Pharmacy SIG Literature Update: ASTCT Consesus Grading for CRS and Neurologic Toxicity

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In this month’s Pharmacy SIG Literature Update: ASTCT consensus grading for CRS and neurologic toxicity, reduced intensity conditioning with fludarabine, melphalan, and total body irradiation, oral versus aerosolized ribavirin for the treatment of respiratory syncytial virus infections 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

**Chen GL, Hahn T, Wilding GE, et al. Reduced-Intensity Conditioning with Fludarabine, Melphalan, and Total Body Irradiation for Allogeneic Hematopoietic Cell Transplantation: The Effect of Increasing Melphalan Dose on Underlying Disease and Toxicity. Biol Blood Marrow Transplant. 2019 Apr;25(4):689-698. Epub 2018 Oct 6. https://www.ncbi.nlm.nih.gov/pubmed/30300731

  • Phase II trial of Flu 160 mg/m2, Mel 50 mg/m2, and TBI 400 cGy (FluMelTBI-50, n = 61), followed by a second phase II trial of Flu 160 mg/m2, Mel 75 mg/m2, and TBI 400cGy (FluMelTBI-75, n = 94) as RIC for alloHCT.
  • Outcomes were compared with a contemporaneous cohort of 162 patients who received Flu 125 mg/m2 and Mel 140 mg/m2. Eligibility criteria were equivalent for all 3 regimens. All patients were ineligible for myeloablative/intensive conditioning.
  • On multivariate analysis, OS (P = .05) and PFS (P = .05) were significantly improved for FluMelTBI-75 versus FluMel and better tolerated.
  • FluMelTBI-75 is better tolerated than FluMel, with improved survival and disease control.

* Salit RB, Scott BL, Stevens EA, et al. Pre-hematopoietic cell transplant ruxolitinib in patients with primary and secondary myelofibrosis. Bone Marrow Transplant. 2019 Apr 8. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/30962501

  • Prospective, phase II, single-center study of adult patients with primary or secondary MF were given ruxolitinib followed by HCT at Fred Hutchinson Cancer Research Center to assess effects of pre-HCT treatment on post-HCT outcomes
  • Primary endpoint was 2-year OS with secondary outcomes of incidence of graft failure/rejection, time to neutrophil engraftment, D+100 NRM, D+365 NRM, relapse at D+365, incidence/severity of GVHD
  • 28 patients (median time on ruxolitinib pre-HCT: 7 months) have been transplanted to date and all patients have achieved sustained engraftment (median ANC engraftment: 19 days)
  • 2/28 patients died from NRM & 2/28 patients have relapsed (OS: 93% at D+365, 86% at 2 years post-HCT)
  • 19/27 (70%) experienced grade II-IV aGVHD (15% experienced grade III-IV aGVHD) and 6/17 (35%) experienced cGVHD during evaluation
  • The authors concluded that pre-HCT ruxolitinib for MF patients is well tolerated and may improve post-HCT outcomes

Autologous Transplantation

* Hasib Sidiqi M, Nadiminti K, Al Saleh AS, et al. Autologous stem cell transplantation in patients with AL amyloidosis with impaired renal function. Bone Marrow Transplant. 2019 Apr 8. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/30962503

  • Retrospective, single-center evaluation of the impact of IRF on post-transplant outcomes in AL amyloidosis patients undergoing aHCT
  • 87 patients with IRF (eGFR < 45 mL/min) were compared to 568 patients with NRF undergoing aHCT, where the IRF group received dose-attenuated melphalan at a higher rate (dose <200 mg/m2: 70% IRF vs 21% NRF, p<0.0001)
  • 44 patients (6.7%) required dialysis within 100 days of aHCT (16% IRF vs 6% NRF, p = 0.0007) and IRF patients were more likely to be hospitalized (80% IRF vs 70% NRF, p= 0.03)
  • 100-day mortality was higher in IRF cohort (14% vs 5% NRF, p = 0.008) but median OS & PFS were similar
  • The authors concluded that IRF predicts for a higher rate of hospitalization, progression to dialysis, and early mortality in patients receiving aHCT for AL amyloidosis

CAR T-cell Therapy

**Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638.  https://www.ncbi.nlm.nih.gov/pubmed/30592986

  • Consensus recommendations and new definitions and grading for cytokine release syndrome and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities

*Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2019;380(18):1726-1737. https://www.ncbi.nlm.nih.gov/pubmed/31042825

  • Phase 1, open-label, dose-escalation study of bb2121, an anti-BCMA/CD3 CAR with a CD28 costimulatory domain in patients with MM who had a measurable disease
  • All patients had at least 3 prior lines of therapy with at least a PI and IMID
  • Successful CAR manufacturing occurred in 100% of patients enrolled
  • The median number of prior regimens was 7 with 67% stage II or III disease and 45% with high risk cytogenetics
  • All 33 patients experienced AEs with 97% (all but 1 patient) with grade 3 or higher; hematologic AEs were most common; 76% experienced CRS and 42% had neurotoxicity
  • CAR T-cell expansion did not appear to be affected by tocilizumab or steroid administration
  • Responses included 85% ORR; 9% CR, 36% sCR and responses appeared dose-dependent. Median time to first response was 1 month and median PFS was 11.8 months
  • CAR T-cells demonstrated persistence of 96%, 86%, 57%, and 20% at 1, 3, 6, and 12 months respectively
  • These data represent encouraging, albeit preliminary, efficacy and safety finding of CAR T-cell therapy in the heavily treated MM population

Graft-versus-host Disease

*Faraci M, Calevo MG, Giardino S, et al. Etanercept as Treatment of Steroid-Refractory Acute Graft-versus-Host Disease in Pediatric Patients. Biol Blood Marrow Transplant. 2019 Apr;25(4):743-748. Epub 2018 Nov 22. https://www.ncbi.nlm.nih.gov/pubmed/30471340

  • Prospective study to evaluate the use of the anti-TNFα monoclonal antibody etanercept as second-line treatment in children with steroid-refractory aGVHD.
  • Etanercept was administered after a median of 14 days (range, 5-135 days) from the onset of aGVHD.
  • Seventeen out of 25 patients (68%) developed a CR or PR to etanercept; overall response rate (CR+PR) was 78% in patients with cutaneous steroid-refractory aGVHD, 78% in those with GI aGVHD, and 57% in those with hepatic aGVHD.
  • OS was 76.5% in responders and 16.7% in non-responders (P = .004).
  • Etanercept used as second-line treatment of steroid-refractory aGVHD showed either CR or PR of 65% in 25 patients, with transplant-related mortality of 34.1% at 5 years.

Infectious Disease

**Foolad F, Aitken S, Shigle TL, et al. Oral versus aerosolized ribavirin for the treatment of respiratory syncytial virus infections in hematopoietic cell transplant recipients. Clin Infect Dis. 2019;68(10):1641–9. https://www.ncbi.nlm.nih.gov/pubmed/30202920

  • Single center, retrospective chart review of 124 patients to compare progression to LRI and mortality in HCT recipients with RSV infections treated with either oral (n=54) or aerosolized RBV (n=70)
  • Both groups had a 27% rate of progression to LRI (P=1) and mortality rates did not significantly differ between groups
  • More than half (55%) presented with LRI and there was no difference in 30 and 90-day mortality between treatment with oral vs aerosolized RBV (13.8% vs 15.4%; P=1 and 17.2% vs 30.8%; P=0.263, respectively)
  • ISI ≥7 was identified to be the most significant predictor of 30-day mortality
  • HCT recipients with RSV infections had similar outcomes when treated with aerosolized or oral RBV. Oral ribavirin may be an effective alternative to aerosolized RBV, with potential significant cost savings

**Papanicolaou GA, Silveira FP, Langston AA, et al. Maribavir for refractory or resistant cytomegalovirus infections in hematopoietic-cell or solid-organ transplant recipients: a randomized, dose-ranging, double-blind, phase 2 study. Clin Infect Dis. 2019;68(8):1255–64. https://www.ncbi.nlm.nih.gov/pubmed/30329038

  • Randomized, double-blind, phase 2 study of 120 HCT and SOT patients with RR CMV infections and plasma CMV DNA ≥1000 copies/mL
  • Patients were randomized 1:1:1 to twice-daily dose-blinded maribavir 400, 800, or 1200 mg for up to 24 weeks
  • Patients achieved undetectable CMV DNA within 6 weeks of treatment at a rate of 70%, 63%, and 68%, respectively, for maribavir 400, 800, and 1200 mg twice daily. Recurrent CMV viremia occurred in 29% of patients on maribavir at the time of recurrence, most commonly due to the development de novo UL97 mutations, known to confer resistance
  • Dysgeusia was the most common TEAE (65%) and led to maribavir discontinuation in 1 patient; myelosuppression was not noted and renal dysfunction occurred in 16% of patients
  • Maribavir therapy was associated with increased calcineurin inhibitor concentrations
  • Maribavir ≥400 mg twice daily was active against RR CMV infections in transplant recipients and no new safety issues were identified

*Weber D, Hiergeist A, Weber M, et al. Detrimental effect of broad-spectrum antibiotics on intestinal microbiome diversity in patients after allogeneic stem cell transplantation: lack of commensal sparing antibiotics. Clin Infect Dis. 2019;68(8):1303–10. https://www.ncbi.nlm.nih.gov/pubmed/30124813

  • Single center, retrospective chart review of 161 patients undergoing allo-HCT to examine the effect of various antibiotics on microbiota diversity
  • Rifaximin followed by systemic antibiotics maintained microbiome diversity compared to ciprofloxacin/metronidazole with or without systemic antibiotics with the Shannon index highest in rifaximin without systemic antibiotics compared with ciprofloxacin/metronidazole with/without antibiotics (P=0.01)
  • Outcomes were superior with regard to GI GVHD (P=0.05) and lower transplant-related mortality (P<0.001) for patients receiving Rifaximin plus systemic antibiotics compared to other types of systemic antibiotic treatment
  • Different types of antibiotic treatments show different impacts on markers of microbiome diversity. Rifaximin allowed a higher intestinal microbiome diversity, even in the presence of systemic broad-spectrum antibiotics

Umbilical Cord Blood Transplantation

**Balligand L, Galambrun C, Sirvent A, et al. Single-Unit versus Double-Unit Umbilical Cord Blood Transplantation in Children and Young Adults with Residual Leukemic Disease. Biol Blood Marrow Transplant. 2019 Apr;25(4):734-742. https://www.ncbi.nlm.nih.gov/pubmed/30385256

  • Randomized study evaluating the influence of pre-transplantation MRD leukemia relapse and survival after single- versus UCBT in children and young adults
  • MRD was considered positive at a level of ≥10-4 (seen in 43 out of 115 patients in this study)
  • Overall, the mean 3-year survival probability was 69.1 ± 4.4%, and it was not significantly influenced by the MRD level
  • In the MRD-positive group, the mean risk of relapse was significantly lower in the double-UCBT arm compared with the single-UCBT arm (10.5 ± 7.2% versus 41.7 ± 10.4%; P = .025) leading to a higher mean 3-year survival rate (82.6 ± 9.3% versus 53.6 ± 10.3%; P = .031).
  • Even with positive pretransplantation MRD, UCBT leads to high cure rate. Double UCBT may have a better graft-versus-leukemia effect in patients with MRD.

 

Abbreviations:

AE: adverse event

aGVHD: acute graft-versus-host disease

alloHCT: allogeneic hematopoietic cell transplantation

ANC: absolute neutrophil count

aHCT: autologous hematopoietic cell transplantation

CAR: chimeric antigen receptor

cGVHD: chronic graft-versus-host disease

CMV: cytomegalovirus

CR: complete response

CRS: cytokine release syndrome

DNA: deoxyribonucleic acid

EFS: event free survival

FLU: fludarabine

GI: gastrointestinal

GVHD: graft-versus-host disease

HCT: hematopoietic cell transplantation

IMID: immunomodulating agent

IRF: impaired renal function

ISI: Immunodeficiency scoring index

LRI: lower respiratory infection

MEL: melphalan

MF: myelofibrosis

MM: multiple myeloma

MRD: minimal residual disease

NRF: normal renal function

NRM: non-relapse mortality

ORR: objective response rate

OS: overall survival

PFS: progression-free survival

PI: proteasome inhibitor

PR: partial response

RBV: ribavirin

RIC: reduced intensity conditioning

RR: refractory or resistant

RSV: respiratory syncytial virus

sCR: stringent complete response

SOT: solid-organ transplant

TBI: total body irradiation

TEAE: treatment-emergent adverse effects

UCBT: umbilical cord blood transplantation

ASTCT Pharmacy SIG Communications Working Committee:

Brandi Anders, Telyssa Anderson, Tiene Bauters, Eileen Chen, Jason Jared, Kathryn Maples, Amanda Peffer, Ryan Shaw, Meg Taylor, Jamie Ziggas

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