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      Providing Ancillary Care in Clinical Research: A Case of Diffuse Large B-Cell Lymphoma during a Malaria Vaccine Trial in Equatorial Guinea

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          Abstract.

          Providing medical care for participants in clinical trials in resource-limited settings can be challenging and costly. Evaluation and treatment of a young man who developed cervical lymphadenopathy during a malaria vaccine trial in Equatorial Guinea required concerted efforts of a multinational, multidisciplinary team. Once a diagnosis of diffuse large B-cell lymphoma was made, the patient was taken to India to receive immunochemotherapy. This case demonstrates how high-quality medical care was provided for a serious illness that occurred during a trial that was conducted in a setting in which positron emission tomography for diagnostic staging, an oncologist for supervision of treatment, and an optimal therapeutic intervention were not available. Clinical researchers should anticipate the occurrence of medical conditions among study subjects, clearly delineate the extent to which health care will be provided, and set aside funds commensurate with those commitments.

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          Most cited references 30

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          The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP.

          Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity, with patients exhibiting a wide range of outcomes. The addition of rituximab to CHOP chemotherapy (R-CHOP)has led to a marked improvement in survival and has called into question the significance of previously recognized prognostic markers. Since randomized controlled trials of R-CHOP in DLBCL have included select subgroups of patients, the utility of the International Prognostic Index (IPI) has not been reassessed. We performed a retrospective analysis of patients with DLBCL treated with R-CHOP in the province of British Columbia to assess the value of the IPI in the era of immunochemotherapy. The IPI remains predictive, but it identifies only 2 risk groups. Redistribution of the IPI factors into a revised IPI (R-IPI) provides a more clinically useful prediction of outcome. The R-IPI identifies 3 distinct prognostic groups with a very good (4-year progression-free survival [PFS] 94%, overall survival [OS] 94%), good (4-year PFS 80%, OS 79%), and poor (4-year PFS 53%, OS 55%) outcome, respectively (P < .001). The IPI (or R-IPI) no longer identifies a risk group with less than a 50% chance of survival. In the era of R-CHOP treatment, the R-IPI is a clinically useful prognostic index that may help guide treatment planning and interpretation of clinical trials.
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            Sterile protection against human malaria by chemoattenuated PfSPZ vaccine

            A highly protective malaria vaccine would greatly facilitate the prevention and elimination of malaria and containment of drug-resistant parasites. A high level (more than 90%) of protection against malaria in humans has previously been achieved only by immunization with radiation-attenuated Plasmodium falciparum (Pf) sporozoites (PfSPZ) inoculated by mosquitoes; by intravenous injection of aseptic, purified, radiation-attenuated, cryopreserved PfSPZ (‘PfSPZ Vaccine’); or by infectious PfSPZ inoculated by mosquitoes to volunteers taking chloroquine or mefloquine (chemoprophylaxis with sporozoites). We assessed immunization by direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated PfSPZ (‘PfSPZ Challenge’) to malaria-naive, healthy adult volunteers taking chloroquine for antimalarial chemoprophylaxis (vaccine approach denoted as PfSPZ-CVac). Three doses of 5.12 × 104 PfSPZ of PfSPZ Challenge at 28-day intervals were well tolerated and safe, and prevented infection in 9 out of 9 (100%) volunteers who underwent controlled human malaria infection ten weeks after the last dose (group III). Protective efficacy was dependent on dose and regimen. Immunization with 3.2 × 103 (group I) or 1.28 × 104 (group II) PfSPZ protected 3 out of 9 (33%) or 6 out of 9 (67%) volunteers, respectively. Three doses of 5.12 × 104 PfSPZ at five-day intervals protected 5 out of 8 (63%) volunteers. The frequency of Pf-specific polyfunctional CD4 memory T cells was associated with protection. On a 7,455 peptide Pf proteome array, immune sera from at least 5 out of 9 group III vaccinees recognized each of 22 proteins. PfSPZ-CVac is a highly efficacious vaccine candidate; when we are able to optimize the immunization regimen (dose, interval between doses, and drug partner), this vaccine could be used for combination mass drug administration and a mass vaccination program approach to eliminate malaria from geographically defined areas.
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              Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era.

              The International Prognostic Index (IPI) is widely used for risk stratification of patients with aggressive B-cell lymphoma. The introduction of rituximab has markedly improved outcome, and R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, prednisone) has become the standard treatment for CD20(+) diffuse large B-cell lymphoma. To investigate whether the IPI has maintained its power for risk stratification when rituximab is combined with CHOP, we analyzed the prognostic relevance of IPI in three prospective clinical trials. In total, 1,062 patients treated with rituximab were included (MabThera International Trial [MInT], 380 patients; dose-escalated regimen of cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (MegaCHOEP) trial, 72 patients; CHOP + rituximab for patients older than age 60 years [RICOVER-60] trial, 610 patients). A multivariate proportional hazards modeling was performed for single IPI factors under rituximab on event-free, progression-free, and overall survival. IPI score was significant for all three end points. Rituximab significantly improved treatment outcome within each IPI group resulting in a quenching of the Kaplan-Meier estimators. However, IPI was a significant prognostic factor in all three end points and the ordering of the IPI groups remained valid. The relative risk estimates of single IPI factors and their order in patients treated with R-CHOP were similar to those found with CHOP. The effects of rituximab were superimposed on the effects of CHOP with no interactions between chemotherapy and antibody therapy. These results demonstrate that the IPI is still valid in the R-CHOP era.
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                Author and article information

                Journal
                Am J Trop Med Hyg
                Am J Trop Med Hyg
                tpmd
                tropmed
                The American Journal of Tropical Medicine and Hygiene
                The American Society of Tropical Medicine and Hygiene
                0002-9637
                1476-1645
                February 2021
                23 November 2020
                23 November 2020
                : 104
                : 2
                : 695-699
                Affiliations
                [1 ]Sanaria, Inc., Rockville, Maryland;
                [2 ]Department of Family Medicine, John Peter Smith Hospital, Fort Worth, Texas;
                [3 ]Ifakara Health Institute, Bagamoyo, Tanzania;
                [4 ]Ministry of Health and Social Welfare, Malabo, Equatorial Guinea;
                [5 ]KEMRI Wellcome Trust Research Programme, Kilifi, Kenya;
                [6 ]Medical Care Development International, Malabo, Equatorial Guinea;
                [7 ]Medical Care Development International, Silver Spring, Maryland;
                [8 ]La Paz Medical Center, Malabo, Equatorial Guinea;
                [9 ]Policlínico Dr. Loeri Comba, Instituto de Seguridad Social, Malabo, Equatorial Guinea;
                [10 ]University of Maryland Medical Center, Baltimore, Maryland;
                [11 ]Cytecare Cancer Hospital, Bengaluru, Karnataka, India
                Author notes
                [* ]Address correspondence to Stephen R. Manock, Department of Family Medicine, John Peter Smith Hospital, 1500 S. Main St., OPC Bldg., 4th floor, Fort Worth, TX 76104. E-mail: smanock@ 123456jpshealth.org

                Disclosure: S. L. H., T. L. R., P. F. B., and L. W. P. C. are employed by Sanaria, Inc., which developed PfSPZ Vaccine and PfSPZ-CVac. S. R. M. was employed by Sanaria, Inc. at the time of the clinical trial, but was not at the time the manuscript was prepared and submitted. A. O. was the recipient of a U.K. Medical Research Council African Research Leader award for work unrelated to this manuscript.

                Disclaimer: Funders did not contribute to study design, or to the collection, analysis, or interpretation of data, the writing of the manuscript, or the decision to submit it for publication.

                Financial support: The government of Equatorial Guinea, Marathon E.G. Production Limited, Noble Energy Equatorial Guinea, and Atlantic Methanol Production Company LLC provided funding for the clinical trial and treatment of this patient.

                Authors’ addresses: Stephen R. Manock, Department of Family Medicine, John Peter Smith Hospital, Fort Worth, TX and Sanaria, Inc., Rockville, MD, E-mail: smanock@ 123456jpshealth.org . Ali Mtoro, Mwajuma Chemba, and Salim Abdulla, Ifakara Health Institute, Bagamoyo, Tanzania, E-mails: amtoro@ 123456ihi.or.tz , mchemba@ 123456ihi.or.tz , and sabdulla@ 123456ihi.or.tz . Vicente Urbano Nsue Ndong and Mitoha Ondo’o Ayekaba, Ministry of Health and Social Welfare, Malabo, Equatorial Guinea, E-mails: viceurb2013@ 123456gmail.com and mitoha_ondo@ 123456yahoo.com . Ally Olotu, Ifakara Health Institute, Bagamoyo, Tanzania and KEMRI Wellcome Trust Research Programme, Kilifi, Kenya. E-mails: ndaskoiolotu@ 123456gmail.com or aolotu@ 123456ihi.or.tz . Antonio E. Sama Roca, Esther Eburi, and Carlos Cortes Falla, Medical Care Development International, Malabo, Equatorial Guinea, E-mails: rocantony@ 123456gmail.com , eeburi@ 123456mcd.org , and ccortes@ 123456mcd.org . Guillermo A. García and Julie Niemczura de Carvalho, Medical Care Development International, Silver Spring, MD, E-mails: ggarcia@ 123456mcd.org and jniemczura@ 123456mcd.org . Jaime Contreras, Baltasar Saturno, and Juan de Dios Riocalo, La Paz Medical Center, Malabo, Equatorial Guinea, E-mails: jaimecdoc@ 123456gmail.com , baltasarsaturno@ 123456gmail.com , and doctorriocalo@ 123456gmail.com . José Luis Nze Mba, Policlínico Dr. Loeri Comba, Instituto de Seguridad Social, Malabo, Equatorial Guinea, E-mail: joseluisnzemba@ 123456gmail.com . Rima Koka and Seung Tae Lee, University of Maryland Medical Center, Baltimore, MD, E-mails: mkoka@ 123456umm.edu and seunglee@ 123456umm.edu . Hari Menon, Cytecare Cancer Hospital, Bengaluru, Karnataka, India, E-mail: hari.menon@ 123456cytecare.com . L. W. Preston Church, Peter F. Billingsley, Thomas L. Richie, and Stephen L. Hoffman, Sanaria, Inc., Rockville, MD, E-mails: lwpchurch@ 123456sanaria.com , pbillingsley@ 123456sanaria.com , trichie@ 123456sanaria.com , and slhoffman@ 123456sanaria.com .

                Article
                tpmd201178
                10.4269/ajtmh.20-1178
                7866340
                33236704
                © The American Society of Tropical Medicine and Hygiene

                This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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