Publications by authors named "Phillip Scheinberg"

86 Publications

Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial.

BMJ 2021 01 20;372:n84. Epub 2021 Jan 20.

BP-A Beneficência Portuguesa de São Paulo, Rua Maestro Cardim, 769-Bela Vista, São Paulo-SP, 01323-001, Brazil.

Objective: To determine whether tocilizumab improves clinical outcomes for patients with severe or critical coronavirus disease 2019 (covid-19).

Design: Randomised, open label trial.

Setting: Nine hospitals in Brazil, 8 May to 17 July 2020.

Participants: Adults with confirmed covid-19 who were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two serum biomarkers (C reactive protein, D dimer, lactate dehydrogenase, or ferritin). The data monitoring committee recommended stopping the trial early, after 129 patients had been enrolled, because of an increased number of deaths at 15 days in the tocilizumab group.

Interventions: Tocilizumab (single intravenous infusion of 8 mg/kg) plus standard care (n=65) versus standard care alone (n=64).

Main Outcome Measure: The primary outcome, clinical status measured at 15 days using a seven level ordinal scale, was analysed as a composite of death or mechanical ventilation because the assumption of odds proportionality was not met.

Results: A total of 129 patients were enrolled (mean age 57 (SD 14) years; 68% men) and all completed follow-up. All patients in the tocilizumab group and two in the standard care group received tocilizumab. 18 of 65 (28%) patients in the tocilizumab group and 13 of 64 (20%) in the standard care group were receiving mechanical ventilation or died at day 15 (odds ratio 1.54, 95% confidence interval 0.66 to 3.66; P=0.32). Death at 15 days occurred in 11 (17%) patients in the tocilizumab group compared with 2 (3%) in the standard care group (odds ratio 6.42, 95% confidence interval 1.59 to 43.2). Adverse events were reported in 29 of 67 (43%) patients who received tocilizumab and 21 of 62 (34%) who did not receive tocilizumab.

Conclusions: In patients with severe or critical covid-19, tocilizumab plus standard care was not superior to standard care alone in improving clinical outcomes at 15 days, and it might increase mortality.

Trial Registration: ClinicalTrials.gov NCT04403685.
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http://dx.doi.org/10.1136/bmj.n84DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815251PMC
January 2021

Eltrombopag monotherapy can improve hematopoiesis in patients with low to intermediate risk-1 myelodysplastic syndrome.

Haematologica 2020 12 1;105(12):2785-2794. Epub 2020 Dec 1.

National Heart, Lung, and Blood Institute.

Myelodysplastic syndromes (MDS) are a group of clonal myeloid disorders characterized by cytopenia and a propensity to develop acute myeloid leukemia (AML). The management of lower-risk (LR) MDS with persistent cytopenias remains suboptimal. Eltrombopag (EPAG), a thrombopoietin receptor agonist, can improve platelet counts in LR-MDS and tri-lineage hematopoiesis in aplastic anemia (AA). We conducted a phase 2 dose modification study to investigate the safety and efficacy of EPAG in LR-MDS. EPAG dose was escalated from 50 mg/day, to a maximum of 150 mg/day over a period of 16 weeks. The primary efficacy endpoint was hematologic response at 16-20 weeks. Eleven of 25 (44%) patients responded; five and six patients had uni- or bi-lineage hematologic responses, respectively. The predictors of response were presence of a PNH clone, marrow hypocellularity, thrombocytopenia with or without other cytopenia, and elevated plasma thrombopoietin levels at study entry. The safety profile was consistent with previous EPAG studies in AA; no patients discontinued drug due to adverse events. Three patients developed reversible grade-3 liver toxicity and one patient had increased reticulin fibrosis. Ten patients discontinued EPAG after achieving a robust response (median time 16 months); four of them reinitiated EPAG due to declining counts, and all attained a second robust response. Six patients had disease progression not associated with expansion of mutated clones and no patient progressed to AML on study. In conclusion, EPAG was well-tolerated and effective in restoring hematopoiesis in patients with low to intermediate-1 risk MDS. This study was registered at clinicaltrials.gov as #NCT00932156.
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http://dx.doi.org/10.3324/haematol.2020.249995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716353PMC
December 2020

Eltrombopag preferentially expands haematopoietic multipotent progenitors in human aplastic anaemia.

Br J Haematol 2020 Nov 20. Epub 2020 Nov 20.

Department of Medical Imaging, Haematology, and Clinical Oncology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, Brazil.

Eltrombopag has been added to first-line treatment of immune aplastic anaemia (AA), resulting in higher responses. We analysed marrow samples of AA patients who responded to immunosuppressive therapy (IST) alone or in combination with eltrombopag for the composition of the haematopoietic stem and progenitor cell (HSPC) compartment. The number of CD34 cells and multipotent progenitors was higher in patients treated with eltrombopag (P < 0·005; P < 0·05; respectively), but not the number of stem cells. No aberrant phenotype was observed. These results indicate that eltrombopag augments CD34 cells in vivo and preferentially expands multipotent progenitors, but not stem cells.
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http://dx.doi.org/10.1111/bjh.17140DOI Listing
November 2020

Rationale and design of the "Tocilizumab in patients with moderate to severe COVID-19: an open-label multicentre randomized controlled" trial (TOCIBRAS).

Rev Bras Ter Intensiva 2020 Jul-Sep;32(3):337-347

BP - A Beneficência Portuguesa de São Paulo - São Paulo (SP), Brasil.

Introduction: Pro-inflammatory markers play a significant role in the disease severity of patients with COVID-19. Thus, anti-inflammatory therapies are attractive agents for potentially combating the uncontrolled inflammatory cascade in these patients. We designed a trial testing tocilizumab versus standard of care intending to improve the outcomes by inhibiting interleukin-6, an important inflammatory mediator in COVID-19.

Methods And Analysis: This open-label multicentre randomized controlled trial will compare clinical outcomes of tocilizumab plus standard of care versus standard of care alone in patients with moderate to severe COVID-19. Two of the following four criteria are required for protocol enrolment: D-dimer > 1,000ng/mL; C reactive protein > 5mg/dL, ferritin > 300mg/dL, and lactate dehydrogenase > upper limit of normal. The primary objective will be to compare the clinical status on day 15, as measured by a 7-point ordinal scale applied in COVID-19 trials worldwide. The primary endpoint will be assessed by an ordinal logistic regression assuming proportional odds ratios adjusted for stratification variables (age and sex).

Ethics And Dissemination: The TOCIBRAS protocol was approved by local and central (national) ethical committees in Brazil following current national and international guidelines/directives. Each participating center had the study protocol approved by their institutional review boards before initiating protocol enrolment. The data derived from this trial will be published regardless of the results. If proven active, this strategy could alleviate the consequences of the inflammatory response in COVID-19 patients and improve their clinical outcomes.
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http://dx.doi.org/10.5935/0103-507X.20200060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595725PMC
October 2020

Novel therapeutic choices in immune aplastic anemia.

F1000Res 2020 10;9. Epub 2020 Sep 10.

Division of Hematology, Hospital A Beneficência Portuguesa, São Paulo, Brazil.

Aplastic anemia (AA) in its severe form has historically been associated with high mortality. With limited supportive care and no effective strategy to reverse marrow failure, most patients diagnosed with severe AA (SAA) died of pancytopenia complications. Since the 1970s, hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) have changed SAA's natural history by improving marrow function and pancytopenia. Standard IST with horse anti-thymocyte globulin plus cyclosporine produces a hematologic response rate of 60 to 70%. In the long term, about one-third of patients relapse, and 10 to 15% can develop cytogenetic abnormalities. Outcomes with either HSCT or IST are similar, and choosing between these modalities relies on age, availability of a histocompatible donor, comorbidities, and patient preference. The introduction of eltrombopag, a thrombopoietin receptor agonist, improved SAA outcomes as both salvage (second-line) and upfront therapy combined with IST. As a single agent, eltrombopag in doses up to 150 mg daily improved cytopenias in 40 to 50% in those who failed initial IST, which associated with higher marrow cellularity, suggesting a pan-stimulatory marrow effect. When eltrombopag was combined with IST as upfront therapy, overall (about 90%) and complete responses (about 50%) were higher than observed extensively with IST alone of 65% and 10%, respectively. Not surprisingly, given the strong correlation between hematologic response rates and survival in SAA, most (>90%) were alive after a median follow-up of 18 months. Longer follow-up and real-word data continue to confirm the activity of this agent in AA. The use of eltrombopag in different combinations and doses are currently being explored. The activity of another thrombopoietin receptor agonist in AA, romiplostim, suggests a class effect. In the coming years, the mechanisms of their activity and the most optimal regimen are likely to be elucidated.
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http://dx.doi.org/10.12688/f1000research.22214.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484718PMC
September 2020

Why do Tregs suddenly disappear in aplastic anemia?

Blood 2020 08;136(7):779-780

Hospital A Beneficência Portuguesa.

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http://dx.doi.org/10.1182/blood.2020006446DOI Listing
August 2020

In search for a haemoglobin threshold in myelodysplastic syndromes.

Br J Haematol 2020 06 6;189(5):813-814. Epub 2020 Feb 6.

Division of Hematology, Hospital A Beneficência Portuguesa, São Paulo, Brazil.

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http://dx.doi.org/10.1111/bjh.16392DOI Listing
June 2020

Stem cell stimulation continues to pay off in aplastic anaemia.

Lancet Haematol 2019 11 29;6(11):e543-e544. Epub 2019 Aug 29.

Division of Haematology, A Beneficência Portuguesa de São Paulo, São Paulo 0 1323-001, Brazil. Electronic address:

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http://dx.doi.org/10.1016/S2352-3026(19)30181-4DOI Listing
November 2019

Anti-complement Treatment for Paroxysmal Nocturnal Hemoglobinuria: Time for Proximal Complement Inhibition? A Position Paper From the SAAWP of the EBMT.

Front Immunol 2019 14;10:1157. Epub 2019 Jun 14.

Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation, Leiden, Netherlands.

The treatment of paroxysmal nocturnal hemoglobinuria has been revolutionized by the introduction of the anti-C5 agent eculizumab; however, eculizumab is not the cure for Paroxysmal nocturnal hemoglobinuria (PNH), and room for improvement remains. Indeed, the hematological benefit during eculizumab treatment for PNH is very heterogeneous among patients, and different response categories can be identified. Complete normalization of hemoglobin (complete and major hematological response), is seen in no more than one third of patients, while the remaining continue to experience some degree of anemia (good and partial hematological responses), in some cases requiring regular red blood cell transfusions (minor hematological response). Different factors contribute to residual anemia during eculizumab treatment: underlying bone marrow dysfunction, residual intravascular hemolysis and the emergence of C3-mediated extravascular hemolysis. These two latter pathogenic mechanisms are the target of novel strategies of anti-complement treatments, which can be split into terminal and proximal complement inhibitors. Many novel terminal complement inhibitors are now in clinical development: they all target C5 (as eculizumab), potentially paralleling the efficacy and safety profile of eculizumab. Possible advantages over eculizumab are long-lasting activity and subcutaneous self-administration. However, novel anti-C5 agents do not improve hematological response to eculizumab, even if some seem associated with a lower risk of breakthrough hemolysis caused by pharmacokinetic reasons (it remains unclear whether more effective inhibition of C5 is possible and clinically beneficial). Indeed, proximal inhibitors are designed to interfere with early phases of complement activation, eventually preventing C3-mediated extravascular hemolysis in addition to intravascular hemolysis. At the moment there are three strategies of proximal complement inhibition: anti-C3 agents, anti-factor D agents and anti-factor B agents. These agents are available either subcutaneously or orally, and have been investigated in monotherapy or in association with eculizumab in PNH patients. Preliminary data clearly demonstrate that proximal complement inhibition is pharmacologically feasible and apparently safe, and may drastically improve the hematological response to complement inhibition in PNH. Indeed, we envision a new scenario of therapeutic complement inhibition, where proximal inhibitors (either anti-C3, anti-FD or anti-FB) may prove effective for the treatment of PNH, either in monotherapy or in combination with anti-C5 agents, eventually leading to drastic improvement of hematological response.
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http://dx.doi.org/10.3389/fimmu.2019.01157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587878PMC
November 2020

Treatment optimization and genomic outcomes in refractory severe aplastic anemia treated with eltrombopag.

Blood 2019 06 16;133(24):2575-2585. Epub 2019 Apr 16.

Translational Stem Cell Biology Branch and.

Eltrombopag (EPAG) received approval from the US Food and Drug Administration for the treatment of refractory severe aplastic anemia (rSAA) based on treatment of 43 patients with doses escalating from 50 to 150 mg daily for 12 weeks. Response kinetics suggested that more prolonged administration of EPAG at a dose of 150 mg could speed and improve response rates. We enrolled 40 patients with rSAA in a study of EPAG 150 mg daily, with a primary end point of response at 24 weeks. Twenty (50%) of 40 patients responded at 24 weeks; 5 (25%) of 20 would have been deemed nonresponders at 12 weeks, the end point of the previous study. Fifteen of the 19 responding patients continuing on EPAG had drug discontinued for robust response; 5 of the 15 required EPAG re-initiation for relapse, with all recovering response. To analyze risk of clonal progression, we combined long-term data from the 83 patients with rSAA enrolled in both studies. Evolution to an abnormal karyotype occurred in 16 (19%), most within 6 months of EPAG initiation. Targeted deep sequencing/whole-exome sequencing was performed pre-EPAG and at primary response end point and/or time of clonal evolution or longest follow-up. Cytogenetic evolution did not correlate with mutational status, and overall mutated allele fractions of myeloid cancer genes did not increase on EPAG. In summary, extended administration of EPAG at a dose of 150 mg for 24 weeks rescued responses in some patients with rSAA not responding at 12 weeks. The temporal relationship between clonal evolution and drug exposure suggests that EPAG may promote expansion of dormant preexisting clones with an aberrant karyotype. The studies were registered at www.clinicaltrials.gov as #NCT00922883 and #NCT01891994.
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http://dx.doi.org/10.1182/blood.2019000478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566590PMC
June 2019

AUGMENT: A Phase III Study of Lenalidomide Plus Rituximab Versus Placebo Plus Rituximab in Relapsed or Refractory Indolent Lymphoma.

J Clin Oncol 2019 05 21;37(14):1188-1199. Epub 2019 Mar 21.

20 Barts Cancer Institute, London, United Kingdom.

Purpose: Patients with indolent non-Hodgkin lymphoma typically respond well to first-line immunochemotherapy. At relapse, single-agent rituximab is commonly administered. Data suggest the immunomodulatory agent lenalidomide could increase the activity of rituximab.

Methods: A phase III, multicenter, randomized trial of lenalidomide plus rituximab versus placebo plus rituximab was conducted in patients with relapsed and/or refractory follicular or marginal zone lymphoma. Patients received lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The primary end point was progression-free survival per independent radiology review.

Results: A total of 358 patients were randomly assigned to lenalidomide plus rituximab (n = 178) or placebo plus rituximab (n = 180). Infections (63% 49%), neutropenia (58% 23%), and cutaneous reactions (32% 12%) were more common with lenalidomide plus rituximab. Grade 3 or 4 neutropenia (50% 13%) and leukopenia (7% 2%) were higher with lenalidomide plus rituximab; no other grade 3 or 4 adverse event differed by 5% or more between groups. Progression-free survival was significantly improved for lenalidomide plus rituximab versus placebo plus rituximab, with a hazard ratio of 0.46 (95% CI, 0.34 to 0.62; < .001) and median duration of 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months), respectively.

Conclusion: Lenalidomide improved efficacy of rituximab in patients with recurrent indolent lymphoma, with an acceptable safety profile.
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http://dx.doi.org/10.1200/JCO.19.00010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035866PMC
May 2019

Activity of eltrombopag in severe aplastic anemia.

Hematology Am Soc Hematol Educ Program 2018 11;2018(1):450-456

Division of Hematology, Hospital A Beneficência Portuguesa, Sao Paulo, Brazil.

Since the approval of horse antithymocyte globulin (ATG) decades ago, there was a long hiatus in therapies with activity in severe aplastic anemia (SAA). This scenario changed in 2014 when eltrombopag, a thrombopoietin receptor agonist, was approved for SAA after an insufficient response to initial immunosuppressive therapy (IST). The basis for this approval was the observation of single-agent activity of eltrombopag in this patient population, where 40% to 50% recovered blood counts at times involving >1 lineage. The achievement of transfusion independence confirmed the clinical benefit of this approach. Increase in marrow cellularity and CD34+ cells suggested a recovery to a more functioning bone marrow. Further in its development, eltrombopag was associated with standard horse ATG plus cyclosporine in first line, producing increases in overall (at about 90%) and complete response rates (at about 40%) and leading to transfusion independence and excellent survival. Interestingly, best results were observed when all drugs were started simultaneously. The cumulative incidence of clonal cytogenetic abnormalities to date has compared favorably with the vast experience with IST alone in SAA. Longer follow-up will help in define these long-term risks. In this review, the development of eltrombopag in SAA will be discussed.
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http://dx.doi.org/10.1182/asheducation-2018.1.450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245975PMC
November 2018

Activity of eltrombopag in severe aplastic anemia.

Blood Adv 2018 11;2(21):3054-3062

Division of Hematology, Hospital A Beneficência Portuguesa, Sao Paulo, Brazil.

Since the approval of horse antithymocyte globulin (ATG) decades ago, there was a long hiatus in therapies with activity in severe aplastic anemia (SAA). This scenario changed in 2014 when eltrombopag, a thrombopoietin receptor agonist, was approved for SAA after an insufficient response to initial immunosuppressive therapy (IST). The basis for this approval was the observation of single-agent activity of eltrombopag in this patient population, where 40% to 50% recovered blood counts at times involving >1 lineage. The achievement of transfusion independence confirmed the clinical benefit of this approach. Increase in marrow cellularity and CD34+ cells suggested a recovery to a more functioning bone marrow. Further in its development, eltrombopag was associated with standard horse ATG plus cyclosporine in first line, producing increases in overall (at about 90%) and complete response rates (at about 40%) and leading to transfusion independence and excellent survival. Interestingly, best results were observed when all drugs were started simultaneously. The cumulative incidence of clonal cytogenetic abnormalities to date has compared favorably with the vast experience with IST alone in SAA. Longer follow-up will help in define these long-term risks. In this review, the development of eltrombopag in SAA will be discussed.
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http://dx.doi.org/10.1182/bloodadvances.2018020248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234374PMC
November 2018

Recent Advances and Long-Term Results of Medical Treatment of Acquired Aplastic Anemia: Are Patients Cured?

Hematol Oncol Clin North Am 2018 Aug 18;32(4):609-618. Epub 2018 May 18.

Division of Hematology, Hospital A Beneficência Portuguesa, Rua Martiniano de Carvalho, 951, São Paulo 01321-001, Brazil. Electronic address:

Horse antithymocyte globulin plus cyclosporine remains standard immunosuppressive therapy in severe aplastic anemia, with hematologic response rates of 60% to 70%. In those refractory to this regimen, a second course of therapy with rabbit antithymocyte globulin plus cyclosporine or alemtuzumab produces responses in 30% to 40%. Eltrombopag, a thrombopoietin receptor agonist, showed activity as a single agent in those refractory to initial immunosuppression with hematologic response rates of 40% to 50%. When combined with immunosuppression as frontline therapy, eltrombopag increased the rate of overall and complete response rates. Longer follow-up is needed to better define these outcomes.
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http://dx.doi.org/10.1016/j.hoc.2018.03.003DOI Listing
August 2018

Rabbit antithymocyte globulin dose does not affect response or survival as first-line therapy for acquired aplastic anemia: a multicenter retrospective study.

Ann Hematol 2018 Nov 5;97(11):2039-2046. Epub 2018 Jul 5.

Department of Internal Medicine, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, SP, Brazil.

In a prospective randomized study, treatment for aplastic anemia (AA) with rabbit antithymocyte globulin (r-ATG) and cyclosporine showed inferior hematological response and survival in comparison to horse antithymocyte globulin (h-ATG) and cyclosporine. However, h-ATG was discontinued in most Asian, South American, and European countries, where r-ATG became the only ATG formulation available. We retrospectively evaluated consecutive patients with acquired AA who received either rabbit (n = 170) or horse (n = 85) ATG and cyclosporine for first-line treatment from 1992 to 2014 in seven referral centers in Brazil and Argentina. Overall response at 3 months was 17% (95%CI, 11-23%) for r-ATG and 44% (95%CI, 33-55%) for h-ATG (p < 0.001). At 6 months, it was 31% (95%CI, 34-39%) for r-ATG and 59% (95%CI, 48-69%) for h-ATG (p < 0.001). Overall survival at 5 years was 57% (95%CI, 47-65%) for r-ATG and 80% (95%CI, 69-87%) for h-ATG (log-rank = 0.001). Relapse was significantly higher in patients receiving h-ATG (28%; 95%CI, 17-43%) as compared to r-ATG (9.4%; 95%CI, 4-21%; log-rank, p = 0.01). The type of ATG was the only factor associated with both response and survival. The r-ATG dose varied from 1 to 5 mg/kg/day, but it did not correlate with outcomes. In summary, this is the largest multicenter study comparing the two ATG formulations in AA. Our results indicate that the dose of r-ATG does not influence hematologic response or survival in first-line therapy for acquired AA. Considering the toxicity and costs of r-ATG, our findings challenge its aggregate benefit to cyclosporine therapy and further strengthen that h-ATG should remain standard therapy in AA.
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http://dx.doi.org/10.1007/s00277-018-3416-4DOI Listing
November 2018

Predictors of early mortality after rabbit antithymocyte globulin as first-line treatment in severe aplastic anemia.

Ann Hematol 2017 Nov 16;96(11):1907-1914. Epub 2017 Aug 16.

BONE - Brazilian Marrow Failure Network, São Paulo, Brazil.

Despite being recommended as first-line immunosuppressive therapy in severe aplastic anemia (SAA), horse antithymocyte globulin (ATG) is still unavailable in many countries outside the USA. Rabbit ATG is more lymphocytoxic than horse ATG, and this might result in a higher incidence of severe infections and early mortality. This study was designed to identify the risk factors for early mortality and overall survival (OS) after rabbit ATG in patients with SAA. We retrospectively reviewed 185 patients with SAA who underwent rabbit ATG and cyclosporine. The incidence of death in 3 months following rabbit ATG therapy was 15.1% (28/185). Early mortality was mainly related to infectious complications, despite adequate antibiotic and/or antifungal treatment. Age > 35 years (odds ratio [OR] 5.06, P = 0.001) and baseline absolute neutrophil count (ANC) ≤ 0.1 × 10/L (OR 7.64, P < 0.001) were independent risk factors for early mortality after immunosuppressive therapy with this agent. Hematological response at 6 months was observed in only 29.7% of all patients. OS at 1 year after rabbit ATG was 75.3%; and age > 35 years (OR 1.88, P = 0.03), baseline ANC ≤ 0.1 × 10/L (OR 2.65, P < 0.001), and lack of response to rabbit ATG (OR 11.40, P < 0.001) were independently associated with mortality. Alternative strategies are needed for the treatment of SAA patients in countries were horse ATG is unavailable, particularly for those at high risk for early mortality after rabbit ATG due to a higher age and very low pre-treatment neutrophil count.
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http://dx.doi.org/10.1007/s00277-017-3086-7DOI Listing
November 2017

Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia.

N Engl J Med 2017 04;376(16):1540-1550

From the Hematology Branch (D.M.T., T.W., R.D., B.D., O.R., B.W., J.V., J.L., X.F., M.D., H.L., A.L., C.E.D., N.S.Y.) and the Office of Biostatistics Research (C.W.), National Heart, Lung, and Blood Institute, and the Nursing Research and Translational Science Section, Department of Nursing (M.B.), and the Hematology Section, Department of Laboratory Medicine (K.R.C.), Clinical Center - all at the National Institutes of Health, Bethesda, MD; and the Division of Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital A Beneficência Portuguesa de São Paulo, São Paulo (P.S.).

Background: Acquired aplastic anemia results from immune-mediated destruction of bone marrow. Immunosuppressive therapies are effective, but reduced numbers of residual stem cells may limit their efficacy. In patients with aplastic anemia that was refractory to immunosuppression, eltrombopag, a synthetic thrombopoietin-receptor agonist, led to clinically significant increases in blood counts in almost half the patients. We combined standard immunosuppressive therapy with eltrombopag in previously untreated patients with severe aplastic anemia.

Methods: We enrolled 92 consecutive patients in a prospective phase 1-2 study of immunosuppressive therapy plus eltrombopag. The three consecutively enrolled cohorts differed with regard to the timing of initiation and the duration of the eltrombopag regimen (cohort 1 received eltrombopag from day 14 to 6 months, cohort 2 from day 14 to 3 months, and cohort 3 from day 1 to 6 months). The cohorts were analyzed separately. The primary outcome was complete hematologic response at 6 months. Secondary end points included overall response, survival, relapse, and clonal evolution to myeloid cancer.

Results: The rate of complete response at 6 months was 33% in cohort 1, 26% in cohort 2, and 58% in cohort 3. The overall response rates at 6 months were 80%, 87%, and 94%, respectively. The complete and overall response rates in the combined cohorts were higher than in our historical cohort, in which the rate of complete response was 10% and the overall response rate was 66%. At a median follow-up of 2 years, the survival rate was 97%; one patient died during the study from a nonhematologic cause. Marked increases in bone marrow cellularity, CD34+ cell number, and frequency of early hematopoietic progenitors were noted. Rates of relapse and clonal evolution were similar to our historical experience. Severe rashes occurred in two patients, resulting in the early discontinuation of eltrombopag.

Conclusions: The addition of eltrombopag to immunosuppressive therapy was associated with markedly higher rates of hematologic response among patients with severe aplastic anemia than in a historical cohort. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT01623167 .).
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http://dx.doi.org/10.1056/NEJMoa1613878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548296PMC
April 2017

A plasma microRNA signature as a biomarker for acquired aplastic anemia.

Haematologica 2017 01 22;102(1):69-78. Epub 2016 Sep 22.

Hematology Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MA, USA.

Aplastic anemia is an acquired bone marrow failure characterized by marrow hypoplasia, a paucity of hematopoietic stem and progenitor cells, and pancytopenia of the peripheral blood, due to immune attack on the bone marrow. In aplastic anemia, a major challenge is to develop immune biomarkers to monitor the disease. We measured circulating microRNAs in plasma samples of aplastic anemia patients in order to identify disease-specific microRNAs. A total of 179 microRNAs were analyzed in 35 plasma samples from 13 aplastic anemia patients, 11 myelodysplastic syndrome patients, and 11 healthy controls using the Serum/Plasma Focus microRNA Polymerase Chain Reaction Panel. Subsequently, 19 microRNAs from the discovery set were investigated in the 108 plasma samples from 41 aplastic anemia patients, 24 myelodysplastic syndrome patients, and 43 healthy controls for validation, confirming that 3 microRNAs could be validated as dysregulated (>1.5-fold change) in aplastic anemia, compared to healthy controls. MiR-150-5p (induction of T-cell differentiation) and miR-146b-5p (involvement in the feedback regulation of innate immune response) were elevated in aplastic anemia plasma, whereas miR-1 was decreased in aplastic anemia. By receiver operating characteristic curve analysis, we developed a logistic model with these 3 microRNAs that enabled us to predict the probability of a diagnosis of aplastic anemia with an area under the curve of 0.86. Dysregulated expression levels of the microRNAs became normal after immunosuppressive therapy at 6 months. Specifically, miR-150-5p expression was significantly reduced after successful immunosuppressive therapy, but did not change in non-responders. We propose 3 novel plasma biomarkers in aplastic anemia, in which miR-150-5p, miR-146b-5p, and miR-1 can serve for diagnosis and miR-150-5p for disease monitoring. Clinicaltrials.gov identifiers:00260689, 00217594, 00961064.
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http://dx.doi.org/10.3324/haematol.2016.151076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5210234PMC
January 2017

How deep can you go into Tregs?

Blood 2016 09;128(9):1158-9

HOSPITAL SÃO JOSÉ; BENEFICÊNCIA PORTUGUESA.

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http://dx.doi.org/10.1182/blood-2016-07-722439DOI Listing
September 2016

Danazol Treatment for Telomere Diseases.

N Engl J Med 2016 May;374(20):1922-31

From the Hematology Branch (D.M.T., B.D., D.L., B.W., C.C., N.H., N.S.Y.), the Cardiopulmonary Branch (A.D.M.), and the Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, the Center for Human Immunology, Autoimmunity, and Inflammation (A.B.), the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (S.L., Y.J.K., T.H.), Radiology and Imaging Sciences, Clinical Center (J.Y., E.J.), and the Medical Genetics Branch, National Human Genome Research Institute (B.R.G.), National Institutes of Health, Bethesda, MD; and the Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto (R.T.C.), and Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José and Beneficência Portuguesa (P.S.), São Paulo.

Background: Genetic defects in telomere maintenance and repair cause bone marrow failure, liver cirrhosis, and pulmonary fibrosis, and they increase susceptibility to cancer. Historically, androgens have been useful as treatment for marrow failure syndromes. In tissue culture and animal models, sex hormones regulate expression of the telomerase gene.

Methods: In a phase 1-2 prospective study involving patients with telomere diseases, we administered the synthetic sex hormone danazol orally at a dose of 800 mg per day for a total of 24 months. The goal of treatment was the attenuation of accelerated telomere attrition, and the primary efficacy end point was a 20% reduction in the annual rate of telomere attrition measured at 24 months. The occurrence of toxic effects of treatment was the primary safety end point. Hematologic response to treatment at various time points was the secondary efficacy end point.

Results: After 27 patients were enrolled, the study was halted early, because telomere attrition was reduced in all 12 patients who could be evaluated for the primary end point; in the intention-to-treat analysis, 12 of 27 patients (44%; 95% confidence interval [CI], 26 to 64) met the primary efficacy end point. Unexpectedly, almost all the patients (11 of 12, 92%) had a gain in telomere length at 24 months as compared with baseline (mean increase, 386 bp [95% CI, 178 to 593]); in exploratory analyses, similar increases were observed at 6 months (16 of 21 patients; mean increase, 175 bp [95% CI, 79 to 271]) and 12 months (16 of 18 patients; mean increase, 360 bp [95% CI, 209 to 512]). Hematologic responses occurred in 19 of 24 patients (79%) who could be evaluated at 3 months and in 10 of 12 patients (83%) who could be evaluated at 24 months. Known adverse effects of danazol--elevated liver-enzyme levels and muscle cramps--of grade 2 or less occurred in 41% and 33% of the patients, respectively.

Conclusions: In our study, treatment with danazol led to telomere elongation in patients with telomere diseases. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01441037.).
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http://dx.doi.org/10.1056/NEJMoa1515319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4968696PMC
May 2016

Alemtuzumab in T-cell large granular lymphocytic leukaemia: interim results from a single-arm, open-label, phase 2 study.

Lancet Haematol 2016 Jan 17;3(1):e22-9. Epub 2015 Dec 17.

Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José and Beneficência Portuguesa, São Paulo, SP, Brazil. Electronic address:

Background: T-cell large granular lymphocytic leukaemia (T-LGL) is a lymphoproliferative disease that presents with immune-mediated cytopenias and is characterised by clonal expansion of cytotoxic CD3+ CD8+ lymphocytes. Use of methotrexate, ciclosporin, or cyclophosphamide as first therapy improves cytopenias in 50% of patients, but long-term use of these can lead to toxicity. We aimed to explore the activity and safety of alemtuzumab, an anti-CD52 monoclonal antibody, in patients with T-LGL.

Methods: We did this single-arm, phase 2 trial in consecutively enrolled adults with T-LGL referred to the National Institutes of Health in Bethesda, MD, USA. Alemtuzumab was given intravenously at 10 mg per day for 10 days. The primary endpoint was haematological response at 3 months after infusion. A complete response was defined as normalisation of all affected lineages, and a partial response was defined in neutropenic patients as 100% increase in the absolute neutrophil count to more than 5 × 10(8) cells per L, and in those with anaemia, as any increase in haemoglobin of 20 g/L or higher observed in at least two serial measurements 1 week apart and sustained for 1 month or longer without exogenous growth factors support or transfusions. Analysis was by intention to treat. We report results from the first stage of this Simon two-stage design trial; enrolment into the second stage is continuing. This study is registered with ClinicalTrials.gov, number NCT00345345.

Findings: From Oct 1, 2006, to March 1, 2015, we enrolled 25 patients with T-LGL. 14 patients (56%; 95% CI 35-76) had a haematological response at 3 months. Four patients with associated myelodysplastic syndrome and two who had received haemopoietic stem cell transplantation had either no response or were not evaluable, meaning 14 (74% [49-91]) of the 19 patients with classic T-LGL responded. All patients had an infusion reaction (24 [96%] patients grade 1-2, one [4%] patient grade 3), which improved with symptomatic therapy. All patients developed lymphopenia, with 22 (88%) patients having grade 3 or 4 lymphopenia. The other most common grade 3 and 4 adverse events were leukopenia (eight [32%]) and neutropenic infections (five [20%]). Seven patients died; all were non-responders.

Interpretation: This is the largest and only prospective study of alemtuzumab in patients with T-LGL. The activity reported with a single course of a lymphocytotoxic drug in patients with mainly relapsed and refractory disease suggests that haematological response can be achieved without continued use of oral immunosuppression.

Funding: National Heart, Lung, and Blood Institute.
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http://dx.doi.org/10.1016/S2352-3026(15)00227-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721315PMC
January 2016

Hematopoietic stem cell transplantation for cutaneous T-cell lymphoma: Summary of 11 cases from two facilities in Japan and Brazil.

J Dermatol 2016 Jun 25;43(6):638-42. Epub 2015 Nov 25.

Department of Dermatology, University of São Paulo Medical School, Sao Paulo, Brazil.

Some patients with cutaneous T-cell lymphoma (CTCL) show a miserable clinical course and the only option that can induce long-term remission for advanced CTCL may be hematopoietic stem cell transplantation (HSCT). So far, studies on HSCT for CTCL patients have been limited. In this study, we summarized 11 cases with CTCL treated with HSCT, including nine cases in Japan and two cases in Brazil. The patients were five cases with mycosis fungoides (MF), two cases with Sézary syndrome (SS), three cases with anaplastic large cell lymphoma, and one case with primary cutaneous peripheral T-cell lymphoma, not otherwise specified (PTL-NOS). Currently, seven out of 11 cases are alive (at 13-108 months after transplantation) and four died at 15 days to 14 months after transplantation. When focusing on the eight patients who received allogeneic HSCT for MF/SS and PTL-NOS, all four patients at 45 years old or under are alive at present. One case showed relapse in the skin. On the other hand, one out of the other four patients at over 45 years old survived. Engraftment failure was seen in one case and all the other three cases experienced relapse. Although this is only a case series with a small number, our study has suggested that we should be careful about age when treating patients with MF/SS by allogeneic HSCT.
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http://dx.doi.org/10.1111/1346-8138.13199DOI Listing
June 2016

Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia.

N Engl J Med 2015 Jul;373(1):35-47

From the Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto (T.Y., K.Y., A.S.-O., Y. Sato, H.S., K.K., Y. Shiozawa, Y.N., A.K., M.S., S.O.), Department of Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa (K.H., T.K., S.N.), Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo (Y. Shiraishi, K.C., H.T., S.M.), and the Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya (Y.O.) - all in Japan; the Hematology Branch (B.D., K.H., D.T., D.L., P.S., N.S.Y.) and Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, Bethesda, MD; and the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland (H.M., M.J.C., J.P.M.).

Background: In patients with acquired aplastic anemia, destruction of hematopoietic cells by the immune system leads to pancytopenia. Patients have a response to immunosuppressive therapy, but myelodysplastic syndromes and acute myeloid leukemia develop in about 15% of the patients, usually many months to years after the diagnosis of aplastic anemia.

Methods: We performed next-generation sequencing and array-based karyotyping using 668 blood samples obtained from 439 patients with aplastic anemia. We analyzed serial samples obtained from 82 patients.

Results: Somatic mutations in myeloid cancer candidate genes were present in one third of the patients, in a limited number of genes and at low initial variant allele frequency. Clonal hematopoiesis was detected in 47% of the patients, most frequently as acquired mutations. The prevalence of the mutations increased with age, and mutations had an age-related signature. DNMT3A-mutated and ASXL1-mutated clones tended to increase in size over time; the size of BCOR- and BCORL1-mutated and PIGA-mutated clones decreased or remained stable. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and longer and a higher rate of overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes. However, clonal dynamics were highly variable and might not necessarily have predicted the response to therapy and long-term survival among individual patients.

Conclusions: Clonal hematopoiesis was prevalent in aplastic anemia. Some mutations were related to clinical outcomes. A highly biased set of mutations is evidence of Darwinian selection in the failed bone marrow environment. The pattern of somatic clones in individual patients over time was variable and frequently unpredictable. (Funded by Grant-in-Aid for Scientific Research and others.).
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http://dx.doi.org/10.1056/NEJMoa1414799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478337PMC
July 2015

Answer to "Confounding effect of cyclosporine dosing when comparing horse and rabbit antithymocyte globulin in patients with severe aplastic anemia".

Haematologica 2015 May;100(5):e213

Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

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http://dx.doi.org/10.3324/haematol.2015.124446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420236PMC
May 2015

CMV-specific T cells generated from naïve T cells recognize atypical epitopes and may be protective in vivo.

Sci Transl Med 2015 Apr;7(285):285ra63

Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. Program for Cell Enhancement and Technologies for Immunotherapy, The Sheikh Zayed Institute for Pediatric Surgical Innovation, the Center for Cancer and Immunology Research, and the Division of Blood and Marrow Transplantation, Children's National Health System and The George Washington University, Washington, DC 20052, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.

Adoptive transfer of cytomegalovirus (CMV)-specific T cells derived from adult seropositive donors can effectively restore antiviral immunity after transplantation. However, CMV-seronegative donors lack CMV-specific memory T cells, which restricts the availability of virus-specific T cells for immunoprophylaxis. We demonstrate the feasibility of deriving CMV-specific T cells from naïve cells for T cell therapy. Naïve T cells primed to recognize CMV were restricted to different, atypical epitopes than T cells derived from CMV-seropositive individuals; however, these two cell populations had similar avidities. CMV-seropositive individuals also had T cells recognizing these atypical epitopes, but these cells had a lower avidity than those derived from the seronegative subjects, which suggests that high-avidity T cells to these epitopes may be lost over time. Indeed, recipients of cord blood (CB) grafts who did not develop CMV were found by clonotypic analysis to have T cells recognizing atypical CMVpp65 epitopes. Therefore, we examined unmanipulated CB units and found that T cells with T cell receptors restricted by atypical epitopes were the most common, which may explain why these T cells expanded. When infused to recipients, naïve donor-derived virus-specific T cells that recognized atypical epitopes were associated with prolonged periods of CMV-free survival and complete remission. These data suggest that naïve-derived T cells from seronegative patients may be an additional source of cells for CMV immunoprophylaxis.
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http://dx.doi.org/10.1126/scitranslmed.aaa2546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479400PMC
April 2015

Repeat course of rabbit antithymocyte globulin as salvage following initial therapy with rabbit antithymocyte globulin in acquired aplastic anemia.

Haematologica 2015 Sep 10;100(9):e345-7. Epub 2015 Apr 10.

Division of Hematology, University of São Paulo at Ribeirão Preto School of Medicine, Ribeirão Preto, Brasil Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José e Beneficência Portuguesa, São Paulo, Brasil.

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http://dx.doi.org/10.3324/haematol.2015.123760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800686PMC
September 2015

Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.

Science 2014 Sep 11;345(6204):1623-1627. Epub 2014 Sep 11.

Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory receptor found on immune cells. The consequences of mutations in CTLA4 in humans are unknown. We identified germline heterozygous mutations in CTLA4 in subjects with severe immune dysregulation from four unrelated families. Whereas Ctla4 heterozygous mice have no obvious phenotype, human CTLA4 haploinsufficiency caused dysregulation of FoxP3(+) regulatory T (Treg) cells, hyperactivation of effector T cells, and lymphocytic infiltration of target organs. Patients also exhibited progressive loss of circulating B cells, associated with an increase of predominantly autoreactive CD21(lo) B cells and accumulation of B cells in nonlymphoid organs. Inherited human CTLA4 haploinsufficiency demonstrates a critical quantitative role for CTLA-4 in governing T and B lymphocyte homeostasis.
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http://dx.doi.org/10.1126/science.1255904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4371526PMC
September 2014

Moderate-dose cyclophosphamide for severe aplastic anemia has significant toxicity and does not prevent relapse and clonal evolution.

Blood 2014 Oct 3;124(18):2820-3. Epub 2014 Sep 3.

Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD;

First-line therapy of severe aplastic anemia (SAA) with high-dose cyclophosphamide causes toxicity and increased short-term mortality. We investigated cyclophosphamide at a lower, more moderate dose in combination with aggressive supportive care to determine whether severe infections might be avoided and hematologic outcomes defined for this regimen. From 2010 to 2012, 22 patients received cyclophosphamide at 120 mg/kg plus cyclosporine and antibacterial, antiviral, and antifungal prophylaxis. Toxicity was considerable, mainly due to prolonged absolute neutropenia, which occurred regardless of pretherapy blood counts, and persisted an average of 2 months. Granulocyte transfusions for uncontrolled infection were required in 5 patients, confirmed fungal infections were documented in 6, and 9 patients died. Nine patients (41%) responded at 6 months. After a median follow-up of 2.2 years, relapse occurred in 2 patients, and cytogenetic abnormalities (including monosomy 7) were observed in 4 patients. Although cyclophosphamide has activity in SAA, its toxicity is not justified when far less dangerous alternatives are available. This trial was registered at www.clinicaltrials.gov as #NCT01193283.
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http://dx.doi.org/10.1182/blood-2014-05-573642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215312PMC
October 2014

Prolonged cyclosporine administration after antithymocyte globulin delays but does not prevent relapse in severe aplastic anemia.

Am J Hematol 2014 Jun;89(6):571-4

In severe aplastic anemia, approximately one-third of responders to standard horse antithymocyte globulin (h-ATG) plus cyclosporine (CsA) will relapse. Anecdotal experience has suggested that a gradual CsA taper might avoid relapse, but this practice has not been rigorously assessed prospectively. In 2003, we adopted a strategy to taper CsA beyond 6 months, with the intention to reduce hematologic relapse compared with our extensive historical experience. In total, 102 patients received h-ATG/CsA for 6 months in two sequential clinical protocols: 67 patients (66%) responded and all had the CsA dose tapered per protocol over the subsequent 18 months (total of 2 years). The rate of relapse at 5 years was 33% (95% CI 27-44%), which did not differ from our large historical relapse experience (patients treated before 2003) of 30-40%, in protocols in which CsA was simply discontinued at 6 months. However, time to relapse was prolonged by about 1 year with the longer CsA course. The rates of clonal evolution and overall survival did not differ between the two cohorts. We infer from this large prospective study that CsA taper as implemented delayed but did not prevent relapse. The kinetics of relapse with long course CsA does suggest that a lower long-term dose might be adequate to maintain patients in remission.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074770PMC
http://dx.doi.org/10.1002/ajh.23692DOI Listing
June 2014