In this month’s Pharmacy SIG Literature Update: Haploidentical stem cell transplantation for patients with lymphoma, RIC with fludarabine and melphalan for patients with AML and myelodysplasia, outcomes of alloHCT after salvage therapy with blinatumomab in relapsed/refractory ALL 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

* Arcese W, Cerretti R, Sarmati L, et al. Matched-pair analysis of transplant from haploidentical, unmanipulated bone marrow donor verses HLA identical sibling for patients with hematological malignancies. Biol Blood Marrow Transplant. 2020 Feb 14.  [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/32068095

• Single-center, matched-pair analysis of transplant-related outcomes using matching on 9 variables: period of transplant, patient and donor age, gender, diagnosis, disease phase, conditioning regimen, donor/recipient sex, and CMV status combinations
• 116 of 255 consecutive patients transplanted were included in the analysis (58 HLA identical siblings & 58 haploidentical related donors)
• All patients received the same anti-infective, transfusion, and supportive care protocols, but differed in GVHD prevention (addition of ATG, mycophenolate, and basiliximab for haploidentical, unmanipulated BM recipients to standard cyclosporine and methotrexate)
• No statistical difference was found between the two patient sets when assessing cumulative incidence of advanced acute and extensive cGVHD, TRM or relapse
• 5-year DFS was 37 +/- 6% and 36 +/- 6% for HLA-identical siblings and haploidentical recipients respectively after a median 3.5 years of follow up
• The authors concluded that HLA-identical siblings and haploidentical donors are comparable and that factors beyond HLA matching might drive the search for the best donor

***Dietrich S, Dreger P, Hermine O, et al.  Haploidentical stem cell transplantation for patients with lymphoma:  a position statement from the Lymphoma Working Party-European Society for Blood and Marrow Transplantation.  Bone Marrow Transplant.  2020;55(2):317-324.  https://pubmed.ncbi.nlm.nih.gov/31150019

• Review of literature to provide a position statement regarding haploHCT in hodgkin lymphoma, high-grade B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma by panel members of the Lymphoma Working Party (LWP) of the EBMT
• HaploHCT is an acceptable and safe option for patients without an HLA 10/10 matched donor but is not preferred over an HLA matched donor
• PTCy in haploHCTs has comparable outcomes to those with MSD and MUD with lower incidence of cGVHD
• Although BM is more frequently used, BM or peripheral blood may be used as the stem cell source
• Additional studies are needed regarding conditioning, selected types of lymphoma, and if haploHCT should be used first line compared to other donor types

**DiMaggio E, Zhou J, Caddell R, et al. Reduced-intensity fludarabine/melphalan confers similar survival to busulfan/fludarabine myeloablative regimens for patients with acute myeloid leukemia and myelodysplasia. Leuk & Lymph. 2020 Mar 5. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/32133897

• Analysis of HCT recipients with AML and MDS who received fludarabine with once-daily intravenous busulfan targeted to either AUC 5300 mM*L/min or AUC 3500 mM*L/min, or Fludarabine/Melphalan
• After 2-year follow-up, no differences in OS or RFS were found between Flu/Bu 5300 or 3500 versus Flu/Mel though relapse rates were significantly higher; 33.1% (P = 0.024), 44.6% (P = 0.002), versus 19.4%, respectively
• Flu/Bu 5300 (P = 0.008) and Flu/Bu 3500 (P < 0.001) groups were prognostic for relapse compared to Flu/Mel
• Flu/Mel yields lower relapse rates and similar survival benefit when compared to Flu/Bu 3500 or 5300

* Martinez C, Carpio C, Heras I, et al. Potential survival benefit for patients receiving allogeneic hematopoietic stem cell transplantation after nivolumab therapy for relapse/refractory Hodgkin lymphoma: real-life experience in Spain (Spanish Group of Lymphoma and Bone Marrow Transplantation, GELTAMO). Biol Blood Marrow Transplant. 2020 Feb 14. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/32068094

• Retrospective, multicenter, observational study of nivolumab use in patients with relapsed or refractory cHL at 34 GELTAMO centers
• 74 patients that were treated with nivolumab were included in the analysis: ORR was 58% (30.6% CR) and 56.8% of patients experienced treatment-related adverse events (grade >3 9.4%); 41.7% of discontinuations were due to referral for alloHCT
• 39 patients went on to alloHCT: Cumulative incidence of grade II-IV aGVHD was 33.3% (grade III-IV in 2 patients), Cumulative incidence of NRM was 13.2%
• Among nivolumab-responding patients, 2-year OS and PFS were higher in patients undergoing consolidative alloHCT (77.5% vs 42.6%, p=0.126; 73.9% v 27.2%, p=0.025 respectively)
• The authors concluded that consolidation alloHCT increases OS and PFS in cHL patients treated with nivolumab

*Roy DC, Walker I, Maertens J, et al. ATIR101 administered after T-cell-depleted haploidentical HSCT reduces NRM and improves overall survival in acute leukemia. Leukemia. 2020 Feb 11. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/32047237

• ATIR101 is a haploidentical, naïve cell-enriched T-cell product, depleted of recipient-alloreactive T cells to minimize the risk of GVHD and provide graft-versus-infection and -leukemia activity
• Phase 2, multicenter study of patients with acute leukemia who received ATIR101 administered after TCD-haplo without post-transplant immunosuppressors
• 6-month NRM was 13% with TCD-haplo + ATIR101. One year post HCT, TCD-haplo + ATIR101 resulted in lower NRM versus TCD-haplo alone (P = 0.008)
• GRFS was higher with TCD-haplo + ATIR101 versus MMUD and UCB (both P < 0.03) and was not statistically different from MUD
• This study suggests haploidentical, selective donor-cell depletion may eliminate requirements for post-transplant immunosuppressors without increasing GVHD risk, with similar GRFS to MUD. Following these results, a randomized Phase 3 trial versus post-transplant cyclophosphamide has been initiated

**Salhotra A, Yang D, Mokhtari S, et al. Outcomes of Allogeneic Hematopoietic Cell Transplantation after Salvage Therapy with Blinatumomab in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia. Biol Blood Marrow Transplant. 2020 Feb 5. [Epub ahead of print]. https://pubmed.ncbi.nlm.nih.gov/32035275

• Investigators looked at outcomes of patients with relapsed/refractory ALL who responded to blinatumomab followed by HCT (n= 89); 43 (48%) of patients were in remission prior to transplant
• OS at 1 and 2 years after alloHCT was 77% and 52%, respectively and LFS at 1 and 2 years were 65% and 40%, respectively
• The incidence of aGVHD (grades II to IV) at 100 days post-transplant was 43%, and the incidence of cGVHD at 2 years was 36%, which is similar to historical controls
• There was no unusual toxicity, delay in engraftment, or graft failure in the treatment group compared to historical controls
• The authors concluded that blinatumomab may be considered as a safe and effective agent for relapsed/refractory ALL patients before HCT.

* Schmidt S, Liu Y, Hu ZH, et al. The role of donor lymphocyte infusion (DLI) in post hematopoietic cell transplant (HCT) relapse for chronic myeloid leukemia (CML) in the tyrosine Kinase inhibitor (TKI) era. Biol Blood Marrow Transplant. 2020 Feb 14. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/32062061

• Observational study of the CIBMTR database of CML patients who had received TKI therapy and subsequently underwent alloHCT but experienced relapse post-transplant at 134 centers during the years of 2002-2014
• 215 recipients were included in the analysis: 128 patients received TKI alone, 48 received TKI+DLI, 39 received DLI alone
• In multivariate analysis, disease status prior to alloHCT had a significant effect on OS; DLI alone as compared to TKI+DLI had inferior survival (HR 2.28, CI 1.23-4.24; p=0.009) but those who received TKI alone had similar survival compared to those who received TKI+DLI (p=0.81)
• The authors concluded that adding a DLI to TKI therapy does not improve OS in relapsed CML post-transplant

*Wedge E, Sengeløv H, Hansen JW, et al. Improved outcomes after allogenic hematopoietic stem cell transplantation with Fludarabine/Treosulfan for patients with myelodysplastic syndromes.  Biol Blood Marrow Transplant. 2020 Feb 20.  [Epub ahead of print].   https://pubmed.ncbi.nlm.nih.gov/32088368

• Investigators enrolled 215 patients with MDS (n=196) or CMML (n=19) to NMA conditioning with TBI and fludarabine (n=124), myeloablative conditioning with TBI and high-dose cyclophosphamide, (n=36), or fludarabine and treosulfan conditioning (FluTreo, n=55)
• Patients receiving myeloablative transplants received GVHD prophylaxis with short-course methotrexate and cyclosporine, patients receiving NMA transplants received tacrolimus and mycophenolate mofetil, and those receiving FluTreo received GVHD prophylaxis with methotrexate and tacrolimus.  Those patients with a mismatched unrelated donor (MMUD) received GVHD prophylaxis with cyclosporine, sirolimus, and mycophenolate mofetil
• The one-year OS was 70.3% with a median survival of 7.7 years for the entire population.  One-year OS was 84.0%, 58.3%, and 68.3%, for the FluTreo, myeloablative, and NMA groups, respectively (P=.04)
• Because FluTreo has a lower toxicity profile, this regimen has become the standard myeloablative conditioning regimen at this particular institution, and the investigators concluded that this regimen shows promising results

Autologous Transplantation

**Sharrack B, Saccardi R, Alexander T, et al.  Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases:  updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE).  Bone Marrow Transplant.  2020;55(2):283-306.  https://pubmed.ncbi.nlm.nih.gov/31558790

• Updated guidelines from the ADWP regarding HCT in patients with multiple sclerosis and other immune-mediated neurological diseases in regards to patient selection, transplant technique, patient follow-up, and future developments
• AHCT should be considered for patients with highly active relapsing remitting multiple sclerosis failing disease-modifying therapy and for patients with “aggressive” multiple sclerosis (severe disability in previous 12 months) despite disease-modifying therapy use.
• Patients with other multiple sclerosis types or refractory chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, neuromyelitis optica, stiff person syndrome, and systemic autoimmune diseases with neurological manifestations may also be considered for aHCT but on a clinical trial if available as data is less robust.
• AHCT should be performed by centers accredited by JACIE or equivalent organizations and in collaboration with neurology specialists.

**Spreafico F, Dalissier A, Potschger U, et al.  High dose chemotherapy and autologous hematopoietic cell transplantation for Wilms tumor:  a study of the European Society for Blood and Marrow Transplantation.  Bone Marrow Transplant.  2020;55(2):376-383.  https://pubmed.ncbi.nlm.nih.gov/31534191

• Retrospective review of 69 patients younger than 18 years old with Wilms tumor who received an aHCT as consolidation of first or second remission within the EBMT registry
• 5-year OS probability was 0.67 (+0.06) and EFS probability was 0.63 (+0.06) with a median follow-up of 7.8 years.  All deaths (n=23) were due to disease
• Statistically significant lower OS probabilities were noted for male patients, relapse in combined multiple sites compared to lung alone, and the use of peripheral blood as the stem cell source
• Melphalan alone conditioning was not found to have inferior EFS compared to regimens containing multiple agents and was associated with improved platelet engraftment
• Due to lack of clinical trials on relapsed/refractory Wilms tumor, the authors conclude that their review provides additional data for clinicians when treating Wilms tumor  

Graft-Versus-Host Disease

*Caballero-Velazquez T, Calderon-Cabrera C, Lopez-Corral L, et al.  Efficacy of bortezomib to intensify the conditioning regimen and the graft-versus-host disease prophylaxis for high-risk myeloma patients undergoing transplantation.  Bone Marrow Transplant. 2020;55(2):419-430.  https://pubmed.ncbi.nlm.nih.gov/31551517

• Multi-center phase I trial of 25 patients with myeloma who received bortezomib as part of their conditioning regimen and as GVHD prophylaxis for an alloHCT
• Patients received bortezomib 1.3mg/m2 IV on days -9, -2, +1, +4, and +7 in addition to fludarabine 30mg/m2 IV on days -6 to -4 and melphalan 140mg/m2 IV on day -3.  Sirolimus monotherapy was given to the first 5 patients, but as all developed aGVHD (including one grade 4) tacrolimus was added
• Cumulative incidence of grade 2-4 aGVHD with the triple regimen was 35% (95% CI: 15-55%) and grade 3-4 was 10% (95% CI:  1-27%).  Overall incidence of cGVHD at 2 years was 55% (95% CI: 6.6-76.2%)
• At D+100 of the 21 patients alive, 67% were in CR (n=14).  Two-year OS was 64% and EFS was 64%
• The authors conclude that the addition of bortezomib for conditioning and GVHD prophylaxis is safe and effective.

Infectious Disease

* Robin C, Thiebaut A, Alain S, et al. Letermovir for secondary prophylaxis of cytomegalovirus infection and disease after allogeneic hematopoietic cell transplantation: results from the French Compassionate Program. Biol Blood Marrow Transplant. 2020 Feb 5. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/32035273

• Retrospective database study evaluating letermovir usage for secondary prophylaxis of CMV infection or diseases after alloHCT using the French compassionate access program
• 80 consecutive CMV-seropositive adult patients who received secondary prophylaxis after at least 1 CMV episode after alloHCT between January 2018 and January 2019 at a French transplant center
• Letermovir dosing followed the package insert and was initiated at a median of 170 days post-transplant; 53% of patients had seronegative donors, 62% had experienced GVHD since transplant, and 17.5% of patients had experienced CMV disease since transplant
• 4 (5.5%) patients developed CMV breakthrough infection or disease after starting letermovir secondary prophylaxis, 3 of which were found to have high-level letermovir resistance mutations
• One or more adverse reactions were identified by local investigators in 19% of patients receiving letermovir secondary prophylaxis, but only 2 patients stopped therapy because of these reactions.
• The authors concluded that letermovir secondary prophylaxis may prevent new CMV reactivation in high-risk patient populations and provide a bridge between pre-emptive treatment and CMV-specific immune reconstitution

* Stern A, Su Y, Lee YJ, et al. A single center, open-label trial of isavuconazole prophylaxis against invasive fungal infection in patients undergoing allogeneic hematopoietic cell transplant (HCT). Biol Blood Marrow Transplant. 2020 Feb 20. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/32088367

• Open-label, single-arm study of adult patients receiving their first alloHCT receiving micafungin 150 mg through D+7, then given isavuconazole (372 mg q8 hours for 6 doses, then 372 mg daily thereafter) through D+98 and were followed through D+182
• 95 patients (median age 57 years old) were included in the analysis; 31% of patients received CD34+ selected product while 67% of patients received PBSC sourced product (18% BM, 15% UCB)
• Isavuconazole prophylaxis was given for a median of 90 days and candidemia occurred in 3 (3.1%) patients, one of whom had grade 3 aGVHD; 7 patients discontinued therapy due to toxicity, most commonly (5/7) being liver toxicity
• 6 patients died during the study (3 during isavuconazole prophylaxis timeframe) but no death was attributed to isavuconazole prophylaxis therapy
• The authors concluded that their data supports the utility of isavuconazole for antifungal prophylaxis after alloHCT

Other

*Amonoo HL, Kurukulasuriya C, Chilson K,et al. Improving quality of life in hematopoietic stem cell transplant survivors through a positive psychology intervention. Biol Blood Marrow Transplant. 2020 Feb 20. [Epub ahead of print]. https://pubmed.ncbi.nlm.nih.gov/32088365

• Investigators looked at the feasibility and acceptability of phone-delivered positive psychology interventions in patients 0.4 to 39 years post-HCT
• The patients were asked to self-report on psychological, functional, and quality of life outcomes both at baseline and at a specified follow-up of 8 weeks
• Of 64 patients eligible to enroll in the study, 29 (45%) were included.  Of the reports completed, the intervention showed an improvement in the resilience scale (mean difference 2.4 [SD 5.4], p=0.03), and patients stated that the positive psychology exercises and intervention helped them to focus on positive emotions,  and the group format fostered a sense of community and social support, showing that this is a feasible and acceptable intervention

* Hsu JW, Shaw BE, Kim S, et al. Collection of peripheral blood progenitor cells in one day is associated with decreased donor toxicity compared to two days in unrelated donors. Biol Blood Marrow Transplant. 2020 Feb 20.  [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/32088366

• Observational study of the CIBMTR database of volunteer donors from the NMDP who underwent filgrastim-mobilized PBSC collection between January 2006 and December 2016
• 22,348 adult unrelated donors in 184 centers were assessed: 20,004 (89.5%) had collections on 1 day vs 2,344 (9.5%) over 2 days but information on why 1 vs 2 day collections occurred was not available
• Donors who underwent apheresis over 1 day were more likely to be male (67% vs 46%, p<0.001), younger (age <30: 48% vs 36%, p<0.001), and have a higher body weight (83.0 kg vs 75.9 kg, p<0.001) and BMI (BMI >30: 30% vs 22%, p<0.001)
• Successful collection of the requested CD34+ cell count was achieved on the first day in 82% of one day collections vs 16% of 2 day collections
• Donors collected in one day were less likely to experience citrate toxicity (36% vs 52%, p<0.001), hospitalizations (1% vs 6%, p<0.001), and other side effects related to apheresis (20% vs 26%, p<0.001)
• The authors concluded that one day apheresis procedures were associated with less overall toxicity and one day collections should be recommended, especially if the requested number of cells has been collected in the first day

Pediatrics

*Kurtzberg J, Abdel-Azim H, Carpenter P, et al. A Phase 3, Single-Arm, Prospective Study of Remestemcel-L, Ex Vivo Culture-Expanded Adult Human Mesenchymal Stromal Cells for the Treatment of Pediatric Patients Who Failed to Respond to Steroid Treatment for Acute Graft-versus-Host Disease.  Biol Blood Marrow Transplant. 2020 Feb 1. [Epub ahead of print]. https://pubmed.ncbi.nlm.nih.gov/32018062

• Investigators looked at the use of mesenchymal stromal cells in the treatment of steroid-refractory aGVHD in pediatric patients under the age of 12 (n=54) in a phase 3, prospective, single-arm, multicenter study
• Treatment with remestemcel-L therapy significantly improved day 28 ORR compared to the prespecified control ORR (70.4% versus 45%, P = .0003), and the ORR was sustained through day 100 with an OS of74.1% at day 100 and 68.5% at day 180
• Authors concluded that remestemcel-L was well tolerated in this patient population and provides evidence for potential use of remestemcel-L as a treatment option in pediatrics with steroid-refractory aGVHD.

*Sauer M, Lang P, Albert MH, et al. Hematopoietic stem cell transplantation for children with acute myeloid leukemia—results of the AML SCT-BFM 2007 trial.  Leukemia. 2020; 34(2):613-24.  https://pubmed.ncbi.nlm.nih.gov/31578451

• Pediatric patients with high-risk AML and in either a CR-1 or in CR-2 after first relapse received HCT with a matched donor and busulfan, cyclophosphamide, and melphalan (BuCyMel) conditioning (n = 81), with cyclosporine and short-term methotrexate for GVHD prophylaxis, along with ATG for those patients with unrelated donors 
• Of the 140 patients enrolled, the 4-year EFS was 61% and the OS was 70%.  The CIR was 22%.  An interim analysis showed that TRM was age-dependent (31% for patients ≥ age 12 and 9% in patients < age 12)
• Patients with a poor response or disease relapse received conditioning with fludarabine, amsacrine, cytarabine, TBI, cyclophosphamide (FLAMSA-RIC) and immunosuppression with mycophenolate mofetil, cyclosporine, and prophylactic DLI, (n = 27)
• The 4-year EFS was 49% and OS was 53%.  CIR was 35% and TRM was 11%
• To note, there was a protocol violation and eight of the children enrolled on the FLAMSA-RIC arm were supposed to receive BuCyMel
• Authors concluded that in patients with a poor response to therapy may benefit from a reduced intensity regimen with FLASMA and prophylactic DLI.

Abbreviations:

aGVHD: acute graft-versus-host disease

aHCT: autologous hematopoietic cell transplantation

alloHCT: allogeneic hematopoietic cell transplantation

ALL: acute lymphoblastic leukemia

AML: acute myeloid leukemia

ATG: antithymocyte globulin

AUC: area under the curve

BM: bone marrow

BMI: body mass index

cGVHD: chronic graft-versus-host disease

cHL: classical Hodgkin lymphoma

CIBMTR: Center for International Blood and Marrow Transplant Research

CIR: cumulative incidence of relapse                               

CMML: chronic myelomonocytic leukemia

CML: chronic myeloid leukemia

CMV: cytomegalovirus

CR: complete response

DFS: disease-free survival

DLI: donor lymphocyte infusion

EBMT: European Society for Blood and Marrow Transplantation

EFS: event-free survival

GRFS: graft-versus-host disease, relapse-free survival

GVHD: graft-versus-host disease

HaploHCT: haploidentical hematopoietic cell transplantation

HCT: hematopoietic cell transplantation

HLA: human leukocyte antigen

LFS: leukemia-free survival

MDS: myelodysplastic syndrome

MMUD: mismatched unrelated donor

MSD: matched sibling donor

MUD: matched unrelated donor

NMA: non-myeloablative

NMDP: National Marrow Donor Program

NRM: non-relapse mortality

ORR: overall response rate

OS: overall survival

PBSC: peripheral blood stem cell

PFS: progression-free survival

PTCy: post-transplant cyclophosphamide

RFS: relapse-free survival

RIC: reduced-intensity conditioning

TBI: total-body-irradiation

TCD-haplo: T-cell-depleted haploidentical hematopoietic stem cell transplant

TKI: tyrosine kinase inhibitor

TRM: treatment related mortality

UCB: umbilical cord blood

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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