Publications by authors named "Ernesto Ayala"

80 Publications

Cellular Therapies for Mantle Cell Lymphoma.

Transplant Cell Ther 2021 May 6;27(5):363-370. Epub 2021 Feb 6.

Division of Hematology-Oncology and Blood and Marrow Transplantation and Cellular Therapy Program, Mayo Clinic, Jacksonville, Florida. Electronic address:

Mantle cell lymphoma (MCL) is a subtype of B cell non-Hodgkin lymphoma characterized by a heterogeneous clinical presentation. Patients who demonstrate an objective response to induction therapy(ies) and are eligible for intensive therapies are offered an autologous hematopoietic cell transplant (HCT) as front-line consolidation followed by rituximab maintenance. Allogeneic HCT is an option for younger and fit patients with high-risk disease or in patients who have relapsed after autologous HCT. Recent advances in T cell engineering brought chimeric antigen receptor T cell (CAR T) therapy from the bench to the bedside, with brexucabtagene autoleucel being the first CAR T product approved by the US Food and Drug Administration for use in relapsed/refractory MCL. In this comprehensive review, we summarize the literature on available cellular therapies for MCL and present a treatment algorithm that incorporates HCT, autologous or allogeneic, and CAR T therapies.
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http://dx.doi.org/10.1016/j.jtct.2021.01.026DOI Listing
May 2021

Systematic Review/Meta-Analysis on Efficacy of Allogeneic Hematopoietic Cell Transplantation in Sickle Cell Disease: An International Effort on Behalf of the Pediatric Diseases Working Party of European Society for Blood and Marrow Transplantation and the Sickle Cell Transplantation International Consortium.

Transplant Cell Ther 2021 Feb 10;27(2):167.e1-167.e12. Epub 2020 Dec 10.

Division of Hematology-Oncology and Blood and Marrow Transplantation and Cellular Therapy Program, Mayo Clinic, Jacksonville, Florida. Electronic address:

Sickle cell disease (SCD) affects more than 300,000 children annually worldwide. Despite improved supportive care, long-term prognosis remains poor. Allogeneic hematopoietic cell transplantation (allo-HCT) is the sole validated curative option, resulting in sustained resolution of the clinical phenotype. The medical literature on allo-HCT for SCD is largely limited to children. Recent studies have evaluated allo-HCT efficacy in adults. Here, we conducted a systematic review/meta-analysis to assess the totality of evidence on the efficacy, or lack thereof, of allo-HCT in treating SCD. We performed a comprehensive literature search using PubMed/Medline, Embase, and Cochrane library databases on November 13, 2019. Four authors independently extracted data on clinical outcomes related to benefits (overall survival [OS] and disease-free survival [DFS]) and harms (acute graft-versus-host disease [aGVHD], chronic graft-versus-host disease [cGVHD], nonrelapse mortality [NRM], and graft failure [GF]). Our search identified a total of 1906 references. Only 33 studies (n= 2853 patients) met our inclusion criteria. We also performed a subset analysis by age. Analyses of all-age groups showed pooled rates of 96% for OS, 90% for DFS, 20% for aGVHD, 10% for cGVHD, 4% for NRM, and 5% for GF. In the pediatric population, pooled rates for OS, DFS, aGVHD, cGVHD, NRM, and GF were 97%, 91%, 26%, 11%, 5%, and 3%, respectively. In adults, pooled rates for OS, DFS, aGVHD, cGVHD, NRM, and GF were 98%, 90%, 7%, 1%, 0%, and 14%, respectively. Our data show that allo-HCT is safe and effective, yielding pooled OS rates exceeding 90%. The high GF rate of 14% in adults is concerning and emphasizes the need to evaluate new strategies.
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http://dx.doi.org/10.1016/j.jtct.2020.10.007DOI Listing
February 2021

Impact of Novel Targeted Therapies and Cytogenetic Risk Groups on Outcome After Allogeneic Transplantation for Adult ALL.

Transplant Cell Ther 2021 Feb 11;27(2):165.e1-165.e11. Epub 2020 Dec 11.

Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, Florida. Electronic address:

Novel high-risk groups have recently been identified in adult acute lymphoblastic leukemia (ALL), including Philadelphia-like, therapy-related, and measurable residual disease after induction therapy. Furthermore, modern targeted therapies have recently been incorporated into ALL management; rituximab for CD20-positive and blinatumomab for measurable residual disease after induction therapy or relapsed or refractory disease. Allogeneic hematopoietic cell transplantation (allo-HCT) is recommended as consolidation therapy for high-risk ALL; however, its relative benefit for these high-risk groups and after novel therapies is unclear. We performed an analysis of posttransplantation outcomes in a cohort of 261 consecutive patients who underwent allo-HCT for ALL at the 3-site Mayo Clinic Cancer Center (January 1, 2008-December 31, 2018). With a median (range) follow-up of 22.4 months (0.5-135.0), the 100-day and 5-year cumulative incidences of nonrelapse mortality rates were 6.5% and 26.7%, respectively. The 5-year cumulative incidences of relapse and death were 22.6% and 46.2%, respectively. The 1-year estimate of the composite endpoint of graft-versus-host disease/relapse-free survival was 39.3%. We observed no associations of novel high-risk groups or modern targeted therapies with overall survival, nonrelapse mortality, or relapse in multivariable analysis. An increased risk of relapse was observed with T-ALL (hazard ratio, 2.16; 95% confidence interval, 1.14-4.09; P = .02) and hypodiploidy/near-triploidy (hazard ratio, 2.84; 95% confidence interval, 1.06-7.62; P = .04). Our analysis suggests that novel high-risk groups derive a similar benefit from allo-HCT as traditional high-risk adult ALL and that novel targeted therapies do not seem to independently predict for posttransplantation outcomes. It also calls for further exploration of maintenance strategies after Allo-HCT to prevent relapse in high-risk subgroups.
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http://dx.doi.org/10.1016/j.jtct.2020.10.015DOI Listing
February 2021

Impact of hypoalbuminemia on the prognosis of relapsed/refractory B-cell lymphoma treated with axicabtagene ciloleucel.

Eur J Haematol 2021 Jul 15;107(1):48-53. Epub 2021 Apr 15.

Division of Hematology-Oncology and Blood and Marrow Transplantation and Cellular Therapy Program, Mayo Clinic, Jacksonville, FL, USA.

Introduction: Hypoalbuminemia is a known adverse prognostic factor in lymphomas. Yet, it is unknown if axicabtagene ciloleucel (axi-cel) overcomes the adverse prognostic impact of hypoalbuminemia in relapsed/refractory large B-cell lymphoma.

Methods: We conducted a retrospective analysis across three Mayo Clinic centers to assess the relationship of hypoalbuminemia (defined as a serum albumin (SA) levels ≤ 3.5 g/dL) on outcomes of patients treated with axi-cel.

Results: This analysis included 81 patients. Two patients had no available SA levels preceding axi-cel infusion. Eighteen patients (22.8%) had hypoalbuminemia with a median SA of 3.3 g/dL. Patients with normal SA had a statistically higher ORR than those without hypoalbuminemia (P = .018). There was no difference in 1-year PFS and OS between the group with hypoalbuminemia and the group with normal SA levels (48% vs 49%, P = .81) and (74% vs 73%, P = .97), respectively. There was no difference in the severity or median duration of cytokine release syndrome or neurotoxicity between the two groups.

Conclusion: Notwithstanding the limitations related to the relatively small sample size, axi-cel therapy appears to overcome the adverse effect of hypoalbuminemia on OS and PFS. Large multicenter clinical studies are certainly needed to validate these findings.
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http://dx.doi.org/10.1111/ejh.13609DOI Listing
July 2021

A phase 2 trial of GVHD prophylaxis with PTCy, sirolimus, and MMF after peripheral blood haploidentical transplantation.

Blood Adv 2021 03;5(5):1154-1163

Blood and Marrow Transplant and Cellular Immunotherapy, and.

The introduction of posttransplant cyclophosphamide (PTCy) made performing allogeneic hematopoietic cell transplantation (HCT) from HLA haplotype-incompatible donors possible. In a setting of PTCy and tacrolimus/mycophenolate mofetil (MMF) as a graft-versus-host disease (GVHD) prophylaxis, a peripheral blood (PB) graft source as compared with bone marrow reduces the relapse rate but increases acute GVHD (aGVHD) and chronic GVHD (cGVHD). This phase 2 trial assessed sirolimus and MMF efficacy following PTCy as a GVHD prophylaxis after PB haploidentical HCT (haplo-HCT). With 32 evaluable patients (≥18 years) enrolled, this study had 90% power to demonstrate a reduction in 100-day grade II-IV aGVHD to 20% from the historical benchmark of 40% after haplo-HCT using PTCy/tacrolimus/MMF. At a median follow-up of 16.1 months, the primary end point of the trial was met with a day-100 grade II-IV aGVHD cumulative incidence of 18.8% (95% confidence interval [CI], 7.5% to 34.0%). There were no graft-failure events and the 1-year probability of National Institutes of Health (NIH) moderate/severe cGVHD was 18.8% (95% CI, 7.4% to 34.0%), nonrelapse mortality was 18.8% (95% CI, 7.4% to 34.0%), relapse was 22.2% (95% CI, 9.6% to 38.2%), disease-free survival was 59.0% (95% CI, 44.1% to 79.0%), GVHD-free relapse-free survival was 49.6% (95% CI, 34.9% to 70.5%), and overall survival was 71.7% (95% CI, 57.7% to 89.2%) for the entire cohort. These data demonstrate that GVHD prophylaxis with sirolimus/MMF following PTCy effectively prevents grade II-IV aGVHD after PB haplo-HCT, warranting prospective comparison of sirolimus vs tacrolimus in combination with MMF following PTCy as GVHD prophylaxis after PB HCT. This trial was registered at www.clinicaltrials.gov as #NCT03018223.
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http://dx.doi.org/10.1182/bloodadvances.2020003779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948297PMC
March 2021

Systemic ALK-positive anaplastic large cell lymphoma with bilateral optic neurolymphomatosis resulting in permanent blindness.

Clin Case Rep 2020 Dec 14;8(12):2629-2633. Epub 2020 Aug 14.

Department of Pathology Mayo Clinic Jacksonville Florida.

ALK-positive ALCL can lead to rapid irreversible destruction of the optic pathway. Early treatment should be instituted in patients with CNS involvement or those at increased CNS risk.
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http://dx.doi.org/10.1002/ccr3.3231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752471PMC
December 2020

Outcomes of Hepatosplenic T-Cell Lymphoma: The Mayo Clinic Experience.

Clin Lymphoma Myeloma Leuk 2021 Feb 5;21(2):106-112.e1. Epub 2020 Oct 5.

Division of Hematology/Oncology, Mayo Clinic Florida, Jacksonville, FL. Electronic address:

Background: Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of peripheral T-cell lymphoma accounting for less than 1% of non-Hodgkin lymphomas. It is generally associated with poor prognosis.

Patients And Methods: We performed a cohort study of patients with HSTCL treated at the Mayo Clinic between 1996 and 2020 exploring the clinical characteristics and therapeutic outcomes.

Results: Twenty-two cases of HSTCL were identified with a median (range) age at diagnosis of 45.5 (15.5-80.6) years and a male predominance (15/22, 68.2%). Clinical characteristics include massive splenomegaly in 16 patients (73%), hepatic involvement in 13 (59%), and chronic immunosuppressed state in 8 (36%). Phenotypically, lymphoma cells had gamma/delta T-cell receptor expression in 18 (82%) and alpha/beta in 4 patients. Cytogenetic abnormalities included isochromosome 7q (i7q) in 8 (62%) of 13 and trisomy 8 in 4 (44%) of 9. The median (range) follow-up of surviving patients was 33 (2.5-137) months. The median progression-free and overall survival were 9.5 months (95% CI, 1.8, 16.3) and 12.4 months (95% CI, 4.9, 18.5), respectively. Long-term survival was seen in 4 (18%) of 22 patients, with survival of 55, 74, 95, and 137 months. Moreover, 3 of 4 long-term survivors had splenectomy as part of initial treatment, and 2 of 4 long-term survivors received an allogeneic hematopoietic cell transplant (allo-HCT).

Conclusion: Liver involvement and chronic immunosuppression were associated with shorter survival. Although splenectomy and allo-HCT have anecdotal benefit in the literature, our data do not show a statistically significant benefit of splenectomy and/or allo-HCT, likely as a result of our small sample size.
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http://dx.doi.org/10.1016/j.clml.2020.09.013DOI Listing
February 2021

C-reactive protein and ferritin levels and length of intensive care unit stay in patients with B-cell lymphomas treated with axicabtagene ciloleucel.

Hematol Oncol Stem Cell Ther 2021 Jun 13;14(2):141-146. Epub 2020 Oct 13.

Division of Hematology-Oncology and Blood and Marrow Transplantation and Cellular Therapy Program, Mayo Clinic, Jacksonville, FL, USA. Electronic address:

Objective/background: Chimeric antigen receptor (CAR) T-cell is an effective therapy in relapsed/refractory large B-cell lymphomas that, due to its unique toxicities, often requires escalation of care to the intensive care unit (ICU) setting. C-reactive protein (CRP) and ferritin are serum inflammatory markers associated with onset and persistence of CAR T-cell-related toxicity.

Methods: We retrospectively analyzed 34 patients treated with axicabtagene ciloleucel (axi-cel) who were divided into two groups: patients requiring admission to the ICU during initial hospitalization (n = 13, 38%) and those who did not (n = 21, 62%). Primary objective was to examine possible relationships between serum ferritin and/or CRP levels with the need for, and length of, ICU stay between these groups.

Results: All 13 patients admitted to the ICU developed cytokine release syndrome (CRS) and 11 of them also developed neurotoxicity (NT). Of the 21 patients in the non-ICU group, 18 developed CRS and 5 patients developed NT. Grade of CRS and NT were higher in ICU versus non-ICU patients (p = .03 and .001, respectively). There was no correlation between CRP levels at time of ICU admission and length of ICU stay (correlation of 0.41, p = .17). Yet, there was an association between serum ferritin levels and length of ICU stay (R = 0.73) which did not reach statistical significance (correlation of 0.21, p = .49).

Conclusion: Notwithstanding the limitations of the small sample size, our study suggests that an elevated ferritin level at the time of escalation of medical care may be possibly indicative of anticipated prolonged ICU hospitalization in patients treated with axi-cel. A large multicenter study is certainly needed to confirm this observation.
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http://dx.doi.org/10.1016/j.hemonc.2020.09.004DOI Listing
June 2021

Efficacy of proteasome inhibitor-based maintenance following autologous transplantation in multiple myeloma: A systematic review and meta-analysis.

Eur J Haematol 2021 Jan 16;106(1):40-48. Epub 2020 Oct 16.

Division of Hematology-Oncology and Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, FL, USA.

Introduction: Lenalidomide maintenance, commonly prescribed in the postautologous transplantation (AHCT) setting for multiple myeloma (MM), is associated with development of secondary primary malignancies (SPM). Proteasome inhibitor maintenance (PIM) has also been evaluated in MM. We conduct a systematic review/meta-analysis to assess the efficacy of PIM in MM.

Methods: Performing a comprehensive search of the medical literature using PubMed/Medline and EMBASE on September 11, 2019, we extracted data on clinical outcomes related to benefits (OS, PFS, and depth of hematologic response [DOHR]) and harms (SPM and adverse events). 2144 references were identified; three studies were eligible for inclusion.

Results: A total of 1760 patients were included in the analysis; 507 patients received bortezomib and 395 received ixazomib maintenance. Control arms were either placebo (n = 261) or thalidomide (n = 358). PIM did not improve OS (HR 0.88, 95% CI 0.73-1.05, P = .15) but improved PFS (HR 0.77, 95% CI 0.69-0.86, P ≤ .00001) and DOHR (HR 0.88, 95% CI 0.79-0.98, P = .02) compared with control. There were no significant differences between PIM and control regarding SPM (p = NS) and ≥grade 3 peripheral neuropathy (PN) (p = NS).

Conclusions: PIM following AHCT in MM improves PFS and DOHR without an increase in development of SPM or severe PN compared with placebo/thalidomide.
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http://dx.doi.org/10.1111/ejh.13506DOI Listing
January 2021

Efficacy of Autologous and Allogeneic Hematopoietic Cell Transplantation in Waldenström Macroglobulinemia: A Systematic Review and Meta-analysis.

Clin Lymphoma Myeloma Leuk 2020 10 2;20(10):e694-e711. Epub 2020 Jun 2.

Division of Hematology-Oncology and Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, FL. Electronic address:

Introduction: Waldenström macroglobulinemia (WM) is an IgM-producing lymphoproliferative disorder that remains incurable. Patients with high-risk disease have an overall survival (OS) of less than 3 years. Both autologous (AHCT) and allogeneic (allo-HCT) hematopoietic cell transplantation (HCT) are prescribed for treatment of WM despite a lack of randomized controlled studies.

Materials And Methods: We performed a comprehensive literature search using PubMed/Medline and EMBASE on September 10, 2019. Data on clinical outcomes related to benefits and harms was extracted independently by 3 authors. Fifteen studies (8 AHCT [n = 278 patients], 7 allo-HCT [n = 311 patients]) were included in this systematic review/meta-analysis.

Results: Pooled OS, progression-free survival (PFS), and nonrelapse mortality (NRM) rates post AHCT were 76% (95% confidence interval [CI], 65%-86%), 55% (95% CI, 42%-68%), and 4% (95% CI, 1%-7%), respectively. Pooled OS, PFS, and NRM rates post allografting were 57% (95% CI, 50%-65%), 49% (95% CI, 42%-56%), and 29% (95% CI, 23%-34%), respectively. OS and PFS rates were reported at 3 to 5 years, and NRM was reported at 1 year in most studies. Pooled ORR (at day 100) post AHCT and allo-HCT were 85% (95% CI, 72%-94%) and 81% (95% CI, 69%-91%), respectively. Pooled complete response rates post AHCT and allo-HCT were 22% (95% CI, 17%-28%) and 26% (95% CI, 7%-50%), respectively. Relapse rates post AHCT and allo-HCT were 42% (95% CI, 30%-55%) and 23% (95% CI, 18%-28%), respectively.

Conclusions: Our results show that both AHCT and allo-HCT are effective in the treatment of WM. A 2-fold lower relapse rate but a 7-fold higher NRM was noted for allo-HCT compared with AHCT. The role of transplant in WM needs to be addressed in the era of novel agents.
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http://dx.doi.org/10.1016/j.clml.2020.05.021DOI Listing
October 2020

Allogeneic hematopoietic cell transplantation is an effective treatment for patients with Richter syndrome: A systematic review and meta-analysis.

Hematol Oncol Stem Cell Ther 2021 Mar 15;14(1):33-40. Epub 2020 May 15.

Division of Hematology-Oncology and Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, FL, USA. Electronic address:

Efficacy of conventional chemoimmunotherapy is limited in patients with Richter syndrome (RS) with anticipated median overall survival (OS) of less than 10 months. Allogeneic hematopoietic cell transplantation (allo-HCT) is commonly offered as a consolidative treatment option in RS. To our knowledge, there are no randomized controlled studies that have compared allo-HCT against other therapies in RS; available allo-HCT data are limited to small case series from single-institution or registry studies. We performed a systematic review and meta-analysis to assess the totality of evidence regarding the efficacy (or lack thereof) of allo-HCT for RS. We extracted data on post-allograft outcomes related to benefits (overall response rate [ORR], complete remission [CR], OS, and progression-free survival [PFS]). For harms, data were extracted on non-relapse mortality (NRM) and relapse post-allografting. Our search strategy identified 240 studies, but only four studies (n = 72 patients) met our inclusion criteria. Pooled ORR, CR, OS, and PFS rates were 79%, 33%, 49%, and 30%, respectively. Pooled NRM and relapse rates were 24% and 28%, respectively. Results of this systematic review and meta-analysis indicate that allo-HCT yields encouraging OS in RS, thus remaining a reasonable treatment option in fit patients whose disease demonstrates a chemosensitive response to pre-transplant salvage therapies. Novel strategies are certainly needed to reduce the risk of relapse to further improve outcomes in these patients.
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http://dx.doi.org/10.1016/j.hemonc.2020.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666647PMC
March 2021

Rapidly Resolving and Recurrent Contralateral Subdural Hematoma From Disseminated Intravascular Coagulation.

J Stroke Cerebrovasc Dis 2020 Aug 18;29(8):104872. Epub 2020 May 18.

Department of Neurology, Mayo Clinic, Jacksonville, Florida, United States; Department of Critical Care Medicine, Mayo Clinic, Jacksonville, Florida, United States; Department of Neurologic Surgery, Mayo Clinic, Jacksonville, Florida, United States. Electronic address:

Background: Acute, recurrent subdural hematoma (SDH) is a rare entity in the absence of trauma. Atraumatic SDH may be due to vascular disorders, coagulopathies, or intracranial hypotension. It is a rare complication of disseminated intravascular coagulation (DIC), with no prior reports in patients with intracranial metastatic colon cancer (MCC). Rapid resolution of the initial acute SDH with contralateral recurrence has not yet been reported in the literature. We present a case of rapidly resolving and recurrent, contralateral acute SDH from DIC secondary to MCC.

Case Description: A 77-year-old woman with MCC presented with severe, acute onset headache. She progressed to unresponsiveness, dilated right pupil, and Glasgow Coma Scale (GCS) score of 4T. Initial computed tomography (CT) of the head demonstrated a right, 17-mm SDH with a right-to-left midline shift. Repeat CT head 8 hours later revealed resolution of the right SDH. She was extubated with notable clinical improvement. Laboratory examination showed international normalized ratio of 3.4, leukocytosis, and thrombocytopenia. The next morning, she became lethargic, GCS score of 3, with bilateral fixed pupils and dilated to 5-mm, and she was then reintubated. Repeat CT head demonstrated a new left SDH with bilateral uncal herniation. A small hyperdense focus in the left parietal region was suspicious for intraparenchymal hematoma versus a hemorrhagic metastatic focus. Shortly after, she was extubated due to do not resuscitate status, and she then passed away.

Conclusions: To our knowledge, this is the first case illustrating rapidly resolving and recurrent, contralateral acute SDH from DIC in a patient with MCC. Clinical recognition of this phenotypic pattern should raise the question of an underlying coagulopathy.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.104872DOI Listing
August 2020

Impact of Depression and Anxiety on Opioid Use in Hospitalized Hematopoietic Cell Transplantation Recipients.

Psychosomatics 2020 Jul - Aug;61(4):363-370. Epub 2020 Mar 26.

Division of Hematology-Oncology and Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, FL. Electronic address:

Background: Hematopoietic cell recipients are reported to have a high prevalence of depression and anxiety. The impact of depression and anxiety on opioid use has not been well characterized. This is of significance as the opioid epidemic continues, and over 60% of deaths secondary to drug overdose involve the use of opioids.

Objective: In this retrospective, single-center study of 275 patients who underwent hematopoietic cell transplantation (HCT) (allogeneic and autologous) for hematological malignancies, we explore the impact of depression and anxiety on opioid use.

Results: Patients who were both anxious and depressed at admission for HCT had increased odds of receiving an opioid (odds ratio of 4.50 [95% confidence interval: 1.75, 11.56]) compared with patients who were neither depressed nor anxious. However, patients who were either depressed or anxious did not have different odds of receiving an opioid compared with those who were neither depressed nor anxious. Autologous HCT recipients had reduced odds of receiving an opioid (odds ratio of 0.17 [95% confidence interval: 0.08, 0.38]) compared with patients undergoing allogeneic HCT. Patients with lower Karnofsky performance status (<90 on a scale of 1-100) had an increased incidence of receiving a higher Morphine milligram equivalent daily dosage (incidence rate ratio of 2.59 [95% confidence interval: 1.18, 5.67]) when modeled by zero truncated negative binomial regression.

Conclusion: Presence of depression and anxiety impacts opioid use in patients undergoing HCT.
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http://dx.doi.org/10.1016/j.psym.2020.03.003DOI Listing
March 2020

Primary diffuse large B-cell lymphoma presenting as acute appendicitis: A report of 2 cases and a literature review.

Clin Case Rep 2020 Feb 7;8(2):293-298. Epub 2020 Jan 7.

Division of Hematology-Oncology Mayo Clinic Jacksonville FL USA.

Primary appendiceal lymphomas (PAL) are a type of primary gastrointestinal non-Hodgkin lymphoma (PGINHL) with an incidence of <1%. There is considerable discordance with regard to the optimal management of PGINHL. We describe two cases of PAL, perform a literature review, and discuss the available evidence for optimal treatment.
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http://dx.doi.org/10.1002/ccr3.2653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044370PMC
February 2020

Corrigendum to 'Efficacy of allogeneic HCT in HTLV-1 associated adult T-cell leukemia/lymphoma: results of a systematic review/meta-analysis' [Biology of Blood and Marrow Transplantation 25/8 (2019) 1695-1700].

Biol Blood Marrow Transplant 2020 Jan 11;26(1):209-212. Epub 2019 Oct 11.

Division of Hematology-Oncology and Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, Florida. Electronic address:

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http://dx.doi.org/10.1016/j.bbmt.2019.09.014DOI Listing
January 2020

Efficacy of Allogeneic Hematopoietic Cell Transplantation in Cutaneous T Cell Lymphoma: Results of a Systematic Review and Meta-Analysis.

Biol Blood Marrow Transplant 2020 01 5;26(1):76-82. Epub 2019 Sep 5.

Division of Hematology-Oncology and Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, Florida. Electronic address:

Mycosis fungoides and Sézary syndrome are the most common types of primary cutaneous T cell lymphomas. The clinical presentation of mycosis fungoides is generally indolent, whereas Sézary syndrome represents a more aggressive disease variant. Stage at diagnosis is the most important determinant of long-term survival outcome. Although most patients present with early-stage disease, those who develop progressive disease or have an advanced stage represent a therapeutic challenge because of a lack of effective therapies. Allogeneic hematopoietic cell transplantation (allo-HCT) has been used as a potentially curative treatment modality with encouraging long-term outcomes. However, a lack of randomized controlled data remains, and the published literature is limited to mostly retrospective studies. We performed a comprehensive search of the medical literature using PubMed/Medline, EMBASE, and Cochrane reviews on September 13, 2018. We extracted data on clinical outcomes related to benefits (overall [OS] and progression-free [PFS] survival) and harms (relapse and nonrelapse mortality [NRM]) independently by 2 authors. Our search strategy identified 289 references. Five studies (266 patients) were included in this systematic review and meta-analysis. Reduced-intensity and nonmyeloablative regimens were more commonly prescribed (76%). Mobilized peripheral blood stem cells were the preferred graft source (78%). The pooled OS and PFS rates were 59% (95% confidence interval [CI], 50% to 69%) and 36% (95% CI, 27% to 45%), respectively. Pooled relapse rate was 47% (95% CI, 41% to 53%) and pooled NRM rate 19% (95% CI, 13% to 27%). Results of this systematic review and meta-analysis show that allo-HCT yields encouraging OS and PFS rates; however; relapse remains a significant cause of allo-HCT failure. Novel strategies to further improve outcomes should focus on offering allo-HCT before the development of resistant disease and reducing relapse by incorporating post-transplant maintenance therapies.
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http://dx.doi.org/10.1016/j.bbmt.2019.08.019DOI Listing
January 2020

Allogeneic Hematopoietic Cell Transplant for HIV Patients with Hematologic Malignancies: The BMT CTN-0903/AMC-080 Trial.

Biol Blood Marrow Transplant 2019 11 4;25(11):2160-2166. Epub 2019 Jul 4.

Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.

We set out to assess feasibility and safety of allogeneic hematopoietic cell transplant in 17 persons with HIV in a phase II prospective multicenter trial. The primary endpoint was 100-day nonrelapse mortality (NRM). Patients had an 8/8 HLA-matched related or at least a 7/8 HLA-matched unrelated donor. Indications for transplant were acute leukemia, myelodysplasia, and lymphoma. Conditioning was myeloablative or reduced intensity. There was no NRM at 100 days. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 41%. At 1 year, overall survival was 59%; deaths were from relapsed/progressive disease (n = 5), acute GVHD (n = 1), adult respiratory distress syndrome (n = 1), and liver failure (n = 1). In patients who achieved complete chimerism, cell-associated HIV DNA and inducible infectious virus in the blood were not detectable. Blood and Marrow Transplant Clinical Trials Network 0903/AIDS Malignancy Consortium 080 was registered at www.clinicaltrials.gov (no. NCT01410344).
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http://dx.doi.org/10.1016/j.bbmt.2019.06.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907401PMC
November 2019

High-dose Therapy and Autologous Hematopoietic Cell Transplantation as Consolidation Treatment for Primary Effusion Lymphoma.

Clin Lymphoma Myeloma Leuk 2019 09 29;19(9):e513-e520. Epub 2019 Mar 29.

Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Background: Primary effusion lymphoma (PEL) is a rare type of non-Hodgkin lymphoma. The limited disease-free survival after chemotherapy has resulted in a poor prognosis. The outcomes data for high-dose therapy followed by autologous hematopoietic cell transplantation (auto-HCT) for PEL are limited owing to the rarity of the disease.

Patients And Methods: The present study included 9 patients with PEL from 2 major academic centers. Of these patients, 4 had received auto-HCT after high-dose therapy. Of the 9 patients, 8 (89%) had immunodeficiency (7 with human immunodeficiency virus seropositivity; 1, a solid organ transplant recipient) at the diagnosis. Human herpesvirus-8 by immunohistochemistry was positive in 8 patients. Anthracycline-based combination chemotherapy was used as first-line treatment in 7 patients; 4 underwent auto-HCT after attaining first complete remission.

Results: The median follow-up of the surviving patients was 25 months (95% confidence interval [CI], 8%-29%). The 2-year progression-free and overall survival for the 8 patients who had received treatment was 58% (95% CI, 22%-95%) and 73% (95% CI, 41%-100%), respectively. The 2-year progression-free and overall survival for the patients who had received auto-HCT was 50% (95% CI, 1%-99%) and 75% (95% CI, 33%-100%), respectively. Of the 4 auto-HCT recipients, all had been in first complete remission at the time of autografting. The cumulative incidence of relapse was 50% (95% CI, 19%-100%). No deaths were attributable to auto-HCT at 2 years after autografting.

Conclusion: Despite the small sample size, our data have shown that consolidative auto-HCT is safe and effective and should be considered for eligible patients with PEL after demonstration of an objective response to induction chemotherapy. However, the high relapse rate remains a concern and warrants the development of new strategies to mitigate post-transplantation relapse.
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http://dx.doi.org/10.1016/j.clml.2019.03.021DOI Listing
September 2019

Efficacy of Allogeneic Hematopoietic Cell Transplantation in Human T Cell Lymphotropic Virus Type 1-Associated Adult T Cell Leukemia/Lymphoma: Results of a Systematic Review/Meta-Analysis.

Biol Blood Marrow Transplant 2019 08 25;25(8):1695-1700. Epub 2019 May 25.

Division of Hematology-Oncology and Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, Florida. Electronic address:

Human T cell lymphotropic virus type 1 (HTLV1)-associated adult T cell leukemia/lymphoma (ATLL) is an aggressive malignant disorder. Intensive conventional chemotherapy regimens and autologous hematopoietic cell transplantation (HCT) have failed to improve outcomes in ATLL. Allogeneic HCT (allo-HCT) is commonly offered as front-line consolidation despite lack of randomized controlled trials. We performed a comprehensive search of the medical literature using PubMed/Medline, EMBASE, and Cochrane reviews on September 10, 2018. We extracted data on clinical outcomes related to benefits (complete response [CR], overall survival [OS], and progression-free survival [PFS]) and harms (relapse and nonrelapse mortality [NRM]), independently by 2 authors. Our search strategy identified a total of 801 references. Nineteen studies (n = 2446 patients) were included in the systematic review; however, only 18 studies (n = 1767 patients) were included in the meta-analysis. Reduced intensity conditioning regimens were more commonly prescribed (52%). Bone marrow (50%) and peripheral blood (40%) were more frequently used as stem cell source. The pooled post-allografting CR, OS, and PFS rates were 73% (95% confidence interval [CI], 57% to 87%), 40% (95% CI, 33% to 46%), and 37% (95% CI, 27% to 48%), respectively. Pooled relapse and NRM rates were 36% (95% CI, 28% to 43%) and 29% (95% CI, 21% to 37%), respectively. The heterogeneity among the included studies was generally high. These results support the use of allo-HCT as an effective treatment for patients with ATLL, yielding pooled OS rates of 40%, but relapse still occurs in over one-third of cases. Future studies should evaluate strategies to help reduce relapse in patients with ATLL undergoing allo-HCT.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.027DOI Listing
August 2019

Primary Cutaneous T-Cell Lymphoblastic Lymphoma: Case Report and Literature Review.

Case Rep Hematol 2019 20;2019:3540487. Epub 2019 Feb 20.

Mayo Clinic, Jacksonville, FL, USA.

Cutaneous involvement by precursor T-cell lymphoblastic leukemia/lymphoma (T-ALL/LBL) is rare, and almost all cases are seen in association with bone marrow, blood, and/or lymph node involvement. Presentation with isolated skin involvement is very rare. Literature review revealed only one case report of primary cutaneous T-cell LBL. We discuss here another patient diagnosed with primary cutaneous T-cell LBL at our institute. This patient was initially misdiagnosed as having peripheral T-cell lymphoma NOS. Cytogenetic analysis showed the CDKN2A deletion (-9p21×2) in addition to three intact copies of ABL1 (+9q34). Although she failed multiple lines of intensive chemotherapy, her disease remained confined to the skin. We believe that this presentation of T-LBL is underreported, and many patients are likely misdiagnosed as having high-grade cutaneous T-cell lymphomas. With this case and literature review, we would like to highlight the importance of keeping lymphoblastic lymphoma on the differential diagnosis of cutaneous T-cell lymphoma-like lesions to avoid delay in diagnosis and inappropriate treatment of this aggressive disease.
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http://dx.doi.org/10.1155/2019/3540487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402200PMC
February 2019

Autologous Stem Cell Transplantation in Central Nervous System Lymphoma: A Multicenter Retrospective Series and a Review of the Literature.

Clin Lymphoma Myeloma Leuk 2019 06 26;19(6):e273-e280. Epub 2019 Feb 26.

Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL; Division of Hematology-Oncology and Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, FL. Electronic address:

Background: Central nervous system (CNS) lymphoma is associated with poor outcomes. Autologous stem cell transplantation (ASCT) has been reported to improve outcomes when used as a consolidation strategy in primary CNS lymphoma (PCNSL) and as a salvage strategy in patients with disease relapse limited to the CNS. Herein, we describe our experience of using ASCT in PCNSL and secondary CNS lymphoma (SCNSL).

Patients And Methods: We evaluated clinical outcomes of 18 patients from 2 major academic centers with a median age of 55 (range, 46-72) years. Thirteen patients had PCNSL and 5 patients had SCNSL. Most of the cases were in the first (CR1) or second (CR2) complete remission (CR1 = 7, CR2 = 7) at the time of ASCT. Carmustine with thiotepa (n = 12, 67%) was the most commonly prescribed preparative regimen.

Results: The median follow-up from ASCT for surviving patients was 12 (range, 0.9-115) months. The 2-year progression-free survival (PFS) and overall survival (OS) were 74% (95% confidence interval [CI], 48%-99%) and 80% (95% CI, 55%-100%), respectively. Two-year non-relapse mortality was 0%. The 2-year cumulative incidence of relapse/progression was 27% (95% CI, 10%-72%). In subgroup analysis of PCNSL patients, 2-year PFS, OS, and relapse were 71% (95% CI, 38%-100%), 71% (95% CI, 38%-100%), and 29% (95% CI, 9%-92%), respectively.

Conclusion: In this retrospective study of patients with CNS lymphoma, consolidation with ASCT after high-dose methotrexate-based chemotherapy is safe and effective in reducing disease relapse.
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http://dx.doi.org/10.1016/j.clml.2019.02.013DOI Listing
June 2019

Reproducibility of BiliCare™ Transcutaneus Bilirrubin Meter in Mexican Newborns.

Int J Pediatr 2019 1;2019:3812152. Epub 2019 Jan 1.

Health Science Department, School of Medicine. Anahuac University State of México, Mexico.

Background: Newborn hyperbilirubinemia is considered a worldwide health problem that demands medical evaluation. Noninvasive transcutaneous bilirubin (TcB) has been used as a screening method with different devices but there has not been any evaluation of reproducibility of the same brand devices. The BiliCare™ system is evaluated to demonstrate consistency between measurements with four different devices.

Methods: 336 TcB measurements were obtained with four BiliCare™ devices in 21 Mexican icteric newborns with a mean postnatal age of 44.1 hours of life and 38 weeks of gestation (33-41). Two measurements were taken in the same ear alternatively at the scaphoid fossa with each device. TcB values were compared between devices. Validity was compared with total serum bilirubin (TB).

Results: intraclass correlation coefficient demonstrates a minimum limit in the study of 0.945 and maximum of 0.988 with the same device. Correlations with serum and between devices gave results above 0.932.

Conclusions: BiliCare™ transcutaneous bilirubin measurement instrument has very good intra- and interdevice reproducibility; also correlation of TcS with serum bilirubin gave statistically the same results.
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http://dx.doi.org/10.1155/2019/3812152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333005PMC
January 2019

Allogeneic Hematopoietic Cell Transplantation Is an Effective Treatment for Blastic Plasmacytoid Dendritic Cell Neoplasm in First Complete Remission: Systematic Review and Meta-analysis.

Clin Lymphoma Myeloma Leuk 2018 11 2;18(11):703-709.e1. Epub 2018 Aug 2.

Program for Comparative Effectiveness Research, Morsani College of Medicine, University of South Florida, Tampa, FL. Electronic address:

Introduction: It is common practice to refer patients to transplantation centers for allogeneic hematopoietic cell transplantation (allo-HCT) for blastic plasmacytoid dendritic-cell neoplasm (BPDCN) despite lack of randomized controlled trials. We performed a systematic review to assess the totality of evidence pertaining to the efficacy of allo-HCT in BPDCN.

Methods: We searched the Cochrane, PubMed, and Embase databases through January 5, 2018, for studies on allo-HCT for BPDCN. Two authors independently reviewed all references for inclusion and extracted data related to benefits (overall [OS] and progression-free/disease-free [PFS/DFS] survival) and harms (relapse and nonrelapse mortality) from included studies. When appropriate, data were pooled using random-effects model.

Results: Four studies (128 patients) were included in analysis. Pooled OS rate was 50% (95% confidence interval [CI], 41-59) for all patients. Among patients who underwent allografting whose disease was in first complete remission (CR1), pooled OS and PFS/DFS rates were 67% (95% CI, 52-80) and 53% (95% CI, 29-76), respectively. For patients who underwent allografting in > CR1, pooled OS and PFS/DFS rates were 7% (95% CI, 0-32) for both outcomes. Relapse rates were higher when reduced-intensity regimens were used (40% [95% CI, 25-56] vs. 18% [95% CI, 7-31]).

Conclusion: This systematic review represents the best available evidence supporting allo-HCT in BPDCN, especially when offered in CR1. Use of myeloablative allo-HCT results in lower pooled relapse rates (18% vs. 40%). A prospective comparative study will be needed to determine the impact of intensity of the conditioning regimen on postallograft relapse.
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http://dx.doi.org/10.1016/j.clml.2018.07.295DOI Listing
November 2018

Allogeneic hematopoietic cell transplantation is potentially curative in mantle cell lymphoma: results from a single institution study.

Leuk Lymphoma 2019 02 2;60(2):309-316. Epub 2018 Jul 2.

c Blood and Marrow Transplantation , University of South Florida/Moffitt Cancer Center , Tampa , FL , USA.

Allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative treatment for mantle cell lymphoma (MCL). We retrospectively analyzed outcomes of 36 patients, median age of 54 (41-68) years, who underwent allo-HCT, mostly (66%) receiving a myeloablative (MAC) regimen. Median overall survival (OS) was 86 months and 5-year OS was 54%. Median progression-free survival (PFS) was 54 months and 5-year PFS was 49%. Cumulative incidence (CI) of non-relapse mortality (NRM) and 2-year progression were 20.1 and 22.1%, respectively. Day +100 CI of grade II-IV acute graft-versus-host disease (GVHD) was 38.1%; 2-year CI of moderate/severe chronic GVHD was 31.7%. Seven patients received allo-HCT as frontline consolidation and had better OS (median = not reached versus 54 months, p = .045). Notwithstanding the small sample size and retrospective study design, our findings suggest a role for allo-HCT in selected MCL patients. Future prospective studies would be needed to better define the role of allo-HCT in this disease.
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http://dx.doi.org/10.1080/10428194.2018.1468894DOI Listing
February 2019

Feasibility and Efficacy of High-Dose Chemotherapy and Autologous Hematopoietic Cell Transplantation for HIV-Associated Lymphoma: A Single-Institution Experience.

Clin Lymphoma Myeloma Leuk 2018 08 23;18(8):548-551. Epub 2018 May 23.

Department of Blood and Marrow Transplantation and Cellular Immune Therapies, Moffitt Cancer Center, Tampa, FL.

Background: HIV-associated lymphomas (HAL) remain an important cause of morbidity and mortality in HIV patients, especially in the setting of treatment-refractory disease. Hematopoietic cell transplantation (HCT) is considered a curative option for patients with refractory HAL.

Patients And Methods: We report the efficacy of autologous HCT in 20 patients with HAL [non-Hodgkin lymphoma = 14 (70%), Hodgkin lymphoma = 6 (30%)]. At the time of transplantation, the median peripheral blood CD4 count was 226 cells/μL. HIV virus load was undetectable in 14 (70%) of 20 patients.

Results: The median follow-up of surviving patients was 47 months (range, 20-119 months). The median time to neutrophil engraftment was 11 days. The median progression-free survival and median overall survival have not been reached. At 4 years after transplantation, progression-free survival and overall survival were 65% and 70%, respectively. Six patients died from disease relapse or progression (n = 5) and infection (n = 1). Nonrelapse mortality was 0 and 5% at 100 days and 4 years after transplantation, respectively.

Conclusion: Autologous HCT is an effective therapy for refractory/relapsed HAL with manageable toxicity, similar to non-HIV patients.
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http://dx.doi.org/10.1016/j.clml.2018.05.011DOI Listing
August 2018

Sezary syndrome manifesting as posttransplant lymphoproliferative disorder.

Leuk Res Rep 2018 1;9:72-75. Epub 2018 May 1.

Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, USA.

Posttransplant lymphoproliferative disorders (PTLDs) of T-cell orgin are rare biologically heterogeneous diseases of mature lymphoid cells manifesting in immunosuppressed patients. Only a few cases of mycosis fungoides diagnosed post allogeneic hematopoietic cell transplant (alloHSCT) have been described so far. We present a patient with myelodysplastic syndrome (MDS) post matched unrelated donor alloHSCT who was on long-term immunosuppressive therapy due to graft versus host disease. Three years after an alloHSCT, she developed generalized erythroderma and peripheral blood lymphocytosis. Both skin biopsy and peripheral blood flow cytometry revealed atypical CD4+ T-cell population consistent with diagnosis of Sezary syndrome. Chimerism studies revealed 100% donor engraftment. Therapy with extracorporeal photopheresis resulted in complete response in blood and skin.
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http://dx.doi.org/10.1016/j.lrr.2018.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5948470PMC
May 2018

Allogeneic hematopoietic cell transplantation in T-cell prolymphocytic leukemia: A single-center experience.

Leuk Res 2018 04 31;67:1-5. Epub 2018 Jan 31.

Department of Blood & Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL, USA.

Background: T- cell prolymphocytic leukemia (T- PLL) is a rare aggressive hematological malignancy. Alemtuzumab, an anti-CD52 humanized monoclonal antibody, is the treatment of choice for remission induction. Allogeneic hematopoietic cell transplantation (allo-HCT) has been described to induce durable remissions and improve survival, but data is limited.

Patients And Methods: We evaluated clinical outcomes of 11 patients, median age of 56 (range, 43-71) years who underwent allo-HCT for T-PLL. The majority of cases were in the first complete remission (CR1 = 9, CR2 = 1, second partial response PR2 = 1) at time of allo-HCT. Myeloablative conditioning was the most commonly prescribed preparative regimen (n = 8, 73%) and tacrolimus plus sirolimus was most commonly prescribed regimen for graft-versus-host disease prophylaxis (n = 5, 46%).

Results: The median follow-up for surviving patients was 48 (range, 6-123) months. The 4-year progression-free survival (PFS) and overall survival (OS) were 45% (95% confidence interval (CI) = 13-78%) and 56% (95% CI = 24-89%), respectively. Cumulative incidence of non-relapse mortality (NRM) at 4-year post-transplantation was 34% (95%CI = 14-85%). The 4-year cumulative incidence of relapse/progression was 21% (95% CI = 6-71%).

Conclusion: Allo-HCT is an effective treatment for T-PLL. Patients must be evaluated for their candidacy for allo-HCT as soon as the diagnosis is confirmed. Efforts are needed to decrease NRM and relapse.
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http://dx.doi.org/10.1016/j.leukres.2018.01.009DOI Listing
April 2018

Hypoalbuminaemia segregates different prognostic subgroups within the refined standard risk acute graft-versus-host disease score.

Br J Haematol 2018 03 18;180(6):854-862. Epub 2018 Jan 18.

Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL, USA.

Hypoalbuminaemia has been previously described to predict worse non-relapse mortality (NRM) and inferior overall survival (OS) in allogeneic haematopoietic cell transplant (allo-HCT) recipients. Here, we evaluate the role of hypoalbuminaemia (<35 g/l) at time of onset of acute graft-versus-host disease (aGVHD) when incorporated into the refined aGVHD score. The study population consisted of 522 patients, median age 53 (18-75) years, who underwent an allo-HCT mostly for haematological malignancies. Standard risk (SR) aGVHD comprised 467 patients (89%) and the number of high risk (HR) cases was 55 (11%). Median follow-up for all surviving patients was 26 (3-55) months. Two-year OS was significantly better in patients with SR aGVHD with a serum albumin ≥35 g/l compared to SR with albumin <35 g/l [70% (95% CI = 64-76%) vs. 49% (95% CI = 42-56%), P < 0·0001]. Also, patients with SR aGVHD and a serum albumin level of ≥35 g/l had a significantly lower NRM at 1-year post-transplantation [6% (95% CI = 3-10%) vs. 25% (95% CI = 20-32%), P < 0·0001]. After our findings are validated in a large cohort of patients, we propose that hypoalbuminaemia should be incorporated into the refined aGVHD risk score to further its ability to predict outcomes within this group.
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http://dx.doi.org/10.1111/bjh.15105DOI Listing
March 2018

IL-12/IL-23p40 neutralization blocks Th1/Th17 response after allogeneic hematopoietic cell transplantation.

Haematologica 2018 03 14;103(3):531-539. Epub 2017 Dec 14.

Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.

T-helper 1 and T-helper 17 lymphocytes mediate acute graft--host disease (GvHD). Interleukin 12 is critical for T-helper 1 differentiation and interleukin 23 for T-helper 17 maintenance. Interleukin 12 and 23 are heterodimeric cytokines that share the p40 subunit (IL-12/IL-23p40). In a randomized, blinded, placebo-controlled trial, we examined the biological impact and clinical outcomes following IL-12/IL-23p40 neutralization using ustekinumab. Thirty patients received peripheral blood mobilized hematopoietic cell transplantation (HCT) from HLA-matched sibling or unrelated donors, received sirolimus plus tacrolimus as GvHD prophylaxis, and were randomized to ustekinumab placebo with 1:1 allocation after stratification by donor type. The primary end point of the trial was the mean percentage (%) T-regulatory (Treg) cells on day 30 post HCT. Ustekinumab was delivered by subcutaneous injection on day -1 and day +20 after transplantation. On day 30 post transplant, no significant difference in % Treg was observed. Ustekinumab suppressed serum IL-12/IL-23p40 levels. Host-reactive donor alloresponse at days 30 and 90 after transplantation was polarized with significant reduction in IL-17 and IFN-α production and increase in IL-4. No toxicity attributed to ustekinumab was observed. Overall survival and National Institute of Health moderate/severe chronic GvHD-free, relapse-free survival were significantly improved among ustekinumab-treated patients. No significant improvements were observed in acute or chronic GvHD, relapse, or non-relapse mortality. These data provide first evidence that IL-12/IL-23p40 neutralization can polarize donor anti-host alloresponse and provide initial clinical efficacy evidence to be tested in subsequent trials. (Trial registered at ).
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http://dx.doi.org/10.3324/haematol.2017.171199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830373PMC
March 2018