Pharmacy SIG Literature Update: PTCy for GVHD Prophylaxis and More

By Content Administrator posted 7 days ago

  

In this month’s Pharmacy SIG Literature Update:  PTCy versus ATG for GVHD prophylaxis, cost and outcomes with once-daily busulfan dosing, carfilzomib for the treatment of chronic GVHD 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

Allogeneic Transplantation

**Alatrash G, Kidwell KM, Thall PF, et al.  Reduced intensity vs. myeloablative conditioning with fludarabine and PK-guided busulfan in allogeneic stem cell transplantation for patients with AML/MDS. Bone Marrow Transplant. 2019;54(8):1245-1253. https://www.ncbi.nlm.nih.gov/pubmed/30532055

  • Retrospective study of 242 patients with AML or MDS receiving conditioning with fludarabine and PK-guided dosing of IV busulfan
  • An AUC of 4000 µMol min was used for RIC regimens for a total course of 16,000 µMol min, and AUC of 5000–6000 µMol min for the MAC regimens, with a range of 20,000–24,000 µMol min
  • In the RIC group, there was a trend towards significantly increased donor chimerism and decreased cGVHD, with no significant differences in PFS and OS between the groups
  • These findings suggest efficacy of PK-dosing of busulfan in patients undergoing alloHCT for AML or MDS

**Battipaglia G, Labopin M, Kroger N, et al.  Posttransplant cyclophosphamide vs antithymocyte globulin in HLA-mismatched unrelated donor transplantation. Blood. 2019;134(11):892-899.  https://www.ncbi.nlm.nih.gov/pubmed/31270102

  • Retrospective analysis of AML patients who received a 9/10 HLA-mismatched unrelated alloHCT with PTCy or ATG as part of their GVHD prophylaxis
  • Utilizing the registry data of the Acute Leukemia Working Party of the EBMT, 93 patients who received PTCy were matched to 179 patients receiving ATG. To eliminate confounding factors matches were made based on disease status at time of transplant, conditioning intensity, age, source of stem cells, secondary AML, CMV serology status, female donor/male recipient
  • PTCy had a statistically significant lower incidence of grade III-IV aGVHD compared to ATG (9% vs 19%, p<0.04). Also, PTCy had a significantly higher probability of GVHD/relapse-free survival at 2 years (37% vs 21%, p<0.03)
  • PTCy was associated with a higher probability of leukemia-free survival (55% vs 34%, p<0.05) and a trend for higher probability of OS (56% vs 38%, p<0.07)
  • The authors conclude that PTCy is effective in preventing GVHD in mismatched alloHCT and may improve long-term disease control

*Cao Y, He Y, Zhang S, et al. Conditioning regimen of 5-day decitabine administration for allogeneic stem cell transplantation in patients with myelodysplastic syndrome and myeloproliferative neoplasms. Biol Blood Marrow Transplant. 2019. [ePub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31494229

  • Retrospective assessment of the efficacy of a new conditioning regimen: Dec/Bu/Cy/Flu/Ara-c for alloHCT in patients with MDS (n=44) and CMML (n=4)
  • All patients received PBSCs with 60% receiving cells from a related donor
  • OS was 86%, relapse incidence was 12%, and NRM was 12% at a mediam follow up of 522 days
  • At 2 years, OS was 100%, 83%, 100%, 74%, and 86%, respectively for extremely low, low, intermediate, high-risk, and very-high-risk patients with MDS respectively
  • Incidence of grade III-IV aGVHD was 23% and that of cGVHD was 15%
  • This regimen was associated with a low relapse rate, low incidence and severity of GVHD, and satisfactory survival in alloHCT recipients with MDS and MDS/MPN. Given the retrospective nature and small patient population, further study is warranted

*Dimitrova D, Gea-Banacloche J, Steinberg SM, et al. Prospective study of a novel, radiation-free, reduced-intensity bone marrow transplantation platform for primary immunodeficiency diseases. Biol Blood Marrow Transplant. 2019. [ePub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31493539

  • Evaluation of a novel RIC, T-cell-replete BMT approach for PID using pentostatin, low-dose cyclophosphamide, and busulfan for conditioning with PTCy-based GVHD prophylaxis
  • The study oberseved an 80% GVHD-free and graft failure free survival at day +180 (primary endpoint)
  • Cumulative incidences of grade II to IV and grade III to IV aGVHD were 15% and 5%, respectively. All aGVHD was steroid responsive. No patients developed cGVHD
  • One-year OS was 90% and evidence of phenotype reversal was observed for all engrafted patients. Graft failure incidence was 10%
  • This novel RIC BMT approach for patients with PID has yielded promising results, even for high-risk patients

*Pratz KW, Rudek MA, Smith D, et al. A prospective study of peri-transplant sorafenib for FLT3-ITD AML patients undergoing allogeneic transplantation. Biol Blood Marrow Transplant. 2019. [ePub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31550496

  • Prospective study of 44 patients with FLT3-ITD AML undergoing allogeneic transplant to evaluate the safety, tolerability, and outcomes with sorafenib peri-transplant
  • Sorafenib was started (or resumed) between day +30 and +120 at a dose of 200 mg by mouth BID and dose reduced or escalated to a maximum of 400 mg BID based on tolerability. Pre-transplant sorafenib was given to 48% of patients enrolled and post-transplant was given to 98%
  • OS was 76% at both 24 and 36 months. EFS at 24 and 36 months was 74% and 64%, respectively
  • Grade 3/4 elevatations in hepatic enzymes occurred in 23% of patients and grade 3/4 thrombocytopenia occurred in 16%
  • Only 4 patients were able to be maintained on 400 mg BID however plastma inhibitory activity assay was consistent at ~90% or higher even with dose reduction. Plasma inhibitory activity of at least 80% appeared to be correlated to favorable outcomes
  • These findings indicate sorafenib dosed according to patient tolerance represents an important peri-transplant therapeutic option for FLT3-ITD AML. Ongoing studies of FLT3-ITD inhibition post-transplant will continue to clarify the role of these agents in the transplant setting

*Singhal S, Kim T, Jenkins P, Bassett B, Tierney DK, Rezvani AR. Costs and outcomes with once-daily versus every-six-hour intravenous busulfan in allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2019. [ePub ahead of print].  https://www.ncbi.nlm.nih.gov/pubmed/31525492

  • Retrospective analysis of cost and outcomes associated with q24h (n=45) vs. q6h (n=59) IV busulfan in patients receiving Bu/Cy conditioning regimens for alloHCT
  • An average cost savings of $19,990 per patient per year was observed with q24h busulfan compared to q6h busulfan, which translated into an annual busulfan cost savings of $899,550.00
  • Significantly lower day +90 mortality in the q24h busulfan cohort was seen compared to the q6h busulfan cohort (0% vs 10%, P=0.028)
  • No significant differences were observed in mean peak bilirubin concentrations (2.6 vs. 1.7, P=0.268) nor in the incidence of sinusoidal obstruction syndrome (9% vs. 18%, P=0.324) in the q6h vs. q24h cohorts, respectively
  • These data support the adoption of q24h IV busulfan dosing as a standard of care to improve value-based care in alloHCT

Chimeric Antigen Receptor T-cell Therapy

**Frigault M, Dietrich J, Martinez-Lage M, et al.  Tisagenlecleucel CAR T-cell therapy in secondary CNS lymphoma.  Blood. 2019;134(11):860-866.  https://www.ncbi.nlm.nih.gov/pubmed/31320380

  • Report on 8 patients treated with tisagenlecleucel for high grade B-cell lymphoma with secondary CNS involvement at Massachusetts General Hospital
  • Patients received a single infusion of CAR T cells following lymphodepletion with cyclophosphamide (250mg/m2) and fludarabine (25mg/m2) on days -5, -4, and -3 in addition to prophylactic anticonvulsants and no growth factor support prior to day +7
  • All patients were receiving CNS-directed therapy up until lymphodepletion, for parenchymal involvement (n=3), leptomeningeal involvement (n=3) or both areas involved (n=2)
  • No patients required tocilizumab or high-dose steroids for the management of CRS and/or NT
  • At day 28, two patients had died secondary to disease progression, two patients achieved a CR, two patients achieved a PR, and two patients had progressive disease
  • Due to results and lack of NT the authors will proceed to a pilot study using the product in primary CNS lymphoma

*Hu Y, Wang J, Wei G, et al.  A retrospective comparison of allogenic and autologous chimeric antigen receptor T cell therapy targeting CD19 in patients with relapsed/refractory acute lymphoblastic leukemia. Bone Marrow Transplant. 2019;54(8):1208-1217. https://www.ncbi.nlm.nih.gov/pubmed/30518980            

  • Retrospective review of 31 patients; Patients received either autologous (n = 17), DD allogeneic (n = 3), or RD allogeneic CAR T cells (n = 11)
  • At a median of 9 months, CR rate was 88.2% in the auto group, and 100% in the RD allogeneic group, and the RD allogeneic group also had lower rates of CRS. Rates of aGVHD were similar between the RD allogeneic group (2/11, 18.2%) and the DD allogeneic group (2/3, 33%)
  • Investigators have found that CAR T sources impact clinical outcomes

Graft Versus Host Disease Treatment

**Kebriaei P, Hayes J, Daly A, et al. A Phase 3 randomized study of Remestemcel-L versus placebo added to second line therapy in patients with steroid refractory acute graft versus host disease. Biol Blood Marrow Transplant. 2019. [ePub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31505228

  • Multicenter, randomized Phase 3 study enrolling patients between 2006 to 2009 to assess the efficacy of using Remestemcel-L in addition to second-line therapy to treat steroid-refractory aGVHD
  • Patients were randomized 2:1 to receive 8 IV infusions of remestemcel-L (n=173) or placebo (n=87), given over 4 weeks, in addition to second-line therapy according to institutional standards. Four additional infusions over 4 weeks were indicated for patients with incomplete response at day 28
  • Remestemcel-L did not meet the primary endpoint of greater DCR (CR for at least 28 days within first 100 days of enrollment) in the intent-to-treat population (35% versus 30%; P=0.42), but some improvement in response was observed in post-hoc subgroup analyses; notably liver involvement or high-risk patients
  • Similar rates of adverse events were observed between treatment groups
  • Results of this study did not demonstrate superior DCR compared with placebo when added to institutional standard of care. The landscape and understanding (as well as therapies) have significantly changed since the initiation of the trial. Comptemorary studies assessing MSCs in certain subgroups are underway

**Pidala J, Jaglowski S, Im A, et al. Carfilzomib for treatment of refractory chronic graft-versus-host disease: a Chronic GVHD Consortium pilot phase II trial. Biol Blood Marrow Transplant. 2019. [ePub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31499215

  • Multicenter pilot phase II trial to explore the safety and activity of carfilzomib in advanced cGVHD
  • Twenty patients from 4 centers were enrolled to receive carfilzomib days 1, 8, and 15 of a 28 day cycle and therapy continued until resolution of GVHD, unresolved toxicity, patient nonadherence, additional GVHD therapy, or relapse with a planned 6 cycles of therapy
  • Chronic GVHD was NIH category moderate (30%) or severe (70%), predominantly classic (90% versus overlap 10%), and involved multiple diverse organ sites. Number of previous lines of systemic therapy for cGVHD was < 2 in 30% and > 3 in the other 70%
  • Six-month treatment failure rate was not significantly improved versus the historical benchmark rate (40% versus 44%; P=0.36). OS was 80% at 6 months and 65% at 12 months. FFS at 12 months was 32%
  • Serious adverse effects occurred in 40% of the patients, and 7 patients died, between 0.3 and 9 months after the last carfilzomib dose, but no deaths were attributed to carfilzomib
  • These data suggest that carfilzomib therapy in this advanced cGVHD population did not improve over the expected 6-month treatment failure rates achieved under conventional practices and is not recommended for further study for this indication

*Solomon SR, Sizemore CA, Ridgeway M, et al.  Safety and efficacy of rituximab-based first line treatment of chronic GVHD.  Bone Marrow Transplant. 2019;54(8):1218-1226. https://www.ncbi.nlm.nih.gov/pubmed/30518977

  • Evaluation of 69 patients that received rituximab as part of their initial treatment. Median follow-up for surviving patients was 47 (11-81) months
  • Resolution of cGVHD was seen in 49 patients at a median follow up of 47 (11-81) months. The majority of patients received corticosteroids
  • OS was 87%, 79%, and 77% at 1, 2, and 3-years, respectively
  • These findings are promising for minimizing corticosteroid use

Haploidentical Transplantation

** Bazarbachi A, Boumendil A, Finel H, et al. Influence of donor type, stem cell source and conditioning on outcomes after haploidentical transplant for lymphoma – a LWP-EBMT study. Br J Haematol. 2019.  [Epub ahead of print].  https://www.ncbi.nlm.nih.gov/pubmed/31498883           

  • Retrospective, registry-based, multicenter analysis of adult patients at EBMT centers with lymphoma who received a haplo HCT with PTCy between 2010 and 2016
  • 474 patients were included (HL, n=240; PTCL, n=88; DLBCL, n=77; MCL, n=40; FL, n=29) and had a median follow up of 32 months
  • On multivariate analysis, aGVHD grade 2-4 was lower with offspring donors (HR 0.54, P = 0.015) or BM stem cells in comparison to PBSC (HR 2.15, P<0.001), while extensive cGVHD was higher in partial response patients (HR 2.53, P=0.032) or those who received sister donors (HR 34.44, P=0.037), haplo donors beyond 1st degree (HR31.95, P=0.008), or female donors to male patients (HR 3.64, P=0.035)
  • PFS was better for FL (HR 0.47, P=0.03), HL (HR 0.5, P<0.001) and PTCL (HR 0.59, P=0.017) whereas OS was better for HL (HR 0.48, P<0.001) and PTCL (HR 0.53, P=0.006)
  • CR at haploHSCT improved PFS (P<0.001) and OS (P=0.015), but were negatively affected by CMV donor +/recipient – status (OS P=0.029; PFS P=0.027)
  • The authors concluded that PFS and OS are mostly influenced by disease status and lymphoma subtype, supporting the use of any first degree haploidentical family member as a donor

Infectious Disease

* Mohty R, Brissot E, Battipaglia G, et al. Infectious complications after post-transplantation cyclophosphamide and anti-thymocyte globulin-based haploidentical stem cell transplantation. Br J Haematol. 2019. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/31487392             

  • Retrospective, single-center evaluation of 72 consecutive patients who underwent haplo HCT with PTCy at the Saint-Antoine University Hospital, Paris, France between December 2012 and December 2016
  • All patients received PTCY 50 mg/kg/day for either 1 (BM, n=20; PBSC, n=1) or 2 days (BM, n=1; PBSC, n=50) to prevent GVHD along with cyclosporin and mycophenolate while 60 patients (83%) received ATG (5 mg/kg, n=40; 2.5 mg/kg, n=20)
  • After a median of 23 months follow up, OS was 51% and PFS was 40% with a 2-year CIR & NRM of 18% and 33% respectively
  • There were 14 (39%) infection-related deaths and the D+100 CI of bacterial infections was 46%; D+100 CI of CMV reactivations was 56%; D+100 CI of BK virus cystitis was 31%; and D+100 CI of fungal infections was 24%
  • The authors concluded that T-cell replete haploHSCT is feasible in high-risk patients, but further strategies that aim to enhance immune recovery and improve patient outcomes after haplo HCT are needed

Other

***Dehn J, Spellman S, Hurley C, et al.  Selection of unrelated donors and cord blood units for hematopoietic cell transplantation:  guidelines from the NMDP/CIBMTR.  Blood. 2019;134(12):924-934.  https://www.ncbi.nlm.nih.gov/pubmed/31292117

  • Update on evidence-based guidelines for unrelated and cord blood unit selection focusing on the impact of HLA and non-HLA factors with OS as the primary outcome of interest
  • In unrelated donor transplants, sufficient high-resolution donor-recipient HLA match is a primary importance
  • In cord blood transplants, the optimal selection must consider unit quality, cell dose, and HLA-match
  • Early evaluation for the prospect of a successful unrelated donor search can help determine if alternative donor sources such as cord blood, haploidentical, or mismatched unrelated donor should be pursued

**Terakura S, Nishida T, Sawa M, et al. Prospective phase 2 study of umbilical cord blood transplantation in adult acute leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant. 2019. [ePub ahead of print].  https://www.ncbi.nlm.nih.gov/pubmed/31546004

  • Prospective phase 2 study to assess efficacy and safety of single-unit myeloablative CBT in adult leukemia and MDS
  • The authors determined the hypothesis of expected day 180 survival with successful engraftment rate as 80% to match that observed with matched unrelated donor transplantation

and set the null hypothesis threshold rate as 65%

  • Of 61 patients, 85% (95% CI, 74–93%) successfully engrafted and survived at day 180 and the null hypothesis was rejected (p<0.001)
  • Incidences of grades II–IV acute and chronic GVHD were 30% and 32%, respectively
  • This study showed favorable survival outcomes with single-unit CBT suggesting this method may be considered if a well-matched unrelated donor transplantation cannot be obtained

*Xu ZL, Zhou M, Jia JS, et al.  Immunosuppressive therapy versus haploidentical transplantation in adults with acquired severe aplastic anemia. Bone Marrow Transplant. 2019;54(8):1319-26. https://www.ncbi.nlm.nih.gov/pubmed/30670825

  • Retrospective review of 113 patients with SAA who received IST with either rabbit ATG or cyclosporine (n= 37), or haplo HCT (n =76) within 6 months of diagnosis. Patents were assessed for OS, and FFS
  • At 8 years, OS was comparable between the IST and the haplo HCT groups (75.6 v. 83.7, P = 0.328), and FFS was lower in the IST group (38.5 v. 83.7%, P = 0.001). Additionally, more patients in the haplo HCT group had a complete recovery (83.1% versus 38.2%, P < 0.001)
  • This study shows that haplo HCT may be a treatment option for adult patients with SAA

Pediatrics

** Ottaviano G, Lucchini G, Breuer J, et al. Delaying haematopoietic stem cell transplantation in children with viral respiratory infections reduces transplant-related mortality. Br J Haematol. 2019. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/31566733             

  • Retrospective, single-center evaluation of all children undergoing alloHCT at Great Ormond Street Hospital for Children in London between November 2007 and November 2017
  • 585 children undergoing alloHCT were administered NPAs for VRIs before and weekly after transplant, while 75 (12%) of children were NPA+ and transplant was delayed in 25 of those cases
  • NPA+ patients undergoing alloHCT had a significantly lower OS (54% vs 79%) and increased TRM (26% vs 7%, P<0.001) when compared to NPA- patients
  • NPA+ patients who delayed alloHCT to clear VRI had improved OS (90%) and lower TRM (5%)
  • Pre-transplant NPA+ children required PICU admission more frequently (30% vs 8%, P<0.005)
  • Multivariate analysis showed that only NPA+ status and the use of HLA mismatched donors were independently associated with early TRM
  • The authors concluded that transplant delay, whenever feasible, in case of a positive NPA screen for VRIs can positively impact survival of children undergoing HSCT

Abbreviations:

aGVHD: acute graft-versus-host disease

aHCT: autologous hematopoietic cell transplantation

alloHCT: allogeneic hematopoietic cell transplantation

AML: acute myeloid leukemia

Ara-c: cytarabine

ATG: antithymocyte globulin

AUC: area under the curve

BM: bone marrow

BMT: bone marrow transplant

Bu: busulfan

CAR: chimeric antigen receptor

CBT: cord blood transplant

cGVHD: chronic graft-versus-host disease                     

CIBMTR: Center for International Blood and Marrow Transplant Research

CI: cumulative incidence

CIR: cumulative incidence of relapse

CMML: chronic myelomonocytic leukemia

CMV: cytomegalovirus

CNS: central nervous system

CR: complete response

CRS: cytokine release syndrome

Cy: cyclophosphamide

DCR: durable complete response

DD: donor-derived

Dec: decitabine

DLBCL: diffuse large b-cell lymphoma

EBMT:  European Society for Blood and Marrow Transplantation

EFS: event-free survival

FFS: failure free survival

FL: follicular lymphoma

Flu: fludarabine

GVHD: graft-versus-host disease

Haplo: haploidentical

HCT: hematopoietic cell transplantation

HL: hodgkin lymphoma

HLA:  human leukocyte antigen

IST: immunosuppressive therapy

LTBI: latent tuberculosis infection

MAC: myeloablative conditioning

MCL: mantle cell lymphoma

MDS: myelodysplastic syndrome

MPN: myeloproliferative neoplasm

MSC: mesenchymal stem cell

NIH: National Institutes of Health

NMDP:  National Marrow Donor Program

NPA: nasopharyngeal aspirates

NRM: non-relapse mortality

NT: neurotoxicity

OS: overall survival

PBSC: peripheral blood stem cell

PFS: progression-free survival

PICU: pediatric intensive care unit

PID: primary immunodeficiency

PK: pharmacokinetic

PR: partial response

PTCL: peripheral T-cell lymphoma

PTCy: post-transplant cyclophosphamide

RD: recipient-derived

RIC: reduced-intensity conditioning

SAA: severe aplastic anemia

TRM: treatment-related mortality

VRI: viral respiratory infection

ASTCT Pharmacy SIG Communications Working Committee:

Brandi Anders, Telyssa Anderson, Tiene Bauters, Eileen Chen, Jason Jared, Kathryn Maples, Amanda Peffer, Ryan Shaw, Meg Taylor, Jamie Ziggas

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