In this month’s Pharmacy SIG Literature Update: Novel GVHD prophylaxis regimens, the impact of foscarnet on long-term renal function, transplant for rare diseases, 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

*Gran C, Wang J, Nahi H, et al. Treosulfan conditioning for allogeneic transplantation in multiple myeloma – improved overall survival in first line haematopoietic stem cell transplantation – a large retrospective study by the Chronic Malignancies Working Party of the EBMT. Br J Haematol. 2020;189(5):e213-e217. https://pubmed.ncbi.nlm.nih.gov/32301111/

• Retrospective study comparing outcomes of MM patients undergoing first alloHCT after receiving treosulfan (treo)-based conditioning (n = 508) vs. non-treo RIC (n = 2830) and non-treo MAC (n = 1177)
• Out of 4515 total patients, 1098 (24.3%) were transplanted first line, defined as first alloHCT either as single alloHCT or in tandem as autoHCT/alloHCT
• In univariate analysis, five-year OS (62%, 57%, and 47%, p = 0.04) was significantly superior with first line treo vs. RIC and MAC patients, respectively. In multivariate analysis, both treo and RIC resulted in superior OS vs MAC, respectively (HR 0.58 (95% CI: 0.39-0.88), p = 0.009 and HR 0.66, (95% CI: 0.52-0.84), p < 0.001).
• Trend towards lower NRM (10%, 17%, and 19%, p = 0.10) and higher relapse (59%, 50%, and 49%, p = 0.08) were observed with treo vs RIC and MAC, respectively. RFS was not significantly different between all 3 groups in first line (p = 0.70).
• For patients transplanted as second- or third-line treatment, there was no significant difference in OS for treo vs. RIC and MAC in either univariate or multivariate analysis
• Authors conclude that despite slightly increased relapse rate, use of treo-based conditioning first line is superior to other RIC or MAC regimens for reducing NRM without affecting long-term OS

Autologous Transplant

*Kazandjian D, Mo CC, Landgren O, et al. The role of high-dose melphalan with autologous stem-cell transplant in multiple myeloma: is it time for a paradigm shift? [published online ahead of print, 2020 Jun 5]. Br J Haematol. 2020;10.1111/bjh.16764. https://pubmed.ncbi.nlm.nih.gov/32501533/

• With the rapid development of new and efficacious MM therapies, the conventional role of high-dose melphalan with autoHCT (HDM-ASCT) as standard of care for HCT-eligible patients early in their treatment course may be challenged
• HDM-ASCT is associated with significant morbidity and rarely TRM. Potential long-term effects include fatigue, cytopenias, recurrent infections, cataract formation, infertility, pulmonary fibrosis and most importantly, increased risk of secondary malignancies.
• IMiD-PI based triplet regimens followed by maintenance have become a new standard of care for newly diagnosed MM, and iMiD-PI-mAb-based quadruplet regimens have a potential to further advance this standard in the future
• Although real-time utility of MRD in MM has yet to be validated by prospective randomized trials, MRD negativity appears to strongly predict good outcome regardless of treatment modality and may help advance risk stratification
• Authors conclude that although prospective data is limited, HDM-ASCT may not be considered mandatory for eligible newly diagnosed patients who achieve deep and sustained remissions with highly effective regimens but rather a treatment option for those who may benefit from it

Cellular Therapy

*Shah NN, Highfill SL, Shalabi H, et al. CD4/CD8 T-Cell selection affects Chimeric Antigen Receptor (CAR) T-Cell potency and toxicity: updated results from a phase I anti-CD22 CAR T-Cell trial. J Clin Oncol. 2020;38(17):1938‐1950. https://pubmed.ncbi.nlm.nih.gov/32286905/

• Single-center, phase 1, 3+3 dose-escalation study that tested a novel CD22-targeted CAR T-cell for children and young adults (age 3-30 years) with relapsed/refractory CD22+ malignancies (n = 58)
• Median age was 17.5 years, all had ALL except for 2 patients (one had DLBCL and the other had CML with ALL blast crisis), and 51 patients (87.9%) had received prior CD19-targeted therapy
• 50 patients (86.2%) developed CRS, which was grade 1-2 in 45 patients (90%) and comparable to reports with CD19 CAR T-cells
• Incidence of HLH-like manifestations was higher in those who underwent CD4/CD8 T-cell selection and was reported in 19 patients (32.8%), requiring use of anakinra. Neurotoxicity was generally minimal and transient, which seemed to be less severe than with CD19 CAR T-cells.
• CR rate was 70%, and median OS was 13.4 months (95% CI, 7.7 to 20.3 months). Of those who achieved CR, median RFS was 6 months (95% CI, 4.1 to 6.5 months).
• Authors conclude that CD22 CAR T-cells are a highly effective salvage option for patients with B-cell malignancies resistant to CD19-targeted immunotherapy and should be further studied in a pivotal phase II trial

Graft-Versus-Host Disease

*Huang Y, Han M, Yang D et al. Comparative study of mizoribine and mycophenolate mofetil combined with a calcineurin inhibitor-based immunosuppressive regimen in patients with alternative donor hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2020: Jun 3:S1083-8791(20)30343-8. https://pubmed.ncbi.nlm.nih.gov/32504862/

• Prospective, randomized single center study comparing mizoribine (MZR) and MMF combined with a CNI based immunosuppressive regimen in patients with alternative donor alloHCT
• Eighty patients enrolled in the study, 40 to each the MMF and MZR cohorts
• There was no difference in time to engraftment, incidence of engraftment, development of secondary poor graft function or GVHD between groups
• There was no difference in the estimated OS, PFS or 1-year NRM between groups
• Patients receiving MZR had a reduced rate of 1 year NRM caused by viral infections compared to the MMF cohort (p=0.05) but had a higher incidence of hyperuricemia (p = 0.045)
• Authors concluded that combined with CNIs, MZR functioned well both in immunosuppression and reduction in the severity of CMV infection and could be used as an alternative to MMF following alternative donor HCT but further studies are needed

Infectious Disease

**Foster G, Grant M Thomas S et al. Treatment with foscarnet after allogeneic hematopoietic-cell transplant (AlloHCT) is associated with long-term loss of renal function. BBMT.May 22:S1083-8791(20)30295-0. https://pubmed.ncbi.nlm.nih.gov/32450288/

• Single-center, retrospective chart review of 987 adult patients transplanted over a 12-year period comparing patients with foscarnet exposure to those with no foscarnet exposure
• Multiple significant differences in baseline characteristics between patients  
• There was no difference in eGFR changes from baseline to 3 months, baseline to 6 months; however from 6 months to 12 months foscarnet exposed patients’ median eGFR continued to decline compared to unexposed patients’ eGFR improved
• Foscarnet more than doubles the odds of > 30% decline in GFR at 1-year and is associated with a 10% incremental decline in eGFR at 12 months, but exposure is not associated with survival
• Authors conclude that foscarnet is an independent predictor of long term decline in renal function after alloHCT and should be reconsidered for those indications without compelling data

Pediatrics

*Burroughs LM, Petrovic A, Brazauskas R, et al. Excellent outcomes following hematopoietic cell transplantation for Wiskott-Aldrich syndrome: a PIDTC report. Blood. 2020;135(23): 2094-2105. https://pubmed.ncbi.nlm.nih.gov/32268350/

• A reported analysis of outcomes from WAS patients who underwent alloHCT from 29 Primary Immune Deficiency Treatment Consortium centers from 2005 to 2015. 65% patients received a myeloablative, busulfan-based conditioning regimen.
• At 4.5-year follow-up, overall survival (OS) was 91%. Patients that were <5 years of age at the time of transplant had a superior 5-year OS, compared to patients ≥5 years (94% vs 66%, p=0.0008).
• OS was not statistically significantly impacted by donor type or conditioning regimen intensity. Higher platelet counts were observed among recipients who achieved full (>95%) vs low-level (5%-49%) donor myeloid engraftment
• Fludarabine/melphalan-based reduced-intensity regimens were more likely to have donor myeloid chimerism <50% early after HCT

Abbreviations:

ALL: acute lymphoblastic leukemia

alloHCT: allogeneic hematopoietic cell transplantation

autoHCT: autologous hematopoietic cell transplantation

CNI: calcineurin inhibitor

CML: chronic myeloid leukemia

CMV: cytomegalovirus

CR: complete response

CRS: cytokine release syndrome

DLBCL: diffuse large B-cell lymphoma

eGFR: estimated glomerular filtration rate 

GVHD: graft-versus-host disease

HCT: hematopoietic cell transplantation

HDM-ASCT: high-dose melphalan with autoHCT

HLH: hemophagocytic lymphohistiocytosis

iMiD-PI-mAb: immunomodulatory agent-proteasome inhibitor-monoclonal antibody

MAC: myeloablative conditioning

MM: multiple myeloma

MMF: mycophenolate mofetil

MRD: minimal residual disease

MZR: mizoribine

NRM: non-relapse mortality

OS: overall survival

PFS: progression-free survival

RIC: reduced intensity conditioning

RFS: relapse-free survival

TRM: transplant-related mortality

WAS: Wiskott-Aldrich syndrome

 

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

Tags: Pharmacy SIG, GVHD