Relapsed/Refractory Chronic Lymphocytic Leukemia: Chemoimmunotherapy, Treatment until Progression with Mechanism-Driven Agents or Finite-Duration Therapy?
1 Hematology, Department of Medical Sciences, University of Ferrara, Italy.
2 Hematology, Department of Cellular Biotechnologies and Hematology , Policlinico Umberto 1, 'Sapienza' University , Rome , Italy.
Received: 27 January, 2019
Accepted: February 1, 2019
Mediterr J Hematol Infect Dis 2019, 11(1): e2019024 DOI 10.4084/MJHID.2019.024
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of relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) has
dramatically improved thanks to the development of mechanism-driven
agents including drugs that inhibit kinases in the BCR pathway or BCL2.
The treating physician has now the opportunity to decide i) which
patient can be still offered chemoimmunotherapy as salvage treatment,
ii) which patient at relapse is a candidate to receiving, continuous
treatment with ibrutinib, idelalisib and rituximab or venetoclax and
iii) which patient may benefit from a fixed-duration treatment using
the BCL2 antagonist venetoclax in association with rituximab.
While these new agents were initially developed and received marketing approval as continuous oral treatment given until disease progression or unacceptable toxicity, the design of new trial using venetoclax with the anti-CD20 monoclonal antibody rituximab for a predefined number of cycles, led to the demonstration that a fixed-duration treatment without chemotherapy in R/R CLL may produce complete responses, with many patients becoming MRD-negative in the peripheral blood (PB) and bone marrow (BM).[12-16]
Since these findings appear to hold promise at an extended follow-up[17,18] and since the regulatory agencies granted market authorization to venetoclax and rituximab based on the 24-month schedule of the MURANO study, we are witnessing a rapid paradigm shift in the treatment of R/R CLL. Indeed, the treating physician has now the opportunity to decide i) which patient can be still offered CIT as salvage treatment, ii) which patient is a candidate to receiving continuous treatment at relapse and iii) which patient may benefit from a fixed-duration treatment.
A Role for CIT in the R/R Setting?
Treatment Until Progression
Ibrutinib is the most actively investigated drug in R/R CLL and data at a 5-year follow-up of 101 R/R patients were published and recently updated with a 7-year follow-up. Patients had a median age of 64 years, had a good performance status (PS) and had received a median of 4 previous therapies. In this phase 1b-2 study, ibrutinib was able to provide excellent disease control for a prolonged period in the majority of patients, with 52% of patients alive at 7 years and with 5- and 7-year PFS rates of 44% and 32%, respectively. Grade ≥3 cumulative toxicity events after a median exposure to the drug of 39 months included pneumonia in 27% of patients, hypertension in 25% and atrial fibrillation in 9%. At 7 years, 55% of patients developed a serious infection and 9% a major hemorrhage. However, observational studies of ibrutinib clearly showed that elderly patients with comorbidities and/or an ECOG PS >1 were more likely to discontinue treatment due to toxicity[34-38] and that atrial fibrillation occurred more frequently in elderly patients with previous arterial hypertension and pre-existing cardiologic comorbidities. In the real world experience of the Swedish registry an updated analysis at 30-month follow-up of 95 R/R patients (median age of 69 years, del(17p)/TP53 mutation in 63% of the patients, PS grade 2-3 in 27%) showed that 51% of patients had a grade 3-4 infection, 15% developed any grade atrial fibrillation and 20% discontinued due to adverse events. In another analysis, 116 out of 536 R/R patients (21.6%) treated in the U.S. discontinued ibrutinib due to toxicity at a median follow-up of 17 months.
Idelalisib given continuously in association with 8 doses of rituximab showed efficacy in a heavily pre-treated patient population with unfavorable baseline characteristics (median age 71 years, grade ≥3 cytopenia in 1/3 of the cases advanced stage in 2/3 of the cases, high burden of comorbidities in 85% of cases), with an estimated PFS of 66% at 12 months and a discontinuation rate of 8% due to adverse events after a median time of exposure to the dug of 3.8 months.
Venetoclax, given as single-agent until progression, is the only drug of proven efficacy which has been used in phase II trials for CLL progressing after ibrutinib or idelalisib.[30,31] A response was observed in approximately 2/3 of patients, with approximately 3/4 of patients alive without progression at 12 months. The most frequent treatment-emergent adverse events were primarily hematological and included mainly neutropenia in approximately 50% of patients, with grade 3-5 infections occurring in approximately 15% of patients. Laboratory tumor lysis syndrome was recorded in 5% of patients. In a real-world analysis of 141 patients treated in the U.S (median age 67 years, 17p- in 45% of patients, previous exposure to a BCR antagonist in 89%), 72.1% of patients responded, with a projected PFS and OS for the entire cohort at 12 months of 68% and 88%, respectively. Venetoclax was discontinued in 41 patients (29%) due to disease progression (53.8%, n=21), toxicity (20.5%, n=9) or other reasons (25,7%, n=10).
|Table 1. Efficacy of recently developed fixed-duration approaches based on novel agents for the treatment of R/R CLL.|
Recently, the results of the phase-3 MURANO trial comparing venetoclax for a maximum of 24 months associated with rituximab (VR) for the first six months with the classical bendamustine and rituximab (BR) regimen given for six months in R/R CLL have been reported.
Ninety-two % of patients responded to VR, and 62% attained an undetectable MRD (uMRD) in the PB at six months, compared to 12% in the BR cohort. Sixty-four % of 130 patients who completed the two years of planned treatment with venetoclax had uMRD. Patients with uMRD or detectable MRD at low levels (10-2 to 104 residual cells) had a longer PFS than the remaining patients. At a median of 9.9 months after cessation of venetoclax only 12% of 130 patients who completed the planned treatment progressed and 90% of all patients assigned to the VR arm had not undergone a further treatment for their disease at two years.
In the intention to treat analysis, the VR regimen significantly improved PFS (HR: 0.16; IC 95%: 0.12-0.23; p <0.0001) and OS (HR: 0.50; 95% CI: 0.30-0.85; p = 0.0093; OS rate at 3 years: 87.9% vs 79.5%) compared to BR, which represents one of most widely employed CIT regimen in R/R CLL. Noteworthy, though crossover to venetoclax at progression in the BR arm was not pre-planned, the majority of patients received effective salvage regimen with new drugs.
These findings show for the first time that a fixed-duration treatment may achieve deep and durable response and improve survival in R/R CLL, and are likely to have a significant impact in the treatment of R/R CLL in the clinical practice as the regulatory agencies FDA and EMA granted this regimen marketing authorization.
Advantages and Disadvantages of Finite Duration vs Continuous Treatment
- Ibrutinib has been tested in many trials which have now reached a mature follow-up[43,10] and is the only drug with a large body of literature describing the outcome in the real world patient population.[34,36,37,40] Importantly, the excellent efficacy and safety profile was consistent throughout trials which included patients with a good PS. Notably, treatment-limiting adverse events were more frequent during the first year of follow-up; however, the incidence of newly diagnosed hypertension and atrial fibrillation appeared to be constant over a long follow-up period. Outside of clinical trials, elderly patients with comorbidities showed a higher discontinuation rate compared to those on trial. Patients with ECOG PS >1, patients with cardiac disease, hypertension, and on anticoagulant therapy are not ideal candidates for continuous therapy with ibrutinib. Severe infections, including fungal infections represent an emerging issue, even though their incidence is clearly influenced by the longtime of exposure to the drug.
- Idelalisib has been used in a phase 3 trial that mostly included patients >70 years with unfavorable characteristics, many of whom were not enrolled in phase-2 trials of ibrutinib and venetoclax. The short follow-up and treatment-emergent adverse events limit its role to patients unlikely to get a benefit with ibrutinib or venetoclax. The emergence of immune-mediated side effects under treatment may be attenuated in elderly patients with multiple prior therapies.
- Venetoclax and rituximab is the only effective chemo-free approach for the treatment of R/R with a fixed duration (up to 24 months) schedule capable of inducing a response in virtually all cases, with a majority of patients attaining an uMRD in the PB and BM. A complete response was observed in a minority of patients due to a small residual size (<30 mm) adenopathies. Even though the durability of response needs to be established with a longer follow-up, preliminary data on patients attaining an uMRD are unprecedented in this setting of patients. Importantly, preliminary data on few patients indicate that responses can be observed when venetoclax is resumed at disease progression after cessation of treatment.[17,33] The safety profile at a 30-month follow-up is reassuring, and fixed-duration treatment will translate into a lower incidence of treatment-related adverse events compared to continuous treatment.
Treating physicians bear today a great responsibility in offering the best treatment option to each patient with R/R CLL. While a deep knowledge of the growing body of scientific evidence is required to inform and guide the appropriate treatment choice and management, physicians cannot disregard the growing problem of sustainability. In high-income countries, with or without a universal health system coverage, the prices of pharmaceuticals are among the major drivers of the differences in overall health care costs between countries.[46,47] The possibility of using effective regimens for a fixed-duration period may represent a unique opportunity to guarantee a lower cost of treatment and, in the absence of a documented advantage of a given treatment over another potentially equally effective and tolerable, the payer can suggest the practicing hematologist to consider the economic implication of his/her choice. Meanwhile, and most importantly, the regulatory agencies should be able to undertake some recommended actions to negotiate fair prices. Moreover, the definition of validated approaches to stratify the magnitude of clinical benefit along with payment-by-result strategies are urgently required to guarantee the sustainability on national health systems.
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