Approach Considerations
In the era of HAART, patients with AIDS-related lymphomas (ARLs) are generally being treated with standard or only slightly modified chemotherapy regimens. Autologous bone marrow and stem-cell transplantation approaches in lymphoma patients have been successful [96] . Case reports suggest that allogeneic transplantation for patients with HIV and hematologic malignancies merits further investigation.
Addition of rituximab to EPOCH (etoposide, prednisone, vincristine [Oncovin], and doxorubicin hydrochloride [hydroxydaunorubicin hycrochloride]), CHOP, CODOX/MIVAC and other standard regimens is likely beneficial [97, 98, 99, 100, 101] .
Steroids are often given when a symptomatic brain mass lesion is identified in patients with ARLs. These agents can shrink the tumor and also convert contrast-enhancing lesions into nonenhancing lesions. [71]
Surgical Care
The role of surgery in lymphomas is limited to diagnostic biopsies (eg, excisional biopsy of a lymph node or orchiectomy in the case of a testicular mass). Surgery may also be of benefit when the tumor causes compression, obstruction, or perforation of the gastrointestinal tract.
Consultations
See the list below:
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Surgical consultation – Usually requested for diagnostic biopsies
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Radiation oncology consultation – Usually requested for adjunctive treatment of CNS lymphomas or painful bone lesions, or to shrink tumor size
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Interventional radiology consultation – Usually requested for placement of a venous access device for the administration of chemotherapy
Diet
No special diet is required in patients with AIDS-related lymphomas (ARLs) except under special circumstances. Please see the Patient Education section.
Activity
The patient's activity can be as tolerated except under special circumstances. Please see the Patient Education section.
Role of HAART Therapy
Since the introduction of HAART, there has been a decrease in the incidence of systemic and central nervous system (CNS) non-Hodgkin lymphoma (NHL) among patients with AIDS. Among patients with systemic AIDS-related NHL, there has been decreased high-grade histology, increased use of chemotherapy, and improved survival. Immune recovery induced by HAART leads to dramatic improvement in patient survival, but the prognosis still remains poor. The data supporting these facts are as follows [79, 80, 9] :
Table. Role of HAART Therapy (Open Table in a new window)
| Before HAART | After HAART | |
| Incidence of NHL per 1000 person-years | 29.6 | 6.5 |
| Proportion of PCNSL | 28% | 17% |
| Intermediate grade NHL | 33% | 49% |
| High-grade NHL | 38% | 19% |
| Patients receiving chemotherapy | 54% | 72% |
PCNSL
PCNSL usually occurs in patients who have very low CD4 counts and who are severely immunosuppressed. The median CD4 count of such patients has been found to be as low 15/μL in some studies. The tumor has very bad prognosis. Pre-HAART studies have indicated a median survival of only 1-2.5 months for untreated patients with PCNSL. [81]
Radiotherapy in combination with steroids has been the cornerstone of therapy, but median survival remains around 3.5 months. [78] A high performance status is one of the most important prognostic factors in this patient population. [82]
High-dose chemotherapy combined with whole-brain radiation therapy improves tumor response rates and survival compared with whole-brain radiation therapy alone. [83]
High-dose methotrexate has been suggested as an alternative to radiation therapy for primary CNS lymphoma, [84] but there is lack of extensive data in this regard. In the small study that suggested the use of high-dose methotrexate in these patients, the maximum survival benefit was seen in patients who did not have biopsy-proven PCNSL. [84] Patients who had the biopsy diagnosis had a median survival of 73 days only.
Methotrexate-based multiagent chemotherapy without whole-brain radiation therapy is associated with similar tumor response rates and survival compared with regimens that include whole-brain radiation therapy, although controlled trials have not been performed with such multiagent chemotherapy regimens either. [83]
Systemic NHL
Chemotherapeutic options commonly used in the treatment of systemic NHL include the following:
CHOP regimen
The components of CHOP include cyclophosphamide, doxorubicin, vincristine, and prednisone.
A multicenter prospective study in Germany evaluated simultaneous treatment with CHOP chemotherapy and HAART in patients with AIDS-related lymphomas (ARLs); the results showed this regimen to be safe and that it improved survival. [85]
There were some unique unanswered questions that were addressed in this trial. As HAART therapy was shown to improve survival, it would seem unwise to stop the treatment during chemotherapy. At the same time, it would not be prudent to reduce the intensity of chemotherapy in such patients; in addition, a combination of both therapies was thought to increase toxicity, thus reducing the chances of remission and overall survival. [85]
However, the results of the trial showed that it is safe to combine both CHOP and HAART treatments. In the high-risk group, the complete remission was 29%, with a median survival of 7.2%. In the standard risk group the complete remission was 79%. [85]
Dose-adjusted (DA)-EPOCH regimen
The components of EPOCH include etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin.
The poor survival of patients and the toxicity of standard chemotherapy regimens was the reason for the development of the DA-EPOCH regimen. The rationale of the regimen is that the tumor cells are relatively less resistant to prolonged, low concentrations of chemotherapeutic agents used in vitro. Also, at the same time, a prolonged and low concentration of the agent is less toxic to the bone marrow. In this regimen, the dose of cyclophosphamide is adjusted by the CD4 count cutoff of 100 cells/μL. In some studies, the DA-EPOCH regimen has achieved complete remission in as many as 74% of the patients, with disease-free survival as high as 92% and an overall survival of 60% at a median follow-up of 53 months. [86]
Intrathecal methotrexate is given for CNS prophylaxis. However, if CNS involvement is confirmed, The Eastern Cooperative Oncology Group (ECOG) recommends an intrathecal administration of methotrexate, cytarabine, and hydrocortisone. Trials involving the addition of rituximab with EPOCH are under way in some centers, but the role of rituximab is undefined in patients with AIDS-related lymphomas (ARLs), and it is not recommended at the moment. [87]
NOTE: HAART is a cornerstone in addition to chemo-immunotherapy for AIDS associated NHL [102] .
CDE regimen
The components of CDE are cyclophosphamide, doxorubicin, and etoposide.
The CDE regimen is another well-tolerated and effective regimen that can be given concomitantly with HAART. The regimen is given by continuous infusion over 4 days. Complete response occurs in 44% of the patients with an overall survival of 43% at 2 years. [88]
CODOX-M / IVAC regimen
The components of the CODOX-M / IVAC regimen are cyclophosphamide; doxorubicin; high-dose methotrexate/ifosfamide; etoposide; and high-dose cytarabine.
This regimen is recommended in patients with AIDS-related Burkitt lymphoma when the CD4 count is less than 100. CODOX-M/IVAC is given in combination with HAART. The regimen was developed with the view that for an aggressive lymphoma like Burkitt lymphoma, a moderate dose chemotherapy is substandard.
Response rates after intensive chemotherapy has been reported around 67%, with a disease-free survival of 60% at 2 years. [89]
The regimen is well tolerated and has similar rates of complications in HIV-infected and non-HIV-infected patients. [89]
Treatment of lymphomatous meningitis
This involves administration of intrathecal cytarabine, methotrexate with leucovorin rescue, and whole brain irradiation. [90]
Primary Effusion Lymphoma
Primary effusion lymphoma has very bad prognosis, with a median survival of 2-3 months. No specific guidelines are available for the treatment of this disease. Participation of such cases in clinical trials in encouraged. Regimens such as CHOP, da EPOCH and CODOX/MIVAC have been used with limited success [103, 104] .
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Burkitt lymphoma under low magnification showing sheets of atypical mononuclear cells. Scattered macrophages can be seen (as demonstrated by the green arrows) giving rise to classical "starry-sky" pattern.
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Burkitt lymphoma under high magnification showing sheets of atypical mononuclear cells. The cells are intermediate to large in size with scant cytoplasm, round to irregular nuclear contour, smudged chromatin and some with nucleoli. Mitosis and apoptosis are frequent with scattered macrophages giving focal "starry-sky" pattern. Green arrows = macrophages; yellow arrows = mitosis.
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Diffuse large B cell lymphoma under low magnification showing diffuse proliferation of large atypical lymphoid cells in this lymph node specimen.
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Diffuse large B cell lymphoma under high power showing cells that have moderate to abundant cytoplasm, round to irregular nuclear contour, vesicular nuclear chromatin and one to multiple nucleoli. Scattered small mature lymphocytes are seen. Green arrows = atypical lymphocytes; yellow arrows = small lymphocytes.
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Gallium scans of a patient diagnosed with small, noncleaved cell lymphoma (SNCCL). These scans show a prominent area of increased uptake in the right cervical region that is suggestive of a gallium-avid tumor.
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Sagittal magnetic resonance image (MRI) section of the neck area in a patient diagnosed with small, noncleaved cell lymphoma (SNCCL) (same patient as in Image 5). This image shows a large mass invading the cervical spine with epidural encroachment that also correlates with the site of the tumor in the gallium scan in Image 4. MRI was performed to rule out cord compression.
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2-Dimensional (2-D) flow cytometry. These images demonstrate the highlighted cells to be CD5 negative, CD23 negative, as well as lambda negative. The cells are typically CD19+, CD20+, CD22+, and CD10+.
Tables
| Stage | Definition |
| I | Only a single lymph node region is involved. |
| IE | A single extralymphatic site or organ is involved. |
| II | Two or more lymph node regions are involved on the same side of the diaphragm. |
| IIE | A single extranodal site and adjacent nodes are involved. |
| III | Nodal regions on both sides of the diaphragm are involved. |
| IIIE | Stage III, plus a single extranodal site is involved. |
| IIIS | Stage III, plus spleen involvement |
| IIISE | Stage III, plus a single extranodal site and spleen are involved. |
| IV |
Liver, brain, or bone marrow involvement
Diffuse or disseminated involvement of one or more extralymphatic organs |
|
A or B classification |
The disease is classified as "B," if B symptoms (eg, fevers, night sweats, or unexplained weight loss >10%) is present. If none of these symptoms are present, the disease is classified as "A." |
| Before HAART | After HAART | |
| Incidence of NHL per 1000 person-years | 29.6 | 6.5 |
| Proportion of PCNSL | 28% | 17% |
| Intermediate grade NHL | 33% | 49% |
| High-grade NHL | 38% | 19% |
| Patients receiving chemotherapy | 54% | 72% |
