In this month’s Pharmacy SIG Literature Update: Updates on GVHD prophylaxis, risk assessment for SOS and TMA and more!

Literature summaries are provided as information only. Please refer to the original published articles for complete details on study methodology, results and discussion.

***        Must read. Landmark publication that affects practice

**           Recommend reading. Secondary paper that adds to literature

*             Consider reading. Cursory importance to the practice

Allogeneic Transplant

*Díaz-Beyá M, Labopin M, Maertens J, et al. Allogeneic stem cell transplantation in AML with t(6;9)(p23;q34);DEK-NUP214 shows a favourable outcome when performed in first complete remission. Br J Haematol. 2020;189(5):920-925. https://pubmed.ncbi.nlm.nih.gov/32020596/

• Retrospective analysis from the EBMT registry of patients with t(6;9) AML who received first alloHCT between 2000-2016 (n = 195)
• Disease status at time of alloHCT was strongest independent risk factor with 2-year LFS and RI of 57% and 19% in patients in CR1, 34% and 33% in CR2, and 24% and 49% in patients not in remission, respectively (p < 0.001)
• In multivariate analysis, status at the time of alloHCT (CR1 vs other) was associated with RI (HR 0.20, 95% CI: 0.08–0.54, p=0.0014), LFS (HR 0.38, 95% CI: 0.19–0.76, p=0.006), OS (HR 0.41, 95% CI: 0.20–0.84, p=0.015), and GRFS (HR 0·48, 95% CI: 0.25-0.92, p=0.027)
• FLT3-ITD was present in 46 out of 72 patients (64%) with available information. It was found to have no prognostic impact on RI in entire patient population or CR1 cohort (26.7% vs. 16.4% at 2 years in FLT3-ITD(+) and FLT3-ITD(-), respectively; p=0.46).

Graft-Versus-Host Disease

**Aziz MD, Shah J, Kapoor U, et al. Disease risk and GVHD biomarkers can stratify patients for risk of relapse and non-relapse mortality post hematopoietic cell transplant. Leukemia. 2020;34:1898-1906. https://pubmed.ncbi.nlm.nih.gov/32020045/

• The recently validated MAGIC algorithm probability (MAP) that predicts the risk for severe GVHD and NRM in asymptomatic patients using serum biomarkers. This multicenter study evaluated whether the MAP could identify patients whose risk for relapse is higher than their risk for severe GVHD and NRM
• The total study population (n = 1604) was divided into two cohorts: historical (2006–2015, n = 702) and current (2015–2017, n = 902) with similar NRM, relapse, and survival
• On day 28 post-transplant, patients who had not developed GVHD (75%) and who possessed a low MAP were at much higher risk for relapse (24%) than severe GVHD and NRM (16 and 9%); this difference was even more pronounced in patients with a high disease risk index, with relapse rates of 33%, and NRM of 9%

*Shiratori S, Sugita J, Ota S, et al. Low-dose anti-thymocyte globulin for GVHD prophylaxis in HLA-matched allogeneic peripheral blood stem cell transplantation. Bone Marrow Transplant. 2020 Jul 5. doi: 10.1038/s41409-020-0985-3. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/32624582/

• Phase II multicenter trial to evaluate safety and efficacy of low-dose thymoglobulin (1 mg/kg/day on day -2 and -1) given in combination with a CNI and short-term methotrexate for MAC HLA-matched peripheral blood transplantation in adults ages 15-60
• The study enrolled 72 patients with a median age of 46.5, with most patients having acute myeloid or lymphoblastic leukemias in CR
• Cumulative incidence of grade III-IV acute GVHD (graded by NIH consensus criteria) at 100 days was 1.4%, and grades II-IV was 22.2%. Cumulative incidence of all-grade chronic GVHD at 1 year was 15.3%, and grades moderate to severe chronic GVHD was 5.6%.
• Infection related death at 1-year was 4.2% and no patients developed post-transplant lymphoproliferative disorder.
• The authors conclude that low-dose thymoglobulin is a promising approach to reduce severe acute and chronic GVHD in HLA-matched peripheral blood transplantation following MAC

*Agrawal V, Ranganath P, Ervin KD, et al. Effect of sirolimus levels between days 11 and 20 after allogeneic stem cell transplantation on the risk of hepatic sinusoidal obstruction syndrome. Bone Marrow Transplant. 2020 Jul 4. doi: 10.1038/s41409-020-0987-1. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/32623447/

• Retrospective analysis of 260 adult patients receiving sirolimus and tacrolimus for GVHD prophylaxis after MAC regimens (excluding busulfan) between 2007 and 2016
• Sirolimus (goal trough 5-12 ng/mL) and tacrolimus (goal trough 5-10 ng/mL) levels were assessed in three time frames to assess the impact on incidence of SOS: days 0 to +10, days +11 to +20, and days +21 to +30
• In patients who developed SOS (by EBMT criteria) the mean sirolimus trough level between days +11 and +20 was statistically higher (10.3 vs 8.5 ng/mL, p=0.008). No differences in mean tacrolimus trough levels were observed.
• After multivariable analysis, a mean sirolimus level >9 ng/mL between days +11 and +20 increased the risk of SOS with a corresponding hazard ratio of 3.67 (p=0.003). Time from diagnosis to transplant (p=0.004) and use of TBI-based conditioning (p=0.006) also increased the risk of SOS.
• The authors conclude that sirolimus trough levels >9 ng/mL between days +11 and +20 after transplant should be avoided after MAC

**Akahoshi Y, Igarashi A, Fukuda T, et al. Impact of graft-versus-host disease and graft-versus-leukemia effect based on minimal residual disease in Philadelphia chromosome-positive acute lymphoblastic leukemia. Br J Haematol. 2020;190(1):84-92. https://pubmed.ncbi.nlm.nih.gov/32119132/

• Retrospective study of patients with Philadelphia chromosome-positive ALL (Ph-positive ALL) in CR1 who underwent first alloHCT between 2005-2017 in Japan (n =1022). MRD status at HCT was negative in 791 (77.4%) vs. positive in 231 (22.6%).
• In multivariate analysis, mild acute GVHD (HR 0.90, 95% CI: 0.70-1.16; p=0.901) and chronic GVHD (HR 0.82, 95% CI: 0.58-1.14; p = 0.238) were not significantly associated with overall mortality. Severe acute GVHD (HR 2.26, 95% CI: 1.64–3.11; p<0.001) resulted in inferior OS due to high non-relapse mortality.
• In subgroup analysis which stratified according to MRD status, acute and chronic GVHD were not significantly associated with better OS
• Authors concluded that using less intensive GVHD prophylaxis to achieve a GVL effect is not recommended for Ph-positive ALL, even in high-risk patients

Supportive Care

**Epperla N, Li A, Logan B., et al. Incidence, risk factors for and outcomes of transplant-associated thrombotic microangiopathy. Br J Haematol. 2020;189(6):1171-1181. https://pubmed.ncbi.nlm.nih.gov/32124435/

• Retrospective analysis from the CIBMTR evaluating incidence, risk factors for and outcomes of TA-TMA in patients receiving first alloHCT between 2008-2016 (n = 23,665)
• Median time from HCT to TA-TMA was 3 months (range 1.5-6.5 months), and 3-year cumulative incidence of TA-TMA was 3%
• Risk factors included African American race, female sex, prior autoHCT, primary disease (ALL and SAA), donor type (MMUD, MUD, cord blood), MAC regimen, GVHD prophylaxis (sirolimus + CNI), non-ATG or non-alemtuzumab containing regimen, pre-HCT renal dysfunction (GFR < 60), and aGVHD (time-varying effect)
• TA-TMA associated with higher mortality (HR 3.1, 95% CI: 2.8-16.3) and renal replacement therapy requirement (HR 7.1, 95% CI: 5.7-311.6)
• Authors concluded that this study provides epidemiologic data on TA-TMA and impact on HCT outcomes which may be useful for future clinical studies

Infectious Disease

*Nguyen MVH, Davis MR, Wittenberg R, et al. Posaconazole serum drug levels associated with pseudohyperaldosteronism. Clinical Infectious Dis. 2020;70(12):2593-2598. https://pubmed.ncbi.nlm.nih.gov/31403165/

• Single center, retrospective study described the occurrence and characteristics of patients with posaconazole-induced pseudohyperaldosteronism (PIPH), which may present as secondary hypertension, hypokalemia, with occasional metabolic acidosis
• Sixty-nine patients were reviewed; nearly one in every four met criteria for PIPH (16/69, 23.2%).  Time to PIPH was a median of 46 days (range, 14-96). Those with PIPH were significantly older, had a baseline diagnosis of hypertension, or were prescribed posaconazole as treatment rather than prophylaxis. Concurrent use of a CNI exhibited a protective effect against PIPH.
• Those with a PIPH diagnosis had significantly higher median serum posaconazole levels. All patients with posaconazole levels ≥ 4 µg/mL were diagnosed with PIPH.
• The authors conclude posaconazole may contribute to pseudohyperaldosteronism. The development of this syndrome has been seen with higher serum posaconazole levels, older age, and a diagnosis of hypertension at baseline.

*Rodriguez-Lobato LG, Martinez-Roca A, Moreno D, et al. Impact of intensifying primary antibiotic prophylaxis in at-home autologous stem cell transplantation program for lymphoma patients. Leukemia Lymphoma. 2020;61(7):1565-1574. https://pubmed.ncbi.nlm.nih.gov/32208787/

• Retrospective review of patients with NHL undergoing autoHCT with BEAM cytoreduction therapy (n= 154) in Spain analyzing the impact of intensifying primary prophylaxis with the addition of piperacillin/tazobactam 4.5 g IV every 8 hours to a fluoroquinolone for antibacterial prophylaxis
• Between January 2002 and August 2018, 154 lymphoma patients conditioned with BEAM were included. 40% received ceftriaxone plus a fluoroquinolone and 60% piperacillin-tazobactam plus a fluoroquinolone.
• Neutropenic fever and hospital readmission were required in 84 vs 41% (p<0.0001) and 12 vs 1% (p=0.007) of patients in the ceftriaxone and piperacillin/tazobactam groups, respectively
• Authors conclude that the use of piperacillin/tazobactam in addition to fluoroquinolone prophylaxis may effectively prevent episodes of neutropenic fever and hospitalizations in lymphoma patients managed in their at-home autoHCT-care model

Abbreviations:

ALL: acute lymphoblastic leukiemia

alloHCT: allogeneic hematopoietic cell transplantation

AML: acute myeloid leukemia

ATG: anti-thymocyte globulin

autoHCT: autologous hematopoietic cell transplantation

BEAM: carmustine, etoposide, cytarabine, melphalan

CIBMTR: Center for International Blood and Marrow Transplant Research

CNI: calcineurin inhibitor

CR: complete response

EBMT: European Society for Blood and Marrow Transplantation

GRFS: GVHD-free, relapse-free survival

GVHD: graft-versus-host disease

GVL: graft-versus-leukemia

HCT: hematopoietic cell transplantation

HLA: human leukocyte antigen

LFS: leukemia-free survival

MAC: myeloablative conditioning

MAGIC: Mount Sinai Acute GVHD International Consortium

MAP: MAGIC algorithm probability

MRD: minimal residual disease

MUD: matched unrelated donor

MMUD: mismatched unrelated donor

NIH: National Institutes of Health

NRM: non-relapse mortality

OS: overall survival

RI: relapse incidence

RFS: relapse-free survival

SAA: severe aplastic anemia

SOS: sinusoidal obstruction syndrome

TA-TMA: transplant-associated thrombotic microangiopathy

TBI: total body irradiation

 

ASTCT Pharmacy SIG Research Working Committee:

Kelly Gaffney, Katie Gatwood, Binni Kunvarjee, Andrew Linn, Anne McDonnell, Monank Patel,

Ashley Teusink-Cross, Jigar Trivedi, Theresa Urban, Lily Yan

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