Joost Lips summary of the EHA meeting Berlin 2009
Joost Lips Summary of the EHA meeting, Berlin June 2009.
News from the EHA congress 4 – 7 June 2009 in Berlin.
There were quite a lot of presentations about CML. The educational presentations were this year about leukemic stem cells, mutations in the BCR/ABL gene and second generation tyrosine kinase inhibitors (tki’s).
The first of these presentations, about leukemic stem cells, stressed the importance of further investigations on CML for these cells. The reasons for this are:
- The aim must be to cure the patients definitively.
- The disease often returns when one stops with tki’s; so it isn’t cured.
- Because of the long life expectancy, costs of use of tki’s increase greatly.
Mutations in the BCR/ABL gene can lead to resistance for TKI’s. The most known here is the T315I mutation, which gives resistance to each of the three TKI’s. By treating a patient with this mutation with a tki, CML cells with this mutation have an advantage over other cells and they survive. This can be seen by the relapse the patient experiences. Some other thing to be worried of is the question if TKI’s therapy itself as a cause of mutations. However this seems to be not the case. Standard mutation investigation of the BCR/ABL gene at diagnosis of CML is not recommended.
During the presentation of the second generation TKI’s :- dasatinib, nilotinib and bosutinib, it appearD that the choice of the second generation TKI’s depended on the kind of mutation observed in the BCR/ABL gene. One mutation can be more sensitive to a second generation TKI, than a different mutation. But in nearly all cases one third to half of the patients in chronic phase, treated with a second generation TKI, reached a CCR-complete cytogenetic response.
The earlier CCR is reached the better the prognosis. In patients in AP-accelerated phase or BC-blast crisis the number of responders is lower. If a second generation TKI doesn’t give a response, allogeneic stem cell transplantation is an option. One reason for this lack of response in AP and BC can be the T315I mutation which is insensitive to all present TKI’s. Therefore the pharmaceutical industries is looking eagerly for third generation TKI’s. Possibilities are: XL228, PHA, AP24534, and DCC-2036. In in vitro (in lab) experiments, these inhibitors show activity against the BCR/ABL protein. In some cases a phase I trial has started.
Regarding CML there are different other developments. Imatinib (Glivec©) stays the first line choice of treatment, however good results have been described with other TKI’s, namely dasatinib (Sprycel©) and nilotinib (Tasigna©). The results obtained with these medicines are comparable with those of imatinib (Glivec). They have potential when resistance against imatinib happens or when imatinib is not tolerated. Resistance or intolerance against dasatinib and nilotinib also has been described. With nilotinib treatment compared to imatinib, most patients reach a response faster in the form of a cytogenetic remission or even a molecular remission. This was shown by different clinical trials independently.
An interesting study was a treatment, which combined imatinib with cytarabine or interferon. Although many patients in the course of the first year stopped with interferon (probably because of the dose) it appeared in this study that the combination therapy (interferon + imatinib) gave a quicker MMR- major molecular response- than treatment with imatinib alone (400 or 600 mg per day), or with imatinib combined plus cytarabine. This is important because the earlier a molecular response is reached, the greater the chance for a progression free survival.
In another study results were shown of treatment of patients, who were resistant or didn’t tolerate at least two TKI’s. About 70 of these patients were treated with omacetaxine mepesuccinate. This is a protein synthesis inhibitor, which hopefully inhibits synthesis of the Bcr/Abl protein. Of the 71 patients, 37 were in chronic phase, 18 in AP-accelerated phase and 16 in BC-blast crisis. All these patients did not respond to imatinib and at least one other TKI, some did not react to any of the three TKI’s.
The most important side effects were low white blood cell and/or blood platelet counts. Other sideeffects were rare. From the patients in CP-chronic phase, who could be evaluated, 75% had a response. For the accelerated phase this was 44 % and 67 % of patients in BC-blast crisis returned to the CP-chronic phase. This last group did not reach a cytogenetic response. For patients with the T315I mutation, the numbers were comparable. An inhibitor (MLN8237) of another type kinase, the aurorakinase, was tested in the laboratory with tissue culture. In combination with nilotinib, it was very effective in inhibiting cells with different mutations (amongst which the T315I mutation) occurring with CML. The results of these experiments were so good, that clinical studies in patients resistant for imatinib are planned.
In an Italian study, one was looking for mutations present in the BCR/ABL gene at diagnosis. They found that with all patients, at that moment, mutations are present, but many were silent and had no consequences for the TKI treatment (meaning no resistance occurs). Themore important tki resistances do not lead to a relapse (return of the disease). The conclusion in the end is that high sensitivity screening for mutations for CML and ALL Ph+ patients before start of the TKI treatment is not necessary. In another Italian study it was shown that the ends of the DNA molecule in the chromosomes (called: telomeres) after a successful treatment of CML were significantly shorter. Moreover, the DNA molecules lost part of their function. Unknown is at this moment what this means.
In yet another Italian study it was found that treatment of CML patients with TKI’s, can lead to new mutations in the BCR/ABL gene, but when this happens, it happens mostly in the first year of treatment. Older patients (above 65 years) also react well on imatinib treatment, but it takes longer to reach a CCR -cytogenetic or MMR-molecular response. This was repeated in different independent studies. The same applies for older patients treated with dasatinib. There was also a study which didn’t show any predictive connection between plasma levels ofimatinib and outcome of the treatment.
The Sokal score of a CML patient predicts the response and outcome of the imatinib treatment. The higher the score the lower the chance of success. This was also shown in different independent studies. A study was presented in which it was investigated, whether patient with a complete molecular response CMR could stop imatinib treatment and if the CML eventually returned. It appeared that in about half of the patients the CML did return. As it is unpredictable in which patient the CML relapses,it is unwise to stop without any supervision. But it also appeared that patients who relapsed, reacted well on restarting of imatinib.
There was also a symposium, sponsored by Novartis, regarding current and future clinical strategies of managing CML patients. In the presentation of Andreas Hochhaus about imatinib as standard of care, he showed the results of the IRIS study. The IRIS study compared interferon combined with cytarabine and imatinib. The potential of imatinib is best shown by the fact that most patients receiving interferon and cytarabine turned to imatinib (and still are). Most patients on imatinib reach a cytogenetic response which deepens in the course of time to a major molecular response. The adverse effects, shown in the beginning of the imatinib therapy diminish with time and the chance that resistance or intolerance occur are the largest in the first two years.
Michele Baccarini from Italy presented the recommendations of the European Leukemia Net. A provisional outline of treatment recommendations is as follows:
- Imatinib: 400 mg in all patients
- In imatinib-intolerant patients, give dasatinib or nilotinib
- In imatinib-suboptimal responders, increase the dose of imatinib, or give dasatinib or nilotinib
- In imatinib-failures, dasatinib or nilotinib, or allo-stem cell transplantation in case of accelerated or blast phase and in case of T315I mutation
- In case of dasatinib or nilotinib -suboptimal response, either continuation of dasatinib or nilotinib, or allo-stem cell transplantation, particularly in patients with an EBMT risk score ≤2;
- In case of dasatinib or nilotinib -failure, allo-stem cell transplantation, whenever possible.
The definition for low response or failure to dasatinib or nilotinib is at 3 months no cytogenetic response (Ph+ > 95%), at 6 months only a minimal cytogenetic response (Ph+ 66-95%), at 12 months less than partial cytogenetic (Ph+ > 35%). Moreover, the detection of new mutations during dasatinib or nilotinib treatment should also be considered as a marker of failure.
Hagop Kantarjian from the M.D. Anderson Cancer Centre presented imatinib dose escalation strategies in CML management. As known, in some patients imatinib gives not enough results, meaning no hematologic or cytogenetic response is reached within a short time. In that cases, one can choose for a second generation tki. But it is also possible to increase the imatinib dose.
Imatinib has been proven to be an effective and well tolerated therapy at doses of 400 and 800 mg/d. Most CML-chronic phase patients will achieve major molecular response when taking imatinib, and average survival of CML-chronic phase patients, who attain a molecular response has been recently estimated at greater than 20 years. Emerging data indicate that patients who fail to achieve cytogenetic response and perhaps more importantly, patients who experience cytogenetic relapse may be effectively treated with imatinib dose escalation up to 800 mg/d.
François Mahon presented a study about the role of imatinib blood level testing in the management of CML patients. He found a association between the blood level of imatinib and a higher major molecular response. Moreover, there might be a correlation between the imatinib plasma concentration and the durability of the complete cytogenetic response. Overall, imatinib trough blood level testing is a simple and rapid way to determine if imatinib exposure is within the expected range. Several studies have demonstrated large inter-patient variability in imatinib through levels which could possibly lead to inadequate exposure.
The measurement of imatinib plasma concentration can be a helpful tool to alert physicians when imatinib exposure is not within the expected range. Physicians may consider imatinib blood level testing in patients who:
- are not responding to imatinib as well as expected
- are suspected to be poorly compliant to their imatinib regimen
- experience adverse events that are unusually severe for the prescribed dosage
- when a drug-drug interaction is suspected.
Imatinib blood level testing is a useful supportive tool to help monitor imatinib therapy. Further investigations are required to ascertain whether there is a different imatinib plasma threshold for complete molecular response, and whether it is possible to define an imatinib plasma threshold for adverse events.