May 2018: Pharmacy SIG Literature Update

By Content Administrator posted 06-11-2018 18:11

  

In this month's Pharmacy SIG literature update:
What is the role/value added of HCT-Pharmacists? Can you stop tacrolimus at day +60 after haplo transplants? Does palifermin help reduce mucositis with TBI-based allogeneic transplants? Plus, improving mortality in AL Amyloidosis, long-term outcomes and tandem transplants for Hodgkin lymphoma, and more!

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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

**Kasamon YL, Fuchs EJ, Zahurak M, et al. Shortened-duration Tacrolimus after nonmyeloablative, HLA-haploidentical bone marrow transplantation. Biol Blood Marrow Transplant. 2018;24(5):1022-1028. http://www.ncbi.nlm.nih.gov/pubmed/29353109

  • Single-arm, phase I/II conducted at Johns Hopkins University in 105 evaluable patients with hematologic malignancy patients who underwent NMA haploidentical BMT to evaluate the feasibility and safety of reduced duration tacrolimus with PTCy. Tacrolimus was pre-specified to stop without taper at day +90, +60, or +120, contingent on having ≥5% donor T-cells, no relapse, and no grade II-IV acute or significant chronic GVHD. Safety stopping rules were based on ≥5% graft failure, ≥10% NRM, or a ≥20% combined incidence of severe acute and chronic GVHD from the tacrolimus stop date through day +180.
  • Median age was 61 years with 34% age ≥65 years. Seventy-eight percent of grafts had ≥4 antigen mismatches at HLA class I and II combined, with <5% having <3 antigen mismatches. The most common diagnoses were AML (51%), MDS or MPN (18%), and aggressive NHL (17%).
  • In the day +90 arm, with a median follow-up of 48 months, the 1-year probabilities of relapse, PFS, and OS were 52%, 40%, and 59%, respectively. In the day +60 arm, with a median follow-up of 18 months, the 1-year probabilities of relapse, PFS, and OS were 33%, 63%, and 78%, respectively. In both arms, at day +180, the probability of grade II-IV acute GVHD was <40%, of grade III-IV acute GVHD was <8%, and of NRM was <5%. The 1-year probabilities of chronic GVHD and NRM were <15% and <10%, respectively, in both arms. The 1-year GRFS was higher in the day +60 arm.
  • Stopping tacrolimus as early as day +60 is feasible and carries acceptable risks after NMA haploidentical BMT with PTCy.

Other

**Clemmons AB, Alexander M, DeGregory K, Kennedy L. The hematopoietic cell transplant pharmacist: roles, responsibilities, and recommendations from the ASBMT Pharmacy Special Interest Group. Biol Blood Marrow Transplant. 2018;24:914-922. http://www.ncbi.nlm.nih.gov/pubmed/29292057

  • This review article provides justification for the various roles pharmacists fulfill with respect to medication management, transitions of care, patient and provider education, policy development, quality improvement, and research within the HCT setting.
  • Multidisciplinary care is required to effectively manage the complex care of the HCT patient. Pharmacists provide a positive impact through providing direct management for these patients.

Hematopoietic Cell Transplantation

**Sidiqi MH, Aljama MA, Buadi FK, et al. Stem Cell Transplantation for Light Chain Amyloidosis: Decreased Early Mortality Over Time. J Clin Oncol. 2018;36:1323-1329. https://www.ncbi.nlm.nih.gov/pubmed/29558277  

  • Retrospective review of all patients with biopsy-proven systemic AL amyloidosis who underwent auto-HCT between March 8, 1996, and August 31, 2016, at Mayo Clinic.
  • A total of 672 patients received an auto-HCT and were divided into three study cohorts based on date of HCT: cohort 1 (1996-2002 [n=124]), cohort 2 (2003-2009 [n=302]), and cohort 3 (2010-2016 [n=246]). These time periods were chosen to assess changes in patient characteristics, treatment practices, and outcomes over time.
  • Median age for the entire cohort was 59 years, with patients in cohort 3 being slightly older (54 vs 58 vs 60 for cohorts 1, 2, and 3, respectively; p<0.001).
  • Median OS for the entire cohort was 122 months and improved over time (75 months vs 120 months vs not reached for cohorts 1, 2, and 3, respectively; p<0.001); further, treatment-related mortality declined over time (14.5% vs 8.6% vs 2.4% for cohorts 1, 2, and 3, respectively; p<0.001).
  • Auto-HCT is highly effective for AL amyloidosis. The improvement in survival and reduction in treatment-related mortality over time indicates auto-HCT will remain an important treatment option for these patients even in the era of novel agents.

*Deau B, Amorim S, Perrot A, et al. Tandem haematopoietic stem cell transplantation for High Risk relapsed/refractory Hodgkin Lymphoma: a LYSA study. Br J Haematol. 2018;151:341-349. https://www.ncbi.nlm.nih.gov/pubmed/29611187

  • Multicenter, observational study of high-risk R/R HL patients that were prospectively registered in French nationwide database to evaluate the feasibility and efficacy of tandem auto-HCT/auto-HCT or auto-HCT/allo-HCT
  • One hundred and twenty patients were included, with median age at relapse of 26 years and 57% of patients being male. Sixty-one (51%) had primary refractory disease and 59 (49%) had relapsed HL, with median time to relapse from first-line chemotherapy of 6 months
  • Overall, 115 (96%) of patients underwent a first HCT (112 of which were auto-HCT) and 73 (61%) received a tandem HCT, including allo-HCT in 44 (60%) and auto-HCT in 29 (40%)
  • After a median follow-up of 43 months, the 2-year PFS and OS rates for the entire population were 56% and 82%, respectively; while, 2-year PFS and OS rates for those receiving tandem transplants were 71% and 85%, respectively, without significant difference between auto-HCT and allo-HCT
  • Tandem HCTs is effective in high-risk relapsed/refractory HCT; however, post-auto-HCT consolidative strategies, such as brentuximab vedotin, can also be considered.

*Smith EP, Li H, Friedberg JW, et al. Tandem autologous hematopoietic cell transplantation for patients with primary progressive or recurrent Hodgkin lymphoma: A SWOG and Blood and Marrow Transplant Clinical Trials Network Phase II Trial (SWOG S0410/BMT CTN 0703). Biol Blood Marrow Transplant. 2018;24:700-707. http://www.ncbi.nlm.nih.gov/pubmed/29289757

  • Phase II, single-arm trial in 89 R/R HL patients to determine if long-term PFS could be improved with tandem HCT. Patients who relapsed after a prior CR had to be treated with a minimum of 2 cycles of salvage chemotherapy or a minimum of 25 Gy involved field radiation therapy to determine disease sensitivity. Patients with >5 cm bulk disease after salvage had to agree to pre-HCT treatment with 18 Gy involved field radiation therapy.
  • Cycle 1 consisted of melphalan 150 mg/m2 with half of the stem cells. For stable disease or better, patients received cycle 2 consisting of single doses of etoposide 60 mg/kg and cyclophosphamide 100 mg/kg and either total body radiation 12 Gy in 8 fractions over 4 days or BCNU 150 mg/m2/day for 3 days with the remaining stem cells.
  • 82 patients completed both cycles of tandem transplants, 47 (53%) had primary refractory HL, and 72 (81%) were resistant to salvage therapy. No treatment-related deaths occurred in the first year after HCT.
  • With a median follow-up of 6.2 years (range, 2-7.7), the 2-year and 5-year PFS were 63% (95% CI, 52% to 72%) and 55% (95% CI, 44% to 64%) respectively; the 2-year and 5-year OS were 91% (95% CI, 83% to 95%) and 84% (95% CI, 74% to 90%), respectively. The authors concluded that the observed 5-year PFS of 55% suggests the tandem approach appears to be effective in treating HL.

*Spina F, Radice T, De Philippis C et al. Allogeneic transplantation for relapsed and refractory Hodgkin lymphoma: long-term outcomes and graft-versus-host disease-free/relapse-free survival. Leuk Lymphoma. 2018;1:1-9. https://www.ncbi.nlm.nih.gov/pubmed/29716416

  • Single-center, retrospective study including 70 consecutive relapsed/refractory Hodgkin lymphoma (RR-HL) patients receiving reduced-intensity allo-HCT
  • Evaluation of OS, PFS, GRFS, and cGVHD-free OS (defined as OS without moderate-to-severe cGVHD).
  • Patients median age was 33 years (range, 18–60 years), 23% with refractory disease (SD/PD). Donors were HLA identical-related (39%), unrelated (30%), or haploidentical (31%). Median follow-up was 6.2 years.
  • Five-year OS was 59% and PFS was 49%. NRM was 16% at 1 year. A total of 44% of patients had cGVHD, and 14% moderate-to-severe cGVHD at last follow-up. GRFS and cGVHD-free OS were 26% and 48% at 5 years, respectively. In multivariate analysis, resistant disease at allo-HCT impacted survival and GRFS.
  • Disease response before allo-HCT impacts survival and GRFS. GVHD outcomes may help comparing the long-term effects of the new salvage treatments that bridge patients to allo-HCT in RR-HL.

*Sweiss K, Oh A, Calip G, Rondelli D, Patel P. Similar survival but increased toxicity with a sequential verses concurrent FluBu4 regimen. Bone Marrow Transplant. 2018 Apr 27. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/29703968             

  • Retrospective, single-center study of consecutive patients who underwent FluBu4 and allo-HCT between January 2003 and December 2016 at the University of Illinois-Chicago to assess the efficacy and safety of sequential vs concurrent FluBu4.
  • Outcomes assessed included engraftment, OS, relapse rates, PFS, treatment-related toxicity, GVHD-free and relapse-free survival, and incidence of GVHD.
  • 37 patients (36%) received the 5-day regimen of fludarabine 40 mg/m2 IV daily and busulfan (target AUC 4800 mmol-min per dose) IV daily on days -5,-4,-3,-2 while 65 patients (64% received the 9-day regimen of equivalent doses (fludarabine on days -9 through -6, busulfan days -5 through -2). All patients in the study received standard tacrolimus and methotrexate GVHD prevention, but unrelated donor transplant recipients received 4.5 mg/kg rabbit anti-thymocyte globulin. Patients in the 5-day group were older (51 years vs 45 years, p=0.003) and received a higher mean CD34+ cell dose (7.17 +/- 3.25 vs 4.25 +/- 1.84, p=0.03).
  • Median time to neutrophil (16 vs 18 days, p=0.58) and platelet (12 vs 19 days, p=0.7) engraftment were not different between the two groups. More patients receiving the 9-day regimen experienced grade 4 mucositis (81.5% vs 16.2%, p<0.0001) and required subsequent day+11 methotrexate dose reduction or omission (p=0.02). This may have contributed to a higher cumulative incidence of grade 3-4 aGVHD (11% vs. 34%, p=0.006) in the 9-day group. Extensive cGVHD was seen at a higher rate in the 9-day group (19% vs 40%, p=0.047). No differences were observed in OS, PFS, or relapse rates.
  • Concurrent conditioning chemotherapy (FluBu4 over 5 days) may not improve disease response, but is associated with less mucositis, more methotrexate administration, and lower rates of aGVHD.

*Jung SH, Lee JJ, Kim JS, et al. Phase 2 Study of an intravenous busulfan and melphalan conditioning regimen for autologous stem cell transplantation in patients with multiple myeloma (KMM150). Biol Blood Marrow Transplant. 2018;24:923-929. http://www.ncbi.nlm.nih.gov/pubmed/29339269             

  • Prospective, multicenter, phase II trial evaluating efficacy and toxicity of intravenous busulfan and melphalan as a conditioning regimen for autologous HCT in 99 MM patients aged 20-65 years old in Korea. IV busulfan 3.2 mg/kg was administered over 3 hours once daily from day -6 to days -4 and melphalan 70 mg/m2/day was administered on day -3 and day -2.
  • Median age was 57 years old. According to ISS criteria, 32 (32.3%) patients were classified as stage I, 34 (34.3%) as stage II, and 33 (33.3%) as stage III at initial diagnosis and 22.7% patients had high-risk cytogenetic characteristics. The majority (89.9%) of the patients received thalidomide-based frontline treatment and 53.5% had received maintenance therapy.
  • ORR was 94.0%, which included 17.2% with sCR, 26.3% with CR, and 27.3% with VGPR. Compared with the pre-HCT response, sCR/CR significantly increased by 17.2% (P<0.001). No difference in sCR/CR was observed between patients with high-risk cytogenetics and patients with standard risk (40.0% vs. 47.1%; P=0.619). The median time to platelet engraftment and neutrophil recovery was 9 days (range, 7 to 44 days) and 10 days (range, 9 to 18 days), respectively. After a median follow-up of 26.1 months, median PFS was 27.2 months (range, 13.0 to 41.4 months) and median OS was not reached.
  • The most common severe non-hematologic toxicity (grade 3-4) was infection and stomatitis. Three (3.2%) patients developed VOD. Therefore, the authors concluded that BU-MEL conditioning is an effective and tolerable conditioning regimen for transplant-eligible patients with MM.

*Deeg JH, Stevens EA, Salit RB, et al. Transplant conditioning with treosulfan/fludarabine with or without total body irradiation: a randomized phase II trial in patients with myelodysplastic syndrome and acute myeloid leukemia. Biol Blood Marrow Transplant. 2018;24:956-963. http://www.ncbi.nlm.nih.gov/pubmed/29274396             

  • Phase II randomized trial to determine whether the addition of 2 Gy TBI to treosulfan/fludarabine would result in lower relapse incidence and superior 6-month PFS in MDS and AML patients
  • Patients received treosulfan IV days -6 to -4 at 14 g/m2/day and fludarabine IV on days -6 to -2 at 30 mg/m2/day. Patients randomized to receive TBI were given a single dose of 2 Gy on day 0.
  • There was no difference in neutrophil engraftment or donor chimerism between the 2 arms. After follow-up of 12 to 40 months, 1-year interim analysis showed a significantly lower relapse incidence and superior PFS at 6 months in the TBI-containing arm (P=0.04). The largest difference was among patients with unfavorable cytogenetics, with 1-year relapse incidences of 31% and 63% (P=0.18), respectively. The final analysis confirmed this trend, although the difference did not reach statistical significance; the 1-year overall survival was 80% for the TBI arm and 69% for the non-TBI arm (P=0.06). NRM did not differ between arms.
  • This randomized phase II trial confirmed the excellent tolerability of fludarabine/treosulfan conditioning, even with the addition of low-dose TBI.

Supportive Care

**Schmidt V, Niederwieser D, Schenk T, et al. Efficacy and safety of keratinocyte growth factor (palifermin) for prevention of oral mucositis in TBI-based allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2018 Mar 15. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/29545592             

  • Prospective, controlled multicenter study to evaluate efficacy and safety of palifermin for prevention of oral mucositis in TBI-containing allo-HCT patients.
  • Primary outcome was severity of oral mucositis (WHO grade >III) and secondary outcomes included days of intravenous opioid-containing analgesia, total parenteral nutrition, febrile neutropenia, and therapy-related mortality until day +100.
  • 60 total patients were assessed (40 patients received palifermin, 20 patients did not receive intervention). All patients received a conditioning regimen of hyper-fractionated TBI (total dose 12 Gy) followed by cyclophosphamide (2 x 60 mg/kg) with a graft cell dose of 4.0 x106 CD34-positive PBSCs per kg bodyweight (no graft manipulation performed). All patients received post-transplant cyclosporine (3-5 mg/kg per day) and low-dose methotrexate (15 mg/m2 on day 1 and 10 mg/m2 on day 3,6,11) for GVHD prophylaxis. Palifermin was given as 60 mcg/kg/day IV for 3 consecutive days prior to TBI and for 3 days after allo-HCT.
  • The incidence of severe mucositis (WHO grade >III) decreased from 75% in the control group to 62.5% in the palifermin group (p=0.11). Secondary outcomes failed to show significant improvement in the palifermin group, aside from therapy-related mortality (15% vs 0%, p=0.03). Palifermin had no influence on platelet or neutrophil engraftment as well as relapse at 1 year after allo-HCT. A 10% higher incidence was seen in the palifermin group for dermal reactions (erythema, pruritis, burn) sensory neuropathy, or taste alterations and hyperglycemia.
  • Palifermin was generally well tolerated and positively influenced severity, duration and clinical management of oral mucositis but the clinical benefit fell short of expectations and did not reach statistical significance.

Maintenance Therapy

*Huang J, Phillips S, Byrne M, et al. Lenalidomide vs bortezomib maintenance choice post-autologous hematopoietic cell transplantation for multiple myeloma. Bone Marrow Transplant. 2018 Apr 27. [Epub ahead of print). http://www.ncbi.nlm.nih.gov/pubmed/29703965             

  • Retrospective single center analysis of newly diagnosed MM patients who received auto-HCT (melphalan conditioning) at Vanderbilt University Medical Center and received post-transplant maintenance therapy with either lenalidomide or bortezomib; Maintenance therapy was continued for at least 2 years unless the patient experienced progression or intolerable toxicity.
  • Primary outcome was PFS with secondary outcomes including OS and treatment-related toxicities.
  • 156 total patients were assessed for post-transplant maintenance efficacy with 92 receiving lenalidomide (starting dose of 10 mg/day and increased to 15 mg/day as tolerated) and 64 receiving bortezomib (1.3 mg/m2 subcutaneously every 2 weeks). The median follow-up time post auto-HCT was 33.7 months and there were no differences in ISS stage, Durie-Salmon stage, or cytogenetic risk between cohorts. At the time of analysis, 47% (n=43) and 52% (n=33) of lenalidomide and bortezomib patients experienced progression respectively. Mortality occurred in 21% (n=19) and 9% (n=6) respectively. Secondary primary malignancies were seen in 5.4% of lenalidomide patients and 3% of bortezomib patients. After multivariate analysis, PFS and OS were not significantly different for lenalidomide or bortezomib therapy post-transplant, but pre-maintenance disease response and ISS stage had the greatest impact on PFS.
  • The authors concluded that there is no difference in PFS or OS for the comparison of lenalidomide and bortezomib after auto-HCT for MM.

*Maples KT, Sabo RT, McCarty JM et al. Maintenance azacitidine after myeloablative allogeneic hematopoietic cell transplantation for myeloid malignancies. Leuk Lymphoma. 2018;4:1-6. https://www.ncbi.nlm.nih.gov/pubmed/29616863

  • Single-center, retrospective review evaluating the effectiveness of maintenance azacitidine in high-risk AML and MDS adults to reduce the probability of relapse.
  • Total of 25 patients receiving maintenance azacitidine were matched to historical controls (2:1 ratio) based on diagnosis, donor type, conditioning regimen intensity, and age. Over 90% of patients received myeloablative conditioning.
  • There was no difference in time to hematologic relapse, OS, or NRM. Maintenance therapy was stopped early in 72% of patients due to GVHD, relapse, infection, and intolerance (13 of 25 patients received less than 4 cycles). There was a trend towards higher toxicity in the azacitidine group.
  • Maintenance azacitidine was not associated with a change in time to disease relapse or increase in OS in patients with AML and MDS post-myeloablative allo-HCT. Authors suggest avoiding maintenance azacitidine outside the setting of clinical trials at this time.

 

Abbreviations

aGVHD: acute graft versus host disease

Allo-HCT: allogeneic hematopoietic stem cell transplant

AML: acute myeloid leukemia

Auto-HCT: autologous hematopoietic stem cell transplant

BCNU: carmustine

BMT: bone marrow transplant

cGVHD: chronic graft versus host disease

CR: complete response

EFS: event-free survival

GRFS: GVHD-free relapse-free survival

GVHD: graft-versus-host disease

HCT: hematopoietic cell transplantation

HL: Hodgkin lymphoma

HLA: human leukocyte antigen

ISS: International Staging System

IV:  intravenous

MDS: myelodysplastic syndrome

MM: multiple myeloma

MPN: myeloproliferative neoplasm

MRD: matched related donor

NHL: non-Hodgkin lymphoma

NMA: non-myeloablative

NRM: non-relapse mortality

ORR: overall response rate

OS: overall survival

PBSC: peripheral blood stem cells

PFS: progression-free survival

PR: partial response

PTCy: post-transplant cyclophosphamide

R/R: relapsed/refractory

sCR: stringent complete response

TBI: total body irradiation

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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