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1242 Part IX: Lymphocytes and Plasma Cells Chapter 81: Hematologic Manifestations of Acquired Immunodeficiency Syndrome 1243

reservoir) is the impediment to cure for nearly all HIV-infected peo- patients, supporting the importance of age-appropriate standard cancer
ple. 87,106–109 Although combination ART is highly effective at controlling screening. 115
HIV replication in activated cells, it has no effect on the latent HIV The Centers for Disease Control estimates that 20 percent of HIV+
reservoir, which will persist as long as the cells harboring HIV sur- people in the United States do not know that they are HIV+, and
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vive. Because most HIV genomes reside in central and effector mem- HIV testing is strongly recommended in all patients who present to the
ory T cells that decay at a negligible rate, there is no possibility of cure hematologist with NHL, Hodgkin lymphoma, or idiopathic thrombo-
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with ART alone. The only individual cured of chronic HIV infection cytopenic purpura (ITP), or other malignancies. This recommenda-
(Timothy Brown, the Berlin patient) developed acute myelogenous leu- tion is made because approximately 5 percent of those with diffuse large
kemia that was treated with high-dose conditioning and transplantation B-cell lymphoma and 22 percent of patients with Burkitt lymphoma in
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of HIV-resistant (CCR5D32/D32) allogeneic blood stem cells. While the United States are HIV+ (Fig. 81–1). These proportions vary sub-
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this case provides proof-of-principle that the latent HIV reservoir can stantially by demographic group : among men, 10 percent of those
be eliminated by allogeneic hematopoietic cell transplantation, the with diffuse large B-cell lymphoma are HIV+, in contrast to 1 percent of
approach is impractical for widespread application because of the high women, and approximately 40 percent of those 30 to 59 years old with
toxicity associated with this procedure, the morbidity of graft-versus- Burkitt lymphoma are HIV+. It is important to diagnose HIV infection
host disease, and the scarcity of CCR5D32/D32 donors. To date, most when present, as effective treatment of HIV is essential for successful
HIV cure efforts have focused on the strategy of reversing latency with treatment of the malignancy or ITP.
the notion that once resting cells begin producing HIV they will be tar-
geted by the immune system or die from apoptosis. However, early stud- HUMAN IMMUNODEFICIENCY
ies suggest that activating latent cells to express HIV does not reliably
lead to their death and additional treatments including vaccination to VIRUS–ASSOCIATED DIFFUSE
boost cytotoxic responses will be needed. 109A Gene therapy is also being LARGE B-CELL LYMPHOMA
pursued as a means to control or cure HIV; specifically, DNA editing Among HIV+ patients in the United States, diffuse large B-cell lym-
enzymes that disrupt CCR5 have been used to eliminate CCR5 expres- phoma is now more common than Kaposi sarcoma, although Kaposi
sion in cells that are then expanded ex vivo and reinfused into patients, sarcoma remains the most common malignancy in people living with
creating a population of HIV-resistant CD4+ T cells. 110,111 HIV worldwide. The pathophysiology of diffuse large B-cell lym-
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phoma in HIV has been reviewed. 119,120 In a recent case series, HIV+
HUMAN IMMUNODEFICIENCY patients presented with diffuse large B-cell lymphoma at a median age
of 43 years, 2 decades younger than HIV– patients. Patients often
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VIRUS–ASSOCIATED MALIGNANCIES present with a rapidly growing lymph node or extranodal mass, and
frequently have B symptoms (drenching night sweats, fever, or loss of 10
When AIDS was first identified as a clinical syndrome it was quickly percent of body weight). Involvement of extranodal sites, including the
appreciated that these patients were at greatly increased risk for cer- gastrointestinal tract, liver, CNS, lung, and other sites is common. 121,122
tain types of malignancies, including Kaposi sarcoma, various types of Diagnosis is most commonly made by excisional lymph node biopsy.
non-Hodgkin lymphoma (NHL), and invasive cervical cancer. Each Evaluation should include careful examination of all lymph nodes sites,
of these AIDS-defining cancers is frequently associated with an onco- and the oral cavity. Standard staging with positron emission tomogra-
genic virus (Table 81–6). As effective ART was developed and patients phy–computed tomography (PET-CT), marrow evaluation, and lum-
began living into their 50s, 60s, and 70s, 112,113 it became apparent that bar puncture for cerebrospinal fluid cytology and flow cytometry
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many non–AIDS-defining malignancies were also more common in should be performed. Patients should be evaluated for hepatitis B prior
this population compared to HIV-uninfected patients. Anal cancer is to initiation of chemotherapy. If active hepatitis B is found (hepatitis
120-fold more common in people living with HIV, particularly B DNA+), it must be managed in the context of the HIV treatment,
among men who have sex with men. Hodgkin lymphoma incidence is as several commonly used medications for hepatitis B are also active
increased approximately 20-fold, hepatocellular cancer fivefold, and the against HIV. Although initial studies in the pre-ART era focused on
risk of lung cancer is increased twofold. In contrast, the risks of other low-dose chemotherapy, it is now appreciated that full-dose multi-
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common cancers, including breast cancer, prostate cancer, and colon agent systemic chemotherapy with appropriate supportive care using
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cancer, are not increased in comparison to HIV-negative people. filgrastim or peg-filgrastim and prophylaxis against infectious com-
In the ART era, non–AIDS-defining malignancies comprise approxi- plications, offers the best chance for permanent cure. Cohort studies
mately half of the cancers in people living with HIV, and overall can- show that the 5-year overall survival in the ART era is far better than
cer causes approximately 25 to 33 percent of all deaths in HIV-infected the pre-ART era. A National Cancer Institute study using six cycles
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of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide,
and doxorubicin (EPOCH), in which the initial cyclophosphamide dose
TABLE 81–6. AIDS-Defining Malignancies and Oncogenic was adjusted based on the CD4 count, and subsequent cycles cyclophos-
Viruses phamide dosing was adjusted based on the neutrophil nadir, showed an
AIDS-Defining Malignancy Oncogenic Virus overall survival of 60 percent at 53 months (39 patients, 79 percent had
diffuse large B-cell lymphoma, 18 percent had Burkitt lymphoma, and
Kaposi sarcoma HHV8
none were on ART during chemotherapy). CD4 counts dropped by
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Aggressive non-Hodgkin lymphoma EBV, HHV8 190 cells/μL during chemotherapy, but recovered to baseline by 6 to 12
Primary central nervous system EBV months following chemotherapy. All patients received P. jiroveci pro-
lymphoma phylaxis, and if CD4 counts were less than 100 cells/μL, M. avium com-
plex prophylaxis. All patients also received filgrastim following each
Invasive cervical cancer HPV
cycle of chemotherapy. This key study demonstrated that EPOCH is safe
EBV, Epstein-Barr virus; HHV, human herpesvirus; HPV, human and effective in HIV+ patients with aggressive lymphoma. Outcomes
papillomavirus. differed markedly depending on the initial CD4 count: patients with an

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