Updates on Commercial Cellular Therapy Products, ECP for cGVHD and More

By Content Administrator posted 18 days ago


In this month’s Pharmacy SIG Literature Update: Updates on commercial cellular therapy products, ECP for cGVHD, and more data for lenolidamide maintenance. Plus αβ haplos in pediatrics and much 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

Cellular Therapy

**Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20:31-42. https://www.ncbi.nlm.nih.gov/pubmed/30518502

  • Updated results from the ZUMA-1 study evaluating safety and efficacy of CD-19 targeted CAR T-cell therapy
  • Assessed 101 patients from the phase 2 study with median follow up of 27.1 months
  • ORR was 83% with 58% CR and 25% PR; also reported 10% with SD
  • Median time to response was 1 month but 22 addition patients initially with SD/PR subsequently achieved a CR
  • The duration of response was estimated at 11.1 months per investigator assessment; duration of response was not yet reached in patients achieving a CR
  • Median PFS was 5.9 months; estimated 2 year PFS in patients achieving CR or PR at 3 months was roughly 75%; median OS was not reached with an estimated 2-year survival of 50.5%
  • No new safety signals were identified with CRS, cytopenias, infections, and neurologic events being relatively common
  • This was an important update of the early phase trials showing a single infusion of CD-19 CAR T-cells inducing durable responses in heavily treated patient population

**Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large b-cell lymphoma. N Engl J Med. 2019;380:45-56.  http://www.ncbi.nlm.nih.gov/pubmed/30501490             

  • International, phase 2 study of centrally manufactured tisagenlecleucel for adult patients with relapsed or refractory DLBCL (previously received at least 2 lines of therapy including rituximab and an anthracycline) who were ineligible for or had disease progression after autoHSCT; patients excluded if they had previously received CD19-directed therapy, had primary mediastinal DLBCL, previously received alloHSCT, or had active CNS involvement of DLBCL
  • Primary endpoint was the best overall response rate (CR+PR) as judged by an independent review committee and secondary endpoints included response duration, overall survival, safety, and cellular kinetics data.
  • 165 patients were enrolled in the study (111 received CAR-T infusion; 12 could not have CAR-T cells manufactured) with a median time from enrollment to infusion of 54 days (92% received bridging therapy) and 49% had a previous autoHSCT
  • Best overall response (CR+PR) was 52% with 40% CR and the median response duration had not been reached; relapse-free survival at 12 months post-infusion was 65% (79% among CR group)
  • Most common grade 3-4 AEs were CRS (22%), neurologic events (12%), cytopenias lasting longer than 28 days (32%), infections (20%), and febrile neutropenia (14%). 3 patients died of disease progression within 30 days of infusion, but no deaths were attributed to tisagenlecleucel, CRS or cerebral edema.
  • The authors concluded that high rates of durable responses were produced with tisagenlecleucel in adult patients with relapsed or refractory DLBCL

Graft-Versus-Host Disease

**Gandelman JS, Song DJ, Chen H, et al. A prospective trial of extracorporeal photopheresis for chronic graft-versus-host disease reveals significant disease response and no association with frequency of regulatory T cells. Biol Blood Marrow Transplant. 2018;24:2373-2380. https://www.ncbi.nlm.nih.gov/pubmed/29981848

  • Prospective, multicenter trial to assess ECP response rates and to assess the relationship between regulatory T cells (Tregs) and treatment response
  • 77 patients with any NIH subtype of cGVHD were enrolled, with a median of 2 prior lines of therapy
  • 3% of patients had a provider-assessed response to ECP and 43.5% had a response by NIH criteria, with a meaningful decrease in prednisone dose observed
  • Response was not associated with frequency of Tregs and no significant difference was observed in percentage of Tregs in blood leukocytes at study entry versus study completion
  • Overall, ECP delivered a response in a heavily pretreated cohort with moderate and severe cGVHD


**Thomas NJ, Spear D, Wasserman E, et al. CALIPSO: A randomized controlled trial of calfactant for acute lung injury in pediatric stem cell and oncology patients. Biol Blood Marrow Transplant. 2018;24:2479-86. https://www.ncbi.nlm.nih.gov/pubmed/30059785

  • Multicenter, randomized, placebo-controlled, double-blinded trial to assess if calfactant reduces mortality among children with leukemia/lymphoma or after HCT with pediatric acute respiratory distress syndrome (PARDS)
  • 43 patients ages 18 months to 25 years who required invasive mechanical ventilation for bilateral lung disease with an oxygenation index (OI) > 10 and < 37 were included; 26 were assigned to calfactant and 17 to placebo
  • No significant differences in survival to PICU discharge (p=0.35), OI, functional outcomes, or ventilatory-free days between calfactant and placebo groups
  • Allo-HCT patients had a nonsignificant higher likelihood of death at PICU discharge (adjusted odds ratio, 3.02; 95% CI, 0.76-12.06; p=0.12)
  • The authors conclude this data does not support the use of calfactant among this high mortality group of pediatric leukemia/lymphoma and/or HCT patients with PARDS to increase survival

*Bertaina A, Zecca M, Buldini B, et al. Unrelated donor vs HLA-haploidentical α/β T-cell- and B-cell-depleted HSCT in children with acute leukemia. Blood. 2018;132:2594-2607. https://www.ncbi.nlm.nih.gov/pubmed/30348653

  • Retrospective, multi-center analysis of 127 MUD, 118 MMUD, and 98 αβ haplo-HCT recipients, transplanted between 2010-2015, in children with acute leukemia after complete morphological remission
  • In MUD vs MMUD-HCT recipients, the cumulative incidence of grade II to IV and grade III to IV acute GVHD was 35% vs. 44% and 6% vs. 18%, respectively, compared with 16% and 0% in αβ haplo-HCT recipients (p<0.001)
  • With a median follow-up of 3.3 years, the 5-year probability of leukemia-free survival in the 3 groups was 67% (MUD), 55% (MMUD), and 62% (αβ haplo-HCT). When compared with patients given MMUD-HCT, αβ haplo-HCT recipients had a lower cumulative incidence of non-relapse mortality and a better GRFS (p<0.001)
  • Αβ haplo-HCT is a suitable therapeutic option for children with acute leukemia in need of transplantation, especially when a MUD is not available

*Ukeba-Terashita Y, Kobayashi R, Hori D, et al. Long-term outcome of renal function in children after stem cell transplantation measured by estimated glomerular filtration rate. Pediatr Blood Cancer. 2019;66:e27478. https://www.ncbi.nlm.nih.gov/pubmed/30350912

  • Retrospective analysis of estimated Glomerular Filtration Rate (eGFR) in 83 pediatric patients who received HCT. Median follow-up time was 127.7 months (range 12.0-268.8 months)
  • Eighteen patients (21.7%) had low eGFR (<90 ml/min/1.73 m2) post SCT (cumulative incidence of low eGFR was 25.8 ± 2.0%)
  • Nine (10.6%) patients had a low eGFR pre-SCT. However, pre- and post-SCT incidence of low eGFR were not correlated. Meanwhile, only two patients (2.4%) exhibited severe renal dysfunction, with eGFRs < 60 ml/min/1.73 m2
  • Independent post-HCT long-term risk factors for low eGFR in children were solid tumor and use of fludarabine. Moreover, age at SCT ≥ 7 years was a post-HCT long-term risk factor for low eGFR across all patients

Maintenance Therapy

*Jackson GH, Davies FE, Pawlyn C, et al. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20:57-73.. https://www.ncbi.nlm.nih.gov/pubmed/30559051

  • Randomized, phase 3, open label study evaluating 1971 patients to maintenance. Patients were divided into pre-planned subgroups of transplant (~64%) or transplant-ineligible (~36%) as well as by cytogenetic risk; lenolidamide was ultimately given at 10 mg/day until progression or toxicity after a protocol amendment
  • Overall median PFS was 39 month with LEN vs 20 months with observation (p<0.0001); median OS was not reached with either group and 5-year OS was 61.3% with LEN vs 56.6% with observation (p=NS)
  • Second PFS after relapse continued to favor LEN over observation (64 vs 45 months; p<0.001)
  • The median duration of LEN maintenance was 18 cycles with 69% of patients requiring dose-modification
  • Subgroup analysis of transplant eligible patients found a PFS of 57 months with LEN vs 30 months with observation (p<0.001) and a 3-year OS of 87.5% vs 80.2% respectively (p=0.014)
  • Subgroup analysis of transplant-ineligible patients found a PFS of 26 months with LEN vs 11 months with observation (p<0.001) and a 3-year OS of 66.8% vs 69.8% respectively (p=0.88)
  • PFS favored LEN maintenance across all cytogenetic risk groups
  • This study adds to existing data on lenolidamide maintenance. Previous reports have suggested a possible reduced PFS after subsequent relapse that was not demonstrated in this study.  Conversely, PFS continued to favor the lenolidamide group.  Although OS was not demonstrated in the entire populations, it was significantly improved in transplant eligible patients.  High risk cytogenetics continue to be a poor prognostic indicator but also favored lenolidamide maintenance 

Allogeneic Transplant

*Jeong SH, Song HN, Park JS, et al. Allogeneic stem cell transplantation for patients with natural killer/T cell lymphoid malignancy: a multicenter analysis comparing upfront and salvage transplantation. Biol Blood Marrow Transplant. 2018;24:2471-78. https://www.ncbi.nlm.nih.gov/pubmed/30064012

  • Retrospective review of 36 patients (ENKTL, n=26; ANKL, n=10) who underwent either upfront (n=19) or salvage (n=17) allogeneic HCT at 6 hospitals
  • More patients with ANKL (8/10) received upfront alloHCT than ENKTL (11/26); disease status before alloHCT, conditioning regimen, and donor source did not differ
  • Median OS was 11.8 months and median PFS was 10 months after alloHCT; 12 patients died from disease relapse and 12 from non-disease related causes
  • The OS after alloHCT did not differ between upfront and salvage HCT (p=0.862) or between ENKTL and ANKL (p=0.55)
  • AlloHCT may be beneficial for patients with NK/T cell lymphoid malignancy as some were able to maintain their remission after HCT, but risks must be considered and timing of HCT should be patient specific

*Rondon-Clavo C, Scordo M, Hilden P, et al. Early fluid overload is associated with an increased risk of nonrelapse mortality after ex vivo CD34-selected allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2018;24:2517-22. https://www.ncbi.nlm.nih.gov/pubmed/30055353

  • Retrospective review of 169 patients who underwent myeloablative-conditioning for ex vivo CD34+ selected alloHCT to assess the effect of fluid overload (FO) on NRM using the validated definition in this subset of patients
  • 30 patients (17.8%) had grade ≥ 2 FO within 30 days after ex vivo CD34+ selected alloHCT, with a median onset of day 11 (range -8 to 28)
  • Age ≥ 55 years (odds ratio: 3.43; p=0.005) and chemotherapy-based conditioning (odds ratio: 3.89; p=0.007) were associated with increased risk of grade ≥ 2 FO
  • Patients with early grade ≥ 2 FO had significantly higher NRM when compared to patients with grade < 2 FO (24.1% versus 3.6% at day 100, p=0.01)
  • Despite the absence of a CNI-based GVHD prophylaxis, FO remains an important early post-HCT toxicity that should be assessed routinely


AE: adverse event

alloHSCT: allogeneic hematopoietic stem cell transplant

ANKL: aggressive NK cell leukemia

autoHSCT: autologous hematopoietic stem cell transplant

CAR: chimeric antigen receptor

cGVHD: chronic graft-versus-host disease

CNI: calcineurin inhibitor

CNS: central nervous system

CR: complete response

CRS: cytokine release syndrome

DLBCL: diffuse large b-cell lymphoma

ECP: extracorporeal photopheresis

ENKTL: extranodal NK/T cell lymphoma

HCT: hematopoietic cell tranpslant

LEN: lenolidamide

NIH: National Institutes of Health

NRM: non-relapse mortality

ORR: overall response rate

OS: overall survival

PFS: progression free survival

PICU: pediatric intensive care unit

PR: partial response

SD: stable disease

ASBMT Pharmacy SIG Communications Working Committee:

Brandi Anders, Tiene Bauters, Eileen Chen, David Eplin, Katie Gatwood, Jason Jared, Kathryn Maples, Shreya Shah, Ryan Shaw