In this month’s Pharmacy SIG Literature Update:  Autologous HCT in myeloma patients aged >75 years, improved outcomes for male germ cell tumors, haploidentical hematopoietic cell and kidney transplantation for hematological malignancies and end-stage renal failure 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

*Chamoun K, Milton DR, Ledesma C, et al.  Allogeneic Transplantation after Myeloablative Rituximab/BEAM ± Bortezomib for Patients with Relapsed/Refractory Lymphoid Malignancies: 5-Year Follow-Up Results. Biol Blood Marrow Transplant. 2019;25(7):1347-54. https://www.ncbi.nlm.nih.gov/pubmed/30826465.

• Phase I/II trial assessing bortezomib in combination with rituximab (R) and BEAM (carmustine, etoposide, cytarabine, melphalan) in patients with relapsed lymphoma undergoing alloHCT.
• Patients received bortezomib 1 to 1.3 mg/m2 IV days –13, –6, –1, and +2 and GVHD prophylaxis with tacrolimus and methotrexate. Of 39 patients, 56% (n=22) had matched related donors, and 44% (n=17) had matched unrelated donors.
• The maximum tolerated dose of bortezomib was 1 mg/m2 due to C.diff colitis. Grade II to IV and III to IV GVHD incidence was similar to historical groups.
• Median survival was not reached in patients less than age 50 at a follow-up of 60.7 months, suggesting a survival benefit in this patient population.
• Bortezomib had no impact on survival or GVHD data suggesting that in lymphoma patients receiving alloSCT, the addition of bortezomib to the R-BEAM myeloablative conditioning regimen given with standard GVHD prophylaxis does not result in a lower cumulative incidence of clinically significant GVHD. However, the R-BEAM regimen alone may have a survival benefit in young, heavily pretreated lymphoma patients and should be investigated further in patients who are not eligible for non-myeloablative conditioning.

*Harada K, Tachibana T, Ohashi K, et al.  The effect of melphalan dose and total body irradiation as reduced-intensity conditioning for acute lymphoblastic leukemia patients undergoing allogeneic stem cell transplantation.  Leuk Lymphoma. 2019 Jul 10. [Epub ahead of print].  https://www.ncbi.nlm.nih.gov/pubmed/31290354

• Single center, retrospective review of ALL patients conditioned with 3 different regimens: higher-dose melphalan 120-140mg/m2 with 2-4Gy TBI (HDM/TBI+, n=118), higher-dose melphalan without TBI (HDM/TBI-, n=152), or lower-dose melphalan 80-110mg/m2 with 2-4Gy TBI (LDM/TBI+, n=237).
• At 3 years, the OS, DFS, relapse rates, and NRM did not statistically differ between the regimens.
• Patients who received BM or PBSC and HDM/TBI+ had increased CNS complications compared to the LDM/TBI+ group (10.9% vs 1.9%, p=0.43).
• Cumulative incidence of grades II-IV aGVHD at 100 days and incidence of cGVHD did not statistically differ between the 3 regimens.
• Higher doses of melphalan, regardless of TBI, was not associated with increased OS or improved relapse rates.

*Narayan R, Benjamin JE, Shah O, et al. Donor-derived cytokine-induced killer cell infusion as consolidation after nonmyeloablative allogeneic transplantation for myeloid neoplasms. Biol Blood Marrow Transplant. 2019;25(7):1293-1303. https://www.ncbi.nlm.nih.gov/pubmed/30951840

• Single-center, nonrandomized, open-label phase II trial evaluating the effects of a one-time infusionof donor-derived CIK cells following alloHCT with TLI-ATG conditioning for patients with MNs (including MDS, MPN, s-AML, or t-MN).
• Patients underwent NMA transplant with TLI 1200 cGy and rabbit-derived ATG 7.5 mg/kg (total dose) conditioning with PBSC infusion.
• A one-time infusion of 1 × 10⁸/kg CD3+donor-derived CIK cells were administered between day +21 and day +35 as a fresh infusion after ex-vivo cellular expansion.
• The rate of FDC by day +90, 2-year NRM, EFS, OS, and 1-year cumulative incidence of grade II-IV aGVHD were similar to the values seen in the historical cohort.
• Overall, a one-time CIK cell infusion following TLI-ATG conditioning was safe as post-transplant consolidation. Varied dosing strategies or CIK cell modification may enhance the antitumor efficacy of this treatment modality.

Autologous Transplantation

**Bashir Q, Chamoun K, Milton D, et al.  Outcomes of autologous hematopoietic cell transplantation in myeloma patients aged >75 years.  Leuk Lymphoma. 2019 Jul 8. [Epub ahead of print].  https://www.ncbi.nlm.nih.gov/pubmed/31282244

• Single center, retrospective review of 72 aHCT patients with MM who were conditioned with melphalan 140-200mg/m2.
• Fifty-four (75%) patients underwent aHCT for first remission consolidation with 26% (n=19) classified as ISS stage I, 38% (n=27) stage II, and 24% (n=17) stage III disease.
• Median PFS was 31.4 months and median OS was 72.8 months with an 82% 2-year and 58% 5-year OS.
• Statistically significant factors associated with decreased OS included high-risk cytogenetics and ISS Stage III disease.
• GI toxicity grade II-IV was most common in 58% (n=26) of patients receiving melphalan 140mg/m2 and 44% (n=12) who received >140mg/m2 (p=0.33). NRM was 1% at 1-year.
• The authors conclude that aHCT can be a safe and effective option for patients >

**Gagelmann N, Eikema DJ, Koster L, et al. Tandem autologous stem cell transplantation improves outcomes in newly diagnosed multiple myeloma with extramedullary disease and high-risk cytogenetics: a study from the chronic malignancies working party of the European Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2019 Jul 6. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31288095

• Retrospective review of clinical and cytogenetic data from adult myeloma patients with EMD undergoing single autologous, tandem autologous, or autologous followed by RIC allogeneic transplant.
• At least 1 high-risk abnormality was present in 41% of patients and 54% of those patients had more than 1 high-risk abnormality.
• 6-month OS and PFS were 70% and 43% for single autologous versus 83% and 52% for tandem autologous and 88% and 58% for autologous followed by allogeneic (P=0.06 and P=0.3 respectively).
• In multivariate analysis, high-risk cytogenetics were associated with worse OS (HR, 2.0; P=0.003), whereas tandem autologous significantly improved OS and PFS versus single autologous transplant (HRs, 0.46 and 0.64; P= 0.02 and P=0.03).
• Tandem auto-allo transplant had encouraging results but the small patient population (n=31) makes these data difficult to interpret.
• High-risk cytogenetics is frequently observed in newly diagnosed myeloma with EMD and significantly worsens outcome after single autologous, whereas a tandem autologous transplant strategy may overcome poor prognosis.

**Kilari D, D’Souza A, Fraser R, et al. Autologous Hematopoietic Stem Cell Transplantation for Male Germ Cell Tumors: Improved Outcomes Over 3 Decades. Biol Blood Marrow Transplant. 2019;25(6):1099-1106. https://www.ncbi.nlm.nih.gov/pubmed/ 30794931

• Analysis of outcomes of patients with relapsed/refractory male GCT who underwent aHCT and were reported to the CIBMTR.
• Day +100 NRM was 8% in 1990 to 1994 versus 4% in 2010 to 2015 (P=0.2) and 3-year probability of relapse/progression decreased from 68% in 1990 to 1994 to 42% in 2010 to 2015 (P<0.001).
• 3-year PFS improved from 24% in 1990 to 1994 to 47% in 2010 to 2015 (P<0.0001) and 3-year OS improved from 35% in 1990 to 1994 to 54% in 2010 to 2015 (P<0.0001).
• Residual disease at aHCT, >1 line of chemotherapy before HDCT, nonseminoma histology, and single transplant vs. tandem transplant were associated with inferior PFS and OS
• Post-transplantation survival has improved significantly over time for relapsed/refractory male GCT and is associated with the increased use of tandem transplants (compared with single transplants) and performance of aHCT earlier in the disease course.

Haploidentical Transplantation

***Chen YB, Elias N, Heher E, et al.  Haploidentical hematopoietic cell and kidney transplantation for hematological malignancies and end-stage renal failure.  Blood. 2019;134(2):211-215.  https://www.ncbi.nlm.nih.gov/pubmed/31151984

• Report on the first 6 patients who received HCT and kidney transplant from a haploidentical donor at Massachusetts General Hospital for treatment of hematologic malignancies with end-stage renal failure.
• Patients were conditioned with fludarabine, cyclophosphamide and 200cGy of TBI with GVHD prophylaxis of PTCy (50mg/kg/day on days +3 and + 4), tacrolimus and MMF.
• Patient 1 received thymoglobulin and experienced hematopoietic graft rejection, thus prompting fludarabine substitution, with hemodialysis 6-12 hours post infusion.
• Fludarabine was dose adjusted from 24mg/m2 on days -6 through -2 to 24mg/m2 on days -4 through -2 after death of a patient from presumed fludarabine neurotoxicity.
• Overall, two patients developed grade I aGVHD, no patients developed ≥ grade 2 aGVHD, and 2 patients developed cGVHD.
• At 1-yr post-transplant, 5 patients were without relapse or rejection of their kidney; 4 patients remain alive at time of publication.
• The authors conclude that HCT and kidney with a haploidentical donor appears to be a viable option for patients.

Other

*Corbacioglu S, Jabbour EJ, Mohty M.  Risk Factors for Development of and Progression of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome. Biol Blood Marrow Transplant. 2019;25(7):1271-80. https://www.ncbi.nlm.nih.gov/pubmed/30797942.

• Updates to risk factors for development of VOD, including acute kidney injury, female sex in pediatrics, platelet refractoriness, as well as drug therapies and biomarkers.

*Moody K.  Neutropenic Dietary Restrictions for Hematopoietic Stem Cell Patients: Time for a Change.  Biol Blood Marrow Transplant. 2019;25(7):e223-225. https://www.ncbi.nlm.nih.gov/pubmed/31136798.

• Updated discussion on lack of evidence supporting the need for neutropenic diet restrictions.

*Yuan C, Boyd A, Nelson J, et al.  Eltrombopag for Treating Thrombocytopenia after Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transplant T. 2019;25(7):1320-1324.  https://www.ncbi.nlm.nih.gov/pubmed/30710685.

• Retrospective study of alloHCT recipients who developed persistent thrombocytopenia after transplantation and were treated with 25 to 50 mg of eltombopag (dose per physician discretion).
• Primary thrombocytopenia was defined as a requirement for platelet transfusion owing to inadequate platelet recovery (<20 × 10 9 /L) for ≥100 days after alloSCT, and secondary thrombocytopenia was defined as inadequate platelet recovery (<20 × 10 9 /L) occurring after the initial engraftment of >50 × 10 9 /L without transfusions and in the absence of relapse of the original disease.
• Platelet recovery without need for transfusion for 7 or more days was seen in 62% (8/13) patients, with a median time to response of 33 days. The drug was well-tolerated.  Only 3 patients were still alive at the end of treatment, due to GVHD or disease relapse.
• Eltrombopag was effective in 62% of cases of primary prolonged thrombocytopenia after HCT.

Pediatrics

**Balduzzi A, Dalle JH, Wachowiak J, et al. Transplantation in children and adolescents with acute lymphoblastic leukemia from a matched donor versus an HLA-identical sibling: is the outcome comparable? Results from the International BFM ALL SCT 2007 Study. Biol Blood Marrow Transplant. 2019 Jul 15. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31319153

• International prospective study to assess the impact of donor type (MSD vs. MD) on the outcomes of transplantation in pediatric ALL.
• Mean 4-year EFS, OS, CIR and NRM were not significantly different between MSD and MD graft recipients.
• Extensive cGVHD was lower in MD graft recipients than in MSD graft recipients (HR, 0.38; P=0.002), and severe aGVHD and cGVHD were higher in PBSC graft recipients than in BM graft recipients (HR, 2.06; P=0.026).
• Outcomes of transplantation were not significantly different between MSD and MD graft sources and donor sources should be reviewed in pediatric ALL. Based on the results in this study, the preferred stem cell source appears to be bone marrow.

*Cuvelier G, Nemecek E, Wahlstrom J, et al.  Benefits and challenges with diagnosing chronic and late acute GVHD in children using the NIH consensus criteria.  Blood. 2019;134(3):304-316.  https://www.ncbi.nlm.nih.gov/pubmed/31043425

• Prospective, multicenter trial to evaluate the 1-year incidence, clinical presentation, and risk factors for cGVHD and late aGVHD (L-aGVHD) in patients < 18 years old by utilizing the NIH consensus criteria (NIH-CC) with oversight by a central review committee.
• Of 243 evaluable patients 21% (n=51) developed cGVHD at a median day of +161 (range, day 41-385) while 24.7% (n=60) were diagnosed with L-aGVHD only.
• The committee reclassified 28.2% of presumed cGVHD cases.
• The most frequent organ systems involved were the mouth, skin, eyes, lungs, scalp, musculoskeletal systems, and nails.
• Risk factors for cGVHD included history of aGVHD grade 2-4 (OR, 5.38; p=0.0001), use of PBSC (OR, 4.11; p=0.0064), and patient age >12 years (OR, 3.07; p=0.015).
• The authors conclude that the use of the NIH-CC for diagnosing cGVHD in children is supported but may need refinement as pulmonary cGVHD diagnosis was difficult in children.

*Neven B, Diana JS, Castelle M, et al.  Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide for Primary Immunodeficiencies and Inherited Disorders in Children. Biol Blood Marrow Transplant. 2019;25(7):1363-73. https://www.ncbi.nlm.nih.gov/pubmed/30876929.

• Pediatric patients with primary immunodeficiencies received a haploidentical alloHCT with PTCy.
• At a median of 25.6 months, 24 of 27 patients engrafted, 21 patients were alive and were cured of disease, and 2-year survival was 77.7%. The incidence of aGVHD grade 2 or greater, cGVHD, or autoimmune disease was 45.8%, 24,2%, and 29.6%, and there was evidence of viral infections. 
• These findings suggest that in patients without a HLA-matched donor, a haploidentical alloHCT is a treatment option for patients with life-threatening inherited disorders.

 

Abbreviations:

aGVHD: acute graft-versus-host disease

aHCT: autologous hematopoietic cell transplantation

ALL: acute lymphocytic leukemia

alloHCT: allogeneic hematopoietic cell transplantatio

ATG: antithymocyte globulin

BM: bone marrow

CIK: cytokine-induced killer

cGVHD: chronic graft-versus-host disease                     

CIBMTR: Center for International Blood and Marrow Transplant Research

CIR: cumulative incidence of relapse

CNS: central nervous system

DFS: disease-free survival

EFS: event free survival

GI: gastrointestinal

GVHD: graft-versus-host disease

EFS: event-free survival

EMD: extramedullary disease

FDC: full donor chimerism

GCT: germ cell tumor

HCT: hematopoietic cell transplantation

HDCT: high-dose chemotherapy

HR: hazard ratio

ISS: international staging system

MD: matched donors

MDS: myelodysplastic syndrome

MM: multiple myeloma

MMF: mycophenolate mofetil

MN: myeloid neoplasm

MPN: myeloproliferative neoplasm

MSD: HLA-identical sibling donors

NIH: National Institutes of Health

NMA: nonmyeloablative

NRM: non-relapse mortality

OS: overall survival

PBSC: peripheral blood stem cell

PFS: progression-free survival

PTCy: post-transplant cyclphosphamide

RIC: reduced-intensity conditioning

s-AML: secondary acute myeloid leukemia

TBI: total body irradiation

TLI: total lymphoid irradiation

t-MN: treatment related myeloid neoplasm

VOD: veno-occlusive disease

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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