Page 1564 - Williams Hematology ( PDFDrive )

1538 Part XI: Malignant Lymphoid Diseases Chapter 92: Chronic Lymphocytic Leukemia 1539

in the vast majority of patients with CLL. The responses observed CDK inhibitors like flavopiridol and dinaciclib have also demon-
294
with CLL are mostly PRs in 40 to 60 percent of patients, with approxi- strated promising activity in patients with CLL, and are able to induce
mately 10 percent of the patients experiencing a CR. However, response durable remissions even in patients with high-risk del 17p disease with
improves with ongoing therapy. Cytopenias are the most common, and or without concomitant chemotherapy. 308–311 Therapy with CDK inhib-
dose-limiting, side effect. Patients can also experience tumor flare and itors is complicated by fulminant hyperacute tumor lysis that requires
tumor lysis, especially at the start of therapy. Care should be taken to aggressive supportive care including hemodialysis. Diarrhea and fatigue
minimize these reactions with the early use of steroids and aggressive are also seen as off target effects.
hydration and uricosuric agents. In a recent phase III study, lenalido-
mide was shown to increase mortality in patients older than 80 years STEM CELL TRANSPLANTATION IN PATIENTS
of age and thus is not recommended for the elderly. Combination of
lenalidomide with monoclonal antibodies has also resulted in improved WITH CHRONIC LYMPHOCYTIC LEUKEMIA
sustained responses. 295–297 Despite the advent of kinase inhibitors, With the advent of effective therapy for patients with relapsed and
lenalidomide continues to be an exciting agent for the treatment of CLL refractory disease and even for patients with high-risk disease, the
as it is one of the only agents that appears to have the potential to reverse role of stem cell transplantation (SCT) for the routine management of
the immune dysfunction associated with CLL; it also appears to have patients with CLL is diminishing. Autologous transplantation has the
efficacy in patients with del 17p disease. 49,298–301 ability to induce deeper and more frequent remissions that may result in
longer disease-free remission, but does not translate into an OS advan-
CHIMERIC ANTIGEN RECEPTOR T CELLS tage and is associated with significantly higher morbidity and mortality
and secondary cancers, including therapy-related myeloid neoplasms
Chimeric antigen receptor T (CAR-T) cells are engineered autologous that may impact long-term survival. 312–314 Moreover, autologous trans-
lentiviral modified T cells that contain an altered TCR targeting a sur- plantation, which is essentially high-dose chemotherapy, is unable to
face antigen (e.g., CD19) on the surface of CLL B cells. The modified overcome the chemoresistance conferred by del 17p or TP53 mutation.
TCR has a higher affinity and specificity toward the target antigen and Consequently, autologous transplantation has no role in the routine
is not major histocompatibility complex (MHC) restricted. Multiple management of patients with CLL.
CAR-T cells have been developed and tested in clinical trials with excit- Allogeneic SCT potentially offers a curative approach for patients
ing results. 302,303 These modified T cells persisted in vivo for an extended with CLL, but its utility and timing is currently under considerable
period and were able to induce prolonged clinical responses in the debate given the availability of multiple novel agents. Myeloablative
majority of patients. The treatment is associated with severe cytok- conditioning prior to allogeneic SCT is associated with an unaccept-
304
ine release syndrome and macrophage activation syndrome that require ably high transplant-related mortality (TRM) in excess of 30 percent
aggressive and intensive supportive care and anti–IL-6–directed ther- and is not generally recommended. 314–316 Nonmyeloablative condition-
apy. These modified CAR-T cells also result in the sustained elimination ing regimens afford the opportunity to reduce TRM without impacting
of normal B cells and subsequent sustained hypogammaglobulinemia the graft-versus-leukemia (GVL) effect. Long-term disease-free survival
that require ongoing supportive care and infection prophylaxis to limit is generally in the 30 to 45 percent range. However, nonrelapse mor-
the incidence of infectious complications in these patients. Develop- tality (NRM) is still in the 15 to 30 percent range, but decreasing with
303
ment of these agents on a larger scale is ongoing to allow for larger stud- improvements in supportive care techniques. Moreover, chronic graft-
ies to confirm their promising effect. versus-host disease still impacts long-term quality-of-life after nonmye-
loablative allogeneic SCT in approximately 25 percent of survivors. 317–320
OTHER AGENTS Various patient-, disease-, and transplant-specific factors at the time of
transplantation impact SCT outcomes. In particular, the number of
321
Venetoclax (ABT-199) is an oral Bcl-2–targeting agent that has shown prior treatments and the presence of a complex karyotype contribute
impressive activity with deep remissions in patients with relapsed and to success and also toxicity observed after transplantation. 322–324 Studies
305
refractory CLL, including those who have del 17p. Bcl-2 is an antiap- have identified that implementation of an effective quality management
optotic protein overexpressed in CLL and causes disruption of apoptosis system and experience of the transplantation center are associated with
in CLL cells. Early efforts with the first-generation compound navito- a significant decrease in NRM. 325–327 Patients who relapse after SCT can
clax, demonstrated single-agent activity, but also resulted in profound sometimes be effectively salvaged with the use of currently approved
thrombocytopenia as a result of off-target effects on Bcl-xl expressed in novel therapeutic agents. Given the availability of kinase inhibitors such
platelets. Venetoclax is significantly more potent and more specific to as ibrutinib, we recommend that patients be offered therapy with these
Bcl-2 with limited off-target effects. Combination studies are already novel agents and nonmyeloablative SCT evaluation should be reserved
306
underway with kinase inhibitors and monoclonal antibodies to improve for those failing ibrutinib unless no other cytoreductive therapy is avail-
outcomes. Therapy with venetoclax has been complicated by fulminant able after receipt of this agent. Moreover, we recommend that patients
tumor lysis syndrome, especially in patients with a high burden of dis- who progress after treatment with kinase inhibitors be referred to a
ease that has greatly slowed down clinical development of this agent. treatment center with established expertise for treating CLL, as this can
Blinatumomab is an engineered bi-specific T-cell engaging (BiTE) significantly impact their therapeutic options and outcomes. 325–327
antibody that has shown promising activity in CD19+ B-cell malig-
248
nancies, including CLL and ALL. It was approved in 2014 for the
treatment of relapsed ALL. Blinatumomab engages the CD19+ cell and SPLENECTOMY
brings it in close proximity to a CD3+ T-cell that is also activated upon Splenectomy is rarely used today given the availability of effective ther-
binding to the bi-specific antibody. The resultant interaction leads to the apeutic agents to treat CLL. It can be an effective option for ameliorat-
apoptosis of the CD19+ B cells. The antibody has shown promising and ing refractory autoimmune hemolytic anemia and thrombocytopenia
durable responses and is currently in clinical trials for CLL. Therapy is for which medical management has been unsuccessful. It can also be
328
complicated by hypogammaglobulinemia, cytokine release and neuro- used to provide relief to patients with symptomatic splenomegaly sec-
logic symptoms. 307 ondary to refractory disease. 329–331

Kaushansky_chapter 92_p1527-1552.indd 1539 9/18/15 10:47 AM