Page 1097 - Clinical Immunology_ Principles and Practice ( PDFDrive )

ChaPTEr 78 Lymphoid Leukemias 1061

ThEraPEUTiC PriNCiPLES others), and immune checkpoint inhibitors. Some immunological
Chronic Lymphocytic Leukemia (CLL) Is Incurable, novel approaches include expanded autoreactive activated T cells
(chimeric antigen receptor–modified T cells [CAR-T]), which
but It Is Possible to Ameliorate Symptoms is showing promise. 39
• High rates of complete remissions and encouraging survival curves Allogeneic hematopoietic stem cell transplantation (allo-
for high-risk patients HSCT) is the only curative treatment for CLL. Allogeneic HSCT
• Watch and wait approach in the case of asymptomatic patients with relies on myeloablative doses of chemoradiotherapy, which makes
early-stage CLL the treatment unacceptably risky for the majority of patients
• Supportive care (immunoglobulins, blood supplements and erythro- with CLL. In nonmyeloablative, or reduced-intensity, approaches,
poietin, treatment of infections) rates of engraftment are similar to fully ablative conditioning
• Steroids with or without chemotherapy, especially for autoimmune
phenomenon regimens, but with lower rates of early toxicity. Early evidence
• Conventional chemotherapy (alkylating agents, such as chlorambucil suggests that the graft-versus-leukemia (GVL) effect is present.
and cyclophosphamide; purine analogues, such as fludarabine and Patients with deletion 17p (p53 involvement) with an extremely
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cladribine; other lymphoma regimens; bendamustine) poor prognosis are physically fit candidates for allo-HSCT, even
• Targeted therapy with or without chemotherapy (i.e., rituximab, ofa- as newer agents (i.e., ibrutinib, idelalisib, and venetoclax) are
tumumab, obinutuzumab (all anti-CD20 antibodies) and alemtuzumab showing high efficacy in this high-risk population. Studies
(anti-CD52 antibody)
• B-cell receptor pathway inhibitors—BTK (ibrutinib), PI3K-d (idelalisib), involving autologous transplantation and high-dose chemotherapy
and BCL2 antagonists (venetoclax) for CLL have a limited survival advantage.
• Allogeneic (mostly with reduced intensity) stem cell transplantation With treatment advances, the overall survival of patients with
CLL has improved across the globe as a result of targeted therapy,
even in high-risk and in patients with relapsed and refractory
CLL. Thus classic prognostication (as presented in Table 78.5)
The CD52 antigen is present on lymphocytes (B, T, and NK is becoming less accurate as treatment improves.
cells), monocytes, and some granulocytes. The humanized
anti-CD52 monoclonal antibody (mAb; CAMPATH-1, alemtu- Immunological Aspects of CLL
zumab) has demonstrated high activity in previously treated
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patients and those with refractory CLL. Nevertheless, because CLiNiCaL PEarLS
of significant B- and T-cell depletion, patients are exposed to Chronic Lymphocytic Leukemia (CLL):
severe infectious complications, particularly reactivation CMV Immunologic Manifestations
infection.
The anti-CD20 mAb rituximab (Mabthera) as a single agent • Panhypogammaglobulinemia
has shown limited efficacy in CLL, possibly because of the weak • A monoclonal immunoglobulin peak, usually of the immunoglobulin
M type
receptor expression on CLL cells. However, in combination with • Downregulation of T-cell function and aberrant cytokine production
chemotherapy, particularly with fludarabine and cyclophospha- • Defects in the complement system
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mide or bendamustine, it appears to act synergistically and to • High risk of recurrent infections—encapsulated bacteria and opportu-
achieve high rates of response, including molecular complete nistic infections
remission and prolongation of disease-free and overall survival. • Autoimmune-associated phenomena:
A newer fully human mAb targeting CD20 (ofatumumab) has • Autoimmune hemolytic anemia
a very potent effect as a single agent in both rituximab-naïve • Autoimmune thrombocytopenia
• Pure red cell aplasia and autoimmune neutropenia
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and rituximab-treated patients. It targets a different epitope • Other autoimmune disorders (myositis, vasculitis, pemphigus vulgaris,
on the CD20 antigen. A second-generation anti-CD20 antibody, acquired angioedema, glomerulonephritis)
obinutuzumab, was added to chlorambucil in the treatment of
the older adult population. When compared with chlorambucil,
alone or in combination with rituximab and chlorambucil, CLL is characterized by multiple immune deficiencies and
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obinutuzumab was shown to be superior and relatively safer. autoimmune phenomena. It is reasonable to hypothesize that
Other investigational agents showing efficacy include lenalidomide immune incompetence and autoimmunity are two sides of the
(an immune modulator related to thalidomide), albeit with an same coin.
interestingly initial flair-up phenomenon of disease-enlarged
lymph nodes. The Pathophysiological Rationale
A major breakthrough in treatment was achieved through CLL cells secrete TGF-β, which is a potent inhibitor of B-cell
drugs targeting the BCR pathway. A BTK inhibitor, ibrutinib, proliferation. They also release high levels of circulating IL-2
has shown an impressive progression-free survival in relapsing receptor, which downregulates the T-helper (Th) cell function.
patients and as first-line treatment 35,36 for patients with resistant Unlike normal cells, activated B cells, both B-cell CLL cells and
or high-risk 17p-deleted CLL. In combination with rituximab, anergic normal B cells, fail to present soluble antigen and
another pathway inhibitor, the PI3Kδ inhibitor idelalisib had alloantigens. Moreover, the T cells in patients with CLL often
an efficacy superior to rituximab alone in frail, older patients demonstrate profound abnormalities of their antigen receptor
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who were relapsing. Furthermore, clinical trials with small (TCR) repertoire and appear dysfunctional in terms of cytokine
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molecules targeting BCL2, venetoclax, have shown promising secretion. This cytokine imbalance may be the cause of upregula-
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results, even in patients with relapsing and highly resistant CLL. tion of the BCL-2 antiapoptotic activity. T-cell dysfunction could
Under investigation are various novel agents targeting other also explain the higher incidence of autoimmune complications,
surface molecules (CD23, CD79b, and other CD20 inhibitors), such as autoimmune hemolytic anemia, among patients receiving
pathway inhibitors (SYK, PI3K, second-generation BTK, and purine analogues therapy, which induce T-cell depletion. Certain