractory (n=160) or intolerant (n=161) to IFN. Dose escalation up to 800 mg/d was allowed for lack of efficacy. Pts were evaluated for best major and complete cytogenetic response (MCyR and CCyR), time to progression to accelerated phase (AP) or blast crisis (BC), and overall survival (OS). Beyond July 31, 2002, no adverse events or laboratory values were collected. Results: As of July 31, 2005, median duration of treatment was 60 mos (with average of 48 mos). A total of 244 (54%) pts had their dose increased to 600 or 800 mg/d, 42% received 800 mg/d at least once. Of 227 pts who are still on treatment, 85 (37%) had their dose increased to 600 mg/d or 800 mg/d for lack of efficacy. Overall actual dose intensity was 444 mg/d (median 400mg/d). The table below summarizes reasons for discontinuation, best observed responses rates and estimated long term outcomes at 60 mos. n (%) [95% conf. intervals] N=454 Still on treatment 227 (50) Discontinued 227 (50) Unsatisfactory therapeutic effect 117 (26) Deaths from any cause 18 (4) AEs & abnormal laboratory values 33 (7) BMT 5 (1) Withdrew consent/Lost/Others 54 (12) Pts with MCyR (incl CCyR) 304 (67) Pts with CCyR 259 (57) % Estimated freedom of progression to AP/BC at 60 mos 69% [64–74] % Estimated OS at 60 mos 79% [75–83] The MCyR (CCyR) rate was 57% (48%) for hematologic failures to IFN, 70% (60%) in cytogenetic failures to IFN and 72% (62%) in IFN intolerant pts. A CCyR was achieved after more than 36 mos of treatment in 28 pts; 22 (79%) of these pts had achieved CCyR after dose increase to 600 or 800 mg. Landmark analyses confirmed the effect of cytogenetic responses on long-term outcomes. The estimated survival rates free of AP/BC at 60 mos were 91%, 82%, 77%, 62% and 42% for pts who by 12 months achieved CCyR, PCyR, Minor CyR, Minimal CyR and no CyR, respectively (p<0.001). This corresponds to a rate of 88% in pts with MCyR at 12 mos. The estimated overall survival rates at 60 mos were 93%, 92%, 88%, 71% and 64% for pts who achieved CCyR, PCyR, Minor CyR, Minimal CyR and no CyR at this landmark, respectively (p<0.001). This corresponds to an overall survival rate of 93% in patients who had achieved MCyR at 12 mos. Conclusion: Imatinib substantially improves the duration of CP-CML in pts who previously failed IFN. The follow-up confirms the beneficial effect of cytogenetic responses on long-term outcomes with imatinib. These results will be updated for the meeting to include 72 mos data up to July 31, 2006.

Time to Complete Cytogenetic Response (CCyR) Does Not Affect Long-Term Outcomes for Patients on Imatinib Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 27-27 ◽  
Author(s):  
Francois Guilhot ◽  
Richard A. Larson ◽  
Stephen G. O’Brien ◽  
Insa Gathmann ◽  
Brian J. Druker
Keyword(s):  
Overall Survival ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Imatinib Therapy ◽  
Imatinib Treatment ◽  
Long Term Outcomes ◽  
Term Survival ◽  
Significant Difference

Abstract Background: Results from the International Randomized Study of Interferon and STI571 (IRIS) trial showed that achievement of a CCyR is prognostically relevant for long-term survival in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP). With the advent of next generation tyrosine kinase inhibitors (TKIs), there is a need to understand factors that may influence long term outcomes. Here we analyze whether time to achievement of a CCyR affects long term outcomes. Methods: The relationship between time to CCyR and long-term outcomes was examined for 551 imatinib-treated patients with newly diagnosed CML-CP at the 6-year follow up of the IRIS trial. As evaluations included non-responders, landmark analyses were conducted in which only pts who were treated for ≥1 year were included (n=509). Patients were stratified according to time to achieving a CCyR as follows: ≤6 months (n=265), >6≤12 months (n=99), >12≤18 months (n=34), >18 months (n=49), or no CCyR during imatinib treatment (n=62). In each category patients were assessed for duration of cytogenetic response, event free survival (EFS; any event while on study), freedom from progression to accelerated phase (AP) or blast crisis (BC), and overall survival (OS). Results: In the 447 patients who were treated for at least 1 year and achieved a CCyR (<1% Ph+) during therapy, the durability of major cytogenetic response (1%–35% Ph+) did not differ significantly regardless of when CCyR was achieved (P=0.76). For the overall population, estimated 6-year rates were 88% for OS, 83% for EFS, and 93% for freedom from progression to AP/BC. No statistically significant difference was observed between the responders when categorized according to time to response. However, patients who did not achieve a CCyR had significantly worse outcomes than those who achieved CCyR (P<0.001). Estimated 6-year OS rates were 94%, 95%, 91% and 98% for patients who first achieved a CCyR within 6, 12, 18 months and after 18 months, respectively (P=0.55 for overall comparison of the response categories), compared with 63% for pts without CCyR during imatinib therapy. Estimated EFS rates at 6 years were 93%, 90%, 87% and 89% (P=0.58) and 33% for patients who do not achieve a CCyR, respectively. At 6 years the estimated rates of freedom from progression to AP/BC were 97%, 97%, 97% and 98% (P=0.98), respectively, but only 63% for pts who do not achieve a CCyR. Overall Survival by Time to CCyR. Conclusion: Long-term outcomes on imatinib for patients in CML-CP are independent of time to achieve CCyR. Therefore, achievement of a “late” CCyR does not increase the potential for progression or portend a worse overall survival for patients treated with imatinib. Figure Figure

scholarly journals Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis

Leukemia ◽  
2021 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Timothy P. Hughes ◽  
Richard A. Larson ◽  
Dong-Wook Kim ◽  
Surapol Issaragrisil ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Chronic Phase ◽  
Individual Treatment ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Treatment Free Remission

AbstractIn the ENESTnd study, with ≥10 years follow-up in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, nilotinib demonstrated higher cumulative molecular response rates, lower rates of disease progression and CML-related death, and increased eligibility for treatment-free remission (TFR). Cumulative 10-year rates of MMR and MR4.5 were higher with nilotinib (300 mg twice daily [BID], 77.7% and 61.0%, respectively; 400 mg BID, 79.7% and 61.2%, respectively) than with imatinib (400 mg once daily [QD], 62.5% and 39.2%, respectively). Cumulative rates of TFR eligibility at 10 years were higher with nilotinib (300 mg BID, 48.6%; 400 mg BID, 47.3%) vs imatinib (29.7%). Estimated 10-year overall survival rates in nilotinib and imatinib arms were 87.6%, 90.3%, and 88.3%, respectively. Overall frequency of adverse events was similar with nilotinib and imatinib. By 10 years, higher cumulative rates of cardiovascular events were reported with nilotinib (300 mg BID, 16.5%; 400 mg BID, 23.5%) vs imatinib (3.6%), including in Framingham low-risk patients. Overall efficacy and safety results support the use of nilotinib 300 mg BID as frontline therapy for optimal long-term outcomes, especially in patients aiming for TFR. The benefit-risk profile in context of individual treatment goals should be carefully assessed.

scholarly journals Early and Long-Term Follow-Up for Chronic Type B and Type Non-A Non-B Aortic Dissection Using the Frozen Elephant Trunk Technique

2021 ◽  
Vol 8 ◽  
Author(s):  
Congcong Luo ◽  
Ruidong Qi ◽  
Yongliang Zhong ◽  
Suwei Chen ◽  
Hao Liu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Aortic Dissection ◽  
Type B ◽  
Frozen Elephant Trunk ◽  
Long Term Outcomes ◽  
Chronic Type ◽  
Elephant Trunk ◽  
Long Term Follow Up

Background: This study aimed to evaluate the early and long-term outcomes of a single center using a frozen elephant trunk (FET) procedure for chronic type B or non-A non-B aortic dissection.Methods: From February 2009 to December 2019, 79 patients diagnosed with chronic type B or non-A non-B aortic dissection who underwent the FET procedure were included in the present study. We analyzed operation mortality and early and long-term outcomes, including complications, survival and interventions.Results: The operation mortality rate was 5.1% (4/79). Spinal cord injury occurred in 3.8% (3/79), stroke in 2.5% (2/79), and acute renal failure in 5.1% (4/79). The median follow-up time was 53 months. The overall survival rates were 96.2, 92.3, 88.0, 79.8, and 76.2% at 1/2, 1, 3, 5 and 7 years, respectively. Moreover, 79.3% of patients did not require distal aortic reintervention at 7 years. The overall survival in the subacute group was superior to that in the chronic group (P = 0.047).Conclusion: The FET technique is a safe and feasible approach for treating chronic type B and non-A non-B aortic dissection in patients who have contraindications for primary endovascular aortic repair. The technique combines the advantages of both open surgical repair and endovascular intervention, providing comparable early and long-term follow-up outcomes and freedom from reintervention.

scholarly journals Long-term outcomes after coronary artery bypass surgery in patients with diabetes

2020 ◽  
Vol 30 (5) ◽  
pp. 685-690
Author(s):  
Tomas Andri Axelsson ◽  
Jonas A Adalsteinsson ◽  
Linda O Arnadottir ◽  
Dadi Helgason ◽  
Hera Johannesdottir ◽  
...  
Keyword(s):  
Overall Survival ◽  
Coronary Artery ◽  
Coronary Artery Bypass ◽  
Artery Bypass ◽  
Long Term Outcomes ◽  
Cerebrovascular Events ◽  
Increased Risk ◽  
Patients With Diabetes

Abstract OBJECTIVES Our aim was to investigate the outcome of patients with diabetes undergoing coronary artery bypass grafting (CABG) surgery in a whole population with main focus on long-term mortality and complications. METHODS This was a nationwide retrospective analysis of all patients who underwent isolated primary CABG in Iceland between 2001 and 2016. Overall survival together with the composite end point of major adverse cardiac and cerebrovascular events was compared between patients with diabetes and patients without diabetes during a median follow-up of 8.5 years. Multivariable regression analyses were used to evaluate the impact of diabetes on both short- and long-term outcomes. RESULTS Of a total of 2060 patients, 356 (17%) patients had diabetes. Patients with diabetes had a higher body mass index (29.9 vs 27.9 kg/m2) and more often had hypertension (83% vs 62%) and chronic kidney disease (estimated glomerular filtration rate ≤60 ml/min/1.73 m2, 21% vs 14%). Patients with diabetes had an increased risk of operative mortality [odds ratio 2.52, 95% confidence interval (CI) 1.27–4.80] when adjusted for confounders. 5-Year overall survival (85% vs 91%, P &lt; 0.001) and 5-year freedom from major adverse cardiac and cerebrovascular events were also inferior for patients with diabetes (77% vs 82%, P &lt; 0.001). Cox regression analysis adjusting for potential confounders showed that the diagnosis of diabetes significantly predicted all-cause mortality [hazard ratio (HR) 1.87, 95% CI 1.53–2.29] and increased risk of major adverse cardiac and cerebrovascular events (HR 1.47, 95% CI 1.23–1.75). CONCLUSIONS Patients with diabetes have significantly lower survival after CABG, both within 30 days and during long-term follow-up.

scholarly journals Liver Transplantation from Voluntary Organ Donor System in China: A Comparison between DBD and DCD Liver Transplants

2019 ◽  
Vol 2019 ◽  
pp. 1-7
Author(s):  
Wei Chen ◽  
Dipesh Kumar Yadav ◽  
Xueli Bai ◽  
Jianying Lou ◽  
Risheng Que ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Organ Donation ◽  
Survival Rates ◽  
Organ Donor ◽  
Long Term Outcomes ◽  
Significant Difference ◽  
Short And Long Term ◽  
Donor System

Background. In China, the cases of liver transplantation (LT) from donation after citizens’ death have rose year by year since the citizen-based voluntary organ donor system was initiated in 2010. The objective of our research was to investigate the early postoperative and late long-term outcomes of LT from donation after brain death (DBD) and donation after circulatory death (DCD) according to the current organ donation system in China. Methods. Sixty-two consecutive cases of LT from donation after citizens’ death performed in our hospital between February 2012 and June 2017 were examined retrospectively for short- and long-term outcomes. These included 35 DCD LT and 27 DBD LT. Result. Subsequent median follow-up time of 19 months and 1- and 3-year graft survival rates were comparative between the DBD group and the DCD group (81.5% and 66.7% versus 67.1% and 59.7%; P=0.550), as were patient survival rates (85.2% and 68.7% versus 72.2% and 63.9%; P=0.358). The duration of ICU stay of recipients was significantly shorter in the DBD group, in comparison with that of the DCD group (1 versus 3 days, P=0.001). Severe complication incidence (≥grade III) after transplantation was identical among the DBD and DCD groups (48.1% versus 60%, P=0.352). There was no significant difference in postoperative mortality between the DBD and DCD groups (3 of 27 cases versus 5 of 35 cases). Twenty-one grafts (33.8%) were lost and 18 recipients (29.0%) were dead till the time of follow-up. Malignancy recurrence was the most prevalent reason for patient death (38.8%). There was no significant difference in incidence of biliary stenosis between the DBD and DCD groups (5 of 27 cases versus 6 of 35 cases, P=0.846). Conclusion. Although the sample size was small to some extent, this single-center study first reported that LT from DCD donors showed similar short- and long-term outcomes with DBD donors and justified the widespread implementation of voluntary citizen-based deceased organ donation in China. However, the results should be verified with a multicenter larger study.

Long-term Outcomes of Autologous Chondrocyte Implantation in Adolescent Patients

2017 ◽  
Vol 45 (5) ◽  
pp. 1066-1074 ◽  
Author(s):  
Takahiro Ogura ◽  
Tim Bryant ◽  
Tom Minas
Keyword(s):  
Autologous Chondrocyte Implantation ◽  
Survival Rates ◽  
Long Term Outcomes ◽  
Adolescent Patients ◽  
Chondrocyte Implantation ◽  
Standard Radiographs ◽  
Articular Cartilage Lesions ◽  
Autologous Chondrocyte

Background: Treating symptomatic articular cartilage lesions is challenging, especially in adolescent patients, because of longer life expectancies and higher levels of functional activity. For this population, long-term outcomes after autologous chondrocyte implantation (ACI) remain to be determined. Purpose: To evaluate long-term outcomes in adolescents after ACI using survival analyses, validated outcome questionnaires, and standard radiographs. Study Design: Case series; Level of evidence, 4. Methods: We performed a review of prospectively collected data from patients who underwent ACI between 1996 and 2013. We evaluated 27 patients aged <18 years old (29 knees; mean age, 15.9 years) who were treated by a single surgeon for symptomatic, full-thickness articular cartilage lesions over a mean 9.6-year follow-up (median, 13 years; range, 2-19 years). A mean of 1.5 lesions per knee were treated over a mean total surface area of 6.2 cm2 (range, 2.0-23.4 cm2) per knee. Survival analysis was performed using the Kaplan-Meier method, with graft failure as the end point. The modified Cincinnati Knee Rating Scale, Western Ontario and McMaster Universities Osteoarthritis Index, visual analog scale, and Short Form 36 scores were used to evaluate clinical outcomes. Patients also self-reported knee function and satisfaction. Standard radiographs were evaluated using Kellgren-Lawrence grades. Results: Both 5- and 10-year survival rates were 89%. All clinical scores improved significantly postoperatively. A total of 96% of patients rated knee function as better after surgery, and all patients indicated that they would undergo the same surgery again. Approximately 90% rated knee-specific outcomes as good or excellent and were satisfied with the procedure. At last follow-up, 12 of 26 successful knees were radiographically assessed (mean, 5.6 years postoperatively), with no significant osteoarthritis progression. Three knees were considered failures, which were managed by autologous bone grafting or osteochondral autologous transplantation. Twenty knees required subsequent surgical procedures. These were primarily associated with periosteum and were arthroscopically performed. Conclusion: ACI resulted in satisfactory survival rates and significant improvements in function, pain, and mental health for adolescent patients over a long-term follow-up. ACI was associated with very high satisfaction postoperatively, despite the subsequent procedure rate being relatively high primarily because of the use of periosteum. If periosteum is used, this rate should be a consideration when discussing ACI with patients and their parents.

IRIS 6-Year Follow-Up: Sustained Survival and Declining Annual Rate of Transformation in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 25-25 ◽  
Author(s):  
Andreas Hochhaus ◽  
Brian J. Druker ◽  
Richard A. Larson ◽  
Stephen G. O’Brien ◽  
Insa Gathmann ◽  
...  
Keyword(s):  
Adverse Events ◽  
Blast Crisis ◽  
Randomized Study ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Continuous Treatment ◽  
Annual Rate ◽  
Interferon Α

Abstract Background: The International Randomized study of Interferon versus STI571 (IRIS) study demonstrated that imatinib has superior safety and efficacy relative to interferon-α plus cytarabine (IFN+ara-C). Patients on the imatinib arm achieved an estimated 5-year OS of 89%. To monitor the long-term responses achieved by patients on imatinib, the 6-year follow-up of the IRIS patient population is summarized. Methods: 1106 patients were randomly assigned to either imatinib or IFN+ara-C and evaluated for hematologic and cytogenetic responses, event-free survival, progression to accelerated-phase (AP) or blast crisis (BC), overall survival (OS), and frequency of adverse events and discontinuations. Results: The downward trend in the risk of disease progression on imatinib has continued with a 0.4% event rate (including loss of response) and a 0% rate of transformation to AP/BC attained between years 5 and 6. Of 553 who were randomized to imatinib, 364 (65.8%) remain on study drug at 6 years: 14 (2.5%) crossed over to the IFN arm, and 175 (31.6%) pts have discontinued from imatinib study therapy for any reason. The following reasons were cited for discontinuation from the IRIS study: adverse events, 23 patients (4.2%); unsatisfactory therapeutic effect, 66 patients (11.9%); protocol violation, 15 patients (2.7%); withdrawal of consent, 32 patients (5.8%); administrative problems, 6 patients (1.1%); and 16 patients (2.9%) elected to undergo a stem cell transplantation (SCT). Death was the reason for discontinuation for 10 (1.8%) patients, and 7 patients (1.3%) were lost to follow-up. The best observed complete hematologic response rate among patients receiving first-line imatinib was 97%. The best observed major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) rates were 89% and 83%, respectively, with 2 additional CCyR observed since the prior 5-year analysis. At the current 6-year follow-up, 325 patients are still in CCyR, another 24 had lost CCyR but regained it, 6 patients lost CCyR but remain in MCyR, and the remaining 9 patients never had a documented CCyR. Overall, an estimated 83% of patients were event-free, and 93% were free of progression to AP or BC at 6 years on imatinib study treatment, as patients were followed only for OS after discontinuation. After the second year on imatinib, the annual rate of events decreased every year, as did the annual relapse rate. Based on the current follow-up, a total of 66 (12%) patients have died (19 after SCT, 27 not due to CML). Estimated 6-year OS rate for all patients who received imatinib as initial therapy was 88%. When survival is censored at time of SCT for patients who proceeded to transplant, the estimated OS at 6 years is 91%. In an analysis of serious adverse events, no new safety issues were identified between the 5-year report and this analysis. Conclusions: The 6-year follow-up analysis of the IRIS population indicates that continuous treatment of chronic-phase CML with imatinib induces durable responses in a high percentage of patients with a decreasing rate of relapse and a favorable long-term safety profile.

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.

Nilotinib Versus High-Dose Imatinib in Early Chronic Phase CML Patients Who Have Suboptimal Molecular Responses to Standard-Dose Imatinib: Updated Data From RE-Nice Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3775-3775 ◽  
Author(s):  
Soo-Young Choi ◽  
Sung-Eun Lee ◽  
Soo-Hyun Kim ◽  
Eun-Jung Jang ◽  
Jin-hwa Lee ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Standard Dose ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
High Dose ◽  
Molecular Response ◽  
Long Term Outcomes ◽  
First Line

Abstract Abstract 3775 Background. In chronic myeloid leukemia (CML), achievement of optimal responses by time point has improved long-term outcomes. In contrast, several clinical studies investigating the clinical implications of suboptimal response showed that patients with suboptimal responses tend to have poor long-term outcomes. In IRIS study, patients who achieved major molecular response (MMR) at 18 months had event-free survival (EFS) benefit, compared to those who achieved complete cytogenetic response (CCyR) without MMR. However, the best treatment for these patients is still not confirmed. By the previous studies, sustaining standard-dose of imatinib (IM) is expected to yield less than 20 percent of additive MMR. In this prospective study, we investigated whether switching to nilotinib (NIL) or high-dose IM may be more effective for patients with suboptimal molecular response to IM as first-line therapy. Methods. Early chronic phase (CP) CML patients who have achieved CCyR but no MMR after at least 18 months and up to 24 months (≤ 18 to ≥24 months) on first-line IM therapy at a daily dose of 400 mg were enrolled in this clinical trial, and informed consents were obtained from all patients. In NIL arm, patients received oral dose of 400 mg BID (800 mg/day) and in high-dose IM arm, patients received 800 mg/day administrated as 400 mg BID. Primary endpoint is to evaluate the cumulative MMR rates by 12 months, and secondary endpoints are to evaluate the cumulative MMR, MR4.0 and undetectable molecular residual disease (UMRD) rates during further 24 month follow-up. Safety profiles will also be assessed. Patients showing lack of response (lack of complete hematologic response (CHR) at 6 months, increasing WBC, no major cytogenetic response (MCyR) at 24 months), loss of response (loss of CHR or MCyR) or severe intolerance to treatment were allowed to crossover to the alternative treatment. Results. With a data cut-off date of 10 Jul 2012, a total of 43 patients were randomized into NIL arm (n = 22) or high-dose IM arm (n = 21). With a median follow-up of 15 months (range, 1–36), all patients have maintained CCyR without progression to advanced disease, and progressive decrease in BCR-ABL1 transcript levels was observed in all patients. Cumulative incidence (CI) of MMR by 12 months showed no significant difference between NIL arm and high-dose IM arm (37.8 ± 11.9% vs 34.8 ± 10.6%, P = 0.789). In NIL arm, 3 in 22 (14%) and 2 in 22 (9%) patients achieved MR4.0 and UMRD, respectively, and in high-dose IM arm, 1 in 21 (5%) patients achieved MR4.0. Overall, the patients treated with high-dose IM showed toxicities more frequently, such as fatigue, dyspnea and decreased phosphate. In addition, 10 patients in high-dose IM arm have cross-over to NIL treatment due to lack of response (n=9) and intolerance (n=1), and the median duration of NIL treatment was 14 months (range, 7–26 months). Among them, 5 (50%) patients have achieved MMR with a median NIL treatment duration of 12 months (range, 3–18). Conclusions. These results demonstrate that early switching to NIL or dose escalation of IM could be recommended, considering the results of standard dose of IM in suboptimal molecular responders. When the tolerability of treatment was considered for switching to NIL or high-dose IM, NIL may be preferred. Through further clinical investigation on a large patient population and longer period observation, the efficacy and safety of early intervention of suboptimal molecular response using NIL or dose escalation of IM will be needed. Updated data with longer follow-up duration will be presented in the meeting. Disclosures: No relevant conflicts of interest to declare.

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

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