OHD 2024: What’s New in Data and Experiences from Real Practice with Venetoclax Regimens?

Treatment with venetoclax has already become standard in the therapy of CLL in both newly diagnosed patients and those with relapsed or refractory disease. Venetoclax is also a drug of choice for AML – especially in older patients who cannot undergo intensive therapy or in preparation for allogeneic transplantation.

We offer a brief summary of the key information presented at the symposium, along with a mini-interview in both audio and text versions with each speaker.

   

Practical Experiences in 1st Line Treatment of CLL Patients

MUDr. Peter Turcsányi, Ph.D.
Department of Hemato-Oncology, Faculty of Medicine, Palacky University and University Hospital Olomouc

Therapeutic Indications

Venetoclax in combination with obinutuzumab (Ven+Obi) is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukemia (CLL).

Reimbursement

Ven+Obi combination therapy is reimbursed for adults with previously untreated CLL and comorbidities that prevent them from undergoing full-dose fludarabine-based therapy. These patients must have an ECOG performance status of 0–1. The drug is reimbursed for up to 12 therapy cycles or until disease progression or unacceptable toxicity, whichever occurs first, in patients with significant comorbidities (e.g., CIRS score > 6) or creatinine clearance < 70 ml/min, making them unsuitable for full-dose FCR protocol treatment.

The approval of this indication was based on the CLL14 study, which showed that venetoclax helps achieve deep responses. After completing treatment, 50% of complete remissions were confirmed, and the majority of patients achieved minimal residual disease (MRD) negativity, which was associated with longer progression-free survival (PFS).

Efficacy and Safety of Treatment

Even more significant is the long-term treatment effect, where 6 years post-randomization in the CLL14 study, PFS was 53%, time to next treatment (TTNT) was 65%, and overall survival (OS) was 79%.

Common grade 3/4 adverse events included neutropenia. Tumor lysis syndrome (TLS) occurred in 3 patients in the Ven+Obi arm and 5 on chlorambucil + obinutuzumab (Clb+Obi), but none met Howard's criteria for clinical TLS.

Venetoclax treatment also proved effective in high-risk patients with TP53 mutation and 17p deletion, with a median PFS of about 52 months.

  

We asked Dr. Turcsányi about practical experiences with 1st line CLL treatment:

   

What are your experiences with using the venetoclax + obinutuzumab regimen in the 1st line treatment of previously untreated CLL patients? Who is the “ideal” patient for this regimen?

We have very good experiences with this regimen and consider it a safe modality with a very good therapeutic response. The ideal patient is essentially anyone suitable for this regimen – particularly those with some cardiac comorbidity. We are somewhat disappointed that the indication for treatment is not extended to younger patients without significant comorbidities, as it offers much greater benefits than the existing regimens available to this population – which is a combination of immunochemotherapy.

Time-limited therapy brings many benefits not only for patients. Where do you see its greatest advantages?

There are several aspects. The first is the quality of life. The treatment lasts 1 year, and the patient does not have to think for many years about taking any medications or that they are being treated. Another aspect is the spectrum of side effects, which, if they occur, last only for a limited time and we do not have to deal with them in the long-term. General adverse effects also include immunity deterioration, specifically the decrease of immunoglobulins during CLL therapy. Clonal evolution in CLL under long-term chronic treatment is also discussed. From this perspective, time-limited therapy provides substantial benefits. Lastly, it is also very cost-effective.

  

Practical Experiences in 2nd Line Treatment of CLL Patients

MUDr. Anna Panovská, Ph.D.
Department of Internal Hematology and Oncology, Faculty of Medicine, Masaryk University and University Hospital Brno

Therapeutic Indications

Venetoclax in combination with rituximab is indicated for the treatment of adult patients with CLL who have received at least one prior therapy.

Reimbursement

Venetoclax + rituximab combination therapy is reimbursed for adult patients with relapsed or refractory CLL and with an ECOG performance status of 0–1, who meet at least one of the following criteria:

a) Refractoriness to the last therapy
b) Relapse within 24 months after the completion of the previous therapy
c) Relapse and unsuitability for chemo-immunotherapy
d) Proven TP53 mutation or del17p

The drug is reimbursed until disease progression (i.e., even after the completion of 6 prescribed rituximab cycles) or the occurrence of unacceptable toxicity, but for no longer than 24 months from the first day of the first cycle with rituximab administration, whichever occurs first.

Treatment Efficacy

The venetoclax + rituximab regimen is highly effective in 2nd line CLL treatment. It is effective even in those with negative molecular genetic changes. This treatment is well tolerated and its advantage lies in its time-limited administration, which is greatly appreciated among CLL patients. Most achieve MRD negativity that correlates with up to a 95% probability of 5-year survival. Comparing these results with previous therapy options in 2019 (63%), it represents a dramatic improvement in the prognosis of CLL patients.

   

We asked Dr. Panovská about practical experiences with 2nd line CLL treatment:

   

What are your experiences with the venetoclax + rituximab regimen in patients in the 2nd and subsequent lines of CLL treatment? Which patients benefit the most?

From my perspective, the vast majority of patients benefit from treatment with venetoclax + rituximab. I could even turn this question around and say that only a small group is unsuitable for this regimen at the time of CLL relapse. Particularly, these are patients with severe renal insufficiency, where we might fear worsening of this condition when starting venetoclax. Then there are patients with a gene defect of TP53, especially 17p deletion, where results are inferior compared to continuous treatment with BTK inhibitors. Otherwise, the vast majority of patients, including older individuals with comorbidities, benefit from this regimen. We have diverse concomitant therapy options, where we can work with dose reductions of venetoclax or adjust concomitant medication after consulting with specialists.

Thus, I can offer this therapy to most patients in the 2nd and further lines for three main reasons: Firstly, it is highly effective, even in genetically unfavorable changes. Secondly, it is very well tolerated – we are familiar with the spectrum of adverse events and know how to manage them. Lastly, and very importantly, it is time-limited. This provides treatment for a certain period followed by drug-free intervals, which is something the CLL community increasingly desires.

In your department, you focus on the determination of minimal residual disease. Could you explain the significance of MRD negativity in CLL therapy?

Achieving MRD negativity means undetectability and is an independent positive prognostic marker. Patients who achieve MRD negativity have longer times to progression and the need for further therapy, regardless of the treatment type. Minimal residual disease is also an excellent tool for monitoring the treatment response and allows early detection of disease progression. That means catching the change to MRD positivity earlier than symptomatic CLL relapse.

We use two approaches for MRD monitoring. Firstly, flow cytometric analysis – this method is more practical for real-world hematology practice, with very high sensitivity, detecting MRD up to 10⁻⁵. Secondly, molecular genetic methods, such as patient-specific probes for IgH rearrangement. These methods are more time-consuming and costly. We use them, for instance, when monitoring disease after allogeneic transplantation.

In conclusion, we now have therapy modalities capable of achieving high MRD negativity (64% in the MURANO study) in CLL, significantly prolonging time to further therapy and disease progression.

  

Practical Experiences with AML Patients

Assoc. Prof. MUDr. Barbora Weinbergerová, Ph.D.
Department of Internal Hematology and Oncology, Faculty of Medicine, Masaryk University and University Hospital Brno

Therapeutic Indications

Venetoclax in combination with a hypomethylating agent is indicated for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are not eligible for intensive chemotherapy.

Reimbursement

Venetoclax is reimbursed in combination with azacitidine for newly diagnosed adults with AML who are not eligible for intensive chemotherapy. These patients should not have been previously treated with hypomethylating agents. The drug is reimbursed until disease progression or the occurrence of unacceptable toxicity, whichever occurs first.

CELL Project for Czech Patients

Venetoclax with azacitidine (Ven+Aza) offers hope for prolonged survival. The VIALE-A registration study demonstrated a high response rate (> 60%) and significant survival extension. AML patients on this combination are now also being monitored within the ongoing project of the Czech Leukemia Study Group – for Life (CELL), aiming to find the ideal molecular marker for minimal residual disease (MRD) and optimize therapy.

Management of Ven+Aza Therapy

One challenge clinicians often face is the toxicity of Ven+Aza therapy, which can be managed by dose reduction and postponing the next treatment cycle. Real-world data from the University Hospital Brno, evaluating the effect of this therapy on 102 AML patients, confirm this approach. Out of 394 total cycles, dose reductions were implemented in 258 (65%) cases. Even with dose reductions, efficacy is maintained, preventing the need for premature therapy discontinuation. Additionally, it was shown that the number of patients needing hematopoietic stem cell transplantation decreases as they achieve a response to the Ven+Aza combination.

Optimization and Personalized Treatment

Based on real-world data, it is recommended to perform antifungal prophylaxis with this regimen only in at-risk patients. AML treatment should be correctly indicated and personalized. The CELL project also evaluates geriatric syndromes affecting treatment progression and tolerance to select the appropriate AML therapy.

   

We asked Assoc. Prof. Weinbergerová about practical experiences with AML patients:

   

What are your experiences with venetoclax in combination with azacitidine in newly diagnosed AML patients who are not eligible for intensive chemotherapy? Where do you see the major advantages of this regimen, and what should clinicians pay attention to?

Venetoclax with azacitidine has fundamentally changed the treatment options and outcomes for AML patients who are ineligible for intensive therapy. The combination has a high response rate and significantly improves survival for these patients. We can also use this regimen as a bridge to allogeneic transplantation for some patients, including older comorbid AML patients, further improving their outcomes.

The challenges of this regimen lie in its toxicity, which must be managed in routine clinical practice. For patients who achieve complete remission, we should not hesitate to reduce the drug dose, adjust the dosing schedule, and use granulocyte colonystimulating factors to shorten neutropenia duration, thus maintaining the 28-day treatment cycle frequency.

Beyond newly diagnosed AML patients, where else do you use the venetoclax + azacitidine regimen? What developments in AML treatment do you foresee in the coming years?

We successfully use venetoclax + azacitidine in relapsed patients. Whether after the first complete remission, primary treatment with allogeneic transplantation or not, this combination can induce a second complete remission. This is with approval from the reviewing physician regarding reimbursement. We also use venetoclax with salvage regimens in patients receiving traditional FLAG-IDA or HAM protocols. We can also explore this combination within studies for maintenance therapy in patients in their first complete remission after primary treatment with or without allogeneic transplantation.

  

Summary by the Symposium Chair

Professor Tomáš Papajík provided a concluding summary:

   

How has venetoclax influenced CLL and AML therapy in the Czech Republic, and what developments do you expect in the coming years?

The symposium provided answers to these questions based on data from extensive clinical studies. These data are already mature for CLL and are maturing for AML therapy. This is interesting from the perspective of venetoclax's potential in treating hematologic malignancies. The data are so compelling that venetoclax has significantly influenced CLL therapy worldwide and in the Czech Republic in real practice, where it can be administered both in the 1st line and in relapsed/refractory patients with poor prognosis.

The drug is well tolerated, can be combined with monoclonal antibodies, and has advantages, including its time-limited therapy. Treatment is given for a certain period, and after achieving a very good response, including CLL cell negativity in peripheral blood, patients have very long drug holidays, meaning they are only monitored further, enhancing their quality of life.

For AML, this drug has also brought revolutionary change, especially in combination with azacitidine, for patients we previously could not effectively treat due to age or comorbidities. It shows a therapeutic response in up to two-thirds of patients and prolongs their survival. For younger relapsed patients, it can be used as a regimen to reduce leukemic burden, allowing for hematopoietic stem cell transplantation.

I expect future developments to involve new combination regimens, new indications, and new applications in CLL and AML treatment.

  

MUDr. Andrea Skálová
proLékaře.cz Editorial Team