Autologous hematopoietic cell transplantation for HIV-related lymphoma: results of a single center (CIC725) matched case-control study

Introduction

Infection with human immunodefi ciency virus (HIV) is associated with a signifi cantly increased risk of cancer, including Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) even when patients are treated successfully with contemporary antiretroviral therapy [1, 2]. AIDS related malignancies remain a leading cause of mortality [3]. Before the introduction of highly active anti-retroviral therapy (HAART), HIV-infected patients were not candidates for standard, combination chemotherapeutic regimens because of the signifi cant risk of opportunistic infection and poor malignancy response rates [4]. Th erapy outcome in patients with HIV-related malignancies have improved since the improvement of HAART availability [5-8]. In the HAART era, treatment of HIV-related lymphomas with standard doses of chemotherapy became possible for HIV positive patients [9-14].
The role of autologous hematopoietic stem cell transplantation (ASCT) in the care of patients with HIV-related lymphoma, however, remains unclear. In the non-HIV setting, patients with relapsed refractory NHL and HL have benefits from treatment with high-dose chemotherapy and ASCT [15, 16]. Early pivotal studies come from Europe and the United States demonstrated safety and effi cacy the use of ASCT in the care of patients with high-risk, relapsed refractory HIV-related lymphoma [17, 18]. Th ese initial experiences were encouraging and spurred other investigators to study the use of ASCT for patients with lymphoma and HIV. Th e summary of the studies of high-dose chemotherapy followed by autologous hematopoietic cell transplantation in HIV-related lymphoma adapted from the Serrano et al. [19] is outlined in Table 1. Th e limitation of these studies is their retrospective nature with a large variety in patient population, status of the disease, conditioning regimen and HAART strategy. Th at is why the role of high-dose chemotherapy followed by ASCT in lymphoma patients with HIV is still a subject of controversy.
There is an urgent need for prospective comparative matched case-controlled studies to prove the safety and efficacy of ASCT in HIV-related lymphoma and their number is limited. There are three studies have been published that in one way or another meet the criteria prospective, comparative, matched case-controlled studies [26, 27, 28]. Here we report the early results of a single institution, EBMT center CIC725, matched case-control study. Th is was an observational trial designed to prospectively evaluate the safety and effectiveness of ASCT for patients with HIV-related lymphoma.

Patients and methods

Study design

Between January 2016 and October 2017, an observational study was conducted at Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, The First State I. Pavlov Medical University of St. Petersburg (CIC725). Seven patients with HIV-related NHL or HL were enrolled in a trial. An approval for the trial was issued by the University Institutional Review Board. All the patients signed an approved informed consent, in accordance with the Declaration of Helsinki. The data on twenty-eight non-HIV-infected lymphoma patients who underwent ASCT at the same time period (control group, n=28) were also collected to compare the effi cacy and safety of the procedure (1:4). The patients were matched for age at ASCT, disease status at ASCT, number of prior regimens of chemotherapy, time from lymphoma diagnosis to ASCT, conditioning regimen and tumor histology.

Eligibility criteria

The indications for ASCT included NHL or HL if they met standard transplant criteria. HIV positive patients were required to exhibit a viral load of <50,000 copies/ml, being free of overt opportunistic infections at the time of ASCT, and receiving HAART for more than 6 months.

Stem cell mobilization and conditioning regimen

For stem cell mobilization, the patients received cyclophosphamide (CY) at 4000 mg/m2 with hydration, and Mesna (15 mg/kg) before and 3, 6, and 9 hours aft er CY for uroprotection, or an alternative salvage chemotherapy to which the lymphoma was responding. Granulocyte colonystimulating factor (G-CSF) was administered at a dose of 10 μg/kg/day starting 2 days aft er the chemotherapy. Leukapheresis was performed since the white blood count (WBC) reached ≥0.5×109/L, a maximum of 3 harvests, until an intended number of 2×106 CD34+ cells/kg has been collected. In cases of poor stem cell mobilization (failed leukapheresis), bone marrow (BM) served as a source of hematopoietic stem cells (HSC) using a standard surgical procedure. Patients who met trial eligibility criteria underwent ASCT following a preparative regimen that consisted of modifi ed BEAM to BeEAM treatment where the carmustine 300 mg/m2 (day -6) was replaced by Bendamustine 160 mg/ m2/day at day -7, day -6. Etoposide 100 mg/m2 daily (days -5 to -2), cytarabine200 mg/m2 twice daily (days -5 to -2), and melphalan 140 mg/m2 (day -1) [29]. Patients underwent ASCT on day 0 and received growth factor, transfusion, and antimicrobial supportive care as per the respective institutional standards.
Autologous peripheral stem cells were thawed in a 37°C water bath and infused through the patient’s central venous catheter on transplantation day 0.

Clinical endpoints

This study was designed to assess the safety and tolerability of intensive chemotherapy and ASCT for the treatment of HIV-related NHL and HL. Th e primary end point for the trial was one-year OS aft er ASCT. The secondary endpoints were as follows: hematopoietic recovery and organ toxicity, transplant-related mortality (TRM), progression free survival (PFS), the cumulative incidence of relapse/progressionat 12 months aft er ASCT.
The patients underwent daily routine post-transplant blood tests from day 0 through the period of neutrophil recovery, and as per the respective institutional standards. The time to hematopoietic recovery was defi ned as the fi rst of day of >500 neutrophils/μL following nadir and time to platelet count >20,000/μL at the fi rst of day with no platelet transfusions for 2 preceding days. Post-AHCT toxicities were graded using the Common Terminology Criteria for Adverse Events, version 4. Microbiologically documented infections were classifi ed by clinical site, date of onset, and severity of the disease. Th e disease status was assessed in the patients before ASCT, at day +100 or earlier if signs of the disease re-appeared, and 1 year aft er ASCT. Responses of lymphoma to therapy were assessed using the Cheson criteria for determination of complete remission (CR), and CR+ partial remission (PR) rates at day +100 [30]. Th e data of tests for HIV status (CD4+ cells, viral load) were collected from the HIV Department where the patients were assigned and observed.

Statistical analysis

Survival estimates were calculated based on the Kaplan-Meier method. Differences between survival curves were assessed by the log-rank test. Potential baseline diff erences between the two groups were examined using the Mann-Whitney test for continuous variables or Fisher’s exact test for categorical variables. Patients who were alive at the time of analysis were censored at the last contact date. Overall survival was defi ned as the interval from day 0 ASCT to the death from any cause. Transplant-related mortality was defi ned as death occurring in a patient from causes other than relapse/progression. Progression free survival was defined as the  interval from day 0 ASCT to death, disease relapse, or progression.
The cumulative incidence of relapse/progressionwas defined as relapse or progressionoccurring in a patient the interval from day 0 ASCT to 12 months.

Results

Patient characteristics

A consecutive case-series of 7 HIV-group patients and 28 matched control group treated with ASCT between January 2016 and October 2017 were included. Patient, disease, and treatment characteristics for both groups are provided in Table 2. Both groups were comparable for all clinical and transplantation characteristics except for the higher proportion of male sex (p=0.03) in HIV-group, misbalance in type of lymphoma: presence of non-Hodgkin T-cell lymphoma and prevalence of Hodgkin lymphoma in control group.

One patient was diagnosed with HIV infection concomitant with the lymphoma diagnosis and started on antiretroviral therapy together with chemo. Meanwhile, six patients in HIV group had a long history of HIV infection before the lymphoma was diagnosed. Median time from the registration of HIV-positive status to lymphoma diagnosis was 1734 days (57.8 months). HIV status in study group at the moment of transplantation was as follows: HIV viral load was undetectable (100%); the median number of CD4+ cells was 265 cells/mcl; all the subjects received HAART. Neither patient had any planned or needed interruptions in their HAART during ASCT. All individual patient and HAART regimen have been consulted with the HIV specialist and changed the regimen before ASCT taking into account drug-drug interactions. Only in two patients before ASCT the modifi cation of the scheme HAART was required.
Six patients in HIV group received peripheral blood stem cell graft s, and BM was transfused in one case. The median transplanted HSC dose was 3.9×106 CD34+ cells/kg (range, 1.6-11.0). A median of 2 apheresis collections was performed (range, 1-3). A median of 3.4×106 CD34+ cells/kg (range, 2.6-6.0×106/kg) was transfused to the patients.

Engraftment

The median time to achievement of an absolute neutrophil count (ANC) of ≥0.5×109/L was similar for both groups: 14 days (range, 11-30 days) in HIV-infected group and 16 days (range, 10-30 days) in control group (Fig. 1a). The median time to achievement of an unsupported platelet count of ≥20×109/L was 15 days (range, 11-30 days) in HIV-infected group and 14 days (range, 11-30 days) in control group (Fig. 1b).

Toxicities

No fatal regimen-related toxicity occurred. Neither patient developed grade III or IV nausea or vomiting. Three patients developed oropharyngeal mucositis (3 cases – grade I-II, no one grade III). Tree patients experienced febrile neutropenia. Three patients had a documented bacteremia within 100 days post-ASCT (1 coagulase-negative staphylococcus, 2 Klebsiella pneumoniae). Comparative characteristics of non-hematologic toxicities (≤100 days post-ASCT) are listed
in Table 3.

Outcomes

With a median follow-up of 12 months (range, 1.2-20.7 months) in HIV group and 8 (1-20) months in control group, 2 patients died in control group; one of them died within 1 year of transplant. Relapse of the underlying disease was a cause of death in both cases. There were no registered events classifi ed as transplant-related mortality. Th e overall one-year survival (n=35) was 97.1%. Overall survival at 1 year was 100% in HIV group, 96.4% – control group, and were not significantly diff erent between the groups (Fig. 2a). At the time of transplant, 4 (57%) patients in HIV group and 17 (60.7%) patients in control group were in CR, three patients (42.8%) in HIV group and 8 (28.5%) patients in control group were in PR, whereas three (10.7%) patient in control group had active diseaseat the moment of ASCT after achieving a PR to salvage therapy. During the first year aft er ASCT, 1 (3.6%) patient in control group had relapse of the disease and died on day +73 and 1 patient (14.2%) in HIV group with HL where the anticancer immunotherapy was initiated. Th e probability of 1-year PFS for all patients was 88.6%, in HIV group – 85.7% and 89.3% for control group (p=0.98) (Fig. 2b). Th e cumulative incidence of relapse/progression at 1 year was 11.4%. Th e cumulative incidence of relapse/ progression was 14,3% in HIV group and did not differ from the control group 10.7% (p=0.98).

Discussion

Wide application of effective anti-HIV therapy allowed patients with HIV-related lymphoma to benefi t from standard chemotherapeutic regimens [9-14]. Clinical outcomes after treatment of these patients, including OS and PFS of treatment these patients similar comparable with those of non–HIV-infected individuals both in NHL and HL cases [7, 11, 13, 14, 31].
In the early 90’s clinical studies established ASCT as the standard of care for managing patients with chemotherapy-sensitive, relapsed/refractory NHL and HL [15-16, 32]. HIV infection historically has been considered as a contraindication to ASCT. With the improvement of supportive care, and the accumulation of experience in ASCT, as well as long-term results of the use of HAART there was an opportunity to extend implementation of high-dose chemotherapy followed by ASCT to HIV-infected patients. Series of the studies has been reported ASCT as a feasible, safe, and useful approach to either rescue or consolidate HIV-related lymphoma patients [19, 20-26].
Alvarnas JC et al. highlighted that published ASCT studies were largely limited to centers with signifi cant HIV-related expertise. Th is has prevented full acceptance of ASCT as the standard of care for patients with relapsed and resistant HIV-related lymphoma [26]. We cannot disagree with the statement of Dr. Alvarnas. Our transplant activity confirms the fact that ASCT for patients with lymphoma and HIV remain largely limited to centers with signifi cant HIV-specifi c expertise [33].
Today we need prospective comparative matched case-controlled studies in order to confi rm safety and effi cacy of ASCT in HIV-related lymphoma. Th ree studies that in one way or another meet these criteria were published. One study is a single-institution one, from the City of Hope – the United States center that pioneered the use of hematopoietic stem cell transplantation for HIV positive patients [27]. Two other comparative trials represent a registry-based studies from the EBMT and CIBMTR databases [26, 28]. Table 4 presents a summary of trials with appropriate comparative analyses of HIV-infected patients and matched cohorts from non–HIV-infected patients who underwent ASCT for treatment of NHL and HL. Th e well-designed single center and multicenter studies have shown that HIV status does not affect the outcome of ASCT performed for NHL and HL. Such a conclusion is based on a total group of 122 HIV-infected individuals with lymphoma observed in the three studies.
This study and early-stage data confi rm some previously published statements that high-dose chemotherapy with ASCT is a safe and eff ective procedure in patients with highrisk, relapsed refractory HIV-related lymphoma. The issues of ASCT safety in this category of patients become actual given that HSCT is a platform for development and application of gene therapy, both with classic and more advanced genome editing techniques aimed to eradicate HIV infection [34-37]. In the last few years with a development of the genome editing technology based on autologous hematopoietic stem cell transplantation is becoming one of the most promising methods of HIV one shot therapy procedure. Hematopoietic stem cells are one of the most popular and promising target for gene therapy protocols for the treatment of numerous disease and conditions, due to their tissue-specific homing, ability for diff erentiation and production of various blood cells, as well as broad clinical experience with their transplantation [38, 39].

There is no doubt that further research in this field and every new patient treated with ASCT procedure is of great value, and multicenter prospective comparative matched case-controlled studies are required. Our pilot study involved a modest number of patients observed for limited terms. However, it contributes to the solution of an urgent problem. Our preliminary data provide further evidence that HIV status does not aff ect the outcome of ASCT for lymphoma. Patients with HIV-related lymphoma should be considered candidates for ASCT if they meet standard transplant criteria.

Acknowledgments

The authors would like to acknowledge all medical staff at our University’ BMT clinic CIC725. Special thanks to our transplant nurses for their particular care of our patients. Many thanks to the HIV specialists at the First Pavlov State Medical University of Saint-Petersburg, especially to Prof. Lioznov D. A., Chief of the Department, and to entire medical staff of St. Petersburg HIV Center for detailed clinical and laboratory data provided for the patients.

Conflict of interest

No conflict of interests is declared.

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