ASH Report #2: First-line trial updates, STOP trials, early switching, comorbidities, side effects

In this second report from the annual meeting of the American Society of Hematology (ASH), we would like to cover some of the long-term follow-up data on first-line CML therapies: the 5-year update on the Nilotinib first-line trial ENESTnd, as well as the 4-year update on the Dasatinib first-line trial DASISION. The results of all three approved first-line TKIs Imatinib, Nilotinib and Dasatinib continue to be excellent when applied in first line, with low rates of progression,  increasing rates of deep molecular responses. For those with resistance and intolerance against these three TKIs, at least two additional TKIs are becoming available in an increasing number of countries. CML has turned from a life-threatening disease into a chronic condition for most patients with a near-normal life expectancy. Given research conferences mostly cover unresolved topics, this year's CML sessions at ASH seemed to focus on mainly three topics: how safe and successful is stopping all therapy in deep molecular response, how do we manage serious side effects in some patients, and what role do pre-existing other diseases (e.g. cardiovascular risks that are more frequently present in elderly patients) play when we choose TKI therapy? This (lay) report focuses on ASH presentations that focused on these topics.   

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Table of contents

DSC05103 -- END SAGLIO ENEST 5y5 year update on Nilotinib in first line therapy

Dr Giuseppe Saglio presented the 5 year update of the ENESTnd study which compared Nilotinib with Imatinib in newly diagnosed patients. Survival continues to be very good: By 5 years, 96.5% of patients (on 2x300mg Nilotinib/day) on study remained alive without progression, and 94.7% on Imatinib. 62% of Nilotinib patients (on 2x300mg daily dose) and 51% of Imatinib patients were still on initial study treatment. Since the last report a year ago, an additional 3.5% of Nilotinib patients and 6% of Imatinib patients had discontinued treatment. At 5 years, 77% of Nilotinib and 60% of Imatinib patients had reached an MMR, and 54% vs. 31% had achieved an MR4.5 remission.

The risk of progression to advanced phases continues to be double on Imatinib - 3.5% of Nilotinib patients and 7.1% of Imatinib patients had progressed to accelerated phase or blast crisis. Late relapses are rare, as only a single patient each on Nilotinib and Imatinib progressed in year 5, and both patients had failed to achieve the early 10% BCR-ABL mark at 3 months after starting treatment, so four years earlier. The overall 5-year survival without progression was 95% on Nilotinib and 92.6% on Imatinib.

Cardiovascular events were more common on Nilotinib than on Imatinib: 19 events in 279 Nilotinib (2x300mg) patients, 35 events in 277 Nilotinib (2x400mg) patients, and 6 events in 280 Imatinib patients. 85% of these patients with cardiovascular events had at least one prior risk factor and were not optimally managed for hyperglycemia and hypercholosterolemia.  As shown in earlier years, early response is prognostically significant on both treatments: patients with BCR-ABL >10% at 3 months have significantly worse 5-year overall survival and barely any chance to achieve MR4.5 within 5 years.

More than half of Nilotinib-treatment patients had achieved MR4.5, a key eligibility criterion for many treatment-free remission studies. Dr. Saglio concluded that the long-term data confirms Nilotinib 2x300mg/day as standard-of-care with newly diagnosed CML patients in chronic phase. (ASH-Abstract #92)

DSC011214 year update on first line dasatinib in first line therapy

Dr Jorge Cortes presented the 4 year update of the DASISION study which compared Dasatinib 100mg/day with Imatinib 400mg/day in newly diagnosed patients. Results remained to be excellent, with a 4-year overall survival of 93% on Dasatinib and 92% on Imatinib. 84% of patients on Dasatinib and 64% of patients on Imatinib met the 10% BCR-ABL milestone at 3 months. 74% of patients on Dasatinib and 60% of patients on Imatinib achieved an MMR. The rates of MR4 were 47% and 30% respectively.

3.1% of Dasatinib patients and 5.4% of Imatinib patients progressed on study to accelerated phase or blast crisis within 4 years. Common adverse events like edema, myalgia, nausea, arthralgia, nausea, vomiting and rash and were more frequent on Imatinib treatment, diarrhea, fatigue and headache occurred as often on both treatments, while pleural effusion was only prevalent on Dasatinib (affecting 22% of Dasatinib patients and no Imatinib patients). (ASH-Abstract #653)

Does early switching improve responses?

Dr Brian Leber presented the 36 month results of the ENESTcmr trial. When entering this study, the patients had already been treated with Imatinib for at least 2 years, had achieved a complete DSC05141cytogenetic response but had still detectable BCR-ABL. Half of the patients were switched to Nilotinib immediately, and the other half continued Imatinib with the same dose, but switched to Nilotinib 2x400mg if BCR-ABL was still detectable after another year, or if they had lost of response. By the time of this report, of the 207 patients, 106 were on Nilotinib and 37 on Imatinib, the other 62 had discontinued due to adverse events (35 patients), withdrawal of consent (13), pregnancy (2), death (2) and other reasons (14). Switching or not had no influence on progression, as no case of progression was reported on both treatments.

Those switching to Nilotinib resulted in significantly deeper molecular responses, with 47% of Nilotinib and 24% of Imatinib patients achieving MR4.5 by 36 months, plus 21% of Imatinib patients after crossover to Nilotinib. However, the switch came at some prize, as more cardiovascular events were reported in the nilotinib treatment arm than in the imatinib arm, and the rates of drug-related adverse events were significantly higher on Nilotinib, with a considerable proportion of new events occurring in year 3.

In conclusion, in may be a viable strategy to switch from Imatinib to Nilotinib when patients have achieved good but not very deep responses, if the goal is to achieve deeper molecular responses, e.g. to be able to stop therapy at a later time. (ASH-Abstract #94)

What role do comorbidities play?

Pre-existing diseases that have occurred independent of CML (= comorbidities) can have an influence on the safety of CML patients treated with TKIs. Given  the side effect profiles of TKIs differ, the presence of certain comorbidities may have an influence on the selection of TKIs. However, the influence of pre-existent comorbidities on overall survival had not been studied so far.

DSC05091To better understand this issue, the German study group analyzed the data of 1519 patients from the CML-IV study. 511 comorbidities were documented in 384 of these patients, with the most frequent ones being chronic pulmonary disease, diabetes mellitus, renal disease and other tumours. The severity of comorbidities was weighted by disease. No significant influence of comorbidities on achieving a good remission or having a progression could be observed. However, overall survival is greatly influenced by comorbidities: patients with little comorbidities had an 8-year survival of 94% while patients with the highest score on comorbidities had a 8-year survival of only 46%. The researchers concluded that the majority of CML patients do not die from leukemia any more, but comorbid patients die from their accompanying diseases. (Abstract #91)

Is a pre-existing cardiovascular risk relevant when using Nilotinib?


Several Nilotinib studies have reported a treatment-associated risk of arterial events, especially in patients with pre-existing risk factors for cardiovascular disease. In a study presented by Dr Emir Hadzijusufovic from Vienna, the cellular and molecular mechanisms that may contribute to vascular events in Nilotinib-treated patients was further assessed. (ASH-Abstract #257)

Since cardiovascular diseases result from complex interactions between multiple risk factors, Dr. Delphine Rea led a research aimed at determining whether these risk factors could be a useful tool to identify patients at high risk of arterial occlusive events during nilotinib therapy. The researchers considered as high risk for cardiovascular disease if patients had a history of cardiovascular disease, diabetes mellitus, severe arterial hypertension, familial dyslipidemia (an abnormal amount of lipids, e.g. cholesterol or fat), or a systematic coronary risk. Their retrospective analysis on 75 patients revealed that patients with a high/very high risk of cardiovascular disease by the time of starting treatment, which made up 15 of the 75 patients, were at very high risk of developing arterial events during Nilotinib therapy. Therefore, the authors recommend that assessment of cardiovascular risk should be performed in all patients considered for Nilotinib therapy. Alternative TKI treatment may be chosen whenever possible in those high risk patients. In those treated with Nilotinib, cardiovascual risk should be reassessed throughout therapy and risk factors should be tightly controlled according to current guidelines. (ASH-Abstract #2726)

Should assessment of cardiovascular health be done at the time of diagnosis and during follow-up?

The introduction of BCR-ABL inhibitors has turned CML into a manageable, chronic disease. As BCR-ABL inhibitors are used more widely and for longer, some distinctly different or late occurring adverse events have become apparent from clinical studies and literature reports, e.g. peripheral arterial occlusive disease. It has been described in a varying percentage of pts receiving nilotinib in the ENESTnd trial with nilotinib versus imatinib (1.2%) and the literature (0.5%–12.5%).  Arterial thrombotic events have also been reported in patients receiving ponatinib (11%).

To assess whether peripheral arterial occlusive disease (PAOD) may be an effect occuring in all TKI therapies or whether it is a side effect specific to certain TKIs, a pooled database of 2705 pts in 11 clinical trials of Dasatinib was assessed by an international team of CML experts. In those studies, the incidence of pulmonary arterial occlusive disease was low (8 patients), similar to the rates reported under Imatinib. It occurred in patients which had significant predisposing risk factors for PAOD (prior cardiovascular events in 5, metabolic conditions in 4, tobacco use in 3 patients). 7 of these 8 patients had received concomitant medications on these diseases. These researchers conclude that peripheral arterial occlusive disease is most likely not an effect of dasatinib treatment, and that careful assessment of cardiovascular health and risk factors at the time of diagnosis should be integrated into treatment for CML patients (ASH-Abstact #1489).

Update on therapy discontinuation (STOP) studies

DSC05269Dr Francois Mahon from France presented an update on the STIM1 study. In the study, patients were stopping therapy after sustained PCR negativity on Imatinib treatment for at least 2 years. After the stop, PCR was performed every month in the first year and every 2nd month thereafter, and recurrence was assumed when detectable PCR was following by a one-log increase in two successive assessment, or a loss of MMR at any point in time. 100 patients were recruited into this study. 39% of patients maintained PCR negative at 60 months, with most relapses occurred in the first 6 months and none after 24 months. Only Sokal risk score (based on age, spleen size, platelets and blasts at time of diagnosis) was predictive for molecular relapse, but not gender, prior interferon therapy, time from diagnosis to PCR negativity, duration of PCR negativity or duration of prior Imatinib therapy. When looking at the Sokal risk score, 47% of patients with low sokal risk score relapsed, while 73% with high Sokal risk score. Economically, the drug cost savings of the participants on trial was around 4.6 million EUR. The researchers again underlined that discontinuation should be proposed only in a clinical trial with strict molecular monitoring and long-term follow-up. (ASH-Abstract #255)

DSC05376To assess less stringent failure criteria of therapy-free remission, the French group conducted the A-STIM ("According to STop-IMatinib") study. While eligibility criteria were similar to STIM1, loss of MMR (BCR-ABL >0,1%) was the criterion to restart treatment. Of 81 patients that discontinued, 51 (61%) were still in MMR without medication after a median of 31 months. Of these 51 patients, 45% were in sustained BCR-ABL negativity, 24% had occasional BCR-ABL positivity, and 31% had BCR-ABL fluctuations meaning at least 2 consecutive positive PCRs. Of those that relapsed, all patients regained MMR, but one patient experienced progression on Imatinib. In summary, the treatment-free remission rate is at 60% on Imatinib when MMR is the failure criterion, while only 40% on STIM1 study remained in remission. (ASH-Abstract #381)

DSC05376Similar results like STIM1 were presented by the French group in the STIM2 study. In this study with 127 patients who had been PCR negative for at least 2 years, more than half (75 patients) remained in treatment-free remission. Of the 52 patients who had relapsed, 48 relapses occurred during the first 4 months, and 4 more relapses until month 9. Of the 75 patients that remained treatment-free, 40 patients had detectable PCR above MR4.5 for short periods (= fluctuating PCR results), but did not relapse. The researchers conclude that positive fluctuation of PCR results on very low molecular levels do not lead to CML relapse or progression, therefore complete eradication of residual leukemic stem cells may not be necessary to discontinue Imatinib therapy in deep molecular response of at least 2 years duration. (ASH-Abstract #654)

DSC05346 -- END Nordic EUROSKIThe Nordic CML study group presented first findings from an immunology sub-study of the EURO-SKI trial. Their research suggests that patients who relapse after TKI discontinuation may have a lower proportion of natural killer cells and their functioning at the time of drug discontinuation. While mechanisms need to be further investigated to predict individual relapse after discontinuation, targeting these mechanism might also lead to improved treatment-free rates in the future. (ASH-Abstract #379)

See also ASH Education Session: "An Embarrassment of Riches" (18 Dec 2013)

Report by Giora and Jan
23 December 2013
More ASH reports will follow



Ros Fedorov Community Builder Avatar   30.12.2013 (18:17:41)
Yes No All a Merry Christmas and Happy New Year!

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