In this month's Pharmacy SIG literature update: Third auto, K-Mel conditioning and transplant in the setting renal impairment for patients with multiple myeloma. Plus, how does ideal versus total body weight dosing impact busulfan PK? As well as real-world use of defibrotide, reviews of EBV/PTLD 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
New Drug Highlight
FDA Approves Ivosidenib for Relapsed or Refractory Acute Myeloid Leukemia
**Costa LJ, Landau HJ, Chhabra S, et al. Phase 1/2 Trial of Carfilzomib Plus High-Dose Melphalan Preparative Regimen for Salvage Autologous Hematopoietic Cell Transplantation Followed by Maintenance Carfilzomib in Patients with Relapsed/Refractory Multiple Myeloma. Biol Blood Marrow Transplant. 2018;24: 1379-1385. https://www.ncbi.nlm.nih.gov/pubmed/?term=29410301.
- Phase 1/2 trial investigating safety and activity of carfilzomib (K) on days -3/-2 in combination with melphalan 200 mg/m2 (MEL200) on day -2 in patients with relapsed MM undergoing auto-HCT (phases 1 and 2).
- During phase 1 (n = 15), the maximum tolerated dose of K in combination with MEL200 was not reached, so the maximum tested dose of 27 mg/m2 (on day -3) and 56 mg/m2 (on day -2) was used in phase 2. Patients without progression received 12 cycles of K maintenance at 36 mg/m2days 1, 8, and 15 (schedule A) or days 1, 2, 15, and 16 (schedule B). Melphalan at dose of 200 mg/m2 was administered on day -2, at 60 to 120 minutes after the end of infusion of carfilzomib.
- The rate of VGPR after K-MEL therapy (n = 44) was 59.2%, compared with 13.7% before K-MEL therapy. Among patients starting maintenance therapy (n = 27), 12-month PFS was 66.7% and 12-month OS was 88.1%. There was no strong patient preference for either schedule.
- All patients who received K-MEL conditioning and underwent auto-HCT achieved neutrophil and platelet engraftment after a median of 10 days (range, 8 to 16 days) and 15 days (range, 9 to 24 days), respectively. The most common grade 3-4 adverse events were infection (15%), acute kidney injury (11%), and neutropenia (11%).
- K-MEL as an auto-HCT preparative regimen for relapsed MM is effective and was well tolerated.
**Garderet L, Iacobelli S, Koster L, et al. Outcome of a Salvage Third Autologous Stem Cell Transplantation in Multiple Myeloma. Biol Blood Marrow Transplant. 2018;24:1372-1378. https://www.ncbi.nlm.nih.gov/pubmed/29408334.
- Analysis of EBMT data of 570 patients undergoing a third auto-HCT between 1997 and 2010
- 482 tandem auto-HCT and a third auto-HCT at first relapse (AARA group)
- 88 patients upfront auto-HCT with second and third transplantations after subsequent relapses (ARARA group)
- Engraftment was similar in the 2 groups (96% and 95%; P = .352). D+100 NRM in the 2 groups was 4% (AARA) and 7% (ARARA) (96% and 95%; P = 0.352). Median PFS was 13 and 8 months, and median OS was 33 and 15 months. The best response after the third auto-HCT was superior in the AARA group compared with the ARARA group: CR, 34% VS 12%; VGPR or PR, 59% VS 74%; MR or SD, 3% vs 11%; disease progression, 4% vs 3% (P<0.001)
- Multivariate analysis of the AARA group showed favorable prognostic factor was an RFI after second auto-HCT of ≥18 months. Progressive disease and a KPS score of <70 at third auto-HCT were unfavorable factors.
- A salvage third auto-HCT can be considered for patients with relapsed myeloma, particularly for those with a long duration of response and chemosensitive disease at the time of transplantation.
**Augeul-Meunier K, Chretien ML, Stoppa AM, et al. Extending autologous transplantation as first line therapy in multiple myeloma patients with severe renal impairment: a retrospective study by the SFGM-TC. Bone Marrow Transplant. 2018;53:749-755. http://www.ncbi.nlm.nih.gov/pubmed/29523884
- Retrospective, multicenter database assessment of patients with advanced renal failure (dialysis dependent or CrCl < 30 mL/min) at time of auto-HCT from January 2002 to November 2012. Patients received single or tandem auto-HCT as a first or second line therapy for myeloma. All patients received melphalan conditioning, but melphalan dosing was variable among centers according to physician choice.
- Outcomes assessed were time to neutrophil engraftment (ANC >500 for two consecutive days), platelet engraftment (20 x109/L for 2 consecutive days without a platelet transfusion during a 5-day period), disease response, NRM, OS, and PFS.
- 55 myeloma patients with renal failure were included in this assessment. Median neutrophil recovery was 12 days (range: 10-34) and median platelet recovery was 16 days (range: 7-331). Response to auto-HCT was at least a VGPR in 58% of patients and 96% achieved at least a PR if they also received bortezomib-based induction. Median OS was 76 months and median PFS was 55 months, which is similar to MM patients without renal failure.
- In a multivariate analysis, melphalan dosing of 140 mg/m2 was correlated with better PFS (18 months, p=0.005). Toxicities in the renal failure population included febrile neutropenia (75%) and grade 3-4 mucositis (34%). Three patients experienced TRM (aspergillus sepsis, cerebral bleeding, and severe denutrition).
- The authors concluded auto-HCT conditioning with 140mg/m2 melphalan is a beneficial procedure for myeloma patients with renal failure.
**Griffin SP, Wheeler SE, Wiggins LE, et al. Pharmacokinetic and clinical outcomes when ideal body weight is used to dose busulfan in obese hematopoietic stem cell transplant recipients. Bone Marrow Transplant. 2018 June 08. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/29884851
- Retrospective, single-center evaluation of the pharmacokinetic impact of using IBW as the initial dosing weight in obese as compared to non-obese transplant recipients. Patients were divided into obese (>130% IBW) and non-obese (100-130% IBW) and all patients were included if they received 16 doses of busulfan (0.8 mg/kg IBW) intravenously every 6 hours. Pharmacokinetic samples were drawn after the first dose and dosing was adjusted to achieve the target Css of 600-900 ng/mL.
- Primary objective was to assess the pharmacokinetic impact of using IBW as the initial dosing weight in obese as compared to non-obese transplant recipients. Secondary objectives were to describe alternative dosing weights, OS, PFS, and rates of toxicities.
- 63 obese patients and 82 non-obese patients were included in the evaluation. The Css was 779.3 ng/mL in the non-obese and 673.7 ng/mL in the obese cohorts (p<0.001) and the proportion of levels below goal and at goal were significantly different between cohorts. There was no difference in OS (p=0.18) but there was a difference in PFS (1078 vs 500 days, p=0.045) in the non-obese vs obese cohorts.
- Toxicity rates were similar between cohorts with no significant difference seen in rates and severity of seizures or VOD. There was an increase in grade of mucositis in the non-obese group which was statistically significant (p=0.039).
- The authors concluded that the use of IBW to dose busulfan resulted in lower steady-state concentrations, a larger proportion of subtherapeutic concentrations, and worse PFS in obese patients.
*Kernan NA, Grupp S, Smith AR, et al. Final results from a defibrotide treatment-IND study for patients with hepato veno-occlusive disease/sinusoidal obstruction syndrome. British Journal of Haematology. 2018; 181:816-827. https://www.ncbi.nlm.nih.gov/pubmed/29767845
- Open label, single-arm treatment protocol (T-IND: NCT00628498) was designed to provide expanded-access to defibrotide and access safety and survival.
- Patients were included if they had VOD/SOS, diagnosed by the Baltimore criteria by day +35 post-HCT, or by a biopsy, as well as MOD (renal or pulmonary dysfunction) by day +45 post-HCT; patients were excluded for hemodynamic instability or acute bleeding.
- Defibrotide 25 mg/kg/day in 4 divided doses was recommended to be given for ≥ 21 days
- The estimated day +100 survival for 1000 patients with documented defibrotide treatment was 58.9% (95% CI, 55.7-61.9%).
- Day +100 survival in pediatric patients was 67.9% and 47.1% in adults; all patient subgroups without MOD had higher day +100 survival; earlier defibrotide initiation was also associated with higher day +100 survival.
- The study also reports late-onset VOD/SOS occurring in 26.4% of patients treated with defibrotide and an estimated day +100 survival of 60.4% in pediatrics and 48.7% in adults (similar to the classic onset group)
- The study provides real-world data for defibrotide use in a large patient population. The estimated survival and safety profile of defibrotide appear comparable to previous reports.
*Picod A, Bonnin A, Battipaglia G, et al. Defibrotide for Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease Prophylaxis in High-Risk Adult Patients: A Single-Center Experience Study. Biol Bone Marrow Transplant. 2018;24:1471-1475. https://www.ncbi.nlm.nih.gov/pubmed/29477779.
- Retrospective review of 63 high-risk of SOS/VOD patients who underwent an alloHCT with defibrotide in combination with UDCA prophylaxis between May 2012 and August 2016.
- Defibrotide was dosed at 25 mg/kg/day divided in 4 daily doses of 6.25 mg/kg from the start of the conditioning regimen to engraftment. Defibrotide therapy was stopped in case of severe bleeding or need for antithrombotic therapy. All patients received UDCA for SOS/VOD prophylaxis until day +90 after transplant.
- The median duration of defibrotide therapy was 23 days. Bleeding occurred in 14 patients (21.5%). Defibrotide prophylaxis was discontinued in 7 patients (10.8%): 4 cases (6.3%) due to bleeding and 3 cases (4.6%) because of the need for antithrombotic therapy.
- SOS/VOD occurred in 4 cases (6.3%) within 21 days after HCT in 2 cases and late-onset SOS/VOD in the other 2 cases. SOS/VOD was moderate in 1 case, very severe in 3 cases, with 2 deaths related to SOS/VOD.
- Rates of 2-year OS, PFS, incidence of relapse, and NRM were 56.5%, 49%, 28.7%, and 22.3%, respectively.
- Defibrotide seems effective in preventing SOS and prophylaxis might reduce the incidence of other early complications with acceptable bleeding rates.
*Jain T, Kosiorek HE, Grys TE, et al. Single dose versus multiple doses of rituximab for preemptive therapy of Epstein–Barr virus reactivation after hematopoietic cell transplantation. Leuk Lymphoma. 2018 Jul 6:1-8. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/29979906
- Rituximab is commonly used for EBV reactivation after HCT but the number of doses of rituximab to use is unclear
- Retrospective study to compare risk factors and outcomes of patients who needed 1 dose vs >1 doses of preemptive rituximab to clear EBV viremia were compared
- Out of 488 patients who underwent HCT during the defined study period, 61 patients (12.5%) received pre-emptive rituximab for EBV reactivation.
- Patients whose EBV viremia cleared with 1 dose of rituximab were more likely to have a preceding reduction of immunosuppression. OS in these 2 cohorts was not different (18.7 vs 26.6 months, respectively, p = 0.96).
- Preemptive rituximab is an effective and safe strategy for patients with EBV reactivation and for preventing progression to life-threatening PTLD.
- Patients with higher EBV viral load may require more than 1 doses of rituximab to clear EBV viremia. Survival of patients requiring single or multiple doses of rituximab were not different in the study.
*Romero S, Montoro J, Guinot M, et al. Post-transplant lymphoproliferative disorders after solid organ and hematopoietic stem cell transplantation. Leuk Lymphoma. 2018 Jul 3:1-9. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/29966464
- Single-center, retrospective study comparing clinical, biological, and histological features, as well as outcomes of PTLD after SOT and allo-HCT.
- 82 PTLD cases (61 after SOT and 21 after allo-HCT) were identified. PTLD had an earlier onset in allo-HSCT than in SOT cohort (4 vs. 64 months, p < 0.0001). PTLD was EBV-positive in 100% of allo-HSCT, in contrast to 47% of SOT (p =0.0002).
- Four years after PTLD diagnosis, median overall survival was 32% (95% CI, 22-48) and 10% (95% CI, 2-49) in SOT and allo-HSCT recipients, respectively (p = 0.002).
- Clinical presentation and outcome of PTLD varies greatly depending on the type of transplant.
Allo-HCT: allogeneic hematopoietic stem cell transplant
AML: acute myeloid leukemia
Auto-HCT: autologous hematopoietic stem cell transplant
CI: confidence interval
CR: complete response
CrCl: creatinine clearance
Css: concentration at steady state
DLI: donor lymphocyte infusion
EBMT: European Society for Bone and Marrow Transplantation
GVHD: graft-versus-host disease
EBV: Epstein-Barr virus
HCT: hematopoietic cell transplantation
IBW: ideal body weight
KPS: Karnofsky Performance Status
MM: multiple myeloma
MOD: multi-organ dysfunction
MR: molecular response
NRM: non-relapse mortality
OS: overall survival
PBSC: peripheral blood stem cells
PFS: progression-free survival
PR: partial response
PTLD: post-transplant lymphoproliferative disorder
RFI: relapse-free interval
SD: stable disease
SOS: sinusoidal obstructive syndrome
SOT: solid organ transplant
T-IND: treatment-investigational new drug
UDCA: ursodeoxycholic acid
VGPR: very good partial response
VOD: veno-occlusive disease
ASBMT Pharmacy SIG Communications Working Committee:
Brandi Anders, Tiene Bauters, Eileen Chen, David Eplin, Katie Gatwood, Jason Jared, Kathryn Maples, Shreya Shah, Ryan Shaw