**3. Acute lymphocytic leukemia**

Acute lymphocytic leukemia (ALL), also known as acute lymphoblastic leukemia or acute lymphoid leukemia, is the most common malignancy in children and the least common type of leukemia in adults. It is an acute type of cancer invading blood and spreading throughout the body to other organs, such as the liver, spleen, lymph nodes, and central nervous system. Without treatment, it can be fatal within a few months. ALL is characterized by a malignant transformation and proliferation of lymphoid progenitor cells in the bone marrow, blood, and extramedullary sites, which replace normal blood cells [79]. The exact causes of ALL remain largely unknown, but it is thought to result from genetic alterations such as structural chromosome rearrangements, aneuploidy, and mutations in genes that encode for transcription factors regulating lymphoid development, tumor suppressors, proteins that regulate cell cycle progression, and epigenetic modifiers. Such defects result in abnormal growth [80].

*Advances in Hematologic Malignancies*

treatment [53].

ally recommended [18].

relapsed CLL patients [63].

was unable to demonstrate a benefit due to these therapeutic interventions in CLL patients [52]. The standard treatment for patients with early disease is a "watch-and-wait" strategy. Treatment should only be initiated in patients with progressive or symptomatic/active disease. In order to determine the best approach to treatment, crucial factors such as the stage of disease, physical status, and cytogenetic risk should be assessed on a per-patient basis [18]. Additionally, the "Go-Go," "Slow-Go," and "No-Go" comorbidity classifications present another important set of factors in determining the optimal avenue for

Monotherapy with alkylating agents (chlorambucil) and purine analogs (fludarabine, pentostatin, cladribine, bendamustine) has served as an initial, frontline therapy for CLL and was the therapeutic "gold standard" for several decades [52]. Compared to monotherapy, the combination of fludarabine with alkylating cyclophosphamide is more widely used, leading to an increased effect on malignant lymphocytes and greater remission inductions [54]. The onset of biological treatment using monoclonal antibodies has led to significant changes in the approach to treatment. As CD20 is expressed on most B-cell malignancies, the introduction of the anti-CD20 antibody rituximab improved the treatment of most CD20-positive non-Hodgkin lymphomas, including CLL. Rituximab is less active as a single agent; however, combinations of rituximab with chemotherapy have shown to be very efficacious therapies for CLL [55]. The combination of rituximab, fludarabine, and cyclophosphamide is considered to be the standard first-line therapy (FCR chemoimmunotherapy) [56]. Ofatumumab and obinutuzumab are another set of CD20 antibodies used for the treatment of patients with relapsed/refractory CLL [57, 58]. Alemtuzumab is a recombinant, fully humanized, monoclonal antibody against the CD52 antigen. Monotherapy with alemtuzumab is used in patients with advanced CLL or relapsed patients after second-line fludarabine therapy and with poor prognostic features [59]. Autologous stem-cell transplantation is not useful in CLL. Maintenance therapy in CLL patients with higher risk of relapse may have some benefit but is not gener-

Lenalidomide is an immunomodulatory agent that induces only mild apoptosis of leukemic cells but also reduces CLL proliferation through a cereblon-/p21-dependent mechanism. Lenalidomide has pleiotropic effects on the CLL microenvironment: it increases CD4+ T-mediated antigen presentation, proliferation, and activity and enhances NK and CD4+ T-cell mediated antitumor immune responses [60]. It is active alone, in CLL relapsed/refractory patients, or as an initial treatment

The CXCR4/CXCL12 signaling axis represents another important therapeutic target in CLL. CXCR4 antagonists have been developed, including peptide CXCR4 antagonists (BKT140), small molecule CXCR4 antagonists (AMD3100, plerixafor), and antibodies to CXCR4 (MDX-1338) [62]. Plerixafor inhibits CXCL12-mediated signaling activation on CLL cells and is used in combination with rituximab in

Proteins in the Bcl-2 family are key regulators of the apoptotic process with proapoptotic and prosurvival activities. Venetoclax is a so-called BH3-mimetic drug designed to block the function of the Bcl-2 protein and inhibits the growth of BCL-2-dependent tumors in vivo. Monotherapy with this drug is active and well tolerated in patients with relapsed or refractory del(17p) CLL, providing a new

B-cell receptor signaling seems to play an important role in the survival of CLL cells. Inhibitors targeting BCR-associated kinases have changed the landscape of

for elderly patients or in combination with rituximab [61].

therapeutic option for this very poor prognosis population [64].

**78**
