Page 1413 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 77 Chronic Lymphocytic Leukemia 1259

fulminant tumor lysis syndrome especially in patients with high with CLL and the immune modulatory effects could be used as
burden of disease and mitigation strategies have been developed to a strategy for earlier control of the disease or as an adjuvant to
improve its safety and reduce the incidence of hyperacute tumor lysis. vaccine-based approaches. Because of its relative modest activity in
Early results have demonstrated impressive activity of this agent in heavily pretreated patients, other alternatives for first-line therapy,
patients with relapsed disease with an ORR of 88% with 31% CRs and the potential for life-threatening tumor flare and other toxicities
including in patients with del17p. Venetoclax use also resulted in associated with lenalidomide, this agent should only be considered
deep MRD-responses that have persisted for sustained periods. It was as part of a well-designed clinical trial despite its FDA approval for
generally well tolerated and the most common adverse events were other indications (MDS and multiple myeloma).
cytopenias. Multiple studies are currently ongoing to further establish
the role of venetoclax as monotherapy or in combination with other
agents for patients with CLL. Other Agents
Therapeutic antibodies or small modular immune pharmaceuticals
Chimeric Antigen Receptor T-Cell Therapy targeting surface antigens, including CD19 (Xm5574), CD37
(otlertuzumab, IMGN529, and MAb 37.1), and BAFF-R (VAY736),
To date, efforts at directing T-cell immune suppression toward the are under development. In addition, therapeutic agents targeting
tumor cells have been relatively limited. A major development has signal transduction pathways (HSP-90 inhibitors, Syk inhibitors,
been preclinical and early phase I studies demonstrating that ex vivo AKT inhibitors, ILK inhibitors, NFκB inhibitors, and PP2A activat-
transfected T cells with chimeric T-cell receptors bearing both CD3 ing agents) are in early clinical development. Finally, agents targeting
and also a B-cell–specific antigen (most often CD19) have great epigenetic events or innate immune activation (CpG oligonucleotides
potential to eradicate established B-cell tumors after administration or IL-21) have promising data to support their ongoing early clinical
into both xenograft models and, recently, patients with refractory investigation.
CLL. Even though chimeric antigen receptor T cell (CAR-T) therapy
has preliminarily shown deep and durable responses, toxicity remains
a major concern and it continues to require significant development Stem Cell Transplantation
and optimization before this can be readily administered widely.
For many years, autologous and allogeneic SCT was extensively used
for treatment of CLL late in the course of the disease. However, trials
Lenalidomide of SCT have indicated that patients with multiply relapsed and
chemotherapy-resistant disease are at highest risk for both relapse and
Lenalidomide (Revlimid), is an immunomodulatory drug that is TRM. In addition, many patients with heavily treated CLL cannot
a more potent analog of thalidomide. Lenalidomide is approved be adequately cytoreduced or disease control cannot be maintained
for marketing in multiple myeloma and transfusion-dependent for a sufficient period of time to obtain insurance approval and find
myelodysplasia. Lenalidomide has clinical activity in a variety of a suitable allogeneic donor, producing a selection bias that often
other malignancies, including CLL. Two initial studies examining excludes patients with the most refractory or aggressive disease from
either an intermittent 25 mg PO daily for 21 days or 5 mg with actually receiving a SCT. The recognition that patients with poor
dose escalation to 10 mg PO as tolerated given as continuous prognostic features such as del(11q22.3) and del(17p13.1) and
therapy were pursued initially in relapsed CLL. The higher dose, patients who fail to achieve CR after receiving regimens such as FCR
intermittent schedule was active with an ORR of 47% and 9% have a short remission duration, had prompted many transplant
CR. Major side effects of therapy were cytopenias, rash, and tumor centers to consider earlier application of allogeneic SCT as therapy
flare, which in some cases can be life threatening. The continuous, for CLL, including its use as consolidation treatment after induction
low-dose regimen had a 32% intent-to-treat ORR with a 7% CR therapy for the highest risk patients. The timing of SCT has been
rate. Toxicity was less with this schedule but still included cytopenias thrown into a bigger conundrum with long-term disease control seen
in most. On the basis of these promising phase II clinical studies, a in patients with relapsed disease including patients with high risk
large, multicenter trial randomizing patients to low-dose (10 mg) or disease receiving ibrutinib. Recent data has identified a subgroup of
high-dose (25 mg) lenalidomide was undertaken, which was halted patients with a complex karyotype that have a shorter PFS despite
early because of life-threatening adverse events in patients receiving kinase inhibitor therapy. Referral of such high-risk CLL patients at
the higher dose of therapy. Subsequent studies have shown that the time of treatment to an experienced transplant center for evalu-
lower doses of lenalidomide administered as continuous treatment in ation, potential tissue typing of the patient and his or her siblings,
patients with relapsed CLL are feasible. These data have prompted and initiation of an unrelated donor search (if needed) should be
several single agent studies in symptomatic, previously untreated CLL considered. Although autologous SCT has been used historically as
in which the clinical activity has ranged from an ORR of 56% to a treatment for CLL, nonmyeloablative allogeneic SCT is the pre-
65% with up to 10% CR. Most provocative of these studies was the ferred modality for most patients requiring a transplant unless a
observation that lenalidomide reversed the hypogammaglobulinemia suitable allogeneic donor is not available. Autologous SCT is no
observed in CLL patients. PFS with this treatment is approximately longer used in CLL because of a lack of a survival advantage, only
2 years. Associated toxicity, includes tumor flare, cytopenias, rash, modest benefit in PFS, and a high risk of tr-MN with this modality.
and infection, but these events are manageable. Lenalidomide Therefore, autologous SCT is not reviewed in this chapter.
was subsequently combined with other agents, most notably anti-
CD20 antibodies such as rituximab and ofatumumab, or used as
consolidation therapy after purine analog or bendamustine-based Myeloablative Allogeneic Stem Cell Transplantation
induction therapy. Antibody combination therapy diminished the
tumor flare but was associated with increased cytopenias. Similarly, The use of an allogeneic donor provides an immunologic graft-versus-
lenalidomide as consolidation therapy after PCR-based treatment, leukemia (GVL) effect for patients with CLL. Limited data suggest
appeared to potentially extend PFS over that previously seen with that total body irradiation (TBI)-containing conditioning regimens
PCR alone. Unfortunately, a pivotal trial comparing chlorambucil are superior to chemotherapy-only regimens in CLL transplant
with lenalidomide was halted because of higher mortality observed patients. A small study of 25 patients demonstrated a 100-day TRM
in elderly patients on the lenalidomide arm. No obvious cause of of 57% in patients who received busulfan and cyclophosphamide
the increased mortality has been identified. This has significantly (Bu/Cy; n = 7), compared with 17% for patients who received a
limited the prospects of further development of this agent in CLL. TBI-containing regimen (n = 18). Five-year actuarial survival was
However, lenalidomide has profound immunologic effects in patients 56% for 14 patients transplanted with TBI regimens during