In this month’s Pharmacy SIG Literature Update: Sorafenib maintenance after allogeneic transplantation, ixazomib for cGVHD treatment, recommendations for managing infections in CAR T-cell patients, 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

***Xuan L, Wang Y, Huang F, et al. Sorafenib maintenance in patients with FLT-ITD acute myeloid leukemia undergoing allogeneic hematopoietic stem-cell transplantation: an open-label, multicenter, randomized phase 3 trial. Lancet Oncol. 2020;21:1201-12. https://pubmed.ncbi.nlm.nih.gov/32791048/    

• Phase III trial of 202 adult patients 18-60 years old with FLT3-ITD mutated AML who received sorafenib maintenance (n = 100) vs control (n = 102) after MAC alloHCT with busulfan and cyclophosphamide
• Sorafenib was given as 400 mg orally twice daily starting within 30-60 days after transplantation and continued until day 180. Adverse effects of grade 3 or worse warranted dose reductions to 200 mg twice daily or 200 mg daily.
• Cumulative incidence of relapse at 1 year was 7% in the sorafenib group vs 24.5% in the control (p=0.001). Median time to relapse was 11.6 months with sorafenib vs 5.7 months in the control group (p=0.16).
• Common grade 3-4 side effects were similar between the two groups, with the most common being infections (23% vs 21%), aGVHD (23% vs 21%), cGVHD (18% vs 17%) and hematologic toxicity (15% vs 7%)
• The authors conclude that sorafenib maintenance after transplant is well tolerated and a suitable option for prevention of relapse in FLT3-ITD AML

**Salas MQ, Chen S, Lam W, et al. Less is more: superior graft-versus-host disease-free/relapse-free survival with reduced-intensity conditioning and dual T-cell depletion in acute myelogenous leukemia. Biol Blood Marrow Transplant. 2020;26(8):1511-1519. https://pubmed.ncbi.nlm.nih.gov/32422253/    

• Transplant outcomes of patients with AML who received either MAC or reduced-intensity conditioning RIC were compared in a retrospective cohort. The efficacy of dual T-cell depletion using ATG and PTCy for prevention of GVHD was assessed in the RIC subcohort.
• The MAC regimen consisted of fludarabine 50 mg/m²/day on days -5 to -2, busulfan 3.2 mg/kg/day on days -5 to -2, and 400 cGy TBI on day -1. The RIC regimen consisted of fludarabine 30 mg/m²/day on days-5 to -2, busulfan 3.2 mg/kg/day on days -3 and
  -2, and 200 cGy TBI on day -1. Various GVHD prophylaxis regimens were used and included: methotrexate + cyclosporine, ATG + methotrexate + cyclosporine, cyclosporine + MMF.
• The study cohort was comprised of 356 adults (MAC, n=111; RIC, n=245) with a median age of 57 years. Of those who received RIC conditioning, 68.4% received ATG, PTCy, and cyclosporine for GVHD prophylaxis.
• The intensity of the conditioning regimen did not have a significant impact on overall or relapse-free survival. The combination of RIC with ATG-PTCy-cyclosporine was associated with a significantly lower cumulative incidence of acute and chronic GVHD and was a significant predictor for higher GRFS (p = 0.0001).
• The authors conclude that use of RIC allografts and dual T-cell modulation with ATG and PTCy may result in better long-term quality of life for alloHCT in AML

**Paul S, Zahurak M, Luznik L, et al. Non-myeloablative allogeneic transplantation with post-transplant cyclophosphamide after immune checkpoint inhibition for classical Hodgkin lymphoma: A retrospective cohort study. Biol Blood Marrow Transplant. 2020;26(9):1679-1688. https://pubmed.ncbi.nlm.nih.gov/32592857/

• Single-center, retrospective review of 105 relapsed/refractory patients with cHL who had or had not received previous ICI and then underwent alloHCT with PTCy
• 35.2% of patients received ICIs and 64.7% received chemotherapy without ICIs (no-ICI) before alloHCT
• 3-year OS in patients in the ICI and no-ICI groups was 94% versus 78% (HR = 0.35; 95% CI 0.08 - 1.56, p=0.17), respectively and 3-year estimated PFS was 90% vs 65% (HR = 0.3; 95% CI 0.09- 1; p = 0.05), respectively
• There was no statically significant difference in the 12-month cumulative incidence of grade II to IV aGVHD or in the 24-month incidence of cGVHD.
• Authors concluded that ICIs do not increase acute or chronic GVHD incidence compared with salvage chemotherapy and use of ICI therapy prior to transplant is considered safe in patients with cHL when undergoing alloHCT with PTCy and may improve post-transplant disease progression and survival

*Popat U, Mehta RS, Bassett R, et al. Optimizing the conditioning regimen for hematopoietic cell transplant in myelofibrosis: long-term results of a prospective phase II clinical trial. Biol Blood Marrow Transplant. 2020;26(8):1439-1445. https://pubmed.ncbi.nlm.nih.gov/32438043/ 

• The use of FluBu in patients with MF and the effect on day 100 NRM was assessed in a nonrandomized, prospective, phase II trial.

• Patients received a conditioning regimen of fludarabine 40 mg/m²/day from days -5 to -2 and either high- or low-dose busulfan. Originally, patients received busulfan 130 mg/m²/day on days -3 and -2 (low-dose).  After an interim analysis showing higher than expected rates of relapse, patients received pharmacokinetic-guided busulfan 32 mg/m² on day-7 with a target AUC = 4000 µmol/min for days -5 to -2 (high-dose).
• Results for 46 patients were assessed. Median age was 58 years, international prognostic score-plus was intermediate to high, and median time from diagnosis to transplant was 23 months
• Cumulative incidence of day 100 NRM was 9.7% [95% CI 0-20.3] in those who received high-dose and 0% for those who received low-dose busulfan. Cumulative incidence of 3-year NRM was 9.7% versus 20% and rate of relapse at 3 years was 32.3% and 53.5% in the high- and low-dose group respectively. In a multivariable analysis, high-dose busulfan showed a trend towards lower rates of relapse with no significant effect on NRM [HR 0.44, 95% CI 0.18-1.07].
• The authors conclude the use of myeloablative pharmacokinetic-guided busulfan reduces relapse and may be considered safe in older patients with MF as no increase in NRM was reported

**Ahmed S, Ghosh N, Ahn KW, et al. Impact of type of reduced-intensity conditioning regimen on the outcomes of allogeneic hematopoietic cell transplantation in classical Hodgkin lymphoma. British Journal of Haematology. 2020;190:573-82. https://pubmed.ncbi.nlm.nih.gov/32314807/

• Retrospective review of 492 adult cHL patients receiving HLA-MSD or 8/8 MUD with one of 3 RIC regimens: FluBu (busulfan 6.4 mg/kg) (n=102), FluMel (melphalan 140 mg/m2) (n=318), or FluCy (n=72)
• The primary endpoint of OS at 4 years was 62% for FluBu, 59% for FluMel, and 55% for FluCy (p=0.64). FluCy conditioning was associated with significantly higher mortality after 11 months from transplant (HR 2.46, p=0.005) when compared to FluBu. PFS between the two cohorts were not significantly difference, suggesting late NRM as a probable influence of this observation.
• Cumulative incidence of grade 2-4 aGVHD at 180 days was 46%, 34%, and 26%, respectively (p=0.02). Grade 3-4 aGVHD was 16%, 15%, and 12% (p=0.77). Cumulative incidence of cGVHD was 50%, 49%, and 43% respectively (p=0.56).
• The authors concluded that choice of RIC conditioning does not impact the overall risk of NRM, PFS, or GVHD, with the potential exception of FluCy being associated with increased late NRM

*Fox ML, García-Cadenas I, Pérez AM, et al. Feasibility of thiotepa addition to the fludarabine-busulfan conditioning with tacrolimus/sirolimus as graft vs host disease prophylaxis. Leuk Lymphoma. 2020;61(8):1823-1832. https://pubmed.ncbi.nlm.nih.gov/32654570/

• Retrospective analysis of alloHCT patients with myeloid malignancies who were conditioned with either TBF or FluBu and received sirolimus/tacrolimus as GVHD prophylaxis from January 2009 to January 2017 (n = 104)
• Both groups (46 patients in TBF vs 58 in FluBu) were well-balanced for baseline characteristics except TBF group had more male patients who had female donors (35% vs. 14%; P = 0.02) and higher HCT-CI ≥ 3 (54% vs. 33%; P = 0.03)
• PFS and OS at 2 years were significantly reduced with TBF vs FluBu (48.5% vs. 73.6%; p<0.01 and 51.8% vs 77.8%; p<0.01, respectively)
• Cumulative incidence of NRM was increased with TBF vs FluBu especially in early (100-day) vs late (2-year) events (15.2% vs. 1.7%; p=0.01 and 31.6% vs 12.3%; p=0.01)
• Other outcomes including relapse, incidence of aGVHD and cGVHD, VOD, and TMA were similar between both groups
• Authors conclude that TBF conditioning regimen does not seem to improve outcomes vs traditional RIC FluBu regimen when used with sirolimus/tacrolimus GVHD prophylaxis in a cohort of elderly and comorbid patients

Graft-Versus-Host Disease

***Pidala J, Bhatt VR, Hamilton B, et al. Ixazomib for treatment of refractory chronic graft-versus-host disease: a chronic GVHD consortium phase II trial. Biol Blood Marrow Transplant. 2020;26(9):1612-1619. https://pubmed.ncbi.nlm.nih.gov/32464285/

• Phase II, single-arm, multicenter trial examining the efficacy of ixazomib (4 mg PO weekly on days 1, 8, and 15 of a 28-day cycle for up to 6 total cycles) in 50 patients with cGVHD who had progressed after at least 1 previous line of systemic immunosuppressive therapy
• Median time from the onset of chronic GVHD to enrollment was 2.8 years and the degree of cGVHD (NIH-defined) at enrollment was moderate (16%) or severe (84%), with 52% of patients having involvement of ≥4 organs. Patients were heavily pretreated, with 78% receiving ≥3 previous lines of systemic therapy for cGVHD.
• 52% of patients completed 6 months of planned therapy; the ORR was 40% at 6 months and the 6-month treatment failure rate was significantly lower than the historical benchmark previously established with second-line therapy (28% vs 44%; p=0.01). No patient, transplantation, or cGVHD variables were significantly associated with 6-month treatment failure. OS was 92% at 6 months, and 90% at 12 months.
• Authors conclude that ixazomib is active in treatment of advanced cGVHD

*Giannoni L, Morin F, Robin M, et al. Human-derived α1-antitrypsin is still efficacious in heavily pretreated patients with steroid-resistant gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant. 2020;26(9):1620-1626. https://pubmed.ncbi.nlm.nih.gov/3245421/

• Retrospective review of 16 patients treated with human-derived AAT for advanced stage GI SR-GVHD, with two-thirds of the patients having failed at least 1 treatment for SR-GVHD.
• The ORR was 44%, with a CR rate of 27% and median time to best response was 21 days (range 6-26 days).
• At day 56 following AAT treatment, all CRs were maintained, and the ORR was 39%. The 1-year OS was 48%. AAT levels consistently rose after exogenous administration, but no correlation was found between serum levels and response, however REG3α and IL-33 levels were associated with response in this study.
• Authors conclude that this study supports previous reports of use of AAT for the management of GI SR-GVHD

Pediatrics

*Chiesa R, Wang J, Blok HJ, et al. Hematopoietic cell transplantation in chronic granulomatous disease: a study of 712 children and adults. Blood. 2020;136(10):1201-1211. https://pubmed.ncbi.nlm.nih.gov/32614953/

• Retrospective multicenter analysis of CGD patients who underwent alloHCT between March 1993 and December 2018 in the EBMT registry (n = 712), including 635 children (ages < 18 years) and 77 adults
• OS and EFS at 3 years were 85.7% (95% CI: 82.8-88.5%) and 75.8% (95% CI: 72.3-79.3%), respectively. In multivariate analysis, older age was associated with significantly reduced OS (HR 1.69; 95% CI: 1.30-2.20; p=0.0001) and increased cGVHD (HR 1.35; 95% CI: 1.05-1.75; P = 0.01)
• When compared to the use of a MSD graft, patients with 1-antigen-mismatched donors (n = 105) had reduced OS (HR 2.29; 95% CI: 1.18-4.42; p=0.01) and a significantly reduced EFS (HR 2.37; 95% CI: 1.38-4.08; p=0.001). Type of conditioning regimen had no significant impact on OS and EFS
• Authors conclude that alloHCT in CGD should be strongly considered at a younger age and particularly in the presence of a well-matched donor

Supportive Care

**Arango M, Cardona D. Hemorrhagic cystitis after haploidentical transplantation with post-transplantation cyclophosphamide: protective effect of MESNA continuous infusion. Biol Blood Marrow Transplant. 2020;26(8):1492-1496. https://pubmed.ncbi.nlm.nih.gov/32417488/

• The incidence of hemorrhagic cystitis after haploHCT with two different methods of MESNA administration was reported in a patient cohort (n=85) from a large academic center
• Following transplant, patients received PTCy 50 mg/kg/day on days +3 and +4 with oral MMF and a CNI starting on day +5. MESNA was dosed 1:1 with cyclophosphamide dose and was administered either as a continuous 24-hour infusion or as three intermittent boluses delivered at four hour intervals.
• The cumulative incidence of hemorrhagic cystitis was lower in patients who received a continuous infusion of MESNA compared to those who received intermittent boluses (5.6% versus 27.8% respectively, p=0.01). In a multivariable analysis, continuous infusion MESNA was identified as a protective factor for the development of hemorrhagic cystitis (HR 0.21, 95% CI 0.4-0.88).
• The authors conclude administration of MESNA via continuous infusion is a simple and useful way to prevent hemorrhagic cystitis after PTCy

Infectious Disease

**Hill JA, Seo SK. How I prevent infections in patients receiving CD19-targeted chimeric antigen receptor T cells for B-cell malignancies. Blood. 2020;136(8):925-935. https://pubmed.ncbi.nlm.nih.gov/32582924/

• General recommendations for infection prevention in patients receiving CD19-targeted CAR T-cells
• Required ID screening pre-infusion includes HIV, HBV panel, and HCV IgG
• Infectious disease prophylaxis
  • Unclear role of antibacterial prophylaxis although some centers may give fluoroquinolone prophylaxis if severe neutropenia (ANC<0.5 x 10⁹/L)
  • Recommend prophylactic acyclovir/valacyclovir starting with lymphodepleting chemo and continuing for at least 6 months post CAR T-cells
  • Recommend prophylactic entecavir in patients at high risk for HBV reactivation
  • Recommend prophylactic fluconazole during severe neutropenia (ANC<0.5 x 10⁹/L) until neutrophil recovery or mold-active azole if severe neutropenia > 3 weeks or requires additional immunosuppression after CAR T-cells
  • Recommend PJP prophylaxis in all patients with trimethoprim/sulfamethoxazole in all patients by day 28 after infusion
• Patients with CRS and/or ICANS should be started on empiric broad-spectrum antibiotics according to neutropenic fever guidelines
• Consider ID consult, mold-active prophylaxis and weekly CMV monitoring in high-risk patients (require >1 dose of tocilizumab, >3 days of ≥10 mg dexamethasone per day within 7 days, ≥1 g/day IV methylprednisolone, or second-line agents such as anakinra)
• Consider vaccinations ≥6 months after CAR-T-cell infusion for inactivated vaccines and ≥1 year for live and non-live adjuvant vaccines

Abbreviations:

AAT: α1-antitrypsin

aGVHD: acute graft-versus-host disease

ALL: acute lymphoblastic leukemia

alloHCT: allogeneic hematopoietic cell transplantation

AML: acute myeloid leukemia

ANC: absolute neutrophil count

ATG: anti-thymocyte globulin

autoHCT: autologous hematopoietic cell transplantation

CAR: chimeric antigen receptor

CGT: chronic granulomatous disease

cGVHD: chronic graft-versus-host disease

cHL: classical Hodgkin lymphoma

CMV: cytomegalovirus

CNI: calcineurin inhibitor

CR: complete response

CRS: cytokine release syndrome

EBMT: European Society for Blood and Marrow Transplantation

EFS: event-free survival

FluBu: Fludarabine and busulfan

FluCy: Fludarabine and cyclophosphamide

FluMel: Fludarabine and melphalan

GRFS: GVHD-free, relapse-free survival

GVHD: graft-versus-host disease

haploHCT: haploidentical hematopoietic cell transplantation

HBV: hepatitis B

HCV: hepatitis C

HCT: hematopoietic cell transplantation

HIV: human immunodeficiency virus

HLA: human leukocyte antigen

ICANS: immune effector cell-associated neurotoxicity

ICI: immune checkpoint inhibitor

MAC: myeloablative conditioning

MF: myelofibrosis

MMF: mycophenolate mofetil

MSD: matched sibling donor

MUD: matched unrelated donor

NMA: nonmyeloablative

NIH: National Institutes of Health

NRM: non-relapse mortality

ORR: overall response rate

OS: overall survival

PFS: progression-free survival

PJP: Pneumocystis jirovecii

PR: partial response

PTCy: post-transplant cyclophosphamide

RIC: reduced intensity conditioning

SR: steroid-refractory

TBF: thiotepa, fludarabine, busulfan

TBI: total body irradiation

TMA: thrombotic microangiopathy

TRM: transplant-related mortality

VOD: veno-occlusive disease

 

ASTCT Pharmacy SIG Research Working Committee:

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

Ashley Teusink-Cross,

Tags: