Pharmacy SIG Literature Update: BuCY versus CY/TBI for Standard Risk B-ALL in CR1 and More

In this month’s Pharmacy SIG Literature Update: BuCY versus CY/TBI for standard risk B-ALL in CR1, PTCy and sirolimus based GVHD prophylaxis, RIC versus NMA conditioning regimen for haploidentical transplantation, ATG plus PTCy based GVHD 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 stem cell transplantation

**Zhang H, Fan Z, Huang F, et al. Busulfan plus cyclophosphamide versus total body irradiation plus cyclophosphamide for adults acute B lymphoblastic leukemia: an open-label, multicenter, phase III trial. JCO. 2022; 1-12. https://ascopubs.org/doi/pdf/10.1200/JCO.22.00767. PMID: 36084276.

  • Phase III, randomized, multicenter (13 hospitals in China) study investigating the efficacy and toxicity of busulfan plus cyclophosphamide (BuCy) and TBI plus cyclophosphamide (TBI-Cy) conditioning in HLA-matched (10/10) alloHCT for adult standard-risk B-ALL in CR1
  • A total of 550 patients (275 in each group) were randomly assigned (1:1) to BuCy (busulfan 0.8 mg/kg IV q6H on day -7 to -4 + cyclophosphamide 60 mg/kg IV daily on day -3 to -2) or TBI-Cy (4.5 Gy TBI on day -5 to -4 + cyclophosphamide 60 mg/kg IV daily on day -3 to -2)
  • 2-year OS was 76.6% in the BuCy group and 79.4% in the TBI-Cy group (p = 0.457); 2-year relapse was 20.2% vs. 18.4%, respectively (p = 0.616) and NRM was 11.0% in both groups (p = 0.988) Post-hoc subgroup analysis showed that OS was not significantly different for all subgroups of patients after BuCy compared with TBI-Cy
  • Median time to neutrophil and platelet engraftment was similar in both groups. No differences between groups were seen in terms of grade > 3 hematologic or non-hematologic AEs. Three patients died in the BuCy group (intracranial hemorrhage, VOD, hemorrhagic cystitis) vs. no deaths in the TBI-Cy group.
  • The incidence of grade 2-4 aGVHD on day 100 was 30.8% in the BuCy group vs. 27.9% in the TBI- Cy (p = 0.463);  2-year cGVHD was 31.1% vs. 28.7%, respectively (p = 0.524)
  • Authors concluded that the BuCy regimen is non-inferior to TBI-Cy for patients with standard- risk B-ALL in CR undergoing HLA-matched alloHCT

**Lazzari L, Balaguer-Rosello A, Montoro, et al. Post-transplant cyclophosphamide and sirolimus based graft-versus-host disease prophylaxis after allogeneic stem cell transplantation for acute myeloid leukemia. Bone Marrow Transplant. 2022; 57(9):1389-1398. https://pubmed.ncbi.nlm.nih.gov/35680995/

  • Retrospective, multicenter study of 242 AML patients undergoing a myeloablative first alloHCT between January 2017 and December 2020. Patients received post-transplant cyclophosphamide (PTCy) and sirolimus starting day +5 with goal levels of between 8 and 14-16 ng/ml. In the absence of GVHD or relapse, sirolimus was tapered starting on day +90 and discontinued by day +150/+180. Goal sirolimus levels and sirolimus stop dates were dependent on the specific French or Spanish centers.
  • A total of 77 patients (32%) received a MRD, 101 (42%) received a MUD, and 64 (26%) received a haploHCT. Recipient age was lower whereas donor age was higher in the MRD cohort (p=0.02 and p < 0.0001, respectively).
  • The median time to neutrophil recovery was longer in the haploHCT group at 21 days compared to 17 days and 19 days for MRD and MUD, respectively. There was a lower cumulative incidence of neutrophil recovery at 60 days in the haplo group at 92% compared to 97% and 94% for MRD and MUD, respectively (p=0.003).
  • The median time to platelet recovery was 20/26/33 days in the MRD/MUD/haplo groups, respectively. The cumulative recovery rate at 180 days was lower in the haplo group at 93%, compared to 98% and 95% for MRD and MUD, respectively (p=0.01).
  • There was no difference in aGVHD rates between transplant types or other post-transplant complications between the types of donor. There was also no difference in OS, LFS, or GRFS between the arms.
  • While haploHCT led to a longer time to neutrophil and platelet recovery, there was no difference in other endpoints compared to MRD and MUD.

**Devillier R, Galimard JE, Labopin M, et al. Reduced intensity versus non-myeloablative conditioning regimen for haploidentical transplantation and post-transplant cyclophosphamide in complete remission acute myeloid leukemia: A study from the ALWP of the EBMT. Bone Marrow Transplant. 2022; 57(9):1421-1427. https://pubmed.ncbi.nlm.nih.gov/35752739/

  • Retrospective EBMT review comparing NMA regimen (FluCyTBI) with RIC regimen (thiotepa + busulfan + fludarabine; TBF) in two different populations of AML patients: age <60 (n = 203) and age ≥60 (n = 287)
  • In patients aged <60 years, the NMA group had a higher relapse rate (HR 3.59; p<0.01), lower leukemia-free survival (LFS) (HR 1.98; p<0.01), and lower OS (HR 1.73; p=0.04) but no difference in NRM, aGVHD, cGVHD, and GRFS.
  • In patients aged ≥60 years, there was no difference in LFS (HR 0.9; p=0.65), OS (HR 0.81; p=0.39), and relapse rate (HR 1.78; p=0.1), but the NMA regimen was associated with lower NRM (HR 0.48; p=0.03). There was also no difference in aGVHD, cGVHD, and GRFS.
  • The authors concluded that younger patients (age <60 years) may benefit from RIC regimens compared to NMA regimens, while older patients do not get as much of a benefit from increased conditioning intensity.

**Battipaglia G, Labopin M, Blaise D, et al. Impact of the addition of antithymocyte globulin to post- transplant cyclophosphamide in haploidentical transplantation with peripheral blood compared to post- transplantation cyclophosphamide alone in acute myelogenous leukemia. Transplant Cell Ther.

2022;28(9):587.e1-587e7. https://pubmed.ncbi.nlm.nih.gov/35714906/

  • Retrospective study from EBMT working group looking at adult patients with AML in first CR undergoing haplo-PBSCT. Patients received either PTCy alone or PTCy plus ATG. Patients received adjuvant immunosuppressive therapy with CSA and MMF.
  • Of 441 patients included, 374 received PTCy alone and 67 ATG+PTCy. Median interval from diagnosis to haplo-PBSCT was longer in the PTCy alone group, but cohorts were otherwise similar. Most patients received RIC conditioning and the ATG dose varied widely (2.5 - 40 mg/kg).
  • The median follow-up was 19 months in the PTCy group versus 15 months in the ATG+PTCy group, and neutrophil engraftment was 97% and 98%, respectively. A longer interval to neutrophil engraftment was noted in the PTCY alone group (19 days) versus the ATG+PTCy group (17 days). In univariate analysis, there were no statistical differences in transplantation outcomes between the 2 groups. In multivariate analysis, ATG+PTCy was associated with a lower risk of cGVHD compared with PTCy alone (HR = .46; P = .03). No between-group differences in the other transplantation outcomes were seen, including aGVHD.
  • Overall mortality was 35% in the PTCy group and 34% in the ATG+PTCy group, with majority being due to infections (35% in both groups), followed by original disease (32% in PTCy group and 25% in ATG+PTCy group). Death from GVHD was noted to be 14% in the PTCY group and 5% in the ATG+PTCy group.
  • Authors concluded the study provides data on the feasibility of adding ATG to PTCy in the haplo- PBSCT setting. The finding of a lower incidence of cGVHD and greater and faster neutrophil engraftment, in the absence of differences in RI and NRM, if confirmed in larger series of patients, could make this schedule of GVHD prophylaxis more popular in haplo-PBSCT.

*Aldoss I, Yang D, Tomasian V, et al. Outcomes of allogeneic hematopoietic cell transplantation in adults with fusions associated with Ph-like ALL. Blood Adv. 2022 Sep 13;6(17):4936-4948. doi: 10.1182/bloodadvances.2022007597. https://pubmed.ncbi.nlm.nih.gov/35816633/

  • Retrospective analysis of 127 patients with ALL and Ph-like molecular alterations in CR receiving alloHCT between 2006-2020
  • Transplant conditioning was myeloablative in 69% (n= 87), all total body irradiation-based, with Fludarabine/melphalan-based conditioning used for all but 1 RIC patient receiving clofarabine/melphalan; peripheral blood stem cells were used in 95% (n=121), with donors including matched sibling (32%) matched unrelated (29%), mismatched unrelated (13%), haploidentical (23%), and cord blood (2%)
  • After median 3.5 years follow-up, patients with Ph-like ALL fusions had similar post-transplant outcomes vs other B-cell ALL patients (n = 71): 3-year RFS 41% vs 44% (p = 0.36), OS 51% vs 50% (p= 0.59), and relapse 37% vs 31% (p= 0.47). Grade II-IV aGVHD was 47% and III-IV was 16%, with one- year any-grade and extensive cGVHD in 48% and 42% respectively
  • Authors concluded alloHCT should be considered for patients with Ph-like ALL in CR as survival outcomes did not differ between ALL with and without Ph-like fusions

*Del Galy AS, Rousseau A, Capes A, et al. Life expectancy and burden of late complications after reduced intensity conditioning allogeneic transplantation. Bone Marrow Transplant. 2022; 57(9):1365-1372. https://pubmed.ncbi.nlm.nih.gov/35654824/

  • Single-arm, retrospective analysis of 465 patients who underwent RIC alloHCT and were alive and relapse-free 2 years after HCT
  • The primary underlying disease states were AML (31.4%) and lymphoma (22.8%). Approximately 50% of patients were in a CR at time of HCT. 90.1% of patients received peripheral blood stem cells; 47.7% were MRD and 38.5% were MUD
  • Among the 412 patients who did not relapse, 206 (50%) patients and 161 (39.1%) patients experienced grade II-IV aGVHD and severe cGVHD, respectively
  • The median survival was not reached with 84.1% alive at 10 years
  • 10-year cumulative incidence of cancer was 12.9%, with the most common being skin (N=32) and head & neck (N=9). Age was the only continuous variable associated with secondary cancer occurrence on multivariate analysis (HR 1.046; p=0.01)
  • There was an increase in vascular complications, notably cardiovascular complications (CVC) (cardiac failure, myocardial infarction, stroke, arrhythmia, and obliterating arteriopathy) with a 10-year cumulative incidence of 15.05%, as well as venous thromboembolism (VTE) with a 10- year cumulative incidence of 11.67%. Older age was the only independent risk factor for CVC and VTE (HR 1.031; p<0.001 and HR 1.04; p=0.006, respectively)

*Holtan SG, Yu J, Paranagama D, et al. Disease progression, hospital readmissions, and clinical outcomes for patients with steroid-refractory acute graft-versus-host disease: A multicenter, retrospective study. Bone Marrow Transplant. 2022; 57(9):1399-1404. https://pubmed.ncbi.nlm.nih.gov/35739326/

  • Retrospective, multicenter review of 168 patients who underwent first alloHCT between January 2014 and June 2016, subsequently developed grade II-IV aGVHD, and were refractory to or dependent on corticosteroids
  • The grade at diagnosis was 51.8%, 28%, and 7.1% for grade II-IV aGVHD, respectively. Approximately 50% of the patients with grade II disease at diagnosis progressed to a higher grade during follow-up. In those who progressed, there was an increase in those with lower GI involvement (37.5% to 54.2%) and those with ≥2 organs involved (36.9% to 54.2%)
  • Among 146 patients who had grades II-IV aGVHD at diagnosis, 119 (81.5%) were started on first- line systemic steroids vs. topical steroids. Of these 119 patients, the mean starting dose of steroids was 0.9 mg/kg/day for prednisone and 1.8 mg/kg/day for methylprednisolone. 36.3% of all 168 patients had an increase in the steroid dose during the follow-up period, and 87.5% were unable to taper below 10 mg/day
  • Eighty-nine (53%) of patients received ≥1 line of therapy, and 33.7% of these patients increased their steroid dose before receiving additional therapy whereas 25.8% used ≥2 additional therapies
  • Hospital readmissions occurred in 56.5% of patients within the first 100 days, and 24.4% of patients had ≥2 readmissions within 100 days. 70.2% of patients died at a median of 117.5 days from aGVHD diagnosis
  • The authors concluded that steroid-refractory and dependent aGVHD is associated with a rapidly progressing clinical course that leads to high morbidity and mortality

*Jiang W, Clancy LE, Avdic S, et al. Third-party CMV- and EBV-specific T-cells for first viral reactivation after allogeneic stem cell transplant. Blood Adv. 2022 Sep 13;6(17):4949-4966. doi: 10.1182/bloodadvances.2022007103. https://pubmed.ncbi.nlm.nih.gov/35819448/

  • Prospective, single-arm, multicenter, phase 1 clinical trial of allogeneic virus-specific T-cells (VSTs) in 30 HCT patients with first CMV (n=27) or EBV (n=3) infection
  • VSTs were matched from donor to recipient at a minimum of 1 of 6 HLA antigens, preferentially by highest number of HLA matches, and dosed as 2.0 x 107/m2 VSTs with up to 3 additional doses allowed for persistent viral replication ≥2 weeks after first VST infusion. Concomitant standard of care antiviral therapy was allowed at physician discretion
  • Overall viral response rate was 100%, with 28 patients (94%) having complete response; 23 remained virus PCR negative (n=9) or below quantitation (n=13) throughout follow-up, with only one subject requiring second infusion after initial CR, remaining PCR negative after. All 3 patients treated for EBV PTLD had sustained CR
  • Rates of aGVHD and cGVHD after infusion were 13% and 23%, respectively, with no serious infusion- related adverse events. At 1-year post-HCT, non-relapse mortality was 10%, cumulative relapse incidence 7%, OS 88%
  • Authors concluded that third-party VSTs used with antiviral treatment appears safe and leads to excellent viral control and clinical outcomes

CAR-T cell therapy

**Jacobson CA, Locke FL, Ma L, et al. Real-world evidence of axicabtagene ciloleucel for the treatment of large B cell lymphoma in the United States. Transplant Cell Ther. 2022;28(9):581.e1-581.e8. https://pubmed.ncbi.nlm.nih.gov/35609867/

  • Retrospective review of 1297 patients that received commercial axi-cel with at least 6 months of follow-up between October 2017 to August 2020
  • Within the cohort, 739 (57%) were considered ZUMA-1 ineligible. CNS involvement was present in 19 patients, 5% had an ECOG PS ≥2, 28% had moderate to severe pulmonary disease, 13% had cardiac, cerebrovascular, or heart valve disease, 5% had inflammatory bowel or rheumatologic disease, 2% had renal disease, 2% hepatic disease, 4% had active infection, and 13% had prior malignancy other than nonmelanoma skin cancer.
  • At a median follow-up of 12.9 months, ORR was 73%, with a 56% CR rate. Median OS and PFS were 21.8 months (95% CI, 17.4 to 28.8 months) and 8.6 months (95% CI, 6.5 to 12.1 months), respectively. DOR was comparable in the ZUMA-1 ineligible patients and ZUMA-1 eligible patients, 62% by 1 year versus 67%. Patients aged 65 years had favorable ORR despite having a higher risk of CRS (OR, 1.41) and ICANS (OR, 1.77). ECOG PS ≥ 2 was associated with inferior efficacy outcomes (OR for ORR, 0.32; HR for OS, 3.27) and higher incidence of ICANS (OR, 2.63; 95% CI, 1.40 to 4.93).
  • Authors concluded that patients not meeting the eligibility criteria for ZUMA-1 trial still had durable response with axi-cel. Elderly patients had favorable efficacy outcomes, despite higher rates of CRS and ICANS. Patient selection for standard-of-care axi-cel should consider comorbidities and the risk-to-benefit ratio rather than be based strictly on ZUMA-1 eligibility.

Pediatric stem cell transplantation

*Lin F, Zuo Y, Zhang Y, et al. The impact of pretransplant serum ferritin on haploidentical hematopoietic stem cell transplant for acquired severe aplastic anemia in children and adolescents. Pediatr Blood Cancer. 2022; 69(9):e29845. https://pubmed.ncbi.nlm.nih.gov/35731841/

  • Retrospective review of 147 child and adolescent patients who received haploHCT for severe aplastic anemia (SAA) between January 2012 and December 2018. Serum ferritin was obtained one week prior to transplant, and patients were classified as either high (≥ 1000 ng/mL) (n=97) or low ( < 1000 ng/mL) (n=50).
  • High serum ferritin was associated with an increased risk of grade II-IV aGVHD (HR 2.596; p=0.007) and grade III-IV aGVHD (HR 3.35; p=0.025).
  • High serum ferritin was associated with a higher proportion of fungal and bloodstream infections (21.65% vs 16%; p=0.015); however, there was no difference in infection-related deaths between the two groups.
  • There was no difference in the secondary endpoints, including rates of 28-day neutrophil or 100- day platelet engraftment, secondary graft failure (2.06% vs 2%; p=0.976), 100-day TRM (6.19% vs 8%; p=0.168), and 2-year OS (85.29% vs 92%; p=0.746) between high vs low serum ferritin groups, respectively.
  • The authors concluded that while elevated pre-transplant ferritin (≥1000 ng/mL) was associated with increased grade II-IV and grade III-IV aGVHD, it was not associated with worse survival in children and adolescents undergoing haploHCT for SAA.


AE: adverse events

GRFS: GVHD free relapse free survival

Axi-cel: axicabtagene ciloleucel

HaploHCT: haploidentical stem cell transplantation

alloHCT: allogeneic hematopoietic cell transplant

HCT: hematopoietic cell transplant

aGVHD: acute graft versus host disease

HLA: human leukocyte antigen

ALL: acute lymphoblastic leukemia

ICANS: immune effector cell-associated neurotoxicity syndrome

AML: acute myeloid leukemia

MA: myeloablative

ASCT: autologous stem cell

MASP-2: mannan-binding lectin-associated serine protease-2

ATG: anti-thymocyte globulin

MDS: myelodysplastic syndrome

AUC: area under the curve

MM: multiple myeloma

BCMA: B-cell maturation antigen

MMF: mycophenolate mofetil

BM: bone marrow

MMUD: mismatched unrelated donor

Bu-Flu: busulfan-fludarabine

MRD: minimal residual disease

Bu-Flu-Cy: busulfan-fludarabine-cyclophosphamide

MSD: matched sibling donor

CART: chimeric antigen receptor T-cell

MTX: methotrexate

cGVHD: chronic graft versus host disease

NMA: non-myeloablative

CIBMTR: Center for International Blood and Marrow Transplant Research

NRM: non-relapse mortality

CML: chronic myelogenous leukemia

ORR: overall response rate

CNI: calcineurin inhibitor

OS: overall survival

CNS: central nervous system

PBSC: peripheral blood stem cell

CR: complete response

PFS: progression-free survival

CRS: cytokine release syndrome

PTCy: post-transplant cyclophosphamide

CSA: cyclosporine

Ph-like: Philadelphia-like

DOR: duration of response

RFS: relapse-free survival

EBMT: European Society of Blood and Marrow Transplantation

RI: relapse incidence

ECOG: Eastern Cooperative Oncology Group

RIC: reduced intensity conditioning

EFS: event free survival

TAC: tacrolimus

FA: Fanconi anemia

URD: unrelated donor

Flu-Cy: fludarabine-cyclophosphamide


GVHD: graft-versus-host disease


ASTCT Pharmacy SIG Research Working Committee:

Arpita Gandhi, Jonathan Ptachcinski, Katie Gatwood, Andrew Lin, Jennifer Collins, Jitesh Kawedia, Dennis Marjoncu, Julianna Roddy, Lily Yan, Thomas Hughes, Sorana Ursu, Haval Norma

Tags: SIG update, SIG, Literature, CAR T

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