Pharmacy SIG Literature Update: Cryotherapy as Prophylaxis Against Oral Mucositis and More

In this month’s Pharmacy SIG Literature Update: Cryotherapy as prophylaxis against oral mucositis, CD19 CAR T cells in non-Hodgkin lymphoma, risk of latent tuberculosis reactivation after HCT, fertility preservation in HCT patients 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

*Candoni A, Rambaldi A, Fanin R, et al. Outcome of allogeneic hematopoietic stem cell transplantation in adult patients with Philadelphia positive acute lymphoblastic leukemia in the era of tyrosine kinase inhibitors. A registry-based study of the Italian Blood and Marrow Transplantation Society (Gitmo). Biol Blood Marrow Transplant. 2019 Aug 7. [Epub ahead of print].


  • Registry-based analysis to describe the clinical outcome of adult patients with Ph+ ALL who underwent an alloHCT after a TKI-based treatment (n = 441) over a 10 year period
  • OS at 1, 2, and 5 years was 69.6%, 61.1% and 50.3%, respectively, with a median OS of 62 months. PFS at 1, 2, and 5 years was 60.2%, 52.1% and 43.7%, respectively
  • OS and PFS were significantly better in patients who were in CR and MRD-negative at the time of HCT compared with patients who were in CR but MRD-positive (50% OS not reached versus 36 months; P = 0.015; 50% PFS not reached versus 26 months, P = 0.003)
  • NRM after 1, 2, and 5 years was 19.1%, 20.7%, and 24.1%, respectively and was significantly lower with a modified EBMT risk score of 0 to 2 compared with >3 (15% versus 25%; P = 0.016)
  • TKIs were used in 40% post-transplant with 74% of these patients receiving TKIs as preemptive or prophylactic therapy
  • This data suggests HCT is a potentially curative treatment for Ph+ ALL with especially promising outcomes in MRD-negative patients. The authors also echo the EBMT Acute Leukemia Working Party position emphasizing post-transplant MRD assessments with prompt prophylactic or preemptive use of TKIs

Autologous Transplantation

*Blocka J, Hielscher T, Mueller-Tidow C, et al.  Salvage therapy versus upfront autologous stem cell transplantation in multiple myeloma patients with progressive disease after first-line induction therapy.  Leuk Lymphoma. 2019 Aug 19. [Epub ahead of print].  https://www.ncbi.nlm.nih.gov/pubmed/31423866

  • Retrospective analysis of 1599 newly diagnosed MM patients to analyze if patients with progressive disease after induction should receive salvage therapy or proceed directly to aHCT
  • 5% (n=120) had progressive disease after first-line induction and 1.4% of patients (n=23) received salvage therapy prior to aHCT
  • PFS and OS were not statistically different for those with progressive disease versus those with at least stable disease (n=1479) after induction therapy (HR=1.23; 95% CI, 0.93-1.65; p=0.1)
  • Deepening of response with salvage therapy did not lead to a difference in PFS (HR=0.71, p=0.5) or OS (HR=0.77, p=0.6) versus those with progressive disease
  • The authors conclude that patients with progressive disease may benefit from direct aHCT rather than salvage induction, but due to small sample size the results of their study should be interpreted with caution

*Ghilardi G, Pabst T, Jeker B, et al.  Melphalan dose in myeloma patients ≥65 years of age undergoing high-dose therapy and autologous stem cell transplantation: a multicentric observational registry study.  Bone Marrow Transplant.  2019 Jul;54(7):1029-1037. https://www.ncbi.nlm.nih.gov/pubmed/30390061

  • Patients over the age of 65 (n=388) receiving melphalan 200 mg/m2 or 140 mg/m2 were assessed for mortality, PFS, and OS
  • Patients who received Melphalan 200 mg/m2 were slightly younger and had a better renal function, but did not differ with regards to ISS stage, cytogenetic risk, remission status, and performance status
  • There was no meaningful association seen with melphalan dose and patient PFS (median PFS in melphalan 200 mg/m2 was 27.7 months and 22.1 months in the melphalan 140 mg/m2 group [p = 0.294]). Median OS in the melphalan 200 mg/m2 and in melphalan 140 mg/m2 group was 91.2 and 61.2 months, respectively (p = 0.015). However, multivariate analysis showed no significant association between the melphalan dose and OS (HR 0.734; CI95% 0.264-2.038; p = 0.553)
  • There are no significant differences in safety and PFS for elderly myeloma patients treated with melphalan 200 mg/m2 or with lower melphalan doses

*Johansson JE, Bratel J, Hardling M, et al. Cryotherapy as prophylaxis against oral mucositis after high-dose melphalan and autologous stem cell transplantation for myeloma: a randomised, open-label, phase 3, non-inferiority trial. Bone Marrow Transplant. 2019 Sep;54(9):1482-1488. https://www.ncbi.nlm.nih.gov/pubmed/30718802

  • Prospective, randomized trial of 94 patients with a diagnosis of MM undergoing aHCT. Patients were randomized 1:1 to receive cryotherapy for 7 h (N = 46) or 2 h (N = 48)
  • No significant difference was observed with respect to the proportion of patients who showed grades 3 and 4 toxicity according to the World Health Organization scale (2.1 and 4.3% for 2 and 7 h, respectively; 95% CI −0.09 to 0.049; p = 0.98)
  • Two hours of cryotherapy was as effective as 7 hours in terms of protecting against severe oral mucositis in connection with aHCT for MM

Chimeric Antigen Receptor (CAR) T-cell Therapy

*Sauter C, Senechal B, Riviere I et al.  CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma.  Blood. 2019;134(7):626-635. https://www.ncbi.nlm.nih.gov/pubmed/31262783

  • Phase I study of 15 patients given autologous second-generation 19-28z CAR T-cells after myeloablative conditioning and aHCT
  • Patients were conditioned with standard BEAM (carmustine, etoposide, cytarabine, and melphalan) followed by aHCT and pegfilgrastim on day + 1. CAR T-cells were given on day +2 (two-thirds of dose) and day +3 (one-third of dose).
  • First patient treated at dose level 2 (1 x 107 19-28z CAR T-cells/kg) experienced grade 4 CRS, all other patients treated at dose level 1 (5 x 106/kg)
  • 67% (10/15) experienced grade 3-4 neurotoxicity with median onset of 5 days post CAR T-cell infusion and median resolution of 9.5 days. 6 of the 10 patients also experienced grade 2-4 CRS.  Nine received tocilizumab and 4 also received dexamethasone as treatment.
  • The 2-year PFS is 30%, and there was no association between CAR T-cell expansion or persistence and PFS.
  • The authors conclude that the use of CAR T-cells post aHCT may benefit those patients with high-risk lymphoma.

Graft versus Host Disease

*Yang J, Jiang J, Cai Y, et al.  Low-dose anti-thymocyte globulin plus low-dose posttransplant cyclophosphamide as graft-versus-host disease prophylaxis in haploidentical peripheral blood stem cell transplantation combined with unrelated cord blood for patients with hematologic malignancies: a prospective, phase II study.  Bone Marrow Transplant. 2019 Jul;54(7):1049-1057. https://www.ncbi.nlm.nih.gov/pubmed/30446741

  • Eligible patients (n=32) with myeloablative haploidentical unrelated cord blood transplants received a novel regimen of GVHD prophylaxis with ATG at 5 mg/kg and PTCy at 50 mg/kg
  • All patients received myeloablative conditioning regimens except for 3 patients. The GVHD prophylaxis consisted of ATG 2.5 mg/kg administered on day -2 to -1 and Cy 50 mg/kg on day +3, as well as CSA and MMF initiated on day +4
  • Grade II-IV and III-IV aGVHD were seen in 19.4% and 6.9% of patients by day 100, respectively. The 1-year probability of relapse, DFS, and OS was 25.1% (95% CI 7.3-49.2%), 59% (95% CI, 33.3−84.7%) and 78.4% (95% CI, 63−93.8%), respectively. Rates of CMV and EBV reactivation by day 180 were around 40%
  • This prospective study shows that low-dose ATG + PTCy in patients receiving haploidentical unrelated cord blood transplant is a potential option

Infectious Disease

*Cheng MP, Kusztos AE, Bold TD, et al. Risk of latent tuberculosis reactivation after hematopoietic cell transplantation. Clin Infect Dis. 2019;69(5):869-72.  https://www.ncbi.nlm.nih.gov/pubmed/30689792

  • Single center, retrospective cohort study assessed adult patients who underwent HCT to determine LTBI prescription practices and tuberculosis rates
  • From 2010 to 2015, of the 2531 patients who underwent HCT (1252 aHCT, 1279 alloHCT), 91 (3.6%) had positive LTBI screening tests prior to HCT and 63 of those patients were identified for preventative therapy post-HCT
  • Among the 63 patients identified for preventative therapy, 30 (47.6%) were treated within 3 months of HCT, 4 (6.3%) initiated treatment later than 3 months post-HCT, and 29 (46%) did not receive treatment
  • No cases of active tuberculosis were identified in the cohort of 2531 patients undergoing HCT throughout the duration of the study, more specifically, no cases were identified in those patients with LTBI
  • Authors concluded that data suggest LTBI therapy may be deferred in the immediate post-HCT setting and that the optimal timing to start LTBI therapy and minimal duration remain undefined


**Curran D, Matthews S, Rowley SD, et al. Recombinant zoster vaccine significantly reduces the impact on quality of life caused by herpes zoster in adult autologous hematopoietic stem cell transplant recipients: a randomized placebo-controlled trial (ZOE-HSCT). Biol Blood Marrow Transplant. 2019 Aug 5. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31394276

  • Randomized, placebo-controlled, phase III multicenter study to assess the efficacy, immunogenicity, and safety of RZV in aHCT recipients aged >18 years
  • Recipients were randomized 1:1 to receive 2 doses of RZV or placebo, given 1 to 2 months apart starting between day +50 and day +70
  • QoL was measured by the Short Form Survey-36 and Euro-QoL-5 Dimension at baseline, 1 month, and 1 year post-dose 2 and during suspected HZ episodes with the ZBPI
  • The ZBPI maximum worst pain score was significantly lower in the RZV than placebo group (mean: 5.8 versus 7.1, P = 0.011)
  • RZV showed significantly better QoL scores than placebo 1 week following rash onset among patients with confirmed HZ
  • In addition to reducing the risk of HZ and its complications (see Bastidas et al. JAMA. 2019;322:122-133), RZV significantly reduced the impact of HZ on patients’ QoL in those who developed breakthrough disease

** Loren A, Senapati, S.  Fertility preservation in patients with hematologic malignancies and recipients of hematopoietic cell transplants.  Blood. 2019;134(9): 746-760.  https://www.ncbi.nlm.nih.gov/pubmed/31292116

  • Review on the causes of infertility and methods for preservation in male and female patients with acute leukemias, lymphoma, CML, and patients undergoing HCT
  • The authors recommend assessing the clinical need for urgent cancer-directed therapy based on the presence of leukostasis, cytopenias, DIC, TLS, fever/infection, or mediastinal mass with cardiopulmonary compromise to help determine fertility preservation options
  • Specifically, for females: if an urgent need is present, consider starting a gonadotropin-releasing hormone agonist prior to cancer-directed therapy; if no urgent need is present, refer to reproductive specialist for oocyte/embryo cryopreservation
  • Recommend referring patients to a reproductive specialist for post-remission fertility evaluations if desired by the patient

 *Sabloff M, Chhabra S, Wang T, et al. Comparison of high doses of total body irradiation in myeloablative conditioning prior to hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2019 Aug 7. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31473319

  • CIBMTR study evaluating 2721 patients receiving Cy/TBI, with TBI at varying doses, as conditioning in anticipation of a first alloHCT from a well-matched sibling or unrelated donor
  • At 5 years post-HCT, NRM was 28% for the SD-TBI group, 32% for the IH-TBI group and 34% for the HD-TBI group (P = 0.02)
  • 5-year OS was 42% , 40% and 45% in SD-TBI, IH-TBI and HD-TBI  groups, respectively  (P = 0.39)
  • 5-year cumulative incidence of relapse was 36% in SD-TBI group, 32% in IH-TBI and 26% in HD-TBI group (P < 0.001)
  • TBI dose of 12 Gy (standard-dose TBI) was shown to reduce NRM, but this advantage was hampered by an increased incidence of relapse, and that likely translated into no significant impact on OS. Doses over 12 Gy may lead to greater morbidity and were numerically associated with higher incidence of organ failure. Paradoxically HD-TBI was also associated with lower rates of cGVHD. The mix of findings lead to the authors recommending TBI at 12 Gy as the optimal dose to be included in conditioning regimens


aGVHD: acute graft-versus-host disease

aHCT: autologous hematopoietic cell transplantation

ALL: acute lymphocytic leukemia

alloHCT: allogeneic hematopoietic cell transplantation

ATG: antithymocyte globulin

CAR:  chimeric antigen receptor

cGVHD: chronic graft-versus-host disease

CI: confidence interval                                                           

CIBMTR: Center for International Blood and Marrow Transplant Research

CMV: cytomegalovirus

CML: chronic myeloid leukemia

CR: complete response

CRS: cytokine release syndrome

CSA: cyclosporine A

Cy: cyclophosphamide

DFS: disease-free survival

DIC: disseminated intravascular coagulation

EBMT: European Society for Blood and Marrow Transplantation

EFS: event free survival

GI: gastrointestinal

GVHD: graft-versus-host disease

HCT: hematopoietic cell transplantation

HD-TBI: high-dose TBI (14 Gy)

HR: hazard ratio

HZ: herpes zoster

IH-TBI: Intermediate-dose TBI (13-13.75 Gy)

ISS: international staging system

LTBI: latent tuberculosis infection

MM: multiple myeloma

MMF: mycophenolate mofetil

MRD: minimal residual disease

NRM: non-relapse mortality

OS: overall survival

Ph+ ALL: Philadelphia chromosome-positive acute lymphoblastic leukemia

PFS: progression-free survival

PTCy: post-transplant cyclophosphamide

QoL: quality of life

RZV: recombinant zoster vaccine

SD-TBI: standard-dose TBI (12 Gy)

TBI: total body irradiation

TKI: tyrosine kinase inhibitor

TLS: tumor lysis syndrome

ZBPI: Zoster Brief Pain Inventory

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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