Hello Folks,
The abstract was pre-published in June I think, so some of the data might be familiar to you. It is a long paper and I have been going through it to pick out the salient data that was all done through multivariate analysis. This work compares two study groups, IM study 110 and 113 with historical information collective over a 13 year period before IM. The results are interesting, and although we sometimes complain of fatigue, bone pain and other side effects, we are collectively doing much better than those courageous troopers, our CML comrades from days gone by. We must remember them and their struggles.
Today in spite of our side effects we can think in terms of questioning starting a family, staying at work, and planning for retirement. Not so long ago these issues were replaced by just the daily struggles of being able to make it from one day to the next. Yes, life isn't perfect but funny enough we are all well enough now to know life isn't perfect and to question why it isn't.
Lately we've read about how doctors are shying away from the use of the word "cure". That isn't really so upsetting is it? CML is a part of our life, and we are managing to live long and relatively better lives in spite of it. Maybe I am not so sure I want to talk in the terms of a cure either. I like me better now with CML than prior to my diagnosis. Some of the symptoms and side effects I endure today, might really have nothing to do with IM, maybe it's just the aging process. The one thing I know about life, is that nobody get's out of it alive, so maybe I shouldn't be looking for a cure. I am happy to sustain it as long as I can, and I am really happy to be here in this time and place where we can positively think about long term survivability.
This paper reflects many of us who have had and continue to have good response with IM, and it also reflects those among us who did not have a good response. This paper is important as it makes us realize the new "gold standard" in therapy approaches to CML. So, look at the rates and analysis results for those who've had a good response with IM, that's the very least the next drug must achieve. That's pretty powerful stuff! We are witnessing the magic of the new drugs now in clinical trials and we are a fortunate group to be part of this dynamic life sustaining break-through of IM.
I know many of us endure nasty side effects on our way to winning the battle over this disease, and there are many of us who must suffer through the side effects without the benefit of gain in reducing the burden of this disease. Let's all hold on together - we are on the winning side of the war against cancer!
Cheers and good reading!
Long term survival benefit and improved complete cytogenetic and molecular response rates with IM in CML after failure with IFN.
By: Kantarjian, Crotes, O;Brien et al MDACC
Cheryl’s synopsis:
This is a clinical observation paper that reviewed the results of patients from 2 Novartis-sponsored phase 2 pivotal study of CML after IFN failure. Study 110 – 149 patients and study 113, 112 patients. This patient group was compared with an historical group of 251 patients treated with nonimatinib therapies.
The median follow up time was 45 months, the major cytogenetic response rate was 73% and the complete cytogenetic response rate was 63%. The estimated 4 year survival rate was 86%.
Multivariate analysis for survival identified 3 key factors which would have independent poor prognostic significance: 1.) haematological resistance, 2.) splenomegaly, 3.) lack of any cytogenetic response after 3 months of therapy. Patients results could be divided into risk groups: 1.) good- no adverse factors, 2.) intermediate (1 adverse factor), and 3.) Poor-risk (2 -3 risk factors).- 12% of the patients in this group were in the poor-risk factor. Based on these groupings the 4-year survival rates were: group 1 (good) 96%, group 2 (intermediate), 86% and group 3 (poor) 49%.
The 4 year cumulative major molecular response (as by Q-PCR and described as BCR-ABL/ABL at less than 0.05%) rate was 43% and complete molecular response rate (BCR-ABL undetectable) 26% for these two study groups.
The results of the imatinib group were compared to the historical group. Not surprisingly, the IM group was associated with a better 4-year survival rate (86 % versus 43%), this survival rate advantage was confirmed by multivariate analysis.
Giving what has previously been studied and is highlighted below, the following 5 questions are the subject of this analysis:
(1) will CCR be sustained or even improved with long-term follow up, (2) whether the low annual mortality rates will persists in later years (3) whether a prognostic model, based on pre-treatment characteristics and early response to therapy, could accurately predict patients who ultimately achieve complete cytogenetic responses (4) the incidences of major molecular (BCR-ABL/ABL ratios less than 0.05%) and complete molecular response (PCRU) which predict excellent long-term prognosis and (5) the significance of chromosomal abnormalities other than Ph. – These 5 questions are the subject of this analysis
Key points of the paper:
1.) key therapies in CML attempted to suppress the PH+ of the PH related BCR-ABL kinase activity to alter the natural course of the disease.
2.) SCT – allo produced long-term (not the lack of the use of the word cure) event-free survival rates of 30% to 80% and 1-year mortality rates of 5% to 50% (depending on patients age, donor status etc)
3.) IFN therapy induced cytogenetic response rates of 30% - 70%, which were complete (0% PH+ cells) in 5% - 30%. Median survival rates for IFN was 5 – 7 years (9 years for patients in the “good” risk category). A complete cytogenetic response rate on IFN was associated with 10-year survival rates of 70% to 85%
4.) IM has showed encouraging results in all three phases of CML (CP, AP & BP) after IFN failure, IM induced major cytogenetic response rates of 60% and CCR rates of 40%. 18 month estimated freedom-from-progression and survival rates of 89% and 95% respectively.
Study groups
IM group: study 110 – 149 patients and expanded study 113 (112) patients. Entry criteria was IFN failure and adequate performance in Oncology group scores, renal functions, cardiac function (those with New York Heart Association grades 3 to 4 cardiac disease were excluded) Hydrea within 7 days, IFN within 14 days, or other investigational agents within 28 days of starting IM were not allowed. All patients had to be in chronic phase.
Patients were given 400 mg orally of IM, dose escalation to 400 mg twice daily was considered for patients who did not achieve CHR at least three months of therapy, those who relapsed, or those who did not achieve a major cytogenetic response after 12 months or those with a cytogenetic relapse.
Response Criteria
Based on the scale and lasting for at least 4 weeks: Complete response = PH+ of 0%, Partial = Ph+ 1%-34%, minor = Ph+ 35% to 90%. Major cytogenetic responses included complete plus partial cytogenetic responses.
Historical group: Patients in early CP and treated on institutional protocols from 1982 until 1995 and whose disease subsequently progressed while on IFN and in CP. Total of 251 patients, Median age 45 (range 19 to 77 years), 110 patients were on Hydrea/Busulfan, 42 patients on HHT, 27 patients on chemo combinations, 38 patients went to SCT, and other treatments – 34 patients.
Patients
Median follow up time was 45 months for both study group 110 was 48 months and for 113 it was 35 months. At the time of the last follow up, 230 of the 261 patients (88%) were alive, 196 (75%) were in CP on IM and 31 patients had died.
Responses
For IM: CHR (complete haematological response) – 96% in patients with active disease, cytogenetic response was 79%, major cytogenetic response was 73% and CCR was 63% . Interestingly there was a continued increase in the cumulative major and complete cytogenetic response rates with therapy, even after 2 years. In patients who had achieved only a minor cyto response who later continued to improve to CCR were 62 – 76%. That rate decreased to only 10% in patients who still had a minor cyto response after 12 months. Patients in a partial cyto response after 12 months still had a 73% incidence of later achieving a CCR. Patients who only had a minor response or no cyto response had worse estimated 4-year survival rates (70% to 79%), when compared to those who had achieved better response rates (88% to 100%).
74 of the 261 patients had dose escalations to either 800mg or 600mg. 23 patients in the dose-escalation category, 16 (70%) improved their cyto response to complete (n=9) partial (n-6) or minor (n=1) and were sustained in 7 of the patients (30%) Among 28 patients treated for cyto refractoriness, 16 (57%) improved their cyto response to complete (n-6) partial (n-6) or minor (n_4) and were sustained in 7 (25%) patients.
Among 23 patients treated for haematological resistance, 9 (39%) achieved a CHR, 2 of them with cyto response (1 partial, 1 minor) and 5 patients (22%) had a partial hem response. 5 patients are in sustained hem. response.
Of the 261 patients – 196 (75%) remain alive in CP on IM, 31 have died, 34 are alive in different CML phases or other therapies. Of the 31 who died, 27 died after discontinuation of IM, 4 during IM therapy. 18 patients have died after disease progression to accelerated (n-5) or blastic (n-13), 13 patients died of other causes (2 infections, e cardiac events, and 2 after allo sct and 6 from other causes).
Estimated 4 – year freedom-from-transformation rate was 80%, the estimated 4 year progression-free survival rate was 86%.
256 patients alive on IM at 3 months, 219 had evaluable cyto response, 142 (55%) achieved a cyto response (complete, partial or minor) . The estimated 4-year survival rates were 95% for those who had achieved a cr and 72% for those who did not.. 4 year progression-free survival was better for CR patients than not (93% versus 55%).
246 alive at 6 months, 199 had evaluable CR and 112 (46% of total) had a major cyto response. Estimated 4-year survival (95% versus 78%) and progression-free survival (93% versus 65%) were better in patients with a major response.
Durability patients (4 were not followed up at MDACC) , 147 patients (93%) continue to have durable complete (n=122) or partial (n-25) cr while 11 (7%) showed loss of major cyto. Among 26 patients with partial , 10 have lost the response. 14 patients who achieved a minor cyto 9 (64%) have so far shown loss.
Comparison of survival with IM to previous historical experience – TO BE CONTINUED ON MY NEXT POST – Later on today
Cheers,
Cheryl-Anne
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