In this month's Pharmacy SIG literature update: Is tocilizumab effective for SR-GVHD? Can you prevent HHV6 infections in cord blood transplants by using prophylactic foscarnet? Is defibrotide effective in non-transplant VOD/SOS? Extended follow up data of patient receiving nivolumab post auto-HCT. As well as additional data affirming safety of HCT in the HIV-positive population, 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
* Ganetsky A, Frey NV, Hexner EO, et al. Tocilizumab for the treatment of severe steroid-refractory acute graft-versus-host disease of the lower gastrointestinal tract. Bone Marrow Transplant. 2018 May 24. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/29795429
- Retrospective evaluation of the efficacy of tocilizumab for the treatment of steroid-refractory, biopsy-proven GVHD isolated to the GI tract at the University of Pennsylvania between October 2015 and July 2016.
- Tocilizumab was administered intravenously at a dose of 8 mg/kg every 2 weeks (max 6 doses) until achievement of a complete response, progression, or initiation of other therapy.
- Primary outcome was CR as defined by the resolution of all manifestations of GI GVHD (graded according to the modified Glucksberg criteria). Secondary outcomes included partial response rate (improvement by at least 1 GVHD stage), OS, and toxicity (via CTCAE version 4).
- 16 patients were treated with tocilizumab for steroid-refractory acute GVHD and were generally high risk due to older age (median 58 years), disease risk index (56% high/very high), and HCT-CI (score >3 63%).
- Tocilizumab was administered at a median of 9 days (range 3-75 days) from GVHD tissue diagnosis and 10 days (range 3-75 days) from start of high-dose steroids. 63% (10/16) achieved a CR after a median of 11 days from tocilizumab initiation and median time to response onset was 1 day (range 1-4 days). 37.5% (6/16) were alive and free of underlying hematologic malignancy at a median follow-up of 7.6 months.
- The authors concluded that tocilizumab appears to be a highly effective agent for the treatment of severe, steroid-refractory lower GI acute GVHD and prospective studies are warranted.
* Schroeder MA, Choi J, Staser K, DiPersio, JF. The Role of Janus Kinase Signaling in Graft-Versus-Host Disease and Graft Versus Leukemia. Biol Blood Marrow Transplant. 2018;24: 1125-1134. https://www.ncbi.nlm.nih.gov/pubmed/29289756
- A review of how JAKs regulate both acute and chronic GVHD pathogenesis.
- Clinical studies have demonstrated that utilizing JAK inhibition is associated with prolonged survival and reduction in severity of acute and chronic GVHD. It will be important to identify future patients who are most likely to benefit from JAK-targeted therapy.
* Shenoy S, Walters MC, Ngwube A, et al. Unrelated Donor Transplantation in Children with Thalassemia using Reduced-Intensity Conditioning: The URTH Trial. Biol Blood Marrow Transplant. 2018;24:1216-1222. https://www.ncbi.nlm.nih.gov/pubmed/29374585
- Phase II prospective, multi-center trial conducted in collaboration with the Thalassemia Clinical Research Network and the PBMTC that investigated the efficacy of reduced-intensity conditioning before URD HCT in 33 children with TDT.
- Eligible patients with TDT ages 1-16.99 years were eligible. The first 20 patients were enrolled in NCT01005576 and the next 13 in an extension NCT00920972 (stratum 2) after 2012. Patients with uncontrolled infections or previous HCT were excluded.
- All patients received hydroxyurea (30 mg/kg/day PO) between days –50 and –22, alemtuzumab (3-mg test dose and then 10, 15, and 20 mg daily IV) between days –22 and –18, fludarabine (30 mg/m2/day i.v.) between days –8 and –4, thiotepa (4 mg/kg × 2 IV) on day –4, and melphalan (140 mg/m2 IV) on day –3. For GVHD prophylaxis, URD BM recipients received tacrolimus or cyclosporine between days -3 and +100, methotrexate (7.5 mg/m2 i.v. on days +1, +3, and +6), and methylprednisone/prednisone (1 mg/kg/day) between days +7 and +28. CBT recipients received tacrolimus or cyclosporine as above with mycophenolate mofetil (15 mg/kg every 8 hours) between days +1 and +45.
- The primary endpoint was 2-year TFS. With a median follow-up of 58 months (range, 7 to 79), OS and TFS was 82% (95% CI, 0.64% to 0.92%) and 79% (95% CI, 0.6% to 0.9%), respectively. Median time to neutrophil engraftment was 13 days (range, 10 to 25) and 24 days (range, 18 to 49) after BM and UCB allografts, respectively. The cumulative incidence of grades II to IV acute GVHD after BM and UCB allografts was 24% and 44%; the 2-year cumulative incidence of chronic extensive GVHD was 29% and 21%, respectively.
- Outcomes after this RIC compared favorably with URD HCT outcomes for TDT and supported engraftment in 32 of 33 patients. Efforts to reduce GVHD and infectious complications are being pursued further.
* Ogata M, Takano K, Moriuchi Y. Effects of Prophylactic Foscarnet on Human Herpesvirus-6 Reactivation and Encephalitis in Cord Blood Transplant Recipients: A Prospective Multicenter Trial with an Historical Control Group. Biol Blood Marrow Transplant. 2018;24:1264-1273. https://www.ncbi.nlm.nih.gov/pubmed/29454651
- Multicenter, open-label, single-arm, prospective trial, which included an historical control group, to determine the effectiveness and safety of foscarnet at 90 mg/kg for 21 days to prevent HHV-6 reactivation, HHV-6 encephalitis, and acute GVHD in patients who received CBT.
- Standard treatment group was a historical control who included patients >16 years or older who participated in a multicenter prospective observation study for HHV-6 reactivation and received CBT between April 2010 and March 2014. The intervention group consisted of patients were >16 years or older who were scheduled to receive first CBT.
- The cumulative incidence of high-level HHV-6 reactivation, defined as plasma HHV-6 DNA ≥ 104 copies/mL, at 60 days after CBT was significantly lower in the foscarnet-prophylaxis group than in the standard-treatment group (18.3% vs 57.3%, P < .001). Multivariate analysis revealed that myeloablative preconditioning and standard treatment were significant risk factors for high-level HHV-6 reactivation.
- The cumulative incidence of HHV-6 encephalitis at 60 days after CBT was not different between the groups (foscarnet-prophylaxis group, 12.4%; standard-treatment group, 4.9%; P = 0.14). The cumulative incidences of grades II to IV and grades III to IV acute GVHD at 60 days after CBT were not different between the groups (grades II to IV acute GVHD: foscarnet-prophylaxis group, 42.0%; standard-treatment group, 40.5%; P = 0.96; grades III to IV acute GVHD: foscarnet-prophylaxis group, 14.5%; standard-treatment group, 14.5%; P = 1.00).
- Foscarnet significantly suppressed systemic HHV-6 reactivation in CBT recipients but failed to prevent the development of HHV-6 encephalitis. Suppression of HHV-6 reactivation by foscarnet did not show any effects against the incidence of acute GVHD.
* Mehta K, Im A, Rahman F, Wang H, Veldkamp P. Epidemiology and Outcomes of Hematopoietic Stem Cell Transplantation in Human Immunodeficiency Virus-Positive Patients From 1998 to 2012: A Nationwide Analysis. Clin Infect Dis. 2018;67:128-133. https://www.ncbi.nlm.nih.gov/pubmed/29325063
- Registry study using Nationwide Inpatient Sample data from 1998 to 2012 to compare transplant outcomes in HIV-positive vs HIV-negative populations.
- The database represents a 20% stratified sample of all US hospitals and the authors assigned a projected number of transplants nationwide.
- A higher proportion of HIV-positive patients were male, African American, and underwent auto-HCT, with a lower proportion receiving TBI-based conditioning.
- Overall the number of HIV-positive patient receiving transplants increased over time with 81 transplants between 1998-2002 increasing to 278 transplants between 2008-2012.
- Allo-HCT in HIV-positive patients was associated with higher rates of NTM and CMV (NTM: 5.4% vs 0.2%, P<0.001; CMV: 22.2% vs 6.3%, P=0.04) which was consistent on univariate, multivariate and matched-pairs analyses. Invasive fungal infections and stomatitis were significantly higher in HIV-positive patients in univariate and multivariate analyses but not in matched-pairs. No difference was observed in mortality, GVHD, sepsis, or VTE.
- Auto-HCT was associated with higher rates of HSV infection (10.7% vs 2%, P<0.001). Mortality, sepsis, VTE, stomatitis, CMV, or NTM were noted between HIV-positive and HIV-negative auto-HCT patients
- This retrospective registry data confirms previously published recommendations that HIV infection alone is not a strict contraindication to HCT. However, higher rates of infections are noted, especially within the HIV-positive, allo-HCT population.
* Micallef IN, Stiff PJ, Nademanee AP, e tal. Plerixafor Plus Granulocyte Colony-Stimulating Factor for Patients with Non-Hodgkin Lymphoma and Multiple Myeloma: Long-Term Follow-Up Report. Biol Blood Marrow Transplant. 2018;24:1187-1195. https://www.ncbi.nlm.nih.gov/pubmed/29410180
- Long-term, observational follow-up to the 2 phase III multicenter, randomized, double-blind, placebo-controlled, comparative trials of 240 µg/kg plerixafor plus 10 µg/kg G-CSF, or placebo plus 10 µg/kg G-CSF to mobilize and collect CD34+ cells for autologous HCT in patients with NHL (Study 3101) and patients with MM (Study 3102)
- The primary endpoint analysis was OS and PFS. Data for survival and disease state were collected up to 5 years after the first study drug administration. Patients who failed to mobilize or who did not achieve at least 2 × 106 CD34+ cells/kg within ≤4 days of apheresis after treatment with either placebo or plerixafor were allowed to enter a “rescue” procedure. Those patients received open-label plerixafor with the aim of collecting a transplantable dose of CD34+ cells, and were assigned to the plerixafor treatment group for analysis.
- The probability of OS was not significantly different in patients with NHL or MM between groups (NHL: 64%; 95% CI, 56% to 71% vs 56%; 95% CI, 44% to 67%, respectively; MM: 64%; 95% CI, 54% to 72% vs 64%; 95% CI, 53% to 73%, respectively).
- There was also no statistically significant difference in the probability of PFS between groups in patients with NHL (50%; 95% CI, 44% to 67% for plerixafor vs 43%; 95% CI, 31% to 54% for placebo) or those with MM (17%; 95% CI, 10% to 24% for plerixafor vs 30%; 95% CI, 21% to 40% for placebo).
- The results from this study suggest that the addition of plerixafor to G-CSF did not have a detrimental effect on long-term survival.
* Kernan NA, Richardson PG, Smith AR, et al. Defibrotide for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome following nontransplant-associated chemotherapy: Final results from a post hoc analysis of data from an expanded-access program. Pediatr Blood Cancer. 2018 Jun 6. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/29873895
- Retrospective assessment of patients receiving defibrotide through an expanded-access program. Patients were diagnosed with VOD via Baltimore or modified Seattle criteria after non-transplant chemotherapy administration. Defibrotide was to be started within 30 days of chemotherapy administration and subsequent VOD diagnosis and was dosed as per the package insert (6.25 mg/kg IV every 6 hours and dosing weight was based upon weight prior to chemotherapy).
- Primary outcome was OS at day +70 after the start of defibrotide. Secondary outcomes included adverse events that began or worsened after the first dose of defibrotide, incidence of hypotension and hemorrhage.
- 137 patients were diagnosed with VOD after nontransplant-associated chemotherapy, including 82 who initiated defibrotide within 30 days of first chemotherapy dose. Of these 82 patients, 38 (46.3%) had multi-organ failure and 80.5% were aged 16 or younger. The most commonly administered agents prior to nontransplant VOD were cyclophosphamide (53.7%), cytarabine (51.2%), vincristine (47.6%), methotrexate (34.1%), and thioguanine (30.5%).
- Kaplan-Meier estimated day +70 survival was 74.1% (65.8% in multi-organ failure group and 81.3% in patients without multi-organ failure). Day +70 estimated survival was 80.1% in pediatric patients (age <16) and 50% in adults (age >16). Treatment-related adverse events occurred in 26.8% of patients.
- The authors concluded that defibrotide for nontransplant-associated VOD is a feasible therapeutic option and that treatment may be more beneficial before multi-organ failure develops.
Cellular and Immunotherapy
** Armand P, Engert A, Younes A, et al. Nivolumab for Relapsed/Refractory Classic Hodgkin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort Single-Arm Phase II Checkmate 205 Trial. Journal of Clinical Oncology. J Clin Oncol. 2018;36:1428-1439. https://www.ncbi.nlm.nih.gov/pubmed/29584546
- Multicenter, single-arm, phase II study in patients with relapsed/refractory cHL after auto-HCT treatment failure.
- A total of 243 patients were treated with nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity; 63 in cohort A (BV naïve), 80 in cohort B (BV received after auto-HCT), and 100 in cohort C (BV received before and/or after auto-HCT).
- After median follow-up of 18 months, 40% of all patients were still receiving treatment; the overall objective response rate was 69% and median PFS was 14.7 months.
- There were 70 patients who continued treatment past conventional disease progression, and 61% of those evaluable had stable or further reduced tumor burdens.
- Adverse events included lipase increases (5%), neutropenia (3%), and ALT increases (3%)
- With extended follow-up, responses to nivolumab were maintained with a favorable safety profile in patients with relapsed/refractory cHL after auto-HCT.
** Perica K, Curran KJ, Brentjens RJ, Giralt SA. Building a CAR Garage: Preparing for the Delivery of Commercial CAR T Cell Products at Memorial Sloan Kettering Cancer Center. Biol Blood Marrow Transplant. 2018;24:1135-1141. https://www.ncbi.nlm.nih.gov/pubmed/29499327
- A review of an institutional experience of a CAR T-cell program at Memorial Sloan Kettering Cancer Center.
- CAR-T therapy is a complex process which requires a significant undertaking. This review describes various “tasks” that must be performed in order to ensure a smooth process and may provide your individual institution with more ideas/approaches for CAR-T program management.
Allo-HCT: allogeneic hematopoietic stem cell transplant
Auto-HCT: autologous hematopoietic stem cell transplant
BM: bone marrow
BV: brentuximab vedotin
CAR: chimeric antigen receptor
CBT: cord blood transplant
cHL: classic Hodgkin lymphoma
CR: complete response
CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events
EFS: event-free survival
G-CSF: granulocyte-colony stimulating factor
GVHD: graft-versus-host disease
HCT: hematopoietic cell transplantation
HCT-CI: hematopoietic cell transplantation-specific comorbidity index
HIV: human immunodeficiency virus
JAK: Janus-associated kinases
MM: multiple myeloma
NHL: non-Hodgkin lymphoma
NTM: nontuberculous mycobacterium
OS: overall survival
PBMTC: Pediatric Blood and Marrow Transplant Consortium
PBSC: peripheral blood stem cells
PFS: progression-free survival
RIC: reduced intensity conditioning
TDT: transfusion-dependent thalassemia
TFS: thalassemia-free survival
URD: unrelated donor
VOD: veno-occlusive disease
VTE: venous thromboembolism
ASBMT Pharmacy SIG Communications Working Committee:
Brandi Anders, Tiene Bauters, Eileen Chen, David Eplin, Katie Gatwood, Jason Jared, Kathryn Maples, Shreya Shah, Ryan Shaw