FEATURE with similar findings ; these data , though , only apply to a relatively small subset of patients with CLL who are young , fit , and have IGHV-mutated , low-risk CLL without other cytogenetic features like del11q or del17p . 5 Still , for patients like these trial participants , who can tolerate more aggressive therapy , I believe FCR should be the standard of care and the backbone regimen upon which combination approaches with novel agents should be studied .
We should not forget that another approach with curative potential in CLL is allogeneic hematopoietic cell transplantation ( alloHCT ). We have data about this approach going back for decades , and experience suggests that around 40 percent of patients will have long-term , disease-free survival , even in patients with high-risk CLL . 6
Of course , alloHCT has many potential risks and toxicities , such as graft-versus-host disease and infection . I am hopeful that newer cellular-based therapies such as CAR T-cell therapies will induce similar response and survival rates to alloHCT , but with less toxicity .
Dr . Woyach : Right , we obviously do not have as much longterm data on the novel agents as we do for chemotherapy , which has been the standard approach for years . With ibrutinib , which has the longest follow-up of the newer agents , we still only have five- to seven-year follow-up .
Focusing on studies conducted in this setting , the phase Ib / II PCYC-1102 trial evaluated single-agent ibrutinib in 132 patients with symptomatic , treatmentnaïve or relapsed / refractory CLL , including a subset of 31 treatment-naïve patients older than 65 years . 7 At five years after treatment initiation , 29 out of the 31 remained in remission . This is an excellent outcome , but does not indicate a path to a cure , as most of these patients still had detectable disease , despite remaining on drug . We also don ’ t know what happens if patients discontinue therapy .
It seems that , for ibrutinib at least , combination therapy will be required to permit treatment discontinuation , and hence the potential for a cure . As Dr . Davids mentioned before , there are data looking at ibrutinib in combination with FCR , with great response rates – including both MRD negativity and duration of remission in the short term .
Researchers also have been evaluating ibrutinib in combination with the BCL2 inhibitor venetoclax , as well as venetoclax plus obinutuzumab , which look promising – with the caveat that limited follow-up data are available . 8 , 9 For either of these combinations , though , it remains to be seen whether patients will be able to discontinue treatment without risking relapse .
Dr . Davids : The definition of cure also will affect our choice of which patients we will attempt to cure . For me , to cure CLL , we need to reach an MRD-undetectable state , both in the blood and in the bone marrow . However , getting to an MRD-undetectable state is just the first step , because we have certainly seen patients who reach that state and then later relapse once therapy is discontinued .
MRD-negative status is a useful surrogate for outcome , but clinicians ’ ultimate goal is to prolong patients ’ survival . The challenge is knowing how long we need to wait until we can tell a patient that his or her disease is cured . Getting to MRD-undetectability is certainly not enough . In other cancers , we use five years of disease-free survival as a benchmark ; in CLL , that ’ s not long enough . We know that patients can experience late relapses . In the long-term FCR data that I mentioned , the number of relapses decreases as patients near five or 10 years of disease-free survival ; still , there were almost no relapses after 10 years . 1 So , I think if a patient with IGHV-mutated CLL has remained bone marrow MRD-undetectable 10 years after finishing FCR , he or she is likely to be cured .
Dr . Woyach : I agree with you . Ten years is probably a good benchmark . There definitely are some relapses after FCR between five and 10 years , and we don ’ t have much data to say whether achieving an MRD-negative state in patients receiving a novel therapy alone is clinically important , or whether it signifies long-term survival . MRD negativity clearly is important for remission duration after chemoimmunotherapy , but we don ’ t know if the same will hold true with novel therapy combinations .
“ It ’ s important for us , as a field , to decide for which patients curing disease should be our treatment goal . ... ”
— JENNIFER WOYACH , MD
Dr . Davids : There are some early data that patients with CLL who achieve an MRD-undetectable state while taking venetoclax have better PFS at two or three years , compared with patients who remain MRD-positive . But , with such short follow-up , we don ’ t know if that will translate into a longer-term , disease-free survival benefit .
It ’ s true : MRD-undetectability after treatment with newer agents may not be the same as what we have seen with chemoimmunotherapy . Theoretically , if a patient achieves MRD-undetectability , it shouldn ’ t matter which way he or she gets there ( chemotherapy or novel agents ), but we actually need to show that with clinical trial data .
Dr . Woyach : It might be a sampling difference , too . If a patient is truly MRD-negative , it probably doesn ’ t matter how he or she got there , but we don ’ t know that MRD-negativity in bone marrow or peripheral blood also means that the lymph nodes are completely clear of disease . The ability to eradicate malignant cells from the lymph nodes might differ between chemoimmunotherapy and newer therapies .
With MRD , we also have to consider the level of detection with available MRD analyses . Both chemoimmunotherapy and novel agent combinations can produce MRD-negative bone marrow to a sensitivity of 1 × 10 – 4 , but there could still be differences in the absolute number of remaining malignant cells below the level of detection .
Dr . Davids : If we ’ re defining cure in terms of MRD status , we also should mention that patients taking ibrutinib often do not get to an MRD-undetectable state . As long as they stay on ibrutinib , though , they can do extremely well for long periods of time . So , for many patients with CLL , particularly those who are older and frailer , achieving MRD-undetectability may not be important .
Another consideration for deciding our ultimate treatment goal – and how we will get there – is that there are not many predictive biomarkers in CLL . The most important one we have is TP53 status , which is a solid predictor of poor response to chemoimmunotherapy . Also , if patients have a somatic mutation of TP53 or del17p , they are unlikely to have a durable response to chemoimmunotherapy . These are patients for whom we could recommend a newer agent – based approach , even in the frontline setting .
The other important predictive biomarker in CLL is IGHV mutation status . Patients with IGHV-unmutated disease tend to have shorter responses to chemoimmunotherapy . For these patients in our practice , we are increasingly recommending starting with an approach incorporating novel agents .
Dr . Woyach : I think that age is going to end up being important , as well . With chemoimmunotherapy , only the FCR combination has demonstrated curative potential , and we know that this regimen is not suitable for older patients . Looking at the gold-standard regimens in older patients ( including fludarabine , chlorambucil , or rituximab combinations ), most don ’ t appear to have the potential to induce cures , or even very durable remissions .
Dr . Davids : We have seen excellent responses early in the disease course when patients are treated with combinations containing novel agents , like ibrutinib plus venetoclax with or without obinutuzumab . CAR T-cell therapy development has great potential in CLL , both alone and possibly in combination with other new agents . For example , results from a small study of patients treated with ibrutinib and anti-CD19 CAR T-cell therapy suggested that adding this new agent may increase the curative potential of CAR T cells in CLL . 10 I ’ m optimistic that we will be able to cure more patients with CLL by using the novel agents in the future .
Dr . Woyach : New agents may be able to induce cures in certain patients with CLL , but , I would argue that if a patient is doing well on a novel agent like ibrutinib or other single-agent therapy , and he is not experiencing much toxicity , he may have an excellent quality of life , despite being on indefinite drug therapy . For these patients , the potential toxicity of combination therapy may not be worth the potential benefit , particularly because their treatment goal likely is not a cure . Instead , we want these patients to maintain a remission that allows them to continue to experience an excellent quality of life for as long as possible . ●
REFERENCES
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2 . Davids MS , Kim HT , Brander DM , et al . A multicenter , phase II study of ibrutinib plus FCR ( iFCR ) as frontline therapy for younger CLL patients . Abstract # 496 . Presented at the 2017 ASH Annual Meeting , December 12 , 2017 ; Atlanta , GA .
3 . ClinicalTrials . gov . First-line therapy with ibrutinib , fludarabine , cyclophosphamide , and obinutuzumab ( GA-101 ) ( iFCG ) for patients with chronic lymphocytic leukemia ( CLL ). Accessed July 26 , 2018 , from https :// clinicaltrials . gov / ct2 / show / NCT02629809 .
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8 . Wierda WG , Siddiqi T , Flinn I , et al . Phase 2 CAPTIVATE results of ibrutinib ( ibr ) plus venetoclax ( ven ) in first-line chronic lymphocytic leukemia ( CLL ). Abstract # 7502 . Presented at the 2018 American Society of Clinical Oncology Annual Meeting , June 3 , 2018 ; Chicago , IL .
9 . Flinn IW , Gribben JG , Dyer MJS , et al . Safety , efficacy and MRD negativity of a combination of venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia – results from a phase 1b study ( GP28331 ). Abstract # 430 . Presented at the 2017 ASH Annual Meeting , December 10 , 2017 ; Atlanta , GA .
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