In this month’s Pharmacy SIG Literature Update: CAR-T cells for mantle cell lymphoma, several registry studies on transplant outcomes, updated guidelines on GVHD management, the impact of letermovir on mortality from CMV, 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

*Heinicke T, Labopin M, Polge E, et al. Fludarabine/busulfan versus fludarabine/total-body-irradiation (2 Gy) as conditioning prior to allogeneic stem cell transplantation in patients (≥60 years) with acute myelogenous leukemia: a study of the acute leukemia working party of the EBMT. Bone Marrow Transplant. 2020;55(4):729-739. https://www.ncbi.nlm.nih.gov/pubmed/31645668

• Retrospective analysis comparing outcomes of patients ≥ 60 years with AML in CR1 who received an alloHCT following NMA conditioning with fludarabine/busulfan (FB2, n=553) or fludarabine/TBI 2Gy (FluTBI2Gy, n=535) within EBMT registry. In vivo TCD with ATG or alemtuzumab in 79% and 0% of patients in FB2 and FluTBI2Gy groups, respectively.
• Comparable engraftment between FB2 and FluTBI2Gy groups (99.3% and 98.5%, respectively)
• In MSD group, no significant differences in LFS, OS, CIR, NRM, aGVHD and cGVHD but NRM was significantly higher in FB2 without in vivo TCD vs FluTBI2Gy (HR 2.14, CI 1.04-4.39, p=0.04) and trend towards less extensive cGVHD in FB2 with TCD vs. FluTBI2Gy (HR 0.49, CI 0.23-1.08, p=0.08)
• In MUD group, no significant differences in LFS, OS, RI, NRM and aGVHD but significantly higher incidence in total cGVHD with FluTBI2Gy vs FB2 (HR 2.44, CI 1.60-3.72, p<0.0001)
• Authors conclude that the choice of FluTBI2Gy vs FB2 is guided by center experience and preference

**DeFilipp Z, Li S, Avigan D, et al. A phase II study of reduced intensity double umbilical cord blood transplantation using fludarabine, melphalan, and low dose total body irradiation. Bone Marrow Transplant. 2020;55(4):804-810. https://www.ncbi.nlm.nih.gov/pubmed/31616065

• Multicenter, phase 2 single arm study investigating whether substitution of low dose TBI for ATG in a RIC regimen in adult UCB HCT recipients (n=31) would reduce risk of significant viral reactivations or infections at 1 year post-HCT
• Compared to historical control of 53%, 19 patients experienced total of 24 clinically significant viral reactivations or infections, with 1-year cumulative incidence rate of first significant viral event of  64%, and most common viral reactivations were CMV and HHV6
• 2-year NRM, OS and PFS were 28%, 53%, and 47%, respectively
• Authors conclude that fludarabine/melphalan/TBI is an acceptable ATG-sparing RIC regimen with low incidence of visceral infections and not associated with excess NRM although it did not decrease incidence of significant viral events after UCB alloHCT

*Leick M, Hunter B, DeFilipp Z, et al. Post-transplant cyclophosphamide in allogeneic bone marrow transplantation for the treatment of nonmalignant hematological diseases. Bone Marrow Transplant. 2020;55(4):758-762. https://www.ncbi.nlm.nih.gov/pubmed/31649343

• Single center, retrospective analysis assessing outcomes of patients with nonmalignant hematological malignancies who received alloHCT with PTCy from 2013-2019. Donors were haploidentical (n=6), MUD (n=2), and MSD (n=1), and bone marrow grafts were used for all patients.
• Neutrophil and platelet engraftment occurred at median of 21 days and 33 days, respectively, after transplantation. At median follow-up of 24 months, all patients alive with donor-derived hematopoiesis with no significant aGVHD or cGVHD. No patient required systemic immunosuppression beyond 12 months post-HCT. 
• Authors conclude that PTCy-based NMA alloHCT is safe and effective for nonmalignant hematologic conditions with minimal long-term complications and should be prospectively compared with historical regimens

*Beelen DW, Trenschel R, Stelljes M, et al. Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukemia or myelodysplastic syndrome (MC-FludT.14/L): a randomized, non-inferiority, phase 3 trial. Lancet Haematol. 2020;7(1):e28-e39. https://www.ncbi.nlm.nih.gov/pubmed/31606445

• Open-label, randomized, non-inferiority, phase 3 trial in 31 transplant centers across Europe comparing two RIC regimens of treosulfan/fludarabine (n=221) vs busulfan/fludarabine (n=240) in adult patients with AML or MDS
• Primary outcome of 2-year EFS was 64% vs 50.4% in the treosulfan and busulfan groups, respectively (p<0.0001 for non-inferiority, and 0.0051 for superiority). EFS benefit was predominantly attributed to reduction in TRM.
• The authors concluded that treosulfan was non-inferior to busulfan when used in combination with fludarabine as a RIC regimen for alloHCT for older patients

*Baron F, Labopin M, Savani BN, et al. Graft‐versus‐host disease and graft‐versus‐leukemia effects in secondary acute myeloid leukemia: a retrospective, multicenter registry analysis from the Acute Leukemia Working Party of the EBMT. Br J Haematol. 2020;188(3):428-437. https://www.ncbi.nlm.nih.gov/pubmed/31612473

• A retrospective, registry-based survey study performed by the EBMT to assess the susceptibility of sAML to GVL effects. Data from 2414 sAML patients in first (n=2194) or second (n=220) CR were included
• The 100‐day incidence of grade II‐IV aGVHD was 25%. The 2‐year incidence of cGVHD was 38%. Grade III-IV aGVHD (HR = 7.04, p <0.001) and both limited and extensive cGVHD was associated with a higher NRM, (HR=1.42, p = 0.03) and (HR=3.97; p < 0.001), respectively.
• Relapse rates were significantly lower in patients with cGVHD (HR = 0.52, p < 0.001), and in those with extensive cGVHD (HR=0.66, p < 0.001)
• Together, these results translated to better OS in patients with limited cGVHD, but worse OS in patients with grade III-IV aGVHD and extensive chronic GVHD. The authors conclude that sAML is susceptible to GVL effects, however while MUD recipients had a lower risk of relapse, they had higher NRM which offset any potential OS benefit.

**Nagler A, Dholaria B, Labopin M, et al. The impact of anti-thymocyte globulin on the outcomes of patients with AML with or without measurable residual disease at the time of allogeneic hematopoietic cell transplantation. Leukemia. 2020;34:1144-1153. https://www.ncbi.nlm.nih.gov/pubmed/31728052

• Retrospective multicenter analysis by the EBMT registry to evaluate the impact of ATG on the outcomes of patients with AML stratified by MRD status
• In patients with MRD- status: ATG did not affect relapse incidence.  ATG use was associated with lower incidence of grade II-IV aGVHD, grade III-IV aGVHD, cGVHD, extensive cGVHD, and NRM.  ATG use was also associated with improved LFS, OS, and GRFS survival.
• In patients with MRD+ status: ATG was associated with lower incidence of cGVHD and extensive cGVHD. No significant impact was observed with other transplant-related outcomes.
• No interaction between ATG and cytogenetics, FLT3 mutation status, and donor type was observed.
• The authors conclude the use of ATG was associated with a lower incidence of aGVHD and cGVHD without negatively impacting LFS and OS in AML patients undergoing transplant in CR1 and did not increase risk of relapse in patients with pre-transplant MRD+ disease

Autologous Transplantation

**Domingo-Domènech E, Boumendil A, Climent F, et al. Autologous hematopoietic stem cell transplantation for relapsed/refractory systemic anaplastic large cell lymphoma. A retrospective analysis of the lymphoma working party (LWP) of the EBMT. Bone Marrow Transplant. 2020;55(4):796-803. https://www.ncbi.nlm.nih.gov/pubmed/31695174

• Retrospective analysis assessing outcomes of adult patients with relapsed/refractory sALCL who received first autoHCT between 2010-2014 (n=65) within EBMT registry
• Three-year NRM and CIR were 1.7% and 34%, respectively and no prognostic factors were identified. Three-year PFS and OS were 64% and 73%, respectively and no differences between ALK+ve and ALK-ve patients
• Ten patients (15%) received brentuximab vedotin (BV) before autoHCT and 8 patients (12%) received BV after autoHCT with no significant differences in any outcomes between BV treated vs non-treated patients
• Authors conclude that autoHCT is an effective treatment with promising PFS and OS in the high-risk population of relapsed/refractory sALCL

Cellular Therapy

***Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382:1331-1342. https://www.ncbi.nlm.nih.gov/pubmed/32242358

• Prospective, multicenter study of 74 patients with relapsed or refractory MCL all with prior exposure to BTK inhibitor therapy receiving KTE-X19 CAR-T therapy from October 2016-April 2019 
• 71/74 patients had cells manufactured of which 68 patients received lymphodepleting chemotherapy followed by KTE-X19 cell dose of 2x10⁶/kg body weight on Day 0
• Efficacy analysis of 60 patients revealed 93% patients achieving OR (CR+PR) with 67% achieving CR. ITT analysis of all 74 patients revealed an OR of 85% and a CR of 59%. At a median follow-up of 12.3 months (range, 7-32.3), 57% of patients were in remission. At 12 months, the estimated PFS and OS were 61% and 83%, respectively .
• Grade 3 or higher adverse events included cytopenias in 94% and infections in 32%. Grade 3 or higher CRS and CRES occurred in 15% and 31% respectively; none were fatal. There were two grade 5 infectious adverse events.
• Authors concluded that KTE-X19 induced durable remissions in a majority of patients with relapsed or refractory MCL. Serious and life-threatening toxic effects were consistent with those reported with other CAR-T therapies

*Jin X, Cao Y, Wang L, et al. HLA-matched and HLA-haploidentical allogeneic CD19-directed chimeric antigen receptor T-cell infusions are feasible in relapsed or refractory B-cell acute lymphoblastic leukemia before hematopoietic stem cell transplantation. Leukemia. 2020;34:909-913. https://www.ncbi.nlm.nih.gov/pubmed/31628429

• Describe the first in-human use of HLA-matched allogeneic CAR-T cells prior to alloHCT in eight patients with relapsed/refractory B-cell ALL
• Three of four patients who received MCART19 cells developed neurotoxicity and grade ≥ 3 cytokine release syndrome; none of the patients who received HCART19 cells experienced these adverse effects.
• Three of four patients who received MCART19 cells achieved CR. Of those, 2 proceeded to alloHCT with remission lasting 3 and 14 months. The four patients who received HCART19 cells had mild responses to therapy but relapsed shortly after.
• The authors conclude allogeneic CAR-T cells have properties similar to that of CAR-T cells derived from autologous or post-transplant donors. Allogeneic CAR-T cell therapy is feasible in relapsed/refractory ALL and overcome limitations of autologous CAR-T cells and may therefore be a possible regimen before “off-the-shelf” CAR-T cell therapy.

Graft-Versus-Host Disease

*** Penack O, Marchetti M, Ruutu T, et al. Prophylaxis and management of graft versus host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation. Lancet Haematol. 2020;7(2):e157-e167. https://www.ncbi.nlm.nih.gov/pubmed/32004485

• Update to 2014 consensus guideline on management of GVHD based on culmination of review of published trials, meta-analysis, and systemic reviews, in additional to expert opinion
• Key updates include:
  • Broader use of ATG in MSD alloHCT using PBSC
  • Lower steroid doses (1 mg/kg/day) for grade 2 aGVHD isolated to skin or upper GI tract
  • FAM regimen for initial treatment of BOS in combination with systemic steroids
  • Addition of newer treatment options for SR-GVHD, including ruxolitinib, vedolizumab, and ibrutinib

**Walker I, Panzarella T, Couban S, et al. Addition of anti-thymocyte globulin to standard graft-versus-host disease prophylaxis versus standard treatment alone in patients with hematological malignancies undergoing transplantation from unrelated donors: final analysis of a randomized, open-label, multicenter, phase 3 trial. Lancet Haematol. 2020; 7(2):e100-e111. https://www.ncbi.nlm.nih.gov/pubmed/31958417

• Randomized, controlled, multicenter, parallel group, open label, phase 3 trial comparing pre-transplantation ATG (4.5 mg/kg on days -1, 0, and +1) + standard GVHD prophylaxis (n=203) vs standard GVHD prophylaxis alone (n=101) in patients undergoing transplant from unrelated donors receiving either MA or NMA conditioning regimens
• 38% of 99 evaluable patients in the ATG group were free from immunosuppressive therapy at 24 months vs 19% in the standard GVHD prophylaxis group (OR = 3.49; p=0.00016). Cumulative incidence of cGVHD at 24 months was 26.3% vs 41.3% in the ATG group and standard GVHD prophylaxis group, respectively (p=0.032).
• At 24 months, the CIR and NRM were similar between both groups. However, OS was 70.6% in the ATG group compared with 53.3% in the standard GVHD prophylaxis group (p=0.017).
• The authors conclude that pretreatment with ATG decreases use of immunosuppressive therapy, cGVHD, and improves OS, and should be considered in patients undergoing unrelated donor transplantation

Infectious Disease

**Ljunjgman P, Schmitt M, Marty F, et al. A mortality analysis of letermovir prophylaxis for

cytomegalovirus (CMV) in CMV-seropositive recipients of allogeneic hematopoietic cell transplantation. Clin Infect Dis. 2020;20(8):1525–1533. https://www.ncbi.nlm.nih.gov/pubmed/31179485

• This is a post hoc analysis of phase 3 data further investigating effects of letermovir on all-cause mortality in 495 patients with no detectable CMV DNA at randomization, 437 patients had vital-status data available through week 48 post-HCT
• Following letermovir prophylaxis, the HR for all-cause mortality was 0.58 (95% CI, 0.35–0.98; p=0.04) at week 24 and 0.74 (95% CI, 0.49–1.11; p=0.14) at week 48 post-HCT versus placebo.
• There was no difference in incidence of all-cause mortality through week 48 post-HCT in the letermovir group in patients with or without CS-CMVi (15.8 vs 19.4%; p=0.71); however all-cause mortality at week 48 post-HCT in the placebo group was higher in patients with vs those without CS-CMVi (31% vs 18.2%; p=0.02) respectively
• In patients with CS-CMVi, the mortality rate in the letermovir group was lower than in the placebo group (15.8% vs 31%). In the letermovir group 43.9% developed CS-CMVi through week 14 post-HCT (early CMV reactivation) compared with 94% in the placebo group; late CMV reactivation was defined as group developing CS-CMVi between weeks 14 and 24 post-HCT
• The HR for all-cause mortality in patients with CS-CMVi was 0.45 (95% CI, 0.21–1.00; p=0.05) at week 48 for letermovir versus placebo
• Authors conclude that letermovir may reduce mortality by preventing or delaying CS-CMVi in alloHCT recipients

*Modi A, Rybicki L, Majhail NS, et al. Severity of acute gastrointestinal graft-vs-host disease is associated with incidence of bloodstream infection after adult allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis. 2020;22(1):e13217. https://www.ncbi.nlm.nih.gov/pubmed/31769584

• Single center, retrospective analysis assessing adults who underwent alloHCT from 2011-2017 and were clinically diagnosed with GI GVHD, non-GI GVHD, or no GVHD within first 100 days of HCT (n=441) and the association with incidence of BSI within first 180 days of HCT

Pediatrics

**Mahadeo KM, Bajwa R, Abdel-Azim H, et al. Diagnosis, grading, and treatment recommendations for children, adolescents, and young adults with sinusoidal obstructive syndrome: an international expert position statement. Lancet Haematol. 2020;7(1):e61-e72. https://www.ncbi.nlm.nih.gov/pubmed/31818728

• An expert position statement paper providing consensus recommendations for the international implementation of guidelines for the diagnosis, severity grading, and treatment of SOS among children, adolescents, and young adults developed by a panel of international multi-disciplinary experts
• Key recommendations include use of liver biopsy, portal venous wedge pressure, and reversal of portal venous flow on Doppler ultrasonography for diagnosis and refined definitions for monitoring parameters such as platelet refractoriness, hepatomegaly, and ascites

Abbreviations:

aGVHD: acute graft-versus-host disease

autoHCT: autologous hematopoietic cell transplantation

alloHCT: allogeneic hematopoietic cell transplantation

ALL: acute lymphoblastic leukemia

ATG: antithymocyte globulin

AML: acute myeloid leukemia

BOS: bronchiolitis obliterans syndrome

BSI: bloodstream infections

BTK: Bruton’s tyrosine kinase

CAR-T: chimeric antigen receptor T-cells

cGVHD: chronic graft-versus-host disease

CIR: cumulative incidence of relapse

CMV: cytomegalovirus

CR: complete response/remission

CRES: CAR-T-related encephalopathy syndrome

CRS: cytokine release syndrome

CS-CMVi: clinically significant cytomegalovirus infections

DFS: disease-free survival

EBMT: European Society for Blood and Marrow Transplantation

FAM: fluticasone, azithromycin, and montelukast

GRFS: graft-versus-host disease-free, relapse-free survival

GVHD: graft-versus-host disease

GVL: graft-versus-leukemia

HaploHCT: haploidentical hematopoietic cell transplantation

HCT: hematopoietic cell transplantation

HHV6: human herpesvirus 6

HLA: human leukocyte antigen

ITT: intent-to-treat

LFS: leukemia-free survival

MA: myeloablative

MCL: mantle cell lymphoma

MDS: myelodysplastic syndrome

MSD: matched sibling donor

MRD: minimal residual disease

MUD: matched unrelated donor

NMA: non-myeloablative

NRM: non-relapse mortality

OS: overall survival

ORR: overall response rate

PBSC: peripheral blood stem cell

PFS: progression-free survival

PR: partial response

PTCy: post-transplant cyclophosphamide

RFS: relapse-free survival

RIC: reduced intensity conditioning

sALCL: systemic anaplastic large cell lymphoma

sAML: secondary acute myeloid leukemia

SOS: sinusoidal obstruction syndrome

SR: steroid-refractory

TBI: total body irradiation

TCD: T-cell depletion

TRM: transplant-related mortality

UCB: umbilical cord blood

 

ASTCT Pharmacy SIG Research Working Committee:

Kelly Gaffney, Katie Gatwood, Binni Kunvarjee, Andrew Linn, Anne McDonnell, Monank Patel,

Ashley Teusink-Cross, Jigar Trivedi, Theresa Urban, Lily Yan

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