Pharmacy SIG Literature Update: MMUD with PTCy based GVHD prophylaxis vs. HaploHCT in AM

In this month’s Pharmacy SIG Literature Update:  MMUD with PTCy based GVHD prophylaxis vs. HaploHCT in AML, two-step haploHCT in in elderly patients with hematologic malignancies, axatilimab for chronic graft-versus-host disease after failure of at least two prior systemic therapies, ibrutinib treatment of pediatric cGVHD and 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/haploidentical stem cell transplantation

**Baron F, Labopin M, Tischer J, et al. Comparison of HLA-mismatched unrelated donor transplantation with post-transplant cyclophosphamide versus HLA-haploidentical transplantation in patients with active acute myeloid leukemia. Bone Marrow Transplant. 2022; 57(11):1657-1663. https://pubmed.ncbi.nlm.nih.gov/35978005/

  • Retrospective, multicenter review comparing 9/10 MMUD (N=73) and haploHCT (N=146) in patients with active AML undergoing first alloHCT and receiving PTCy as GVHD prophylaxis
  • There were no differences in baseline characteristics except for more patients in the haplo arm having a bone marrow source compared to the MMUD arm (31.5% vs 11%; p=0.009). The MMUD arm subsequently had more patients receiving a peripheral blood source.
  • There were more patients in the MMUD arm receiving cyclosporine alone (6.8% vs 1.4%), whereas the haplo arm had more patients receiving tacrolimus + MMF (30.1% vs 13.7%; p=0.0002).
  • There was no difference in 2-year relapse rates (p=0.23), NRM (p=0.18), LFS (p=0.1), or OS (p=0.061) between MMUD and haplo patients.
  • The authors concluded that in AML patients with active disease at HCT, MMUD is at least comparable to haploHCT when PTCy is utilized as GVHD prophylaxis.

*Finke J, Schmoor C, Stelljes M, et al. Thiotepa-fludarabine-treosulfan conditioning for 2nd  allogeneic HCT from an alternative unrelated donor for patients with AML: A prospective multicenter phase II trial. Bone Marrow Transplant. 2022; 57(11):1664-1670. https://pubmed.ncbi.nlm.nih.gov/35982219/

  • Open-label, single-arm, prospective review of 50 patients with AML undergoing 2nd allo PBSCT greater than 6 months from first alloHCT
  • All patients received TFT (thiotepa 5 mg/kg/day IV on days -8 to -6, fludarabine 30 mg/m2/day IV on days -8 to -6, and treosulfan 12 g/m2/day IV on days -5 to -3) and GVHD prophylaxis with ATG 10 mg/kg/day IV on days -3 to -1, cyclosporine starting on day -1, and MMF from day 0 to +48.
  • The median time to relapse after first HCT was 17.2 months. 32% were in CR prior to 2nd alloHCT, and 66% were in active relapse.
  • The primary endpoint of DFS at 1-year was 46% (95% CI 0.32-0.61).
  • 86.8% of patients were in CR at 100 days post-transplant. The 3-year rates of DFS, relapse, NRM, and OS were 24%, 36%, 40%, and 24%, respectively.
  • The authors concluded TFT is a feasible option for conditioning in the setting of second alloHCT, though there are still significant challenges with NRM and relapse.

**Bi Xia, Gergis, U, Wagner JL, et al. Outcomes of two-step haploidentical allogeneic stem cell transplantation in elderly patients with hematologic malignancies. Bone Marrow Transplant. 2022; 57(11):1671-1680. https://pubmed.ncbi.nlm.nih.gov/35986105/

  • The two-step approach separates lymphoid and myeloid portions of the graft to avoid exposure of CD34+ cells to cyclophosphamide and allow fixed T-cell doses to improve consistency in outcomes.
  • A total of 76 patients aged 65 and older were included and received either MAC (TBI) or RIC (Flu/TBI or Flu/Bu/TBI) on days -10 to -6 prior to the first infusion of CD3+ T-cells (Step 1). Two days later, patients received Cy 60 mg/kg/day on days -3 and -2 with CD34+ cells given on day 0 (Step 2). All patients received tacrolimus/MMF starting on day -1. MMF was stopped on day +28 and tacrolimus was tapered starting on day +60.
  • The median time to neutrophil engraftment was 11 days; the median time to platelet engraftment was 18 days.
  • The 3-year rates of OS and PFS were 36.3% and 35.6%, respectively. On multivariate analysis, HCT-CI of 3 or more was an adverse prognostic factor (HR 3.1; p=0.006). Flu/TBI was a favorable prognostic factor for survival (HR 0.093; p=0.002).
  • The 3-year rates of NRM and relapse were 43.5% and 21%, respectively.
  • The cumulative incidence of grade III-IV aGVHD was 11.1% at 6 months. The cumulative incidence of grade II-IV aGVHD was 39.5% at 6 months, which remained consistent at 1 year. The cumulative incidence of cGVHD requiring treatment at 2 years was 15.1%.
  • The authors concluded that a two-step haploHCT approach is tolerable and should be considered for elderly patients with hematologic malignancies.

*Nagler A, Labopin M, Dholaria B, et al. Impact of cytogenetic risk on outcomes of non-T-cell-depleted haploidentical hematopoietic cell transplantation in patients with relapsed or refractory acute myeloid leukemia. Transplant Cell Ther. 2022; 28(11):773.e1-773.e8.

  • Retrospective, multicenter analysis using dataset of the Acute Leukemia Working Party of EBMT. Included adult patients with de novo AML with active disease defined as primary refractory, first or second relapse with >5% morphologic blasts with available intermediate or high-risk cytogenetics and received a non-T-cell-depleted HCT with PTCy from a haploidentical donor.
  • 440 patients were included, 291 (66.1%) with intermediate-risk cytogenetics (AMLint) and 149 with adverse-risk (AMLadv. Groups differed in presence of FLT3-ITD (AMLint 40.4% vs AMLadv 18.8%, p=.0006), presence of NMP1 (AMLint 42.4% vs 6.9%, p<.0001), and the proportion with primary refractory disease (AMLint 51.9% vs AMLadv 73.2%, p<.0001).
  • The proportion of patients who achieved a CR after transplant did not significantly differ. Time to engraftment, rates of grade II-IV and grade III-IV aGVHD at day 180 were not significantly different. Higher overall cGVHD incidence was seen in the AMLint patients (24.4% vs 15.6%), but not statistically significant different extensive cGVHD at 2 years in AMLint patients. Two-year RI was lower in AMLint patients (39.9% vs 64.3%), leading to superior 2-year LFS (35.5% vs 15.5%), GRFS (26% vs 13.2%), and OS (39.2% vs 20.1%). Two-year NRM did not significantly differ between groups and presence of FLT3-ITD was not associated with a higher RI. Multivariate analysis confirmed significantly lower relapse risk in AMLint patients, with HR of 2.1.
  • There were 288 deaths (65.5%) total, with relapse disease being the most common cause (67.8%), followed by infection (11.9%) and GVHD (4.2%). No statistical difference was reported between groups.
  • Results indicate that adverse cytogenetic risk, despite not influencing initial post-transplantation relapse risk, translated into an inferior LFS and OS.

*Ponce DM, Alousi AM, Nakamura R, et al. A phase 2 study of Interleukin-22 and systemic corticosteroids as initial treatment for acute GVHD of the lower GI tract. Blood. 2022 Nov 18;blood.2021015111. doi: 10.1182/blood.2021015111. https://pubmed.ncbi.nlm.nih.gov/36399701/

  • Multicenter single-arm phase 2 study evaluating a novel recombinant human Interleukin-22 dimer promoting epithelial regeneration, F-652, in combination with systemic corticosteroids for treatment of newly diagnosed lower gastrointestinal acute GVHD
  • F-652 administered as 45 mcg/kg IV weekly for up to 4 doses, with steroids initiated at 2 mg/kg/day prednisone (or equivalent) required for a minimum 3 days after F-652 initiation before allowing taper per institutional practice to a minimum 0.25 mg/kg/day prednisone required through day 28 of treatment
  • Out of 27 evaluable acute GVHD patients treated with F-652 and systemic corticosteroids, 19 (70%) achieved a day-28 response in the lower GI tract, including CRs (n=13), VGPRs (n=3), and PRs (n=3) with responses across all grades of acute GVHD severity; response remained through day-56 in 16 (59%) of patients and responders had expansion of commensal anaerobe fecal microbiota suggesting improvement of GVHD-associated dysbiosis
  • Of 30 patients evaluable for toxicity, 17 (57%) had an AE potentially attributable to study drug, with most common TEAEs including anemia (40%), thrombocytopenia (43%), lymphopenia (37%),hypokalemia (50%), hypomagnesemia (44%); 9 (30%) patients had grade 3 TEAEs, most commonly cytopenias and liver function test abnormalities, but there were no dose-limiting toxicities
  • Authors concluded that F-652 demonstrates potential for combining immunosuppression with tissue-supportive strategies to enhance mucosa recovery and promote microbial health in gastrointestinal GVHD

**Kitko CL, Arora M, DeFilipp Z, et al. Axatilimab for chronic graft-versus-host disease after failure of at least two prior systemic therapies: results of a phase I/II study. JCO. 2022; 1-10. https://ascopubs.org/doi/pdf/10.1200/JCO.22.00958. PMID: 36459673.

  • Phase I/II open-label, dose escalation study of axatilimab (0.15 mg/kg, 0.5 mg/kg, and 1 mg/kg every two weeks and 3 mg/kg every two or four weeks) to target colony-stimulating factor 1 receptor (CSF-1R) signaling in patients age > 6 years with active chronic GVHD (cGVHD) after > 2 prior systemic therapy lines.
  • 40 patients who received at least one dose of axatilimab between February 2019 and April 2021 were included.  17 patients were enrolled in the phase I portion, and 23 patients were enrolled in the phase II portion (1 mg/kg every two weeks). Patients had received a median of four prior lines of treatment (ibrutinib = 26, ruxolitinib = 21, belumosudil = 8) and a median of four organ systems affected.
  • 30 patients (75%) experienced treatment-related AEs, with 8 patients (20%) experiencing grade > 3 events. The most common AEs were increased AST/ALT (37.5/32.5%), CPK (35%), LDH (30%), amylase/lipase (27.5/25%), and creatinine (20%).
  • 39 patients were evaluable for response, and the 3 mg/kg every four weeks demonstrated the highest rate of biologic activity. ORR in the phase II cohort and overall was 82% (n = 18 of 22) and 67% (n = 26 of 39), respectively, by C7D1. ORR in the phase II cohort at C7D1 was 50% (n = 11 of 22). The best ORR at any point was 69% (n = 27 of 39), and was similar in patients treated previously with ibrutinib, ruxolitinib, and belumosudil.
  • Median time to response was 4 weeks in the phase II cohort and 5 weeks in the phase I cohort. In responding patients, median duration of use was 29 weeks.  FFS at 12 months was 77% overall and 68% for the phase II cohort. Median duration of response in phase II responders was not reached, with 33% of patient sustained response > 20 weeks. Among responders, a dose decrease in steroids was observed in 52% of patients with a mean reduction of 22%.
  • Lower GI (n = 5 of 5) and upper GI (n = 4 of 4) had a 100% response rate, with 100% CR and 80% CR rates, respectively. Response rates in other involved organs were 61% for joints/fascia, 31% for lung, and 14% for skin.
  • Authors conclude that targeting profibrotic macrophages with axatilimab is therapeutically promising novel strategy.

**Mishra A, Tamari R, DeZern A, et al. Eprenetapopt plus azactidine after allogeneic hematopoietic stem cell transplantation for TP53-mutant acute myeloid leukemia and myeldysplastic syndromes. JCO. 2022; 40:3985-3993. https://ascopubs.org/doi/pdf/10.1200/JCO.22.00181. PMID: 35816664.

  • Phase II, multicenter, open-label trial of eprenetapopt (APR-246; first-in-class small molecule p52 reactivator) and azacitidine (preclinical synergy observed against neoplastic myeloid cells) as maintenance therapy after alloHCT. Eprenetapopt 3.7 mg was administered IV once daily on Days 1-4 with azacitidine 36 mg/m2 IV or SQ once daily on Days 1-5 of each 28-day cycles, and continued for a maximum of 12 cycles. Maintenance was initiated between Day +30 and +100 after allo HCT upon engraftment confirmation and disease assessment.
  • 84 patients were screened pre-HCT, 55 patients post-HCT, and 33 patients were enrolled and treated. Majority of patients were excluded due to transplant-related toxicities.  Median age was 65 years, 14 patients had AML and 19 patients had MDS, and most received a RIC regimen (67%). Median time to initiation was 68 days post-HSCT, median number of cycles was 7, and 13 patients (39%) completed 12 cycles.
  • Median RFS was 12.5 months and OS was 20.6 months. 1-year CIR rate was 38.3% and 1-year NRM was 3.8%. Median time to progression was 15.2 months. Median time to relapse was 9.9 months in the MDS patients and not evaluable in the AML patients.
  • The most common treatment related AEs were nausea (61%), vomiting (46%), dizziness (36%), tremor (33%), headache (21%), dyskinesia (18%), and ataxia (12%). The most common grade > 3 AEs were decreased PLT (36%), WBC (36%), neutrophils (27%), hemoglobin (27%), and hypertension (12%). 30-day and 60-day mortality rates from the first dose were 0% and 6%, respectively.
  • Authors conclude that post-HCT maintenance therapy with eprenetapopt plus azacitidine in this high-risk population led to favorable survival.

Supportive Care

*Bhatia A, Dai C, Hageman L, et al. Financial burden in blood or marrow transplantation survivors during the COVID-19 pandemic: a BMTSS report. JCO. 2022; 1-13. https://ascopubs.org/doi/pdf/10.1200/JCO.22.00461. PMID: 36455192.

  • Survey study of autologous and allogeneic HCT recipients of age > 2 years who completed the BMTSS survey during the pandemic. The survey included employment status, out-of-pocket medical costs, and financial burden.
  • 2370 survivors and 750 siblings completed the BMTSS_2020 survey. Median age at survey completion was 63.7 years (19.9-91.3) after a median follow-up of 14.7 years (6-45.1). Allogeneic recipients constituted 50.5% of the cohort, MA conditioning was used in 73.5% of the transplants, and 44.4% received total body irradiation.
  • Compared with siblings, survivors were less likely to have an annual household income > $100k (31.2 vs. 40.8%), have completed college (48.4% vs. 56.4%), and have private insurance (68.8% vs. 80.9%). Survivors were also more likely to have chronic kidney disease (15.2% vs. 5.6%), heart disease (19.7% vs. 8.1%), and subsequent neoplasms (34.5% vs. 17.7%).
  • Survivor characteristics associated with high out-of-pocket medical costs included younger age (aOR per year younger = 1.02), lower prepandemic annual household income and/or education (< $50k and/or < college graduate = aOR 1.96), > 1 chronic health condition (aOR 2.82), > 1 hospitalization during the pandemic (aOR 2.11), and unemployment during the pandemic (aOR 1.52).
  • Among BMT survivors, high out-of-pocket medical costs were significantly associated with problems in paying medical bills (aOR 10.57), deferring medical care (aOR 4.93), taking a smaller dose of medication than prescribed (aOR 4.99), and considering filing for bankruptcy (aOR 3.8).
  • Authors conclude that during the COVID-19 pandemic, financial burden was prevalent among adult BMT survivors and high out-of-pocket costs. Those with high out-of-pocket costs were more likely to engage in behaviors that could adversely affect their health outcomes

Pediatric stem cell transplantation

**Carpenter PA, Kang HJ, Yoo KH, et al. Ibrutinib treatment of pediatric chronic graft-versus-host disease: primary results from phase 1/ 2 iMAGINE study. Transplant Cell Ther. 2022;28(11):771.e1- 771.e10. https://pubmed.ncbi.nlm.nih.gov/36044977/

  • An international, open-label, multicenter, phase 1/ 2, dose-finding, safety, and efficacy study of ibrutinib in cGVHD in pediatric patients age ≥ 1 year to < 22 years with a history of an alloHCT. Study part A consisted of ibrutinib 120 mg/m2 oral initial dose with dose escalation to 240 mg/m2 oral after 14 days in the absence of TEAEs to determine RPED. Part B assessed the PK and safety of ibrutinib in new-onset (TN) or R/R moderate or severe cGVHD.
  • Of 59 patients enrolled, 12 had TN cGVHD (20%) and 47 patients R/R cGVHD (80%). Median age was 13.0 years (range, 1-19 years). Malignant disease was indication for transplant in 64% of patients, with 70% receiving an HLA-matched graft, and 51% an unrelated donor graft. Median time from initial cGVHD diagnosis to study enrollment was 12.4 months. Baseline cGVHD involvement was skin (80%), mouth (63%), and eyes (58%) most frequently. For R/R disease, median number of prior regimens was 2 (range 1 to 12). Most common systemic therapies were corticosteroids (83%), cyclosporine (40%), and tacrolimus (30%). Median duration of ibrutinib treatment was 8.2 months.
  • The PK plasma concentration-time profiles of ibrutinib in children were not associated with any unexpected toxicities or new safety signals. The RPED was determined to be ibrutinib 240 mg/m2 oral once daily in patients ≥1 year and <12 years. Dose adjustments were not warranted in covariate analysis of age, weight, and body surface area due to no observed.
  • Overall, 58 of 59 patients had a TEAE (98%), and grade ≥3 TEAEs occurred in 38 patients (64%). Ibrutinib dosage reductions were required in 9 patients and discontinuation in 14 patients. TEAEs leading to death were reported in three patients.
  • At median follow-up of 20 months, ORR was 78%. By 24 weeks the ORR was 64% and at 48 weeks, 75%. Of patients with a PR or CR, the estimated 18-month DOR was 58% and the overall median DOR was not reached. Sustained responses of ≥20 weeks were observed in 61% of patients. Median time to first response was 4 weeks and best response was 6 weeks. The 12- month and 18-month OS estimates were 95% and 91%, respectively. Median EFS was 17 months and median FFS was not reached.
  • Authors concluded the treatment of children and adolescents with moderate or severe cGVHD with ibrutinib resulted in an acceptable toxicity profile and durable responses comparable to those observed in adults.

CART-Cell Therapy

The cost-effectiveness of axicabtagene ciloleucel as second-line therapy in patients with large b-cell lymphoma in the United States: An economic evaluation of the ZUMA-7 trial. Transplant Cell Ther 2022;28:750.e1-750.e6. DOI: https://doi.org/10.1016/j.jtct.2022.08.010 PMID: 35970302

  • The ZUMA-7 trial has recently shown axi-cel to have superior outcomes when compared with standard of care salvage therapy for large b-cell lymphoma (LBCL) though at a cost significantly higher than current standard of care (SOC) options. This study aimed to evaluate the cost- effectiveness of axi-cel versus standard second-line therapy for LCBL.
  • Authors developed a partitioned survival model based on patients included in the ZUMA-7 trial for a theoretical cohort of patients with relapsed or refractory LBCL undergoing second-line therapy and estimated clinical outcomes based on those reported in ZUMA-7, including a 10 year estimated OS of 48% for axi-cel and 38% for SOC. Median OS was estimated to be 59 months and 24 months for patients receiving axi-cel and SOC, respectively.
  • The model thus estimated 7.08 and 5.56 quality adjusted life years (QALYs) for axi-cel and SOC, respectively with an estimated incremental QALY of 1.51 and total cost of $100,366. The estimated incremental cost-effective ratio was $66,381 per QALY which remains below a willingness-to-pay threshold of $150,000. Analyses made with other survival estimations all remained below $120,000 per QALY.
  • All drug costs were based on current list price (Red Book) and costs for administration of treatment were based on the Center for Medicaid Services Physician Fee Schedule with adjustments for inflation.
  • Authors conclude that axi-cel is cost-effective and provides favorable outcomes when compared to standard of care salvage therapy for patients with relapsed or refractory LBCL though they state that the model estimated that patients would receive CAR-T therapy as a subsequent salvage therapy option after failure of earlier second-line options.



A-CHP: brentuximab, cyclophosphamide, doxorubicin, and prednisone

MAC: myeloablative chemotherapy

AE: adverse events

MDS: myelodysplastic syndrome

Axi-cel: axicabtagene ciloleucel

MLFS: morphologic leukemia-free state

alloHCT: allogeneic hematopoietic cell transplant

MM: multiple myeloma

aGVHD: acute graft versus host disease

MMF: mycophenolate mofetil

ALL: acute lymphoblastic leukemia

MMUD: mismatched unrelated donor

AML: acute myeloid leukemia

MRD: matched related donor

ASCT: autologous stem cell

MSD: matched sibling donor

ATG: anti-thymocyte globulin

MUD: matched unrelated donor

cGVHD: chronic graft versus host disease

MTX: methotrexate

CR: complete response

NMA: non-myeloablative

CRS: cytokine release syndrome

NRM: non-relapse mortality

CSA: cyclosporine

ORR: overall response rate

DOR: duration of response

OS: overall survival

DRI: disease risk index

PBSC: peripheral blood stem cell

EBMT: European Blood and Marrow Transplantation

PFS: progression-free survival

ECOG: Eastern Cooperative Oncology Group

PR: partial response

EFS: event free survival

PTCy: post-transplant cyclophosphamide

FFS: failure-free survival

PTCL: peripheral T-cell lymphoma

GRFS: GVHD-free relapse-free survival

RFS: relapse-free survival

Haplo: haploidentical

RI: relapse incidence

HCT: hematopoietic cell transplant

RIC: reduced intensity conditioning

HCT-CI: hematopoietic stem cell transplantation comorbidity index

R/R: relapsed/refractory

HLA: human leukocyte antigen

RPED: recommended pediatric equivalent dose

IC: intensive chemotherapy

SCT: stem cell transplant

GVHD: graft-versus-host disease

TAC: tacrolimus

LFS: leukemia free survival

TEAE: treatment-emergent adverse events

ICANS: immune effector cell-associated neurotoxicity syndrome

UCB: unit cord blood

IMS: immunosuppression

URD: unrelated donor


VGPR: very good partial response


ASTCT Pharmacy SIG Research Working Committee:

Arpita Gandhi, Jonathan Ptachcinski, Kaily Kurzweil, Andrew Lin, Jennifer Collins, Jitesh Kawedia, Dennis Marjoncu, Julianna Roddy, Lily Yan, Thomas Hughes, Sorana Ursu, Haval Norman

Tags: Pharmacy SIG, SIG update, SIG, AML, GVHD, pediatric, transplantation, Transplant, disease, CAR T-cells, post-transplant, bone marrow, transplants, graft-versus-host, acute myeloid leukemia, pharmacological, HaploHCT