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Chronic lymphocytic leukemia (CLL) treatment

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.

Recent studies show there is an improved progressive free survival with BTK inhibitor-based therapy over chemoimmunotherapy.

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.

The downsize 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%.

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:A MPLIFY study with acalbrutinib, venetoclax, obinutuzumab therapy is being investigated.

 

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