September 2018: Pharmacy SIG Monthly Literature Update

By Content Administrator posted 13 days ago

  

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

Graft Versus Host Disease

**Nygaard M, Andersen NS, Moser CE, et al. Evaluation of infliximab as second-line treatment of acute graft versus host disease – validating response on day 7 and 28 as predictors of survival.  Bone Marrow Transplant. 2018;53:844-851. https://www.ncbi.nlm.nih.gov/pubmed/29391524

  • Retrospective evaluation to validate if response on day 7 and day 28 after second-or-further line infliximab treatment is predictive of survival. Furthermore, this study assessed the composite endpoint 6 months freedom from treatment failure (6MFTF).
  • Sixty-eight patients treated with infliximab for aGVHD were evaluated. The majority of patients had grade III-IV aGVHD.
  • Sixty percent responded on day 7 and 46% on day 28. Twenty-four patients (35%) achieved 6MFTF. The main reasons for failure within 6 months were death (n = 31) or additional immunosuppression (n = 16). Patients with response to infliximab on day 7 and 28 had significantly higher OS probability than non-responders. Both having CR, VGPR or PR on day 7 and having either CR or VGPR on day 28 are predictive of survival.
  • Response to infliximab on day 7 and 28 identifies high and low risk groups. Patients who fail to respond should be identified early and offered alternative therapy.

Pediatrics

**Dvorak CC, Satwani P, Stieglitz E, et al. Disease burden and conditioning regimens in ASCT1221, a randomized phase II trial in children with juvenile myelomonocytic leukemia: A Children's Oncology Group study. Pediatr Blood Cancer. 2018;65:e27034. https://www.ncbi.nlm.nih.gov/pubmed/29528181

  • Phase II, randomized trial to see if reduced toxicity myeloablative conditioning regimen with Bu-Flu (busulfan-fludarabine) would be associated with equivalent outcomes to Bu-Cy-Mel (busulfan-cyclophosphamide-melphalan) in 27 patients with de novo juvenile myelomonocytic leukemia (JMML).
  • ASCT1221was terminated early due to concerns that the Bu-Flu arm had inferior outcomes. The 18-month EFS of the entire cohort was 47% (95% CI, 21-69%), and was 83% (95% CI, 27-97%) and 22% (95% CI, 03-51%) for Bu-Cy-Mel and Bu-Flu, respectively (P = 0.04).
  • Bu-Flu is inadequate to provide diseasecontrol in patients with JMML who present for HCT with large burdens of disease.

*Giulino-Roth L, O’Donohue T, Chen Z, et al. Outcome of children and adolescents with relapsed Hodgkin lymphoma treated with high-dose therapy and autologous stem cell transplantation: the Memorial Sloan Kettering Cancer Center (MSKCC) experience. Leuk Lymphoma. 2018;59:1861-70. https://www.ncbi.nlm.nih.gov/pubmed/29183202

  • Single center, retrospective review of 36 consecutive pediatric patients at MSKCC with relapsed HL treated with auto-HCT from 1989 to 2013.
  • Median follow-up of 9.6 years, the 10-year OS and EFS were 74.1 and 67.1%, respectively.
  • In a subset of patients (n=22), Childhood Hodgkin International Prognostic Score at relapse (R-CHIPS) was calculated and a lower score was associated with improved OS (HR 0.29, p=0.0352) and a trend toward improved EFS (HR 0.38, p=0.0527).
  • Auto-HCT yields durable remission for majority of pediatric patients with relapsed HL and R-CHIPS may be a useful tool but should be evaluated in larger cohorts.

Immunotherapy

*Hernandez I, Prasad V, Gellad WF. Total costs of chimeric antigen receptor T-cell immunotherapy. JAMA Oncol. 2018;4:994-996. https://www.ncbi.nlm.nih.gov/pubmed/29710129

  • Hypothetical cost model with 11 identified scenarios incorporating drug costs (tocilizumab and CAR-T cells), leukapheresis costs (by 2017 Medicare Physician Fee Schedule), facility costs, physician costs, and potential facility costs of hospitalization related to CRS.
  • Probabilities of response and CRS were extrapolated from CAR T-cell approval documents and clinical trial data.
  • The costs were also calculated with the Novartis drug cost waiver for non-responders after 1 month.
  • In total the cost per patient for tisagenlecleucel was ~$430,000 to $511,000 with the lower figure taking into account the Novartis outcomes-based pricing. The cost for patients without CRS averaged almost $480,000 and about $532,000 with severe CRS. Estimating 600 patients per year could be treated would make the annual expenditure $259 million.
  • In total, the cost per patient for axicabtagene ciloleucel was about $403,000; ranging from $377,000 to $415,000 depending on severity of CRS. Estimating 7500 patients per year could be treated would make the annual expenditure more than $3 billion.

*Herbaux C, Merryman R, Devine S, et al. Recommendations for managing PD-1 blockage in the context of allogeneic HCT in Hodgkin lymphoma: taming a necessary evil. Blood. 2018;132:9-16. https://www.ncbi.nlm.nih.gov/pubmed/29720488

  • PD-1 blockade is an effective therapy in relapsed/refractory cHL who have relapsed post-auto-HCT or are ineligible for auto-HCT.
  • Early reports suggest that an allo-HCT after receiving anti-PD-1 agents may be associated with increased toxicity.
  • This working group recommends holding PD-1 therapy for at least 6 weeks before allo-HCT; to use VOD prophylaxis; and to reduce the risk of GVHD by favoring a bone marrow course, RIC, and PtCy-based GVHD prophylactic regimen.
  • In the case of noninfectious febrile syndrome, these authors recommend rapid initiation of IV methylprednisolone at 1 mg/kg/day.
  • For relapse post-allo-HCT, it is important to consider history of GVHD and timing of relapse before initiating an anti-PD-1 agent; if patient will receive anti-PD-1 therapy, the authors recommend starting at a low dose (i.e. Nivolumab 0.5 mg/kg) and escalating as tolerated.
  • If GVHD occurs, the authors recommend stopping anti-PD-1 therapy immediately.

Allogeneic HCT

*Gribben JG. How and when I do allogeneic transplant in CLL. Blood. 2018;132:31-39. https://www.ncbi.nlm.nih.gov/pubmed/29752258

  • The role of allo-HCT in CLL has been decreasing as novel agents, such as ibrutinib, acalabrutinib, idelalisib, and venetoclax have shown success with less morbidity and mortality.
  • Patients with a TP53 abnormality are candidates for ibrutinib as front-line therapy; while those without the abnormality can be treated with chemoimmunotherapy or a clinical trial.
  • Relapsed/refractory disease can be treated with ibrutinib or venetoclax (with or without rituximab).
  • Patients responding to a second novel agent can either proceed to allo-HCT or continue with the novel agent.
  • The optimal timing of allo-HCT in setting of the novel agents remains a question that needs to be better characterized.

*Schmitz N, Lenz G, Stelljes M. Allogeneic hematopoietic stem cell transplantation for T-cell lymphomas. Blood. 2018;132:245-53. https://www.ncbi.nlm.nih.gov/pubmed/29699989

  • T-cell lymphomas are a group of heterogeneous disorders with generally unfavorable outcomes.
  • High-dose chemotherapy followed by auto-HCT is recommended for consolidation after a complete or partial remission is achieved.
  • Approximately one-third of patients never reach auto-HCT due to early relapse or refractory disease.
  • Allogeneic HCT remains a valuable treatment option for these patients and with the utilization of haploidentical HCT, more patients may be considered for allo-HCT.
  • For aggressive T-cell lymphomas (i.e. ATLL, HSTL), allo-HCT in the first CR could be considered.

Autologous HCT

**Nieto Y, Thall P, Ma J, et al. Phase II Trial of High-Dose Gemcitabine/Busulfan/Melphalan with Autologous Stem Cell Transplantation for Primary Refractory or Poor-Risk Relapsed Hodgkin Lymphoma. Biol Blood Marrow Transplant. 2018;24:1602-1609. https://www.ncbi.nlm.nih.gov/pubmed/29501779

  • Single center, phase II study evaluating the effect of Gem/Bu/Mel of PFS in 80 patients with relapsed/refractory Hodgkin lymphoma with 31% remaining PET positive at the time of transplant.
  • Overall 2-year PFS was 65% with OS of 96%; PET-negative patients had a 2-year PFS of ~80% compared to ~29% in the PET-positive group (p=0.00001).
  • The study was powered to compare Gem/Bu/Mel to historical, concurrent BEAM conditioning; patients were well-matched.
  • The BEAM patients had a 2-year PFS of ~50% and OS of ~69% which was statistically inferior to the above results (p=0.05 and p=0.0008 respectively) which remained significant when stratified for PET and disease free interval.
  • The major toxicities were mucositis (49%), dermatitis (22%), and hepatic function changes (~45%).
  • The results of the study provide an encourage option for patients with relapsed/refractory Hodgkin. The results comparison to BEAM was however non-randomized with a concurrent retrospective cohort.  The regimen is moving forward in a phase III comparative study to BEAM.

*Chen AI, Leonard JT, Okada CY, et al. Outcomes of DA-EPOCH-R induction plus autologous transplant consolidation for double-hit lymphoma. Leuk Lymphoma. 2018;59:1884-89. https://www.ncbi.nlm.nih.gov/pubmed/29199519

  • Single center analysis of 36 patients with previously untreated double-hit lymphoma who were treated with DA-EPOCH-R followed by BEAM autologous transplant from 2010 to 2015.
  • At median follow-up of 38 months, the overall 2-year PFS and OS were 69% and 71%, respectively.
  • Of 28 responders to induction chemotherapy, 17 proceeded to transplant while 11 were observed due to age or co-morbidities.
  • The 3-year PFS and OS were both 94% for patients in the transplant group versus a 3-year PFS and OS of 79% in those patients who underwent observation (p=0.59 for both PFS and OS).
  • The treatment algorithm of DA-EPOCH-R followed by consolidative autoSCT was effective in majority of patients with double-hit lymphoma; however, a significant proportion of patients had primary refractory disease with poor outcomes.

Supportive Care

**Bubalo J, Mulverhill K, Meyers G, et al. A randomized, placebo-controlled pilot trial of aprepitant combined with standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting in patients undergoing cyclophosphamide-based conditioning regimens prior to hematopoietic stem cell transplant (HSCT). Bone Marrow Transplant. 2018;53:1010-1018. https://www.ncbi.nlm.nih.gov/pubmed/29459665

  • Prospective, randomized, double blind, placebo-controlled study at a single institution to evaluate the safety and efficacy of aprepitant when used prophylactically to prevent nausea and vomiting during cyclophosphamide-based conditioning regimens prior to HCT.
  • Twenty patients were randomized to receive aprepitant, ondansetron, and dexamethasone, and 20 were randomized to receive placebo, ondansetron, and dexamethasone. In the aprepitant arm, the dose of dexamethasone was reduced in a blinded fashion.
  • The average number of emesis-free days was 14.25 (SD 1.48 days) in the aprepitant group compared to 12.45 days (SD 2.16 days) for patients in the placebo group. Eight patients (40%) in the aprepitant group achieved CR (defined as the absence of emesis and the absence of mild to moderate nausea) as compared to four patients (20%) in the placebo group.
  • When utilizing cyclophosphamide-containing conditioning regimens, the addition of aprepitant to a standard antiemetic regimen decreased the incidence of emesis as compared to placebo.

Abbreviations

aGVHD: acute graft versus host disease

ATLL: adult T-cell leukemia/lymphoma

BEAM: carmustine, etoposide, cytarabine, melphalan

cHL: classical Hodgkin lymphoma

CIBMTR: Center for International Blood and Marrow Transplant Research

CLL: chronic lymphocytic leukemia

CR: complete response

CRS: cytokine release syndrome

DA-EPOCH-R (dose-adjusted etoposide prednisone vincristine cyclophosphamide rituximab)

GVHD: graft versus host disease

EFS: event free survival

HCT: hematopoietic cell transplantation

HSTL: hepatosplenic lymphoma

OS: overall survival

PD-1: programmed death-ligand 1

PET: positron emission topography

PFS: progression-free survival

PR: partial response

PtCy: post-transplant cyclophosphamide

RIC: reduced-intensity conditioning

SD: standard deviation

VGPR: very good partial response

VOD: veno-occlusive disease

ASBMT Pharmacy SIG Communications Working Committee:

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

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