In this month’s Pharmacy SIG Literature Update: Haploidentical transplantation in aplastic anemia, novel conditioning regimen and maintenance strategies for multiple myeloma, nilotinib for cGVHD, 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
*Novak P, Zabelina T, Wolschke C, et al. Allogeneic Stem Cell Transplantation for Patients with Lower-Risk Myelodysplastic Syndrome. Biol Blood Marrow Transplant. 2020;26(11):2047-2052. https://pubmed.ncbi.nlm.nih.gov/32717435/
- Retrospective, single center analysis of 60 patients with very low risk (n=2), low risk (n=30) or intermediate risk (n=28) MDS according to International Prognostic Scoring System (IPSS-R) who underwent alloHCT between 2000 and 2018
- Rates of grade 2-4 and grade 3-4 aGVHD were 32% and 7% respectively, resulting in TRM of 17% at 3 years (95% CI: 7-27%). Cumulative incidence of relapse at 5-years was 7% (95% CI: 0-17%) and not influenced by intensity of conditioning regimen.
- 5-year estimated OS was 79% (95% CI: 67-91%), and only significant factor for OS was HLA-matched donor vs HLA-mismatched donor (86% vs. 55%, p=0.008)
- Authors conclude that in patients with IPSS-R low or intermediate risk MDS and good performance status, alloHCT from a fully matched donor results in significantly improved OS and a low risk of relapse
**Lee SE, Min GJ, Park SS, et al. Outcomes of haploidentical stem cell transplantation using total body irradiation (600 cGy) and fludarabine with antithymocyte globulin in adult patients with severe aplastic anemia: a prospective phase II study. Biol Blood Marrow Transplant. 2020;26: 1906-1914. https://pubmed.ncbi.nlm.nih.gov/32634577/
- The optimal conditioning regimen and graft strategy in adults with acquired SAA is unknown. This prospective, phase II trial was designed to verify the feasibility of a conditioning regimen consisting of rabbit ATG 5 mg/kg with 600 cGy of fractionated TBI and fludarabine 150 mg/m2 for a haploHCT in 47 adult patients with SAA.
- Median age at time of transplant was 36 years. All patients achieved primary engraftment. The incidence of ≥grade 2 GVHD was reported as 27.7% at 100 days and 13.5% at 3 years.
- Three-year OS was 91%; FFS was 88.6%. Three-year GFFS was reported as 71.5%. A high OS rate of 89.1% and 65.8% at 1 and 5 years respectively was reported. Rates of GVHD and NRM were low at both 1 and 5 years. The primary cause of mortality was disease relapse, with a cumulative incidence of 23.9% at one year and 45.7% at 5-years.
- The authors conclude the use of a haploHCT with a conditioning regimen consisting of fludarabine, TBI, and ATG is an effective option for patients with SAA when a fully matched donor is not available
**DeZern AE, Elmariah H, Zahurak M, et al. Shortened-Duration Immunosuppressive Therapy after Nonmyeloablative, Related HLA-Haploidentical or Unrelated Peripheral Blood Grafts and Post-Transplantation Cyclophosphamide. Biol Blood Marrow Transplant. 2020;26(11):2075-2081. https://pubmed.ncbi.nlm.nih.gov/32818556/
- Prospective, single center trial of stopping immunosuppression at day 90 (n=57) or day 60 (n=60) after NMA PBSCT with PTCy. Median patient age, disease risk index distribution, degree of HLA mismatch, and graft dose were similar between cohorts.
- Shortened immunosuppression was feasible in 75 patients (64%) overall, whereas ineligibility was most commonly due to GVHD (n = 17), early relapse (n = 11), NRM (n = 7), patient/physician preference (n = 4) or graft failure (n = 3). Graft failure rate was 2.6% for all patients. 2-year OS was 67% for both cohorts, 2-year PFS was 47% (95% CI: 36-62%) for D90 and 52% (95% CI: 40-66%) for D60 cohort, and 2-year GRFS was < 35% for both cohorts.
- After immunosuppression cessation, median time to diagnosis of grade 2-4 aGVHD was 21 days in D90 cohort and 32 days in D60 cohort, and approximately 33% of these patients resumed immunosuppression. Cumulative incidence of grade 3-4 aGVHD at 180 days was 2% (95% CI: -2 to 5%) in D90 and 7% (95% CI: 0-13) in D60 cohort.
- Authors conclude that although reduced-duration immunosuppression in patients undergoing NMA PBSCT with PTCy is feasible and has an acceptable safety profile, further multicenter trials are needed to establish this as standard of care
*Song GY, Jung SH, Lee JJ, et al. Intravenous busulfan and melphalan versus high-dose melphalan as a conditioning regimen for early autologous stem cell transplantation in patients with multiple myeloma: a propensity score-matched analysis. Leuk Lymphoma. 2020;61(11): 2714-21. https://pubmed.ncbi.nlm.nih.gov/32580672/
- A retrospective, propensity score-matched analysis comparing efficacy and safety of busulfan plus melphalan (BUMEL) and high-dose melphalan (HDMEL) as conditioning therapies for autoHCT in patients with MM, who received thalidomide-based induction therapy
- After a median follow up of 37.3 months in the BUMEL group and 50.8 months in the HDMEL group, median PFS was 32.9 months and 25.2 months, respectively (p=0.995). No differences were found between groups for the following outcomes: median OS, PFS or OS according to cytogenetic risk.
- Any grade of infection was more frequently reported in BUMEL group compared with HDMEL group (69.8 vs. 34.2%; p=0.001). VOD occurred in 3 patients (3.9%) in BUMEL group; all of whom were successfully treated with supportive care measures.
- Numerous limitations worth noting: thalidomide based induction and maintenance therapy; different time frames compared for both cohorts; pharmacokinetics not performed for busulfan; MRD assessment not performed
- Authors concluded that BUMEL is an effective alternative conditioning therapy prior to autoHCT in patients with MM, however patients must be monitored closely for toxicities
*Goldschmidt H, Dimopoulos MA, Rajkumar V, et al. Deepening responses associated with improved progression-free survival with ixazomib versus placebo as posttransplant maintenance in multiple myeloma. Leukemia. 2020;34:3019-27. https://pubmed.ncbi.nlm.nih.gov/32327729/
- Comprehensive analysis of TOURMALINE-MM3 study, a phase 3, double-blind, placebo controlled study investigating use of oral proteasome inhibitor, ixazomib, vs placebo as post-autoHCT maintenance therapy in newly diagnosed MM patients
- In patients who had a response of VGPR or PR at study entry; PFS was longer in the ixazomib vs placebo group (26.2 versus 18.5 months; HR 0.636; p<0.001)
- Confirmed deepening of responses was seen in 46% of patients in the ixazomib group vs 32% of patients in the placebo group (RR: 1.41, p=0.004). Median time to best confirmed deepened response was shorter with ixazomib versus placebo (19.9 vs. 30.8 months).
- PFS was prolonged among those who had deepening of responses versus those who had no improvement in their response, regardless of treatment arm; median PFS not reached versus 15.9 months in ixazomib and placebo arm, respectively (HR 0.252, p<0.001)
- Caution must be exercised in extrapolating results of this analysis since comparative arm was placebo rather than lenalidomide, which is the current standard of care
- Authors concluded that post autoHCT maintenance with ixazomib resulted in a significantly higher rate of deepening of response compared with placebo and patients who achieved deepening of response had substantially longer PFS than those who did not
*Olivieri A, Mancini G, Olivieri J, et al. Nilotinib in steroid-refractory cGVHD: prospective parallel evaluation of response, according to NIH criteria and exploratory response criteria (GITMO criteria). Bone Marrow Transplantation. 2020; 55(11):2077-2086. https://pubmed.ncbi.nlm.nih.gov/32332918/
- Phase I/II study evaluating nilotinib safety and pharmacokinetics in adult patients with SR cGVHD (n = 22). Secondary objectives included assessment of ORR (NIH criteria and GITMO criteria). After dose escalation up to 600 mg/day, maximum tolerated dose was not reached.
- The ORR at 6 months based on 2005 NIH, 2014 NIH, and GITMO criteria, were 27.8%, 22.2%, and 55.6%, respectively. 2-year OS was 75%, and FFS, according to NIH and GITMO criteria, was 30% and 25%, respectively.
- Major toxicities included asthenia, headache, nausea, pruritus, cramps, and mild anemia
- Authors conclude that the safety profile of nilotinib and long-term outcomes demonstrated makes nilotinib an attractive option in SR cGVHD, and warrants further investigation for use in this indication
*Bondeelle L, Chevret S, Hurabielle C, et al. Effect of Ruxolitinib on Lung Function after Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2020;26(11):2115-2120. https://pubmed.ncbi.nlm.nih.gov/32738501/
- Retrospective analysis of effect of ruxolitinib on lung function in 70 patients diagnosed with sclerotic-type skin cGVHD. Thirty-six patients (51%) received ruxolitinib vs 34 patients (49%) were unexposed. 1:1 matching used to match exposure groups based on age, myeloablative conditioning, TBI, BOS, FEV1, FVC, tobacco use and time from HCT.
- Median duration of follow up in 46 matched patients was 58 months (32-84 months)
- In matched sample, ten patients were diagnosed with restrictive lung disease (6 exposed, 4 unexposed, p=0.21), and 13 patients were diagnosed with BOS (8 exposed, 5 unexposed, p=0.26)
- Since pre-HCT PFT measurement, FEV1 decreased significantly over time independent of exposure to ruxolitinib (p<0.001). FEV1 trajectory was similar in exposed patients and unexposed patients (p=0.11).
- Authors conclude that ruxolitinib administration did not demonstrate any improvement in the course of respiratory function in alloHCT recipients with sclerotic-type skin GVHD
*Imlay H, Krantz EM, Stohs EJ, et al. Reported Beta-lactam and other antibiotic allergies in solid organ and hematopoietic cell transplant recipients. Clin Infect Dis. 2020;71(7):1587-94. https://pubmed.ncbi.nlm.nih.gov/31621829/
- Retrospective review of 2153 SOT (65%) and HCT (35%) patients to characterize antibiotic allergy reporting at time of transplantation. At least one antibiotic allergy was reported in 29% of all patients and BLAs were reported in 16% of the total population (12% penicillin, 5% cephalosporin, and 1% carbapenem).
- Among the 393 patients with BLA, only 11% had an allergy evaluation prior to transplantation. Among these, 58% had all BLA removed from their chart.
- Patients with BLA had significantly higher use of vancomycin and clindamycin, and within the SOT population higher use of fluoroquinolones for treatment indications. Mortality was significantly higher in univariate analysis but was not significant in multivariable analysis (HR 1.52, p=0.08).
- The authors conclude that transplant candidates have a high prevalence of reported antibiotic allergies that is associated with differences in post-transplant prescribing, highlighting the benefits for allergy evaluations before transplantation
**Di Renzo N, Musso M, Scime R, et al. Efficacy and safety of multiple doses of NEPA without dexamethasone in preventing nausea and vomiting induced by multiple-day and high-dose chemotherapy in patients with non-Hodgkin’s lymphoma undergoing autologous hematopoietic stem cell transplantation: a phase IIa, multicenter study. Bone Marrow Transplantation. 2020;55(11):2114-2120. https://pubmed.ncbi.nlm.nih.gov/32346078/
- A multicenter, open-label and phase IIa study evaluating the efficacy of multiple doses of NEPA (netupitant/palonosetron) given as an every-other-day regimen without dexamethasone in preventing CINV in 70 adult patients with R/R NHL, autoHCT
- The CR values were 87.1% (primary endpoint, overall phase: days 1-8), 88.6% (acute phase: days 1-6), and 98.6% (delayed phase: days 7-8), while complete control (CR with no more than mild nausea) was 85.7% (overall phase), 88.6% (acute phase), and 95.7% (delayed phase)
- Moderate and severe episodes of nausea were reported by less than 10% of patients in the overall phase and less than 5% in both the acute and delayed phases
- NEPA was well tolerated with only one adverse event of constipation
- Authors conclude that this study demonstrated that multiple alternate dosing of NEPA without the addition of dexamethasone is highly effective and tolerable for preventing CINV in R/R NHL undergoing autoHCT
*Bar M, Ott SM, Lewiecki EM, Sarafoglou K, et al. Bone health management after hematopoietic cell transplantation: an expert panel opinion from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. 2020;26:1784-1802. https://pubmed.ncbi.nlm.nih.gov/32653624/
- Bone health disturbances, including decreased bone mineral density and avascular necrosis, are common after hematopoietic cell transplant due to various causes. This expert panel uses the data available to answer frequently asked questions on how to manage patient bone health in the peri-transplant period.
- The risk factors, pre-transplant evaluation, post-transplant monitoring, and lifestyle and pharmacological recommendations for bone health disturbances are discussed
- The authors acknowledge the limitations of available evidence, clinical judgement and sound medical practice should dictate each patient’s individual care
aGVHD: acute graft-versus-host disease
alloHCT: allogeneic hematopoietic cell transplantation
ATG: antithymocyte globulins
autoHCT: autologous hematopoietic cell transplantation
BLA: Beta-lactam allergies
BOS: bronchiolitis obliterans syndrome
cGVHD: chronic graft-versus-host disease
CINV: chemotherapy-induced nausea and vomiting
CR: complete response
FEV1: forced expiratory volume
FFS: failure-free survival
FVC: forced vital capacity
GFFS: GVHD-free, failure-free survival
GITMO: Gruppo Italiano Trapianto di Midollo Osseo (Italian Group for Blood and Marrow Transplantation)
GRFS: GVHD-free, relapse-free survival
GVHD: graft-versus-host disease
haploHCT: haploidentical hematopoietic cell transplantation
HCT: hematopoietic cell transplantation
HLA: human leukocyte antigen
IPSS-R: International Prognostic Scoring System
MDS: myelodysplastic syndrome
MM: multiple myeloma
MRD: minimal residual disease
NIH: National Institutes of Health
NRM: non-relapse mortality
ORR: overall response rate
OS: overall survival
PBSC: peripheral blood stem cells
PFS: progression-free survival
PFTs: pulmonary function tests
PR: partial response
PTCy: post-transplant cyclophosphamide
RIC: reduced intensity conditioning
R/R NHL: relapsed-refractory aggressive non-Hodgkin's lymphoma
SAA: severe aplastic anemia
SOT: solid organ transplantation
TBI: total body irradiation
TRM: transplant-related mortality
VGPR: very good partial response
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