【Am J Hematol Review】Treatment of relapsed/refractory chronic lymphocytic leukemia

Over the past 10 years, the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) has changed
dramatically with the approval of novel drugs targeting the B-cell receptor signaling pathway and the anti-apoptotic protein BCL2.
These drugs include the covalent BTK inhibitors (BTKis) ibratinib, acalabrutinib, and zebutinib, and the BCL2 inhibitor Venectari, which significantly alters the treatment of relapsed and initial patients
.
According to NCCN guidelines, the recommended therapy for relapsed/refractory CLL is usually the same as for patients with initial treatment, so the choice of treatment for recurrent CLL is largely driven
by which agent is given in first-line therapy.

Recently, the American Journal of Hematology published two treatment reviews of CLL at the same time, one is first-line treatment and the other is relapsed/refractory treatment
.

BTK inhibitors treat relapsed/refractory CLL

Ibutinib

The RESONATE study compared ibratinib with anti-CD20 antibody olfamumumab
.

Large single-center retrospective analysis showed that complex karyotypes (defined as ≥ 3 cytogenetic abnormalities in post-excitation karyotypes) were associated
with PFS shortening in the ibretinib group.

Given the expected need for long-term treatment in most patients, the safety of ibratinib has been a major focus
of recent research.

In the ibratinib RESONATE study, only 16% of patients stopped treatment due to toxicity; In addition to hypertension and bruising, toxicity tends
to decrease over time.

Arcotinib

Arcotinib is a covalent BTK inhibitor designed to reduce toxicity compared to ibratinib
.

The ASCEND study compared acotinib with idelalisib/rituximab and phendamustine/rituximab, resulting in a 36-month PFS rate of 63% for acotinib compared to 21% for standard treatment, and similar performance of phendamustine/rituximab and idelalisib/rituximab; Neither the del17p/TP53 mutation nor the IGVH mutation state affected the PFS
of acrotinib.

The first head-to-head trial of BTK inhibitor monotherapy was the ELEVATE RR study, which compared ibratinib and acotinib in patients with high-risk (defined as del(17p) or del(11q)) relapsed/refractory CLL
.

Zebutinib

Another newer selective BTK inhibitor is zebutinib, which has been shown to have less effect on platelet aggregation than ibretinib
among other differentiating properties.

The safety data for zebutinib are consistent with the expected results of selective BTKi, and a large pooled analysis of multiple B-cell malignancies shows that the most common side effects are consistent with other BTKis
.

Venecra is treated with relapsed/refractory CLL

Vinectra is an orally bioavailable, selective BCL2 inhibitor that exhibits excellent activity in recurrent CLLs
.

The confirmatory study of relapsed/refractory CLL in the treatment of relapsed/refractory CLL by a 2-year fixed course of VILACRA + rituximab was compared with a 2-year fixed-dose course of venectiximab with a total response rate of 92.

A common finding in Venecla's research is that uMRD can be used as a predictor of subsequent PFS
.

Venecra is usually well
tolerated.

The BTKi and Venecra regimens are the most effective regimens for relapsed/refractory CLL and should therefore be treated in most patients unless specific contraindications
exist.

Other drugs for relapsed/refractory CLL

PI3k inhibitors

There are currently two FDA-approved PI3 kinase δ inhibitors for relapsed/refractory CLL: idelalisib and duvelisib
.
In patients with relapsed/refractory CLL, idelalisib combined with rituximab had a total response rate of 85.
5% and a median PFS of 20.
3 months
.
The toxicity of idelalisib and these drugs is usually immune-mediated, short-term toxicity includes elevated inflammation of diarrhoea, pneumonia, and transaminases, and long-term exposure to idelalisib increases the risk of diarrhea/colitis (16.
4% of ≥grade 3 diarrhea, 8.
2% of
colitis) and pneumonia (6.
4% of grade 3 ≥).
。 Duvelisib was studied in the Phase 3 DUO study, which compared Duvelisib with opamumab in recurrent CLL and resulted in a total response rate of 74% and a median PFS of 13.
3 months; 12% of patients developed grade 3 colitis, 15% had ≥grade 3 diarrhea, and 3% developed ≥≥grade 3 pneumonia
。 However, while PFS advantages were observed in these studies, the latest data from the FDA Oncology Drugs Advisory Committee (ODAC) Conference on PI3 kinase inhibitors shows that multiple randomized clinical trials of idelalisib and duvelisib have shown that long-term overall survival tends to support the control group, so ODAC questions whether these drugs are used in the CLL
.

Lenardomide

The total response rate of lenalidomide in relapsed/refractory CLL was 47%, with a median PFS of 19.
4 months
.
At doses tolerated by other malignancies, CLL can show severe toxicity including tumor lysis syndrome, cytopenia, and tumor recurrence, so most patients receive a dose of 2.
5 to 5 mg
.
Combination therapy with lenalidomide and rituximab also had some encouraging results, with an overall response rate of 66% and a median time to treatment failure of 17.
4 months
.

graft

Over the past decade, transplantation has diminished in the treatment of relapsed/refractory CLL due to the availability of effective and more tolerable treatment, but transplantation remains one of the few curative options for CLL and remains a viable treatment option
for specific patients.
There are no randomized clinical trials comparing transplantation with other therapies for CLL, and the results of transplant studies must be interpreted with caution, as transplants
are generally only accepted in very high-risk patients.
Long-term results from many studies suggest that reduced intensity allogeneic stem cell transplantation induces lasting remission as well as cure
in about 40% of patients.
Long-term results from the German CLL3X study that included 100 patients showed a 10-year PFS of 34% and an overall survival of 51%.

TP53 status does not affect outcomes, but active disease at transplantation significantly shortens PFS
.
For young, fit, extremely high-risk disease patients, stem cell transplantation can play a role despite advances after multiple treatments, but with the availability of targeted drugs approved and clinical trials, as well as the availability of clinical trials of CAR-T cell therapy, very few patients and physicians may continue to choose transplantation
.

Treatment Order: BTKi or Venekla

First-line therapy may include BTK inhibitors or Venecra in most patients with CLL, and many patients are or have received chemoimmunotherapy
in the past 。 All studies leading to FDA-approved relapse/refractory CLL therapy were conducted before other novel treatments were approved, so patients in the RESONATE study who had not previously received Venekla and patients in the MURANO study who had not previously received BTKi were easily cited when choosing treatment for patients who had previously received chemotherapy, but for patients who had previously received novel drugs, the data must be interpreted with caution
。 The most important consideration when choosing the optimal treatment sequence for patients with relapsed/refractory CLL is what their previous treatment is
.
The recommended treatment strategy is shown in
Figure 1.

Initial treatment is the order of treatment at chemotherapy

Clinical trials of relapsed CLL with BTKi and Vinaykla therapy consisted mainly of patients who had previously undergone chemoimmunotherapy, whose choice at the time of relapse was very similar to that of patients who had initially treated and whose efficacy, safety, and intangible factors must be considered and discussed
.
For patients with standard crisis, BTKi and Venecra have similar PFS
in the event of a relapse.
Differences in analytical methods between studies make it difficult to compare outcomes in high-risk patients, however patients with TP53 abnormalities appear to have better
PFS in BTKi-based regimens.

Differences in safety considerations and toxicity may help help with the choice
between BTKi and Venekla.
Patients with heart disease, arrhythmias, or high blood pressure may wish to avoid BTKi or at least ibratinib
.
Patients with a high risk of tumor lysis, renal disease, or volume overload may avoid the use of vinekra, because increased doses are required for hydration
.

It is important to consider intangible factors when choosing BTKi and Venetoc-based treatment options, similar to first-line therapy
.
Most patients prefer time-limited therapy, although some prefer the convenience of starting therapy with BTKi and consider indefinite treatment to weigh the convenience of initiating therapy
.
Also during the surge in COVID-19, patients and doctors may prefer BTKi to limit visits
to hospitals or infusion centers.
Of course, it is more important to discuss the risks and benefits of each treatment so that patients can make informed decisions
.

Treatment sequencing when the initial treatment is BTKi

In patients with CLL who initially received BTKi and whose relapse requires treatment, consideration should first be given to whether the patient relapsed during BTKi or after discontinuation due to intolerance or other factors
.

In patients who have stopped BTKi due to toxicity and have a recurrence of the disease, it will be determined whether other BTKi
can be considered depending on the reason for discontinuation.
Data on acotinib in patients with ibretinib intolerance and zebutinib in patients with ibretinib or acotinib intolerance have been obtained
.
Switching to acotinib or zebutinib can relieve many of the irritating side effects of ibratinib such as arthralgia, skin/hair changes, or rash; Similarly, acotinib or zebutinib may be considered in patients with atrial fibrillation or uncontrolled hypertension treated with ibretinib
.
Available data suggest that the zebutinib group had the lowest incidence of atrial fibrillation, while the arakotinib group had the lowest
incidence of hypertension.
In addition, in patients with ventricular arrhythmias or heavy bleeding, the risk/benefit ratio may be entirely skewed to switch drug classes
.

If the patient stops BTKi due to relapse during treatment, treatment with a vinekra or other class of drugs should be switched to
.
All covalent BTKi (including ibratinib, acotinib, and zebutinib) have the same drug binding site and common resistance mechanism, so resistance to one BTKi indicates resistance to all covalent inhibitors
.
Venecra has been studied in patients who relapse after treatment with ibratinib, most of whom progress
during treatment.
The total response rate for this study of continuous monotherapy in Vinectla was 65%, with a median PFS of 24.
7 months, but uMRD was uncommon
at this time.
Most patients currently receive vinecra plus anti-CD20 antibodies, but it is unclear whether patients after BTKi should receive fixed-duration or continued veneca therapy; In this case, knowing the status of MRD at 2 years may help guide discontinuation decisions
.

The initial treatment is the order of treatment at the time of Venecla

In patients who relapse after treatment with a Venekla regimen, factors to consider when considering the next line of therapy include whether to discontinue the Venekla earlier due to intolerance, MRD status at the end of treatment, and duration
of remission.
Unfortunately, there is no robust forward-looking data in this case, and smaller forward-looking cohorts and retrospective data provide some evidence
.

If the patient has a prior intolerance to the Venekla, re-treatment is likely to be inappropriate, but may also be considered
in some cases.
For example, if treatment is discontinued due to cytopenia that occurs early in treatment (when bone marrow involvement is significant) or if treatment is discontinued prior to a growth factor test, retreatment may be considered and anti-CD20 antibodies
may not be required.

Retreatment may also be considered in patients with a long duration of remission after previous venecra treatment
.
Long-term data from the MURANO study show that many patients can be successfully treated again, with an overall response rate of 72.
2%, but the duration of
remission is unclear.
In a retrospective study of 25 patients, ORR was the same as the MURANO study (72.
2%), with an estimated 12-month PFS of 69.
1%, suggesting that patients receiving Venekla retreatment may have a shorter
remission time.
Research to evaluate the benefits of retreatment in Venecra is ongoing
.

BTKi may also be considered after treatment with Venetok, although data are scarce, but available data can demonstrate the validity of
this sequence.
In the MURANO study follow-up, the response rate for BTKi as a follow-up treatment was 100%, but the duration of remission was unknown
.
In a large retrospective study of 74 patients receiving BTKi after Vännetok, the estimated median PFS was 32 months for patients who had not previously received BTKi
.
Other small retrospective studies have also confirmed the benefits
of this programme.

Future therapies for relapsed/refractory CLL

There are multiple drugs currently undergoing clinical trials of CLLs that have the potential to change the criteria for treatment of relapsed/refractory CLLs
.
BTK's reversible inhibitors, including pirtobrutinib and nemtabrutinib, have shown outstanding efficacy in early clinical trials, especially the safety of pirtobrutinib makes it a valuable drug
.
Although the resistance mechanisms associated with pirtobrutinib suggest that the drug should be sequenced after covalent inhibitor administration, if the drug is sufficiently effective at the initial treatment of BTKi, pirtobrutinib may form a microenvironment before other BTKis
.
Other drugs that inhibit the B cell receptor signaling pathway are also promising in early clinical trials
.

CAR-T cells have also shown exciting efficacy in patients with relapsed/refractory CLL
.
In general, the remission and remission persistence of CAR-T in CLL is lower than that of other FDA-approved diseases due to inhibitory T cell proliferation in vitro and in vivo disease-related immunosuppression
.
Over time, however, improved antibody engineering and more efficient co-stimulating molecules have similar reactions, and the incorporation of small molecules that enhance the effects of T cells, such as BTKi, is also of interest
.

Most CAR-T cells are currently targeting CD19, but other targets are also of interest and are being actively studied in clinical trials
.
As CAR-T improves, it has the potential to move beyond transplantation as a cell therapy for CLL and may incorporate early treatment lines
for younger and high-risk genetics patients.

summary

Fortunately, there are many safe and effective treatment options for patients with relapsed/refractory CLL at this time
.
However, for patients with multi-line relapse, high-risk patients, and very young patients, more options
are still needed.
One challenge for CLL over the next decade will be to continue high-quality large-scale clinical trials, launch new drugs in the CLL, and determine which drugs and combinations are best
for individual patients.
Only through sustained research can the goal of curing CLL, or at least effectively inhibiting the disease, allow patients to reach a natural lifespan
.

References

Jennifer A Woyach.
Management of relapsed/refractory Chronic Lymphocytic Leukemia.
Am J Hematol .
2022 Nov; 97 Suppl 2:S11-S18.
doi: 10.
1002/ajh.
26683.

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