EHA Endorsement of ESMO Clinical Practice Guidelines for Diagnosis, Treatment, and Follow-up of Chronic Lymphocytic Leukemia

European Hematology Association (EHA) and European Society for Medical Oncology (ESMO) recently agreed to collaborate on the production of European Guidelines for different hematological malignancies. As a first step, a number of completed guidelines have been reviewed by the corresponding EHA Scientific Working Groups in a standardized review process. Representing an example of this collaboration, in the case of chronic lymphocytic leukemia (CLL), the European Research Initiative on CLL—which is also the corresponding EHA Working Group on CLL—has recently endorsed the ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up for CLL released on October 19, 2020, in accordance with the ESMO standard operating procedures for Clinical Practice Guidelines development.^1,2

CLL is the most common leukemia in the Western world with an incidence of 4.2/100 000 per year and an increasing prevalence due to the impaired overall survival.³ As in other indolent lymphoma, treatment is still only required in advanced stages with clinical symptoms and cure is not yet a goal of therapy. Early stages, including the CLL precursor the monoclonal B-cell lymphocytosis defined by less than 5 × 10⁹/L monoclonal B-lymphocytes, should be observed with 3- to 12-monthly controls by blood count and physical examination. Early intervention studies have not shown an overall survival benefit.

Dramatic progress in CLL therapy has been obtained thanks to the introduction of targeted agents that effectively interfere with pathogenetically relevant mechanisms such as the B-cell receptor pathway or the imbalance of the apoptotic process.⁴ For this reason, biological features of the leukemic clone rather than patient’s characteristics such as age and fitness have become key to select the most appropriate therapy. Thus, testing for del(17p), TP53 mutations, and immunoglobulin heavy chain variable (IGHV) status is now strongly recommended at treatment initiation to guide the choice between chemoimmunotherapy or targeted treatments (Table 1).

For the highest risk group in CLL carrying TP53 mutation or del(17p), BTK inhibitors or venetoclax monotherapy or the PI3K inhibitor idelalisib plus rituximab as well as venetoclax plus obinutuzumab are appropriate treatment options (Table 1) as these patients should be spared from being exposed to immunochemotherapy. While BTK, PI3Kd inhibitors, or venetoclax monotherapy are given as a continuous oral therapy, the combination of venetoclax plus obinutuzumab is given for 6 months followed by 6 additional months of monotherapy with venetoclax (Figure 1). For all other patients, several phase III studies have demonstrated a highly superior progression-free survival with BTK inhibitors with or without anti-CD20-antibodies or with the combination of venetoclax plus obinutuzumab over different regimen consisting of different chemotherapy backbones and rituximab. Younger patients particularly benefit from the continuous administration of ibrutinib as longer overall survival has been demonstrated in comparison to fludarabine, cyclophosphamide, and rituximab. While the addition of rituximab to ibrutinib has not demonstrated any benefit, the role of obinutuzumab is unclear in that setting. Hence, the addition of anti-CD20-antibodies to BTK inhibitors is only optional and not generally recommended.

Figure 1.

Treatment algorithm for treatment-naive patients with CLL. The order of the recommended treatments for each subgroup is based on expert opinion considering time-limited as more valuable therapy, if there is equal evidence for 2 different treatment options. BR = bendamustine plus rituximab; CIT = chemoimmunotherapy; CLL = chronic lymphocytic leukemia; FCR = fludarabine, cyclophosphamide and rituximab; IGHV = immunoglobulin heavy chain variable. #If approved and available. *If available. **CIT as alternative treatment, only if reasons against treatment with targeted therapies or nonavailability.

In general, only patients with favorable mutated IGHV and devoid of TP53 mutation or deletion may still be candidates for chemoimmunotherapy. Because data on the combination of venetoclax plus obinutuzumab in unfit patients has demonstrated superiority over chemoimmunotherapy even in patients with favorable mutated IGHV status, time-limited targeted therapy appears to be a preferable choice compared to chemoimmunotherapy. Though venetoclax plus obinutuzumab has been approved in frontline for all patients by the European Medical Agency, data on fit patients treated with this combination are still pending.

As in first-line therapy, treatment at relapse should only be started in symptomatic patients and not immediately at the time of reappearance of the disease. For treatment choice in symptomatic relapsed disease, type of prior therapy as well as duration of remission have become more relevant than genetic prognostic factors. In case of symptomatic relapse within 3 years after fixed-duration therapy or nonresponse to therapy (“early relapse”), the therapeutic regimen should be changed, regardless of the type of first-line therapy. The choice of therapy is primarily between venetoclax for 24 months plus rituximab during the first 6 months or BTK inhibitor (ibrutinib or acalabruitnib) as continuous therapy. In late relapse and if no del(17p) or TP53 mutation is present, repetition of front-line therapy remains an option only in a minority of patients, with the notable exception of the fludarabine, cyclophosphamide, and rituximab regime that is strongly recommended not to be repeated regardless the length of the response.

For the choice between the treatment modalities of time-limited BCL2 inhibitor or continuous BTK inhibitor, the following aspects should be discussed with the patient in any line of therapy:

• Treatment duration (continuous versus fixed duration)

• Administration (oral [p.o.] versus intravenous [i.v.])

• Compliance (i.v. versus p.o.)

• Evidence

• Risk of complications (in particular in the presence of specific comorbidities: bleeding and cardiac comorbidities with ibrutinib or other BTKs versus impaired renal function and neutropenia with venetoclax)

• Response to and side effects of prior therapies

• Number and complexity of clinical controls (2–4 wk for ibrutinib versus dose ramp-up with 3 controls every week for 5 wk to prevent tumor lysis syndrome and potential hospitalization in case of high risk for tumor lysis under venetoclax).

Allogeneic stem cell transplantation should now only be considered as treatment option in a small minority of patients with very high-risk profile of CLL and being fit enough for transplantation; in particular, those who are refractory not only to chemoimmunotherapy but also to at least 1 novel inhibitor therapy.

Besides the treatment of this very high risk group of patients, treatment of transformed CLL (more frequently diffuse large B-cell lymphoma [DLBCL]), defined as Richter transformation (RT), remains the major challenge in CLL treatment nowadays. Response duration of RT is typically short, and allogeneic stem cell transplantation should be recommended to all patients with clonally-related RT with an available donor and sufficient fitness. In clonally-unrelated disease (as detected by IGHV rearrangement), the RT should be treated as a de novo DLBCL. The rarer transformation of CLL into the Hodgkin lymphoma variant being treated with conventional chemotherapy has a significantly better prognosis than transformation into DLBCL.

One important open question, which is currently addressed within clinical study protocols, is the role of measurement of minimal residual disease (MRD) outside the setting of allogeneic stem cell transplantation. So far, MRD measurement is not yet recommended as clinical routine test, but in the future, duration of combination therapies based on targeted agents might be decided based on MRD measurements in peripheral blood or bone marrow.

In conclusion, the updated ESMO guidelines for CLL provide practical, evidence-based guidance for clinicians and demonstrate the progress in the stratification of patients and the choice of treatment obtained thanks to a deeper understanding of the pathogenesis of the disease.

Disclosures

BE has reported honoraria from Celgene, Gilead, Novartis, Janssen, Roche, AbbVie, & ArQule, has participated at advisory boards for the same companies, and has received research grants from Roche, AbbVie, Janssen, Gilead, & BeiGene. PG has reported honoraria from AbbVie, Acerta/AstraZeneca, ArQule, BeiGene, Gilead, Janssen, Juno/Celgene, Lilly/Loxo, MEI, & Sunesis, and research grants from AbbVie, Janssen, Gilead, & Sunesis.