In this month’s Pharmacy SIG Literature Update: Maintenance therapies for Hodgkin and Non-Hodgkin lymphomas, autologous transplantation for newly diagnosed multiple myeloma in the era of novel agents, prophylactic low-dose azacitidine and donor lymphocyte infusions for high-risk acute myeloid leukemia and myelodysplastic syndrome 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
*Gagelmann N, Ditschkowski M, Bogdanov R, et al. Comprehensive clinical-molecular transplant scoring system for myelofibrosis undergoing stem cell transplantation. Blood. 2019;133(20):2233-42. http://www.ncbi.nlm.nih.gov/pubmed/30760453
- Development of a prognostic score for patients receiving alloHCT for MF to determine prognosis after transplantation itself, using clinical, molecular, and transplant-specific information
- 205 patients with MF were used as a training cohort to create a clinical-molecular myelofibrosis transplant scoring system (MTSS), which was then externally validated in a cohort of 156 patients
- Multivariable analysis on survival identified age at least 57 years, Karnofsky performance status lower than 90%, platelet count lower than 150 × 109/L, leukocyte count higher than 25 × 109/L before transplantation, HLA-mismatched unrelated donor, ASXL1 mutation, and non-CALR/MPL driver mutation genotype being independent predictors of outcome.
- Risk factors were incorporated into a 4-level MTSS: low (score, 0-2), intermediate (score, 3-4), high (score, 5), and very high (score, >5) and the 5-year survival according to risk groups in the validation cohort was 83% (95% CI, 71%-95%), 64% (95% CI, 53%-75%), 37% (95% CI, 17%-57%), and 22% (95% CI, 4%-39%), respectively (P < 0.001)
- Increasing score was predictive of NRM (P < 0.001) and authors concluded that MTSS predicts the outcome of patients with MF undergoing alloHCT
* Guaillaume T, Malard F, Magro L, et al. Prospective phase II study of prophylactic low-dose azacitadine and donor lymphocyte infusions following allogeneic hematopoietic stem cell transplantation for high-risk acute myeloid leukemia and myelodysplastic syndrome. Bone Marrow Transplant. 2019 May. [Eub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31089280
- Prospective, multicenter, open-label phase II study at 5 transplant centers in France for adult patients with high-risk AML or MDS
- Post-alloHCT patients received azacitidine (32 mg/m2/day for 5 days every 4 weeks) starting 8 weeks after transplant while also receiving preemptive, escalating-dose DLI after 3rd (1x106 CD3+ cells/kg), 5th (5x106 CD3+ cells/kg), and 7th (1x107 CD3+ cells/kg) cycles of azacitidine
- Median number of azacitidine cycles was 5 (range: 1-12) with 10 patients (33%) completing all 12 planned cycles; 17/30 patients received at least 1 cycle of DLI (1 cycle: n=5; 2 cycles: n=2; 3 cycles: n=8)
- CI of grade I-III aGVHD was 31.5%, CI of cGVHD was 53% at 2 years post-transplant while the 2-year OS & DFS was 65.5%; CI of relapse at 2 years post-transplant was 27.6% with a median time to relapse of 7 months (range: 2.5-58 months)
- The authors concluded that azacitidine was well tolerated as a prophylactic treatment to reduce the risk of post-transplant relapse and compared favorably to those patients who received no post-transplant maintenance
*Kroger N, Eikema DJ, Beelen D, et al. Impact of primary disease on outcome after allogeneic stem cell transplantation for transformed secondary acute leukaemia. Br J Haematol. 2019;185(4): 725-732. https://www.ncbi.nlm.nih.gov/pubmed/30820933
- Retrospective review of 4214 patients who received HLA-matched alloHCTs from 2000- to 2014 for transformed secondary AML to identify risk factors associated with OS, PFS, relapse and NRM
- Primary disease was noted to be MDS (n=3541), CMML (n=251), or MPN (n=422) with median age of 58 years (18-78)
- Estimated 3-year OS for entire cohort was 41% (40-43%), PFS 36% (34-37%), relapse 37% (35-39%), and NRM 27% (26-29%).
- No difference was found in NRM between the three groups but incidence of relapse was highest in MPN- 50% (45-56%), followed by CMML- 43% (36-49%), and MDS- 35% (33-37%), (p<0.001).
- PFS was lower and relapse was significantly higher in CMML and MPN compared to MDS, while only MPN had significantly lower OS compared to MDS (p=0.003).
**Patriarca F, Masiculli A, Bacigalup A, et al. Busulfan- or Thiotepa-Based Conditioning in Myelofibrosis: A Phase II Multicenter Randomized Study from the GITMO Group. Biol Blood Marrow Transplant. 2019;25(5):932-940. https://www.ncbi.nlm.nih.gov/pubmed/30579966
- Phase II, randomized study that compared fludarabine in combination with busulfan (FB) or thiotepa (FT) as conditioning regimen in 60 patients with a diagnosis of primary or secondary MF.
- Donors were HLA-identical sibling (n = 25), matched unrelated (n = 25) or single allele mismatched unrelated (n = 10).
- There were no statistically significant differences in any outcome, including OS, PFS, NRM, and graft failure. However, a better PFS was observed in the subset of patients with intermediate-1 DIPSS score (P = 0.03).
- In conclusion, the clinical outcome after HCT was comparable when using either a busulfan or thiotepa based conditioning regimen.
Autologous Transplantation
* Biran N, Rowley SD, Vesole DH, et al. A phase I/II study of escalating doses of thalidomide in conjunction with bortezomib and high-dose melphalan as a conditioning regimen for autologous stem cell transplantation in patients with multiple myeloma. Bone Marrow Transplant. 2019 May. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31101891
- Prospective, single-center, phase I/II trial of thalidomide/bortezomib/melphalan conditioning for MM patients who had relapsed or achieved less than a CR following a prior aHCT
- Conditioning was administered as follows: thalidomide was dose escalated from 600 mg to 1000 mg on days -5 to -1 (3x3 design), bortezomib 1.6 mg/m2 days -4 and -1, melphalan 200 mg/m2 on day -2; phase II thalidomide dosing was 1000 mg daily (-5 to -1)
- Time to neutrophil engraftment was 10 days (range: 9-14 days), platelet engraftment was 12 days (range: 9-15 days)
- 69% of patients responded (38% CR) with a median PFS of 9.3 months and OS of 65.4 months (median follow up of 17.8 months)
- Most common grade III-IV AEs were NF (58.6%), mucositis (6.9%), and diarrhea (6.9%)
- The authors concluded that bortezomib, thalidomide, and melphalan followed by aHCT is a well-tolerated conditioning regimen and a potentially valuable treatment option for MM patients with suboptimal response to melphalan alone
* Jaimovich G, Ostriz MBR, Castro M, et al. CBeV (cyclophosphamide, bendamustine and etoposide) pre-transplant conditioning in persons with lymphoma. Bone Marrow Transplant. 2019 Apr. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31015577
- Prospective, multi-center, phase 2 trial to evaluate the safety and efficacy of CBeV in Argentinian patients with lymphoma
- 115 consecutive patients at five transplant centers were included in this investigation
- CBeV consists of bendamustine (200 mg/m2 days -6 & -5), cyclophosphamide (1500 mg/m2 days -6 to -3), and etoposide (1000 mg/m2 days -6 to -4)
- Median interval to granulocyte recovery was 11 days (range: 8-23 days) and all but 1 patient recovered bone marrow function while 1 patient died before day+100 post-transplant
- Two-year EFS was 65%, and two-year OS was 85% while 19/27 patients transplanted in PR achieved a CR by day+100
- The most common AEs were NF (n=89, 77%), diarrhea (n=25, 22%), N/V (n=21, 18%), and mucositis (n=18, 16%)
- The authors concluded that a randomized trial comparing CBeV to CBV should be considered in patients with lymphoma receiving an aHCT
**Kanate AS, Kumar A, Dreger P, et al. Maintenance Therapies for Hodgkin and Non-Hodgkin Lymphomas After Autologous Transplantation: A Consensus Project of ASBMT, CIBMTR, and the Lymphoma Working Party of EBMT. JAMA Oncol. 2019 Feb 28. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/30816957
- Consensus recommendations for maintenance and/or consolidation therapies in patients with lymphoma post-aHCT.
*Su B., Zhu X., Jiang Y., et al. A meta-analysis of autologous transplantation for newly diagnosed multiple myeloma in the era of novel agents. Leuk Lymphoma. 2019;60(6):1381-8. http://www.ncbi.nlm.nih.gov/pubmed/30516074
- Meta-analysis conducted to evaluate the role of high-dose melphalan plus aHCT as consolidation therapy for patients with newly diagnosed MM in the era of novel agents
- Four randomized controlled trials of aHCT versus novel agent-based consolidations and 10 single-arm prospective trials of aHCT alone were included
- Pooled analysis indicated that response quality improved further after aHCT in the era of novel agents (≥CR rates of 13% pre-aHCT versus 29% post-aHCT, p = 0.003)
- When compared to novel agent-containing consolidation regimens, high-dose chemotherapy plus aHCT significantly improved PFS (HR =0.56, p < 0.001), however no significant difference in OS was found (HR =0.66, p = 0.22), with the exception of a subgroup analysis indicating that aHCT could significantly improve OS (HR =0.49, p = 0.0004) when compared to alkylating agent-based regimens plus lenalidomide consolidation
- Response quality and PFS improved further over aHCT in the era of novel agents and aHCT could improve survival compared to alkylating agent-based regimens plus lenalidomide consolidation for patients with newly diagnosed MM
Graft-versus-host Disease
** Axt L, Naumann A, Toennies J, et al. Retrospective single center analysis of outcome, risk factors and therapy in steroid refractory graft-verses-host disease after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2019 May. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31089279
- Retrospective, single-center to analyze the incidence, therapy and outcomes of srGVHD
- 721 patients receiving alloHCT between 2004-2016 at the Medical Center University Hospital (Tuebingen, Germany) were assessed – 49.2% (n=355) experienced aGVHD while 37.3% (n=269) experienced cGVHD (35.7% and 31.4% of each population progressed to srGVHD respectively)
- In the aGVHD cohort, 27.4% of srGVHD patients responded to 2nd line GVHD treatment (MMF and mTOR inhibitor use led to superior response rates, ORR 50% & 53.3% respectively)
- In the cGVHD cohort, 44.4% of srGVHD patients responded to 2nd line GVHD treatment (CNI ORR: 45.5%; MMF ORR: 50%; mTOR ORR: 60%; ECP ORR: 56.3%)
- The authors concluded that GVHD still bears a high burned of morbidity and mortality and hope that this data may improve the design of future prospective clinical studies in GVHD
Infectious Disease
**Hakki M, Humphries RM, Hemarajata P, et al. Fluoroquinolone Prophylaxis Selects for Meropenem nonsusceptible Pseudomonas aeruginosa in Patients With Hematologic Malignancies and Hematopoietic Cell Transplant Recipients. Clin Infect Dis. 2019;68(12):2045–52. https://www.ncbi.nlm.nih.gov/pubmed/30256922
- Retrospective review of aeruginosa bloodstream infections in adult HM and HCT patients
- Of breakthrough bacteremia episodes, 47.3% occurred while on fluoroquinolone prophylaxis and 15.4% of these infections were susceptible to meropenem
- Fluoroquinolone prophylaxis was independently predictive of bacteremia with a meropenem-nonsusceptible isolate (OR 14.4; 95% CI 4.1-62), but did not predict resistance to antipseudomonal β-lactams or aminoglycosides
- The mechanism of resistance was primarily due to upregulation of efflux pumps and downregulation of OprD
- Fluoroquinolone prophylaxis in HM patients and HCT recipients is associated with breakthrough bacteremia with meropenem-nonsusceptible aeruginosa strains, likely due to both mutations conferring resistance and the epidemiology of P. aeruginosa bloodstream infections in this patient population
*Pinana JL, Perez A, Montoro J, et al. Clinical Effectiveness of Influenza Vaccination After Allogeneic Hematopoietic Stem Cell Transplantation: A Cross-sectional, Prospective, Observational Study. Clin Infect Dis. 2019;68(11):1894–903. https://www.ncbi.nlm.nih.gov/pubmed/30239624
- Prospective, cross-sectional, observational study to analyze the effect of the seasonal inactivated trivalent influenza vaccination on the prevalence of influenza RVI in a consecutive cohort of alloHCT adult recipients
- Active GVHD, steroid therapy, ongoing immunosuppression therapy, and hypogammaglobulinemia were significantly over-represented in the non-vaccinated group as compared to the vaccinated group (P < 0.05)
- Influenza vaccination was associated with a lower prevalence of influenza RVI (P = 0.01) and a lower likelihood of an influenza-related hospital admission (P = 0.04)
- A multivariate risk factor analysis identified influenza vaccination to be associated with a lower probability of LRTD progression (P = 0.05)
- Influenza vaccination may have a clinical benefit in alloHCT recipients with virologically-confirmed RVI, in terms of a lower influenza RVI prevalence, slower LRTD progression, and lower likelihood of hospital admission
*Zeigler M, Landsburg D, Pegues D, et al. Fluoroquinolone Prophylaxis Is Highly Effective for the Prevention of Central Line–Associated Bloodstream Infections in Autologous Stem Cell Transplant Patients. Biol Blood Marrow Transplant. 2019 May;25(5):1004-1010. https://www.ncbi.nlm.nih.gov/pubmed/30481595
- Retrospective study evaluating the impact of levofloxacin prophylaxis on reducing CLABSIs in the aHCT population at a tertiary care hospital.
- The rate of CLABSIs was reduced from 18.4% during the baseline period to 6.0%. On multivariable analysis, levofloxacin prophylaxis significantly reduced CLABSI incidence (hazard ratio, 0.33; 95% confidence interval [CI], 0.16 to 0.69; P = 0.003). There was also a reduction in the risk of neutropenic fever (odds ratio [OR], 0.23; 95% CI, 0.14 to 0.39; P < 0.001) and a trend toward a reduction in intensive care unit transfer for sepsis (OR, 0.33; 95% CI, 0.09 to 1.24; P = 0.10) in patients receiving levofloxacin prophylaxis. There was no increased Clostridium difficile.
- In conclusion, compared to a historic group of patients, those receiving prophylaxis had a reduction of CLABSI and a reduced risk of neutropenic fever, with the absence of increased Clostridium difficile
Multiple Myeloma
***Mikhael J, Ismaila N, Cheung M, et al. Treatment of multiple myeloma: ASCO and CCO joint clinical practice guideline. J Clin Oncol. 2019 May 10;37(4): 1228-1263. https://www.ncbi.nlm.nih.gov/pubmed/30932732
- Multidisciplinary expert panel performed a literature review (2005-2018) to develop evidence-based guideline recommendations for the treatment of MM
- Up-front single aHCT should be offered to all transplant-eligible patients; while alloHCT is not routinely recommended, it may be considered in high-risk patients or in context of a clinical trial
- At least 3-4 cycles of induction therapy is recommended prior to stem-cell collection with an immunomodulatory drug, proteasome inhibitor (PI), and steroids while avoiding stem-cell toxic agents such as melphalan or prolonged exposure to immunomodulators (>4 cycles)
- High-dose melphalan is recommended for the conditioning therapy
- Lenalidomide maintenance for standard-risk patients for 2 years is associated with improved survival. Bortezomib every 2 weeks may be substituted for those unable to receive lenalidomide. In high-risk patients, may consider dual maintenance with PI and immunomodulator
- For relapsed disease aHCT should be offered in transplant-naïve patients or if PFS after first aHCT was > 18 months. AlloHCT may be considered in context of clinical trial or in select patients.
Pediatrics
* Selim A, Alvaro F, Cole CH, et al. Hematopoietic stem cell transplantation for children with acute myeloid leukemia in second remission: A report from the Australasian Bone Marrow Transplant Recipient Registry and the Australian and New Zealand Children’s Haematology Oncology Group. Pediatr Blood Cancer. 2019 Aug [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31111633
- Retrospective registry evaluation of the ABMTRR of pediatric patients (up to 15 years old) who received an HCT for AML in CR2 between 1998 and 2013
- 83 patients were included for analysis (76% were undergoing 1st HCT)
- The majority of patients received high-dose cytarabine for their 1st (81%) and 2nd (85%) cycles of chemotherapy at relapse
- Patients who received 2 cycles of chemotherapy pre-transplant had an improved 5-year OS (73.3% vs 46.5% & 40%, p=0.04) as compared to those patients receiving 1 cycle or 3+ cycles
- 100% of patients had died at 5 years post-HCT (55% due to relapse/progression, 15% due to GVHD, 12% due to organ toxicity)
- The authors concluded that two cycles of chemotherapy pre-transplant led to improved outcomes in relapsed childhood AML and warrant further investigation in prospective studies
Relapsed Disease
*Gopalakrishnan S, D’Souza A, Scott, E, et al. Revised International Staging System (R-ISS) Is Predictive and Prognostic for Early Relapse (<24 months) after Autologous Transplantation for Newly Diagnosed Multiple Myeloma. Biol Blood Marrow Transplant. 2019;25(4):683-688. https://www.ncbi.nlm.nih.gov/pubmed/30579965
- Patients with increased R-ISS III, compared to II and I, have an increased incidence of early relapse, as well as shorter PFS and OS.
*Zeiser R, Beelen DW, Bethge W, et al. Biology-Driven Approaches to Prevent and Treat Relapse of Myeloid Neoplasia after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2019 Apr; 25(4):e128-140. https://www.ncbi.nlm.nih.gov/pubmed/30658222
- Review on options to prevent and treat relapse post-alloHCT for AML and MDS, including improved GVHD prophylaxis, DLI, and maintenance therapies.
Abbreviations:
AE: adverse event
aGVHD: acute graft-versus-host disease
alloHCT: allogeneic hematopoietic cell transplantation
AML: acute myeloid leukemia
aHCT: autologous hematopoietic cell transplantation
CBV: cyclophosphamide, carmustine, etoposide
CBeV: cyclophosphamide, bendamustine and etoposide
cGVHD: chronic graft-versus-host disease
CI: cumulative incidence
CLABSI: central line–associated bloodstream infection
CMML: chronic myelomonocytic leukemia
CNI: calcineurin inhibitors
CR: complete response
DFS: disease-free survival
DLI: donor lymphocyte infusion
ECP: extracorporeal photophoresis
EFS: event free survival
GVHD: graft-versus-host disease
HCT: hematopoietic cell transplantation
HM: hematologic malignancy
LRI: lower respiratory infection
LRTD: lower–respiratory tract disease
MDS: myelodysplastic syndrome
MF: myelofibrosis
MM: multiple myeloma
MMF: mycophenolate
MPN: myeloproliferative neoplasm
NF: neutropenic fever
NRM: non-relapse mortality
ORR: objective response rate
OS: overall survival
PFS: progression-free survival
PI: proteasome inhibitor
PR: partial response
RVI: respiratory virus infection
srGVHD: steroid-refractory GVHD
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