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Vol 4 October 2017


Only 5 years ago, when Anna Maria Fink and colleagues’



started recruiting patients, lenalidomide was

judged as a drug that was worthwhile further exploring

in chronic lymphocytic leukaemia as a potential

practice changing new agent. Nowadays, the fast

pace of drug development in chronic lymphocytic

leukaemia has dropped lenalidomide out of the group

of newer compounds. Due to the rapid advances in

therapeutics for chronic lymphocytic leukaemia leading

to the approval of a new class of highly e ective and

tolerated agents, including kinase inhibitors and BCL2

inhibitors, the results of this study are unlikely to

a ect the current clinical practice. However, the study

by Fink and colleagues


provides the opportunity of

speculating on three major domains of active research

in the eld of chronic lymphocytic leukaemia—namely,

minimal residual disease, maintenance therapy, and


Treatment of haematological malignancies is based on

successful applications of residual disease measurement

as a clinical grade biomarker for the early and accurate

identi cation of chemorefractory patients. Patients

with positive minimal residual disease are candidates

for treatment intensi cation to maximise the chances

of cure. Minimal residual disease monitoring can

also allow the early and accurate identi cation of

good-risk patients, who are candidates for treatment

de-escalation, and can potentially avoid long-term

complications of therapy. Levels of residual disease

after chemoimmunotherapy is a validated dynamic

prognostic factor anticipating progression-free survival

in symptomatic patients with chronic lymphocytic

leukaemia receiving rst-line chemoimmunotherapy.


Given the strong association between minimal

residual disease levels and eventual outcome, minimal

residual disease is also accepted in clinical research

as an early surrogate endpoint of progression-free



Whether minimal residual disease in chronic

lymphocytic leukaemia can be successfully validated

as a dynamic predictive biomarker is still under

investigation, and a new generation of clinical trials is

incorporating minimal residual disease as an instrument

to decide whether treatment can be de-escalated in case

of minimal residual disease negativity, or treatment

has to be intensi ed in case of minimal residual disease

positivity. The randomised, double- blinded, placebo-

controlled study by Fink and colleagues,



assigned 60 (67%) patients to the lenalidomide group

and 29 (33%) to the placebo group, of whom 56 (63%)

received lenalidomide and 29 (33%) placebo. Median

progression-free survival was 13·3 months (95% CI

9·9–19·7) in the placebo group and not reached (not

evaluable) in the lenalidomide group. Despite some

limitations that are fairly discussed by the authors, the

study provides, for the rst time, the proof of principle

that minimal residual disease guided treatment

intensi cation a ects patients’ outcome, and prompts

studies based on an minimal residual disease guided

application of sequential blocks of therapies pointing to

minimal residual disease eradication and tumour clone


By delaying disease progression, and, in some entities,

by also improving survival, maintenance therapy turned

out to be a successful approach in all incurable mature

B-cell tumours, including follicular lymphoma, mantle

cell lymphoma, and multiple myeloma.



it is not surprising that, as in other incurable mature

B-cell tumours, also in chronic lymphocytic leukaemia,

maintenance successfully prolongs progression-free

survival, independent of whether the disease was

treatment naive or previously treated, and independent

of the depth of response achieved before the start of



While previous phase 3 studies testing

maintenance therapy in chronic lymphocytic leukaemia

have broadly included all responding patients,



study by Fink and colleagues


elegantly use a risk

strati cation model to select among responding

patients only those who would gain the larger bene t

from maintenance—namely, patients still persisting

in a minimal residual disease positive status after

chemoimmunotherapy induction. The positive study

of Fink and colleagues


shows a bene t of maintenance

Lenalidomide maintenance in high risk chronic lymphocytic

leukaemia: practice changing study or hypothesis generating




September 12, 2017 S2352-3026(17)30178-3



page e475

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