Page 1274 - Williams Hematology ( PDFDrive )

1248 Part IX: Lymphocytes and Plasma Cells Chapter 81: Hematologic Manifestations of Acquired Immunodeficiency Syndrome 1249

Antiretroviral Therapy and Chemotherapy multidisciplinary consultation with the pharmacist and infectious dis-
Controversy persists regarding whether ART should be initiated or eases physician.
continued during multiagent systemic chemotherapy. In the pre-ART
era, the outcomes for treatment of lymphoma in HIV+ patients were HUMAN IMMUNODEFICIENCY
markedly inferior to the present era. Some clinical trial groups stop
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or do not initiate ART during systemic chemotherapy, whereas others VIRUS–ASSOCIATED CASTLEMAN DISEASE
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continue ART or initiate ART after the first cycle of chemotherapy in Castleman disease is a rare polyclonal lymphoproliferative disorder
those patients not on ART at time of lymphoma diagnosis. 199,200 Certain characterized by periodic flares (an inflammatory illness accompanied
classes of ART medications, notably protease inhibitors and nnRTIs can by lymphadenopathy and splenomegaly), and a high risk of progres-
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alter the metabolism of other medications primarily though inhibition sion to lymphoma. Castleman disease occurs with higher frequency
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or induction of the cytochrome P450 enzymes, potentially leading to in people living with HIV. The pathophysiology of Castleman dis-
higher or lower concentrations of other drugs (including chemotherapy ease is related to IL-6 (reviewed in Ref. 210). Virtually all patients with
agents). Unfortunately, there are limited pharmacokinetic data from HIV-associated Castleman disease are infected with HHV8, whose
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clinical trials to elucidate these potential drug interactions and their viral genome encodes a viral homologue of IL-6. Sequential analysis of
effects on drug levels. Chemotherapy agents eliminated by non-P450 human IL-6, viral IL-6, and a variety of other cytokines in patients with
routes are less likely to be affected by ART. A study of 154 HIV+ patients HIV-associated Castleman disease during and after flares showed that
with a broad range of malignancies (many with hematologic malignan- either human IL-6, viral IL-6, or both were elevated during the flare
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cies) treated at the MD Anderson Cancer Center showed that clinically and diminished during remission. IL-6 is a proinflammatory cytok-
relevant drug interactions between ART and chemotherapy drugs were ine and stimulates polyclonal proliferation of B lymphocytes. Serologic
rare (4 percent of cases) and confined to the protease inhibitor class. evidence of HHV8 infection is present in 7 percent of healthy U.S. blood
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The nnRTIs and the integrase strand-transfer inhibitors had a better donors, but few healthy adults or HIV+ patients without Castleman
safety profile when combined with chemotherapy than did the protease disease, Kaposi sarcoma, or primary effusion lymphoma have detectable
inhibitors, in this retrospective series. Others have also found that pro- HHV8 virus in the blood. More than 80 percent of HIV+ patients with
tease inhibitors may exacerbate chemotherapy-induced neutropenia, symptomatic multicentric Castleman disease have detectable HHV8
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although this is controversial. 204,205 A retrospective review of 34 patients viremia, often at a high level. A retrospective analysis of 52 HIV+
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with diffuse large B-cell lymphoma showed similar complete response patients with multicentric Castleman disease at time of presentation
rates and toxicities in those receiving CHOP while also on an HIV showed that more than 50 percent of the patients had a prior diagnosis
protease inhibitor as those who were receiving a nonprotease inhibitor of Kaposi sarcoma, and 80 percent were on ART. The mean CD4 count
ART regimen. In another study of HIV+ patients with Hodgkin lym- at time of diagnosis of Castleman disease was 287 cells/μL, indicating
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phoma receiving ABVD chemotherapy, the use of the protease inhibitor that Castleman disease occurs in moderately immunocompromised
ritonavir appeared to increase the risk of peripheral neuropathy. More patients. Symptoms at presentation included fever, lymphadenopathy,
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accurate information regarding drug interactions between ART and and splenomegaly in 98 to 100 percent, pulmonary symptoms in 60
chemotherapy agents will become available through the AMC, which percent, and edema in 40 percent of patients. A single-institution study
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is currently conducting clinical trials in which patients are stratified of 113 patients with Castleman disease also reported that approxi-
by the type of ART and its potential for inducing or inhibiting cyto- mately half of the patients had a prior diagnosis of Kaposi sarcoma. The
chrome P450 enzymes, and obtaining detailed pharmacokinetic data. median CD4 count in this study was 188 cells/μL. The ECOG perfor-
With the growing number of available ART agents, including integrase mance status at diagnosis of Castleman disease was greater than 2 in 45
strand-transfer inhibitors, it is usually possible to adjust an ART regi- percent of patients, 36 percent had hemophagocytosis, and 30 percent
men that minimizes potential drug interactions but still suppresses HIV required an ICU stay, illustrating how ill these patients often are. During
replication throughout the course of chemotherapy. a Castleman disease flare, patients may rapidly develop cytopenias: half
A second issue is overlapping toxic effects between ART and the patients in this series had a hemoglobin of less than 8 g/dL and 29
chemotherapy drugs. Zidovudine causes marrow suppression, and percent had a platelet count of less than 150,000/μL. High C-reactive
should be avoided in patients receiving myelosuppressive chemother- protein (often 10-fold higher than normal) and plasma HHV8 levels
apy. Didanosine and stavudine (older, infrequently used agents) cause (median 30,000 copies/mL, range: 60 to 1 million copies/mL) are found
peripheral neuropathy, and their use should be reconsidered in patients during a flare, 215,216 and these values can be helpful. Diagnosis requires a
who will receive potentially neurotoxic chemotherapy. Atazanavir, a lymph node biopsy that is consistent with Castleman disease, ideally an
commonly prescribed protease inhibitor, causes unconjugated hyperbi- excisional biopsy rather than a needle biopsy. The morphology of mul-
lirubinemia similar to Gilbert syndrome and can complicate the admin- ticentric Castleman disease in HIV+ patients shows plasmablastic cells
istration of some chemotherapy agents. However, if there is no other in the mantle zone of the follicles; HHV8 is detectable in the plasmab-
217
evidence of hepatotoxicity, chemotherapy can be given at standard lasts. Often, lymph nodes diagnostic of Castleman disease also con-
doses. Earlier studies suggested some ART drugs (saquinavir, efavirenz, tain malignant appearing spindle cells characteristic of Kaposi sarcoma.
nelfinavir) might cause cardiac conduction abnormalities (prolonga- Castleman disease is rare, and treatment recommendations are
tion of the electrocardiographic “QTc interval”), but this has not been largely based on case series and small clinical trials. Several clinical
confirmed in subsequent studies. If the patient is stable on ART with trials show that the anti-CD20 monoclonal antibody rituximab is very
excellent HIV virologic control, a reasonable approach is to consult effective for treatment of Castleman disease. Prospective studies 213,218,219
2
the infectious diseases physician who is managing the patient and also demonstrate that 375 mg/m of rituximab administered intravenously
the chemotherapy pharmacist to identify potential drug interactions weekly for 4 doses resulted in rapid symptomatic improvement, and
between ART and the planned chemotherapy, to adjust ART as neces- 90 percent of patients achieved a response that lasted for more than 6
sary, and then proceed with chemotherapy with concurrent ART. If the months. Clinical improvement with rituximab may begin within hours
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patient is not on ART, it is reasonable to give one cycle of chemotherapy to days and is associated with diminished levels of serum IL-6. In one
and then start ART with the second cycle of chemotherapy following series of 113 HIV+ patients with multicentric Castleman disease, some

Kaushansky_chapter 81_p1239-1260.indd 1249 9/21/15 11:19 AM