In this month’s Pharmacy SIG Literature Update: Transplantation in relapsed APL, post-transplant cyclophosphamide in cord transplantation, and early tocilizumab in BCMA-directed CAR-T therapy in relapsed/refractory multiple myeloma, 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 Transplant

**Sanz J, Labopin M, Sanz MA, et al. Hematopoietic stem cell transplantation for adults with relapsed acute promyelocytic leukemia in second complete remission. Bone Marrow Transplant. 2021 Jun; 56 (6):1272-1280. https://pubmed.ncbi.nlm.nih.gov/33323947/

• Retrospective analysis of the EBMT database of 569 patients with relapsed APL in CR2. Patients received either an alloHCT (n = 228) or an autoHCT (n = 341) from 2004 to 2018.
• There were fewer patients in the alloHCT arm who received MAC (68% vs 86%; p<0.0001) and were also less likely to receive a TBI-based conditioning (68% vs 85%; p<0.0001)
• The primary endpoint was the comparison of OS between the alloHCT and autoHCT arms. The 2-year OS was 64.3% in the alloHCT arm and 82.4% in the autoHCT arm (p=0.001)
• The 2-year LFS was 54.7% in the alloHCT arm compared to 74.5% in the autoHCT arm (p=0.001). For both OS and LFS, lower recipient age and longer time from diagnosis to transplant were associated with improved outcomes.
• NRM at 2 years was 17.3% for alloHCT and 2.7% for autoHCT (p=0.001).
• MRD negativity was associated with decreased incidence of relapse at 2 years (23% vs 42.4%; p=0.003), increased LFS at 2 years (71.2% vs 47.7%; p=0.001), and increased OS at 2 years (79.5% vs 61.7%; p=0.002), with no difference in NRM at 2 years (5.7% vs 9.8%; p=0.35)
• The authors concluded that autoHCT improved survival over alloHCT in patients with relapsed APL in CR2, with the majority of benefit arising from decreased NRM.

*Al Malki MM, Tsai N, Palmer J, et al. Posttransplant cyclophosphamide as GVHD prophylaxis for peripheral blood stem cell HLA-mismatched unrelated donor transplant. Blood Advances 2021: June 22 online. https://pubmed.ncb.nlm.gov/34156440

• Prospective pilot cohort study evaluating 38 patients with hematologic malignancies who received MMUD-HCT (≥6/8 HLA-matched donors) receiving either MAC (Flu/TBI, n=19) or RIC (Flu/Mel, n=19). Graft source was PBSCs, and GVHD prophylaxis was PTCy, tacrolimus, and MMF.
• Baseline characteristics: median age, 53 years; male, 50%; racial/ethnic minorities, 61%; HCT indication of acute leukemia/MDS, >80%; HCT-CI >2, 45%; median number of mismatches, 2; and median CD34+ cell dose, 5.45 x 106/kg.
• Primary survival outcomes: with a median follow-up of 18.3 months, 1-year GRFS was 68% for entire cohort (84% in MAC and 53% in RIC); 1-year OS was 84% for entire cohort (100% in MAC and 68% in RIC); and 1-year PFS was 76% for entire cohort (95% for MAC and 57% for RIC). Cumulative incidence of NRM at 100 days and 1-year were 0% and 13% whereas relapse/progression was 11%.
• Secondary GVHD outcomes: cumulative incidence of 100-day aGVHD grades 2-4 and 3-4 were 50% and 18% for entire cohort. Grade 2-4 aGVHD was 53% for MAC and 47% for RIC; grade 3-4 aGVHD was 11% for MAC and 26% for RIC. 1-year cGVHD was 49% with 3% as moderate/severe for the entire cohort (58% for MAC and 37% for RIC). 21/31 patients who survived for at least 1 year were able to completely discontinue immunosuppression.
• Secondary toxicity outcomes: most common non-hematologic were grade 1/2 stomatitis and GI; most common infection was CMV viremia (42%) and bacterial (50%); CRS (majority grade 1) occurred in 71% of patients and most commonly in the RIC arm (p=0.03).
• Authors concluded that the study demonstrated promising OS/GRFS rates with an acceptable adverse risk profile after PBSC-MMUD-HCT with PTCy, which supports further development of PTCy in the MMUD setting.

**Goldsmith SR, Abid MB, Auletta JJ, et al. Post-Transplant Cyclophosphamide (PTCy) is Associated with Increased Cytomegalovirus Infection: A CIBMTR Analysis. Blood 2021: online June 10. https://pubmed.ncbi.nlm.gov/33624095

• Retrospective CIBMTR study of patients who received HaploCy (n=757), MSD with PTCy (SibCy, n=403), or MSD with CNI-based prophylaxis (SibCNI, n=1605) for AML/ALL/MDS between 2012- 2017. The effect of donor source and PTCy on incidence of CMV infection as well as impact of CMV serostatus and occurrence of CMV infection by day 180 on HCT outcomes was evaluated.
• Primary analysis: Univariate analysis showed cumulative incidence of CMV infection by Day 180 were 42% (99% CI: 37-46) for HaploCy, 37% (99% CI: 31-43) for SibCy, and 23% (99% CI: 20-26) for SibCNI (p<0.001). Overall, CMV organ disease was low. Cumulative incidence were 2.8%, 3.4%, and 1.4% by Day 100, respectively (p=0.026). 3
• Secondary analysis: CMV infection risk was highest for CMV-seropositive recipients (R+), but significantly higher with PTCy regardless of donor [HaploCy: HR 50.3 (14.4-175.2); SibCy: HR 47.7 (13.3-171.4); SibCNI: HR 24.4 (7.2-83.1); p<0.001].
• Multivariate analysis found only CMV serostatus affected CMV infection; other variables including donor source did not. In R+ subgroup, the use of PTCy doubled risk of CMV infection regardless of donor source (p=0.0001). D+/R-subgroup of each cohort had significantly higher risk compared to D-/R- (p<0.0001).
• Additional multivariate analysis showed that R+ HaploCy had significantly higher risk for NRM (p=0.0001). Similar results with R+ SibCy and D+/R- SibCy, but was not statistically significant. R+ was associated with inferior OS regardless of donor source or PTCy; highest significant risk in R+ HaploCy (p=0.0001).
• Authors concluded that PTCy, regardless of donor, is significantly associated with higher incidence of CMV infection; most pronounced in R+. D+/R-should also be considered at high risk. CMV infection may negate the cGVHD protection of PTCy. Prophylaxis should strongly be considered in all patients receiving PTCy.

Cord Blood Transplant

*Al Malki MM, Tsai N, Palmer J, and et al. Posttransplant cyclophosphamide as GVHD prophylaxis for peripheral blood stem cell HLA-mismatched unrelated donor transplant. Blood Advances 2021: June 22 online. https://pubmed.ncb.nlm.gov/34156440

• Prospective pilot cohort study evaluating 38 patients with hematologic malignancies who received MMUD-HCT (≥6/8 HLA-matched donors) receiving either MAC (Flu/TBI, n=19) or RIC (Flu/Mel, n=19). Graft source was PBSCs, and GVHD prophylaxis was PTCy, tacrolimus, and MMF.
• Baseline characteristics: median age, 53 years; male, 50%; racial/ethnic minorities, 61%; HCT indication of acute leukemia/MDS, >80%; HCT-CI >2, 45%; median number of mismatches, 2; and median CD34+ cell dose, 5.45 x 106/kg.
• Primary survival outcomes: with a median follow-up of 18.3 months, 1-year GRFS was 68% for entire cohort (84% in MAC and 53% in RIC); 1-year OS was 84% for entire cohort (100% in MAC and 68% in RIC); and 1-year PFS was 76% for entire cohort (95% for MAC and 57% for RIC). Cumulative incidence of NRM at 100 days and 1-year were 0% and 13% whereas relapse/progression was 11%.
• Secondary GVHD outcomes: cumulative incidence of 100-day aGVHD grades 2-4 and 3-4 were 50% and 18% for entire cohort. Grade 2-4 aGVHD was 53% for MAC and 47% for RIC; grade 3-4 aGVHD was 11% for MAC and 26% for RIC. 1-year cGVHD was 49% with 3% as moderate/severe for the entire cohort (58% for MAC and 37% for RIC). 21/31 patients who survived for at least 1 year were able to completely discontinue immunosuppression.
• Secondary toxicity outcomes: most common non-hematologic were grade 1/2 stomatitis and GI; most common infection was CMV viremia (42%) and bacterial (50%); CRS (majority grade 1) occurred in 71% of patients and most commonly in the RIC arm (p=0.03).
• Authors concluded that the study demonstrated promising OS/GRFS rates with an acceptable adverse risk profile after PBSC-MMUD-HCT with PTCy, which supports further development of PTCy in the MMUD setting.

Autologous Transplant

**Pettengell R, Uddin R, Boumendil A, et al. Durable benefit of rituximab maintenance post-autograft in patients with relapsed follicular lymphoma: 12-year follow-up of the EBMT lymphoma working party Lym1 trial. Bone Marrow Transplant. 2021 Jun; 56 (6):1413-1421. https://pubmed.ncbi.nlm.nih.gov/33452448/

• 12-year follow-up of EBMT LYM1 trial in 288 patients with relapsed follicular lymphoma in CR or VGPR. Patients were randomized to receive rituximab 375 mg/m2 weekly x4 weeks or no rituximab (rituximab purging or no purging (RP or NP) prior to stem-cell collection and rituximab monotherapy (RM) every 2 months for 4 doses or no maintenance (NM) after autoHCT. Patients received BEAM as conditioning therapy.
• After a median follow-up of 12 years, the 10-year PFS was 47% in the overall group, with 58% in the RM arm (NP+RM or RP+RM) and 36% in the non-rituximab maintenance arm (NP+NM or RP+NM); HR 0.548; p=0.002, with only 4 relapses after 7.5 years.
• There was no difference in 10-year NRM, with it occurring in 7% in the whole cohort; 35% in patients who had maintenance (NP+RM or NP+RM); 58% for NM patients (NP+NM or RP+NM). A PFS benefit was also seen in anyone who received rituximab (RP+RM, RP+NM, or NP+RM) vs no rituximab (HR 0.603; p=0.05).
• There was also no difference in 10-year OS, with 79% in the rituximab maintenance group (NP+RM or RP+RM) vs 70% in the no maintenance group (NP+NM or RP+NM) (HR 0.716; p=0.196).
• The authors concluded that rituximab maintenance has shown continued benefit after 12 years in preventing relapse post-autoHCT.

*Dahi PB, Lee J, Devlin SM, and et al. Toxicities of high-dose chemotherapy and autologous hematopoietic cell transplantation in older patients with lymphoma. Blood Advances 2021: June 21 online. https://pubmed.ncbi.nlm.gov/34152404

• Retrospective study comparing HCT-related toxicities and outcomes of 346 NHL patients ≥60 years of age who underwent BEAM auto-HCT between 2000-2018 in 2 age groups: older (age ≥70 years; n=67) vs younger (ages 60-69 years; n=279).
• Baseline characteristics: median age, 65.8 years; majority DLBCL (39.3%) and MCL (34.4%); ≥2 prior LOTs (54.6%); and all had chemosensitive disease (295 CR, 51 PR). Age groups were balanced regarding histology, # of prior LOTs, remission status, HCT-CI, KPS, albumin, and stemcell dose.
• Overall toxicity outcomes: febrile neutropenia (63%), oral/GI (51%, mostly mucositis/diarrhea), infection (31%), and cardiovascular (29%). Older patients were at higher risk for grade ≥3 5 cardiotoxicity (HR 3.36; 95% CI: 2.25-5.00; p<0.001) and skin toxicity (HR 2.45; 95% CI: 1.08-5.54, p=0.032). Most occurred within day -7 to day + 30.
• Higher cardiotoxicity risk was observed in patients with lower than the median ALC (0.5K/µL) and lower than the median albumin value pre-HCT (4.10 g/dL). Patients with a stem-cell count below the median (5.05 x 106 CD34 cells/kg) had higher risk for oral/GI toxicity whereas male sex and those with KPS ≥90 were at lower risk.
• HCT outcomes: median time to engraftment was similar between groups; NRM in older group at 100 days and 2 years was 2.99% (95% CI: 0.55-9.32) and 6.2% (95% CI: 1.97-13.95) vs 1.79% (95% CI: 0.68-3.92) and 2.91% (95% CI: 1.37-5.42) with younger group. Adjusting for the number of grade ≥3 toxicities within the first 100 days, older patients had 1.71-fold (95% CI, 1.08-2.71) increased risk for progression or death vs younger patients.
• The authors concluded that although BEAM auto-HCT is effective, it is associated with significant toxicities, especially in patients aged ≥ 70 yrs. Interventions to mitigate toxicities while maintaining efficacy are much needed.

Pediatrics

**Granger MM, Naranjo A, Bagatell R, et al. Myeloablative Busulfan/Melphalan Consolidation following Induction Chemotherapy for Patients with Newly Diagnosed High-Risk Neuroblastoma: Children's Oncology Group Trial ANBL12P1. Transplant Cell Ther 2021; 27: 490.e1-490.e8. https://pubmed.ncbi.nlm.nih.gov/33823167/

• 101 of 146 enrolled patients with high-risk neuroblastoma underwent consolidative ASCT with BuMel conditioning (busulfan [every 24 hours for 4 doses based on age and weight] and melphalan [140 mg/m2 for 1 dose]). Busulfan doses were adjusted to achieve to an average daily area under the curve (AUC) <5500 µM × minute
• From the time of study enrollment, the mean 3-year EFS for all 146 eligible patients was 55.6 ± 4.2%, and the mean 3-year OS was 74.5 ± 3.7%
• The overall incidence of protocol-defined unacceptable toxicity was 6.9% (7 of 101 patients). Six patients (5.9%) developed SOS, with 4 (4%) meeting the criteria for severe SOS. An additional 3 patients (3%) experienced grade ≥4 pulmonary complications during consolidation.
• Busulfan pharmacokinetics shows a higher area under the curve in patients who develop SOS.
• The authors concluded that the regimen was well-tolerated with promising 3-year EFS and OS.

Cellular Therapy

**Banerjee R, Marsal J, Huang CY, et al. Early time-to-tocilizumab after B cell maturation antigendirected chimeric antigen receptor T cell therapy in myeloma. Transplant Cell Ther 2021; 27: 77.e1- 477.e7. https://pubmed.ncbi.nlm.nih.gov/33831353/

• Analysis of 50 myeloma patients following BCMA-directedCAR-T therapy (idecabtagene vicleucel, bb21217, ciltacabtagene autoleucel, and orvacabtagene autoceucel). Comparisons weremade between the early-toci (time-to-toci ≤50th percentile) and late-toci (time-to-toci >50th percentile) groups. 6
• The 2 groups (n = 19 each) had similar CRS grade distributions, hours to CRS onset, CRS-related biomarkers, and incidences of neurotoxicity or severe infections; however, weight-adjusted CAR-T cell doses were higher in the early-toci group (median 5.99 vs. 3.80x 106cells/kg, P<0.01).
• The median CRS duration was 18.6 hours for the early-toci group versus 84.7 hours for the latetoci group
• The authors concluded that preemptive toci strategies for BCMA-directed CAR-T therapy do not appear to increase rates of therapy-related toxicities or compromise efficacy, but total CRS duration can be shortened with early-toci workflows.

*Hines MR, Keenan C, Maron G, et al. Hemophagocytic lymphohistiocytosis-like toxicity (carHLH) after CD-19-specific CAR T-cell therapy. BJH 2021;doi: 10.1111/bjh.17662

• Single-center review of 27 pediatric patients treated with tisagenlecleucel or institutional CD19- CAR T-cell product to determine the real-time incidence of carHLH using clinical criteria (ferritin, high grade fever, organ dysfunction). The Shah, et al. criteria (elevated ferritin and at least 2 of the following: transaminitis, elevated creatinine, pulmonary edema, hemophagocytosis on bone marrow biopsy) was used retrospectively to define the onset of HLH.
• Four (14.8%) patients had CRS and carHLH, 40% CRS alone, and 44% had no CRS. CarHLH occurred at a median of 10 days (range 7-12) after CAR T-cell infusion. Using the Shah et al. criteria, the median onset of retrospectively defined carHLH was 11.5 days (range 8-20). Patients who developed carHLH had increased disease burden in the bone marrow, peripheral blood, and extramedullary disease when compared to patients who did not develop carHLH.
• Survival was significantly worse in patients who developed carHLH when compared to CRS alone or no CRS, with 2-month survival at 25% vs. 90.9% and 100%, respectively. Disease response was also significantly diminished in the carHLH group, 0% vs. 90.9% and 75%.
• The authors conclude that pediatric patients who develop carHLH had both reduced response to CAR T-cell therapy and poor overall survival.

*Mian A, Wei W, Winter A, et al. Outcomes and factors impacting use of axicabtagene ciloleucel in patients with relapsed or refractory B-cell lymphoma: results from an intention-to-treat analysis. Leuk Lymphoma 2021;62:1344-52. https://pubmed.ncbi.nlm.nih.gov/33375873/

• Retrospective review of patients with r/r LBCL for whom letters of medical necessity were sent for axi-cel therapy (ITT population).
• Primary objective was to identify baseline clinical, disease, and treatment-related characteristics between patients who received axi-cel therapy and those who did not.
• Secondary objectives were to estimate OS in the ITT population and identify factors that precluded axi-cel use in some patients.
• Reviewed 38 total consecutive patients, 27 (71%) of whom received axi-cel.
• Patients not receiving axi-cel had higher baseline HCT-CI (median 4 vs. 2, p=0.04) and also more likely to have bulky disease (6 vs. 1, p<0.01).
• Median OS (months) among those in the ITT group, axi-cel, and non-axi-cel groups was 10, 13, and 1, respectively.
• At last follow-up, 8/27 (30%) and 10/11 (91%) of patients had died in the axi-cel and non-axi-cel groups, respectively. 7
• Factors limiting use of axi-cel were disease progression, sepsis, manufacturing failure, and socioeconomic barriers.
• Authors conclude that improvements in wait-time for therapy are necessary given that progression was the most common reason patients did not receive axi-cel.

*Zhang C, Wang X, Zhang R, et al. Donor-derived CD19 CAR-T cell therapy of relapse of CD19-positive BALL post allotransplant. Leukemia 2021;35:1563-70. https://pubmed.ncbi.nlm.nih.gov/33077866/

• Retrospective review of post-allogeneic HCT patients receiving donor-derived anti-CD19 CAR-T cells after bone marrow relapse of ALL (n = 43); median age = 24 years(range 4-60 years)
• Patients had confirmed bone marrow relapse of CD19-positive B-ALL, ECOG ≤ 2, estimated survival > 3 months, no prior aGVHD, and refusal to have second transplant.
• Of the 43 patients, 18 received a CD19-28z CAR-T product and 25 receiveda CD19-BBz CAR product.
• Thirty-four (79%) patients achieved a complete histological remission (14/18 receiving CD19-28z and 20/25 receiving CD19-BBz).
• 1-year EFS and survival were 43%; one-year cumulative incidence of relapse was 41% in patients with prior complete histological remission not receiving second HCT.
• CRS developed in 38 (88%) patients and was grade ≥ 3 in 7 patients (16/18 receiving CD19-28z and 22/25 receiving CD19-BBz). Nine (21%) patients developed ICANS (3/18 receiving CD19-28z and 6/25 receiving CD19-BBz, all grade 1/2). Two patients developed grade ≤ 2 aGVHD.
• Authors conclude that therapy of recurrent B-ALL with donor-derived anti-CD19 CAR-T after alloHCT is safe and effective and outcomes are comparable to alternative approaches.

Abbreviations:

aGVHD: acute graft-versus-host disease

ALC: absolute lymphocyte count

ALL: acute lymphoblastic leukemia

alloHCT: allogeneic hematopoietic cell transplantation

AML: acute myeloid leukemia

APL: acute promyelocytic leukemia

autoHCT: autologous hematopoietic cell transplantation

axi-cel: axicabtagene ciloleucel

BEAM: carmustine (BCNU), etoposide, cyatarbine, melphalan

Bu: busulfan

CAR: chimeric antigen receptor

CMV: cytomegalovirus

CNI: calcineurin inhibitor

CR: complete remission

Flu: fludarabine

GRFS: GVHD-free, relapse-free survival

Haplo: haploidentical

HCT: hematopoietic cell transplantation

HLH: hemophagocytic lymphohistiocytosis 8

ITT: intention to treat

LFS: leukemia-free survival

MAC: myeloablative conditioning

MDS: myelodysplastic syndrome

Mel: melphalan

MMUD: mismatched unrelated donor

MRD: minimal residual disease

MSD: matched sibling donor

NRM: non-relapse mortality

OS: overall survival

PBSC: peripheral blood stem cell

PFS: progression-free survival

PTCy: post-transplant cyclophosphamide

RIC: reduced-intensity conditioning

SOS: sinusoidal obstructive syndrome

TBI: total body irradiation

VGPR: very good partial response

ASTCT Pharmacy SIG Research Working Committee:

Jennifer Collins, Kelly Gaffney, Katie Gatwood, Arpita Gandhi, Jitesh Kawedia, Binni Kunvarjee, Andrew Lin, Dennis Marjoncu, Jonathan Ptachcinski, Julianna Roddy, Lily Yan

 

Tags: CAR-T, Literature, multiple myeloma, transplantation, Relapse, Refractory, Cord Blood, APL, Cyclophosphamide, Special interest group, T-Cell, CAR T-Cell Therapy