02.03.21

Pharmacy SIG Literature Update: Autologous Transplantation for Multiple Myeloma and More

In this month’s Pharmacy SIG Literature Update: Autologous transplantation for multiple myeloma, assessment of novel SOS diagnostic criteria, use of GCSF post-allo HCT, 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

*Ibrahim U, Petrone GEM, Mascarenhas J, et al. Peritransplantation Use of Ruxolitinib in Myelofibrosis. Biol Blood Marrow Transplant. 2020;26(12):2177-2180.

https://pubmed.ncbi.nlm.nih.gov/32818555/

  • Ruxolitinib is an oral Janus kinase (JAK) 1/2 inhibitor used in myelofibrosis, and its impact on HCT outcomes is relatively unknown. The authors reviewed published literature on the peri-transplant use of ruxolitinib in patient with MF and discuss their findings.
  • Current literature reports various ruxolitinib tapering schedules prior to HCT without consensus on optimal schedule. Use of steroids to blunt ruxolitinib withdrawal syndrome is not well-studied.
  • If ruxolitinib discontinuation before conditioning is planned, it should be tapered and not discontinued until close to start of conditioning due to potential risk of cytokine rebound syndrome after JAK inhibitor discontinuation
  • Ruxolitinib appears to be safe and well-tolerated if continued during conditioning and until engraftment although these patients should be monitored for CMV reactivation and cytopenias
  • More prospective studies are needed to validate peri-HCT initiation and cessation strategies for ruxolitinib

*Iftikhar R, Chaudhry QUN, Mahmood SK, et al. Single-Agent Cyclosporine for Graft-versus-Host Disease Prophylaxis in Patients with Acquired Aplastic Anemia Receiving Fludarabine-Based Conditioning. Biol Blood Marrow Transplant. 2020;26(12):2245-2251. https://pubmed.ncbi.nlm.nih.gov/32717437/

  • Single-center, retrospective analysis of 106 acquired AA patients undergoing MSD HCT
    • Graft source: BM (n=71) vs combined BM/PB (n=34) vs PB (n=1)
    • Median age was 20 years (range, 3-52)
  • Cumulative incidence of neutrophil engraftment at day 28 was 93.4% (95% CI: 87.3%-97.1%), and platelet engraftment at day 100 was 90.5% (95% CI: 84%-96%)
  • Cumulative incidence of primary graft failure at day 28 was 6.6% (95% CI: 4%-8%), and secondary graft failure at median of 190 days was 3.7% (95% CI: 2%-5%)
  • Cumulative incidence of grade 2-4 acGVHD at day 100 was 3.8% (95% CI: 1.4%-9.9%), and 1-year probability of cGVHD was 7.5% (95% CI: 2.6%-15%). OS was 84.9%, DFS was 80.2%, and GRFS was 76.3%.
  • Authors conclude that single-agent cyclosporine for GVHD prophylaxis in MSD HCT using is feasible and associated with very low rates of GVHD

Autologous Transplant

*Hagen P, D’Souza A, Hari P, et al. Busulfan, Melphalan, and bortezomib compared to Melphalan as a high dose regimen for autologous hematopoietic stem cell transplantation in multiple myeloma: long term follow up of a novel high dose regimen. Leuk Lymphoma. 2020;61(14):3484-349. https://pubmed.ncbi.nlm.nih.gov/32865474/

  • Open-label phase I/II trial prospectively evaluating a novel conditioning regimen consisting of high-dose intravenous busulfan, melphalan and bortezomib (BuMelVel, n=43) for autoHCT in patients with MM. Results were compared with a matched cohort of patients receiving single dose of IV melphalan 200 mg/m2 (n=162).
  • BuMelVel consisted of busulfan 130 mg/m2 IV on day -6 through -3; day -4 and -3 dose adjusted to target total AUC of 20000; melphalan 140 mg/m2 and bortezomib 1.6 mg/m2 IV on day -2 and -1.
  • No one received consolidation or maintenance therapy post autoHCT in BuMelVel group compared with 69.6% of patients receiving post-transplant maintenance therapy in Mel200 arm.
  • At a median follow up of more than 7 years, no differences were found between groups in terms of OS or TRM. The 5-year PFS was 47% in the BuMelVel group vs 30% in the Mel200 group (p=0.05).
  • In a multivariate analysis for PFS, BuMelVel (HR 0.65; p=0.036), shorter interval from diagnosis to transplant of less than 12 months (HR 1.64 for >12 months; 95% CI 1.18 - 2.27), and disease status at transplant (complete remission HR 1.00; p=0.006) were associated with improved PFS
  • The authors conclude that additional research investigating novel intensive conditioning prior to autoHCT in MM is warranted

*Gagelmann N, Eikema D, de Wreede LC, et al. Upfront stem cell transplantation for newly diagnosed multiple myeloma with del(17p) and t(4;14): a study from the CMWP-EBMT. Bone Marrow Transplant. 2021; 56(1): 210–217. https://pubmed.ncbi.nlm.nih.gov/32710010/

  • Retrospective analysis of newly diagnosed MM patients with del(17p) and/or t(4;14) undergoing either upfront single autologous (auto), tandem autologous (auto-auto) or tandem autologous/RIC allogeneic (auto-allo) HCT between 2000 and 2015 (n = 623: auto, n = 446; auto-auto, n = 105; or auto-allo, n = 72). 46% of patients had t(4;14), 45% had del(17p); 9% had both aberrations.
  • 5-year OS was 51% for single auto, 60% for auto-auto, and 67% for auto-allo (p=0.187). 5-year PFS was 17%, 33%, and 34%, respectively (p=0.048).
  • 5-year relapse rate was 82%, 63%, and 56%, while non-relapse mortality was 1%, 4%, and 10%, respectively.
  • In patients with t(4;14). auto-auto appeared to improve OS compared with single auto (HR, 0.49; p=0.096). In patients with del(17p), PFS was similar between single auto and auto-auto, while auto-allo appeared to improve PFS (HR, 0.65; p = 0.097), however there was no significant difference in OS identified between the groups in patients with del(17p).

*Khurana A, Micallef IN, LePlant BR, et al. Outcomes of autologous stem cell transplant consolidation in primary central nervous system lymphoma: A Mayo Clinic experience. Biol Blood Marrow Transplant. 2020;26:2217-22. https://pubmed.ncbi.nlm.nih.gov/32818553/

  • Single center retrospective review comparing BEAM (n=25) and BCNU/TT (n=31) as conditioning for autoHCT over a 9-year period. Patients receiving BCNU/TT were statistically older (50 vs 61 years), had prognostic scores for higher risk disease, and increased proportion of elevated CSF protein at time of transplant.
  • 2-year OS was similar in both arms, 84% in BEAM and 81.6% in BCNU/TT. Median PFS at 2-years was also similar, 68% in BEAM vs 65.5% in BCNU/TT.
  • Disease response at time of transplant had significantly different outcomes when comparing complete response and partial responses within each arm. For patients in CR, OS at 2-years were comparable at 94.7% vs 90.5%. Patients with PR at time of transplant had improved OS with BCNU/TT 57.1% vs 50% in BEAM (p<0.0001).
  • The authors conclude that this retrospective cohort study adds to the current available literature and identifies that disease status before transplant is a significant factor affecting survival

Pediatrics

*Ragoonanan D, Khazal SJ, Wang J, et al. Improved detection of sinusoidal obstructive syndrome using pediatric–AYA diagnostic criteria and severity grading. Bone Marrow Transplant. 2020; 56(1):175-184. https://pubmed.ncbi.nlm.nih.gov/32665674/

  • New diagnostic criteria and severity grading for SOS among pediatric and AYA patients were recently published by the Pediatric Diseases Working Party of the EBMT and endorsed by international consensus
  • Retrospective, single-center study aimed to assess the potential impact of the use of these criteria among pediatric/AYA patients who underwent HCT between July 2009 and 2019. The incidence of SOS was assessed using historic Baltimore and Seattle diagnostic criteria and compared with recent guidelines (pEBMT).
  • In 226 patients reviewed, the application of the pEBMT diagnostic criteria was associated with a higher incidence (15.9%) and earlier time to diagnosis of SOS (by 3 days) compared with the modified Seattle (12.3%), and Baltimore (6.6%) criteria, respectively
  • Refractory thrombocytopenia was present in 75% of patients at diagnosis. Approximately 61% of patients with SOS were anicteric at diagnosis, though the majority (94%) developed hyperbilirubinemia as SOS progressed over a median time of 4 days.
  • Authors conclude that the pEBMT criteria may have resulted in earlier indication for definitive treatment by 3 days, thereby effectively ensuring timely diagnosis and administration of definitive treatment of SOS, which has previously been associated with improved outcomes for SOS

Supportive Care
*George G, Martin AS, Chhabra S, et al. The Effect of Granulocyte Colony-Stimulating Factor Use on Hospital Length of Stay after Allogeneic Hematopoietic Cell Transplantation: A Retrospective Multicenter Cohort Study. Biol Blood Marrow Transplant. 2020;26(12):2359-2364. https://pubmed.ncbi.nlm.nih.gov/32818554/

  • Retrospective, multicenter analysis assessing effects of GCSF administration on duration of index patient hospitalization in 3562 MDS/acute leukemia patients who received alloHCT reported to the CIBMTR
  • 1487 MSD HCTs: GCSF (n=313) vs no GCSF (n=1174)
    • Median hospitalization duration was 17 vs 18 days with GCSF vs no GCSF, respectively (p=0.06)
    • Significantly shorter median time to neutrophil recovery with GCSF vs no GCSF (12 vs 15 days, respectively; p<0.001) but incidence of neutrophil recovery by day +28 did not differ between the 2 groups (98% vs 98%, respectively; p=0.32)
    • 3-month probability of survival was 92% with GCSF vs 94% without GCSF (p=0.17)
  • 2075 MUD HCTs: GCSF (n=417) vs no GCSF (n=1658)
    • Median hospitalization duration was significantly shorter with GCSF vs no GCSF (15 vs 19 days, respectively; p<0.001)
    • Faster median time to neutrophil recovery with GCSF vs no GCSF (11 vs 15 days; p<0.001) but incidence of neutrophil recovery by day +28 did not differ between the 2 groups (97% vs 98%, respectively; p=0.38)
    • 3-month probability of survival was 88% with GCSF vs 91% without GCSF (p=0.09)
  • Authors conclude that this study does not support use of empiric GCSF for MSD HCT whereas for MUD HCT, shorter hospitalization was observed without any improvement in OS

*Salas MQ, Prem S, Remberger R, et al, High incidence but low mortality of EBV-reactivation and PTLD after alloHCT using ATG and PTCy for GVHD prophylaxis. Leuk Lymphoma. 2020;61(13):3198-3208. https://pubmed.ncbi.nlm.nih.gov/32715815/

  • Retrospective study investigating the risk factors affecting incidence of EBV reactivation (EBV-R) and PTLD, in addition to impact of PTLD on post-transplant outcomes in 270 patients who underwent RIC alloHCT using dual T-cell depletion (rabbit ATG, PTCy, and cyclosporine used as GVHD prophylaxis) at a Canadian hospital
  • A total of 63.7% of patients had EBV-R at some point post alloHCT (median onset: 68 days). OS and RFS at 1-year was significantly higher for patients with EBV-R compared to those without EBV-R (68.2% vs 62.1% and 60.6% vs 50.1%, respectively).
  • Receipt of alloHCT from MSD was more likely to cause EBV-R compared with other donor sources (HR 1.47; p=0.034).
  • A total of 25 patients had probable or possible EBV-associated PTLD. 22/25 patients were treated with rituximab for PTLD (median number of doses received = 3) with an ORR of 84%.
  • Among the 25 patients with PTLD, 1-year OS was 59.7% (95% CI 38–75.9) and NRM at day +100 and at 6-months were 12.1% (95% CI 3–28%) and 32% (95% CI 15–51%), respectively. The NRM of patients with PTLD was significantly higher than the NRM of patients with EBV-R and no PTLD (p=0.003), and higher than the NRM of the rest of patients without PTLD (p=0.048).
  • Multi-variate analysis showed protective effect EBV-R on RFS, however additional research is warranted to better understand complex interplay between EBV-R, immune reconstitution and post-transplant outcomes

*Chemaly RF, Dadwal SS, Bergeron A, et al. A phase 2, randomized, double-blind, placebo-controlled trial of presatovir for the treatment of respiratory syncytial virus upper respiratory tract infection in hematopoietic-cell transplant recipients. Clin Infect Dis. 2020; 71(11):2777-86. https://pubmed.ncbi.nlm.nih.gov/31793991/

  • Phase 2 study randomized 189 patients to presatovir (an oral RSV fusion inhibitor) 200 mg vs placebo on days 1, 5, 9, 13, and 17. Patients were stratified by lymphopenia (<200/uL), ribavirin use, and hospitalization at time of treatment start. 
  • The primary endpoints were average change in nasal RSV viral load between days 1 and 9 and the proportion of patients who developed lower respiratory tract complications through day 28. Presatovir did not significantly reduce the RSV viral load (-1.26 vs -0.91 log10 copies/mL, p=0.04) or development of LRTC (11.2% vs 19.5%, p=0.11).
  • In subgroup analysis, patients with lymphopenia who received presatovir had decreased development of LRTC, 13.3% vs 64.5%, p=0.008. Patients who did not receive ribavirin also had a trend toward decreased LRTC, 6.3% vs 17.6%, p=0.61. There were no differences in adverse events.
  • The authors conclude that presatovir had a favorable safety profile but did not achieve the primary endpoints in reduction of RSV viral load or LRTC, and future trials should explore its role in suitable high-risk patients (e.g. lymphopenia)

Abbreviations:

AA: aplastic anemia

aGVHD: acute graft-versus-host disease

alloHCT: allogeneic hematopoietic cell transplantation

ATG: antithymocyte globulin

autoHCT: autologous hematopoietic cell transplantation

AYA: adolescent young adult

BCNU/TT: carmustine, thiotepa

BEAM: carmustine, etoposide, cytarabine, melphalan

BM: bone marrow

cGVHD: chronic graft-versus-host disease

CIBMTR: Center for International Blood and Marrow Transplant

CMV: cytomegalovirus

DFS: disease-free survival

EBMT: European Society for Blood and Marrow Transplantation

EBV-R: Epstein Barr virus reactivation

GCSF: granulocyte colony-stimulating factor

GRFS: GVHD-free, relapse-free survival

GVHD: graft-versus-host disease

HCT: hematopoietic cell transplantation

LRTC: lower respiratory tract infection

MAC: myeloablative conditioning

MDS: myelodysplastic syndrome

MF: myelofibrosis

MM: multiple myeloma

MSD: matched sibling donor

NMA: non-myeloablative

NRM: non-relapse mortality

ORR: overall response rate

OS: overall survival

PB: peripheral blood

PFS: progression-free survival

PR: partial response

PTCy: post-transplant cyclophosphamide

PTLD: post-transplant lymphoproliferative disorder

RFS: relapse-free survival

RIC: reduced intensity conditioning

RSV: respiratory syncytial virus

SOS: sinusoidal obstruction syndrome

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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