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Tackling Resistance in CML

By Esther Palmer,2014-05-09 22:39
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Tackling Resistance in CML

    Tackling resistance in Chronic Myeloid Leukemia: Integrating Therapeutic Advances for Improved Outcomes” Sponsored by an unrestricted educational grant from Bristol Myers Squibb

    The panel consisted of: Jorge Cortes, Neil Shah, Gianantonio Rosti and Jane Apperley

    1.) Neil Shah presented the pathophysiology and Mechanisms of Resistance in Chronic Myeloid Leukemia

    Summary of his presentation: Although the majority of patients on Gleevec respond well, there is 30% or more who do not. Patients who do not achieve a good response may be more likely to develop resistance to Gleevec. Resistance can happen in a couple of ways: (1) not taking the drug properly due to intolerance issues, or lifestyle habits. (2) Less stable disease due to higher risk SOKAL score at diagnosis.

    Loss of response to Gleevec shows that in most cases the BCR ABL pathway is reactivated. My note: the BCR ABL Oncoprotein activates many other pathways that are only “deactivated” by SRC kinase inhibitors (i.e. Dasatinib and Bosutinib). Restoration of the BCR ABL pathway can lead to mutations in the Kinase Domain. Both the newer TKI’s address most of these mutations,

    which then restores response to therapy.

    He showed that only Dasatinib inhibits, albeit weakly, the CML Quiescent stem cell population.

Dr. Shah worked with Dr. Sawyers and BMS to develop Dasatinib. Dr. Shah’s specialty is

    resistance in CML.

2.) Gianantonio Rosti presented “First-Line Therapy for Chronic-Phase Chronic Myeloid

    Leukemia: Can We Improve on Current Therapy?

Showed historical data on CML Overall Survival from 1898 1977, which showed a maximum 6-

    year survival rate, pretty dismal....

    This is in contrast with the new TKI’s:

    IRIS at 7 years based on the Intention to Treat shows and Estimated Overall Survival at 7 years is 86%, 94% when considering only CML Deaths

    Rates of progression for patients on TKI’s after achieving CCR is 3% of patients progressed to AP/BC of the 456 who had achieved CCR. Of the 456 patients who had achieved CCR, 2% died from CML

    He postulates (1) that some Ph+ CML are intrinsically TKI resistant, it doesn’t even matter how fast the response is. (2) Most if not all with CML are sensitive to TKI’s at the onset: an early response reduces/abolishes the risk of refractoriness and late progression.

    He mentioned three ways to study sequential changes in patients with CML: 1.) Gene Expression profiling 2.) SNP Arrays 3.) Array comparative genomic hybridization (CGH)

    Importantly he pointed out: (1) Early response is associated with (a) higher probability of MMR,

    higher rates of event free survival (EFS) and progression free survival (PFS) (b) achievement of MMR is associated with longer duration of CCyR, higher rates of EFS and PFS (C ) Durable MMR is associated with prolonged PFS

    He presented data for high dose Gleevec comparing studies done at (1) MD Anderson (206 patients), the (2) RIGHT trial (115 patients), (3) GIMEMA study (78 patients) and the (4) TIDEL Study- 600mg Gleevec (103 patients) with the (5) IRIS (553 patients) results. I am not going to reconstitute the charts, just summarize them.

    These were all De novo patients (newly diagnosed not having received any prior treatment). Only the patients in the TIDEL trial received 600 mg.

    The rates of CCR for each of the studies was: 1=91%, 2=85%, 3=88% 4=88% versus IRIS = 65% The rates for MMR for each of the studies was: 1=85%, 2=54%, 3=49%, 4=47% versus IRIS = 38%

    Interesting to not that only the MD Anderson site achieved a much more significant rate of MMR on the 800mg than the other centers, when you compare the centers 2 and 3 results to center 4 which was the only center testing 600mg, the results were very similar, which makes the argument for trying 600 mg before switching TKI’s.

    He made an interesting comparison with the Spirit trial and TOPS trial which compares 400 mg to 800mg of Gleevec saying that although the 800mg group of patients achieved higher rates of MMR, they were not very significant and the side effects made it difficult for patients. He mentioned that the story about the rabbit and the hare is not about speed, but about perseverance. I have my own perspective on this and will share it a bit later on in this review.

    Next, he presented the front line information on both Nilotinib and Dasatinib: Dasatinib: MD Anderson, 52 patients two dosing schedules were compared (1) 140 mg at twice daily dosing of 70mg and 100mg at twice daily 50mg. The study also allowed the patient to drop down to 80mg at 40 mg twice daily dosing and 40 mg at 20 mg twice daily. One patient discontinued therapy after three doses. 49 patients were evaluable, that is 49 patients that achieved a 3 month follow up.

    All patients achieved a CHR, 47 achieved CCyR, 24 of those achieved MMR, and 3 of those achieved CMR (PCRU). During this study, they realized that the twice daily dosing was causing the problems with pleural effusion and no patients are receiving the twice-daily dosing regimen any more. The study looked at MMR rates, that is better than CCR and noted that 20% of the patients who stay on therapy achieved this after 6 months, 35% achieve it after 12 months and 48% achieve it after 18 months.

    Looking at the Nilotinib front line: 73 patients 400mg BID (twice daily) after three months, 78% of the patients achieved CCR, after 6 months 96% achieved CCR and this was the same result for 12 months. When you compare frontline of Dasatinib and Nilotinib :

    Dasatinib MD Anderson Trial: CCR @ 6 months = 93%, 12 months = 95% and MMR @ 12 months = 35%

    For Nilotinib the Italian trial: CCR @ 6 months = 96% and at 12 months = 96% and MMR @ 12 months = 85%

    For Nilotinib MD Anderson trial: CCR @ 6 months = 95% @ 12 months = 93% and MMR @ 12 months = 47%

    IRIS 72 months follow up sorted by SOKAL (risk) score you get the following scenario: Low Risk: EFS = 91%, PFS = 97% and OS (Overall survival) = 94%

    Medium Risk: EFS = 81%, PFS = 92% and OS = 87%

    High Risk = WFS=67%, PFS = 83% and OS = 76%

ELN (European Leukemia Network) Recommendations:

    At diagnosis 400 mg of Gleevec @ 3 months response should be: CHR, and >minor Cyr (minor cytogenetic response)= Ph+ <65%

    @ 6 months response should be: ? Pcgr )Partial cytogenetic response) = Ph+< 35% @ 12 months 2nd generation TKI response should be CCgR

    @ 18 months on 2nd generation TKI response should be MMoIR (Major molecular response) Anytime thereafter response should be stable or improving MMolR

    3.) Jane Apperley spoke, but I am awaiting her slides from her. However, I can say that Dr. Apperley made the strongest argument for a cure. She absolutely demanded and insisted that nothing less than a cure is needed for this disease and now is not the time to become complacent. Did I mention how much I admire Dr. Apperley? I think I admire her equally as much as Dr. Tessa Holyoake and Dr. Shah..

4.) Dr. J. Cortes Spoke - “Emerging Strategies for the Treatment of Chronic Myeloid Leukemia”

    Do we need new treatment options with CML? Why?: we do have excellent results with Imatinib frontline and Dasatinib/Nilotinib (2nd generation),

    However:

    ~30 % fail frontline therapy (18% no CCR, 4 8% intolerant, 10-15% lost CCR)

    Most patients have residual disease

    Need for treatment indefinitely

    Chronic “low grade” toxicity

    In Addition:

    ~ 50% of patients do not achieve CCR with 2nd generation TKI (my personal theory, me as in Cheryl-Anne Simoneau, is that most patients wait too long to go to 2nd generation, not a good choice in my opinion in the battle against cancer).

    ~ 10% have lost CCR after 2 years

Are more TKI’s needed?

What we have:

    Effective frontline and effect 2nd line therapy

What could be improved?

    Toxicity profile

    Response rate and duration

    Development of resistance

    Coverage of “Achilles heel” mutations

What is Missing?

T315I inhibition

    Eliminate the leukemic stem cell

    TREATMENT DISCONTINUATION (my caps)!!!!

He showed the profile of new drugs coming up for T315I:

    AP24534 = 32 patients in six dose cohorts (2-6 mg/d) 27 pats w/ T315I or refractory to 2nd generation TKI, Mutations in 23 (12 had T315I)

    Of the 23 patients on the highest dose cohort, 19 remain on trial (9/12 with T315I) No Dose Limiting Toxicities seen yet

    Responses: CHR= 16/18, MHR 2/4 AP, 4 CCR, 2 PCR (partial cytogenetic response) For those with T315I CHR 5/6 CP, MHR 2/2 AP, HI 1 BP, 2 CCR and 1 partial cytogenetic response

    He spoke about DCC 2036 a novel TKI inhibitor: Binds into a switch pocket mechanism on BCR ABL kinase, stabilizes the kinase in the inactive form, goes against the P-Loop gatekeeper and the A loop mutants, in a mouse model it shows it can be effective against T315I and it is orally bio-available.

    He spoke about Danusertib Hydrochloride (PHA-739358) An Aura Kinase Inhibitor: Phase II 7 patients CML with T315I or TKI failure: 1 CP, 1 AP and 5 BP the responses showed that 1 AP achieved CCR & CMR at greater than 6 months 1 CP patient with T315I had a major cytogenetic response treatment on going at 20 months. Well tolerated no grad 3 or higher nonhematologic toxicity PD analysis = inhibition of CRKL Phosophorylation.

XL 228

    35 patients treated: 9= T315I, 5+F317L, 6= multiple mutations including T315I Well tolerated overall response: 7/35 = 1 RCP, 2 minor cytogenetic, 2 major cytogenetic, 2 CCR Of those with T315I = 1 minor cytogenetic response, 1 major cytogenetic response, 1 CCR

Omacetaxine note this is the one furthest along in trials 66 with T315I 40 in CP, 16 in AP and

    10 in BP

    CP - CHR = 34/40, AP CHR = 8/16, BP CHR = 4/10

    CP MCyR = 6/40, AP = 0, BP = 0

    CP CCR = 4/40, AP CCR = 1/16 none for blast

    Partial Cytogenetic response in CP = 2/40, none for AP or BP

    Minimal cytogenetic response in CP = 5/40

    In another study looking at multi TKI resistance in CML, 55 patients, CP = 30, AP = 20 and BP = 15 CHR CP = 24/30, AP = 16/20, BP = 8/15

    Major Cyto CP= 6/30, AP = 1/20, BP = 0

    CCR CP= 3/30, AP=0, BP=0

    Partial cyto CP= 3/30, AP=1/20, BP = 0

Dr. Cortes spoke about how CML Stem cells survive Gleevec Treatment in vitro

    These stem cells increase the expression of BCR ABL mRNA, protein and Kinase activity, they also increase expression of IL-3 and GM-CSF, and it lowers the expression of OCT1 It also increases ABCB1 and ABCG2

Strategies to eliminate CML Stem Cells:

New TKI, or combinations?

    Immune modulation: IFN, Vaccines, CTLA4 monoclonal antibodies

    Alternative pathways Hedgehog

    Other Mechanism Omacetaxine

Talked about Junction Peptide Vaccine Studies

    I will do another report on this.

What do new agents offer?

    Bosutinib, responds to the need to improve toxicity profile

    We need to improve response rate and duration no drug guarantees that at the moment

    Development of Resistance no agent stops resistance from happening

    Coverage of the “Achilles heel” mutations = AP24534, DCC-2036, Omacetaxine, XL-228, PHA-

    739358

    T315I mutation= AP24534, DCC-2036, Omacetaxine, XL-228, PHA-739358

    Eliminate the Leukemic Stem Cell no agent is proven to do this at this time

    Discontinue Therapy no agent is proven to do that at this time

My personal thoughts:

    My thought is this is cancer and we do not have the luxury of waiting too long to see if our drugs work. Gleevec frontline 400mg is fine, with a caveat, I would like to see tighter control and watch the response rates. At three months if you are not CCR, you have a choice, go to 600 mg of Gleevec or 2nd generation. If you respond well, stay on the drug unless you have severe intolerance issues that cause you not to be adherent to therapy. Taking holidays on Gleevec or really any drug (exception Sprycel, based on new evidence presented at ASH),is not a good idea. Lowering blood levels of the drug may promote eventual resistance. It is very imperative to speak to your doctor about anything that is preventing you from adhering to treatment.

    If you are not having a good response to Gleevec after 3 months, do your homework, talk to your doctor. It is your life, only you can decide how aggressive you need to be with your disease. If you are young and healthy, you have more leverage room and it is more important as the stakes are high, you theoretically have more life in front of you. I still consider my self young so, my option would be go to a 2nd generation TKI (in fact I am on a 2nd generation TKI with IFN). I need to stay neutral on saying which one I would choose. I will only say that the BCR ABL Oncoprotein activates many pathways and I think science is showing us that this causes genomic instability that leads to mutations and then resistance. These TKI’s do a great job of shutting

    down the BCR ABL Oncoprotein and stopping them from activating the other pathways.

    CML in a chronic stage is a much better disease to deal with than when you start having mutations, resistance and other events.

    What am I looking forward to? Curing this disease. To that extent I will have some things to report on regarding the European combo/trials IFN Gleevec. Their protocols are much better

    than ours here in North America, with the exception of Dr. Talpaz’s protocol in Michigan. In

    Europe they have you stay on Gleevec and IFN for at least two years after achieving PCR, then wean you off of Gleevec and then eventually, if you the patient prefer, wean you off of IFN. They are having very good results with this. I am very excited about Hedgehog inhibitors and using them in combination. Of course I am looking to see what ChemGenex does with

Omacetaxine, in lab test with Both Dr. Tessa Holyoake and Dr. Li, they showed that it kills CML

stem cells. I could handle toxicity issues in order to cure this disease.

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