First case of successful allogeneic stem cell transplantation in an HIV-patient who acquired severe Aplastic Anemia

Abstract

We report on the first successful allogeneic stem cell transplantation (SCT) in an HIV-infected patient with severe aplastic anemia (SAA) performed at a tertiary care institution. Highly active antiretroviral therapy (HAART) was administered until transplantation and restarted 34 days later with sustained virological response. The patient did however develop a rapid rise in HIV load during the interruption of HAART associated with an acute febrile illness. Due to the extended period between the onset of SAA until SCT, the posttransplant course was complicated by bacterial infections. Stage two skin GvHD, but no AIDS-defining opportunistic diseases were experienced. Neutrophils recovered to >0.5/nL on day +18 and the CD4 count reached 250/μL on day +71 and >500/μL on day +182. The patient is in good condition with an ECOG score of 0 twelve months after transplantation. This report demonstrates the feasibility of allogeneic stem cell transplantation in the HIV setting.

A 34 year-old HIV-infected man was referred to our hospital in July 2005 with a four week history of breathlessness on exertion, malaise, multiple hematoma and gingival bleeding. He was in CDC stage A3 with a nadir CD4 count of 192/μL. He had regularly taken HAART as an outpatient for 50 months, last with Tenofovir (TDF, 300 mg qd), Emtricitabine (FTC, 200 mg qd) and Ritonavir-boostered (100 mg bid) Fosamprenavir (FPV, 700 mg bid). His CD4 count hereunder was at 314/μL and the viral load below 400 copies/mL. He did not receive any other medication. His referring physician had found pancytopenia (hemoglobin 6.7 mg/dL, WBC 1.8/nL, neutrophiles 0.47/nL, platelets 12/nL) and stopped antiretroviral therapy as he suspected drug-induced toxicity. Bone marrow cytology and histology (Figure 1) showed a highly reduced hematopoiesis in all three lineages with a cellularity of 5%. The patient required erythrocyte and platelet transfusions and intravenous antibiotics for intermittent bacterial infections. Serologies were positive for CMV (IgG positive, IgM/IgA negative), but negative for hepatitis C, HHV-6, and parvovirus B19. Several blood samples were tested positive for HHV-8 by PCR. CT scans revealed multiple enlarged axillary, cervical, intrathoracic and intraabdominal lymph nodes all less than 2 cm in diameter. Biopsies of cervical and axillary lymph nodes showed only unspecific, HIV-associated lymphadenopathy, but no signs of either NHL or multicentric Castleman’s disease. The patient was given ex juvantibus Cidofovir treatment, since a disseminated HHV8-infection was considered a possible explanation for the pancytopenia. HHV-8 PCR remained positive and pancytopenia persisted, thus Cidofovir was discontinued after 4 weeks. Two weeks later, the patient had to be readmitted due to sudden-onset fever of up to 40°C which was accompanied by diarrhoea, nausea and abdominal cramps. The C-reactive protein (CRP) peaked at 23 mg/dL. Empirical antibiotic therapy with Imipenem resulted in remission of fever and CRP within days without any specific finding in blood, urine, sputum and stool cultures. Eight weeks after the discontinuation of HAART, a new combination therapy was started with Abacavir (ABC), Lamivudin (3TC) and Ritonavir-boosted Saquinavir (SQV). Pausing the antiretrovirals for 2 months did not improve pancytopenia and thus a toxic genesis became increasingly unlikely, particularly because the patient had been on the same HAART regimen for many years before developing SAA. The renewed antiretroviral treatment reduced HIV load from 644.000 to 690 copies/mL within one month (Figure 2C).

Figure 1.Photomicrographs show hypocellular bone marrow before (a) bone marrow transplantation and regenerating hematopoeisis and normal cellularity after bone marrow transplantation (b).

Figure 2.Haematology, clinical chemistry and HIV-therapy. A: Hematological work up shows successful engraftment and improvement of pancytopenia. Neutrophiles reached values < 0.5/nL on day +18 and finally were 10-fold higher than before BMT. Platelets recovered concurrently. B: Clinical chemistry before and after BMT. C: HIV-PCR, CD4 count, HHV-8 PCR and HIV-therapy. HIV load was rapidly elevated in the therapy-free interval day 0 until day +14. After reintroduction of HAART, HIV load was under the limit of detection from day +138. CD4 count reached pretransplant level after the neutropenic period. Qualitative HHV-8 PCR became negative after BMT.

However, bone any marrow aplasia persisted. The Neutrophile count at this stage was at 0.38/nL, leaving the patient below 0.5 neutrophiles/nL for several months (Figure 2A). FACS-staining had excluded paroxysmal nocturnal hematuria (PNH). Thus, the diagnosis of severe aplastic anemia (SAA) was established.1 There is no published experience with conventional immunosuppressive therapy (IT) using antilymphocyte globulin (ALG) in combination with cyclosporine (CsA) and/or steroids in HIV-infected patients, which is the standard therapy for AA. The young age, the good clinical condition before the development of SAA, the requirement for extended immunosuppression when applying IT, the possibility of a truly curative treatment with allogeneic BMT and decreased chances of success by delaying it let us to prefer the latter.5 We consented with the patient to treat him with an allogeneic stem cell transplantation. He had no siblings, thus a search for an HLA-matched unrelated donor (MUD) was initiated (day –37). Two weeks later (day –23), a 10/10 alleles HLA-matched, CMV-seropositive, male donor was identified and the transplant could be scheduled for November 2, 2005 (day 0). HAART was paused on day 0 to avoid potential drug interactions. The conditioning regimen included fludarabine (30 mg/m on days –6 through –3) and cyclophosphamide (60 mg/kg on days -3, -2). The unmanipulated stem cell graft from G-CSF-mobilized peripheral-blood contained 7×10 CD34 cells/kg body weight. Graft-versus-Host-Disease (GvHD) prophylaxis included rabbit anti-thymocyte globulin (ATG) (10 mg/kg on days –5 through –2), cyclosporine A i.v. (target level 180 – 250 ng/mL), and methotrexate (MTX) (15 mg/m day 1, 10 mg/m days +3, +6). The first week after transplantation was clinically uneventful, however CRP increased to 25 mg/dL and the patient was given granulocyte transfusion on day +7 and day +9. On day + 11, he developed SIRS, atrial fibrillation, pericardial and bilateral pleural effusion as well as pulmonary edema necessitating mandatory ventilation on day +14. On day +18, neutrophils regenerated to >0.5/nL after an extensive period of neutropenia of total 70 days. On day +21 he developed a maculopapular rash compatible with a stage two skin GvHD, which promptly resolved to therapy with 100 mg prednisolone. The patient slowly improved clinically, but his CRP remained high around 10 mg/dL (Figure 2B). Interestingly, HIV viral load rapidly rose to 6.8×10/mL after transplantation (Figure 2 C). At that time, he developed an unclear neurological disease with remarkable myocloni, accompanied by high fever. After extubation on day +27, the patient presented dysphagia and a hoarse voice due to paresis of cranial nerves IX, X and XII. Repeated MRIs and lumbar punctures showed a high HIV load in the CSF without any other specific findings. We assumed critical illness polyneuropathy of the affected cranial nerves or HIV reactivation with an associated neurological disease as differential diagnosis. As a result of dysphagia, the patient had chronic aspiration and bronchiolitis which explained the elevated CRP. Antiretroviral therapy was reintroduced with Enfurvitide (T20) s.c., Zidovudine (AZT) i.v. on day + 34 (after a gastro-duodenal feeding tube was installed, this was changed to Zidovudine p.o. and later to Stavudine (d4T) p.o., Emtricitabine (FTC) and Abacavir solution) resulting in a prompt 4-log reduction of the viral load (Figure 2C). The normalization of blood counts as a result of the haematological recovery is shown in Figure 2A. Control bone marrow aspirations showed normal morphology and a 99% donor chimerism. The CD4 count reached >0.25/nL on day +71 and >0.5/nL on day +182 on continuing GvHD-prophylaxis/therapy. On day +120, the patient was transferred to rehabilitative care until day +158. He is currently being treated on an outpatient basis. No opportunistic infections were experienced so far, and HIV therapy can be administered effectively. The patient recovered from his cranial neuropathy is well 8 months after transplantation.