News

This month we have a few special features with brief drug information updates highlighting important basics and monitoring parameter for gilteritinib, glasdegib, and venetoclax!  In this month’s literature updates, results from the NiCord ex-vivo expansion, BEAM vs BuCyVP16, outcomes in pediatrics with partially T-cell depleted grafts, and more!

Please review new drug updates here:

• Gilteritinib
• Glasdegib
• Venetoclax

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

Cord Blood

**Horwitz ME, Wease S, Blackwell B, et al. Phase I/II Study of Stem-Cell Transplantation Using a Single Cord Blood Unit Expanded Ex Vivo With Nicotinamide. J Clin Oncol. 2019 Feb 10;37:367-374. https://www.ncbi.nlm.nih.gov/pubmed/30523748

• Thirty-six patients enrolled at 11 centers received myeloablative conditioning followed by hematopoietic cell transplantation with a nicotinamide, ex-vivo expanded, single umbilical cord blood graft
• The cell dose prior to ex-vivo expansion was 0.2 x 10⁶ CD34+ cells/kg and was increased to 6.3 x 10⁶ CD34+ cells/kg
• Using a retrospective CIBMTR cohort for comparison, the NiCord treated patients had faster neutrophil engraftment (median of 11.5 vs 21 days; p<0.001) and faster platelet engraftment (median of 34 vs 46 days; p<0.001)
• Rates of both aGVHD and cGVHD were similar between NiCord and CIBMTR groups. NRM was improved with NiCord (p=0.02) and relapse at 2 years trended to favor the NiCord treated patients with similar results for DFS
• One NiCord patient had primary graft failure and 2 experienced secondary graft failure
• The NiCord treated group spent an median of 73 days alive and out of the hospital through day +100 whereas the CIBMTR comparator group spent a median of 57 days (p<0.001)
• This represents encouraging data supporting a single, nicotinamide, expanded cord blood transplant can be a stand-alone option with improved engraftment rates compared to a retrospective CIBMTR cohort

Autologous Transplantation

**Singer S, Dean R, Zhao Q, et al. BEAM vs BUCYVP16 conditioning prior to autologous hematopoietic stem cell transplant in patients with hodgkin’s lymphoma. Biol Blood Marrow Transplant. 2019 Feb [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/30716453

• Retrospective analysis of BEAM (carmustine, etoposide, cytarabine, and melphalan, n=128) and BUCYVP16 (busulfan, cyclophosphamide, and etoposide, n=105) for patients with relapsed HL prior to autoHCT
• Hospital LOS was significantly shorter for the BEAM group (18 days vs 21 days, p<0.01) and grade III-IV mucositis was significantly greater in the BUCYVP16 group (50% vs 26%, p=0.01)
• After a median follow up of 4.2 years (BEAM) and 3.8 years (BUCYVP16), the 5-year CIR was 29% with BEAM as compared to 56% with BUCYVP16 (p<0.001)
• Median PFS and OS were not reached in the BEAM cohort (2.0 and 7.8 years for BUCYVP16) and improved PFS (p<0.001) and OS (p=0.001) were observed with BEAM patients who needed transplant within 24 months of diagnosis and non-CR
• The authors concluded that the use of BEAM prior to autoHCT resulted in significantly improved PFS, OS and lower relapse rates, which supports the use of frontline BEAM prior to autoHCT for early relapsed and non-CR HL

Allogeneic Transplantation

**Maymani H, Lin P, Saliba RM, et al. Comparison of outcomes of allogeneic hematopoietic cell transplantation for multiple myeloma using three different conditioning regimens. Biol Blood Marrow Transplant. 2019 Jan [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/30639822

• Retrospective, single-center study of 3 different conditioning regimens for MM alloHCT including busulfan/fludarabine (BuFlu), fludarabine/melphalan 100mg/m² (FM100) and fludarabine/melphalan 140mg/m² (FM140)
• Primary endpoints included NRM, PFS at 3 years and OS at 3 years while secondary end points included time to engraftment and the incidence of aGVHD & cGVHD
• 73 total patients received an alloHCT for MM and NRM (21%, 28%, 24%), PFS (16%, 26%, 11%), and OS (39%, 43%, 32%) were not clinically different between the BuFlu, FM100, and FM140 groups
• High-risk cytogenetics (HR 2.1, p=0.02) and relapsed disease prior to alloHCT (HR 2.6, p=0.004) were found to be independent predictors of inferior OS on multivariate analysis
• The authors concluded that durable clinical remission can be achieved in 11-25% of patients with MM after alloHCT without any significant difference in safety or efficacy of the conditioning regimen

Pediatrics

*Seitz CM, Eyrich M, Greil J, et al. Favorable immune recovery and low rate of GvHD in children transplanted with partially T cell-depleted PBSC grafts. Bone Marrow Transplantation 2019;54:53-62. https://www.ncbi.nlm.nih.gov/pubmed/29795418

• Long-term follow-up results on 25 pediatric patients transplanted with CD34 or CD133 positively selected PBSC from MUDs
• Patients were supplemented with an add-back of unselected T cells resulting in a median T-cell depletion (TCD) of 1.97 log
• Early T-cell recovery was significantly improved compared to those who received CD34-selected grafts without the T-cell add-back and was noted to be similar to unmanipulated bone marrow
• Grade II, III, and IV acute GVHD rates were 8%, 4%, and 0%, respectively; 16/25 (64%) patients were alive after a median follow-up of 10 years
• In pediatric patients who received an alloHCT from MUD PBSC, partial TCD with serotherapy CSA/MTX prophylaxis can effectively reduce GVHD without hampering engraftment or immune reconstitution

Graft-Versus-Host Disease

*Johnson BH, Taylor A, Kim G, et al. Clinical outcomes and healthcare resource utilization for gastrointestinal acute graft-versus-host disease after allogeneic transplantation for hematologic malignancy: a retrospective US administrative claims database analysis. Biol Blood Marrow Transplant. 2019 Jan [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/30625389

• Retrospective cohort study (2008-2015) used US healthcare claims data to identify patients who developed GI aGVHD after alloHCT for hematologic malignancy and compared them with those that did not develop GI aGVHD
• Outcomes of interest included OS, infections, HRU, and overall costs
• Mortality was higher in the aGVHD cohort as compared to the no aGVHD cohort (27.8% vs 19.6%, p = 0.003) and multivariate analysis showed a 66% decrease in likelihood of dying within 1 year of transplant for the no aGVHD cohort (no benefit was shown for aGVHD cohort)
• The GI aGVHD cohort were 3.9-fold more likely to develop an infection in the year after alloHCT as compared to the no aGVHD cohort
• The GI aGVHD cohort were 4.3-fold more likely to have an inpatient admission after alloHCT discharge and these admissions cost 47% more than an admission without aGVHD
• The authors concluded that GI involvement in aGVHD is associated with higher mortality, risk of infection, HRU, and cost compared with absence of aGVHD

**McCurdy SR, Kanakry CG, Tsai HL, et al. Development of grade II acute graft-verses-host disease is associated with improved survival after myeloablative HLA-matched bone marrow transplantation using single-agent post-transplant cyclophosphamide. Biol Blood Marrow Transplant. 2018 Dec [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/30599208

• Retrospective analysis of 298 consecutive adult patients with hematologic malignancies who engrafted after MAC MSD (n=187) or MUD (n=111) t cell-replete BMT with PTCy 50 mg/kg on days +3 and +4
• 35% of MSD and 57% of MUD patients developed grade II aGVHD by day +100 (11% & 14% grade III-IV aGVHD) while 9% and 16% developed cGVHD by day +365
• 4-year OS & PFS rates were 57 % and 40% in patients without grade II aGVHD but were 68% and 54% in those with grade II aGVHD
• After adjusted time-dependent multivariate analyses, grade II aGVHD was associated with improved OS (HR 0.58, P = 0.01) and PFS (HR 0.50, P<0.001)
• The authors concluded that the ability of PTCy to limit grades III to IV aGVHD and cGVHD while maintaining grade II aGVHD may contribute to its effectiveness and further attempts to reduce aGVHD may be detrimental

Supportive Care

**Khimani F, McDonald GB, Shulman HM, et al. Hepatic veno-occlusive disease following sirolimus-based immune suppression. Bone Marrow Transplantation. 2018;54:85-89. https://www.ncbi.nlm.nih.gov/pubmed/29895929

• Retrospective review of 818 consecutive HCT patients (sirolimus (SIR)/ tacrolimus (TAC) n = 308, and methotrexate (MTX) or mycophenolate mofetil (MMF)/TAC n = 510)
• A multivariate analysis revealed that sirolimus-based GVHD prophylaxis increased the risk for VOD (p = 0.006, HR 3.33, 1.94–5.7)
• 58 patients were clinically diagnosed with VOD (38/308 [12.3%] SIR/TAC vs. 20/510 [3.9%] MTX or MMF/TAC)
• In SIR/TAC patients, VOD was characterized by a later time of onset (median 39 vs. 26 days; p = 0.005), less severe hyperbilirubinemia (T.bili > 2, 65% vs. 90% p = 0.04), lesser degree of weight gain (weight gain > 5%, 52% vs 80%, p = 0.04), and more frequent complete resolution of hepatic injury (79% vs. 55%, p = 0.05)
• The presenting features and clinical course of VOD in patients with SIR/TAC prophylaxis appear to differ from MTX or MMF/TAC patients and monitoring for delayed presentation should occur in these patients

*Brown JR, Moslehi J, Ewer M, et al. Incidence of and risk factors for major hemorrhage in patients treated with ibrutinib: An integrated analysis. Br J Haematol. 2019 Feb;184:558-569. https://www.ncbi.nlm.nih.gov/pubmed/30506764

• Incidence and risk for major hemorrhage (MH) were analyzed from 15 ibrutinib clinical studies (N = 1768), including 4 randomized controlled trials (RCTs)
• Low-grade bleeding was more common in ibrutinib-treated than comparator-treated patients (35% and 15%), and early low-grade bleeding was not associated with MH
• The proportion of MH in RCTs was higher with ibrutinib than comparators (4.4% vs. 2.8%), but after adjusting for longer exposure with ibrutinib (median 13 months vs. 6 months), the incidence of MH was similar (3.2 vs. 3.1 per 1000 person-months)
• Use of anticoagulants and/or anti-platelets (AC/AP) during the study was common (~50% of patients) and had an increased exposure-adjusted relative risk for MH in both the total ibrutinib-treated population (1.9; 95% confidence interval, 1.2-3.0) and RCT comparator-treated patients (2.4; 95% confidence interval, 1.0-5.6), indicating that ibrutinib may not alter the effect of AC/AP on the risk of MH in B-cell malignancies
• Relative to comparators, ibrutinib did not have an increased risk for MH when corrected for treatment duration.

Abbreviations:

alloHCT: allogeneic hematopoietic cell transplant

autoHCT: autologous hematopoietic stem cell transplant

aGVHD: acute graft-verses-host disease

cGVHD: chronic graft-verses-host disease

CIBMTR: Center for International Blood and Marrow Transplant Research

CIR: cumulative incidence of relapse

DFS: disease free survival

GVHD: graft-versus-host disease

HL: hodgkin’s lymphoma

HRU: healthcare resource utilization

LOS: length of stay

MAC: myeloablative conditioning

MM: multiple myeloma

MSD: matched sibling donor

MUD: matched unrelated donor

Non-CR: not in complete remission

NRM: non-relapse mortality

OS: overall survival

PBSC: peripheral blood stem cells

PFS: progression-free survival

PTCy: post-transplant cyclophosphamide

T.bili: total bilirubin

VOD: veno-occlusive disease

ASBMT Pharmacy SIG Communications Working Committee: