Page 1567 - Williams Hematology ( PDFDrive )

1542 Part XI: Malignant Lymphoid Diseases Chapter 92: Chronic Lymphocytic Leukemia 1543

used and may decrease the frequency of packed red cell transfusions; vincristine, cyclophosphamide, and doxorubicin) and R-hyperCVXD
however, their use can be complicated by polycythemia and thrombo- (rituximab, fractionated cyclophosphamide, vincristine, liposomal
embolic disease. 379,380 Thrombopoietin agonists can also be considered daunorubicin, and dexamethasone). However, the use of hyperCVXD
in refractory patients, but conclusive data is currently lacking. Refrac- is associated unacceptably high treatment-related mortality and its use
381
tory cases may require definitive treatment with therapeutic agents for is not recommended. 400,401 The OFAR combination also has modest
400
the underlying CLL. Initiating nucleoside analogue-based chemother- but short-lived responses with significant toxicities. The use of dose-
apy in patients with preexisting AIHA or ITP is not contraindicated, but adjusted R-EPOCH is our preferred regimen to debulk patients before
their use is contraindicated if these complications arise while patients we proceed with more definitive therapy, including allogeneic SCT.
are on these agents. In general for patients presenting with both active Along with large B-cell transformation, patients can also experi-
CLL and autoimmune manifestations, our approach is to first treat the ence prolymphocytic leukemia (PLL) transformation, characterized by
autoimmune complication and then the CLL if symptoms persist. the presence of more than 55 percent prolymphocytes in the marrow,
PRCA is a rare complication of CLL that can arise spontaneously. or Hodgkin lymphoma. 402–404 Unlike large cell transformation, patients
PRCA needs to be differentiated from other forms of anemia, including with Hodgkin lymphoma have a similar outcome to de novo disease
AIHA and anemia resulting from extensive marrow infiltration. PRCA is when matched by stage and can be treated with adriamycin, bleomycin,
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characterized by a decrease in red cell precursors. Additionally, select vinblastine, and dacarbazine (ABVD) based therapy (Chap. 97). 405
infections, such as parvovirus, can cause PRCA in CLL. The etiology of The prolymphocytic transformation is similar to the distinct entity
disease-related PRCA is believed to be related to the cytotoxic effect of of B-cell PLL which is characterized by subacute accumulation of pro-
a T-cell large granular lymphoma (T-LGL) clone on erythroid progeni- lymphocytes in a predominantly older, male population with presence
tor cells (Chap. 94). These CD3-, CD8-, and CD57-positive cells slowly of chromosome 14q abnormalities and del 17p. 406–408 Gene-expression
accumulate in the marrow of patients with PRCA. Occasional cases profiling suggests subgroups of patients with PLL that are similar to CLL
409
have been observed after parvovirus B19 infection. Treatment with and others that are similar to mantle cell lymphoma. Patients present
383
immunosuppressive agents like glucocorticoids, cyclophosphamide, with B symptoms, massive splenomegaly, and palpable lymphadenop-
and/or cyclosporine result in reticulocytosis and slow correction of the athy. Occasionally, patients may have organ infiltration and extralym-
anemia over several weeks. IVIG, rituximab, and antithymocyte glob- phatic invasion, including neurologic involvement and leukostasis from
384
ulin have also been used in refractory cases. 385–388 hyperleukocytosis. 410,411 Prolymphocytes have variable expression of
CD5 and are negative for CD23. Indications and therapeutic options for
RICHTER SYNDROME patients with PLL are similar to those used for CLL. 412–414
T-cell prolymphocytic lymphoma (T-PLL) is a distinct clinical
Richter syndrome (RS) is defined as a transformation of CLL into an entity that was previously classified as T-CLL. These patients typically
aggressive, high-grade, large B-cell non-Hodgkin lymphoma. The large present with B symptoms and paraneoplastic phenomenon associated
cell lymphoma is typically of the activated B-cell (ABC) subtype by with rapid splenomegaly and lymphadenopathy with leukocytosis. Eval-
389
immunohistochemistry. Incidence estimates vary from 2 to 10 per- uation results in the demonstration of prolymphocytes on tissue biopsy
390
cent. Transformation typically occurs in patients with unmutated with markers typical for T-cell disorders, including CD3, CD5, CD4,
IGHV genes, but occasionally may be seen in patients with mutated CD7, and CD8. TCR gene rearrangements are also observed. These fea-
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IGHV genes who have been heavily pretreated. The development of tures help distinguish them from B-cell CLL. The most effective treat-
transformation may be related to the evolution of an alternate clone ment for this entity is alemtuzumab, although regimens for aggressive
of malignant B cells distinct from the original CLL clone in a subset T-cell lymphomas have also been used. 412,415–419 In general, all patients
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of patients. Transformation appears to occur independent of disease relapse from these therapies, making consolidation allogeneic trans-
stage, duration of disease, type of therapy, or response to therapy. How- plantation a viable consideration for these patients if a donor is available
ever, the presence of bulky and advanced stage disease, IGHV unmu- and patient comorbid features allow.
tated disease, especially with involvement of 4 to 39 loci, high CD38
expression, absence of del 13q, presence of del 17p or del 2p and trisomy MONOCLONAL B-CELL LYMPHOCYTOSIS
12, typically in combination with NOTCH1 mutations, may predict
the development of RS. 393–396 The syndrome is characterized by rapid Monoclonal B-cell lymphocytosis (MBL) can be characterized as
development of B symptoms and rapidly progressive lymphadenopathy. a precursor state of CLL. Patients who have greater than 5000 B-
Cytopenias may worsen rapidly because of transformation in the mar- lymphocytes/μL in their blood, in the absence of B symptoms, lymph-
row. LDH is also increased in the majority of patients. Patients typically adenopathy, organomegaly, or cytopenias, are classified as having
have complex karyotype and involvement of TP53, ATM, RB (retino- monoclonal B-cell lymphocytosis. Presence of a lymphoid aggregate or
blastoma), and c-myc genes. PET scans have generally no role in the infiltration of lymph node or marrow by cells with a characteristic CLL
397
routine management of patients with CLL but can be very useful in the phenotype establishes the diagnosis of CLL regardless of blood lym-
diagnosis of transformation. A standardized uptake value (SUV) of 5 or phocytosis. The prevalence of MBL varies from 3.5 percent in normal
420
less on a lymph node by PET scan has a high negative predictive value healthy people with normal counts to 13.5 percent to 17 percent in
and patients with a higher SUV require an excisional biopsy for defin- normal healthy people with a family history of CLL, 16,421 which suggests
itive diagnosis. 156,398,399 Prognosis of RS is related to the clonality of the a familial predisposition to the development of CLL. The vast majority
malignant clone in that patients with clones unrelated to the CLL tend of patients with MBL have clonal populations with a characteristic CLL
to have a much better prognosis than patients with a clonally related phenotype on sensitive flow cytometry assay that is positive for CD5
RS. Additionally, patients who present with RS prior to treatment for and CD23, negative for CD10, and dim positive for CD20. Other phe-
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their CLL often have a better outcome. Treatment of patients with RS notypes that have been observed are the atypical CLL phenotype with
has historically been treated with regimens similar to those used for the positive CD5, CD23, and bright CD20, and the non-CLL phenotype
treatment of patients with large cell lymphoma with mixed results. These that is negative for CD5 and CD23 and appears to be more consistent
include R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincris- with low-grade lymphoproliferative disorders like marginal zone lym-
tine, and prednisone) or R-EPOCH (rituximab, etoposide, prednisone, phoma or lymphoplasmacytic lymphoma. MBL is more prevalent in
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