Page 1771 - Williams Hematology ( PDFDrive )

1746 Part XI: Malignant Lymphoid Diseases Chapter 107: Myeloma 1747

and IL-10 suppress IL-2 autocrine pathways, blocking T-cell antitumoral HYPERVISCOSITY
responses 338–340 and stimulate T-regulatory cell proliferation. Moreover, Less than 10 percent of myeloma patients develop signs of hypervis-
341
these cytokines sustain the immature phenotype of dendritic cells, highly cosity syndrome, a condition that manifests in 10 to 30 percent of
specialized antigen-presenting cells (Chap. 21), reducing their expres- patients with Waldenström macroglobulinemia (Chap. 109), because
sion of costimulatory molecules (HLA-DR, CD40, and CD80 antigens) monoclonal IgMs display a higher intrinsic viscosity than other immu-
342
and thereby their antigen stimulatory capacity. IL-6 also inhibits den- noglobulins. 353–355 Cutaneous or mucosal bleeding is very common in
342
dritic cell production from CD34+ progenitor cells. Normal CD19+ B hyperviscosity syndrome, together with blurred vision, headache, ver-
lymphocytes at early and late stages are suppressed in myeloma, result- tigo, dizziness, nystagmus, deafness, and ataxia. Circulatory problems,
ing in hypogammaglobulinemia, inversely correlating with the disease affecting cerebral, pulmonary and renal circulation can rarely ensue in
stage. B-cell dysfunction in myeloma can be related to TGF-β effects, the presence of high blood viscosity (see “Hyperviscosity Syndrome”
343
lack of stimulatory signals from helper T cells, and altered gene expres- in Chap. 109). Relative serum viscosity but not serum immunoglob-
356
sion. Hypogammaglobulinemia is particularly responsible for a myeloma ulin levels correlates with onset and extent of clinical symptoms. Based
patients’ susceptibility to encapsulated organisms, such as Streptococcus on the specific physicochemical properties of classes and subclasses of
pneumoniae and Haemophilus influenzae. T-cell subsets are also abnor- immunoglobulins (Chap. 75), up to one-quarter of patients with IgA
mal, with inversion of the CD4:CD8 ratio and T-helper type 2 (Th2) myeloma can have blood hyperviscosity as a result of the tendency of
344
345
cell–type skewing. Moreover, global T-cell receptor (TCR) diversity is IgA to form dimers or polymers. Patients with IgG subclass mye-
357
reduced, with the presence of oligoclonal expansions of CD4+ and CD8+ loma, whose immunoglobulins have higher propensity to aggregate, can
3
T cells and TCR signaling is compromised 344,346,347 ; χδT cells and NK cells also manifest with hyperviscosity syndrome. 358
are also aberrant in myeloma. The presence of decreased B cell or T cell
348
counts can negatively impact survival. β M is the invariant chain of
2
the major histocompatibility (MHC) class 1 molecule, which is shed by PLASMA CELL LEUKEMIA AND
myeloma cells. Its levels correlates with tumor burden and are impor- EXTRAMEDULLARY DISEASE
tant for patient staging using the International Staging System (ISS)
232
(see section Staging below). β M induces IL-6, IL-8, and IL-10 produc- Plasma cell leukemia (PCL) is diagnosed when more than 2000 mye-
2
tion and activation of STAT3. However, it also has immunosuppressive loma cells/μL are present in the blood or plasmacytosis accounts for
functions, by reducing surface expression of CD83, HLA-ABC, costim- greater than 20 percent of the differential white cell count. PCL is rarely
ulatory molecules, and adhesion molecules on dendritic cells, impairing manifest at the time of primary presentation and more commonly
stimulatory dendritic-allospecific T-cell responses by inactivation of Raf/ arises from preexisting myeloma as end-stage disease. In this case,
349
MEK/ERK cascade and NF-κB in dendritic cells. Vaccines, prophylac- tumor cells have become microenvironment-independent and accumu-
tic antibiotics or antivirals, and intravenous immunoglobulin are pre- late in the marrow, but also recirculate in the blood (extramedullary
359–362
ventative measures apt to decrease infections among myeloma patients. disease). However, low levels of circulating plasma cells can be
Yearly influenza vaccines and a single pneumococcal vaccine at diagno- detected in the majority of myeloma patients. By definition, extramed-
sis is recommended, as myeloma patients can still mount a suboptimal ullary disease (EMD) is the presence of a clonal plasmacytic infiltrate
immunologic response. Antiviral prophylaxis (e.g., acyclovir 400 mg outside the marrow. Specifically, it is now considered EMD only if the
twice daily or valacyclovir 500 mg once daily) is mandatory in patients infiltrate is present at anatomic sites distant from the bone or adjacent
treated with bortezomib combined with glucocorticoid regimens to soft tissue, hence excluding cases where soft-tissue masses arise in con-
363
prevent herpes zoster. Antibiotic prophylaxis is controversial. A study tiguity with the marrow. Indeed, in true EMD, plasma cells have an
where patients were randomized on a 1:1:1 basis to receive either a daily immature, plasmablastic morphology and have a high proliferative
quinolone, trimethoprim-sulfamethoxazole, or placebo for the first 2 index. According to different clinical trials, 6.0 to 7.5 percent of patients
months of treatment did not show a decreased incidence of serious infec- screened with magnetic resonance imaging (MRI) or positron emission
tion (more severe than grade 3 and/or requiring hospitalization) nor of tomography–computed tomography (PET-CT) have EMD at the time
364,365
any infection within the first 2 months of treatment or any improvement of diagnosis. Extramedullary masses can localize to several organs,
in response rate or OS. However, antibiotic prophylaxis with cipro- including liver, lymph nodes, spleen, kidneys, breasts, pleura, meninges,
350
floxacin or trimethoprim-sulfamethoxazole might be still beneficial in and cutaneous sites, and are inevitably associated with elevated levels of
367–369
366
selected patients, such as those patients with a history of repeated infec- LDH and a poor response to treatment. Leptomeningeal mye-
tions, those receiving more intense regimens or those with persistently lomatosis with abnormal cerebrospinal fluid findings is rare but can
370,371
low
low CD4+ counts to prevent Pneumocystis carinii pneumonia or other manifest at advanced stage. EMD cells are often CD56– or , and
372,373
infections. Intravenous immunoglobulin (IVIG) infusion may be con- present t(4;14) and del(17p) more commonly, together with TP53
110,374
sidered in patients with recurrent, serious infections despite antibiotic mutations, TP53 nuclear localization, or high expression levels of
375
prophylaxis. focal adhesion kinase (FAK1). Additionally, it has been speculated
that high-dose melphalan and modern salvage therapies can artificially
increase the incidence of EMD as a result of longer duration of treat-
NEUROPATHY ment, emergence of dormant cells, and poor penetration of the drugs to
sanctuary sites like the central nervous system.
376
Local myeloma growth can cause polyneuropathy by spinal cord or
peripheral nerve compression, even though polyneuropathy is not a
common presenting symptom, unless in the context of perineuronal or SPINAL CORD COMPRESSION
perivascular (vasa nervorum) amyloid deposition. POEMS syndrome, Spinal cord compression can result from an extramedullary plasmacy-
256
or osteosclerotic myeloma, is an exception, where complete polyneuropa- toma or vertebral fracture and present acutely with severe back pain
thy is practically always present along with organomegaly, endocrinopathy, alongside with weakness or paresthesias of the lower extremities, or
monoclonal gammopathy, and skin changes. 351,352 The pathogenesis of bladder/bowel incontinence. It should be considered a medical emer-
POEMS syndrome is largely unknown, but chronic overproduction of gency, evaluated with MRI, and promptly treated with a combina-
proinflammatory cytokines, such as VEGF, plays a major role. tion of local radiotherapy, decompressive laminectomy, and systemic

Kaushansky_chapter 107_p1733-1772.indd 1746 9/21/15 12:34 PM