12.09.19

Pharmacy SIG Literature Update: The Effect of Enteral and Parenteral Nutrition and More

In this month’s Pharmacy SIG Literature Update:  The effect of enteral and parenteral nutrition on the gastrointestinal microbiome post-allogeneic transplantation, outcomes of allogeneic hematopoietic stem cell transplantation in patients age > 69 years with AML, ibrutinib for chronic graft-versus-host disease after failure of prior therapy 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

**Baron F, Labopin M, Savani BN, et al. Graft-versus-host disease and graft-versus-leukaemia effects in secondary acute myeloid leukaemia: a retrospective, multicentre registry analysis from the Acute Leukaemia Working Party of the EBMT. Br J Haematol. 2019. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31612473                              

  • Retrospective registry-based study of 2414 patients to evaluate susceptibility of secondary AML to graft-versus-leukemia effects and incidence of GVHD in patients receiving either a MSD, MUD, or 9/10 MMUD HCT with no ex vivo T-cell depletion of the graft
  • 100-day incidence of grade II-IV aGVHD was 25% while 2-year incidence of cGVHD was 38%
  • Relapse rates were significantly lower in patients with cGVHD
  • Limited and extensive cGVHD and grade 3-4 aGVHD were associated with higher NRM and limited cGVHD led to improved OS
  • In comparison to MSD recipients, MUD recipients had a lower risk of relapse (HR = 0.82, P = 0.03) but higher NRM (HR = 1.38, P = 0.004)
  • These data demonstrate secondary AML is susceptible to graft-versus-leukemia effects. Although GVHD appeared to reduce relapse rate, this benefit was somewhat offset by the increased NRM which limited the impact on OS

*Heinicke T, Labopin M, Polge E, et al. Fludarabine/busulfan versus fludarabine/total-body-irradiation (2 Gy) as conditioning prior to allogeneic stem cell transplantation in patients (≥ 60 years) with acute myelogenous leukemia: a study of the acute leukemia working party of the EBMT. Bone Marrow Transplant. 2019. [Epub ahead of print].  https://www.ncbi.nlm.nih.gov/pubmed/31645668           

  • Single center, retrospective comparison of outcomes related to patients ≥ 60 years of age, with AML, undergoing alloHCT following either fludarabine/busulfan or fludarabine/TBI-2Gy conditioning regimens
  • Of the total 1088 patients, 47% received their graft from MSDs and 53% from MUDs.  T-cell depletion was applied to 79% of patients who received fludarabine/busulfan and none of the patients who received fludarabine/TBI-2Gy
  • cGVHD was lower in MSD patients receiving fludarabine/busulfan with T-cell depletion (HR 0.49, p=0.08) and in patients who did not have worse NRM (HR: 2.14, p=0.04)
  • Patients who were transplanted from MUDs, had higher incidence of cGVHD (HR: 2.44, p<0.0001) and worse GVHD-free, relapse-free survival (HR: 1.35, p=0.03) with fludarabine/TBI-2Gy compared to fludarabine/busulfan
  • Outcomes were similar in regards to OS, NRM, aGVHD, leukemia-free survival, and relapse incidence between the two regimens

*Issa H, Sharma N, Zhao Q et al.  Comparison of two doses of antithymocyte globulin in reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation.  Biol Blood Marrow Transplant. 2019;25(10):1993-2001.  https://www.ncbi.nlm.nih.gov/pubmed/31229641           

  • Retrospective review of 357 patients who received RIC for a matched unrelated or mismatched-related alloHCT including rabbit-ATG at 6mg/kg (R-ATG, n=216) or 4.5mg/kg (r-ATG, n=141) between October 2007 and September 2016 at The Ohio State University Comprehensive Cancer Center
  • Baseline characteristics between the two groups were similar but patients in the r-ATG group were younger, received more bone marrow grafts, and had lower comorbidity indexes
  • Day 180 incidence of aGVHD was higher in the r-ATG group for grade II-IV (59% vs 44%, p=0.006) and grade III-IV (20% vs 12%, p=0.029)
  • No significant differences were found for cGVHD at 24 months, relapse, NRM, PFS, OS, and GVHD-free, relapse-free survival
  • More patients reactivated CMV in the R-ATG group (26% vs 9%, p<0.001) and EBV (9% vs 18%, p=0.03), but bacterial infections were higher in the r-ATG group (29% vs 18%, p=0.01)
  • The authors conclude that despite increased aGVHD in the r-ATG group it did not impact overall clinical outcomes and therefore prospective randomized controlled trials should be performed to determine the appropriate ATG dose for RIC

**Ringden O, Boumendil A, Labopin M, et al.  Outcome of allogeneic hematopoietic stem cell transplantation in patients’ age >69 years with acute myelogenous leukemia:  on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.  Biol Blood Marrow Transplant. 2019;25(10):1975-1983.  https://www.ncbi.nlm.nih.gov/pubmed/31181255           

  • Retrospective review comparing outcomes of 713 patients age >70 years and 16,661 patients age 50-69 years with AML who received an alloHCT between 2004-2014 reported to the EBMT.
  • The older group included more males, secondary AML, advanced disease, KPS <90, peripheral blood stem cell grafts, MUDs, RIC conditioning, and in vivo TCD
  • Cumulative incidence of aGVHD grade II-IV and cGVHD at 2 years were not statistically different between the 2 groups, neither was the risk of relapse at 2 years (33% vs 32%)
  • NRM for older patients was higher at 2 years compared to the younger group at 34% (95% CI, 31%-38%) vs 24% (95% CI, 25%-32%) (p <0.001).  Factors significant for increased NRM included AML status of CR1 and CR2, secondary AML, female donor to male recipient, seronegative CMV patient/donor, KPS <80, MAC conditioning, MUD graft, and in vivo T-cell depletion
  • OS for older patients at 2 years was 38% (95% CI, 34%-42%) vs 50% (95% CI, 49%-50%) in younger patients (p<0.001).  The 2-year OS for patients with advanced AML however, did not differ between the two groups (35% vs 33%, p=0.36)
  • The authors conclude that patients > 70 had inferior outcomes but those with active disease should be considered for transplant

*Vij R, Le-Rademacher J, Laumann K, et al.  A phase II multicenter study of the addition of azacitidine to reduced-intensity conditioning allogeneic transplantation for high-risk myelodysplasia (and older patients with acute myeloid leukemia):  results of CALGB 100801 (Alliance).  Biol Blood Marrow Transplant. 2019;25(10):1984-1992.  https://www.ncbi.nlm.nih.gov/pubmed/31212080           

  • Phase II, multicenter trial of 63 patients with AML (n=13) and high-risk MDS (n=50) who underwent alloHCT followed by maintenance azacitidine to improve 2-year PFS. Median age was 62 years (44-74), with 23 (36.5%) receiving MRD grafts and 40 (63.5%) MUD grafts
  • Conditioning included fludarabine, rabbit-ATG, and PK-targeted busulfan via test dose to achieve an AUC 4000 µM/min.  GVHD prophylaxis was tacrolimus and methotrexate. Six maintenance azacitidine cycles (32mg/m2/d x 5 days, every 28 days) were planned
  • Estimated PFS probability at 2 years post-transplant was 41.2% (80% CI, 33.9%-49.9%) and estimated OS probability at 2 years was 45.7% (95% CI, 34.9%-59.9%).  NRM at 2 years was 33.4% (95% CI, 22%-45%)
  • Fifty-four (87.1%) patients were within 20% of target busulfan AUC based on PK validation sampling
  • Forty-one (65%) patients started azacitidine at a median of 61 days (43-91) post-transplant with only 17 (27%) patients completing all 6 planned cycles
  • Authors conclude that RIC conditioning with PK-targeted busulfan via test dose was possible; however, post-transplant azacitidine may not be feasible for all patients but may benefit a more select group of patients

Graft Versus Host Disease Treatment

*Waller E, Miklos D, Cutler C, et al.  Ibrutinib for chronic graft-versus-host disease after failure of prior therapy:  1-year update of a phase 1b/2 study.  Biol Blood Marrow Transplant. 2019;25(10):2002-2007.  https://www.ncbi.nlm.nih.gov/pubmed/31260802

  • Follow up of multicenter, prospective, open-label study of 42 patients with steroid-dependent or refractory cGVHD who had failed < 3 prior regimens.  Patients were given ibrutinib 420mg daily
  • Primary efficacy endpoint was cGVHD response based on the 2005 NIH criteria
  • At median follow-up of 26 months, best overall response rate was 69%, including 31% who achieved CR and 38% PR.  Sustained responses of >44 weeks were seen in 55% of those who responded.  Patients with multiorgan involvement had multiorgan responses including decrease in sclerosis
  • In responders the median corticosteroid dose decreased from a baseline of 0.3mg/kg/day to 0.1mg/kg/day at week 52. Eight patients discontinued corticosteroids
  • Safety remained consistent from prior analysis with grade 3 AEs being most common in the first 6 months which included 6 episodes of pneumonia.  Patients who were on concomitant moderate-strong cytochrome P450 3A inhibitors did not exhibit higher rates of AEs
  • After an additional year, sustained CR rate increased from 21% to 31% with continued decrease in median corticosteroid dose.  Authors caution that patients should be closely monitored and receive prophylaxis for opportunistic infections

Haploidentical Transplantation

*Peric Z, Mohty R, Bastos J, et al. Thiotepa and antithymocyte globulin-based conditioning prior to haploidentical transplantation with post-transplant cyclophosphamide in high-risk hematological malignancies. Bone Marrow Transplant. 2019. [Epub ahead of print].  https://www.ncbi.nlm.nih.gov/pubmed/31673080

  • Single center, prospective study assessed patients who underwent haploidentical, peripheral blood, HCT with a myeloablative, thiotepa-based conditioning regimen with ATG and PTCy to evaluate efficacy, toxicity, and immune reconstitution
  • From 2013 to 2017, 80 adult patients with hematological malignancies received conditioning with either thiotepa-busulfan-fludarabine if in complete remission (66%) or thiotepa-etoposide-cyclophosphamide if relapsed/refractory (44%)
  • Median time to neutrophil engraftment was 17 days (range, 12-34).  Incidence of aGVHD, severe cGVHD, NRM, and relapse were 16%, 16%, 26%, and 26%, respectively.  Two year OS and disease-free survival were 53% and 47%, respectively.  No significant differences between patients in CR and relapsed/refractory patients were noted
  • Thiotepa-based regimens in combination with PTCy may be modified to contain ATG and use peripheral blood stem cells as a graft source, while still maintaining low toxicities, GVHD prevention, and low rates of relapse

Infectious Disease

** Maertens J, Cordonnier C, Jaksch P, et al. Maribavir for preemptive treatment of cytomegalovirus reactivation. N Engl J Med. 2019;381(12):1136-47. https://www.ncbi.nlm.nih.gov/pubmed/31532960

  • Phase II, open-label, dose-blinded trial to assess the safety, side-effect profile, and antiviral activity of different doses of maribavir as compared with valganciclovir for preemptive treatment of CMV infection in adult patients who had undergone alloHCT or solid organ transplantation experiencing CMV reactivation (1000 to 100,000 DNA copies per milliliter)
  • 161 patients were randomized to receive maribavir at a dose of 400 mg, 800 mg, or 1200 mg twice daily or valganciclovir 900 mg twice daily for weeks 1 through 3 and then 900 mg once daily after week 3 for a total treatment duration of 12 weeks
  • At three weeks, 62% of patients receiving maribavir and 56% of patients receiving valganciclovir had a response to treatment; at six weeks, 79% of patients receiving maribavir and 67% of patients receiving valganciclovir had a response to treatment, with all responses in the maribavir dose groups being similar
  • Incidence of serious AEs occurring or worsening during treatment was higher in the maribavir groups compared to the valganciclovir group (44% vs. 32%) and a greater number of patients discontinued the trial medication in the maribavir group (23% vs. 12%)
  • Maribavir 400 mg twice daily for 12 weeks demonstrated similar efficacy to valganciclovir for clearance of CMV viremia and had a higher incidence of gastrointestinal AEs (e.g., dysgeusia) and a lower incidence of neutropenia

*Morrisette T, Van Matre A, Miller M, et al.  Oral vancomycin prophylaxis as secondary prevention against Clostridioides difficile infection in the hematopoietic stem cell transplantation and hematologic malignancy population.  Biol Blood Marrow Transplant. 2019;25(10):2091-2097.  https://www.ncbi.nlm.nih.gov/pubmed/31255741           

  • Retrospective cohort study to examine the safety and efficacy of subsequent CDI prophylaxis with oral vancomycin compared to no prophylaxis following initial treatment with oral vancomycin 125mg every 6 hours for 14 days
  • Patient population (n=50) included 30 HCT recipients of which 16 received a cord blood transplant
  • Prophylactic vancomycin (125mg twice daily until 7 days after discontinuation of antibiotics) was administered to 29 patients
  • Recurrent CDI was lower in the prophylaxis group (5% versus 35%; p=0.016) without an increase in VRE infection (14% versus 10%; p=0.686)
  • No differences in treatment failures, 30-day readmissions, or 60-day mortality were found between the two groups
  • The authors conclude that prophylaxis appears to be safe and effective for secondary prevention, but further research is needed to determine optimal duration and dosing

Nutrition

*Andersen S, Staudacher H, Weber N, et al. Pilot study investigating the effect of enteral and parenteral nutrition on the gastrointestinal microbiome post-allogeneic transplantation. Br J Haematol. 2019. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31612475

  • Patients were randomized 1:1 to receive proactive EN (nasogastric feeding commencing on day one post-HCT; n = 13) or standard care (PN when required; n = 10) and stool samples obtained on D+30 in those enrolled in this pilot study
  • There was no difference in microbial diversity between patients who received predominantly EN vs. PN; however, patients who received predominantly EN had greater abundance of Faecalibacterium (P < 0.001) and ruminococcus E bromii (P = 0.026)
  • Patients who had minimal oral intake for a longer duration had a different overall microbial profile (P = 0.044), lower microbial diversity (P = 0.004) and lower abundance of faecalibacterium prausnitzii_C (P = 0.03) and Blautia (P = 0.007) compared to patients with greater oral intake
  • Lower microbial diversity was found in patients who received additional beta lactam antibiotics (P = 0.042) or had a longer length of hospital stay (P = 0.019)
  • Post-HCT oral intake should be encouraged to maintain microbiota diversity and, if nutrition support is required, EN may promote a more optimal microbiota profile

Other

**Nickel RS, Horan JT, Abraham A, et al. Human leukocyte antigen (HLA) class I antibodies and transfusion support in paediatric HLA-matched haematopoietic cell transplant for sickle cell disease. Br J Haematol. 2019. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31674662             

  • Multi-center study of 45 pediatric SCD patients undergoing HLA-matched HCT to determine if patients with HLA class I antibodies pre-HCT would require more platelet transfusions in the peri-transplant period
  • The number of platelet transfusions received before day +45 was compared between those with and without antibodies
  • 29% of patients had a positive HLA class I antibody screen, and these patients received significantly more platelet transfusions than patients without antibodies (median 19 vs. 7.5, P = 0.028)
  • Patients with HLA class I antibodies also had a higher incidence of aGVHD: 46% vs. 9%, P = 0.011
  • This study supports the idea that pre-HCT HLA class I alloimmunization is associated with increased platelet transfusion support and aGVHD in pediatric HLA-matched HCT for SCD

Abbreviations:

AE: adverse event

aGVHD: acute graft-versus-host disease

aHCT: autologous hematopoietic cell transplantation

alloHCT: allogeneic hematopoietic cell transplantation

AML: acute myeloid leukemia

ATG: antithymocyte globulin

AUC: area under the curve

cGVHD: chronic graft-versus-host disease

CDI: Clostridioides difficile infection                                 

CMV: cytomegalovirus

CR: complete response

EBMT:  European Society for Blood and Marrow Transplantation

EBV: Epstein-Barr virus

EFS: event-free survival

EN: enteral nutrition

FFS: failure free survival

GVHD: graft-versus-host disease

HCT: hematopoietic cell transplantation

HLA:  human leukocyte antigen

KPS:  Karnofsky performance score

MAC: myeloablative conditioning

MDS: myelodysplastic syndrome

MMUD: mismatched unrelated donor

MRD: matched related donor

MSD: matched sibling donor

MUD: matched unrelated donor

NIH: National Institutes of Health

NRM: non-relapse mortality

OS: overall survival

PFS: progression-free survival

PK: pharmacokinetic

PN: parenteral nutrition

PR: partial response

PTCy: post-transplant cyclophosphamide

RIC: reduced-intensity conditioning

SCD: sickle cell disease

TBI: total-body-irradiation

VRE:  vancomycin-resistant Enterococci

 

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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