CBF

(also see mesenchymal stem cells, transfusion, autoimmune diseases, regulatory issues, acute radiation injury, adverse events during bone marrow and PBSC donation)

v. HIV Positive Patients

  1. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. Hütter G, Nowak D, Mossner M, Ganepola S, Müssig A, Allers K, Schneider T, Hofmann J, Kücherer C, Blau O, Blau IW, Hofmann WK, Thiel E. N Engl J Med. 2009;360:692-698. Full Text

Infection with the human immunodeficiency virus type 1 (HIV-1) requires the presence of a CD4 receptor and a chemokine receptor, principally chemokine receptor 5 (CCR5). Homozygosity for a 32-bp deletion in the CCR5 allele, observed in approximately 1% of the white population, offers a natural resistance to HIV infection. The authors transplanted stem cells from a donor who was homozygous for CCR5 delta32 in a patient with acute myeloid leukemia (AML) and HIV-1 infection. The patient has remained without viral rebound 20 months after transplantation and discontinuation of antiretroviral therapy.

The patient was a 40-year-old male with newly diagnosed AML in whom HIV-1 infection had been diagnosed more than 10 years earlier. The patient had been treated with HAART for the previous 4 years. At the time that AML was diagnosed, the patient’s CD4 T-cell count was 415/m3, and HIV-1 RNA was not detectable (stage A2 according to classification by the Centers for Disease Control and Prevention). Initial treatment of the AML consisted of two courses of induction chemotherapy and one course of consolidation therapy. During the first induction course severe hepatic toxic effects developed and renal failure occurred. Consequently, HAART was discontinued, leading to a viral rebound (6.9 x 106 copies of HIV-1 RNA/mL. The therapy was resumed and 3 months later HIV-1 RNA was undetectable.

Seven months after presentation AML relapsed and the patient underwent allogeneic stem cell transplantation with peripheral blood stem cells from an HLA-identical donor who had been screened for homozygosity for the CCR5 delta 32 allele. HAART was administered until the day before the procedure and engraftment was achieved 13 days after the procedure. The AML relapsed 332 days after transplantation and a second transplant from the same donor was performed. The patient was in remission at month 20 of follow-up.

Although discontinuation of antiretroviral therapy typically leads to a rapid rebound of HIV load within weeks, in this patient, no active replicating HIV could be detected 20 months after HAART had been discontinued. Even after prolonged HAART, the persistence of HIV-1 in various anatomical compartments can be observed in patients without detectable viremia. In particular, the intestinal lamina propria represents an important reservoir of HIV-1, and genomic virus detection is possible in patients without viremia. In this patient HIV-1 DNA could not be detected in the rectal mucosa following a rectal biopsy performed 159 days after transplantation.

In addition HIV-1 virus could not be detected in peripheral blood or bone marrow as assessed with RNA and proviral DNA PCR assays.

In the past, there were several attempts to control HIV-1 infection by means of allogeneic stem cell transplantation without regard to the donor’s CCR5 delta32 status, but these efforts were not successful.

[Comment: Since only about 1% of the white population is homozygous for the CCR5 delta32 allele, it would seem that this approach would not have wide-spread applicability because it is typically true that only a small number of potential donors can be identified for a given patient in need of a transplant. It is obvious that it will never be likely that one of these few available HLA matched donors would be homozygous for the CCR5 delta32 allele. The only practical solution to this problem (at least in the short term) is to use cord blood stem cells for transplantation. This is true because stringent HLA matching between donor and recipient is not required for successful transplantation. It is feasible to test a cord blood banks’ inventory of cryopreserved stem cell products for the CCR5 delta32 allele and, with a rather small sized inventory of such products, one may be able to find adequately matched units for HIV+ patients in need of a transplant.]

  1. Unrelated cord blood transplantation for a human immunodeficiency virus-1-seropositive patient with acute lymphoblastic leukemia. Tomonari A, Takahashi S, Shimohakamada Y, Ooi J, Takasugi K, Ohno N, Konuma T, Uchimaru K, Tojo A, Odawara T, Nakamura T, Iwamoto A, Asano S. Bone Marrow Transplant. 2005;36:261-2.

The authors describe the first case of an HIV-infected patient with ALL who underwent umbilical cord blood transplantation (UCBT).

A 23-year-old woman was confirmed as seropositive for HIV. She was diagnosed as Philadelphia chromosome-positive ALL and achieved hematological complete remission after two courses of chemotherapy. She received HAART (highly active antiretroviral therapy) during and after the chemotherapy and her HIV-RNA level continued to be below detectable levels.

She underwent a UCBT from an unrelated donor with mismatches at two loci. The conditioning regimen included 12 Gy TBI and 120 mg/kg cyclophosphamide. GVHD prophylaxis consisted of cyclosporine and methotrexate. HAART was discontinued on day +28. On day +33 her WBC remained below 100/µl and all bone marrow cells were of recipient origin. Therefore, at day +40 a second UCBT was performed from an unrelated donor with a one-locus mismatch at HLA-DR. The conditioning regimen included 40/m2 fludarabine for 3 days. Cyclosporine was administered for GVHD prophylaxis. Neutrophil engraftment was achieved on day +27 and full donor chimerism was documented on day +28.

The HIV-RNA level increased to 3 x 106 copies/ml on day +38 but returned to below detectable levels from day +195, and the CD4 count increased to above 300/µl from day +170. An RT-PCR analysis showed continuous negative test results for the p190BCR-ABL transcript until the last follow-up evaluation at 15 months post UCBT.

The authors state that these results suggest that UCBT is feasible for HIV-infected patients on HAART, although further studies are warranted.

  1. Treatment of human immunodeficiency virus-related lymphoma with haematopoietic stem cell transplantation. Molina A, Zaia J, Krishnan A. Blood Rev. 2003;17:249-58.

The advent of highly active antiretroviral therapy (HAART) and its co-administration with chemotherapy in patients with human immunodeficiency virus (HIV)-related lymphoma has lead to the exploration of potentially curative combination chemotherapy and myeloablative therapy followed by autologous haematopoietic stem cell transplantation (ASCT). Applying the same principles used for patients with HIV-negative aggressive lymphoma, in 1998 the authors developed a program of high-dose therapy and ASCT for patients with HIV-related lymphoma and Hodgkin's disease. These studies have primarily included patients with chemosensitive lymphoma in relapse or first remission with poor-risk features at diagnosis. Filgrastim (G-CSF)-primed peripheral blood stem cell mobilization and apheresis have been successful while patients were receiving HAART and chemotherapy.

The authors report the results of ASCT in 19 patients with HIV-related lymphoid malignancies, representing the largest single-institution experience reported to date. Most patients received a chemotherapy-based conditioning regimen consisting of high-dose carmustine, etoposide and cyclophosphamide. Early infections, namely bacteremias and neutropenic fever were similar to those observed in the HIV-negative transplant setting. Opportunistic infections were rare and easily treatable. There were three early deaths, two from relapsed lymphoma and one from multi-organ failure in an older patient. The remaining 16 patients are alive and in remission.

The authors conclude that ASCT is well tolerated, can result in long-term remissions, and is potentially curative in selected HIV-related lymphoma patients with chemosensitive relapse and high-risk disease in first remission defined by the age-adjusted International Prognostic Index criteria (i.e., two or three of the following: elevated LDH, advanced stage, and poor performance status). Acquisition of resistance to HAART remains as a potential problem for HIV-positive patients who are cured of their lymphoma.

  1. Should HIV-positive patients with lymphoma be offered stem cell transplants? Krishnan A, Zaia J, Forman SJ. Bone Marrow Transplant. 2003;32:741-8.

Advances in effective antiretroviral therapy for HIV infection have made high-dose therapy and autologous stem cell transplantation possible in patients with HIV-associated lymphomas. Regimen-related toxicity is not significantly increased when antiretroviral therapy is combined with high-dose chemoradiotherapy. Durable engraftment can be seen with autologous stem cell rescue. Infectious complications can be managed with a combination of surveillance and prophylaxis. Long-term remissions of these high-risk lymphomas can be achieved with this approach. This suggests that patients with HIV-associated lymphomas should be considered for autologous transplantation in a manner similar to HIV-negative lymphoma patients.