Page 1491 - Hematology_ Basic Principles and Practice ( PDFDrive )

1326 Part VII Hematologic Malignancies

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higher lymphoma cure rates but were associated with less survival based on the intensity of the chemotherapy regimen. In
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chemotherapy-related morbidity and mortality. However, with the patients with very low CD4 counts, low-dose chemotherapy is a
evolution of supportive care, including PJP prophylaxis and neutro- reasonable treatment option, while maintaining the possibility of
phil growth factors, tolerance of chemotherapy improved. With long-term disease-free survival in some. In a recent uncontrolled
effective antiretroviral therapy, long-term outcomes improved as prospective study where HIV-positive patients with BL were given
well. 84,85 With full-dose therapies, some evidence emerged to suggest a shortened course of EPOCH with a double dose of rituximab
that stage-for-stage outcomes might be as good or better in patients (SC-EPOCH-RR), freedom from progression and overall survival
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with HIV-associated lymphoma compared with those without HIV. outcomes were favorable and comparable to those seen in HIV-
At the outset of therapy, a series of questions related to the chemo- negative patients treated with the standard DA-EPOCH-R, with
therapy regimen, dose, concomitant HAART, and supportive care less toxicity and lower cumulative doses of chemotherapy in the
must be addressed. SC-EPOCH-RR group. 93

Regimen Antiretroviral Therapy

There is general agreement that the inclusion of rituximab with A few key special issues in considering concurrent antiretroviral and
multiagent chemotherapy improves outcome, at least in patients lymphoma therapy include concerns about shared toxicities, drug–
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with CD4 counts of greater than 50 cells/mm . Rituximab, cyclo- drug interactions, and risk for inability to comply with consistent
phosphamide, hydroxydaunomycin, vincristine, and prednisone antiretroviral dosing. Zidovudine is myelosuppressive and can exac-
(R-CHOP) and dose-adjusted, infusional etoposide, prednisone, erbate pancytopenia associated with lymphoma therapy. If patients
vincristine, cyclophosphamide, and hydroxydaunomycin with ritux- are already on a zidovudine-containing regimen, it is generally pos-
imab (DA-EPOCH-R) have emerged as standard regimens. 87,88 As in sible to substitute an alternative regimen before the initiation of
the treatment of DLBCL, in patients without HIV infection, the lymphoma therapy. Many antiretroviral agents alter the metabolism
value of infusional chemotherapy remains controversial. A pooled of drugs used in lymphoma treatment. This has been a particular
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retrospective analysis favored the infusional regimen. However, concern when infusional chemotherapy regimens are used, and some
insofar as the trials were conducted sequentially (R-CHOP between investigators have chosen to stop chemotherapy before initiation of
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1998 and 2002, and R-EPOCH between 2002 and 2006), it is dif- such regimens. However, in trials involving infusional chemotherapy
ficult to exclude other factors, such as the availability of better anti- that allowed patients already on a stable antiretroviral regimen to
retroviral agents, improvements in supportive care, or changes in the remain on that regimen during lymphoma treatment, major problems
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population studied. were not noted. Nausea and vomiting associated with chemotherapy
BL typically requires more intensive treatment regimens than regimens may interfere with regular antiviral dosing. Intermittent
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those used for DLBCL. Thus there has been concern about using antiretroviral therapy raises concerns about the development of a
these regimens in the HIV-seropositive population. A small retrospec- resistant strain of HIV. Because of the concern that initiation of
tive study of cyclophosphamide, vincristine (Oncovin), doxorubicin, antiretroviral therapy with cytotoxic chemotherapy might result in
and methotrexate (CODOX-M)/ifosfamide, etoposide, and cytara- such resistance, many recommend delaying initiation of antiretroviral
bine (IVAC) for BL that included 14 patients with HIV showed therapy until an appropriate regimen to control nausea and vomiting
HIV-seropositive patients to have similar progression-free survival, is established. Stopping antiretroviral therapy also carries with it some
overall survival, and complete response rates as compared with the risks. When antiretroviral therapy includes drugs with different half-
HIV-negative patients with BL. In a multicenter retrospective study, lives, stopping treatment may result in the longest-lived agent being
HIV-positive patients with BL treated with rituximab plus present in the absence of other antiretroviral agents. This is particu-
CODOX-M/IVAC had better progression-free and overall survival larly an issue for long-lived nonnucleoside reverse transcriptase
with no increase in toxicity as compared with HIV-positive patients inhibitors. Even a single dose of such agents in the absence of other
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who received CODOX-M/IVAC without rituximab. In a prospec- antiretroviral agents may lead to resistance to that class of agents.
tive Spanish study, HIV-seropositive and HIV-seronegative patients Thus when an interruption of antiretroviral therapy is planned,
with BL were treated with six cycles of intensive chemotherapy and specific strategies have been advocated, including a “staggered stop”
rituximab and were found to have comparable outcomes, regardless or a change to a regimen with components that have similar
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of HIV status. In this study all HIV-seropositive patients were half-lives. 94
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required to be on HAART to enroll, and the majority had CD4 For patients already on antiretroviral treatment at the time of
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counts of greater than 200 cells/mm . Granulocyte colony-stimulating lymphoma diagnosis, the particulars of the regimen should be con-
factor support was used throughout chemotherapy cycles, as well as sidered during the pretreatment evaluation. Atazanavir and indinavir
PJP and other antimicrobial prophylaxis. Differences in induction- are associated with hyperbilirubinemia as a result of UGT1A1 inhibi-
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related mortality, duration of neutropenia, progression-free survival, tion. This is an unconjugated hyperbilirubinemia similar to that
or overall survival were not detected, although HIV-seropositive occurring with Gilbert syndrome. Elevated total bilirubin in such
patients did have significantly more severe mucositis and infectious patients is not indicative of hepatic involvement or other serious
complications. hepatic dysfunction and should not guide decisions about chemo-
therapy dose adjustments. Ritonavir inhibits the clearance of mid-
azolam, phenytoin, and voriconazole and other agents metabolized
Dose by the cytochrome P-450 CYP3A4 pathway.
Most would agree that dose reduction is appropriate in patients
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with low CD4 count (<100 cells/mm ), history of ongoing Supportive Care
opportunistic infection, performance status below 75%, or com-
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promised organ function. Some regimens begin with a 50% dose Although PJP prophylaxis is recommended only when the CD4
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reduction in cyclophosphamide for a CD4 count of less than 100 count is less than 200 cells/mm for patients with HIV not receiving
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cells/mm with a built-in dose escalation for the next cycle if well cytotoxic chemotherapy, prophylaxis is universally recommended for
tolerated. 84,88 patients with HIV receiving cytotoxic chemotherapy. The following
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Chemotherapy regimens of varying intensity depending on CD4 are also commonly used: fungal prophylaxis with fluconazole; herpes
count, performance status, and International Prognostic Index score simplex and varicella prophylaxis with acyclovir, valacyclovir, or
have been studied, including a comparison of low-dose CHOP famciclovir; quinolone prophylaxis when neutrophil counts fall below
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with standard-dose CHOP, with no differences found in overall 1000 cells/mm ; and granulocyte growth factors.