Until the superiority of novel agents is proven for all prognostically relevant subgroups of patients with CLL, we believe chemoimmunotherapy continues to have a role.
Chemoimmunotherapy has been the backbone of first-line treatment for chronic lymphocytic leukemia (CLL) since the first use of fludarabine, cyclophosphamide, and rituximab (FCR) at MD Anderson Cancer Center in 1999[1,2]; this regimen improved survival compared with fludarabine and cyclophosphamide (FC) in the German CLL Study Group’s CLL8 study. More recently, three independent datasets have demonstrated plateaus in the progression-free survival (PFS) curve after first-line FCR in patients with low-risk genomic features, including mutated IGHV status[4,5] or mutated IGHV and lack of del(11q) and del(17p), suggestive of functional cure. Patients with comorbidities (“unfit” patients, often defined as those with a cumulative illness rating scale score of > 6 and/or an estimated glomerular filtration rate of < 70 mL/min/m2) do not tolerate FCR as well. Less intensive chemoimmunotherapy regimens such as bendamustine and rituximab (BR) or chlorambucil and obinutuzumab (G-Clb) are better tolerated by older and unfit patients and can achieve high response rates. However, these regimens do not produce a plateau in the PFS curve, and PFS after BR is inferior to that of FCR in patients ≤ 65 years old.
Novel targeted therapies, such as the Bruton tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib,[12,13] BCL2 inhibitors such as venetoclax,[14,15] and phosphoinositide 3-kinase (PI3K) inhibitors such as idelalisib, have transformed the outcomes of patients with relapsed CLL; importantly, these drugs are active in patients with chemotherapy-resistant CLL, including those with del(17p).[17,18] In the frontline, ibrutinib has subsequently demonstrated superiority to chlorambucil, a weak chemotherapy comparator, in unfit patients, while the results of similar studies for acalabrutinib-based regimens (ClinicalTrials.gov Identifier: NCT02475681), the BTK inhibitor BGB-3111 (NCT03336333), and regimens based on venetoclax (NCT02242942), as well as phase III studies in fit patients challenging regimens like FCR, are eagerly awaited (Table 1).
Chemoimmunotherapy with 6 cycles of FCR is the only treatment proven to produce high rates of long-term treatment-free remission with undetectable MRD in patients with favorable prognostic features.
In contrast to chemoimmunotherapy, BTK inhibitors and PI3K inhibitors rarely produce undetectable MRD.[19,20] Therefore, they must be given indefinitely, resulting in high cost and cumulative risk of toxicity.
Venetoclax-based regimens may alter this paradigm: venetoclax plus obinutuzumab, venetoclax plus ibrutinib, and venetoclax plus ibrutinib and obinutuzumab in the first-line setting achieve high rates of undetectable MRD. Long-term follow-up from the CLL13 and CLL14 studies will determine whether this translates into prolonged PFS, analogous to that seen after FCR.
There are several ways that outcomes with chemoimmunotherapy can potentially be improved. A pretreatment prognostic assessment should be completed to aid in treatment decision making. CLL is a biologically heterogeneous disease. Poor prognostic factors in patients treated with first-line chemoimmunotherapy are well established and include: del(17p) or del(11q) by fluorescence in situ hybridization (FISH)[5,6]; unmutated IGHV[4-6]; TP53 or SF3B1 mutations; thymidine kinase levels > 10 IU/L; and Î²2-microglobulin levels ≥ 4.0 g/L. Patients with del(17p) or TP53 mutations have a median PFS of < 1 year after FCR.[3,5]
Outcomes with ibrutinib (median PFS, 28 months) or venetoclax (median PFS, not reached at a median follow-up of 18 months) are superior to outcomes with first-line FCR in this setting. Thus, patients with TP53 deletion or mutation should receive novel agents. It is unclear from current data whether IGHV somatic hypermutation status, del(11q) status, and other biomarkers for inferior PFS after FCR should be used to determine the initial therapeutic paradigm (chemoimmunotherapy vs novel agents). However, notably, in patients treated with first-line ibrutinib, those with unmutated IGHV or del(11q) had excellent PFS outcomes compared with those with mutated IGHV or without del(11q). Given that, after first-line FCR, outcomes for patients with unmutated IGHV and/or del(11q) are markedly inferior to those with mutated IGHV and favorable FISH subgroup (median PFS, 51.7 months vs not reached), it is possible that the current generation of randomized studies will eventually show that the novel agents are superior to FCR as frontline therapy in these populations. The patients that stand to benefit the most from chemotherapy, however, are fit patients with mutated IGHV and without del(11q) or del(17p); functional cures are achieved in over 50% of these patients following FCR; therefore, FCR remains the standard of care in this population.
In addition to the use of pretreatment prognostic factors to tailor therapy, interim (post–cycle 3) bone marrow MRD results may further refine treatment strategies: favorable-risk patients have excellent PFS outcomes if MRD is undetectable in bone marrow after course 3, even if no further cycles are given, suggesting that such patients could potentially stop treatment after course 3 of FCR without compromising outcomes, reducing cumulative toxicity.
Finally, the use of chemoimmunotherapy and novel agents need not be mutually exclusive; nonoverlapping toxicities and complementary mechanisms of action suggest that sequencing or combining these agents is possible. Undetectable MRD rates of 83% to 100% have been achieved in phase II studies of ibrutinib combined with FC and either obinutuzumab or rituximab.
Older patients have an increased incidence of comorbidities, which may limit treatment tolerability. The CLL10 study demonstrated that treatment with BR in fit patients > 65 years of age had a PFS (median, 48.5 months) similar to that seen with FCR, with less myelosuppression and fewer infections. Therefore, BR is considered a reasonable alternative to FCR in fit older patients. In unfit patients, G-Clb achieved undetectable MRD in up to 20% of patients, with a median PFS of 29 months. Randomized studies of acalabrutinib vs G-Clb (Elevate CLL TN) and venetoclax plus obinutuzumab vs G-Clb (CLL14) are ongoing and, given the superior single-agent activity of these targeted drugs, they may prove to be better options for unfit patients. For now, however, G-Clb remains a reasonable first-line treatment option for unfit patients desiring a time-limited therapy or in cases in which BTK inhibitors are unavailable or contraindicated.
The toxicity profile of chemoimmunotherapy is known and largely finite. Early treatment-related toxicities from FCR include myelosuppression (grade 3/4 neutropenia, 34% to 52%)[1,3] and infection (grade ≥ 3 in 25%). The most feared late complication is the development of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), which occur in 1.5% to 4.5% of patients.[5,29]
Novel agents, however, are not risk-free. B-cell receptor signaling inhibitors cause minimal myelosuppression[19,20] and thus may be a better option for older and unfit patients. However, they have a number of unique toxicities, which may be severe or life-threatening (Table 3). Notably, during first-line treatment with ibrutinib, 18% of patients aged ≥ 65 years discontinued treatment due to toxicity, despite relatively short follow-up. In patients treated with idelalisib plus rituximab in the first-line setting, 54% discontinued treatment due to toxicity. In the relapsed setting, patients who discontinue ibrutinib due to toxicity have poor outcomes, with a median survival of ~2.5 years.
Despite the lack of myelosuppression seen with ibrutinib and idelalisib plus rituximab, serious opportunistic infections have been reported with both regimens in the first-line setting: the National Institutes of Health reported 5 cases of Pneumocystis pneumonia in 96 patients treated with ibrutinib, 4 of whom were treatment-naive.[32,33] Even more concerning, randomized studies of idelalisib in the first-line setting for CLL and indolent non-Hodgkin lymphoma were stopped due to higher mortality rates in the idelalisib arm, resulting from fatal infections with cytomegalovirus and Pneumocystis jirovecii. Finally, venetoclax as monotherapy is associated with a 41% incidence of grade 3/4 neutropenia, and a 53% incidence in combination with rituximab. Therefore, infection risk remains a significant concern even during treatment with targeted agents.
Consideration must be given to the relative costs of novel regimens and chemoimmunotherapy. In the United States, 6 cycles of FCR have a total cost of approximately $60,000 to $100,000; in contrast, ibrutinib costs approximately $130,000 per year and is given indefinitely. For many patients in the United States, there are substantial insurance copayments, totaling > $2,000/month, which can be prohibitive. In Australia, which has a government-funded scheme to meet the costs of pharmaceuticals, ibrutinib is not yet approved for public reimbursement in the first-line setting, due to cost/benefit considerations.
Chemoimmunotherapy with FCR is currently the only first-line treatment known to be capable of producing highly durable treatment-free remissions and potential cure in favorable-risk fit patients. Although this group constitutes a relatively small proportion of patients with CLL, we believe that this curative potential is highly significant.
A number of strategies to improve on outcomes of treatment with chemoimmunotherapy have been proposed or implemented. Accurate pretreatment prognostication, using a combination of FISH, IGHV mutation status analysis, and next-generation sequencing, will allow us to better identify the “curable” fraction of patients and avoid the toxicity of FCR in the remaining patients. Use of interim MRD analysis may allow treatment de-escalation in patients who achieve early undetectable MRD, limiting therapy-related toxicity. Finally, combining chemoimmunotherapy with novel agents could significantly increase undetectable MRD rates, while reducing total chemotherapy exposure, thus both potentially improving long-term disease-free remission rates and limiting the risk of therapy-related MDS/AML.
The CLL community is justifiably excited about the impact of targeted therapies. However, these agents are costly and not without toxicity. Until the superiority of novel agents is proven for all prognostically relevant subgroups of patients with CLL, we believe chemoimmunotherapy continues to have a role.
Financial Disclosure:Dr. Tam has received honoraria and research funding from AbbVie and Janssen. Dr. Thompson is an advisory board member and has received honoraria from Amgen, Genentech, and Pharmacyclics; he has also received honoraria from AbbVie.
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