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Interview with Dr. Elias Jabbour - ASCO 2014
Assistant Professor in the Department of Leukemia, MD Anderson Cancer Center, Houston, Texas, USA
Interview with Dr. Elias Jabbour, Assistant Professor in the Department of Leukemia, MD Anderson Cancer Center, Houston, Texas, USA.
A lot has been achieved especially for pediatric AML, where survival went from 10% to 90%. Unfortunately, these results have not been reproduced amongst adults. Survival has increased, but after 4-5 years 50% of the patients are alive, compared to 90% of the pediatric patients. With more knowledge about leukemias, pathways and targets, we start targeting them.
For instance, in acute lymphocytic leukemia (ALL), where you have expression of CD20, you improve the outcome for these patients when you add monoclonal anti-CD20. This was the rational of one trial we presented at ASCO, it was a combination of hyper-CVAD regimen (AML backbone regimen) and ofatumumab (anti-CD20 mAb). The hypothesis was that the combination allows for faster eradication, hopefully leading to a better cure in the long run. Thus far 25 patients have been enrolled, follow-up is a bit over a year. Responses are fast and long-lasting. We have an indication of minimal disease and we know this parameter is important for the longer term survival. Thus far, none of the 25 patients have relapse on-trial. One patient with very aggressive disease had a transplant and died. Ofatumumab is given twice per cycle for four cycles. The patient continues on hyper-CVAD chemotherapy regimen. If indeed the effect is sustained for the longer run, that will be a major step for ALL patients.
Another ALL specific feature, for certain patients (30-50%), is that they harbor the Philadelphia chromosome or Philadelphia translocation (a specific chromosomal abnormality that is the result of a reciprocal translocation between chromosome 9 and 22). Therefore, we combined hyper-CVAD with ponatinib, a multi-targeted tyrosine-kinase inhibitor (TKI). For chemotherapy alone, we have an annual mortality of 90%. If we add TKI to hyper-CVAD we can reach 50% 3 year survival rates. This is a good improvement, but still not so high, as patients do relapse. When they relapse, they acquire the T315I mutation, rendering them resistant to current therapies such as imatinib. Only ponatinib can target this mutation. Our rational was that by combining hyper-CVAD with ponatinib, we can prevent the emergence of this mutation. Responses were overwhelming, and with the 16 months follow-up we have thus far, there has been no relapse, 0%, which is phenomenal. There were, however, two deaths on the trial due to side effects. Due to this we have lowered the dose from 45 to 30 mg, to be further reduced to 15 mg in patients that are responding and do not need a higher dose. That is for the future. We now have 37 patients and if they stay relapse free for a longer period, that is a major step, because they have been saved from transplantation.
In summary, ALL will be cured still within Dr. Jabbour’s lifetime. We have several promising targets and inhibitors today. In the near future, we can design the right cocktail of drugs for each patient. We now have the different TKIs, anti-CD20, other antibodies (like anti-CD22), and T-cell-engaging bispecific single-chain (BiTE) antibodies (binding to CD19 and bringing T-cell to that). These are drugs that are available today in the research setting and hopefully will reach approval, which will open the door for more investigations leading to a better cure-rate for these patients.