Pharmacy SIG Literature Update: Major Guideline Updates, Use of Reduced Intensity Conditioning Regimens and More

In this month’s Pharmacy SIG Literature Update: Major guideline updates, use of reduced intensity conditioning regimens, novel treatment and prevention strategies for acute GVHD, 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

Guideline Updates

***Kanate AS, Majhail NS, Savani BN, et al. Indications for Hematopoietic Cell Transplantation and Immune Effector Cell Therapy: Guidelines from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. 2020;26(7):1247-1256. https://pubmed.ncbi.nlm.nih.gov/3216532/

  • Update to 2015 ASTCT consensus guidelines on indications for transplant in the adult and pediatric population, including a major focus on recommended use of IEC therapy
  • IEC
    • For all pediatric patients and adults up to age 25 years with B-ALL beyond a second relapse, tisagenlecleucel was added as SOC
    • For relapsed or refractory large B cell lymphoma after at least 2 prior lines of therapy, tisagenlecleucel and axicabtagene ciloleucel were added as SOC
  • AutoHCT
    • Considered SOC for amyloid light-chain amyloidosis, based on improved outcomes from 2007-2012 study demonstrating improved 5-year OS of 77% (vs 55% previous) and 100-day TRM of 5% with autoHCT
  • AlloHCT
    • Potential treatment option in pediatric/AYA CML in early chronic phase, based on a CIBMTR registry trial showing safety and efficacy of alloHCT with 5-year OS of 75%
    • Systemic mastocytosis and blastic plasmacytoid dendritic cell neoplasm added as rare indications for alloHCT
    • For non-malignant disorders, alloHCT should be considered for sickle cell disease with severe disease phenotypes, based on several single-institution studies demonstrating OS rates of 80-100% and DFS of >70%

***Lehrnbecher T, Fisher BT, Phillips B, et al. Guideline for Antibacterial Prophylaxis Administration in Pediatric Cancer and Hematopoietic Stem Cell Transplantation. Clinical Infect Dis. 2020; 71(1):226-236. https://pubmed.ncbi.nlm.nih.gov/31676904/

  • Clinical practice guideline for the use of systemic antibacterial prophylaxis agents in the pediatric patient diagnosed with cancer and undergoing HCT
  • Routine use of systemic antibacterial prophylaxis is recommended in children receiving intensive chemotherapy for AML and relapsed ALL
  • Routine use of systemic antibacterial prophylaxis was not recommended for children undergoing induction chemotherapy for ALL, autoHCT, and alloHCT.  Routine use was also not recommended in children whose therapy would not result in prolonged severe neutropenia.
  • The antibacterial agent of choice, if used, is levofloxacin
  • The authors conclude antibacterial prophylaxis should be used in select pediatric patient populations and future research is needed to evaluate the long-term effectiveness and adverse effects of this intervention

Allogeneic Transplant

**Holstein SA, Suman VJ, Owzar K, e al. Long-Term Follow-up of CALGB (Alliance) 100001: Autologous Followed by Nonmyeloablative Allogeneic Transplant for Multiple Myeloma. Biol Blood Marrow Transplant. 2020;26(8):1414-1424. https://pubmed.ncbi.nlm.nih.gov/32325171/

  • Phase II study evaluating autoHCT by NMA alloHCT in patients with multiple myeloma who had received no more than 18 months of prior therapy and had experienced no more than 1 prior progression event
  • Patients received conditioning for autoHCT with melphalan 200 mg/m2 and conditioning for alloHCT with fludarabine and cyclophosphamide. Of 60 patients enrolled, 57 (95%) completed ASCT and 49 (82%) completed tandem autoHCT-alloHCT.
  • The TRM rate was 2% (9-% CI, 0.10% to 9.3%). Grade II-III aGVHD was observed in 27% of alloHCT patients. In the patients who underwent subsequent alloHCT, 55% developed cGVHD, as either limited (31%) or extensive (24%) in the first year post-alloHCT.
  • At a median follow-up for survival of 11 years, the median OS time was 6.6 years and median time to disease progression was 3.6 years.
  • Authors conclude that this study confirms that tandem autoHCT/alloHCT is associated with durable disease control in a subset of patients, demonstrated the feasibility of performing tandem autoHCT/alloHCT in a cooperative group setting, and determined that a fludarabine/cyclophosphamide NMA regimen is associated with a very low TRM rate

*Mei M, Tsai N, Mokhtari S, et al. Im. Long-Term Outcomes of Allogeneic Hematopoietic Cell Transplant with Fludarabine and Melphalan Conditioning and Tacrolimus/Sirolimus as Graft-versus-Host Disease Prophylaxis in Patients with Acute Lymphoblastic Leukemia. Biol Blood Marrow Transplant. 2020;26(8):1425-1432. https://pubmed.ncbi.nlm.nih.gov/32416253/ 

  • Single center retrospective evaluation at City of Hope of 72 patients who underwent alloHCT with FluMel conditioning between 2005 and 2018, from either a matched sibling or fully matched unrelated donor while in complete remission, with tacrolimus and sirolimus used as GVHD prophylaxis.
  • OS and PFS at 4 years post-transplant were 58% and 44%, respectively. The cumulative incidences of relapse/progression and non-relapse mortality at 4 years were 34% and 22%, respectively.
  • Patients with Ph+ ALL had a significantly lower cumulative incidence of relapse/progression (20% vs 48% for patients with Ph-negative status, p=0.007).
  • Authors conclude that a RIC alloHCT with FluMel conditioning and tacrolimus and sirolimus GVHD prophylaxis regimen was associated with favorable outcomes in patients with Ph+ ALL and should be considered as a viable consolidative therapy for adult patients with ALL

*Brazauskas R, Scigliuolo GM, Wang HL, et al. Risk score to predict event-free survival after hematopoietic cell transplant for sickle cell disease. Blood. 2020;136(5):623-626. https://pubmed.ncbi.nlm.nih.gov/32518950/

  • SCD patients who received alloHCT between 2008-2017 (n = 1425) were randomly split into training (n = 1070) and validation (n = 355) cohorts. Training data set was used to develop prognostic scoring system for EFS, and validation data set was used to evaluate predictive ability of scoring system.
  • Characteristics were similar between both cohorts with a median follow-up of 3 years (range, 0.75-10.4 years). Median age at transplantation was 11 years (range, 1-48 years), 973 (68%) of patients received matched sibling grafts, and 972 (68%) received MAC regimens.
  • Two of 9 risk factors evaluated were significantly associated with EFS: age at transplantation and donor type. Based on these 2 factors, patients were assigned a good, intermediate, or high-risk score for which the relative risk for graft failure or EFS was based on
  • Based on the training cohort, patients age ≤12 years with MSD were lowest risk with a 3-year EFS of 92% (score, 0). Patients ≥ age 13 years with MSD or age ≤ 12 years with MUD were intermediate risk (3-year EFS, 87%; score, 1). All other groups, including patients of any age with haplo or MMUD and patients ≥ age 13 years with MUD were high risk (3-year EFS, 57%; score, 2 or 3). These findings were confirmed in validation cohort.
  • Authors conclude that this prognostic risk score could guide decision-making on the use of alloHCT as a curative treatment option vs other available options in SCD

Graft-Versus-Host Disease

**Im A, Rashidi A, Wang T, et al. Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide. Biol Blood Marrow Transplant. 2020;26(8):1459-1468. https://pubmed.ncbi.nlm.nih.gov/32434056/ 

  • Retrospective analysis of CIBMTR data on adult patients with AML, ALL, MDS, CML who underwent a PTCy based haploHCT from 2013 to 2016, to evaluate the risk factors of developing GVHD after haploHCT with PTCy (n=646). Patients were categorized into 4 groups based on conditioning regimen (MAC or RIC) and graft source (BM or PBSCT).
  • The incidence of grade 2 to 4 aGVHD at 6 months was highest in MAC PBSCT (44%), followed by RIC PBSCT (36%), MAC BM (36%), and RIC BM (30%) (p=0.002). The incidence of cGVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (p<0.001).
  • In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 aGVHD, however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grades II-IV aGVHD (HR=1.53; 95% CI, 1.11 to 2.12). For graft source, PBSCT compared to BM was a significant risk factor for the development of cGVHD (HR=1.70; 95% CI, 1.11 to 2.62) in the RIC setting.
  • There were no differences in relapse or OS between treatment groups.
  • Authors conclude that in RIC haplo-HCT, the risk of cGVHD is higher with PBSCT, without any difference in relapse or OS

*Frairia C, Nicolosi M, Shapiro J, et al. Sole Upfront Therapy with Beclomethasone and Budesonide for Upper Gastrointestinal Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant. 2020;26(7):1303-1311. https://pubmed.ncbi.nlm.nih.gov/32361010/ 

  • Single-center, retrospective review on the use of localized corticosteroids, BDP and BUD, without systemic glucocorticoids as first-line therapy for isolated upper GI aGVHD. Seventy-six patients were treated with BDP alone and 81 patients with combination BDP + BUD, based on physician discretion.
  • After 28 days of treatment, patients receiving BDP had a CR rate of 46%, and PR rate of 10%; patients receiving BDP+BUD, had a CR rate 67%, and PR rate of 10%. After 200 days, in patients receiving BDP, 80% were alive, 34% maintained a CR, and 3% maintained a PR, whereas 53% required additional immunosuppression; in patients receiving BDP + BUD, 91% were alive, 46% maintained a CR, and 2% maintained a PR, whereas 43% required additional immunosuppression.
  • In the entire cohort, 42% of patients were treated successfully without systemic glucocorticoids.
  • Authors conclude that use of poorly absorbable steroids alone may be efficacious in treating patients with isolated upper GI aGVHD

**Bacigalupo A, Angelucci E, Raiola A et al. Treatment of steroid resistant acute graft versus host disease with an anti-CD26 monoclonal antibody-begelomab. Bone Marrow Transplant. 2020;55(8):1580-1587. https://pubmed.ncbi.nlm.nih.gov/32203257/

  • Results from two prospective studies (a pilot study and a dose finding study) and a compassionate use study evaluating begelomab, an anti-CD26 monoclonal antibody for SR-aGVHD
  • A total of 69 patients treated (28 from the prospective studies and 41 from the compassionate use study) – it should be noted the dose and regimen received differed by study
  • Overall response rate at day +28 for all patients was 67% with a CR of 12%. Non-relapse mortality at 6-months was 28% for the prospective studies and 38% for the compassionate use study. Overall survival at 1-year was 50% for the prospective study patients and 33% for the compassionate use patients.
  • Authors concluded that begelomab induces response in SR-aGVHD, including those with severe liver and gut GVHD

*Toubai T, Magenau J. Immunopathology and biology-based treatment of steroid-refractory graft-versus-host disease. Blood. 2020;136(4):429-440. https://pubmed.ncbi.nlm.nih.gov/32526035/

  • Review article on current SR- acute GVHD management as the complex and distinct pathophysiology of SR-GVHD has proven challenging to understand, and there is a lack of clinically informative animal models that address this
  • Many agents that have demonstrated encouraging response rates in early phase 1/2 trials for prevention and treatment are not successful in improving survival in SR-GVHD
  • Novel strategies of selectively targeting alloreactive T cells and antigen presenting cells by targeting key inflammatory mediators (IL-6), influencing cytokine-driven signal transduction (JAK/STAT), or targeting organ homing have shown impressive response rates with manageable toxicity and are undergoing further testing in larger controlled trials
  • Future directions include emphasizing methods to prevent or pre-emptively treat high-risk disease, using emerging knowledge of the pathophysiology of SR-GVHD to detect subclinical disease


** Yoshida N, Takahashi Y, Yabe, H et al. Conditioning regimen for allogeneic bone marrow transplantation in children with acquired bone marrow failure: fludaraine/melphalan vs. fludarabine/cyclosphosphamide. Bone Marrow Transplant. 2020;55(7):1272-1281. https://pubmed.ncbi.nlm.nih.gov/32444864/

  • Retrospective review of 367 pediatric patients in the Japanese Data Center for Hematopoietic Cell Transplantation with acquired BM failure (aplastic anemia or refractory cytopenia of childhood) who were transplanted from 2010-2016 and received either a FluMel (n=71) or FluCy-based regimen (n=296)
  • Three-year FFS was lower in the FluCy group (97% vs 83%; p=0.002). The incidence of late graft failure was higher in the FluCy group compared to the FluMel group (11% vs 3%; p=0.035). Multivariate analyses showed that the FluMel regimen was associated with better failure-free survival (hazard ration 0.12; p=0.005).
  • Authors concluded that FluMel conditioning is a promising option for children with acquired BM failure

Supportive Care

**Corbacioglu S, Kernan NA, Pagliuca A, det al. Incidence of Anicteric Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome and Outcomes with Defibrotide following Hematopoietic Cell Transplantation in Adult and Pediatric Patients. Biol Blood Marrow Transplant. 2020;26(7):1342-1349. https://pubmed.ncbi.nlm.nih.gov/3220012/

  • Post-hoc analysis to examine the incidence of VOD/SOS with a bilirubin level <2 mg/dL (anicteric) before and after Day 21 post-HCT in T-IND patients enrolled following the amendment allowing for diagnosis by the modified Seattle criteria.
  • Of 803 post-HCT patients with VOD/SOS enrolled following the protocol amendment, 23% had a bilirubin level <2 mg/dL and would not have been diagnosed if hyperbilirubinemia was required.
  • The bilirubin level at diagnosis was <2 mg/dL in 165 of 331 patients (50%) diagnosed by the modified Seattle criteria and in 16 of 23 patients (70%) diagnosed by biopsy. Anicteric VOD/SOS was more common in pediatric patients (29%), although it also occurred in adult patients (15%).
  • Patients with hyperbilirubinemia had lower Day 100 survival (54% versus 87% in patients with bilirubin <2 mg/dL) and a higher incidence of MOD (41% vs 26% in patients with bilirubin <2 mg/dL). The incidence of treatment-emergent adverse events and serious adverse events was lower in patients with a bilirubin level <2 mg/dL.
  • These results indicate that anicteric VOD/SOS occurs in both adult and pediatric patients post-HCT and that survival is worse in patients with bilirubin ≥2 mg/dL, suggesting that requiring hyperbilirubinemia for diagnosis may result in diagnosis at a more advanced disease stage and is associated with worse outcomes

Infectious Disease

*Cao W, Wei J, Wang N, et al. Entecavir prophylaxis for hepatitis B virus reactivation in patients with CAR T-cell therapy. Blood. 2020;136(4):516-519. https://pubmed.ncbi.nlm.nih.gov/32291456/

  • Retrospective analysis of HBV reactivation and impact of HBV infection in refractory/relapsed B-ALL or B-cell NHL patients who received CAR19/22 combination T-cell therapy in China between March 2016 and January 2018 (n = 89)
  • 19 (21.3%) had chronic HBV infection (serologically positive for hepatitis B surface antigen [HBsAg]) and 37 (41.6%) had resolved HBV infection (HBsAg- but positive for antibodies against hepatitis B core antigen [HBcAb])
  • Entecavir prophylaxis was started before CAR T-cell infusion and continued for a median of 7.9 months after B-cell recovery in a total of 21 patients, including all 19 HBsAg+ patients and 2 (5.4%) who were HBsAg−/HBcAb+
  • HBV reactivation was detected 4 months after CAR T-cell infusion in 1 (5.3%) patient with chronic HBV infection. Except for this patient, no other patients had HBV reactivation, severe hepatitis (> 5x the upper limit of normal of aminotransferase or > 3x the upper limit of normal of bilirubin), or death from HBV.
  • Authors conclude that entecavir prophylaxis is essential and effective for prevention of HBV reactivation in patients with chronic HBV infection who are undergoing CAR T-cell therapy, and chronic or resolved HBV infection may not affect safety and efficacy of CAR T-cell therapy


aGVHD: acute graft-versus-host disease

ALL: acute lymphoblastic leukemia

alloHCT: allogeneic hematopoietic cell transplantation

AML: acute myeloid leukemia

autoHCT: autologous hematopoietic cell transplantation

AYA: adolescent and young adult

BDP: beclomethasone dipropionate

BUD: budesonide

CAR: chimeric antigen receptor T-cell

cGVHD: chronic graft-versus-host disease

CIBMTR: Center for International Blood and Marrow Transplant Research

CML: chronic myeloid leukemia

CR: complete response

DFS: disease-free survival

EFS: event-free survival

FFS: failure-free survival

FluCy: fludarabine and cyclophosphamide

FluMel: fludarabine and melphalan

GVHD: graft-versus-host disease

haploHCT: haploidentical hematopoietic cell transplantation

HBV: hepatitis B virus

HCT: hematopoietic cell transplantation

IEC: immune effector cell

MAC: myeloablative conditioning

MDS: myelodysplastic syndrome

MOD: multi-organ dysfunction

MMUD: mismatched unrelated donor

MSD: matched sibling donor

MUD: matched unrelated donor

NHL: non-Hodgkin lymphoma

NMA: nonmyeloablative

NRM: non-relapse mortality

OS: overall survival

Ph: Philadelphia chromosome

PR: partial response

PTCy: post-transplant cyclophosphamide

RIC: reduced intensity conditioning

SCD: sickle cell disease

SOC: standard of care

SOS: sinusoidal obstruction syndrome

SR: steroid refractory

TRM: transplant-related mortality

VOD: veno-occlusive disease


ASTCT Pharmacy SIG Research Working Committee:

Kelly Gaffney, Katie Gatwood, Binni Kunvarjee, Andrew Linn, Anne McDonnell, Monank Patel,

Ashley Teusink-Cross, Jigar Trivedi, Theresa Urban, Lily Yan


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