The rate of hematological malignancies, including non-Hodgkin's lymphoma and Hodgkin's lymphoma, is increased in patients with HIV infection [1,2]. Previous reports have shown the feasibility and safety of autologous hematopoietic stem-cell transplantation (HSCT) in patients with HIV-associated lymphoma [3–5]. Allogeneic stem-cell transplantation is a well established curative procedure for patients with hematologic malignancies. Before the introduction of combination antiretroviral therapy (cART), allogeneic HSCT was not successful in the setting of HIV infection, mainly due to severe infectious complications. Since survival has improved considerably in the cART era, few cases have successfully undergone allogeneic HSCT together with cART since 2000 [6–9]. Moreover, the use of a CCR5 mutated stem-cell source in a patient with acute myeloid leukemia (AML) has shown the possibility of controlling the HIV infection without cART . However, experience of allogeneic HSCT in this population is still scarce, and short and long-term outcomes remain less well known in HIV-infected patients.
We report the Spanish experience treating HIV-infected adult patients with high-risk hematological malignancies with allogeneic HSCT which gathers one of the largest series reported.
Patients, materials, and methods
The study population included all consecutive HIV-infected adults patients with high-risk hematologic disease who underwent allogeneic HSCT between 1999 and 2018 in five Spanish centers within Grupo Español de Trasplante Hematopoyético y Terapia Celular. All patients provided informed consent and the study was approved by each institutional ethical review board.
Conditioning regimen and the donor source were selected according to clinical criteria, considering the type of hematologic malignancy, stage of disease and comorbidity index . Patients were housed in high-efficiency particle air filtered rooms. Prophylaxis against Pneumocystis jirovecii consisted of cotrimoxazole (320/1600-mg sulfamethoxazole/trimethoprim) as per center protocol. Antifungal prophylaxis was performed with micafungin or azoles per center protocol. Acyclovir was used as antiherpesvirus prophylaxis. Galactomannan testing and cytomegalovirus (CMV) PCR analysis were performed twice weekly for preemptive treatment. Epstein–Barr virus PCR analysis was performed every other week until day + 100 or indefinitely for those with active graft-versus-host disease (GVHD). All blood products were irradiated and leukocyte-depleted. Granulocyte colony-stimulating factor was administrated according to conditioning regimen and donor source.
The cART regimen given during hematopoietic cell transplant (HCT) was determined by each consulting infectious disease team and was intended to be maintained throughout all the HSCT procedure.
Laboratory monitoring and methods
Plasma HIV RNA was measured with a real-time HIV-1 real time-PCR assay from 2006 to 2009, with a lower limit of detection of 30 copies/ml, and either an Abbott RealTime HIV-1 assay (Abbott Molecular, Abbott Park, Illinois, USA) since 2009, with a lower limit of detection of 40 copies/ml or Versant HIV kPCR (Siemens, Munich, Germany) with a lower limit of detection of 37 copies/ml. T-cell subsets were measured using an in-house flow cytometry assay for each center.
Overall survival (OS) and event-free survival (EFS) were defined as primary endpoints. Engraftment, nonrelapse mortality (NRM) and disease relapse or progression were established as secondary endpoints. Myeloid engraftment was defined as an absolute neutrophil count of 0.5 × 109/l or greater for 3 consecutive days. Platelet engraftment was defined as a platelet count of 20 × 109/l or higher, without transfusion support for 7 consecutive days. Patients who survived more than 30 days after transplantation and who failed to achieve myeloid engraftment were considered graft failures. NRM was defined as death from any cause without previous disease relapse or progression. EFS was defined as the time from transplantation to disease relapse or progression, retransplantation because of graft failure, or death from any cause, whichever occurred first. OS was defined as the time from transplantation to death from any cause, and surviving patients were censored at last follow-up. Response to therapy before and after transplantation followed the National Cancer Institute criteria, revised by the International Working Group in AML. Acute GVHD and chronic GVHD were scored according to the established criteria. Follow-up of patients was updated in November 2018. Overall and event-free survival were calculated with Kaplan–Meier curves with SPSS. Cumulative incidence of relapse, NRM and GVHD were calculated using a competing risk model with R Studio version 1.1.423.
Twenty-two patients underwent allogeneic HSCT procedures for treatment of high-risk hematologic malignancies (Table 1). The median age at time of transplantation was 44 years (range, 30–57), 77% of the patients were men.
The underlying malignancies included non-Hodgkin lymphoma (n = 9), Hodgkin lymphoma (n = 2), AML (n = 7), acute lymphoblastic leukemia (n = 2), hemophagocytic lymphohistiocytosis (n = 1), and primary myelofibrosis (n = 1). Hematopoietic cell transplant age-comorbidity index was 0–2 in 67% of the cases . Donor was an human leukocyte antigen (HLA)-identical sibling in 11 cases, a matched unrelated donor in five (one of them with a mismatch in HLA-C), an HLA-haploidentical relative in four, and a single cord blood unit in two, one supported by CD34+ cells from third party HLA-mismatched donor (haplo-cord HSCT). Peripheral blood was the graft source in 86% of the cases. Conditioning regimen was myeloablative in 11 cases and nonmyeloablative in 11 cases. Two patients received a sequential conditioning strategy and were transplanted in aplasia. GVHD prophylaxis was provided according to graft and donor source (Table 1). Cyclosporine A with methotrexate was used in 41% of the cases. High-dose posttransplant cyclophosphamide was used in all HLA-haploidentical transplants.
One patient died on day 6 after transplant without evidence of myeloid engraftment. One patient with myelofibrosis experienced primary graft failure and died of graft failure-related complications. The remaining 20 patients achieved engraftment. Cumulative incidence of neutrophil and platelet engraftment was 91 and 86%, respectively. Median time to neutrophil engraftment was 14.5 days (range, 11–22), and median time to platelet recovery was 20.5 days (range, 6–480 days).
HIV infection characteristics and antiretroviral therapy
At the time of allogeneic transplantation, all patients had been receiving suppressive cART for a median of 6 years (Table 2). Most patients received efavirenz or raltegravir-based cART regimens during and after HSCT. cART was temporally stopped in two patients due to significant mucositis. Two patients showed cART interactions. Patient 10 presented neurotoxicity and hepatotoxicity associated with interactions of cART with tuberculostatics which had been started due to tuberculous meningitis. Toxicities resolved after reduction of tuberculostatics. Patient 12 showed early posttransplant fatal renal failure and rhabdomyolisis due to interaction between darunavir/ritonavir and tacrolimus.
At the time of transplantation, two patients showed detectable plasma HIV RNA (patients 10 and 13). Patient 13 showed poor adherence to cART together with the accumulation of multiple resistance mutations (Mut TI: 41L, 44D, 74V, 103S, 184V, 190A, 210W, 215T, Mut P: 54V, 62V, 63P, 71T, 82A, 93L, Mut HR1 36D) which caused the switch of cART scheme accordingly. Relapse of the underlying hematological disease was the final cause of death. Patient 18 required a switch in cART 3 months after transplant due to lack of efficacy with persistence viral replication at last follow-up. All other patients showed undetectable plasma HIV RNA at last follow-up.
Toxicities and infections after hematopoietic stem-cell transplantation
Early posttransplant toxic complications not related to cART included grades II–III mucositis (27%), grades I–II hepatotoxicity (14%), and reversible microangiopathic hemolytic anemia due to tacrolimus (9%) (Table 1). Patient 9 (myelofibrosis) showed primary graft failure with subsequent pulmonary aspergillosis. Patient 12 presented secondary graft failure due to CMV reactivation, followed by hematological relapse. There were no cases of hepatic venooclusive disease. Significant infectious complications were frequent. Sixteen out of 21 patients presented multiple infectious complications after HSCT, most of them from viral origin. Causes included: CMV reactivation (50%), CMV disease (9%), herpes simplex virus disease (9%, one case of encephalitis), BK virus hemorrhagic cystitis (18%), human herpes virus-8 Kaposi sarcoma (one case), Adenovirus hemorrhagic cystitis and colitis (one case), Parainfluenza virus pneumonia (one case). Bacterial infections occurred in 31% of the patients (neumonia = 1, bacteriemia = 4, clostridium difficile colitis = 2). Two patients presented fatal invasive pulmonary aspergillosis (9%), and one patient presented Candida esophagitis. Patient 10 showed disseminated tuberculosis 8 months after HSCT controlled with antituberculous therapy.
Cumulative incidence of grades II–IV acute GVHD at day 100 was 44% [95% confidence interval (CI), 34–77%]. Six patients showed grades III–IV acute GVHD, all of which resolved with immunosuppressive therapy. Moderate/severe chronic GVHD rate at 24 months was 41% (95% CI, 24–69%).
Relapse, survival, and mortality
With a median follow-up of 65 months (8–112), OS and EFS were 46% (95% CI, 24–68, Fig. 1). NRM was 14% at 12 months and 31% at 60 months. Relapse rate was 24% at 24 months (Fig. 2).
Causes of death included infections (50%), relapse (43%), and toxicity (7%). Among the six patients who died due to infections, three had severe chronic GVHD and were under immunosuppressive therapy. Among the six patients who died due to relapse, one exhibited uncontrolled viral HIV load secondary to poor antiretroviral therapy adherence and multiple resistance mutations, followed by relapse of the underlying hematological disease.
HSCT has been increasingly included in the treatment strategy for HIV-infected patients with hematologic malignancies, especially in the autologous setting [4,5]. However, allogeneic HSCT has not been routinely considered in HIV-infected patients and cumulative experience in this population is still scarce. The successful control of HIV viremia with cART over the years has allowed in part the extension of its use.
The present retrospective study includes one of the largest series of HIV-positive patients with high-risk hematological malignancies treated with allogeneic HSCT. Of note, a significant proportion of patients were transplanted using nonrelated or alternative donors including haplo-cord and HLA-haploidentical donors (50%). Engraftment was achieved in all cases except for one case with early toxic death and another with high risk of graft failure (primary myelofibrosis). As previously reported, allogeneic HSCT achieves long-term control of the hematological disease in this population as observed in non-HIV-infected patients [7,12]. Results significantly improved over the years, particularly after the introduction of effective antiretroviral therapy that decreased significantly the rate of death due to severe infectious complications . In our series, one patient with poor antiretroviral therapy adherence and hence high HIV load throughout the transplant process including the posttransplant period, not only presented CMV disease but also showed hematological relapse. HIV-infected donor lymphocytes in the context of persistent viral replication may have their normal function impaired and therefore graft-versus-leukemia effect might have been absent in this case.
Thorough analysis of posttransplant complications comprise small unicentric reports [8,9]. A recent matched-pair registry analysis showed significantly higher rates of nontuberculosis Mycobacterium and CMV infection in HIV patients than those without HIV infection after allogeneic HSCT . On the other hand, there was no difference in intubation, sepsis, bacteremia, acute GVHD, and early mortality. However, only in-hospital complications were analyzed, and mortality and complications after hospital discharge were not assessed. In our series, early posttransplant end-organ complications due to toxicity were not increased in a population mainly transplanted using reduced conditioning regimens. Although most of the patients managed to maintain cART throughout the transplant process, significant interactions were seen in two cases. One case showed interactions between antituberculous therapy and cART which was manageable with dose adjustment of antituberculous drugs. On the contrary, severe renal failure and rhabomyolisis produced by the combination of ritonavir and tacrolimus was fatal in another case. As previously reported and reviewed, protease inhibitors should be actively avoided because of potential drug–drug interactions with immunosuppressants and other commonly used drugs during and after HSCT [14,15].
Significant infectious complications were frequent, especially of viral origin. Infections occurred mainly early after transplant, however infections were the final cause of late death in 75% of nonrelapse deaths in the context of active GVHD. Although case–control registry studies reported similar nonrelapse mortality rates between HIV-infected and noninfected patients after autologous HSCT , infection rates are significantly increased in HIV-infected patients in the autologous HSCT setting, not only in the early posttransplant period but also in the long-term follow-up . Similarly, infections after allogeneic HSCT might be increased in HIV-infected patients, especially if significant GVHD is present. Nevertheless, toxic mortality was not increased due to infectious complications as main cause. In this series, a significant proportion of patients who died due to infections had active chronic GVHD. In fact, GVHD remains the main cause of nonrelapse morbidity and mortality after allogeneic HSCT, especially those resistant to glucocorticoid treatment with a dismal long-term prognosis primarily due to infections associated with the severe immune system impairment produced by potent immunosuppressive therapy . Thus, HIV-infected patients should be considered a particular high-risk population and receive close monitoring together with adequate antiinfectious prophylaxis, especially in the setting of immunossupresive therapy for GVHD. Furthermore, alternative glucocorticoid sparing strategies should be considered whenever possible to prevent long-term profound immunosupression. Association of therapies such as extracorporeal photopheresis or new targeted drugs should be taken into account promptly in this particular setting, especially with resistant/persistent GVHD.
The retrospective nature of this study account for the main limitation of the present analysis. Patients had different underlying diseases, and were treated over a period in which transplant protocols and GVHD prophylaxis have changed. However, in the context of HIV infection and allogeneic HSCT, the inclusion of patients is limited due to the historical restriction of this procedure in HIV-infected patients, and large series are not available . Considering these limitations, the present experience gathers one of the largest series of HIV-infected patients with allogeneic HSCT from centers of one country that contributes to the field. Our data suggest that allogeneic HSCT in patients with HIV infection is feasible, and provides long-term control of underlying hematological malignancy, comparable with non-HIV-infected patients. However, it is limited by the risks of GVHD and severe infectious complications in the setting of immunosuppressive therapy. Interactions of antiretrovirals with immunosuppressants and other frequently used drugs in the transplant setting should be carefully avoided and monitored. Experienced centers with a multidisciplinary approach are required to ensure appropriate approach of the particular issues concerning HIV patients. Although intriguing reports show a striking decrease in HIV reservoir after allogeneic HSCT even using grafts wild type CCR5, suggesting among others a graft-versus-HIV reservoir effect [19,20], in light of the present results, allogeneic HSCT is far ready to be used in the patients with HIV who do not have a standard indication for allogeneic transplantation for treatment of underlying malignancy.
Author contributions: Conception and design: M.K., R.B. and P.B. Provision of study materials or patients: all authors. Collection and assembly of data: M.K., R.B. and P.B. Data analysis and interpretation: all authors. Article writing: M.K. and R.B. Final approval of the article: all authors.
The work was partially supported by the Ministry of Economy and Competitiveness ISCIII-FIS grants PI11/00708, PI14/01731 and RD12/0036/0061, co-financed by ERDF (FEDER) Funds from the European Commission, ‘A way of making Europe’, as well as grants from the Asociación Madrileña de Hematología y Hemoterapia (AMHH), Fundación Mutua Madrileña (FMM) and the American Foundation for AIDS Research (amfAR) through the ARCHE program.
Conflicts of interest
There are no conflicts of interest.
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* Mi Kwon and Rebeca Bailén contributed equally to the article.