In this issue of Blood, Brown and colleagues show an impressive additional value when combining a tyrosine kinase inhibitor, that is, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, with classic chemoimmunotherapy in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma.1
The combination of ibrutinib with bendamustine plus rituximab was well tolerated with no significantly added toxicity reported and induced responses in up to 97% of patients, including a complete remission in 40% of individuals after a prolonged treatment period with ibrutinib.
Nowadays, the combination of chemotherapy with α-CD20 antibodies is an international treatment standard for both treatment-naive and relapsed patients with CLL. Besides the rituximab plus fludarabine and cyclophosphamide (FCR) regimen, bendamustine in combination with rituximab (BR) has become a similarly efficacious though significantly less toxic treatment option.2 Recently, health authorities have approved 2 targeted drugs in relapsed/refractory CLL, that is, the BTK inhibitor ibrutinib and the phosphatidylinositol 3-kinase inhibitor idelalisib, the latter in combination with rituximab.3,4 Both drugs have shown amazing responses in heavily pretreated patients with CLL often harboring a combination of several high-risk features.
Nevertheless, these small molecules have not induced complete remissions in a high proportion of patients and, more importantly, are still new kids on the block: we do not know their long-term efficacy and toxicity. The initial reports describe only a few patients developing resistance, but this phenomenon should be closely monitored on our radar screens.5 Therefore, efforts to aim for deep remissions in CLL, even in the relapsed setting, remain valuable because this could enable us to discontinue treatment while potentially lowering the risk of resistance. Furthermore, patients might appreciate a limited treatment period instead of a permanent intake of cancer pills reminding them daily of their malignancy. Budgetwise this could be good news for some health economics, especially in countries with limited resources in the field of medicine.
In the article by Brown and colleagues, the outcome for patients with relapsed/refractory CLL was shifted from a 59% overall response rate (ORR), including only 9% complete responses (CRs), to a 93.3% ORR with a CR rate of 16.7% when combining BR with ibrutinib. Including a patient with a partial response with typical ibrutinib-associated peripheral blood lymphocytosis, the ORR climbed up to 96.7% and the CR rate increased to 40% when the extended treatment phase with ibrutinib was included. Looking at the response rates for single-agent ibrutinib with an ORR of 71% and a CR rate of 2.4%, the shift to these high remission rates for the triple combination (BR-ibrutinib) is also impressive (Table 11-3,6 ). In contrast to standard chemoimmunotherapy with BR, responses were seen in all prognostic subgroups, including patients harboring del17p. Additionally, the survival data with respect to PFS for BR-ibrutinib compare favorably to BR with the median not being reached during the follow-up of >3 years. Data of a second cohort of patients receiving FCR in combination with ibrutinib are very incomplete in this phase 1b trial due to slow accrual of relapsed patients who were purine analog naive and who were candidates for FCR. The treatment with BR-ibrutinib was quite well tolerated considering that the study population was rather young (median age, 62 years) and not too heavily pretreated (maximum number of prior regimens was 3). Side effects were similar to what is usually observed when the drugs are administered individually with severe neutropenia in 40% of patients being the most frequent adverse event.
Responses and progression-free survival (PFS) in relapsed/ refractory CLL
| Response . | BR,2 N = 78 . | FCR,6 N = 276 . | Ibrutinib,3 N = 85 . | FCR with ibrutinib,1 N = 3 . | BR-ibrutinib,1 N = 30 . |
|---|---|---|---|---|---|
| ORR, % | 59 | 69.9 | 71 | 100 | 96.7* |
| CR, % | 9 | 24.3 | 2.4 | 100† | 40† |
| Median PFS, mo | 15.2 | 30.6 | Not reached (at month 26, 75% were progression free) | Not reached | Not reached (at month 12, 85.9% were progression free) |
| Response . | BR,2 N = 78 . | FCR,6 N = 276 . | Ibrutinib,3 N = 85 . | FCR with ibrutinib,1 N = 3 . | BR-ibrutinib,1 N = 30 . |
|---|---|---|---|---|---|
| ORR, % | 59 | 69.9 | 71 | 100 | 96.7* |
| CR, % | 9 | 24.3 | 2.4 | 100† | 40† |
| Median PFS, mo | 15.2 | 30.6 | Not reached (at month 26, 75% were progression free) | Not reached | Not reached (at month 12, 85.9% were progression free) |
Includes 1 patient with partial response and lymphocytosis.
Includes extended treatment period with ibrutinib.
Whether the high frequency of secondary malignancies (in 11 of 30 patients) observed in this phase 1b study is worrisome or just random needs to be further investigated in subsequent larger trials evaluating this combination treatment. Besides the awaited results on safety and efficacy of a randomized trial comparing BR with or without the addition of ibrutinib, it will also be of interest to study whether the triple-combination BR-ibrutinib would allow for an earlier stopping of ibrutinib compared with a continuous application of single-agent ibrutinib. Nevertheless, the trial by Brown and colleagues sets the stage for many more in order to learn more about the risks and benefits of combining 2 extremes, that is, targeted drugs and classic chemotherapy. Eventually, we also would like to explore whether the use of improved α-CD20 antibodies and other classes of small molecules like BH3 mimetics and Mcl-1 inhibitors might even allow for the omission of the traditional partner in this wedding: that is, instead of the chemo partner a matched pair alliance with an in-house targeted mate.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
