Publications by authors named "Lazaros J Lekakis"

21 Publications

  • Page 1 of 1

Chronic Graft-Versus-Host Disease, Non-Relapse Mortality and Disease Relapse in Older versus Younger Adults Undergoing Matched Allogeneic Peripheral Blood Hematopoietic Cell Transplantation: A CIBMTR Analysis.

Transplant Cell Ther 2021 Oct 9. Epub 2021 Oct 9.

CIBMTR® (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI; Fred Hutchinson Cancer Research Center, Seattle, WA.

Background: The effect of chronic graft-versus-host disease (cGVHD) on the risk of non-relapse mortality (NRM) and relapse has not been specifically studied in older adults, who are increasingly undergoing allogeneic hematopoietic cell transplantation (alloHCT) and surviving long-term to develop cGVHD. In this Center for International Blood and Marrow Transplant Research analysis, we tested our hypothesis that the risk of NRM was higher with the development of cGVHD, particularly among older adults (≥60 years).

Methods: We included 4429 adults ≥40 years who received first HLA-matched peripheral blood alloHCT for acute myeloid leukemia or myelodysplastic syndrome between the years 2008-2017. We compared outcomes of 4 groups: older adults (≥60 years) and younger adults (40-59 years) with or without cGVHD to determine the effect of older age and cGVHD on various outcomes. We used Cox proportional hazard models to determine the risk of NRM, relapse and overall survival (OS). We treated cGVHD as a time-dependent covariate. Severity of cGVHD was based on the CIBMTR clinical definitions.

Results: cGVHD was significantly associated with a higher risk of NRM and lower risk of relapse regardless of age. The risk of NRM was higher among older versus younger adults. Adults who developed cGVHD as a group had longer OS, compared to age-matched cohorts without cGVHD. Older adults had worse OS regardless of cGVHD. Among adults with cGVHD, clinically moderate or severe cGVHD was associated with a significantly higher risk of NRM and lower risk of relapse; severe cGVHD was associated with shorter OS, whereas mild and moderate cGVHD were associated with longer OS.

Conclusions: Among both younger and older adults, the development of cGVHD was associated with a higher risk of NRM, lower risk of relapse and longer OS. Older adults had a higher risk of NRM but the increased risk of NRM associated with cGVHD did not differ based on age. Development of mild-moderate cGVHD offered the most favorable balance between minimizing NRM and decreasing relapses. The relapse risk was lowest for adults with severe cGVHD, but high NRM resulted in shorter OS. Developing strategies to avoid clinically severe cGVHD is critically important.
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http://dx.doi.org/10.1016/j.jtct.2021.10.002DOI Listing
October 2021

Aseptic Meningitis after Recovery from SARS-CoV-2 in an Allogeneic Stem Cell Transplant Recipient.

Clin Med Insights Case Rep 2021 19;14:11795476211009811. Epub 2021 Apr 19.

Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.

SARS-CoV-2 emerged as a worldwide pandemic in late 2019 and initially was described as a primary respiratory illness. The clinical manifestations of COVID-19 are now known to encompass nearly all organ systems, including the central nervous system. We present a case of an allogeneic hematopoietic stem cell transplant recipient who recovered from documented SARS-CoV-2 infection and later presented with symptoms of meningitis. While cerebrospinal fluid analysis did not reveal any bacterial or viral etiologies, evidence of an inflammatory state, including ophthalmologic findings of episcleritis, indicate what is likely the first reported case of aseptic meningitis associated with SARS-CoV-2 infection after initial clinical recovery.
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http://dx.doi.org/10.1177/11795476211009811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058782PMC
April 2021

Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma.

Blood Adv 2020 10;4(19):4898-4911

Kite, a Gilead Company, Santa Monica, CA.

ZUMA-1 demonstrated a high rate of durable response and a manageable safety profile with axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with refractory large B-cell lymphoma. As previously reported, prespecified clinical covariates for secondary end point analysis were not clearly predictive of efficacy; these included Eastern Cooperative Oncology Group performance status (0 vs 1), age, disease subtype, disease stage, and International Prognostic Index score. We interrogated covariates included in the statistical analysis plan and an extensive panel of biomarkers according to an expanded translational biomarker plan. Univariable and multivariable analyses indicated that rapid CAR T-cell expansion commensurate with pretreatment tumor burden (influenced by product T-cell fitness), the number of CD8 and CCR7+CD45RA+ T cells infused, and host systemic inflammation, were the most significant determining factors for durable response. Key parameters differentially associated with clinical efficacy and toxicities, with both theoretical and practical implications for optimizing CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT02348216.
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http://dx.doi.org/10.1182/bloodadvances.2020002394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556133PMC
October 2020

Progressive multifocal leukoencephalopathy after CAR T therapy.

Int J Hematol 2020 Jul 3;112(1):118-121. Epub 2020 Mar 3.

Division of Hematology and Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, US.

Progressive multifocal leukoencephalopathy (PML) remains a life-threatening central nervous system infection in immunocompromised patients. Although outcomes have improved in cases that immune reconstitution is feasible with anti-retroviral therapy (ART) in HIV + patients or natalizumab removal in those with multiple sclerosis, in individuals with hematological malignancies, the prognosis is usually dismal. Anti-viral treatments have been largely ineffective, but immunotherapy-based approaches with checkpoint inhibitors and adoptive virus-specific T cells' transfer are currently explored in clinical trials. PML has not been described as a cause of encephalopathy after CAR T therapy. We report the first case of PML 7 months after lymphodepleting chemotherapy with fludarabine/cyclophosphamide and anti-CD19-directed CAR T therapy in a patient with relapsed diffuse large B-cell lymphoma who relapsed fast after a previous autologous hematopoietic stem cell transplant. She remains alive 12 months after diagnosis with stabilization of her symptoms with a combination of therapies targeting viral replication and immunotherapy.
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http://dx.doi.org/10.1007/s12185-020-02840-xDOI Listing
July 2020

The Role of Autologous Stem Cell Transplantation in the Treatment of Diffuse Large B-cell Lymphoma in the Era of CAR-T Cell Therapy.

Hemasphere 2019 Dec 3;3(6):e295. Epub 2019 Sep 3.

Sylvester Cancer Center, University of Miami, Miami, FL, USA.

For many years now and based on the results of the PARMA trial, relapsed Diffuse Large B-cell Lymphoma (DLBCL) is treated with salvage combination cytotoxic chemotherapy (most often platinum-based) followed by high dose myeloablative chemotherapy and autologous stem cell transplantation (auto-HCT). This approach has resulted in long-term disease free survival in about half of the patients. With the incorporation of rituximab in the upfront treatment (RCHOP), more patients with DLBCL are cured but there has been a signal of inferior outcomes with auto-HCT if DLBCL relapses. Nevertheless, a careful review of the literature still shows very good outcomes with auto-HCT for DLBCL with complete remission to salvage chemotherapy. For those who do not respond well to classic salvage other approaches are reviewed here including chimeric antigen receptor (CAR) T-cell therapy and treatment with antibody-drug conjugates (ADCs) as well as bispecific T-cell engagers (BiTEs). The outcome of auto-HCT after successful treatment with ADCs or BITEs is unknown. It is also unknown if CAR-T cell therapy should be reserved for those who have failed 2 lines of chemotherapy or it should be moved earlier. Finally, we review here the effects of Myc and bcl2 amplifications or translocations to the outcome of the auto-HCT. Some attempts to improve the salvage or conditioning regimens are mentioned. We also discuss the role of allogeneic stem cell transplantation (allo-HCT) in the paradigm of treatment for relapsed DLBCL.
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http://dx.doi.org/10.1097/HS9.0000000000000295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924546PMC
December 2019

Incidence and risk factors associated with a syndrome of persistent cytopenias after CAR-T cell therapy (PCTT).

Leuk Lymphoma 2020 04 3;61(4):940-943. Epub 2019 Dec 3.

Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL, USA.

Anti-CD19 Chimeric Antigen Receptor T cells (CAR-T) have shown dramatic efficacy in treating refractory aggressive B cell Lymphomas leading to FDA approval of axicabtagene ciloleucel and tisagenlecleucel. While long-term remission rate for both is higher than 33%, this treatment is associated with life-threatening complications including cytokine-release syndrome, encephalopathy, and lethal cerebral edema. Here we describe a case series of bone marrow failure syndromes with or without co-existing clonal myelodysplastic syndrome. Bone marrow failure was defined as absolute neutrophil count (ANC) <500 neutrophils/μL day 42 after infusion of CAR-T cells or filgrastim support to reach that number. We use "persistent cytopenias after T-cell therapy (PCTT)" to describe this syndrome which has an incidence of 38% with axicabtagene ciloleucel. Platelets <75,000/μL at the time of initiation of lymphodepleting chemotherapy and occurrence of maximum severity of cytokine-release syndrome (CRS) on day 0 or 1 after infusion of CAR-T cells are independent predictors of PCTT.
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http://dx.doi.org/10.1080/10428194.2019.1697814DOI Listing
April 2020

Saddle Nose Deformity in an Immunosuppressed Patient.

Clin Infect Dis 2019 02;68(4):705-709

Division of Infectious Diseases, University of Miami Miller School of Medicine, Florida.

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http://dx.doi.org/10.1093/cid/ciy396DOI Listing
February 2019

Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial.

Lancet Oncol 2019 01 2;20(1):31-42. Epub 2018 Dec 2.

Kite, Santa Monica, CA, USA.

Background: Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In the previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15·4 months (IQR 13·7-17·3), 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel achieved an objective response, and complete responses were noted in 63 (58%) patients. Here we report long-term activity and safety outcomes of the ZUMA-1 study.

Methods: ZUMA-1 is a single-arm, multicentre, registrational trial at 22 sites in the USA and Israel. Eligible patients were aged 18 years or older, and had histologically confirmed large B-cell lymphoma-including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma-according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue; refractory disease or relapsed after autologous stem-cell transplantation; an Eastern Cooperative Oncology Group performance status of 0 or 1; and had previously received an anti-CD20 monoclonal antibody containing-regimen and an anthracycline-containing chemotherapy. Participants received one dose of axicabtagene ciloleucel on day 0 at a target dose of 2 × 10 CAR T cells per kg of bodyweight after conditioning chemotherapy with intravenous fludarabine (30 mg/m body-surface area) and cyclophosphamide (500 mg/m body-surface area) on days -5, -4, and -3. The primary endpoints were safety for phase 1 and the proportion of patients achieving an objective response for phase 2, and key secondary endpoints were overall survival, progression-free survival, and duration of response. Pre-planned activity and safety analyses were done per protocol. ZUMA-1 is registered with ClinicalTrials.gov, number NCT02348216. Although the registrational cohorts are closed, the trial remains open, and recruitment to extension cohorts with alternative endpoints is underway.

Findings: Between May 19, 2015, and Sept 15, 2016, 119 patients were enrolled and 108 received axicabtagene ciloleucel across phases 1 and 2. As of the cutoff date of Aug 11, 2018, 101 patients assessable for activity in phase 2 were followed up for a median of 27·1 months (IQR 25·7-28·8), 84 (83%) had an objective response, and 59 (58%) had a complete response. The median duration of response was 11·1 months (4·2-not estimable). The median overall survival was not reached (12·8-not estimable), and the median progression-free survival was 5·9 months (95% CI 3·3-15·0). 52 (48%) of 108 patients assessable for safety in phases 1 and 2 had grade 3 or worse serious adverse events. Grade 3 or worse cytokine release syndrome occurred in 12 (11%) patients, and grade 3 or worse neurological events in 35 (32%). Since the previous analysis at 1 year, additional serious adverse events were reported in four patients (grade 3 mental status changes, grade 4 myelodysplastic syndrome, grade 3 lung infection, and two episodes of grade 3 bacteraemia), none of which were judged to be treatment related. Two treatment-related deaths (due to haemophagocytic lymphohistiocytosis and cardiac arrest) were previously reported, but no new treatment-related deaths occurred during the additional follow-up.

Interpretation: These 2-year follow-up data from ZUMA-1 suggest that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable long-term safety profile in patients with relapsed or refractory large B-cell lymphoma.

Funding: Kite and the Leukemia & Lymphoma Society Therapy Acceleration Program.
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http://dx.doi.org/10.1016/S1470-2045(18)30864-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733402PMC
January 2019

Invasive Rhinosinusitis Caused by Lasiodiplodia theobromae in an Allogeneic Hematopoietic Cell Transplant Recipient Case Report and Review of Literature.

Mycopathologia 2018 Oct 22;183(5):841-845. Epub 2018 Jun 22.

Infectious Disease Department, Jackson Memorial Hospital, Miami, FL, USA.

Lasiodiplodia theobromae is a known plant pathogen in tropical and subtropical areas. Few cases have been reported in humans (usually keratitis and endophthalmitis) with only two cases of fungal sinusitis in immunocompromised and immunocompetent patients published to date. We report a case of invasive sinusitis secondary to L. theobromae in an allogeneic hematopoietic cell transplant recipient successfully treated with surgical debridement and triazole antifungals with a review of available literature.
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http://dx.doi.org/10.1007/s11046-018-0262-9DOI Listing
October 2018

Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma.

N Engl J Med 2017 12 10;377(26):2531-2544. Epub 2017 Dec 10.

From the University of Texas M.D. Anderson Cancer Center, Houston (S.S.N., J.R.W.); H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (F.L.L., J.C.C.); Washington University and Siteman Cancer Center, St. Louis (N.L.B., A. Ghobadi); University of Miami, Miami (L.J.L., K.V.K.); Stanford University, Stanford (D.B.M., R.L.), City of Hope National Medical Center, Duarte (T.S.), University of California at Los Angeles, Los Angeles (J.M.T.), University of California at San Diego, San Diego (J.E.C.), and Kite Pharma, Santa Monica (A.B., J.R., L.N., Y.J., J.A., M.E., D.C., J.W., W.Y.G.) - all in California; Dana-Farber Cancer Institute, Boston (C.A.J., E.D.J.); Montefiore Medical Center, Bronx (I.B.), and the University of Rochester School of Medicine, Rochester (J.W.F., P.R.) - both in New York; Vanderbilt University Medical Center (O.O.O.) and the Sarah Cannon Research Institute and Tennessee Oncology (I.W.F.), Nashville; Mayo Clinic, Rochester, MN (Y.L., T.E.W.); Loyola University Medical Center, Maywood, IL (P.J.S.); John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ (A. Goy); Cleveland Clinic, Cleveland (B.T.H., M.R.S.); Karmanos Cancer Center, Wayne State University, Detroit (A.D.); University of Iowa Carver College of Medicine, Iowa City (U.F.); Colorado Blood Cancer Institute, Denver (P.M.S.); Banner M.D. Anderson Cancer Center, Gilbert, AZ (J.M.); and Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel (I.A.).

Background: In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy.

Methods: In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×10 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments.

Results: Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response.

Conclusions: In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).
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http://dx.doi.org/10.1056/NEJMoa1707447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882485PMC
December 2017

Impact of Cytomegalovirus Viral Load on Probability of Spontaneous Clearance and Response to Preemptive Therapy in Allogeneic Stem Cell Transplantation Recipients.

Biol Blood Marrow Transplant 2018 04 5;24(4):806-814. Epub 2017 Dec 5.

Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida; Adult Stem Cell Transplant Program, Sylvester Comprehensive Cancer Center, Miami, Florida.

The optimal viral load threshold at which to initiate preemptive cytomegalovirus (CMV) therapy in hematopoietic cell transplantation (HCT) recipients remains to be defined. In an effort to address this question, we conducted a retrospective study of 174 allogeneic HCT recipients who underwent transplantation at a single center between August 2012 and April 2016. During this period, preemptive therapy was initiated at the discretion of the treating clinician. A total of 109 patients (63%) developed CMV viremia. The median time to reactivation was 17 days (interquartile range, IQR, 7-30 days) post-HCT. A peak viremia ≥150 IU/mL was strongly associated with a reduced probability of spontaneous clearance (relative risk, .16; 95% confidence interval, .1-.27), independent of established clinical risk factors, including CMV donor serostatus, exposure to antithymocyte globulin, and underlying lymphoid malignancy. The median time to clearance of viremia was significantly shorter in those who started therapy at CMV <350 IU/mL (19 days; IQR, 11-35 days) compared with those who started antiviral therapy at higher viremia thresholds (33 days; IQR, 21-42 days; P = .02). The occurrence of treatment-associated cytopenias was frequent but similar in patients who started preemptive therapy at CMV <350 IU/mL and those who started at CMV >350 IU/mL (44% versus 57%; P = .42). Unresolved CMV viremia by treatment day 35 was associated with increased risk of therapeutic failure (32% versus 0%; P = .001). Achieving eradication of CMV viremia by treatment day 35 was associated with a 74% reduction in 1-year nonrelapse mortality (NRM) (adjusted hazard ratio [HR], .26; 95% confidence interval [CI], .1-.8; P = .02), whereas therapeutic failure was associated with a significant increase in the probability of 1-year NRM (adjusted HR, 26; 95% CI, 8-87; P <.0001). We conclude that among allogeneic HCT patients, a peak CMV viremia ≥150 IU/mL is associated with a >80% reduction in the probability of spontaneous clearance independent of ATG administration, CMV donor serostatus, and lymphoid malignancy, and is a reasonable cutoff for preemptive therapy. Delaying initiation of therapy until a CMV value ≥350 IU/mL is associated with more protracted CMV viremia, and unresolved viremia by treatment day 35 is associated with a significant increase in NRM.
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http://dx.doi.org/10.1016/j.bbmt.2017.11.038DOI Listing
April 2018

Increased Foxp3Helios Regulatory T Cells and Decreased Acute Graft-versus-Host Disease after Allogeneic Bone Marrow Transplantation in Patients Receiving Sirolimus and RGI-2001, an Activator of Invariant Natural Killer T Cells.

Biol Blood Marrow Transplant 2017 Apr 16;23(4):625-634. Epub 2017 Jan 16.

Department of Pathology, University of California San Diego, La Jolla, California. Electronic address:

Regulatory T (Treg) cells play a central role in immune tolerance and prevention of aberrant immune responses. Several studies have suggested that the risk of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) can be ameliorated by increasing Tregs. We have developed an approach of in vivo expansion of Tregs with RGI-2001, a novel liposomal formulation of a synthetic derivative of alpha-galactosylceramide, a naturally occurring ligand that binds to CD1 and activates and expands invariant natural killer cells. In preclinical studies, a single intravenous infusion of RGI-2001 expanded Treg and could ameliorate GVHD in a mouse model of allogeneic HCT. To explore the role of RGI-2001 in clinical HCT, we initiated a phase 2A clinical trial (n = 29), testing 2 different doses of RGI-2001 administered as a single infusion on day 0 of allogeneic HCT. RGI-2001 was well tolerated and without infusion reactions or cytokine release syndrome. A subset of patients (8 of 29, 28%) responded to RGI-2001 by inducing a markedly increased number of cells with a Treg phenotype. The Treg had a high Ki-67 index and were almost exclusively Helios and Foxp3, indicating that their accumulation was due to expansion of natural Treg. Notably, the incidence of grade 2 to 4 GVHD in the 8 patients who responded to RGI-2001 was 12.5%, compared with 52.4% in the 21 patients who did not respond. No grade 3 or 4 GVHD was observed in the responder group, compared with a 9.5% incidence among nonresponders. Immunosuppression with sirolimus was also associated with a low incidence of GVHD, suggesting that RGI-2001 may have synergized with sirolimus to promote Treg expansion.
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http://dx.doi.org/10.1016/j.bbmt.2017.01.069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437739PMC
April 2017

The use of brincidofovir for the treatment of mixed dsDNA viral infection.

J Clin Virol 2016 10 4;83:1-4. Epub 2016 Aug 4.

Adult Stem Cell Transplant Program, Sylvester Cancer Center, University of Miami, 1475 NW 12th Ave, Miami, FL 33136, United States; Department of Medicine, Division of Hematology, University of Miami Miller School of Medicine, 1120 NW 14th Street, Miami, FL 33136, United States.

Double-stranded DNA (dsDNA) viral infections constitute a major complication following solid organ and stem cell transplantation. Few therapeutic options are currently available for the treatment of such infections in highly immunocompromised hosts. Brincidofovir is an oral investigational drug with broad antiviral activity against dsDNA viruses in vitro, but clinical experience is limited. Here we report a young female who developed a mixed infection with adenovirus, cytomegalovirus, Epstein-Barr virus and BK polyomavirus after an allogeneic stem cell transplant, and was successfully treated with brincidofovir.
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http://dx.doi.org/10.1016/j.jcv.2016.07.021DOI Listing
October 2016

Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: are we closer to knowing who needs it?

Curr Hematol Malig Rep 2014 Jun;9(2):128-37

Sylvester Cancer Center, University of Miami, Miami, FL, USA.

Acute myeloid leukemia (AML) is a very heterogeneous disease. Prognosis is related not only to intrinsic characteristics such as cytogenetics and molecular markers, but also the patient's ability to tolerate therapy, and treatment response. Allogeneic stem cell transplantation (allo-HCT) has been traditionally indicated for poor-risk disease in first complete remission (CR1) or for treatment of relapsed or refractory AML. 'Poor-risk' disease is now better defined due to genetic subtyping, particularly in chromosomally normal AML. In addition, the presence of comorbid conditions should be included in the decision-making process. Improvements in supportive care and the use of modern conditioning regimens have been associated with improved outcomes, mostly due to a reduction in treatment-related mortality. Therefore, a significant proportion of patients with AML-CR1 can potentially benefit from allo-HCT. We give general guidelines on how to incorporate cytogenetic and molecular risk factors, donor selection, and patient characteristics in order to determine when allo-HCT should be indicated in CR1.
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http://dx.doi.org/10.1007/s11899-014-0207-4DOI Listing
June 2014

Increased polyclonal CD5+ B1a lymphocytes in a haploidentical stem cell transplant recipient.

Cytometry B Clin Cytom 2011 Mar 1;80(2):119-21. Epub 2010 Oct 1.

Department of Pathology and Laboratory Medicine, Chandler Medical Center, University of Kentucky College of Medicine, Lexington, Kentucky 40536, USA.

Background: Atypical lymphocyte populations may be seen in the peritransplant setting. In this case report, we describe an unusually high number of CD5+ B-cells (B1a cells) following transplant.

Methods: B1a cells identified during routine follow-up by immunophenotypic analysis in a middle-aged man who had a haploidentical stem cell transplant for acute myeloid leukemia were compared with a reference set of post-transplant samples.

Results: Increased but polyclonal B1a cells were identified with 100% donor chimerism.

Conclusions: Our case demonstrates that a high absolute number of B1a cells may be seen post-transplant and should not be confused with an atypical CD5+ lymphoproliferative disorder. Furthermore, the population of polyclonal CD5+ B lymphocytes from the patient's donor is prominent 7 months post-transplant. This suggests that the maintenance of CD5+ B1 cells prior to conversion to adult-type CD5⁻ B2 cells is not hindered by the recipient adult stromal environment.
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http://dx.doi.org/10.1002/cyto.b.20572DOI Listing
March 2011

Long-term complete regression of nodal marginal zone lymphoma transformed into diffuse large B-cell lymphoma with highly active antiretroviral therapy alone in human immunodeficiency virus infection.

Am J Med Sci 2009 Dec;338(6):517-21

Infectious Diseases & HIV Division, 5th Department of Internal Medicine, Evaggelismos General Hospital, Athens, Greece.

Since the introduction of combination antiretroviral therapy (cART), there has been a decrease in the incidence of non-Hodgkin lymphoma among the HIV-infected population and also significantly improved survival rates. We describe a remarkable case of a HIV-infected patient whose large B-cell lymphoma, most likely arising by transformation of a nodal marginal zone lymphoma, completely regressed with the use of cART alone. He remained disease-free for almost 3 years and he finally died from presumed flare up of his lymphoma. There are very few cases of spontaneous regression of lymphomas with cART alone in the HIV population. This is an extreme example of the significance of cART in improving survival in HIV-non-Hodgkin lymphoma and changing the face of the HIV epidemic in general.
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http://dx.doi.org/10.1097/MAJ.0b013e3181b51fa3DOI Listing
December 2009

Fatal rhizopus pneumonia in allogeneic stem cell transplant patients despite posaconazole prophylaxis: two cases and review of the literature.

Biol Blood Marrow Transplant 2009 Aug 10;15(8):991-5. Epub 2009 Jun 10.

Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.

Posaconazole is a triazole with broad spectrum of activity against multiple fungi including members of the fungal order Mucorales. This activity has been shown both in clinical and in vitro studies, which are critically reviewed here. It has become very popular in prophylaxis in acute myelogenous leukemia (AML) induction and in the graft-versus-host disease (GVHD) settings after 2 recent prospective trials that showed advantage of posaconazole prophylaxis compared to fluconazole or itraconazole. In this report, 2 patients are presented, in whom, despite posaconazole prophylaxis, invasive and ultimately fatal Rhizopus pulmonary infections developed. These cases are similar to a previously reported case of Rhizopus infection in a stem cell transplant recipient who also received posaconazole, indicating a potential newly recognized pattern of breakthrough infections in patients receiving posaconazole prophylaxis.
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http://dx.doi.org/10.1016/j.bbmt.2009.04.007DOI Listing
August 2009

BK virus nephropathy after allogeneic stem cell transplantation: a case report and literature review.

Am J Hematol 2009 Apr;84(4):243-6

Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.

Polyomaviruses are increasingly recognized as important human pathogens. Among those, BK virus has been identified as the main cause of polyomavirus-associated nephropathy (PVAN), a major cause of renal allograft failure. PVAN has also been well described in the setting of non-renal solid organ transplantation. The reports of PVAN after hematopoietic stem cell transplantation (HCT) are surprisingly very few. Here, we describe a patient with treatment-related myelodysplastic syndrome who received an unrelated donor HCT after ablative conditioning and in vivo T cell depletion with alemtuzumab. He developed a biopsy-proven BK nephropathy, which contributed to his renal failure. Leflunomide as well as cidofovir were given at different times, both in combination with intravenous immunoglobulin. Both treatments were effective in reducing the BK viral load, the cystitis symptoms and both stabilized but did not really improved the renal function. The patient was still dialysis-dependent when he died from Pseudomonas sepsis 13 months after HCT. A critical review of the literature and the treatment modalities for post-HCT PVAN are provided.
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http://dx.doi.org/10.1002/ajh.21358DOI Listing
April 2009

First-time use of bevacizumab for aggressive, metastatic hepatocellular carcinoma in an HIV/hepatitis B virus coinfected patient: a case report.

Eur J Gastroenterol Hepatol 2008 May;20(5):472-3

Infectious Diseases and AIDS Division, Evaggelismos, General Hospital, Athens, Greece.

We present a case of an HIV-1 infected patient with history of chronic hepatitis B and chronic alcohol use without cirrhosis, who presented with aggressive hepatocellular carcinoma with multiple metastases. Systemic chemotherapy combined with use of bevacizumab (anti-vascular endothelium growth factor monoclonal antibody) was without effect and the patient succumbed to his disease within few weeks. To our knowledge, this is the first report in the English literature of bevacizumab use for metastatic hepatocellular carcinoma in HIV-infected patients.
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http://dx.doi.org/10.1097/MEG.0b013e3282f16411DOI Listing
May 2008

Multicentric Castleman's disease in HIV infection: a systematic review of the literature.

AIDS Rev 2008 Jan-Mar;10(1):25-35

Fifth Department of Internal Medicine, Evangelismos Hospital, Athens, Greece.

The objective of this study is to systematically review the epidemiology and the clinical and virologic aspects of multicentric Castleman's disease in HIV-positive patients and to evaluate treatment strategies and outcome, especially in relation to HAART administration. The authors have conducted a systematic review of the English literature for all cases of newly diagnosed multicentric Castleman's disease in HIV-positive patients. The 25 studies which met the selection criteria included 84 HIV-positive patients with multicentric Castleman's disease (20 pre-HAART and 64 post-HAART era). Of them, the majority (90%) were men with 33 months median time from detection of HIV-positivity to multicentric Castleman's disease diagnosis in the HAART era. Fever and lymphadenopathy were the most common presenting symptoms and cytopenias, hypoalbuminemia, polyclonal hypergammaglobulinemia and raised C-reactive protein the most frequently revealed laboratory findings. Kaposi's sarcoma was present in 72% of the patients and respiratory system involvement in 34%. Although the majority of cases reported were positive for human herpesvirus-8, none of the reviewed patients was found to suffer from polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. Of the 48 patients on HAART, 64% were already on HAART at multicentric Castleman's disease diagnosis, having a better immunologic profile and a lower incidence of Kaposi's sarcoma than the 35% of patients who initiated HAART after multicentric Castleman's disease diagnosis. Nevertheless, the two groups did not have significantly different mortality rates (30 vs. 38%). At multicentric Castleman's disease diagnosis, a wide range of CD4 counts was recorded, suggesting that disease presentation could occur at any CD4 count. With regard to treatment, the study confirmed the high rates of response with rituximab (anti-CD20 monoclonal). Monochemotherapy seems to give short-lived responses, which require maintenance to be sustained. Polychemotherapy with CHOP has given long-term remission in a subset of patients. Other regimens used in the treatment of HIV-related multicentric Castleman's disease were antiviral agents, immunomodulatory agents, and thalidomide. The fatality rate among HIV-related multicentric Castleman's disease cases reviewed was 44%, significantly lower than that of HIV-negative individuals (65%), while median survival of the latter was 29 months longer than that of HIV-infected individuals. The fatality rate among pre-HAART patients was 75 vs. 29% among HAART patients. Infection, multiorgan failure, Kaposi's sarcoma, non-Hodgkin lymphoma and progressive multicentric Castleman's disease were the most often reported causes of death. In conclusion, multicentric Castleman's disease is a lymphoproliferative disorder with an increasing prevalence in HIV-infected individuals. Even though life expectancy in multicentric Castleman's disease seems to have significantly improved in the HAART era, it remains a disease with a poor prognosis and an increased incidence of non-Hodgkin lymphoma in the HIV-context.
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August 2008
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