Frontline treatment for chronic lymphocytic leukemia (CLL) has evolved well beyond a “one-size-fits-all” approach, with patient and disease characteristics and physician/patient discussions determining the optimal therapeutic approach.
“For previously untreated patients with CLL who require therapy, you look at the age, the comorbidities, the functional status, and FISH results,” according to Bruce Cheson, MD, professor of Medicine, head of Hematology, deputy Chief, Division of Hematology/Oncology, Georgetown University Hospital, Lombardi Comprehensive Cancer Center.
Based on these factors, Cheson says that 3 key patient subsets have emerged in the frontline CLL setting: patients without a 17p deletion (del[17p]) who are eligible for chemoimmunotherapy, patients without a del(17p) who are not eligible for chemotherapy, and patients who harbor a del(17p).
In a presentation at the PER meeting, Medical Crossfire: Redefining Treatment Paradigms in the Management of Chronic Lymphocytic Leukemia, Cheson described the treatment choices for each of these 3 patient categories, noting that, regardless of the treatment, “a clinical trial is always the preferred option.”
Chemoimmunotherapy Eligible, No del(17p)
Patients who are candidates for chemoimmunotherapy who do not harbor a del(17p) can be treated with fludarabine, cyclophosphamide, and rituximab (FCR); bendamustine and rituximab (BR); or the BTK inhibitor ibrutinib (Imbruvica).
Cheson said that for years there was controversy over whether FCR or BR was the better chemoimmunotherapy regimen, until the phase III CLL10 trial validated both treatment options as acceptable.
The CLL10 trial randomized 564 treatment-naïve patients with CLL to FCR or BR.1
Patients did not harbor del(17p) and were in good physical condition. The results showed that BR was noninferior to FCR and was associated with lower toxicity.
At 37.1 months’ follow-up, the median progression free survival (PFS) was 41.7 months with BR versus 55.2 months with FCR (HR, 1.643; 90.4% CI, 1.308-2.064). Adverse events (AEs) occurring at higher rates in the FCR versus the BR arm included neutropenia (84.2% vs 59%), anemia (13.6% vs 10.4%), thrombocytopenia (21.5% vs 14.4%), infection (39.1% vs 26.8%) and secondary neoplasm (6.1% vs 3.6%).
The efficacy of ibrutinib in frontline CLL was established in the phase III RESONATE-2 trial, which compared the oral agents ibrutinib and chlorambucil in 269 patients aged ≥65 years with previously untreated CLL who did not harbor del(17p) and had not received warfarin.2
The median PFS was not reached with ibrutinib versus 18.9 months with chlorambucil (HR, 0.16; P
= .001). The estimated 2-years OS rate was 98% versus 85%, respectively (HR, 0.16; P
= .001). AEs leading to discontinuation occurred in 9% of the ibrutinib arm compared with 23% in the chlorambucil group.
“This study clearly established ibrutinib as a first-line therapy for patients with CLL,” said Cheson.
When discussing ibrutinib versus chemotherapy options with patients, Cheson covers delivery method (oral ibrutinib vs IV chemotherapy), toxicity (usually higher with chemotherapy), and length of treatment (“indefinitely” with ibrutinib versus “6 months and done” with chemotherapy).
Chemoimmunotherapy Ineligible, No del(17p)
For patients who are unable to tolerate “heavy-duty” chemotherapy (FCR, BR), Cheson said the optimal treatment choices are ibrutinib (based on RESONATE-2, discussed above) or the combination regimen of the anti-CD20 agent obinutuzumab (Gazyva) and chlorambucil.
The efficacy of the obinutuzumab/chlorambucil regimen in frontline CLL was established in the phase III CLL11 trial, which compared obinutuzumab/chlorambucil (n = 333), rituximab/chlorambucil (n = 330), and chlorambucil alone (n = 118) in 781 patients with treatment-naïve CLL, no del(17p), and comorbidities (CIRS score >6 and/or CrCl <70 mL/min).3
The overall response rates were comparable in the obinutuzumab (77.3%) and rituximab (75.7%) arms, and both were significantly better than chlorambucil alone (31.4%). However, the complete response rate was higher with the obinutuzumab combination (22.3%) compared with the rituximab regimen (7.3%) and chlorambucil alone (0). Additionally, the obinutuzumab arm had a greater likelihood of becoming minimal residual disease–negative than the rituximab arm in the bone marrow (19.5% vs 2.6%; P
<.001) and blood (37.7% vs 3/3%; P
Combining obinutuzumab with chlorambucil also improved PFS versus the addition of rituximab to chlorambucil (HR, 0.39; 95% CI, 0.31-0.49; P
<.001). With overall survival (OS), however, there was a trend for improvement with obinutuzumab (HR, 0.66; 95% CI, 0.41-1.06; P =.08), but a benefit had not yet been achieved.
“Based on these data one can conclude that the regimen of obinutuzumab and chlorambucil for this group of patients is superior to rituximab and chlorambucil, and is a useful regimen for these patients,” said Cheson.
For patients with del(17p) CLL, Cheson said there are now data showing that ibrutinib is the optimal treatment choice. One key study was a median 3-year follow-up of 132 patients with symptomatic treatment-naïve or relapsed/refractory CLL or small lymphocytic lymphoma who received single-agent ibrutinib.4
The 30-month PFS rate was 48%, 74%, and 87%, in patients with del(17p), del (11q), and no deletions, respectively. The estimated 30-month OS rates were 65%, 85%, and 90%, respectively.
Cheson said the impressive del(17p) survival curve in this analysis was a refreshing change compared with historical survival data for the del(17p) population. “For those of us who have been around a long time, the typical curve for patients with del(17p) is kind of straight downward, with a median survival that’s rather short.”
Outside of the 3 main frontline CLL treatment subgroups he described, Cheson also noted that for frail patients, “Ibrutinib is a great choice. Some physicians still give an anti-CD20 agent.”
Looking ahead in this setting, Cheson said, “There are some ongoing and recently completed studies in untreated CLL that are of considerable interest.”
These include the phase III PCYC-1130-CA study (NCT02264574) comparing the combination of ibrutinib and obinutuzumab with chlorambucil/obinutuzumab, as well as the phase III ECOG-E1912 study (NCT02048813) comparing the combination of ibrutinib and rituximab with FCR.
Cheson said the ongoing study in this setting he “likes the best” is the phase III ALLIANCE A041202 study (NCT01886872). The study is comparing ibrutinib alone versus ibrutinib/rituximab versus BR in patients aged 65 years or older.
“I think this is a study that may well define frontline therapy for patients with CLL,” said Cheson.
- Eichhorst B, Fink AM, Bahlo J, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17(7):928-942.
- Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25): 2425-2437.
- Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101-1110.
- Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125(16):2497-2506.