Mortality Analysis of Letermovir Prophylaxis for CMV and More

By Content Administrator posted 16 days ago

  

In this month’s Pharmacy SIG Literature Update:  PD-1 blockade with pembrolizumab for classical Hodgkin lymphoma after autologous stem cell transplantation, high-dose bendamustine and melphalan conditioning for patients with multiple myeloma, a mortality analysis of letermovir prophylaxis for CMV 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

*de La Fuente J, Dhedin N, Koyama T, et al.  Haploidentical Bone Marrow Transplantation with Post-Transplantation Cyclophosphamide Plus Thiotepa Improves Donor Engraftment in Patients with Sickle Cell Anemia: Results of an International Learning Collaborative.  BBMT. 2019;25(6):1197-1209. https://www.ncbi.nlm.nih.gov/pubmed/?term=30500440.

  • Multi-institutional learning collaborative based on Phase II trial in patients with SCD receiving NMA, related haploidentical HCT with ATG, fludarabine, cyclophosphamide, thiotepa, and low-dose TBI followed by post-transplant cyclophosphamide, MMF, and sirolimus for GVHD prophylaxis.
  • At median follow-up of 13.3 months, 93% of patients had >95% stable donor engraftment at 6 months, with 100% OS.
  • At 1 year, 86% of patients were off immunosuppression, and there were low rates of a/cGVHD.
  • The addition of thiotepa and post-transplant cyclophosphamide in haploidentical HCT may benefit patients with SCD.

*Park H, Lee J, Lee J, et al.  Fludarabine/Melphalan 100 mg/m2 Conditioning Therapy Followed by Allogeneic Hematopoietic Cell Transplantation for Adult Patients with Secondary Hemophagocytic Lymphohistiocytosis. BBMT.  2019;25(6):1116-21. https://www.ncbi.nlm.nih.gov/pubmed/?term=30508593.

  • Retrospective analysis of 16 patients receiving fludarabine/melphalan RIC alloHCT for HLH.
  • At a median follow-up of 33.8 months, 1 patient had progression of disease, 3 patients relapsed, and 9 patients died [5 of which were due to infection (n=3), bleeding (n=1), and GVHD (n=1)]. OS was 48.6%.
  • Conditioning therapy using a lower dose of melphalan combined with fludarabine appears to be promising in allogeneic HCT for adults with HLH. However, strategies are needed to reduce the risk of early death.

Autologous Transplantation

**Armand P, Chen YB, Redd RA, et al. PD-1 blockade with pembrolizumab for classical Hodgkin lymphoma after autologous stem cell transplantation. Blood. 2019;134(1):22-9.  https://www.ncbi.nlm.nih.gov/pubmed/30952672

  • Multicohort, open-label, multicenter, phase II trial assessing PFS and OS in patients with relapsed/refractory classical Hodgkin lymphoma who received pembrolizumab after aHCT
  • Pembrolizumab was administered at a flat dose of 200 mg IV every 3 weeks for up to 8 cycles, starting within 21 days of post-aHCT discharge
  • The study met the primary endpoint for PFS with 83% of patients remaining in complete remission at 18 months and OS being 100% at 18 months
  • 43% of patients experienced an immune-related AE and five of these AE’s led to discontinuation of the study drug
  • Pembrolizumab administration as post-aHCT consolidation in patients with relapsed/refractory classical Hodgkin lymphoma resulted in promising PFS for patients in whom frontline therapy is ineffective and authors concluded that further testing would be warranted in a randomized controlled trial

** Gomez-Arteaga A, Mark TM, Guarneri D, et al. High-dose bendamustine and melphalan conditioning for autologous stem cell transplantation for patients with multiple myeloma. Bone Marrow Transplant. June 2019. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31190006

  • Phase II, single-arm study of bendamustine with melphalan conditioning to determine the efficacy of bendamustine in combination with melphalan conditioning in patients with MM
  • Dosing from the groups phase I study was chosen for this phase II study: bendamustine 125 mg/m2 D-2 & 100 mg/m2 D-1 (bendamustine total: 225 mg/m2) with melphalan 100 mg/m2 D-2 & D-1 (melphalan total: 200 mg/m2)
  • 35 total patients were transplanted during this study – 18 patients for frontline transplant while 17 patients were in the relapsed/refractory subgroup
  • Median time to ANC engraftment was 11 days (range: 10-14); median platelet engraftment was 21 days (range: 15-29); median time to hospital discharge was 14 days (range: 0-22)
  • Most common grade III AEs were febrile neutropenia (46%), hypokalemia (20%), hypophosphatemia (14%), and fatigue (11%) – one patient (3%) experienced grade IV hyperbilirubinemia
  • 51% of the patients achieved a CR/sCR (44% of the frontline group & 59% of the relapsed/refractory group) at D+100
  • The authors concluded that high-dose bendamustine with melphalan showed favorable safety and encouraging efficacy as an aHCT regimen in myeloma and further investigation into this strategy is warranted

** Miller KC, Gertz MA, Buadi FK, et al. The impact of re-induction prior to salvage autologous stem cell transplantation in multiple myeloma. Bone Marrow Transplant. 2019 June. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31190005

  • Retrospective, single-center study assessing the value of re-induction for those myeloma patients who deferred up-front aHCT and were taken to transplant after disease progression (i.e. salvage aHCT) and whether re-induction improved outcomes
  • 188 patients (80%) were re-induced prior to aHCT while 46 (20%) were not re-induced – the only significant difference between these groups was the time from diagnosis to stem cell collection (11.2 mo 8.2 mo, p=0.0082)
  • Median TNT for the entire cohort was 17.2 months and median OS was 50.4 months - There was no significant difference in the TNT or OS from D0 between the two groups
  • Patients who were re-induced had a nonsignificant trend towards higher rate of CR post-aHCT (45% vs 33%, p=0.12)
  • The authors concluded that there was no detrimental survival effect for patients who proceeded directly to salvage aHCT with relapsed/refractory disease when compared to patients who received re-induction therapy

* Nakagaki M, Button E, Keating A, et al. Hyperhydration is not necessary for high-dose melphalan in stem cell transplantation. Bone Marrow Transplant. June 2019. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31186515

  • Retrospective chart review of two hospital’s (Royal Brisbane and Women’s Hospital & Townsville Hospital in Queensland, Australia) peri-aHCT hydration protocols: hyperhydration (4-6 liters of 0.9% normal saline) vs standard hydration (2 liters of 0.9% normal saline)
  • Primary endpoint of the study was acute renal impairment as defined by the KDIGO clinical practice guideline, while secondary endpoints included weight gain, fluid overload, and acute pulmonary edema
  • 54 patients received hyperhydration while 34 patients received standard hydration: cohort ages, gender, baseline serum creatinine, and weight were not statistically different
  • 11% of hyperhydration patients experienced mild acute kidney injury by D+7 as compared to 6% in the standard hydration cohort (p=0.48)
  • 9% of hyperhydration patients experienced fluid overload as compared to 6% in the standard hydration cohort (p=0.7)
  • The authors concluded that hyperhydration did not show benefits in protecting kidney function for patients receiving melphalan and that hyperhydration should not be performed due to potential toxicities

Infectious Disease

**Ljungman P, Schmitt M, Marty FM, et al. A mortality analysis of letermovir prophylaxis for cytomegalovirus (CMV) in CMV-seropositive recipients of allogeneic hematopoietic-cell transplantation. Clin Infect Dis. June 2019. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31179485 

  • Post-hoc mortality analysis of Phase 3 data to determine the effects of letermovir on all-cause mortality
  • The HR for all-cause mortality was 0.58 (95% CI, 0.35-0.98) at week 24 and 0.74 (95% CI, 0.49-1.11) at week 48 post-HCT for letermovir vs. placebo
  • CS-CMVi defined as CMV infection or CMV viremia leading to preemptive therapy
  • The HR for all-cause mortality in patients with CS-CMVi was 0.45 (95% CI, 0.21-1.00) at week 48 for letermovir vs. placebo
  • Incidence of all-cause mortality through week 48 in the placebo arm was higher in patients who developed CS-CMVi than patients in the placebo arm without CS-CMVi (31% vs 18.2%, p=0.02) despite preemptive therapy
  • Conversely, patients in the letermovir arm had similar incidence of all-cause mortality at week 48 with or without CS-CMVi (15.8% vs 19.4%, p=0.71)
  • CS-CMVi appears to have a negative effect on all-cause mortality that may be abrogated by letermovir prophylaxis
  • Based on the trend to lower all-cause mortality at week 48, perhaps longer letermovir prophylaxis is needed in certain patient populations and could be explored in future trials.

Pediatrics

*Guilcher GMT, Monagel DA, Nettel-Aguirre A, et al.  Nonmyeloablative Matched Sibling Donor Hematopoietic Cell Transplantation in Children and Adolescents with Sickle Cell Disease.  BBMT.  2019;25(6):1179-86. https://www.ncbi.nlm.nih.gov/pubmed/?term=30772511.

  • Using NIH NMA regimen of alemtuzumab + TBI followed by sirolimus for GVHD prophylaxis, 16 children and adolescents received matched sibling HCT.
  • All patients achieved mixed donor-recipient engraftment with no cases of secondary graft failure to date.
  • At a median follow-up of 19.5 months, 100% EFS and OS were seen, with no cases of GVHD. All patients except 1 were off sirolimus.
  • Ongoing follow-up and a larger prospective clinical trial are required to determine the long-term safety and efficacy of this regimen.

Abbreviations:

AE: adverse event

aGVHD: acute graft-versus-host disease

aHCT: autologous hematopoietic cell transplantation

alloHCT: allogeneic hematopoietic cell transplantation

ANC: absolute neutrophil count

ATG: antithymocyte globulin

CS-CMVi: clinically significant cytomegalovirus infections

cGVHD: chronic graft-versus-host disease                     

CI: confidence interval

CR: complete response

DFS: disease-free survival

EFS: event free survival

GVHD: graft-versus-host disease

HCT: hematopoietic cell transplantation

HLH:  hemophagocytic lymphohistiocytosis

HR: hazard ratio

KDIGO: Kidney Disease Improving Global Outcome

MDS: myelodysplastic syndrome

MM: multiple myeloma

MMF: mycophenolate mofetil

NF: neutropenic fever

NIH: National Institutes of Health

NMA: nonmyeloablative

OS: overall survival

PFS: progression-free survival

PR: partial response

RIC: reduced-intensity conditioning

SCD: sickle cell disease

sCR: stringent complete response

TBI: total body irradiation

TNT: time to next therapy

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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