Updates on the Role of Upfront Transplantation in Patients with High-Risk Myelodysplastic Syndrome and More

By Content Administrator posted 05-03-2019 12:36

  

In this month’s Pharmacy SIG Literature Update: Updates on the role of upfront transplantation in patients with high-risk myelodysplastic syndrome and secondary acute myelogenous leukemia, prevention and treatment of GVHD, 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 Mar 1. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/30826465

  • Prospective, single-arm, phase I/II open-label trial of patients with r/r NHL who were not eligible for NMA regimens and were compared to a historical control group who received R-BEAM without bortezomib
  • 31 patients (41% had DLBCL) received R-BEAM with GVHD prophylaxis of tacrolimus and methotrexate in addition to bortezomib (1-1.3 mg/m2 days -13, -6, -1 and +2)
  • The weighted cumulative incidences of grades II-IV and III-IV aGVHD were 50% & 34%, which did not differ from the historical control group; OS was also not significantly different between the two groups
  • 100-day, 365-day and end-of-assessment NRM rates of the study group (23%, 31%, 41%) were not statistically different from those in the control group (14%, 33%, and 50%)
  • The authors concluded that R-BEAM regimen has a survival benefit in lymphoma patients age <50 years and the addition of bortezomib has no impact on OS or incidence of GVHD

** Schroeder T, Wegener N, Lauseker M, et al. Comparison between upfront transplantation and different pre-transplant cytoreductive treatment approaches in patients with high-risk myelodysplastic syndrome and secondary acute myelogenous leukemia. Biol Blood Marrow Transplant. 2019 Mar 15. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/30880268

  • Retrospective, single-center study of 165 patients with MDS and excessive blasts (n=126, 76%) and secondary AML (n=39, 24%)
  • 67 patients (41%) were directly transplanted while 98 (49% received pre-transplant cytoreductive treatment (induction chemotherapy n=64; HMA n=34); the induction chemotherapy group had a higher CR rate (59% vs 18%, p<0.0001)
  • Estimated 5-year OS and RFS for the entire cohort was 54% and 39%, while the 5-year OS for upfront, induction chemotherapy and HMA were 61%, 50% and 45% (p=0.116) and RFS was 38%, 41% and 38% (p=0.926); CIR & NRM did not differ between the treatment groups
  • In multivariate analysis, pre-transplant strategy did not have an effect on OS, RFS, CIR, and NRM while cytogenetics (OS, RFS, CIR), RIC (OS, RFS, and CIR) and unrelated donor (RFS, CIR) were identified as negative predictors
  • Upfront transplant patients had a higher likelihood to respond to HMA as salvage for relapse in comparison to pre-treated patients (CR: 58% vs 10%, p=0.0005) and a higher 2-year OS after relapse (59% vs 19%, p=0.0001)
  • The authors concluded that upfront transplant is at least not inferior to pre-transplant cytoreduction and may be augmented by HMA+DLI strategy in case of relapse after alloHCT

*van der Heiden P, Arbous M, van Beers E, et al.  Predictors of short-term and long-term mortality in critically ill patients admitted to the intensive care unit following allogeneic stem cell transplantation.  Bone Marrow Transplantation. 2019;54:418-424. https://www.ncbi.nlm.nih.gov/pubmed/30082850           

  • Retrospective cohort study to determine 30-day and 1-year mortality and to identify prognostic factors present upon admission to the ICU within 2 years following alloHCT at six university hospitals in the Netherlands.
  • Reason for admission was respiratory failure in 50% of patients (n=251) with median length in ICU of 6 days (0-119 days)
  • 30-day mortality was 55% (137/251). Platelet count <25 x 109/L, serum bilirubin >10 µl/L, non-HLA matched donor, and use of vasoactive medications within the first 24 hours were associated with increased 30-day mortality.  Neutropenia was associated with a decreased 30-day mortality
  • 1-year mortality was 80% (201/251). Serum bilirubin >77 µ/L, non-HLA matched donor, and use of vasoactive medication within the first 24 hours were associated with increased 1-year mortality.  Neutropenia was associated with decreased 1-year mortality.
  • The factors correlated with increased mortality may aide in directed supportive care in critically ill alloHCT patients.

Autologous Transplantation

*Stadtmauer EA, Pasquini MC, Blackwell B, et al. Autologous transplantation, consolidation, and maintenance therapy in multiple myeloma: results of the BMT CTN 0702 trial. J Clin Oncol. 2019;37:589-97. https://www.ncbi.nlm.nih.gov/pubmed/30653422

  • Prospective, randomized, phase 3 trial to test additional interventions to improve PFS by comparing aHCT, tandem aHCT, and aHCT plus four subsequent cycles of lenalidomide, bortezomib, and dexamethasone, all followed by lenalidomide until disease progression
  • Patients with symptomatic MM, aged 20 to 70 years, were randomly assigned to tandem aHCT + lenalidomide (n=247), aHCT, lenalidomide, bortezomib, and dexamethasone, + lenalidomide (n=254), or aHCT + lenalidomide (n=257)
  • 38 month PFS rate was 58% for aHCT + lenalidomide, 57.8% for aHCT, lenalidomide, bortezomib, and dexamethasone, + lenalidomide, and 53.9% for aHCT + lenalidomide; OS rates were 81.8% for aHCT + lenalidomide, 85.4% for aHCT, lenalidomide, bortezomib, and dexamethasone, + lenalidomide, and 83.7% for aHCT + lenalidomide
  • Toxicity profiles and development of second primary malignancies were similar across treatment arms
  • Authors concluded that single aHCT + lenalidomide should remain as the standard treatment approach for this patient population as PFS or OS was not improved with comparator arms

Graft-versus-host disease

**Bolaños-Meade J, Reshef R, Fraser R, et al. Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomized phase 2 trial with a non-randomized contemporaneous control group (BMT CTN 1203). Lancet Haematol. 2019; 6(3):e132-43. https://www.ncbi.nlm.nih.gov/pubmed/30824040

  • Prospective, multicenter phase 2 trial to evaluate regimens containing maraviroc, bortezomib, or PT-Cy for GVHD prophylaxis compared with controls receiving the combination of MTX and tacrolimus
  • 273 patients aged 18-75 years who received RIC HCT were randomly assigned (1:1:1) to tacrolimus, MMF, and PT-Cy; tacrolimus, MTX, and bortezomib; or tacrolimus, MTX, and maraviroc
  • Study groups were compared to a non-randomized prospective cohort control group of patients, at centers not participating in the trial, who were treated with tacrolimus and MTX for GVHD prophylaxis
  • Hazard ratio for GRFS was 0.72 for tacrolimus, MMF, and PT-Cy (p=0.044), 0.98 for tacrolimus, MTX, and bortezomib (p=0.92), and 1.1 for tacrolimus, MTX, and maraviroc (p=0.49).
  • 238 patients experienced grade 3 or 4 toxicities; 79 (86%) with tacrolimus, MMF, and PT-Cy, 78 (87%) for tacrolimus, MTX, and bortezomib, and 81 (88%) for tacrolimus, MTX, and maraviroc, with the most common toxicity being hematological
  • Tacrolimus, MMF, and PT-Cy demonstrated the best GRFS and will move forward into a phase 3 randomized trial for prospective comparison to tacrolimus and MTX for GVHD prophylaxis

***Sarantopoulos S, Cardones AR, Sullivan KM. How I treat refractory chronic graft-versus-host disease. Blood. 2019;133:1191-1200. https://www.ncbi.nlm.nih.gov/pubmed/30674472              

  • cGVHD remains a significant complication following allo-HCT with only 20% of patients achieving a durable partial or complete response and surviving 1-year after initial therapy without additional systemic therapy
  • Refractory cGVHD is relatively common and salvage therapy remains provider specific
  • Evidence is in support of organ-directed topical treatments as adjunctive therapy for cGVHD: dexamethasone rinse for oral cGVHD, topical corticosteroids such as triamcinolone 0.1% for skin disease, and steroid and cyclosporine eyedrops, autologous serum tears, and scleral lenses for ocular cGVHD
  • Suggested treatment of cGVHD flares includes prednisone 0.5-1 mg/kg/day for 3-4 weeks. Patients with moderate or severe cGVHD may be assessed weekly and treatment should be modified if no PR achieved per NIH criteria or are the patient is deemed steroid dependent/intolerant.
  • Immunosuppressive regimens may be altered after 2 unsuccessful attempts to wean steroids within 4 months
  • Assess for comorbidities such as fatigue and depression regularly and reversible causes such as adrenal insufficiency, hypothyroidism, vitamin-deficiency anemia, medication effects, or infection should be appropriately managed
  • Poor prognostic markers such as decreased FEV1, hypoxia following a 2-minute walk test, increase in bilirubin or alkaline phosphatase > 3x ULN, decreasing platelets, acute diarrhea, and >10% weight loss should be identified at regular follow-up and acted upon immediately to attempt to offset the negative impact to the patient

Haploidentical Transplantation

**Bolaños-Meade J, Cooke KR, Gamper CJ, et al. Effect of increased dose of total body irradiation on graft failure associated with HLA-haploidentical transplantation in patients with severe haemoglobinopathies: a prospective clinical trial. Lancet Haematol. 2019;6(4):e183-93. https://www.ncbi.nlm.nih.gov/pubmed/30878319

  • Prospective, phase 2, single-center trial to investigate whether increasing TBI from 200 cGy to 400 cGy would improve engraftment rates for patients undergoing NMA haploidentical HCT with PT-Cy
  • 17 patients aged 6-31 years diagnosed with haemoglobinopathies (71% sickle cell disease; 5% β-thalassemia major) who received rabbit-derived IV ATG, fludarabine, cyclophosphamide, and TBI 400 cGy as a conditioning regimen, followed by GVHD prophylaxis with PT-Cy, MMF, and sirolimus were included
  • 76% of patients achieved full donor chimerism, 18% had mixed donor-host chimerism, and 6% had primary graft failure with recovery of host hematopoiesis
  • Safety profiles were maintained, with 29% of patients developing grades 2-4 aGVHD and 18% of patients developing cGVHD
  • Increasing TBI to 400 cGy reduced graft failure compared to previously reported rates using only 200 cGy and results suggest that engraftment after haploidentical HCT for haemoglobinopathies may be less of a limitation than originally thought

** Dulery R, Bastos J, Paviglianiti A, et al. Thiotepa, busulfan, and fludarabine conditioning regimen in T-cell replete HLA-haploidentical hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2019 Mar 11. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/30871978

  • Retrospective, single-center study of consecutive patients receiving haploidentical HCT after TBF conditioning (August 2013 – December 2017) at Saint Antoine Hospital in Paris, France
  • 51 patients received TBF (thiotepa 5 mg/kg days -7 & -6; fludarabine 30 mg/m2 days -5 through -1; busulfan 3.2 mg/kg days -4 through -2) with stem cell source being PBSC (PT-Cy 50 mg/kg day +3 & +4) or BM (PT-Cy 50 mg/kg day +3)
  • GVHD prophylaxis was CSA (starting day-3 as 3 mg/kg/day continuous intravenous administration) and MMF (day +6 through +35 at 15 mg/kg IV twice daily) for all patients while most patients (76%) received ATG (2.5 mg/kg or 5 mg/kg) for 5 doses
  • Median time to neutrophil engraftment was 17 days, while the cumulative incidence of grade II-IV and III-IV aGVHD were 27.5% and 14%; the use of ATG and lower thiotepa dose (5 mg/kg vs 10 mg/kg) were associated with a reduced cumulative incidence of grade II-IV aGVHD (p=0.03 and p=0.005)
  • 2-year cumulative incidence of cGVHD was 29% (significantly reduced to 13% with lower thiotepa dose, p=0.002)
  • After median follow-up of 25 months, the cumulative incidence of NRM, relapse, OS, DFS, and GFRS were 20%, 22.5%, 67%, 58%, and 51% respectively
  • The authors concluded that the TBF platform is appealing in the haploidentical HCT setting with PT-Cy in terms of engraftment, toxicity and disease control and, while they found no benefit to higher dosing of thiotepa, ATG use reduced the risk of aGVHD without compromising outcomes

*Sugita J, Kagaya Y, Miyamoto T, et al.  Myeloablative and reduced-intensity conditioning in HLA-haploidentical peripheral blood stem cell transplantation using post-transplant cyclophosphamide.  Bone Marrow Transplantation. 2019;54:432-441. https://www.ncbi.nlm.nih.gov/pubmed/30087460

  • Multicenter phase 2 prospective study evaluating safety and efficacy of MAC (n=50) vs RIC (n=77) in haploidentical PBSCT with PT-Cy
  • MAC was associated with increased EFS at 1 year (64% vs 43%), OS at 2 years (68% vs 44%), decreased relapse rate at 2 years (36% vs 45%), and lower NRM (10% vs 20%) compared to RIC.
  • MAC and RIC had similar incidences of grade II-IV GVHD at 100 days (18% vs 14%) and similar overall cGVHD at 2 years (36% vs 27%), respectively.
  • Patients in the RIC arm were older (median age 36 vs 58), had increased comorbidities, higher risk disease, and 39% (n=30) had a prior alloHCT compared to zero in the MAC arm.
  • Both MAC and RIC with PT-Cy are viable options for patients undergoing haploidentical PBSCT.

Mobilization

* Zucenka A, Peceliunas V, Maciutaite E, et al. Etoposide + granulocyte colony-stimulating factor and optional plerixafor in patients who failed chemomobilization with or without plerixafor. Biol Blood Marrow Transplant. 2019 Mar 12. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/30871977

  • Retrospective, single-center study of patients undergoing etoposide + G-CSF as salvage mobilization after previous unsuccessful chemomobilization with or without plerixafor
  • 62 patients were assessed (10 received plerixafor) after receiving etoposide (500 mg/m2 on days 1-4) + G-CSF 10 mcg/kg/day from day 7 until last day of leukapheresis; 1-2 doses of plerixafor (0.24 mg/kg) were used in patients with marginal CD34+ values (10-25 CD34+ cells/microliter)
  • Primary endpoint was the number of patients undergoing aHCT after salvage mobilization with secondary endpoints of maximum CD34+ cells, total number of collected CD34+ cells, the number of apheresis cycles, the time from start of mobilization to the first leukapheresis, 12-month OS and PFS
  • Median peak CD34+ values after mobilization was 54.07 CD34+/μL (9.6 CD34+/μL with previous mobilization attempts, p<0.001) with a medial yield of 6.33x106 CD34+ cells/kg per 2 apheresis sessions
  • Etoposide + G-CSF +/- plerixafor resulted in 91.5% successful mobilizations and 89.8% of patients proceeding to aHCT while all 7 patients that previously failed plerixafor-based mobilization were successfully mobilized with this regimen
  • Most common grade III-IV adverse events were FN (69.3%), mucositis (51.6%), and bacteremia (20.9%) but no fatalities were observed
  • The authors concluded that Etoposide + G-CSF +/- plerixafor is an effective regimen for salvage stem cell mobilization, even in patients who failed previous plerixafor mobilization, and that adverse event rates may warrant a decreased dose of etoposide in practice

*Dosani T, Covut F, Pinto R, et al. Impact of lenalidomide on collected hematopoietic myeloid and erythroid progenitors: peripheral stem cell collection may not be affected. Leuk Lymphoma. 2019 Mar 7:1-8. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/30845862

  • Single center, retrospective chart review to examine the effect of LEN exposure on CD34 collection from 94 patients who underwent aHCT between 2007 and 2016
  • Median age was 59.3 years and the median number of therapies prior to transplant was 2. In those who had previously received LEN, the median number of cycles was 4
  • Mobilization regimens: cyclophosphamide and G-CSF (n=21), G-CSF alone (n=8) and G-CSF + plerixafor  (n=65)
  • 1% of patients failed to collect the minimum of >2 x 106 CD34+ cells/kg with no significant impact of prior LEN exposure. Median collected CD34 cell dose was not significantly different
  • Collected myeloid and erythroid progenitors were decreased in LEN exposed patients if plerixafor was not used. There was no significant difference in collection amounts in the plerixafor mobilized group
  • Median time to neutrophil and platelet engraftment post-HCT was not significantly different between those who had received prior LEN and those who had not
  • Patients receiving LEN therapy had suppression of both myeloid and erythroid progenitors in collected grafts, but plerixafor-based collection may abrogate the negative effect of LEN therapy. The LEN-induced suppression did not translate into delayed engraftment

 

Other

*Zhao H, Huang X, Gao, X, et al. What is the best first-line treatment for POEMS syndrome:

autologous transplantation, melphalan and dexamethasone, or lenalidomide and dexamethasone? Leukemia. 2019;33:1023–1029. https://www.ncbi.nlm.nih.gov  /pubmed/30700844

  • Single center, retrospective chart review of 347 patients with POEMS syndrome treated first-line with either aHCT, MDex, or LDex
  • Hematologic CR was better with aHCT (49.7%) than with MDex (37.7%, p=0.001), primarily in medium-high risk patients. CRV was better with aHCT (66.2%) than with MDex (38.5%, p=0.001) or LDex (47.7%, p=0.008), primarily in medium-high risk patients
  • 3-year PFS was 87.6% with aHCT and 64.9% with LDex (p=0.003). OS in the three regimens did not differ
  • Based on this data, aHCT might have better responses and survivals compared with the other two groups, especially for medium-high risk patients

 

Pediatrics

*McNeer JL, Devidas M, Dai Y, et al. Hematopoietic stem-cell transplantation does not improve the poor outcome of children with hypodiploid acute lymphoblastic leukemia: a report from Children’s Oncology Group. J Clin Onol. 2019; 37:780-9. https://www.ncbi.nlm.nih.gov/pubmed/30742559

  • Retrospective review of 8,522 patients with NCI standard-risk and high-risk B-ALL to evaluate the impact of HCT on outcomes for children and young adults with hypodiploid B-ALL
  • Hypodiploidy occurred in 1.5% of patients and 98.3% of those achieved a CR after induction therapy
  • Five-year EFS and OS were not significantly improved for patients undergoing HCT 57.4% ± 7% and 66.2% ±6% compared with 47.8% ± 7.5% and 53.8% ± 7.6% for those who did not undergo HCT, respectively (p=0.49 and p=0.34)
  • HCT also had no significant impact on outcomes related to patients with MRD at the end of induction
  • Children and young adults with hypodiploid B-ALL do not seem to benefit from HCT and new treatment strategies are needed for this at-risk patient population

 

Abbreviations:

aGVHD: acute graft-versus-host disease

alloHCT: allogeneic hematopoietic cell transplantation

ATG: antithymocyte globulin

aHCT: autologous hematopoietic cell transplantation

AML: acute myeloid leukemia

B-ALL: B-cell acute lymphoblastic leukemia

BEAM: carmustine, etoposide, cytarabine, melphalan

BM: bone marrow

cGVHD: chronic graft-versus-host disease

CI: confidence interval

CIR: cumulative incidence of relapse

CR: complete response

CRV: vascular endothelial growth factor complete remission

CSA: cyclosporine

DFS: disease-free survival

DLBCL: diffuse large b-cell lymphoma

DLI: donor lymphocyte infusion

EFS: event free survival

FN: febrile neutropenia

G-CSF: granulocyte colony-stimulating factor

GFRS: GVHD-free/relapse-free survival

GVHD: graft-versus-host disease

HCT: hematopoietic cell transplantation

HL: Hodgkin lymphoma

HMA: hypomethylating agent

ICU: intensive care unit

Ldex: lenalidomide + dexamethasone

LEN: lenalidomide

MAC: myeloablative conditioning

MDex: melphalan + dexamethasone

MDS: myelodysplastic syndrome

MM: multiple myeloma

MMF: mycophenolate mofetil

MRD: minimal residual disease

MTX: methotrexate

NCI: National Cancer Institute

NHL: non-Hodgkin lymphoma

NIH: National Institutes of Health

NMA: non-myeloablative

NRM: non-relapse mortality

OR: odds ratio

OS: overall survival

PBSCT: peripheral blood stem cell transplantation

PFS: progression-free survival

PR: partial response

PT-Cy: post-transplant cyclophosphamide

R-BEAM: rituximab/carmustine/etoposide/cytarabine/melphalan

RIC: reduced intensity conditioning

RFS: relapse-free survival

r/r: relapsed or refractory

TBI: total body irradiation

TBF: thiotepa/busulfan/fludarabine

ULN: upper limit of normal

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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