Management goals are to eliminate chemoimmunotherapy treatments and replace it with more effective combinations of small molecules inhibitors, to get a deep remission as possible, increase complete remission with undetectable minimal residual disease with well tolerated non-chemo immunotherapy treatment, to improve and lengthen both progression free survival and overall survival, and promote immune reconstitution.
Most patients are asymptomatic at diagnosis, and many never require treatment.
Indications for treatment include progressive, or symptomatic, lymphadenopathy or splenomegaly, worsening, thrombocytopenia, or anemia, and a rapidly rising lymphocyte count.
The specific choice of therapy for initial treatment depends in part of molecular features of CLL such as immunoglobulin gene heavy-chain variable region (IGHV) mutation status, tumor protein 53 alterations (TP 53 mutation or deletion), and chromosome 17p deletion which results in TP 53 deletion.
Other prognostic index include beta2 microglobulin level, Rai stage, and age.
Recent studies show there is an improved progressive free survival with BTK inhibitor-based therapy over chemoimmunotherapy.
Current frontline treatment for CLL consist of either fixed – duration therapy with a B cell lymphoma2 inhibitor venetoclax as a backbone with continuous therapy with a Briton’s tyrosine kinase inhibitor, typically acalabrutinib or zanubrutinib which are less toxic than ibrutinib and thus preferred.
In patients with previously untreated CLL, fixed – duration treatment with venetoclax-obinutuzumab, was non-inferior to continuous ibrutinib with regard to progression free survival. CLL 17 trial investigators.
Fixed-duration treatment advantages include treatment free intervals, and lower rates of treatment related toxic effects in the long-term.
Single agent BTK inhibitors are approved for management of CLL and these agents are meant to be continued long-term, which can mean 5, 10 years or forever.
BCL – 2 inhibitors – Venetoclax, induce deeper remissions in CLL than BTK inhibitors.
The BCL2 inhibitor venetoclax plus CD 20 monoclonal antibody obinutuzumab combination therapy in CLL has deeper remission, allows patients to complete treatment in one year and the doublet avoids some of the adverse events that occur with BTK inhibits such as atrial fibrillation, bleeding issues, and hypertension.
Acalbrutinib-venetoclax with or without obinutuzumab significantly prolonged progressive free survival as compared with chemoimmunotherapy in fit patients with previously untreated CLL.
The downside of a doublet combination such as venetoclax and obinutuzumab include the risk of tumor lysis syndrome and neutropenia.
The doublet combination requires frequent visits to the physicians office, and does not lead to durable long remissions in patients with DEL (17 P) and/or TP 53 mutated CLL.
Management goals are to eliminate chemoimmunotherapy treatments and replace it with more effective combinations of small molecule inhibitors, to get a deep remission as possible, increase complete remission with undetectable minimal residual disease (MRD) with well tolerated non-chemo immunotherapy treatment, to improve and lengthen both progression free survival and overall survival, and promote immune reconstitution.
First line treatments include fixed duration chemoimmunotherapy, a continuous Bruton tyrosine kinase inhibitor, the time-limited B-cell lymphoma 2 inhibitor venetoclax plus anti- CD 20 anybody obinttuzumab and BTK inhibitor plus venetoclax and a combination of venetoclax, obinutuzumab or Rituximab.
The combination of venetoclax-obinutuzumab with or without Ibrutinib lead to longer and deeper responses than the current first line: chemoimmunotherapiesFludarabine/Cyclophosphamide/Rituximab or bndamustine/Rituximab: at 15 months, the percentage of patients with undetectable minimal residual disease with venetoclax- obintizumab was 86.5% and the Venetoclax-obinutuzumab/Ibrutinib group was 92.2%, while the chemo immunotherapy group was 52%.
Undetectable MRD and extended progression free survival were more common with a ibrutinib-venetoclax class than with ibrutinib alone or FCR (fludarabine-cyclophosphamide-rituximab).
BTK inhibitors have revolutionized the treatment of CLL shielding significant improvements in efficacy outcomes versus traditional therapy:Ibrutinib, zanubrutinib, Pirtobrutinib,
Acalabrutinib plus Obinutuzumab have a progression free survival of 72 months.
Lisocabtagene maraleucil CD 19:CAR-T therapy in heavily pretreated patients with CR rate of 20%.
The three drug classes used in CLL:BTK inhibitors, BCL2 inhibitors and CD20 monoclonal antibodies used in combination as triplet therapy is presently being investigated:AMPLIFY study with acalbrutinib, venetoclax, obinutuzumab therapy island has been found to be highly efficacious.
The preferred treatment option for patients with high risk mutations such as TP 53 is continuous BTKi with or without the anti-CD 20 antibody obintuzumab.
Regimens containing acalabrutinib in TP 53 altered CLL is associated with prolonged median survivals, as monotherapy or with obinutuzumab.
Acalabrutinib and zanobrutinib have a better safety profile, than brutinib and are considered the preferred BTKis in this setting.
Patients with mutated IGHV and unaltered TP 53 tend to respond well to fixed duration BCL2i based regimens, demonstrating longer progressive free survival and longer time to treatment failures than those with unmutated IGHV.
In the CLL 17 trial after median observation time of 34.2 months the average three year progressive free survival rate was 80 to 81% making fixed duration treatments noninferior to continuous therapy.
The overall survivor was greater than 90% in groups venclexta/ibrutinib, and venclexta/obinutuzumab, and continuous ibrutinib.