In this month’s Pharmacy SIG Literature Update: The impact of GCSF with thymoglobulin, Flu/Mel vs. Flu/Bu in older patients with MDS, 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

**Orfali N, Zhang MJ, Allbee-Johnson M, et al. Planned granulocyte colony-stimulating factor adversely impacts survival after allogeneic hematopoietic cell transplantation performed with thymoglobulin for myeloid malignancy. Transplant Cell Ther. 2021;27:993e.1-8. https://pubmed.ncbi.nlm.nih.gov/34507002

• Retrospective analysis utilizing CIBMTR database to evaluate allogeneic HCT with ATGcontaining preparative regimen in patients >18 years with AML or MDS and compare outcomes between patients who received planned G-CSF and those who did not. Patients received a PBSC graft from a MSD, MUD, or 1-locus MMUD and received either a MAC or RIC regimen. GCSF administrations for a clinical indication were excluded.
• 459 patients received planned G-CSF, and 415 did not. All regimens contained ATG, at a median dose of 4.5 mg/kg. Median time to neutrophil engraftment was 12 days in the G-CSF group vs. 15 days in the non-G-CSF group (IQ 13-17 days), and for platelet engraftment was 17 days vs. 15 days, respectively. Day 100 incidence of platelet recovery was lower in the G-CSF recipients (93%) vs. the non-G-CSF recipients (96%, p = 0.023). Median hospitalization was 16 days vs. 18 days, respectively.
• The incidence of grade II-IV aGVHD did not differ between groups (39% in G-CSF group vs. 38%, p = 0.74), and similarly with cGVHD (33% in the G-CSF group vs. 37%, p = 0.21). Relapse rates were similar between groups (31% in the G-CSF group vs. 30%, p = 0.70), however NRM (21% vs. 11%, HR 2.03; p = < 0.0001) was significantly lower in the G-CSF group as compared to the non-G-CSF group. DFS and OS were also significantly lower in the G-CSF group (HR 1.42, p = 0.0006 and HR 1.52, p = 0.0005, respectively).
• There were no significant differences in incidence of bacterial or fungal infections, but patients in G-CSF group did have significantly more viral infections at 3 and 6 months (p = 0.007)
• Authors conclude that the use of planned G-CSF resulted in a 2-fold increase in NRM and 10% absolute decrement in survival, so use should be carefully considered on an individual patient basis.

**Oran B, Ahn KW, Fretham C, et al. Fludarabine and melphalan compared with reduced doses of busulfan and fludarabine improve transplantation outcomes in older patients with myelodysplastic syndromes. Transplant Cell Ther. 2021;27:921.e1-10. https://pubmed.ncbi.nlm.nih.gov/34403791

• Retrospective analysis utilizing CIBMTR database of patients >60 years with MDS who received a MSD or MUD HCT to compare the Flu/Bu (busulfan <7.2 mg/kg IV) and Flu/Mel (melphalan <150 mg/m2) RIC regimens in an older population.
• 1045 patients were identified, 448 who received Flu/Mel and 597 who received Flu/Bu. Median age was 67 years, with patients >70 years more likely to receive Flu/Bu (26%) than Flu/Mel (19%). Use of ATG and alemtuzumab for GVHD prophylaxis was also more common in the Flu/Bu group (39%) than the Flu/Mel group (31%).
• OS rates at 1 and 2 years post-HCT did not differ between the groups, but Flu/Mel was associated with decreased OS in the first 3 months (HR 1.62, p = 0.01), but beyond that, improved OS (HR 0.73, p < 0.001) compared to Flu/Bu. After adjusting for prognostic variables, 3-year OS was 46% in the Flu/Mel group vs. 39% in the Flu/Bu group (39%, p = 0.03). In the Flu/Mel group, most common causes of death were relapse (28%), GVHD (21%), and infection (19%) vs. relapse (50%) in the Flu/Bu group.
• DFS was also lower in the Flu/Bu group compared to the Flu/Mel group after the first 3 months (HR 0.75, p < 0.001). Relapse was more likely with Flu/Bu vs. FluMel (HR 0.55, p < 0.001). TRM was higher in the Flu/Mel group during the first 3 months (HR 2.37, p < 0.001), but similar beyond then (HR 0.97, p 0.84), which correlates with the higher incidence of GVHD in the Flu/Mel group during the first 60 days post-HCT (HR 1.66, p < 0.0001).
• Authors conclude that Flu/Mel is associated with superior DFS in older MDS patients compared with Flu/Bu, owed to reduced relapse rate.

*Mehta RS, Salib RM, Alsfeld LC, and et al. Bone Marrow versus Peripheral Blood Grafts for Haploidentical Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide. Transplantation and Cellular Therapy. 2021; 27:1003.e1-1003.e13. https://pubmed.ncbi.nlm.nih.gov/34537419

• A retrospective analysis comparing outcomes of HCT in BM (n = 180) and PBSC (n= 84) in recipients (N = 264) ≥ 18 years old with hematologic malignancies who underwent T cell-replete haploidentical HCT and received GVHD px with post-transplant cyclophosphamide, tacrolimuslimus, and MMF.
• Baseline demographics: median age 50 years; majority (75%) received RIC with fludarabine and melphalan-based regimen; rate of acute leukemia and MDS was higher in the BM group compared to the PB group (85% vs 55%; p < 0.01); approximately 50% had an HCT comorbidity 3 index of ≥ 3; and haploidentical children donors (52% and 55%) were most common donors, followed by siblings (40% and 36%).
• Primary outcomes:
  • Incidence of grade II-IV and grade III-IV aGVHD were comparable in the 2 groups. Rate of SR-aGVHD within the grade II-IV was 9% (95% CI, 5% to 18%) in the BM group versus 32% (95% CI, 19% to 54%) with PBSC [HR 3.7, 95% CI, 1.5 to 9.3; P=0.006]
  • cGVHD at 1 year was 8% (95% CI, 4% to 13%) in the BM group versus 22% (95% CI, 14% to 36%) PBSC [HR 3.0; 95% CI, 1.4-6.6; P=0.005]
  • Rate of systemic therapy-requiring cGVHD was 2.5% (95% CI, 1% to 7%) versus 14% (95% CI, 7% to 27%), respectively [HR, 5.6; 95% CI, 1.7 to 18; P = 0.004].
• Secondary outcomes:
  • Median time to neutrophil and platelet engraftment were similar
  • Multivariate analysis showed no effect of graft source on NRM, PFS, and OS at 1-year PBSC was associated with a significantly worse GFRS [HR, 2.2 95% CI, 1.4 to 3.5; P=0.001] among patients with low/intermediate DRI
  • Infections: Cumulative incidence of any viral infection by day +180 was 7% (95% CI, 4%- 12%) in the BM group and 17% (95% CI, 10%-17%) in the PB group [HR, 2.4; 95% CI, 1.1 to 5; P = 0.02]. Cumulative incidence of bacterial infections by day +180 in the 2 groups was 4% (95% CI, 2% to 9%) versus 13% (95% CI, 8% to 23%) in PBSC [HR, 3.1; 95% CI, 1.3 to 7.7; P = 0.01].
• The authors concluded that PBSC has significantly higher risk of bacterial and viral infections, with no appreciable advantage in the duration of hospitalization, immune reconstitution, relapse, NRM, or survival – suggesting a benefit of the use of BM grafts over PBSC for haplo-HCT.

CAR-T therapy

*Cao Y, Xiao Y, Wang N, et al. CD19/22 chimeric antigen receptor t cell cocktail therapy following autologous transplantation in patients with relapsed/refractory aggressive B cell lymphomas. Transplant Cell Ther. 2021;27:910.e1-11. https://pubmed.ncbi.nlm.nih.gov/34425260

• Prospective, pilot study of the sequential infusion of CD22 and CD19 CAR-T cells following auto HCT in patients with aggressive B-NHL who had a Deauville score of 4 or progressive disease after 2 cycles of salvage chemotherapy. Patients underwent 2 separate apheresis procedures, then started a MAC regimen with BEAM from Days -7 to -1, followed by cell infusion on Day 0, CD22 CAR-T (1-10 x 106/kg) on Day 2, and CD19 CAR-T (1-10 x 106/kg) on Day 3 (which could be delayed up to 6 days after HCT). Fludarabine/cyclophosphamide lymphodepletion was not administered.
• 49 patients consented and underwent leukapheresis, of which 42 completed the HCT and C19/22 cocktail infusion. 50% of patients had received > 4 prior lines of therapy, and 76% had SD or PD before undergoing HCT. Median dose of CD22 and CD19 CAR-T cells was 4.0 x 106kg and 4.1 x 106kg, respectively and median day of administration was 3 days and 4 days, respectively, after HCT.
• 3-month ORR was 91%, with 81% achieving a CR. All 4 patients who had a PR at 3 months improved to CR at a median time of 3 months without additional lymphoma therapy. 6-month ORR was 86%. Median PFS and OS were not reached at a median follow-up of 24.3 months. 2- year PFS and OS was 83% for both.
• All patients developed pancytopenia attributed to chemotherapy along with diarrhea in 67% and mucositis in 69%. 96% of patients developed reversible CRS, of which only 5% were grade 3. Median CRS onset and duration was 2 days and 7 days, respectively. 21% of patients developed neurotoxicity, of which only 5% were grade 3. Median neurotoxicity onset and duration was 6 days and 4 days, respectively. All 42 patients achieved neutrophil recovery at a median of 13 days and 38 patients achieved platelet engraftment within 28 days.
• Authors conclude that the high durable CR rates and favorable safety profiles support the potential of high-dose auto HCT plus CD19/22 CAR-T cell cocktail therapy for patients with relapsed/refractory aggressive B-NHL who are less sensitive or fail salvage chemotherapy.

**Caron A Jacobson, Julio C Chavez et al. Axicabtagene ciloleucel in relapsed or refractory indolent nonHodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncology 2022;23:91-103. https://pubmed.ncbi.nlm.nih.gov/34895487/

• ZUMA-5 trial, a multicenter, single-arm, phase 2 study of axicabtagene ciloleucel for treatment of relapsed or refractory indolent NHL (FL or MZL), who had two or more lines of therapy (including an anti-CD20 monoclonal antibody with an alkylating agent), and an ECOG 0 or 1. Patient received single infusion of axi-cel (2 × 10⁶ CAR T cells per kg) on day 0 after leukapheresis and conditioning chemotherapy (cyclophosphamide at 500 mg/m² per day and fludarabine at 30 mg/m² per day on day’s −5, −4, and −3). Primary endpoint was overall response rate (CR + PR).
• Overall, 153 patients were enrolled, of which 148 received an infusion of axi-cel. Of the 104 patients (84 with FL and 20 MZL) included in primary efficacy analysis 96 (92%; 95% CI 85–97) had an overall response and 77 (74%) had a complete response, with more favorable and earlier responses seen in those with FL than in those with MZL. The 18-month progression free survival was 64·8% (95% CI 54·2–73·5) and overall survival was 87·4% (95% CI 79·2–92·5). Patients with CR had better outcomes, while most partial responders had disease progression. Low-level CAR T-cell persistence was detected in 75% (70 of 93) of evaluable samples at 1 year, and 69% (18 of 23) of evaluable samples at 2 years after infusion.
• Most common adverse events were cytopenias (104 [70%] of 148 patients) and infections (26 [18%]). Grade 3 or worse cytokine release syndrome seen in only ten (7%) patients and grade 3 or 4 neurological events occurred in 28 (19%) patients. Severe neurological events occurred in a higher proportion of patients with MZL than with FL (38% vs 15%), which was potentially related to higher peak and areas under the curve for CAR T-cell expansion in patients with MZL than in those with FL.
• Overall, results show that axi-cel treatment provides durable clinical benefit and a manageable safety profile in patients with relapsed or refractory indolent NHL after at least two lines of therapy.

Post-transplant maintenance therapy

**Bewersdorf JP, Allen C, Mirza AS, and et al. Hypomethylating Agents and FLT2 Inhibitors as Maintenance Treatment for Acute Myeloid Leukemia and Myelodysplastic Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation-A Systematic Review and Meta-Analysis. Transplantation and Cellular Therapy. 2021; 27:997e1-997.e11. https://pubmed.ncbi.nlm.nih.gov/34551341

• A systematic review and meta-analysis search resulted in the inclusion 21 (809 patients total) to synthesize the current evidence on the efficacy and safety of FLT3 inhibitors and HMA for maintenance therapy after allo HCT in AML and MDS.
  • 8 retrospective studies, 4 prospective cohort studies, 2 phase I clinical trial, 6 phase II clinical trials, and 1 phase III clinical trial
  • 11 studies with 366 patients reported outcomes with FLT3 inhibitors (sorafenib, quizartinib and midostaurin)
  • 10 studies with 443 patients reported outcomes with HMA (7 studies with AZA, 2 studies with decitabine, 1 study with AZA or decitabine)
• Population demographics: median age, 24-62yrs; R/R disease reported between 7-36%, majority received a RIC or MAC conditioning regimen; all studies using FLT3 inhibitors had a FLT3 mutation; and studies using HMA maintenance included genetically heterogenous population.
• Primary endpoints:
  • 2- year OS were 81.7% (95% CI 73.8%-87.7%) among FLT3 inhibitors and 65.7% (95% CI 55.1% -74.9%) among HMA
  • Study heterogeneity was significant for both types of maintenance therapy; moderate for FLT3 (Cochran’s Q = 22.63; p = 0.012; I2 = 55.81%) and substantial for HMA (Cochran’s Q = 36.14; P <0.001; I2 = 75.09%
  • Maintenance therapy with either FLT3 (HR for death = 0.41; 95% CI, 0.26-0.62) or HMA (HR = 0.45; 95% CI, 0.31-0.66) appeared superior to no maintenance in a sensitivity analysis restricted to studies with a control group
• Secondary endpoints:
  • 2-year RFS rates were 79.8% (95% CI, 75.0% -83.9%) with FLT3 inhibitors and 62.4% (95% CI, 50.6% - 72.9%) with HMA.
  • Any grade aGVHD and cGVHD were 33.3% (95% CI, 25.4%-41.8%; grade 3-4: 16.5%) and 42.5% (95% CI, 26.3%-60.4%) among FLT3 inhibitors. Any grade aGVHD and cGVHD were 42.7% (95% CI, 33.5%-52.4%; grade 3-4 : 8.1%) and 41.5% (95% CI, 32.0%-51.6%) among HMA.
• The authors concluded that maintenance therapy with either FLT3 inhibitors or HMA post alloHCT can lead to prolonged and improved OS and RFS with a favorable safety profile. Additional studies are needed to define the optimal duration of treatment, the role of measurable residual disease status, and transplant characteristics in patient selection.

Graft-versus-host-disease

**Khaled Sanber, Bipin Savani and Tania Jain. Graft-versus-host disease risk after chimeric antigen receptor T-cell therapy: the diametric opposition of T cells. Br J Haematol 2021;195:660-668. https://pubmed.ncbi.nlm.nih.gov/34036558/

• True-allogeneic (donor-derived) CAR-T Cells
  • Donor-derived CAR T cells expressing a second-generation anti-C19 CAR with the CD28 endodomain (CD28z.CAR T cells), showed relatively low incidence of GVHD. Mouse model of post-HCT relapse using CD28z.CAR T cells suggested potent activation of this CAR T cells causing functional exhaustion and activation-induced cell death in alloreactive CAR T cells. This phenomenon limited GVHD while the non-exhausted, nonalloreactive CD28z. CAR-T cells mediated significant graft-versus-lymphoma.
  • Other CAR T cells [first-generation CAR (carrying the CD3f signaling domain without additional co-stimulatory domains) or a second-generation CAR utilizing the 41BB costimulatory domain (41BBz.CAR)] had lower activation, less exhaustion and an increased incidence of severe GVHD.
• Pseudo-allogeneic (recipient) CAR-T cells
  • CAR-T cells derived from recipient T cells have reduced risk of GVHD because the cells would be either non-alloreactive or peripherally tolerized.
  • Studies utilizing 41BB costimulatory domain, second-generation 41BBz.CAR T cells targeting CD19, reported higher occurrence of GVHD, while study utilizing CD28z.CAR T did not exacerbate GVHD. However, these studies has small number of patients.
• Autologous CAR-T cells do not carry a significant risk of GVHD as they are derived from the patient’s own T cells
• Allogeneic CAR-T cells
  • Gene-editing technologies such as transcription activator-like effector nucleases (TALENS) and clustered regularly interspaced short palindromic repeat (CRISPR)- associated proteins are used to disrupt the native TCR α/β constant (TRAC/TRBC) genes and generate CAR-T cells lacking TCR expression on surface thereby reducing risk of GVHD.
  • Clinical trials using “off-the-shelf” allogeneic anti-CD19 CAR T cells edited using TALENS to disrupt the genes encoding TRAC and CD52 and alemtuzumab for T-cell depletion showed promising results. Of particular interest, only two out of 14 patients (14%) developed Grade I acute skin GVHD. In all, 14 of 21 patients (67%) achieved complete response (CR) or CR with incomplete hematological recovery, and 10 of 14 responders subsequently received an HCT.
• Overall, the field of and CAR T-cell therapy in particular, is moving in exciting directions and careful consideration of the mechanisms and risks of GVHD will be important to safely expand access to CAR T cells to patients who otherwise have limited therapeutic options available.

*Chin KK, Kim HT, Inyang EA, and et al. Ibrutinib in Steroid-Refractory Chronic Graft-versus-Host Disease, a Single-Center Experience. Transplantation and Cellular Therapy. 2021; 27:990.e1-990.e7. https://pubmed.ncbi.nlm.nih.gov/34481113

• Single-center, retrospective study of 53 HCT patients with steroid-refractory (SR) cGVHD treated with ibrutinib between September 2017 to December 2020 characterizing ibrutinib utilization, as well as associated patient outcomes, in the post-approval time period. Median follow-up after start of ibrutinib was 26.3 months.
• Baseline characteristics: median age, 56.5 years; 49% female; NMA conditioning (74%); MUD (74%); PB stem-cell source (94%); most common GVHD px was tacrolimus/MTX (38%), tacrolimus/sirolimus (34%), and tacrolimus/sirolimus/MTX (23%); median Karnofsky performance status 80; and 57% had prior aGVHD.
• Primary endpoints: 2- year FFS after ibrutinib initiation was 9% (95% CI, 2.6%-20%) and median FFS was 4.5 months (95% CI 2.8-7.1). At time of this report, 11 patients remained on ibrutinib.
• Secondary outcomes: 12% had CR or PR in cGVHD; 64% had SD; and 13% had PD.
  • Ibrutinib was associated with no reduction in corticosteroid dose (mean difference, 0.00; P=0.98)
  • Most frequently used non-corticosteroid therapy after ibrutinib was ruxolitinib (33%)
• Adverse events: most common reasons for treatment discontinuation were infection (lung, skin, enterocolitis; n=6), bleeding/bruising (hematoma, epistaxis, GI bleed; n=5), and muscle aches (n=2).
• The authors concluded that in a real-world setting, ibrutnib is associated with a modest response rate and FFS and its use in a narrower, more targeted patient population may be indicated.

Infectious Disease

**Ali H, Ngo D, Aribi A, et al. Safety and tolerability of SARS-CoV2 emergency-use authorized vaccines for allogeneic hematopoietic stem cell transplant recipients. Transplant Cell Ther. 2021;27:938.e1-6. https://pubmed.ncbi.nlm.nih.gov/34274492

• Retrospective, single-center review of HCT patients who received at least one dose of EUA vaccine (Pfizer or Moderna) to describe safety and tolerability, impact on GVHD, and incidence of SARS-CoV2 positivity. 113 patients were included, of which 8 did not have a second dose of vaccine documented.
• 43.4% of patients received the Pfizer vaccine and 56.5% received the Moderna vaccine. Median time to vaccination was 588 days post-HCT. 65% of patients were on immunosuppressants at the time of first dose, with 13.3% on a steroid at a median dose of 5 mg/day. 4 patients had a history of SARS-CoV2 positivity prior to vaccination.
• Only 36 patients responded to the survey to assess ADEs and 16 physicians documented patientreported ADEs. Of those, 2% developed a fever, 7.7% myalgias/arthralgias, 15.4% fatigue, and 15.4% other symptoms (nausea, vomiting, diarrhea, headache, rash) after the first dose. After 8 the second dose – 14.6% myalgias/arthralgias, 29.2% fatigue, and 16.7% other symptoms. Upon clinical laboratory assessment, 18.2% of patients developed hepatic impairment, 13.3% neutropenia, 11.5% thrombocytopenia, 8.8% lymphopenia, 4.4% eosinophilia.
• Baseline cGVHD was present in 40% of patients, with new cGVHD developing in 9.7% of patients after the vaccine and worsening of cGVHD in 3.5%
• Authors conclude that the SARS-CoV2 EUA vaccines are well-tolerated in the HCT patient population

**Yong MK, Shigle TL, Kim YJ, and et al. American Society for Transplantation and Cellular Therapy Series: #4-Cytomegalovirsu treatment and management of resistant or refractory infections after hematopoietic cell transplantation. Transplantation and Cellular Therapy. 2021; 27:957-967. https://pubmed.ncbi.nlm.nih.gov/34560310

• The Practice Guidelines Committee of the American Society of Transplantation and Cellular Therapy (ASTCT) partnered with its Transpl. Infect. Dis. Special Interest Group (TID-SIG) to update its 2009 compendium-style infectious disease guidelines for HCT.
• Series #4 is focused on the management and treatment of refractory and relapsed CMV infections. There are total of 24 FAQs that are addressed and answered within this practice guideline ranging from the definition of refractory/relapsed CMV infections, risk factors, diagnostic criteria, CMV complications, treatment, and future therapies in development. Highlights below:
  • FAQ4: When is the highest risk for developing resistant and refractory CMV infection and disease after HCT?
    • Resistant CMV typically occurs more than 2-4 months after infection
    • It is uncommon during the first 6 weeks of HCT in patients not previously exposed to anti-CMV medication
  • Plasma viral loads ≥1000 IU/ml are recommended for genotype testing (when assessing for CMV resistance)
    • In the setting of letermovir primary prophylaxis, consultation with an infectious disease specialist is recommended for guidance on resistance testing when CMV DNAemia <1000 IU/m
    • Table 5: highlights clinically relevant mutations conferring resistance to current antivirals (e.g., L56, UL89, UL51 conferring resistance to letermovir)

Abbreviations:

ADE: adverse drug event

aGVHD: acute graft-versus-host disease

allo HCT: allogeneic hematopoietic cell transplantation

AML: acute myeloid leukemia

ATG: anti-thymocyte globulin Axi-cel: axicabtagene ciloleucel

B-NHL: B-cell non-Hodgkin lymphoma

BEAM: carmustine, etoposide, cytarabine, melphalan

BM: bone marrow

CAR-T: chimeric antigen receptor T-cell

cGVHD: chronic graft-versus-host disease

CIBMTR: Center for International Blood and Marrow Transplant Research

CMV: cytomegalovirus

CNI: calcineurin inhibitor

CR: complete response

CRS: cytokine release syndrome

DFS: disease-free survival

EUA: emergency use authorization

FFS: failure-free survival

FL: follicular lymphoma

G-CSF: granulocyte colony stimulating factor

GRFS: GVHD-free, relapse-free survival

GVHD: graft-versus-host disease

HCT: hematopoietic cell transplantation

HMA: hypomethylating agent

MAC: myeloablative conditioning

MDS: myelodysplastic syndrome

MMUD: mismatched unrelated donor

MSD: matched sibling donor

MTX: methotrexate

MUD: matched unrelated donor

MZL: marginal zone lymphoma

NHL: non-Hodgkin lymphoma

NMA: non-myleoablative

NRM: non-relapse mortality

ORR: overall response rate

OS: overall survival

PBSC: peripheral blood stem cell

PD: progressive disease

PFS: progression-free survival

RIC: reduced intensity conditioning

SD: stable disease

ASTCT Pharmacy SIG Research Working Committee:

Andrew Lin, Arpita Gandhi, Kelly Gaffney, Binni Kunvarjee, Jennifer Collins, Jitesh Kawedia, Dennis Marjoncu, Jonathan Ptachcinski, Julianna Roddy, Lily Yan, Monank Patel, Katie Gatwood

Tags: SIG, Literature, patient care, transplantation, Patients, Cellular therapy, Pharmacy, Research, Update, Information, articles, published, Thymoglobulin, GCFS