Satellite Symposium – December 7, 2012
Chronic Myeloid Leukemia (CML): Evaluating the Evolving Therapeutic Landscape to Improve Outcomes
Speakers: Neil Shah, MD, PhD, University of California – San Francisco School of Medicine, San Francisco, CA, Paul J. Shami, MD, The University of Utah and Huntsman Cancer Institute, Salt Lake City, UT , Jorge E. Cortes, MD, MD Anderson Cancer Center, Houston, TX, Jerald P. Radich, MD, University of Washington School of Medicine, Seattle, WA, Michael J. Mauro, MD, Oregon Health & Science University, Portland, OR, David S. Snyder, MD, City of Hope, Duarte, CA
The objective of this program is to educate hematologists and oncologists about therapeutic strategies to improve outcomes in patients with CML. Using a case-based format; the program will address the management of CML throughout the disease continuum. Topics for presentation and debate include personalization of care for newly diagnosed CML, outcome measurement, resistance mechanisms, and salvage strategies.
Dr Shami reviewed the results of IRIS and Hammersmith noting that the Hammersmith study showed the “real world” – outside a clinical trial, and the results were quite different from what happened in the IRIS trial. Furthermore he presented a community based outcomes of patients treated with Imatinib and it showed that only a minority of patients do well enough on Imatinib to be able to continue on the drug. A brief summary of the slide he presented: 84 newly diagnosed patients, 16 did not get IM as first line treatment, and 68 patients received Imatinib 400mg. 6 patients failed at 12 months – 3-disease progression, 2 intolerant and 1 loss of CCyR. Of the 62 assessable patients at 12 months only 28 patients achieved CCyr by 24 months. The slide was presented from the Lucas CM et al Leukemia 2008, 22 (10) 1963-1966. He presented the peculiarities of all the drugs, for example Imatinib you take with food and the worst side effects are diarrhea, fluid retention and muscle cramps. Nilotinib taken on an empty stomach twice a day, blood sugar and lipase levels should be watched and although there was an early concern with QTc and instant cardiac death reported in early phase I trials, this was not the case in the ENESTnd trials. My personal thought is because doctors followed and continue to follow their patients very well and manage potential problems better. Nilotinib is a very good drug, but we learn that none of the TKI’s can just be dispensed without proper management – and that is a good thing!
The case for using Imatinib frontline was presented and the key points are that at least with proper management and close follow up patients who do not achieve a good response based on the various CML guidelines, I.e. CCyr by 12 months, the patients can be switched and may still go on to achieve the most optimal outcome. However, this is also a very strong case for the use of Nilotinib and Dasatinib as first line, and indeed in most countries these drugs have been approved for this use. The key point to remember in this setting is that achieving the milestones indicated in the guidelines early is associated with better long-term outcomes. Importantly, it is becoming apparent that there is a window of opportunity of 2 – 3 years after diagnosis to decrease the risk of progression.
The overall suggestions from this part are that the use of nilotinib and dasatinib in the first-line setting is justifiable and particularly so in high-risk patients whereas Imatinib in first line is justifiable in low risk patients. Additionally the clinician should give strong consideration to the individual patient and consider comorbidites and lifestyle choices.
Next up was Jerald P. Radich, MD, who covered molecular monitoring issues and response times for patients on the various treatments available. He showed the statistics that eloquently point out that although the rate of incidence for CML is unchanged, the death rate for patients with CML dramatically decreased with the advent of TKI’s. Additionally he showed a slide highlighting all of the recent studies that have been done that show a significant increase in the ability of patients on those trials to achieve MMR at 12 months just by using different approaches to treatment and management of the disease.. It is well noted that achieving such deeper responses earlier significantly reduces the risk to disease progression and I would add significantly improves the chance for the patient to at some point in time become a good candidate for any future stopping TKI trials. All which is a very good incentive to stay on therapy and remain adherent to how we are supposed to take our drugs. A perfect segue to his next part of his talk on patient adherence. The Adagio study regarding patients self reported levels of adherence point out that only 67% of patients said they were adherent to therapy over a 4 week period. Only 14.2% of the patients were completely adherent to therapy, 14.8 % of the patients took a higher dose than prescribed and 71% took a lower dose than what they were prescribed. He also showed that in a study done by Bazeos et al. (ASH 2009 abstract) patients who maintained a higher than 90% adherence rate had much better success at achieving MMR and CMR. He showed a quote from Hippocrates: “It is better to know what kind of patient has which kind of disease than to know what kind of a disease a patient has”. To this I would personally add, that in today’s crazy health care structure doctors do not have the opportunity to really get to know their patients. In many ways, Doctors, patients, industry and governments – all of us, become our own worst enemies at time and consistently rig the system for failures. Isn’t it time we all came together to rig the system for success? Dr. Radich half jokingly implied that maybe once a year dosing was the perfect idea to achieve 100% compliance – maybe he isn’t so far off….
He presented a very good slide that showed molecular response at early time points are associated with achievement of future MMR, so the earlier the responses are achieved the better. I think this is a good argument for re-visiting guidelines and perhaps allowing switches earlier in the treatment plan for patients not hitting milestones early. He also presented a very nice slide compiled from various ASH abstracts showing that earlier response times, i.e. responses achieved within the first three months provided very favorable long term survival for patients.
Dr Mauro started his presentation with a nice slide showing what we don’t know in 2012: will 2nd TKI’s be better than IM in early CP? Short-term efficacy and better tolerance? Long-term PFS and OS – is it too early to predict? What happens when IM becomes generic?
Do patients have to stay on TKIs forever?
– Probably, except for a lucky few (Cheryl-Anne’s thoughts, this is being too pessimistic, I think a very good proportion of us will be able to stop if we push technology in the right way and advocate better for ourselves)
– Risk that proliferation will breed progression?
Can we predict resistance and progression?
Maybe, but compliance may be biggest deal
Not sure if early intervention for rising MRD or mutations will change the natural history of resistance / progression?
He showed Jane Apperley’s slide about the many facets of TKI resistance, from cell uptake of the drug, intracellular pumps that eject the drug out of the cell, food to drug and food to food resistance and lack of adherence.
He asked: How can we have an impact?
-Drug binding, access to kinase domain? – Identify, switch, preferable avoid resistance
Increased Target: BCR ABL amplification/over expression – increase dose
Drug delivery: increase PgP, decrease hOct-1, adherence, drug-to-drug interactions
Epigenetic modification > altered BCR expression, function – role of HDAC, hypo-methylating agents unclear
Alternative signal pathway activation: BCR ABL independence?
-Multiple candidates: Src family, Ras/Raf/Mek, JakSTAT
TKI mutation negative cases responding to multi kinase inhibitors (Dasatanib, Ponatinib) is key to identifying relevant pathways.
He showed a very eloquent slide depicting the various mutations and which drugs are sensitive to them in vitro. However he noted that while this can help guide therapy choices there are other things to consider: No consideration of drug plasma levels incorporated (Laneuville et al. J Clin Oncolo 2010). In vitro potency alone may not predict in vivo efficacy. We do not know if this mutation is “driving” clinical resistance in this case? Assumptions may thus be incorrect or inconsistent.
He discussed the mutations that were identified during the DASISION and Nilotinib.
His overall conclusions are that:
Resistance is not futile, specialized therapies are being developed to overcome resistance
-Early identification of therapy short of expectation (3 months) and ongoing vigilance for inadequate response (12-18 months) will cut out patients in need of therapy change whom we can salvage
-Kinase domain mutations play an essential role in TKI therapy resistance and management
-Screening for mutations at appropriate times and with highly sensitive techniques is essential
– Therapy choice may be driven by identification of mutations with lower or absent expectations of clinical response.
Dr. Jorge Cortes: He started his talk about resistance and gave a very nice overview of Ponatinib. Key points: Rationally designed BCR ABL inhibitor, active against T315I and a potent activity against an array of BCR ABL variants, suppresses outgrowth of mutational clones in vitro at only 40 nanomolar, hence the 45 mgs once daily oral dose). He re-capped the Phase I trials. He also spoke about Omacetaxine (formerly HHT) stating that it is active against T315I and may also eliminate Leukemic CML stem cells. He concluded with Ponatinib results showing that responses to date are highly durable. He spoke about DCC-2036 and noted that trials have stopped for the time being. He concluded that the T315I mutation is very rare in CP CML patients, Omacetaxine is recently approved and that Ponatinib will more than likely receive rapid review by the FDA in a very short time but there remains a critical unmet need to find effective treatments of T315I associated blast phase CML and Ph+ ALL
Dr. D Snyder finished up the session with a talk on Transplants essentially showing that transplants have significantly dropped in the era of TKIs and showed that transplants are much more successful when patients are in healthy chronic phase CML. He talked about how patients who have been on Gleevec or other TKIs prior to transplant had relatively good outcomes. Transplants are associated with many risks during and after such as moderate to severe GVHD. While there has been much improvement in drugs to offer CML patients, the transplant technology has not changed much.
Adagio study regarding patients self reported levels of adherence point out that only 67% of patients said they were adherent to therapy over a 4 week period. Only 14.2% of the patients were completely adherent to therapy, 14.8 % of the patients took a higher dose than prescribed and 71% took a lower dose than what they were prescribed. He also showed that in a study done by Bazeos et al. (ASH 2009 abstract) patients who maintained a higher than 90% adherence rate had much better success at achieving MMR and CMR. He showed a quote from Hippocrates: “It is better to know what kind of patient has which kind of disease than to know what kind of a disease a patient has”. To this I would personally add, that in today’s crazy health care structure doctors do not have the opportunity to really get to know their patients. In many ways, Doctors, patients, industry and governments – all of us, become our own worst enemies at time and consistently rig the system for failures. Isn’t it time we all came together to rig the system for success? Dr. Radich half jokingly implied that maybe once a year dosing was the perfect idea to achieve 100% compliance – maybe he isn’t so far off….
He presented a very good slide that showed molecular response at early time points are associated with achievement of future MMR, so the earlier the responses are achieved the better. I think this is a good argument for re-visiting guidelines and perhaps allowing switches earlier in the treatment plan for patients not hitting milestones early. He also presented a very nice slide compiled from various ASH abstracts showing that earlier response times, i.e. responses achieved within the first three months provided very favorable long term survival for patients.
Dr Mauro started his presentation with a nice slide showing what we don’t know in 2012: will 2nd TKI’s be better than IM in early CP? Short-term efficacy and better tolerance? Long-term PFS and OS – is it too early to predict? What happens when IM becomes generic?
Do patients have to stay on TKIs forever?
– Probably, except for a lucky few (Cheryl-Anne’s thoughts, this is being too pessimistic, I think a very good proportion of us will be able to stop if we push technology in the right way and advocate better for ourselves)
– Risk that proliferation will breed progression?
Can we predict resistance and progression?
Maybe, but compliance may be biggest deal
Not sure if early intervention for rising MRD or mutations will change the natural history of resistance / progression?
He showed Jane Apperley’s slide about the many facets of TKI resistance, from cell uptake of the drug, intracellular pumps that eject the drug out of the cell, food to drug and food to food resistance and lack of adherence.
He asked: How can we have an impact?
-Drug binding, access to kinase domain? – Identify, switch, preferable avoid resistance
Increased Target: BCR ABL amplification/over expression – increase dose
Drug delivery: increase PgP, decrease hOct-1, adherence, drug-to-drug interactions
Epigenetic modification > altered BCR expression, function – role of HDAC, hypo-methylating agents unclear
Alternative signal pathway activation: BCR ABL independence?
-Multiple candidates: Src family, Ras/Raf/Mek, JakSTAT
TKI mutation negative cases responding to multi kinase inhibitors (Dasatanib, Ponatinib) is key to identifying relevant pathways.
He showed a very eloquent slide depicting the various mutations and which drugs are sensitive to them in vitro. However he noted that while this can help guide therapy choices there are other things to consider: No consideration of drug plasma levels incorporated (Laneuville et al. J Clin Oncolo 2010). In vitro potency alone may not predict in vivo efficacy. We do not know if this mutation
in this case? Assumptions may thus be incorrect or inconsistent.
He discussed the mutations that were identified during the DASISION and Nilotinib.
His overall conclusions are that:
Resistance is not futile, specialized therapies are being developed to overcome resistance
-Early identification of therapy short of expectation (3 months) and ongoing vigilance for inadequate response (12-18 months) will cut out patients in need of therapy change whom we can salvage
-Kinase domain mutations play an essential role in TKI therapy resistance and management
-Screening for mutations at appropriate times and with highly sensitive techniques is essential
– Therapy choice may be driven by identification of mutations with lower or absent expectations of clinical response.
Dr. Jorge Cortes: He started his talk about resistance and gave a very nice overview of Ponatinib. Key points: Rationally designed BCR ABL inhibitor, active against T315I and a potent activity against an array of BCR ABL variants, suppresses outgrowth of mutational clones in vitro at only 40 nanomolar, hence the 45 mgs once daily oral dose). He re-capped the Phase I trials. He also spoke about Omacetaxine (formerly HHT) stating that it is active against T315I and may also eliminate Leukemic CML stem cells. He concluded with Ponatinib results showing that responses to date are highly durable. He spoke about DCC-2036 and noted that trials have stopped for the time being. He concluded that the T315I mutation is very rare in CP CML patients, Omacetaxine is recently approved and that Ponatinib will more than likely receive rapid review by the FDA in a very short time but there remains a critical unmet need to find effective treatments of T315I associated blast phase CML and Ph+ ALL
Dr. D Snyder finished up the session with a talk on Transplants essentially showing that transplants have significantly dropped in the era of TKIs and showed that transplants are much more successful when patients are in healthy chronic phase CML. He talked about how patients who have been on Gleevec or other TKIs prior to transplant had relatively good outcomes. Transplants are associated with many risks during and after such as moderate to severe GVHD. While there has been much improvement in drugs to offer CML patients, the transplant technology has not changed much.
