At ASH 2018, combination therapies were the big buzz, as we discussed in several other interviews (see this recent overview from Dr. Lamanna also from ASH 2018).
Dr. Nitin Jain is a member of the strong CLL treatment and research team at MD Anderson Cancer Center (MDACC), Houston TX.
We reconnected at ASH 2018 where I interviewed Dr. Jain about his single center trial at MDACC that combined arguably the best two drugs we have today for treating chronic lymphocytic leukemia, namely ibrutinib and venetoclax in treatment-naïve high-risk chronic lymphocytic leukemia (CLL) population that needed to start therapy.
- 80 patients were studied. All were treatment naïve. 92% had either an unmutated IGHV, or TP53aberration or del(11q).
- Patients received ibrutinib monotherapy (420 mg daily) for 3 cycles (3 months) followed by the addition of venetoclax (weekly dose-escalation to a target dose of 400mg daily). Combined therapy was administered for 24 cycles (two years), and then stopped.
- At one-year 23/25 (92%) of the patients were in CR/CRi (complete remission/complete remission with incomplete recovery of the all the blood count.)
- 17/25 (68%) achieved U-MRD (undetectable minimal residual disease) in the bone marrow. To better understand U-MRD, please listen to this recent interview with Dr. Wierda, also at MDACC.
- 80% of those with del 17p were U-MRD at 12 months.
- Three patients had laboratory evidence of tumor lysis syndrome (TLS). None had clinical TLS suggesting that the 3-month ibrutinib lead-in led to a lower tumor burden, thus decreasing the risk of TLS.
- 11 (14%) discontinued the trial.
- Grade 3-4 neutropenia (low neutrophil count) occurred in almost half of the patients. The potentially more serious neutropenic fever occurred in 5% of patients.
- Atrial fibrillation occurred in 14% of patients.
- The dose of ibrutinib was reduced in 35%; venetoclax was dose-reduced in 18%.
Conclusions and Unanswered Questions:
Clearly venetoclax and ibrutinib is a safe, potent and appealing non-chemo combination as proven now in several clinical trials including this one. Remember that 92% of patients were high risk and they responded well.
It is also clear that the intention is to be able to safely stop the medications. This offers several advantages, certainly saving money and reducing side effects, but also perhaps lowering the risk of developing resistant mutations.
When to stop is the unanswered question. Different trials use different stopping points—some use reaching U-MRD and others use two years. We don’t know which is the best approach.
What we want are durable remissions. Logic and some related data suggest that reaching U-MRD should best predict lengthy progression free and overall survival.
But what should be done for patients that don’t get there at 2 years? Do we continue? For how long?
It is pretty exciting that we are able to start asking these kinds of questions about fixed duration non-chemo approaches that offer the promise of extended control of our CLL.
Here is the link to the ASH abstract: Combined Ibrutinib and Venetoclax in Patients with Treatment-Naïve High-Risk Chronic Lymphocytic Leukemia (CLL).
Stay strong. We are all in this together