01.04.21

Pharmacy SIG Literature Update: A Novel Risk Assessment Tool for alloHCT in the Elderly and More

In this month’s Pharmacy SIG Literature Update: A novel risk assessment tool for alloHCT in elderly patients, utility of azacitidine maintenance post-alloHCT, the impact of antibiotic use on GVHD, 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

*Ali N, Tomlinson B, Metheny L, et al. Conditioning regimen intensity and low-dose azacitidine maintenance after allogeneic hematopoietic cell transplantation for acute myeloid leukemia. Leuk Lymphoma. 2020 Dec;61(12):2839-2849. https://pubmed.ncbi.nlm.nih.gov/32650686/

  • Retrospective, observational, comparative study at two centers evaluating the impact of azacitidine (AZA) maintenance therapy (n=59) in adults with AML/MDS undergoing alloHCT vs those that do not receive AZA maintenance therapy (historical control arm; n=90)
  • Median age at diagnosis in both arms was around 60 years. Notable differences in demographics includes more patients with FLT3 mutation in the control group (19% vs 5%) compared with AZA maintenance arm.
  • At median follow up of 30.2 months, AZA maintenance was associated with significantly improved EFS (0.019) and OS (p = 0.011). In subgroup analysis, groups most likely to benefit from AZA maintenance included patients younger than 65 years, male gender, low HCT-CI and early disease.
  • In multivariable regression analysis, AZA maintenance was independently associated with significantly improved EFS (HR: 0.52, 95% CI: 0.31 – 0.9, p=0.019) and OS (HR: 0.47, 95% CI: 0.26 – 0.84, p=0.011). Also, patients receiving RIC alloHCT had significantly improved EFS (p = 0.004) and OS (p = 0.004) compared to those that received MAC alloHCT.
  • Authors concluded that AZA maintenance therapy may be associated with an overall beneficial effect following RIC alloHCT, however randomized control trials are warranted to confirm these findings

*Polverelli N, Tura P, Battipaglia G, et al. Multidimensional geriatric assessment for elderly hematological patients (≥60 years) submitted to allogeneic stem cell transplantation. A French-Italian 10-year experience on 228 patients. Bone Marrow Transplant. 2020; 55(12):2224-2233.  https://pubmed.ncbi.nlm.nih.gov/32398784/

  • Evaluation of the feasibility and efficacy of a multidimensional geriatric assessment, the Fondazione Italiana Linfomi (FIL) score, on a cohort of 228 patients >60 years old submitted to alloHCT in Italy and France from 2008 to 2018
  • Based on FIL score, available in 215 patients, 125 (58%) patients were classified as "fit" and 90 (42%) as "unfit/frail." The HCT-CI was measured in 222 patients (97%): 71 (32%) patients scored HCT-CI 0, 75 (34%) patients scored 1-2, and 76 (34%) scored ≥3.
  • A total of 121 (53%) patients died after a median follow-up of 36 months. The FIL score was found to highly predict survival, due to an excess of NRM in unfit/frail group and confirmed its independent prognostic role on OS (HR: 0.37; 95% CI: 0.25-0.55; p<0.0001).
  • The HCI-CI failed in alloHCT outcome prediction (HR: 1.06; 95% CI: 0.96-1.16; p=0.27).
  • Authors conclude that a comprehensive geriatric assessment with FIL score seems to add significant prognostic information in elderly patients prior to alloHCT and that the pre-HCT adoption of this easy-to-use tool could aid in patient selection and management

*Montes de Oca C, Castagna L, De Philippis C, et al. Nonmyeloablative Conditioning Regimen before T-Cell Replete Haploidentical Transplantation with Post-Transplant Cyclophosphamide for Advanced Hodgkin and Non-Hodgkin Lymphomas. Biol Blood Marrow Transplant. 2020;26(12):2299-2305. https://pubmed.ncbi.nlm.nih.gov/32822845/

  • Retrospective analysis of toxicity and efficacy of haploHCT using NMA conditioning and PTCy in patients with advanced lymphoma (NHL, n = 73; HL, n = 74)
  • All patients received NMA regimen of cyclophosphamide 14.5 mg/kg (days -6 and -5), fludarabine 30 mg/m2 (days -6 to -2), and low-dose TBI (2 Gy) on day -1. GVHD prophylaxis was PTCy 50 mg/kg (days +3 and +4), CSA, and MMF starting on day +5.
  • Median time to follow-up was 39 months (range, 6-114 months). Cumulative 6-month incidence of grade 2-4 aGVHD was 30% (95% CI: 23-38%), and cumulative 2-year incidence of overall cGVHD was 13% (95% CI: 8-20%). Cumulative 2-year incidence of disease relapse was 19% (95% CI: 14-27%).
  • Two-year PFS, OS, and GRFS were 66% (95% CI: 59-75%), 73% (95% CI: 66-81%), and 56% (95% CI, 48-65%), respectively.
  • Authors conclude that in patients with aggressive lymphoma, haploHCT with PTCy may be a valuable curative option with low toxicity and effective disease control and warrants further study

Autologous Transplant

**Jasielec J, Kubicki T, Raje N, et al. Carfilzomib, lenalidomide, and dexamethasone plus transplant in newly diagnosed multiple myeloma. Blood. 2020 Nov 26;136(22):2513-2523. https://pubmed.ncbi.nlm.nih.gov/32735641/

  • A multi-center, open-label, single-arm, phase 2 study evaluating the incorporation of autoHCT into carfilzomib-lendalidomide-dexamethasone (KRd) regimen in patients (n=76) with newly diagnosed multiple myeloma, 36% with high-risk cytogenetic abnormalities
  • Patients received four cycles (28-day cycle) of KRd induction followed by autoHCT, 4 cycles of KRd consolidation and then 10 cycles of KRd maintenance, for a total of 18 cycles of KRd. This was followed by single-agent lenalidomide maintenance therapy until disease progression or unacceptable toxicity.
  • The primary endpoint of rate of sCR after 8 cycles of KRd with autoHCT was 60%. Median time to sCR was 11.9 months (0.9 – 26. 4 months) and sCR improved to 76% after extended KRd maintenance.
  • For patients with high-risk cytogenetics, MRD negativity was associated with improved PFS compared with MRD-positive/MRD unknown status (p=0.04) although this was not the case for OS. 
  • Cytopenias and infections were the most common grade 3 and 4 events.
  • Authors concluded that patients treated with extended KRd with autoHCT achieve high rates of sCR and MRD-negative disease with prolonged PFS and OS. There are numerous other studies currently investigating the role of extended KRd with and without autoHCT in a randomized fashion.

**Martinez C, Boumendil A, Romejko-Jarosinsk J, et al. Second autologous stem cell transplantation for relapsed/refractory Hodgkin lymphoma after a previous autograft: a study of the lymphoma working party of the EBMT. Leuk lymphoma. 2020(61);12: 2915-2922. https://pubmed.ncbi.nlm.nih.gov/32654552/

  • This was a retrospective analysis of EBMT registry data evaluating safety and efficacy of second autoHCT (ASCT2) in patients with relapsed/refractory HL after first ASCT (ASCT1) (n=56)
  • 75% of patients included had received <3 lines of chemotherapy prior to ASCT1. Of note, no patient was treated with brentuximab and only one patient received ICI prior to ASCT1. At the time of second ASCT, 36% of the patients were in CR and 33% in PR.
  • The 4-year cumulative incidence of NRM and disease relapse/progression was 5% and 67%, respectively. 4-year OS and PFS was 62% and 28%, respectively. Having a chemo-sensitive disease at ASCT2 was associated with improved 4-year PFS and OS (31% vs. 12%, p=0.015; 72% vs 29%, respectively).
  • Relapse of HL within 12 months of ASCT1 was associated with a worse 4-yr OS (35% vs 76%, p=0.01) and PFS (19% vs 29%, p=0.059).
  • Authors concluded that ASCT2 is a safe and effective option for patients with late relapse after first ASCT1 and with chemo-sensitive disease who are not eligible for alloHCT

*Monahan K, Kleman A, Thapa B, et al. Propylene Glycol-Free Melphalan versus PG-Melphalan as Conditioning for Autologous Hematopoietic Cell Transplantation for Myeloma. Biol Blood Marrow Transplant. 2020;26(12):2229-2236. https://pubmed.ncbi.nlm.nih.gov/32920204/

  • Retrospective single-center analysis of safety and tolerability in MM patients undergoing autoHCT using older propylene glycol melphalan (PG-Mel) vs newer propylene glycol-free (PGF-Mel) formulation between January 2015 and January 2018 (n=294). 162 patients received PG-Mel vs 132 received PGF-Mel.
  • Median age at HCT (65 vs 61.5; p=0.002), use of IMiD before HCT (93.9% vs 66%; p<0.001), and Karnofsky score ≤80 (49.7% vs 38.5%; p=0.06) were higher in PGF-Mel group vs PG-Mel group, respectively
  • PGF-Mel group was associated with faster neutrophil recovery (median 12 days vs 13 days; p<0.001), fewer grade 3-4 infections within 30 days of autoHCT (1.5% vs 8%; p=0.04), and a lower 30-day rehospitalization rate (6.8% vs 17.9%, p=0.04) using propensity-weighted analysis
  • No significant between-group differences were detected in mucositis, organ toxicity, myeloma response, or 100-day mortality
  • Results of this study suggest that PGF-Mel as autoHCT conditioning is safe and well-tolerated with similar toxicity profile as PG-Mel in MM patients with possible advantages of modestly improved neutrophil recovery, lower incidence of severe infections, and a lower rehospitalization rate

*Shouval R, Labopin M, Bomze D, et al. Risk stratification using FLT3 and NPM1 in acute myeloid leukemia patients autografted in first complete remission. Bone Marrow Transplant. 2020; 55(12): 2244–2253. https://pubmed.ncbi.nlm.nih.gov/32388535/

  • Retrospective evaluation of the role of FLT3-ITD and NPM1 in AML patients (n=405) receiving autoSCT in CR1 between 2000 and 2014, using data reported to the EBMT registry
  • Median follow-up was 5.5 years. FLT3-ITDneg/NPM1WT was the leading molecular subtype (50%), followed by FLT3-ITDneg/NPM1mut (30%).
  • In univariate analysis, molecular subtype was associated with LFS, OS, and RI (p<0.001). 5-year LFS was FLT3-ITDneg/NPM1mut: 62%, FLT3-ITDpos/NPM1mut: 38%, FLT3-ITDneg/NPM1WT: 32%, and FLT3-ITDpos/NPM1WT: 21%.
  • At 5-years, OS and RI in the FLT3-ITDneg/NPM1mut subtype were 74% and 35%, respectively. The corresponding OS and RI in other subtypes were below 48% and over 57%, respectively.
  • Authors conclude that AML patients with intermediate-risk cytogenetics and FLT3-ITDneg/NPM1mut experience favorable outcomes when undergoing autoHCT in CR1, suggesting that autoHCT is a valid post-transplant remission option

Graft-Versus-Host Disease

*Tanaka JS, Young RR, Heston SM, et al. Anaerobic antibiotics and the risk of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2020; 26:2053-60. https://pubmed.ncbi.nlm.nih.gov/32682948/

  • Single-center retrospective cohort study of pediatric and adult alloHCT recipients (n=1214) evaluating the association between antibiotic use and GVHD outcomes. Patients were included if they received antibiotics between 7 days pre- and 28 days post-HCT.
  • Two groups were compared: patients receiving anaerobic antibiotics (piperacillin-tazobactam or carbapenems, n=491) vs those receiving antibiotics with minimal anaerobic activity (cefepime, aztreonam, or ceftazidime, n=723).
  • The primary outcome of gut or liver aGVHD was significantly higher in patients receiving anaerobic antibiotics, 41% vs 31% (HR 1.26, p=0.02). Among secondary outcomes, 1-year aGVHD mortality was also increased, 11% vs 6% (HR 1.63, p=0.02) with anaerobic antibiotic use. There were no significant differences in skin aGVHD, cGVHD, or 5-year cGVHD mortality.
  • Anaerobic antibiotic use was associated with a drastic decline in Bifidobacteriales and Clostridiales species, known to produce the short-chain fatty acid butyrate. Butyrate is recognized for its role in maintenance of gut integrity and immune tolerance.
  • The authors conclude that anaerobic antibiotic used for empiric treatment of febrile neutropenia was associated with increased risk of aGVHD of the gut and liver and should be used with caution in this population

Supportive Care

*Imus PH, Tsai HL, DeZern AE, et al. Thrombotic Microangiopathy after Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis. Biol Blood Marrow Transplant. 2020;26(12):2306-2310. https://pubmed.ncbi.nlm.nih.gov/32961372/

  • Retrospective single-center analysis to assess incidence of ta-TMA in adults who received PTCy-based GVHD prophylaxis between January 2015 and August 2018 (n=678)
  • Median age was 58 years (range, 18-78 years) and 95% received NMA conditioning
  • Starting April 2016, monitored weekly LDH and haptoglobin measurements, then blood smears when both those 2 parameters were abnormal
  • One-year cumulative incidence of taTMA was 1.4% (95% CI: 0.5-2.3%) and were diagnosed median of 39 days after HCT (range, 6-363 days). 8 patients were taking tacrolimus at time of diagnosis, and 1 was not on any immunosuppression.
  • Eculizumab was given to 6 patients (0.9%), of whom 2 died and 4 recovered with resolution of end-organ dysfunction
  • Authors conclude that PTCy-based GVHD prophylaxis appears to be associated with a low incidence of severe taTMA although these results may be attributed to limited use of MAC regimens, low incidence of severe GVHD, and use of PTCy

Abbreviations:

aGVHD: acute graft-versus-host disease

alloHCT: allogeneic hematopoietic cell transplantation

AML: acute myeloid leukemia

autoHCT: autologous hematopoietic cell transplantation

cGVHD: chronic graft-versus-host disease

CSA: 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

HCT-CI: hematopoietic cell transplantation comorbidity index

HL: Hodgkin lymphoma

ICI: immune checkpoint inhibitor

IMiD: immunomodulatory agent

LFS: leukemia-free survival

MAC: myeloablative conditioning

MDS: myelodysplastic syndrome

MM: multiple myeloma

MMF: mycophenolate mofetil

MRD: minimal residual disease

NHL: non-Hodgkin lymphoma

NMA: non-myeloablative

NRM: non-relapse mortality

OS: overall survival

PFS: progression-free survival

PR: partial response

PTCy: post-transplant cyclophosphamide

RI: relapse incidence

RIC: reduced intensity conditioning

sCR: stringent complete response

ta-TMA: transplant-associated thrombotic microangiopathy

TBI: total body irradiation

TRM: transplant-related mortality

ASTCT Pharmacy SIG Research Working Committee:

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

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

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