In this month’s Pharmacy SIG Literature Update: TBI myeloablative conditioning in haploidentical transplants, salvage plerixafor for poor mobilizing allogeneic stem cell donors, 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

**Lorentino, F., Labopin, M., Ciceri, F. et al. Post-transplantation cyclophosphamide GvHD prophylaxis after hematopoietic stem cell transplantation from 9/10 or 10/10 HLA-matched unrelated donors for acute leukemia. Leukemia 2021:585–594. https://doi.org/10.1038/s41375-020-0863-4. PMID: 32620146

• Registry-based retrospective study that compared acute leukemia patients receiving 10/10 or 9/10 HLA allele-matched UD-HCT with PTCy-GvHD prophylaxis between 2010 and 2017. A total of 305 and 159 patients were identified for the 10/10 and 9/10 HLA-matched unrelated donor (UD) groups, respectively.
• The 100-day incidence of grade ≥2 and grade ≥3 aGvHD were comparable for 10/10 and 9/10 UD (28% versus 28%, p = 0.8 and 10% versus 8%, p = 0.5, respectively). The 2-year cGvHD and extensive cGvHD were similar (35% versus 44%, p = 0.2 and 21% versus 20%, p = 0.6, respectively).
• The 2-year NRM was 20% after 10/10 and 16% after 9/10 UDHCT (p = 0.1). Relapse incidence at 2-year was 24% for 10/10 and 28% for 9/10 UD-HCT (p = 0.4). Leukemia-free survival at 2-year was the same for 10/10 and 9/10 UD (56 and 56%, p = 0.6, respectively), with comparable OS (62 and 59%, p = 0.9, respectively).
• Multivariate analysis showed no effect of HLA-matching on outcomes.
• The authors concluded that PTCy may alleviate the detrimental effect of HLA-allele mismatching in UD-HCT, expanding the donor pool for acute leukemia.

 

**Dholaria B, Labopin B, Emanuele A, et al. Improved Outcomes of Haploidentical Hematopoietic Cell Transplantation with Total Body Irradiation-Based Myeloablative Conditioning in Acute Lymphoblastic Leukemia. Transplantation and Cellular Therapy 2021;171.e1-171.e8

• This was a retrospective, multicenter analysis comparing the outcomes of patients with ALL who underwent TBI-based (n = 188) versus chemotherapy (CT) based MAC (n = 239) followed by haplo HCT with post-transplant cyclophosphamide. Data was collected from the EBMT registry (2010-2018).  
• In the TBI and CT cohorts, 2-year leukemia-free survival (LFS) was 45% vs. 37% (p = 0.05); OS was 51% vs. 47% (p = 0.18), incidence of relapse was 34% vs. 32% (p = 0.44), and nonrelapse mortality was 21% vs. 31% (p < 0.01).
• In a multivariate analysis, TBI was associated with lower NRM (HR 0.53, p = 0.01), improved LFS (HR 0.71, p = 0.04), and increased risk for grade II-IV aGHVD (HR 1.59, p = 0.02) compared with CT-based MAC. Of note, there was no significant impact on cGVHD rates compared to CT-based MAC.
• Authors concluded that TBI-based MAC was associated with lower NRM and better LFS compared with CT-based MAC in patients with ALL after haplo HCT.
• There were numerous limitations in this study, including but not limited to heterogeneity in conditioning regimens, GHVD prophylaxis, limitation duration of follow, lack of information on notable adverse events (e.g. SOS).

*Oshima MU, Storer BE, Qiu H, et al. Long-term Outcomes with Nonmyeloablative HLA-Identical Related Hematopoietic Cell Transplantation Using Tacrolimus and Mycophenolate Mofetil for Graft-versus-Host Disease Prophylaxis. Transplantation and Cellular Therapy 2021;163e1-163.e7

• Phase II, multi-center trial evaluating the incidence of grade III/IV aGVHD and chronic extensive GVHD after nonmyeloablative conditioning and GVHD prophylaxis with TAC/MMF in patients with hematological malignancies
• Conditioning consisted of TBI for patients who had received auto HCT in the past 6 months (n = 50) or TBI combined with fludarabine (n = 100), however it’s important to note that the study was not designed to compare these groups.
• The cumulative incidence (CI) of day 100 grade II-IV and grade III-IV aGVHD was 27% and 4%, respectively. The 5-year CI of chronic extensive GVHD was 48%.
• 1-yr and 5-yr cumulative estimate of nonrelapse mortality, overall survival and PFS were 9% and 13%, 73% and 53% and 56% and 37%, respectively.
• GVHD ppx with TAC/MMF appears to result in low risk of aGVHD, however comparative, phase III trials are necessary to compare this combination with others (i.e. CSP/MMF, TAC/MTX, etc.) currently used in practice before determining its place in therapy.

*Wang T, Chen S, Chen J, et al. Allogeneic Hematopoietic Stem Cell Transplantation Improved Survival for Adult Core Binding Factor Acute Myelogenous Leukemia Patients with Intermediate- and Adverse-Risk Genetics in the 2017 European LeukemiaNet. Transplantation and Cellular Therapy 2021;173.e1-173.e9

• A retrospective analysis of patients (n = 286) with CBF-AML with intermediate and adverse risk genetics in CR1 who received consolidation with chemotherapy (n = 122), auto-HCT (n = 27) or allo-HCT (n = 137) between Jan 2009 and Dec 2018
• The following are outcomes in alloHCT as consolidation therapy compared with auto-HCT or chemotherapy
  • 5 year OS: 74% vs. 38% or 49%, p < 0.001
  • 5 year PFS: 74% vs. 26% or 49%, p < 0.001
  • Cumulative incidence of relapse (CIR): 9% vs. 61% or 31%, p < 0.001
  • No difference in 5 year NRM
  • Favorable outcomes above mainly observed in patients with t(8;21)
• In patients with inv(16): alloHCT associated with improved PFS (p  < 0.01) and CIR (p < 0.01) compared with alloHCT or chemotherapy, but no differences in outcomes for OS
• As expected, MRD at 2 and 3 months post alloHCT predicted progression and relapse, however MRD pre transplant and at 1 month post alloHCT did not.

*Chang EK, Chanson D, Berano T, et al. Atrial fibrillation in patients undergoing allogeneic hematopoietic cell transplantation. J Clin Oncol. 2021;39(8):902-910. https://pubmed.ncbi.nlm.nih.gov/33417479/

• Retrospective nested case-control study of 487 alloHCT patients from 2014-2016 to describe association between pre-HCT EKG measurements and future AF events
• Median age at HCT was 52.4 years. 5-year cumulative incidence of AF was 10.6% with median time to AF of 117.5 days (4.0-1, 405.0).
• Age ≥50 years (HR 2.76; 95% CI  1.37-5.58), HLA-unrelated donor (HR 2.2; 95% CI 1.18-4.12), dyslipidemia (HR 2.4; 95% CI 1.23-4.68), and pre-HCT prolonged QTc (HR 2.55; 95% CI 1.38-4.72) interval were identified as independent risk factors for AF. Patients who developed AF were more likely to have lower left atrial ejection fraction than patients who did not.
• AF was associated with a significantly increased risk of all-cause mortality (HR 12.76; 95% CI 8.76-18.57) and NRM (HR 15.78; 95% CI 8.7-28.62). The incidence rate of stroke after AF was 143 per 1000 person years.
• Authors concluded that the burden of AF is substantial and associated with poor survival. Key patient demographics and pre-HCT cardiac parameters can aid in identifying patients for targeted prevention during and after HCT.

 

*Sugita J, Kamimura T, Ishikawa T, et al. Reduced dose of posttransplant cyclophosphamide in HLA-haploidentical peripheral blood stem cell transplantation. Bone Marrow Transplant. 2021;56:596-604. https://pubmed.ncbi.nlm.nih.gov/32973350/

• Two consecutive prospective multicenter phase II trials evaluating safety and efficacy of 80 mg/kg of PTCy (40 mg/kg on days +3 and +4) in 137 patients undergoing RIC haploHCT with PBSCT source
• Neutrophil engraftment was achieved in 97% and 96% of patients in the first and second studies, respectively. The incidence of grade II-IV aGVHD was 26% and 23% in the first and second studies, respectively. The incidence of cGVHD was 35% and 18% in the first and second studies, respectively.
• Two-year OS, DFS, and NRM were 51%, 42%, and 18% in the first study and 58%, 48%, and 16% in the second study. The rate of immunosuppression discontinuation at 2 years was 83% and 76% in the first and second studies, respectively.
• The authors suggest that 80 mg/kg of PTCy is a valid option in RIC haploHCT with PBSCT

 

**Hölig K, Schmidt H, Hütter G, et al. Salvage treatment with plerixafor in poor mobilizing allogeneic stem cell donors: results of a prospective phase II trial. Bone Marrow Transplant. 2021;56:635-645. https://pubmed.ncbi.nlm.nih.gov/33028987/

• Prospective trial of plerixafor in 37 allo PBSCT donors with poor response to standard G-CSF (<2x10⁶ CD34+ cells/kg after first apheresis)
• Plerixafor was given as a single dose of 240 mcg/kg at 10pm on the day of first apheresis
• The median CD34+ count was 15 cells/µL on day 1 after G-CSF alone vs 44 cells/µL on day 2 with G-CSF + plerixafor (p<0.001)
• The median yield of CD34+ cells was 1.1×10⁸ on day 1 and 2.8×10⁸ on day 2. In contrast to a median yield of only 1.31×10⁶ on day 1, triggering study inclusion. A median of 3.74×10⁶ were collected with G-CSF plus plerixafor on day 2.
• 21 of 37 donors reached the target cell count of >4.5x10⁶ CD34+ cells/kg (57%, 95% CI 40-73%). No donor experienced a severe adverse event requiring treatment.
• The authors conclude that plerixafor can be considered on a case-by-case basis for healthy allo PBSCT donors with very poor mobilization success after G-CSF alone

 

Supportive Care

**Jurdi NE, Fair C, Rogosheske  J, et al. Effect of Keratinocyte Growth Factor on Hospital Readmission and Regimen-Related Toxicities after Autologous Hematopoietic Cell Transplantation for Lymphoma. Transplantation and Cellular Therapy 2021; 173: 179.e1-179.e4

• A retrospective analysis evaluating the impact of adding palifermin to standard high-dose conditioning with BEAM (n = 35) on hospital readmissions and select oral and GI toxicities in patients with relapsed/refractory lymphoma. Results were compared with a historical group of patients who did not receive palifermin (n = 38).
• The cumulative incidence of oral mucositis of any grade through day 30 was lower in the palifermin group vs. control (23% vs. 42%).
• The median number of hospital readmission days was lower in the palifermin group vs. control (4 days versus 7 days; P< .01).
• The median total number of days of hospitalization through day +30 was lower in the palifermin group vs. control (12 days versus 15 days; P = .05).
• Authors concluded that addition of palifermin limits severe regimen related toxicities and decreases readmissions and duration of hospital stay.

 

Abbreviations:

AF: atrial fibrillation

aGVHD: acute graft-versus-host disease

alloHCT: allogeneic hematopoietic cell transplantation

cGVHD: chronic graft-versus-host disease

CSP: cyclosporine

DFS: disease-free survival

G-CSF: granulocyte colony-stimulating factor

haploHCT: haploidentical hematopoietic cell transplantation

HLA: human leukocyte antigen

MAC: myeloablative conditioning

MMF: mycophenolate mofetil
MTX: methotrexate

NRM: non-relapse mortality

OS: overall survival

PBSCT: peripheral blood stem cell transplant

PFS: progression-free survival

PTCy: post-transplant cyclophosphamide

RIC: reduced intensity conditioning

TAC: tacrolimus

TBI: total body irradiation

UD: unrelated donor

 

ASTCT Pharmacy SIG Research Working Committee:

Jennifer Collins, Kelly Gaffney, Katie Gatwood, Arpita Gandhi, Jitesh Kawedia, Binni Kunvarjee, Andrew Lin, Dennis Marjoncu, Monank Patel, Jonathan Ptachcinski, Julianna Roddy, Lily Yan

Tags: TBI, Myeloablative, Conditioning, Haploidentical Transplants, Salvage, Plerixafor, Mobilizing, Allogeneic, Stem Cells