【Am J Hematol Review】First-line treatment of chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia, with patients aged 65 to 74 years with a median age of 70 years, so physical fitness may range from very fit to unfit with comorbidities and frail, for these patients must be particularly careful to choose treatment options
.

The WHO classifies CLL as an indolent B-cell lymphoma, but its course can range from indolent to highly invasive
.

When selecting the best protocol for an individual patient, the recommended parameters to consider include clinical stage, patient symptoms, fitness, comorbidities, and genetic risk factors
.

The advent of targeted drugs brings about dramatic changes in the first-line treatment of CLL, the toxicity of which is usually manageable, but also exhibits specific side effects, such as cardiac events and bleeding from ibratinib and other BTK inhibitors, as well as tumor lysis syndrome and infection in Venekra, in addition to the risk of accumulation and aggravation of side effects due to the continuous administration of
BTK inhibitors.

In the presence of progressive bone marrow failure or symptomatic/active disease, treatment
should be given according to iwCLL guidelines.

First-line treatment in patients without del17p/mutTP53 CLL

Fit patients with IGHV mutations

Patients with fit are characterized by parameters such as good physical fitness, few comorbidities, and good creatinine clearance, and are low-risk
if the patient has an IGHV mutation and does not have del17p/mutTP53.

For fit-patients with IGHV mutations, one of the most mature and commonly used targeted agents is continuous BTK inhibitor indefinite therapy
.

The E1912 study compared fludarabine, cyclophosphamide, and rituximab (FCR, previous standard protocol) with ibratinib-rituximab in young patients aged < 65 years
.

The UK FLAIR study compared the same regimen in older patients < 75 years, but the first data at 52.

The ALLIANCE A041202 study compared benzdamustine + rituximab (BR) vs ibratinib + rituxib vs ibratinib monotherapy
in elderly patients aged ≥ 65 years 。 Results based on two protocols of ibretinib were superior in PFS (2-year PFS: ibuptinib + rituximab group 88% in all patients, ibuptinib group 87%, BR group: 74%), even in the IGHV mutant subgroup (median PFS was not achieved in ibratinib + rituximab group, ibratinib group was not achieved, BR group was 51 months); This result was also longer than in the IGHV unmutated subgroup (median PFS was not achieved in the ibratinib + rituximab group, not in the ibratinib group, 39 months in the BR group).

The ILLUMINATE study evaluated ibratinib + optizumab and chlorambucil-phenbutyrate + optulizumab in patients with unfit and also gained PFS benefits (median vs.

Another option is the second-generation BTK inhibitor acotinib
.

The ELEVATE RR study compared ibratinib with acotinib in patients with relapsed/refractory CLL and showed similar efficacy, with median PFS of 38.

Another second-generation BTK inhibitor with less off-target effects than ibratinib is zebutinib
.

All BTK inhibitors are continuous and must be used until intolerable toxicity or progression may lead to cumulative long-term side effects
.

Patients may also receive fixed-time treatment
with vinecra + opturizumab for a period of 12 months.

This combination therapy is also approved for first-line treatment
in FIT patients.
The first data from the CLL13 study showed encouraging results
in patients with fit CLL when comparing vinecra + optizumab with FCR or BR in first-line therapy.
The first co-primary endpoint analysis showed that the rate of undetectable MRD (uMRD) in peripheral blood at 15 months was superior to chemoimmunotherapy (86.
5% vs.
52.
0%)
.
The latest data presented at EHA 2022 show that the high incidence of uMRD translates into longer PFS (second common primary endpoint).

At 38.
8 months of follow-up, the 3-year PFS rate (87.
7%) in the venecra + optizumab group was better than in the FCR or BR group (75.
5%) among all patients, but the difference was smaller in patients with IGHV mutations, compared with 93.
6% in the venecra + oltuzumab group and 89.
9%
in the FCR or BR group.
Although OS results remain to be determined, based on long-term data, low-risk patients can still consider chemoimmunotherapy on an individual basis; However, targeted drugs provide a wealth of evidence to support the superiority of targeted drugs over chemoimmunotherapy
even in low-risk patients.

Fit patients with unmutated IGHV

Patients with unmutated IGHV have a poor prognosis and a shorter
survival rate.
After 5 years of follow-up in the RESONATE-2 study, PFS was 67% in ibratinib group of IGHV unmutated patients, compared with 6% in the chlormustard phenylatinate group; Even after 8 years of follow-up, PFS was similar
in IGHV-mutated and unmutated patients in the ibratinib group.

In the E1912 study, 5-year PFS was 75% for patients with IGHV unmutated IGHV treated with ibratinib + rituximab compared with chemoimmunotherapy, compared with 33% for FCR, and 5-year OS was also significantly different (ibratinib + rituximab 95% vs.
FCR 84%)
.
Differences
in PFS were also observed in older patient populations studied by FLAIR.
Similarly, in the elderly patient population studied by Alliance A041202, the median PFS for ibretinib and ibratinib + rituximab treatment was not achieved after a median follow-up of 33.
6 months with IGHV mutation, compared with BR at 39 months
.

After 4 years of follow-up in the ELEVATE TN study, the median PFS given acrotinib therapy to patients with no mutation in IGHV was not achieved, compared with 22.
2 months
in the oxtuizumab + chlorambucil group.
The 48-month PFS rate of acotinib + optizumab was 86%, acartinib alone was 77%, and chlorchlorchloride phenbutyrate + optulizumab was only 4%.

Zebutinib has also shown therapeutic benefit
in patients with unmutated IGHV.
At a median follow-up of 26.
2 months, zebutinib significantly prolonged PFS (HR= 0.
42, P<0.
0001) compared with BR, including patients with no IGHV mutation (HR= 0.
24, P<0.
0001), but there was no significant difference in patients with IGHV mutation (HR= 0.
67, P=0.
0929).

。 Zebutinib and BR have estimated 24-month PFS rates of 85.
5% and 69.
5%, respectively, IRC-assessed ORR of 94.
6% and 85.
3%, CR rates of 6.
6% and 15.
1%, respectively, and estimated OS of 94.
3% and 94.
6%
for 24 months.

In the CLL14 study, outcomes were still inferior to those in patients with IGHV mutations despite the fact that fixed-duration regimens of vinecra + optizumab prolonged the median PFS of IGHV unmutated patients (57.
3 months and 26.
9 months, respectively) compared with chlorambucilus chloride + optizumab
, after 39.
6 months of follow-up.
On the OS side, no difference
was observed in the IGHV unmutated subgroup.

Given that targeted agents can prolong PFS compared to chemoimmunotherapy, targeted agents
should be preferred in patients with no mutation in IGHV.

Unfit patients

Because of comorbidities, patients with unfit should receive a less aggressive regimen and may choose to include BTK inhibitors, especially newer drugs such as acatinib, which are better toxic, or vinecra + optizumab
.
Compared with chlorambucila phenbutyrate + optizumab, vinecra + optusib as a fixed-duration regimen showed prolonged PFS in patients with comorbidities, but the OS was not prolonged
.
Similarly, ibratinib + ortuzumab and actizinib + ortuzumab both improved PFS compared with chlorambucil-plus ortuzumab, but did not prolong OS
.

Therefore, other factors, such as the burden of comorbidities and possible side effects, as well as the choice of continuous versus fixed-duration therapy, which may limit the options
for individual patients, should therefore also be considered.
In pooled analyses of different clinical trials, targeted drug therapy was also feasible and effective
in frail patients ≥ 80 years of age with comorbidities.
These FRAIL patients have historically been thought to have been symptom control and feasibility should be the primary purpose, but in focused studies of targeted drugs, patients have even achieved survival
comparable to those of age and sex match.

First-line treatment in patients with Del17p/mutTP53 CLL

Patients with del17p/mutTP53 have an aggressive course and usually do not respond well
to chemotherapy immunotherapy.
Although the final treatment has not been determined, targeted inhibitors have shown better efficacy and should be recommended (regardless of physical fitness
).

Continued treatment with ibretinib showed promising results
in first-line therapy.
In a phase 2 study that evaluated only patients with del17p or mutTP53, median PFS and OS were not achieved, with an estimated 60% PFS and OS of 79%
at 6 years.
In another Phase II study, TP53 patients treated with ibratinib had a median to progressive time of 53 months
.
One study comparing ibretinib and ibretinib + rituximab with BR resulted in an incalculable median PFS after a median follow-up of 38 months, compared to 7 months
of BR.
In the final analysis of the ILLUMINATE study (ibratinib + optizumab), the 48-month PFS rate in patients with del17p or mutTP53 was estimated at 74%, compared with 77%
in patients without del17p or mutTP53.

In the CLL14 trial, patients with del17p/mutTP53 who received venectalkal + optoxizumab had significantly longer median PFS (49.
0 months) than those receiving chlorambucilin + optizumab (20.
8 months).

Retreatment of venecla-+ optizumab in patients with disease progression is being performed
in the ReVenG study (NCT04895436).

The PI3K inhibitor idelalisib in combination with rituximab has also been active in high-risk CLLs, but should be used with caution and should only be considered for high-risk CLL in the presence of BTK inhibitors and contraindications to the Venekla, as their very serious side effects, such as fatal and/or severe infection, hepatotoxicity, diarrhoea or colitis, pneumonia, and bowel perforation, can only be discussed
as a last resort.

In a retrospective study of 130 patients with TP53 dysfunction, patients who received BTKi in combination/without vinectra and combination/without CD20 antibodies in first-line therapy had a good 4-year outcome and very good
outcomes in patients treated with double or triple therapy.

The CLL16 study is currently recruiting high-risk CLL patients with complex karyotype or del17p/mutTP53 to compare vinecra + optizumab with a triad of vinecra + oklizumab + actitinib for 14 months and an additional 10 cycles of acrotinib therapy (NCT05197192)
with MRD detectable.

However, high-risk patients will eventually progress even if they receive targeted therapy, there is no cure for CLL other than allogeneic stem cell transplantation, and which treatment line to give after allogeneic stem cell transplantation still needs to be discussed on a case-by-case basis because of its higher
mortality and morbidity.

Developed treatment strategies

An adapted version of the treatment strategy proposed by Hallek and Al-Sawaf is shown in Figure 1 and should be adjusted
if there are associated comorbidities or contraindications.
In general, patients should be stratified according to fitness and TP53 and IGHV status: patients with IGHV mutations and no del17p or mutTP53 are best treated with
vinecra plus optimizumab.
Most patients prefer targeted drug therapy due to better side effects, but chemoimmunotherapy may still be an option for low-risk patients
.
Because the E1912 study showed improved OS, BTK inhibitors such as ibratinib or acotinib may be given preferentially to fit-patients with unmutated IGHV
.

In comorbidities, IGHV mutated or unfit patients may be given vinecra plus optizumab or BTK inhibitors
.
Frail and older patients have a higher risk of multiple doses, a high correlation between efficacy and toxicity, and hospitalization should be avoided, and acotinib may be a viable option
.
BTK inhibitor therapy is preferred in high-risk patients with del17p or mutTP53, and in deciding which of these two drugs to prefer, several factors of preference should be considered, in addition to patient factors, such as cardiac comorbidities, co-medications such as anticoagulants and proton-pump inhibitors, and frequency of administration; If rapid reduction of tumor burden is required, oxtuzumab may be considered in addition to actinib
.

However, since continuous therapy with BTK inhibitors has not been directly compared with intravenous regimens based on a fixed duration, it is not possible to clearly recommend which treatment
should be preferred.
This question was previously explored in the CLL17 study of the CLL Study Group in Germany (NCT04608318), which compared ibratinib with vinecra + oltuzumab and venectinib, but the study is still open for recruitment
.

prospect

Oral inhibitors broaden the possibilities of treatment for patients with CLL and can make choices
on a more individual basis.
In addition to continuous therapy with different BTK inhibitors, treatment of a fixed duration is introduced, which may limit the associated toxicity; Vinecra + Oltuzumab is the first fixed-time-targeted regimen approved for first-line treatment of CLL
.
With the prolongation of treatment, the risk of resistance-related mutations increases, and acquired secondary resistance will account for the majority in the progression of continued treatment, and further research on fixed-duration compound preparations
is needed.

Another promising, still time-limited combination regimen is the combination of venetok + ibratinib
consisting only of oral medications.
High-risk and elderly patients with CLL who are treated with a venerra for 24 months after 3 months of first-line ibretinib monotherapy have an estimated 1-year PFS of 98% and OS of 99%.

CAPTIVATE studies enrolled MRD cohorts and separate fixed-duration cohorts
.
In the fixed-duration cohort, patients aged ≥ 18 years and ≤ 70 years of age received 3 cycles of ibuptinib monotherapy followed by 12 months of combined therapy with a Venekla response, with an overall CR rate of 55% and an OS of 98%
at 24 months.
The estimated 24-month PFS rate is 95% in all patients and up to 84%
in patients with del17p/mutTP53.
In the MRD-driven treatment group, patients who achieved uMRD who were randomly assigned to placebo after 12 combination therapy had a 1-year disease-free survival rate of 95% and ibratinib 100%, while the placebo group had an estimated 30-month PFS rate of 95% and ibratinib group of 100%.

The GLOW study also showed a higher rate of MRD negative rates after treatment with ibratinib + Venectra compared with chlorambucil + oxtuzumab (bone marrow: 51.
9% vs.
17.
1%; Peripheral blood: 54.
7% vs.
39.
0%)
.
PFS rates were higher than 90%
in the first 12 months after the end of treatment in the iboutinib + vinetra group, regardless of whether uMRD or MRD could be detected.
However, four deaths were reported during the introduction of ibratinib, so caution should be exercised in safety data suggesting that comorbidities should be considered when selecting specific BTK inhibitors, particularly in older patients
.

Time-limiting protocols for first-line CLL are currently only approved for fixed-duration therapy, and MRD-driven therapy is not recommended in clinical practice
.

Several studies are currently testing MRD-guided regimens (iburitinib + vinecta) for individualized duration of treatment, but if attempts are made to demonstrate that MRD-driven regimens are superior to fixed-duration regimens, they must be evaluated
in phase III trials.

The triplet also showed promising results in Phase 2 of the
study.
One study evaluating 14 cycles of otoltuzumab + ibratinib + vinectra triplet showed a 95%
estimate of PFS at 36 months.
Optizumab + acrotinib + vinecra are administered in combination until day 1 of cycle 16, with the option of stopping treatment on uMRD, or until day 1 of cycle 25, resulting in a complete remission rate of 38%
for uMRD of the bone marrow.

In a study comparing optizumab + zebutinib + verneca in an MRD-driven regimen, uMRD
was achieved in both blood and bone marrow in 89% of patients with a median duration of 10 months of treatment and a median follow-up of 25.
8 months.

Is a triple combination of targeted drugs likely to significantly improve outcomes, or is early development of toxicity and resistance limiting the regimen? Evaluation is currently underway in a Phase III study
.
The EA9161 study compared ibratinib + oxtuzumab with ibratinib with ibratinib with fixed-duration ibretinib + vernetok + oxtuzumab in patients treated with ibratinib + oxtuzumab in patients with initial treatment < 70 years of age (NCT03701282), with results to be determined
.
A similar design of MRD-driven termination of ibratinib after 14 months is still being recruited ≥ 70-year-old patients (NCT03737981
).
In the Phase 3 CLL13 study, the triple therapy of vinecra + obupinib + optusizumab had a higher rate of uMRD and the longest PFS, but also greater toxicity (e.
g.
, grade 3-4 infection).

As long as efficacy outweighs the risks, longer follow-up will provide clearer information
.

With multiple options and new promising drugs on the horizon, the future of CLL treatment looks bright
.
Further studies of the treatment of doubly refractory patients or patients who are unsuitable for targeted drugs due to drug interactions or comorbidities are then required in the heterogeneous population of CLL patients, as well as the optimal sequence
of treatment options.
In addition, patients should be discussed about participating in clinical trials, and global access to targeted drug therapy should be a common goal
to actively pursue.

References

Nadine Kutsch, Anna Maria Fink, Kirsten Fischer .
Management of front line chronic lymphocytic leukemia.
Am J Hematol .
2022 Nov; 97 Suppl 2:S3-S10.
doi: 10.
1002/ajh.
26677.

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