Autologous stem cells transplant (ASCT) in HIV-positive individuals with a relapsed non-Hodgkins lymphoma (NHL) or Hodgkins disease (HD)
Svilen Konov, HIV i-Base
Abbreviations used in the article: ASCT-autologous stem cells transplant, CR-complete response, HD-Hodgkins disease, NHL-Non Hodgkins lymphoma, PBSC-peripheral blood stem cell transplantation, PR-partial response
The diagnosis and treatment of lymphomas in HIV-positive patients still poses significant challenges in clinical practice. Even though HAART has improved survival, lymphomas are still a major cause of morbidity and mortality.
For example, as a part of a broad study on survival rates among patients with particular cancer conditions in New York, Biggar et al. reported higher risk of mortality in HIV-positive patients with non-CNS related NHL between 1996 and 2000 compared to HIV-negative patients (95% CI: 1.6-2.2 and HR=1.9). These researchers concluded that with many cancers there remains an increased risk of dying within 24 months in people with AIDS compared with persons without AIDS who had the same cancers and these survival gaps can focus attention on opportunities to improve cancer care in people with AIDS. 
This article reports on the option for patients with non-refractory relapsed lymphoma of using autologous stem cell transplant (ASCT) which allows 2-3-fold higher dosing of chemotherapy, by providing a stronger defense against toxicity associated with these drugs.
Currently, in the UK, the standard of care for patients with lymphomas includes biopsy for diagnosis. Tissue samples are examined using flow cytometry to describe the clusters of differentiation and genetic examination for abnormal chromosome translocation. Modern genetic testing allows a sample to be tested against an array of 18 000 genes on a single glass chip.
The main difference between the Hodgkins disease (representing about 15% of all lymphomas) and non-Hodgkins lymphomas (about 85%) is the affected lymph cells. While HD affects the B-lymphocytes and is characterised by the presence of Reed-Sternberg cells, NHL can involve T-cells (including natural killer cells). Both diseases occur most commonly in lymph nodes above the collarbone, but HD is also more likely to appear in the mediastenum (especially in younger patients), while the NHL is more likely to appear in the mesenteric nodes as well. In addition, HD is more likely to present systemic B symptoms at the time of diagnosis.
The modern classification of lymphomas recognises that their clinical grouping (i.e. low grade, indolent, aggressive, etc.) is unsatisfactory and puts a particular stress on a combined definition of morphology, immunology, genetic features and clinical manifestation.
Treatment of lymphoma in HIV-positive patients
As different lymphomas have markedly different clinical behaviour, some recommendations emphasise that treatment decisions should be based on the specific lymphoid neoplasm, following the WHO classification shown in Table 1.
Table 1: WHO classification of lymphoid neoplasms
|I. Precursor B-cell neoplasm:|
|II. Mature (peripheral) B-cell neoplasms|
|B-cell proliferations of uncertain malignant potential|
|T-Cell and Natural Killer Cell Neoplasms|
|I. Precursor T cell neoplasm:|
|II. Mature (peripheral) T cell and NK-cell neoplasm:|
|T-cell proliferation of uncertain malignant potential|
|Hodgkins Lymphoma (Hodgkins Disease) (B Cell Origin)|
Source: http://www.lymphomainfo.net/nhl/classify.html Accessed on 21.05.2006
Treatment approaches include:
- Radiotherapy (commonly 4-6 weeks, ex: in adult Hodgkin̳, doses of radiation usually vary between 3,000 and 3,600 cGy to clinically uninvolved sites, and 3,500 to 4,400 cGy to regions of initial nodal involvement);
- Chemotherapy (most commonly CHOP-cyclophosphamide, adriamycin, vincristine, and prednisone, administered in cycles of 4 weeks, where the total treatment lasts for at least 6 cycles);
- Immunotherapy (monoclonal antibodies-rituximab, ibritumomab tiuxetan, tositumomab, 131I Lym-1;
- T-cell immunotherapy with polyclonal activation of T-cells with antibodies); and,
- A combination of the above mentioned treatments.
Bone marrow transplants and peripheral blood stem cells transplants are two newer treatments, that have been used either in combination with, or after, established treatment. Both treatments are steadily moving from the clinical trial area to mainstream therapy, including for HD and aggressive (often relapsed from chemotherapy) NHL.
The treatment of lymphomas, both relapsed and primary refractory, in patients with AIDS or HIV-infection poses a number of difficulties. These include:
- Limitations in individualising HAART (many patients have developed resistance to ARVs)
- Managing interactions with other medications used post-lymphoma therapy (antifungals, antivirals, etc.)
- Discordant immunological responses, and
- General weakness of patients immune systems.
There is also a perception of an insufficient evidence-base to offer autologous stem cells transplants (ASCT) to HIV-positive patients. Other reasons for ASCT exclusion are complex, but include availability of technology in the local oncology centre, availability of expertise of on performing the intervention (both apheresis and application of the collected material), cost, and sometimes, a conservative medical view (based on mainly pre-HAART era studies),
In practice, HAART has allowed broader and more aggressive therapeutic approaches, as patients have better haematological reserves and better tolerability to intensive chemotherapy. In addition, the development of ASCT technology has lead to decreased mortality, to the extent that transplantation is now sometimes used for older HIV-negative patients, as well as patients with comorbidities. Furthermore, the increased experience with HAART and antibiotic co-administration, allows researchers and medical professionals to reconsider the opportunities that ASCT interventions provide.
Data endorsement for ASCT in HIV-seropositive patients with relapsed or primary refractory disease
Recent studies, summarised in Table 2 clearly indicate that patients with AIDS/HIV-infection and relapsed or primary refractory lymphomas benefit from ASCT and its utilisation should be approached.
Table 2: Literature review of recent ASCT studies in HIV-positive patients
|No. of pts, disease types and disease status pre-transplant||CD34+ cells collected (x106/kg)||Median (range) no. of apheresis sessions||Day of engraftment median no:||CD4 count and viral load changes during high dose chemotherapy and autologous peripheral blood stem cell transplantation||Outcome|
|Campbell et al., 1999 |
|1 NHL Pre-transplant:CR||8.2||1||9||10||CD4 count: Baseline: Not available. At 13 months: 220 cells/mm3. VL: Baseline: 5000 copies/mL. At 13 months: 5000 copies/mL||CR alive at 15 months|
|Gabarre et al., 2000 |
|4 HD, 4 NHL. Pre-transplant: 3 CR, 2 PR, 3 Resistant||Mean 7.17 (range 4.5-17.6)||1 (1-4)||12 (9-18)||12 (9-23)||CD4 count: Baseline: Median 122 cells/mm3. VL: Undetectable in 7||5 CR 4 alive at completion of study|
|Molina et al., 2000 |
|2 NHL Pre-transplant: 2 CR||2 CR (at 20 and 28 months)|
|Krishnan et al., 2001 |
|2 HD, 7 NHL, Pre-transplant: 6 CR, 2 PR, 1 relapse||Median 10.6||1 (1-3)||11 (9-12)||10 (7-15)||CD4 count: Post PBSC: Median nadir 138 cells/mm3 (range 25-411 cells/mm3) at a median of 2 months. Recovery: Measured in 6 patients Returned to pretransplant levels by median 14 months (2-28 months). VL: Pre-treatment: Undetectable in all. Post PBSC: 6 pts rise in VL post PBSC, 3 VL remained undetectable. At 12 months post PBSC: Undetectable in 5 of 7 evaluable patients||7 CR, median follow up 19 months (range 12-36 months)|
|Re et al., 2003 |
|8 HD, 8 NHL. Pre-transplant: 15 relapsed or refractory, 1 PR||Assessable in 15, 12 adequate collection: median 6.8 (4.1-8.3), mobilisation failed in 3||2 (2-3)||10 (8-10)||13 (8-18)||CD4 count: Mean Baseline:236 cells/mm3 (Range 17-506), +1 month Post PBSC: 154 cells/mm3, +3 month Post PBSC: 93 cells/mm3, +6 months Post PBSC: 186 cells/mm3, VL Baseline: 5 Median 4,000 copies/mL (Range 690- 36,896) & in 11 undetectable. Post PBSC: Remained undetectable in 8 of 11||9 assessable, 7 CR, 2 PR, 2 relapses at +5 and +12 months, 6 alive and in CR after a median of 8 months (range 2-17 months)|
|Gabarre et al., 2004 |
|6 HD, 8 NHL||5 alive, 4 CR after a median of 25.5 months (range 14-49), 1 PD + 36 months|
|Serrano et al., 2005 |
|3 HD, 11 NHL. Pre-transplant: 10 CR, 4 PR||Median 4.7 (1.8-21.2)||1 (1-3)||16 (9-33)||20 (11-36)||CD4 count: No significant change during PBSCC (median 186 cells/mm3 versus 172 cells/mm3; p=0.349). Transitorily decreased after PBSC +12 months, no significant different before PBSC (200 cells/mm3 vs 172 cells/mm3; p=0.138). VL: Remained undetectable in 3 patients throughout stem cell collection and PBSC||8 CR. Median follow up 30 months (7-36 months)|
|Krishnan et al., 2005 |
|20 2 HD, 18 NHL. Pre-transplant: 6 CR, 5 PR, 9 relapse||Median 10.6||4||11 (9-23)||No data||CD4 count: Baseline: median 175cells/mm3 (25-1064). +6 months: nadir. +12 months: recovery to pretransplant levels, median 187 cells/mm3. +24 months: median 472 cells/mm3. VL: Baseline: 17 undetectable & in 3 ranged from 700-6500cp/mL. +12 months: 12 undetectable & 4 dectectable||17 alive. Median follow up 31.8 months (5.5-70)|
Gabarre et al  in France used ASCT combined with radiation and chemotherapy regimens in HIV-positive patients with Hodgkin disease and non-Hodgkin lymphoma. The study included 14 subjects both primary refractory and multiply relapsed. At reporting time, 6 months after treatment, the survival rate (according to the number of subjects who reported) was 43% .
A multi-centre study from Italy also followed a cohort of 16 patients with both refractory and relapsed conditions. Patients received BEAM (carmustine, cytarabine, etoposide, and melphalan) prior to ASCT. One patient did not undergo stem cells collection and three were unsuccessful in producing quality cells that would allow ASCT. After all treatments, nine patients had data for evaluation. Intent-to-treat analysis showed median disease-free survival was 11 months, with 8 patients achieving CR or PR after ASCT. The projected 2-year survival of the cohort is 39% .
One of the most recent studies is from Spain that also used BEAM as an initial regimen which defined CR as also including patients who have been on more than one line of chemotherapy prior to the ASCT, as well as patients with Burkitt-type lymphoma who achieved a CR after a second, more powerful therapy. All subjects, apart from one, were already in CR upon initiation of ASCT. Survival was 73% (disease free). One patient suffered from herpes zoster and another one from pulmonary aspergillus at time of reporting .
The most convincing results using ASCT for HIV-positive individuals with non-Hodgkin lymphoma is from Krishnan A and colleagues from the City of Hope National Medical Center, Duarte, California, US . The study has the longest follow-up with a median period of observation of 31.8 months. It included HIV-positive patients with non-Hodgkin lymphoma who failed to achieve CR after a standard dose of chemotherapy or had a chemosensitive relapse after an initial CR. The cohort included 20 patients with a median age of 44 (range 11-68) at ASCT. Median CD4 count when diagnosed with lymphoma was 174 cells/mm3 and viral load was 26,120 copies/mL. At study entry, 17 patients had an undetectable viral load and the other three ranged between 700 and 6500. 15 patients used PI-based HAART and the rest used NNRTI-based regimen. 17 received a chemotherapy-based regimen and 3 radiation-based. All patients were exposed to ASCT and were maintained on their HAART regimen. The disease free survival was impressive at 85%.
Studies with long-term follow-up (Krishnan A. et al) verify that ASCT can offer long-lasting remissions, and that it can be a potentially curative option for patients with a poor response (and therefore poor prognosis) from conventional therapy . HIV disease did not progress as a result of the transplants. Even though CD4 cells were still reduced six months month after therapy, they returned to the pre-transplant point about a year after the intervention.
Caveats to be considered include the difficulties at apheresis, and in particular the stem cell mobilisation. Individual ARV treatment regimens often need to be modified, in a way that minimises the risk of resistance after ACST. In this respect, AZT cannot be used both pre- and post-apheresis. Appropriate prophylaxis (for instance, oral acyclovir for a year after the transplantation to avoid herpes zoster complications) may reduce the risk of other opportunistic infections, although trimethoprim sulfamethoxazole cannot be used before apheresis .
These studies clearly show that although more data on the long-term follow-up, or on the dynamics of immune reconstitution after ASCT, are badly needed, there is adequate proof that ASCT is a feasible and beneficial treatment option for HIV-seropositive patients with HIV-related relapsed chemosensitive lymphomas, and this strategy should be offered as a therapeutic option.
This is particularly true if patients have stable HIV-infection, marked by low viremia to optimise the stem cells mobilisation and minimise risk of OIs. ASCT should be considered earlier after demonstration of chemotherapy sensitivity for those patients with first relapse or with primary refractory disease. 
In the UK, hospitals with experience and which can provide expert advice on the ASCT in HIV-seropositive individuals with NHL or HD are Chelsea and Westminster Hospital, Barts Hospital and Hammersmith Hospital.
High dose chemotherapy and ASCT is only likely to be effective in patients with relapsed lymphoma, whose lymphoma remain sensitive (non-refractory) to drug treatment. It is more likely to useful for Hodgkins disease, where most UK experience in HIV-positive patients has been reported (with low numbers of patients having successfully been treated at the Chelsea and Westminster, Barts and Royal London, and Royal Free Hospitals).
ASCT is less likely to be useful for NHL because of the approximate 40% mortality, half of which is attributed to resulting opportunistic infections, and half to the lymphoma itself not responding to chemotherapy; or from a relapse in CSF which is also unlikely to respond to treatment.
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- Krishnan A, Molina A, et al. Durable remissions with autologous stem cell transplantation for high-risk HIV-associated lymphomas. Blood. 2005; 105, 874-878.
- Gabbarre J, Azar N, Autran B et al. High dose therapy and autologous peripheral blood stem-cell transplantation for HIV-1 associated lymphoma. Lancet 2001; 355:1071-2.
- Serrano D, Carrion R, Balsalobre P et al. HIV-associated lymphoma successfully treated with peripheral blood stem cell transplantation. Exp Haem 2002; 33:487-494.
- Re A, Cattaneo C, Michieli M. et al. High dose therapy and autologous peripheral-blood stem-cell transplantation as salvage treatment for HIV-associated lymphoma in patients receiving highly active antiretroviral therapy. JCO 2003; 21: 4423-4427.
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- Gabbarre J, Marcelin AG, Azar N, et al. High-dose therapy plus autologous hematopoietic stem cell transplantation for Human immunodeficiency virus (HIV) related lymphoma: results and impact on HIV disease. Haematologica 2004: 89; 1100-8.
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