11.02.20

Pharmacy Literature Update: Use of Post-Transplant Cyclophosphamide in Haploidentical HCT and More

by Katie Gatewood

In this month’s Pharmacy SIG Literature Update: Updates in the use of post-transplant cyclophosphamide in haploidentical HCT, ixazomib for chronic GVHD prophylaxis, CMV management, 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

*Nagler A, Dholaria B, Labopin M, et al. Bone marrow versus mobilized peripheral blood stem cell graft in T-cell-replete haploidentical transplantation in acute lymphoblastic leukemia. Leukemia. 2020;34(10):2766-2775. https://pubmed.ncbi.nlm.nih.gov/32393841/

  • Retrospective, multicenter analysis of adult ALL patients from the EBMT registry who received haploHCT with PBSC (n=157) vs BM (n=157) grafts, followed by PTCy between 2010 to 2018 (n = 314) with median time to follow-up of 23.9 months (interquartile range: 12-37.3)
  • Cumulative incidence of engraftment at day 30 was higher in PB group compared with BM (93% vs. 88%, p<0.01)
  • In multivariate analysis, there was a tendency towards higher incidence of grade II=IV aGVHD (HR 1.52, 95% CI 0.97-2.38, p = 0.07), cGVHD (HR 1.58, 95% CI 1-2.51, p = 0.05), and NRM (HR 1.66, 95% CI 0.99-2.8, p = 0.06) in patients receiving PB vs BM graft, respectively
  • Use of PB grafts was associated with lower LFS (HR 1.43, 95% CI 1-2.03, p=0.05), OS (HR 1.59, 95% CI 1.08-2.34, p=0.02), and GRFS (HR 1.42, 95% CI 1.03-1.95, p=0.03) compared to BM graft
  • No difference was observed in relapse incidence (HR 1.23, 95% CI 0.76-2, p =0.41) between groups
  • Authors conclude that compared to PB stem cell graft, use of BM graft results in improved outcomes in ALL patients who receive haploHCT with PTCy

Graft-Versus-Host Disease

*Kornblit B, Storer BE, Andersen NS, et al. Sirolimus with CSP and MMF as GVHD prophylaxis for allogeneic transplantation with HLA antigen-mismatched donors. Blood. 2020;136(13):1499-1506.​ https://pubmed.ncbi.nlm.nih.gov/32603426/ 

  • Multicenter phase 2 trial to evaluate efficacy of sirolimus in addition to CSP and MMF for GVHD prophylaxis after NMA conditioning for 76 patients with hematological malignancies who received HLA class I or II mismatched related or unrelated alloHCT between April 2011 and December 2018 

  • Median follow up of 47 months (range: 4-94 months) and 50 patients (66%) had single HLA class I antigen mismatches, and 25 patients (33%) were mismatched for HLA class II

  • In all patients, cumulative incidence of grade II-IV aGVHD at day 100 was 36% (95% CI, 25-46) which was lower than historical incidence. Cumulative incidence of cGVHD was 37% (95% CI, 45-69) and 57% (95% CI, 26-48) at 1 and 4 years, respectively which was similar to historical controls.

  • Cumulative incidence of NRM, relapse/progression, PFS, and OS at 4-years was 18% (95% CI, 9-27), 30% (95% CI, 19-40), 52% (95% CI, 41-64), and 62% (95% CI, 50-73) respectively

  • Authors conclude that the addition of sirolimus to CSP and MMF is well-tolerated and resulted in a lower incidence of aGVHD and NRM, thus translating into superior PFS and OS compared with historical results in older or medically infirm patient

**Chhabra S, Visotocky A, Pasquini MC, et al. Ixazomib for chronic graft-versus-host disease prophylaxis following allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 26(10):1876-1885. https://pubmed.ncbi.nlm.nih.gov/32653622/

  • Phase I/II trial evaluating safety and efficacy of ixazomib administered weekly for a total of 4 doses, beginning days +60 through +90 pot-transplant for cGVHD prophylaxis in patients undergoing alloHCT. All patients received PBSC grafts and standard GVHD prophylaxis of tacrolimus and methotrexate. I

  • In the phase II portion (n= 51), the cumulative incidence of cGVHD at 1-year was 36% (95% CI, 19% to 54%) in the MRD cohort and 39% (95% CI, 21% to 56%) in the MUD cohort. 

  • One-year cumulative NRM and relapse was 0% and 20% in the MRD cohort, respectively and 4% and 34%, in MUD cohort, respectively. Ixazomib administration was safe and well tolerated, with thrombocytopenia, leukopenia, gastrointestinal complaints, and fatigue being the most common adverse events.

  • The post-hoc analysis comparison to contemptuous matched CIBMTR controls showed no significant improvement in cGVHD rates in both the MRD (HR 0.85, p=0.64) or MUD cohorts (HR 0.68, p=0.26) 

  • Authors conclude that the novel strategy of short-course oral ixazomib following alloHCT is safe but did not demonstrate significant improvement in cGVHD incidence in recipients of MRD and MUD transplantation compared with matched CIBMTR controls

**Ruggeri A, Labopin M, Battipaglia G, et al. Timing of post-transplantation cyclophosphamide administration in haploidentical transplantation: a comparative study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2020; 26(10):1915-1922. https://pubmed.ncbi.nlm.nih.gov/32645444/

  • Retrospective registry analysis of the schedules of immunosuppression therapy after haploHCT in 509 patients with acute leukemia receiving PTCy on days +3 and +4 along with tacrolimus (group 1; n=215), with CSP + MMF from day +5 (group 2; n=170), or CSP + MMF from day 0 or +1 with PTCy on days +3 and +5 (group 3; n=124)

  • Patients in group 3 were younger (median age, 46 years; p=0.02) and more often received BM as the stem cell source (77%; p<0.01), and a MAC regimen containing thiotepa, fludarabine, and busulfan (84%; p<0.01) compared to groups 1 and 2 

  • 2-year OS was 44%, 48%, and 59% in groups 1, 2, and 3, respectively (p=0.15). LFS was 43%, 46%, and 53% (p=0.05); and refined GRFS was 33%, 39%, and 36% (p=0.02). Relapse incidence was 36%, 37%, and 26% in groups 1, 2 and 3, respectively (p=0.02).

  • The incidence of grade II-IV aGVHD was 25%, 39%, and 18% (p<0.01) and incidence of cGVHD was 25%, 21%, and 24% in groups 1, 2 and 3, respectively (p=0.50)

  • On multivariate analysis, early start of immunosuppression therapy at day +1 followed by PTCy was associated with a better LFS (HR 0.58, p=0.02) and improved GRFS (HR 0.62, p=0.02) 

  • Authors conclude that the timing of immunosuppression influenced the outcomes of haploHCT with PTCy and an early start of CSP + MMF with PTCy administered on days +3 and +5 improves LFS and GRFS

Immune Effector Cells

**Oluwole OO, Jansen JP, Lin VW, et al. Comparing efficacy, safety, and preinfusion period of axicabtagene ciloleucel versus tisagenlecleucel in relapsed/refractory large B cell lymphoma. Biol Blood Marrow Transplant. 2020;26:1581-1588. https://pubmed.ncbi.nlm.nih.gov/32661336/

  • The registration trials for axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) for the treatment of relapsed/refractory large B-cell lymphoma were compared with a matching adjusted indirect comparison to assess response, overall survival, and adverse events

  • Axi-cel was associated with a greater ORR [RR 1.61, 95% CI 1.29-2.01], CR [RR 1.62, 95% CI 1.16-2.27], and OS from time of infusion [HR 0.51, 95% CI 0.31-0.83]

  • Higher rates of grade 1-2 CRS were seen with axi-cel use compared to tisa-cel [RR 2.03, 95% CI 1.55-2.65] with no difference in grade ≥ 3 CRS or neurological events

  • The authors acknowledge the limitations of this statistical interpretation and conclude axi-cel may have superior efficacy but greater risk of grade 1 or 2 CRS in the treatment of relapsed/refractory large B cell lymphoma

Pediatrics

*Radhakrishnan V, Vishwajeeth P, Rajaraman S et al. Olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced vomiting in children: An open-label, randomized phase 3 trial. Pediatr Blood Cancer. 2020;67(9):e28532. https://pubmed.ncbi.nlm.nih.gov/32568452/

  • Single-center, open-label, superiority design, phase 3 randomized controlled trial at the Cancer Institute Chenai, India comparing olanzapine and metoclopramide for CINV

  • Eighty patients were enrolled (39 olanzapine, 41 metoclopramide) and median age was 12.5 years (range: 5-17) 

  • CR rates were significantly higher in the olanzapine arm compared to the metoclopramide arm for vomiting (72% vs 39%, p=0.003) and nausea (59% vs 34%, p= 0.026). The mean nausea score in the olanzapine arm was significantly lower than the metoclopramide arm.

  • Hyperglycemia and drowsiness were more common in the olanzapine arm 

  • The authors concluded that olanzapine is superior to metoclopramide for the treatment of breakthrough CINV

*Laisne L, Neven B, Dalle JH et al. Ruxolitinib in children with steroid refractory acute graft-versus-host-disease: a retrospective multicenter study of the pediatric group of SFGM-TC. Pediatr Blood Cancer. 2020;67(9):e28233. https://pubmed.ncbi.nlm.nih.gov/32614145/

  • Multicenter, retrospective study in France evaluating the efficacy of ruxolitinib in 29 pediatric patients with aGVHD 

  • Median age was 4.3 years (range: 0.6-14.5) and median ruxolitinib starting dose was 12.6 mg/m2/day in divided doses

  • ORR was 72.4% and 6 patients had a complete response by day 28 of therapy, 19 patients achieved a complete response by day 41 of therapy with no relationship between initial dose and effectiveness

  • Authors concluded that ruxolitinib may constitute a promising second-line treatment for children with steroid-refractory aGVHD that should be validated in a prospective large-scale pharmacokinetic and efficacy trial

*Folloni Fernandes J, Nichele S, Javier L, et al. Outcomes after haploidentical stem cell transplantation with post-transplantation cyclophosphamide in patients with primary immunodeficiency diseases. Biol Blood Marrow Transplant. 26(10):1923-1929. https://pubmed.ncbi.nlm.nih.gov/32653621/

  • Retrospective review of the outcomes of 73 patients with PID who underwent haploHCT with PTCy, (first transplant, n=55; salvage transplant after graft failure of previous HCT, n=18)

  • Diagnoses were severe combined immunodeficiency (n=34), Wiskott-Aldrich syndrome (n=14) chronic granulomatous disease (n=10); other PID (n=15) and median duration of follow-up of survivors was 2 years

  • At 100 days, the cumulative incidence of aGVHD grade II-IV and III-IV was 33% and 14%, respectively

  • Estimated 2-year OS was 66%; it was 64% for SCID patients and 65% for non-SCID patients and 63% for first HCT and 77% for salvage transplantations. Twenty-five patients died, most of them due to infection prior to day + 100.

  • Authors conclude that haploHCT with PTCy is a feasible procedure, can cure two-thirds of children with PID, and can be used as rescue treatment for previous graft failure

Infectious Disease

**Johnsrud J, Nguyen IT, Domingo W, et al. Letermovir prophylaxis decreases burden of cytomegalovirus (CMV) in patients at high risk for CMV disease following hematopoietic cell transplant. Biol Blood Marrow Transplant. 2020; 26(10):1963-1970. https://pubmed.ncbi.nlm.nih.gov/32653623/ 

  • Single-center retrospective analysis of letermovir prophylaxis between January 2018 through December 2019 (n= 114), including UCB (n=30) and haploHCT (n=22) transplant recipients. Patients were compared to a historical control (n=637)

  • By day +100 post-HCT, letermovir prophylaxis significantly decreased the incidence of both CMV DNAemia compared with controls (45% vs 74%; p<0.001) and clinically significant CMV infection (12% vs 49%; p<0.001)

  • Clinically significant CMV infection, defined as administration of antiviral therapy as PET for CMV DNAemia or treatment for CMV disease, was significantly lower in haploHCT recipients (14% vs 73%; p=0.02) and UCB recipients (3% vs 37%; p<0.001) on letermovir prophylaxis compared with the historical control

  • No patients on letermovir prophylaxis developed CMV disease in any treatment group by day +100 compared with controls (0% vs 5%; p=0.006)

  • Authors conclude that letermovir prophylaxis significantly reduces the number of patients who receive CMV-active antiviral therapy for either DNAemia or disease due to CMV

*Fang J, Su Y, Zavras PD, et al. Impact of preemptive therapy for cytomegalovirus on hospitalizations and cost after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2020; 26(10):1937-1947. https://pubmed.ncbi.nlm.nih.gov/32640313/

  • A single-center retrospective study of CMV recipient + adults who underwent HCT at Memorial Sloan Kettering Cancer Center between March 2013 and December 2017

  • Of 357 patients, PET was initiated in 208 (58.3%), at a median of 35 days after HCT.  By day 180, 23 patients (6.4%) had developed CMV end-organ disease and 3 (0.8%) had died of CMV.

  • Compared with the no PET therapy group, the PET group had a longer length of stay for HCT admission (p=0.0276), longer total length of stay by day +180 (p=0.0001), a higher number of readmissions (p=0.0001), a higher mean inpatient cost for HCT admission ($189,389 versus $151,646; p=0.0133), and a higher total inpatient cost ($297,563 versus $205,815; p<0.0001) 

  • Among PET recipients, CMV-related readmissions were associated with a significantly higher mean cost per episode compared with non CMV-related readmissions. CMV-related readmissions comprised 40.6% of total all-cause readmissions and incurred 55.9% of total all-cause readmission costs in PET recipients. 

  • Authors conclude that patients treated with currently available PET had greater inpatient health care resource utilization and cost, by day +180 compared with patients who did not receive PET

Supportive Care

*Ice LL, Bartoo GT, McCullough KB, et al. A prospective survey of outpatient medication adherence in adult allogeneic hematopoietic stem cell transplantation patients. Biol Blood Marrow Transplant. 2020;26: 1627-1634. https://pubmed.ncbi.nlm.nih.gov/32505809/

  • The rate of medication non-adherence to medications in adult recipients of alloHCT was determined in this cross-sectional survey. Non-adherence was determined through an electronic survey sent to patients, immunosuppressant serum drug levels (if applicable), and prescription refill records. 

  • The survey was completed by 200 alloHCT recipients with a median age of 56.5 years. At the time of the survey, patients were prescribed a median of 17 medications (range 3-42). 

  • Approximately half of the subjects (51%) reported non-adherence to non-immunosuppressant medications. Over a third of subjects (37.9%) reported non-adherence to immunosuppressant therapy. Distress and a higher number of as-needed medications increased the odds of medication non-adherence on multivariable analysis. 

  • Medication non-adherence to immunosuppressants was associated with mild cGVHD with a signal towards moderate cGVHD.  There was a trend towards higher mortality in those with non-adherence, although this was not statistically significant [HR=1.33, 95% CI 0.72-2.44].

  • The authors conclude medication adherence should be regularly assessed due to its high prevalence in this patient population

Abbreviations:

aGVHD: acute graft-versus-host disease

ALL: acute lymphoblastic leukemia

alloHCT: allogeneic hematopoietic cell transplantation

BM: bone marrow

cGVHD: chronic graft-versus-host disease

CIBMTR: Center for International Blood and Marrow Transplant Research

CINV: chemotherapy induced nausea and vomiting

CMV: cytomegalovirus

CR: complete response

CRS: cytokine release syndrome

CSP: cyclosporine A

EBMT: European Society for Blood and Marrow Transplantation 

EFS: event-free survival

GRFS: GVHD-free, relapse-free survival

GVHD: graft-versus-host disease

haploHCT: haploidentical hematopoietic cell transplantation

HCT: hematopoietic cell transplantation

HLA: human leukocyte antigen

LFS: leukemia-free survival

MAC: myeloablative conditioning

MMF: mycophenolate mofetil

MRD: matched related donor

MUD: matched unrelated donor

NMA: non-myeloablative

NRM: non-relapse mortality

ORR: overall response rate

OS: overall survival

PBSC: peripheral blood stem cells

PET: pre-emptive therapy

PFS: progression-free survival

PID: primary immunodeficiency 

PR: partial response

PTCy: post-transplant cyclophosphamide 

RIC: reduced intensity conditioning 

SR: steroid-refractory

TRM: transplant-related mortality

UCB: umbilical cord blood

ASTCT Pharmacy SIG Research Working Committee:

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

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

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