03.01.21

Pharmacy SIG Literature Update: Results of the BMT CTN 1101 Trial and More

In this month’s Pharmacy SIG Literature Update: Results of the BMT CTN 1101 trial, conditioning regimens for allogeneic transplantation, letermovir for CMV prophylaxis in haploidentical transplantation, 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

***Bejanyan N, Zhang M, Bo-Subait K, et al. Myeloablative Conditioning for Allogeneic Transplantation Results in Superior Disease-Free Survival for Acute Myelogenous Leukemia and Myelodysplastic Syndromes with Low/Intermediate but not High Disease Risk Index: A Center for International Blood and Marrow Transplant Research Study. Transplantation and Cellular Therapy. 2021; 27: 68.e1-68.e9. https://pubmed.ncbi.nlm.nih.gov/33010430/

  • Compared with RIC, MAC is generally associated with lower relapse risk after alloHCT for AML and MDS. However, disease-specific risk factors in AML/MDS can further inform when MAC and RIC may yield differential outcomes.
  •  HCT outcomes were analyzed after stratification by the DRI in 4387 adults (age 40 to 65 years) to identify the impact of conditioning intensity. In the low/intermediate-risk DRI cohort, RIC was associated with lower NRM (HR 0.74, 95% CI 0.62 to 0.88; P<0.001) but significantly greater relapse risk (HR, 1.54; 95% CI 1.35 to 1.76; P<0.001) and thus inferior DFS (HR, 1.19; 95% CI 1.07 to 1.33; P=0.001).
  • In the high/very high-risk DRI cohort, RIC was associated with marginally lower NRM (HR, 0.83; 95% CI 0.68 to 1.00; P=0.051) and significantly higher relapse risk (HR, 1.23; 95% CI 1.08 to 1.41; P=0.002), leading to similar DFS using either RIC or MAC
  • The authors conclude that MAC is preferred over RIC as conditioning intensity for patients with AML/MDS with low/intermediate-risk DRI, but with a similar benefit as RIC in high/very high-risk DRI. Novel MAC regimens with less toxicity could benefit all patients, but more potent antineoplastic approaches are needed for the high/very-high risk DRI group.

***Fuchs EJ, 0’Donnell PV, Eapen, et al. Double unrelated umbilical cord blood vs. HLA-haploidentical bone marrow transplantation: the BMT CTN 1101 trial. Blood. 2021; 137(3):420-28.

https://pubmed.ncbi.nlm.nih.gov/33475736/ 

  • Randomized, multicenter, phase 3 trial in US comparing double UCB (n=186) and haploidentical donor transplantation (n = 182) for the treatment of leukemia and lymphoma in adults
  • RIC consisted of cyclophosphamide, fludarabine and TBI for both donor types. GVHD prophylaxis for UCB transplantation consisted of MMF 15 mg/kg three times daily from day-3 through day +35 and CSA from day -3 through day 100. For haploidentical transplantation, it consisted of IV cyclophosphamide on day 3-4; MMF 3 times a day from day 5 through 35 and tacrolimus from day 5 to day 180.
  • The primary endpoint of 2-year PFS was 35% and 41% for UCB and haploidentical transplantation, respectively (P=0.41). The 2-year incidence of NRM was higher after UCB compared with haploidentical transplantation (18% vs. 11%, P=0.039). Consequently, 2-year OS was lower for UCB compared with haploidentical transplantation (46% vs. 57%, P=0.04).
  • There was no difference in day-180 incidence of grade II-IV or grade III-IV aGVHD, and 2-year incidence of cGVHD between groups. The 2-year incidence of relapse/progression was 47% and 48% for UCB and haploidentical transplantation (P=0.986) respectively.
  • Due to improved OS and lower NRM, haploidentical transplantation is the preferred approach compared with UCB transplantation

 

*Giebel S, Labopin M, Sobczyk-Kruszelnicka M, et al. Total body irradiation + fludarabine compared to busulfan + fludarabine as "reduced-toxicity conditioning" for patients with acute myeloid leukemia treated with allogeneic hematopoietic cell transplantation in first complete remission: a study by the Acute Leukemia Working Party of the EBMT. Bone Marrow Transplant. 2021;56(2):481-491.

https://pubmed.ncbi.nlm.nih.gov/32892216/

  • Retrospective, multicenter analysis comparing two RIC regimens for AML patients who received first alloHCT reported to EBMT registry (n=518)
    • IV busulfan at total dose 9.6 mg/kg (3 days) + fludarabine (Bu3/Flu) vs. TBI 8 Gy + fludarabine (TBI8Gy/Flu)
  • In entire cohort, probabilities for Bu3/Flu vs. TBI8Gy/Flu were the following:
    • 2-year OS: 62% vs. 72.5%, respectively (P=0.051)
    • 2-year LFS: 59.5% vs. 65%, respectively (P=0.15)
    • 2-year relapse: 30% vs. 20%, respectively (P=0.01)
    • 2- year NRM: 10% vs. 14%, respectively (P=0.18)
  • In multivariate analysis for patients age <50 years, TBI8Gy/Flu was associated with improved LFS (HR 0.5, P=0.04), OS (HR 0.31, P=0.004), GRFS (HR 0.55, P=0.03) and reduced relapse risk (HR 0.53, P=0.08)
  • Among patients age ≥50 years, TBI8Gy/Flu was associated with increased NRM (HR 3.9, P=0.0009) with no significant impact on other outcome measures
  • Authors conclude that use of RIC TBI8Gy/Flu may be more optimal in younger AML patients where it is associated with improved OS, and more prospective studies are needed to verify findings

 

*Alzahrani M, Damlaj M, Jeffries N, et al. Non-myeloablative human leukocyte antigen-matched related donor transplantation in sickle cell disease: outcomes from three independent centres. Br J Haematol. 2021;192(4):761-768.

https://pubmed.ncbi.nlm.nih.gov/33534948/

  • Prospective open-label study of NMA HCT from MRD for SCD across 3 institutions, n=122
  • Patients received cytoreduction with 300 cGy of TBI, alemtuzumab followed by an unmodified PBSCT, with sirolimus for GVHD prophylaxis. The median follow‐up was four years; median age at time of HCT was 29 years.
  • The primary endpoint was engraftment at one year, which occurred in 83% of patients. Median neutrophil and platelet engraftment occurred on day 22 and 19 respectively. One-year OS and 5-year sickle‐free survival were 93% and 85%, respectively.
  • Mean donor myeloid chimerism at 1 and 5-years post HCST were 84% and 88%, and CD3 chimerism was 48% and 53%, respectively. 16 patients (13%) developed graft failure post-transplant.
  • Two patients developed grade 1 and 2 skin aGVHD and no patients developed cGVHD
  • Authors conclude that this study present the results of the largest group of adult SCD patients receiving MRD PBSCT and the regimen was well-tolerated and efficacious, despite compromised organ functions prior to HCT, and without clinically significant GVHD

 

Autologous Transplant

**Bal S, Costa LJ, Sauter C, et al. Outcomes of Autologous Hematopoietic Cell Transplantation in Diffuse Large B Cell Lymphoma Refractory to Firstline Chemoimmunotherapy. Transplantation and Cellular Therapy. 2021; 27: 55.e1-55.e7.

https://pubmed.ncbi.nlm.nih.gov/32949754/

  • This study reports the outcomes of autoHCT in patients with chemosensitive primary refractory DLBCL using the CIBMTR registry. Between 2003 and 2018, 169 patients met inclusion criteria. The majority of patients had advanced stage disease (73%) at diagnosis, 27% patients had stable disease, and 73% had progressive disease after frontline chemoimmunotherapy. Following salvage therapy, 36% patients were in CR and 64% in PR.
  • NRM, progression/relapse, PFS, and OS at 4-years were 10.8% (95% CI, 6-13%), 47.8% (95% CI, 41-52%), 41.4% (95% CI, 41-52%), and 49.6% (95% CI, 44-56%) respectively. Univariate analysis indicates that patients with progressive disease after frontline chemoimmunotherapy did just as well as those with stable disease. As expected, patients who achieved CR to salvage had a lower cumulative incidence of progression/relapse at 1-year (30% versus 46.9%; P =0.02) and experienced superior 1-year PFS compared to patients in PR (63.2% versus 46.7%; P = .03).
  • The authors concluded that autoHCT provides durable disease control and should remain the standard of care in patients with primary refractory DLBCL who respond to salvage therapies

Graft-versus-Host Disease

*Shimoni A, Shem-Tov N, Yerushalmi R, et al. Carfilzomib combined with cyclosporine and methotrexate for the prevention of graft-versus-host disease after allogeneic stem-cell transplantation from unrelated donors. Bone Marrow Transplant. 2021;56(2):451-456.

https://pubmed.ncbi.nlm.nih.gov/32873915/

  • Phase II prospective study in alloHCT patients with unrelated donors comparing addition carfilzomib to cyclosporine/methotrexate (n=26) vs. historical group who received cyclosporine/methotrexate alone (n=100)
    • Carfilzomib 20 mg/m2 given on Days +1 and +2 post-HCT in study group
  • Median follow-up was 34 months (range, 18-56 months)
  • No difference between groups in engraftment or toxicities
  • Cumulative incidence of grades 2-4 aGVHD (6 months post-HCT) was 11% vs. 39% in carfilzomib vs. control group, respectively (P=0.01), and cGVHD (2 years post-HCT) was 49% vs. 41%, respectively (P=0.98). 3-year OS was higher with carfilzomib vs. control group (81% vs. 56%, respectively; P=0.05).
  • Authors conclude that addition of carfilzomib to cyclosporine/methotrexate is safe, may reduce aGVHD and possibly improve OS after unrelated donor HCT but these findings need to be validated in larger comparative studies

 

Supportive Care
*Lin A, Flynn J, Derespris L, et al. Letermovir for Prevention of Cytomegalovirus Reactivation in Haploidentical and Mismatched Adult Donor Allogeneic Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide for Graft-versus-Host Disease Prophylaxis. Transplantation and Cellular Therapy. 2021; 27:85e1-85e6.

https://pubmed.ncbi.nlm.nih.gov/33053449/

  • Haploidentical patients and mismatched adult unrelated donor allo-HCT using PTCy-based GVHD prophylaxis are high-risk for CMV reactivation but were underrepresented in the registry trial. Between 2014-2019, this single-center study had 32 of these patients who received letermovir and 32 who did not.
  • The day-180 cumulative incidence of CMV infection requiring therapy was 45.3% (95% CI, 32.7% to 57.1%) in the entire cohort, 68.8% (95% CI, 48.9% to 82.2%) in the patients who did not receive letermovir, and 21.9% (95% CI, 9.5% to 37.6%; P<0.001) in patients who received letermovir. Adjusting for regimen intensity, disease histology, and age, the hazard ratio for CMV infection was 0.19 (95% CI, 0.08 to 0.47; P<0.001) in patients who received primary prophylaxis with letermovir. Persistent CMV infection requiring >28 days of therapy was more common in patients who did not receive letermovir (31.2% versus 6.2%; P=0.02).
  • The authors concluded letermovir was effective in preventing CMV infection in this high-risk population of HLA-mismatched allo-HCT recipients

 

Abbreviations:

aGVHD: acute graft-versus-host disease

alloHCT: allogeneic hematopoietic cell transplantation

AML: acute myelogenous leukemia

autoHCT: autologous hematopoietic cell transplantation

cGVHD: chronic graft-versus-host disease

CIBMTR: Center for International Blood and Marrow Transplant

CMV: cytomegalovirus

DFS: disease-free survival

DLBCL: diffuse large B-cell lymphoma

DRI: disease risk index

EBMT: European Society for Blood and Marrow Transplantation

GRFS: GVHD-free, relapse-free survival

GVHD: graft-versus-host disease

HCT: hematopoietic cell transplantation

LFS: leukemia-free survival

MAC: myeloablative conditioning

MDS: myelodysplastic syndrome

MRD: matched related donor

NMA: non-myeloablative

NRM: non-relapse mortality

OS: overall survival

PBSCT: peripheral blood stem cell transplant

PFS: progression-free survival

PR: partial response

PTCy: post-transplant cyclophosphamide

RFS: relapse-free survival

RIC: reduced intensity conditioning

SCD: sickle cell disease

TBI: total body irradiation

TRM: transplant-related mortality

UCB: umbilical cord blood

 

ASTCT Pharmacy SIG Research Working Committee:

Kelly Gaffney, Katie Gatwood, Arpita Gandhi, Binni Kunvarjee, Andrew Linn, Anne McDonnell,

Monank Patel, Ashley Teusink-Cross, Theresa Urban, Lily Yan

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