News

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

In this month’s Pharmacy SIG Literature Update: Does CMV reactivation reduce relapse rates? Immune reconstitution post ablative transplants using ATLG, RIC with FLAMSA vs BuFlu, and preemptive azacitidine for MRD positivity.  And more!

 Allogeneic Transplant

*Gooptu M, Kim HT, Bhen YB, et al. Effect of antihuman T lymphocyte globulin on immune recovery after myeloablative allogeneic stem cell transplantation with matched unrelated donors: analysis of immune reconstitution in a double-blind randomized controlled trial. Biol Blood Marrow Transplant. 2018 Nov;24:2216-2223. http://www.ncbi.nlm.nih.gov/pubmed/30006305             

• Companion study to assess the impact of ATLG on IR and correlate IR with clinical outcomes, parent study demonstrated that moderate/severe cGVHD but not cGVHD-free survival was reduced in patients receiving ATLG vs placebo for those patients receiving MA-MUD HCT
• 91 patients consented to the companion IR study (254 included in parent study) where blood samples were collected on days 30, 100, 180, and 360 after HCT and multiparameter flow cytometry was performed in a blinded fashion
• Reconstitution of CD3⁺ and CD4⁺ T cells was delayed up to 6 months post-HCT in the ATLG arm, while absolute Treg numbers were lower only in the first 100 days
• A profound absence of naïve Tregs and Tconv were found in the first 100 days post-HSCT with very slow recovery at 1 year in the ATLG arm, but B cell and natural killer cell recovery were similar in each arm
• Higher absolute counts of CD3⁺, CD4⁺, CD8⁺, Tregs and Tconv were associated with improved OS, PFS, and NRM but not moderate/severe cGVHD
• The authors concluded that ATLG severely compromises the generation of naïve CD4⁺ cells, potentially affecting the diversity of the TCR repertoire and T cell responses against malignancy and infection

*Heinicke T, Labopin M, Schmid C, et al. Reduced relapse incidence with FLAMSA–RIC compared with busulfan/fludarabine for acute myelogenous leukemia patients in first or second complete remission: A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2018;24:2224-32. https://www.ncbi.nlm.nih.gov/pubmed/30009981

• Retrospective registry-based analysis on behalf of Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) to compare FLAMSA regimens with BuFlu
• Patients were included if they underwent first allo-HCT for AML in CR1 or CR2 between January 2005 and June 2016; donors matched related or unrelated with up to 1 mismatch
• BuFlu conditioning was used in 1197 patients, FLAMSA-TBI was used in 258 patients, and FLAMSA-Bu was used in 141 patients
• After median follow-up of 24.72 months, relapse incidence was 30.3%, 21.9%, and 23.1% in BuFlu, FLAMSA-TBI, and FLAMSA-Bu groups, receptively (P<0.01) and non-relapse mortality at 2 years was 16.1%, 16.4%, and 26.7%, respectively (p<0.01)
• There was reduced relapse rate with FLAMSA-TBI compared with BuFlu for AML in CR (HR 0.64; p=0.04) and there was a trend toward improved leukemia-free survival with FLAMSA-TBI

*Law AD, Salas MQ, Lam W, et al. Reduced-intensity conditioning and dual T lymphocyte suppression with antithymocyte globulin and post-transplant cyclophosphamide as graft-versus-host disease prophylaxis in haploidentical hematopoietic stem cell transplants for hematological malignancies. Biol Blood Marrow Transplant. 2018;24:2259-64. https://www.ncbi.nlm.nih.gov/pubmed/30009980

• Review of 50 patients who received haploHCT from August 2016 to February 2018 with reduced-intensity conditioning (RIC) with ATG (4.5 mg/kg over 3 days), PTCy (100 mg/kg over 2 days), and cyclosporine as GVHD prophylaxis
• Median age was 56 years (range 22-70 years); 25 patients (73.5%) were in first CR, 5 (14.7%) were in second CR, and 8 (23.5%) had active disease
• At Day +100, the cumulative incidence of acute GVHD of any grade and grades II to IV were 38.3% and 5.2%, respectively
• CMV reactivation occurred in 37 (74%) cases, with 4 (11.5%) being CMV disease; EBV reactivation occurred in 21 (61.8%) patients; 1-year OS and NRM were noted to be 48.1% and 38.2%, respectively
• HaploHCT after RIC with ATG, PTCy, and cyclosporine is a feasible transplant regimen with low rates of grade II to IV acute GVHD observed; however ATG use associated with higher rates of viral reactivation

*Paviglianiti A, Maio KT, Rocha V, et al. Outcomes of advanced Hodgkin lymphoma after umbilical cord blood transplantation: A Eurocord and EBMT Lymphoma and Cellular Therapy & Immunobiology Working Party Study. Biol Blood Marrow Transplant. 2018;24:2265-70. https://www.ncbi.nlm.nih.gov/pubmed/30031070

• Retrospective registry-based review of 131 patients with Hodgkin lymphoma (HL) who underwent UCBT in EBMT centers from 2003 to 2015
• 59 patients (47%) were in CR at time of UCBT and almost all patients had undergone at least one prior ASCT, with median time from ASCT to UCBT of 16 months (range 2-280 months)
• The 4-year PFS and OS were 26% (95% CI, 36-54%) and 46% (95% CI, 37-55%), respectively; relapse incidence was 44% and non-relapse mortality was 31% at 4 years
• Based on multivariate analysis, conditioning regimen of cyclophosphamide + fludarabine + 2Gy TBI is associated with decreased risk of NRM (HR 0.26, p=0.004), better OS (HR 0.25, p <0.001), and better PFS (HR 0.51, P=0.04)
• UCBT is feasible in heavily pretreated HL patients; however, outcomes are poor for patients not in CR at time of UCBT with relapsed/refractory disease status at time of UCBT being associated with increase relapse incidence (HR 3.14, p=0.005) and lower OS (HR 3.1, p=0.001)

*Puronen CE, Cassaday RD, Stevenson PA, et al. Long-term follow-up of ⁹⁰Y-ibritumomab tiuxetan, fludarabine, and total body irradiation-based nonmyeloablative allogeneic transplant conditioning for persistent high-risk B cell lymphoma. Biol Blood Marrow Transplant. 2018 Nov;24:2211-2215. http://www.ncbi.nlm.nih.gov/pubmed/30454872      

• Long-term follow up of forty patients with high-risk B-NHL who received anti-CD20 RIT-augmented NMA-HCT using ⁹⁰Y-ibritumomab tiuxetan between October 2004 and February 2009
• Previously published data from this trial demonstrated feasibility, safety and early disease control (60% early response rate) of ⁹⁰Y-ibritumomab tiuxetan with fludarabine and low-dose TBI before HLA-matched HCT for a variety of CD20 expressing B cell malignancies in the setting of persistent disease
• Eleven of 40 patients were alive at a median follow-up of 9 years (range, 5.3 to 10.2) while fourteen (35%) deaths were due to disease progression and fourteen (35%) were due to complications from HCT
• 5-year overall and PFS for patients with indolent B-NHL were 40% and 27.5% and none of the DLBCL patients were long-term disease-free survivors regardless of early remission status.
• The authors concluded that ⁹⁰Y-ibritumomab tiuxetan-based allografting represents a viable option in patients with indolent histologies and improved strategies are needed for aggressive B-NHL

Post-Transplant Therapy

*Platzbecker U, Middeke JM, Sockel K, et al. Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial. Lancet Oncol. 2018;19:1668-1679. https://www.ncbi.nlm.nih.gov/pubmed/30442503

• Adult patients were eligible to receiving azacitidine at 75 mg/m² daily x 7 days if they had MDS or AML, were in CR after chemotherapy or allo-HCT, and were MRD-positive by >1% detection of molecular markers or a drop of 80% or less in CD34+ donor chimerism; n=53 with 45% receiving allo-HCT
• Therapy was continued for up to 24 cycles but could be deescalated to a 5-day regimen in patients with a major overall response
• Primary endpoint of relapse-free survival was 58% at 6 months after starting azacitidine; 19 of the 31 responders (61%) had a major response with conversion to MRD negativity; 12 of the 19 major responders (63%) remained relapse-free at 23 months
• Seven of the 19 major responders became MRD-positive at a median of 280 days after starting azacitidine with 4 relapsed disease cases
• In post-hoc analysis, relapse-free survival but not OS differed between responders and non-responders; a higher percentage of non-transplant patients relapsed during the study period (62% vs 33%) and a lower percentage responded to treatment (48% vs 71%) but these were not statistically different with the small number of patients in each group; survival in the MRD-positive patients who responded to azacitidine was similar to that of the MRD-negative group
• While limited by the small number of patients, the study demonstrated prevention or delay in relapse for this high-risk group of patients. Future studies using MRD-guided therapy are recommended

Infectious Diseases

*Lin C, Hsueh P, Wu S, et al. Repurposing nilotinib for cytomegalovirus infection prophylaxis after allogeneic hematopoietic stem cell transplantation: A single-arm, phase II trial. Biol Blood Marrow Transplant. 2018;24:2310-15. https://www.ncbi.nlm.nih.gov/pubmed/30026110

• Single-arm, phase II trial with original design including two parts: prophylaxis cohort and salvage cohort; this reported the outcomes of the prophylactic cohort
• Patients received nilotinib 200 mg/day once engrafted (ANC > 500/µL, PLT > 200,000/µL, and no PLT transfusion for 3 days) and continued until day 100 or until discontinuation of immunosuppressants, whichever occurred first
• All 37 patients and their donors were CMV seropositive, with 30 patients receiving matched sibling transplants, 15 receiving nonmyeloablative, and 15 receiving ATG
• 25 of 31 assessable patients (80.6%) met the predefined definition of successful prophylaxis (plasma CMV DNA copies less than 10,000 copies/mL, no anti-CMV treatment initiated, and no clinical CMV disease by day 100); no patients experienced grade 3/4 toxicities from nilotinib
• Nilotinib 200 mg/day was deemed to be well tolerated in allo-HCT recipients and the highest prophylaxis success rate was observed in patients who did not receive ATG

*Peric Z, Wilson J, Durakovic N, et al. Early human cytomegalovirus reactivation is associated with lower incidence of relapse of myeloproliferative disorders after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2018;53:1450-1456. https://www.ncbi.nlm.nih.gov/pubmed/29662245

• Evaluation of the impact of CMV reactivation on outcomes of 155 consecutive adult HCT patients
• CMV reactivation did not affect cumulative incidence of relapse in patients with lymphoproliferative disorders but the cumulative incidence of relapse in patients with myeloproliferative disorders (AML and MPN) was 37% (95% CI, 21-53%) in patients without CMV reactivation as opposed to 17% (95% CI, 9-28%) in patients with CMV reactivation (p=0.03)
• The cumulative incidence of relapse was higher for MPN patients without CMV reactivation compared to those that had CMV reactivation; 50% vs 7% (p=0.02)
• AML patients who received ATG without CMV reactivation had a 45% relapse rate compared to 0% with CMV reactivation (p=0.01)
• CMV reactivation only affected relapse rates in patients receiving MAC regimens
• Significantly more grade II–IV acute GVHD was observed in patients who developed CMV reactivation (55% vs 30%; p=0.02)
• Cumulative incidence of NRM was similar between the two groups, and there were no deaths attributed to CMV reactivation
• The authors show an association of CMV reactivation with relapse reduction in MPN patients, however with multiple studies published with conflicting results, further research is warranted

*Yan CH, Wang Y, Ziao-dong M, et al. Incidence, risk factors, microbiology and outcomes of pre-engraftment bloodstream infection after haploidentical hematopoietic stem cell transplantation and Comparison with HLA-identical sibling transplantation. Clin Infect Dis. 2018 Nov 13;67(suppl_2):S162-S173. http://www.ncbi.nlm.nih.gov/pubmed/30423054   

• Single-center cohort study of 1847 consecutive patients undergoing haploidentical or HLA-MRD HCT from 2013 to 2016 to assess pre-engraftment BSI and its impact on patient outcomes
• Patients included in the investigation had a diagnosis of AML or MDS and received myeloablative conditioning (busulfan/cytarabine/cyclophosphamide/simustine or TBI/cyclophosphamide/simustine for MRD; busulfan/cytarabine/cyclophosphamide/ATG/simustine or TBI/cyclophosphamide/ATG/simustine for haploidentical) and all patients received the same GVHD prophylaxis (cyclosporine/mycophenolate mofetil/short-course methotrexate)
• All patients received the same infection prophylaxis, including norfloxacin, acyclovir, bactrim, and fluconazole
• BSI was defined as the isolation of a bacterial or fungal pathogen from at least one blood culture (two cultures for coagulase-negative staphylococci and common skin contaminants)
• Cumulative incidence of pre-engraftment BSI was higher (30 day: 9.2% vs 1.7%, p<0.0001) with those patients undergoing haploidentical HSCT as compared to MRD HSCT. Median onset of BSI was earlier (day +3 vs day +9, p=0.001) with the haploidentical patient population
• Multivariate analysis suggested variables associated with BSI after haploidentical HCT included a diagnosis of MDS, interval from diagnosis to HCT >190 days, carbapenem therapy, and grade 3-4 intestinal mucositis. Multivariate analysis also suggested that BSI was a risk factor (hazard ratio 2.281, p=0.003) for increased all-cause mortality at 3 months post haploidentical HCT
• The authors concluded that pre-engraftment BSI was more common after haploidentical HCT than MRD HSCT and that it was an independent factor associated with increased all-cause mortality at 3 months post-HCT

Abbreviations:

allo-HCT: allogeneic hematopoietic cell transplantation

AML: acute myeloid leukemia

ANC: absolute neutrophil count

ASCT: autologous stem cell transplant

ATG: antithymocyte globulin 

ATLG: anti-T lymphocyte globulin

B-NHL: B cell lymphoma

BSI: bloodstream infections

BuFlu: busulfan/fludarabine

cGVHD: chronic graft-verses-host disease

CI: confidence interval

CR: complete remission

CMV: cytomegalovirus

DLBCL: diffuse large B cell lymphoma

FLAMSA: fludarabine + cytarabine + amsacrine chemotherapy

GVHD: graft-versus-host disease

haploHCT: haploidentical hematopoietic cell transplantation

HCT: hematopoietic cell transplant

HLA: humal leukocyte antigen

IR: immune reconstitution

MA: myeloablative

MAC: myeloablative conditioning

MDS: myelodysplastic syndrome

MPN: myeloproliferative neoplasm

MRD: matched related donor

NMA: nonmyeloablative

NRM: nonrelapse mortality

OS: overall survival

PFS: progression free survival

PLT: platelet

PTCy: post-transplant cyclophosphamide

RIC: reduced intensity conditioning

RIT: radioimmunotherapy

TBI: total body irradiation

Tconv: conventional T cells

Treg: regulatory T cells

UCBT: umbilical cord blood transplant

ASBMT Pharmacy SIG Communications Working Committee:

Brandi Anders, Tiene Bauters, Eileen Chen, David Eplin, Katie Gatwood, Jason Jared, Kathryn Maples, Shreya Shah, Ryan Shaw