In this month’s Pharmacy SIG Literature Update: PTCy pharmacokinetics and HaploHCT outcomes, matching-adjusted indirect comparison of axi-cel and liso-cel in relapsed or refractory large B-cell lymphoma, impact of conditioning chemotherapy on lymphocyte kinetics and outcomes in LBCL patients treated with CAR T-cell therapy 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

Autologous stem cell transplantation

*Lachance S, Bourguignon A, Boisjoly JA, et al. Impact of implementing a bendamustine-based conditioning regimen on outcomes of autologous stem cell transplantation in lymphoma while novel cellular therapies emerge. Transplant Cell Ther. 2022 Oct 12;S2666-6367(22)01698-0. doi: 10.1016/j.jtct.2022.10.003. https://pubmed.ncbi.nlm.nih.gov/36243319/

• Single center, retrospective review of 131 lymphoma patients receiving benda-EAM in 2015- 2018 vs. 96 patients receiving carmustine-based conditioning regimens (BEAM or BEAC) in 2012- 2015, with all supportive care identical between groups and baseline characteristics similar except older age in the bendamustine group (mean 55.7 vs 51.1 years, p = 0.02)
• At median follow-up 48 months for the bendamustine group and 60 months for the BCNU group, bendamustine was associated with significantly higher PFS (71% vs 61%; p = .040; HR 1.6 [95% CI 1.0 to 2.7]) and OS (86% vs 71%; p = .0066; HR 2.6 [95% CI 1.3 to 5.4]) than BCNU-based conditioning
• Some toxicities were greater in the bendamustine group: grade ≥3 mucositis (39.5% vs 7.8%; p< 0.001) and necessity for parenteral nutrition (48.9% vs 21.9%; p < 0.001), transient creatinine rise >1.5x ULN (15.3% vs 4.2%; p< 0.008), and intensive care unit admission (6.9% vs 1.1%; p< 0.029)
• Authors concluded that benda-EAM is a highly effective conditioning regimen with robust PFS and OS compared with BCNU-containing regimens, along with acceptable toxicity and low NRM which should be considered a valid alternative and merits confirmation in a prospective clinical trial

*Shuman K, Palmer S, Anders B, et al. Correlation of Engraftment and Time from Melphalan Administration to Stem Cell Infusion. Transplant Cell Ther. 2022 Oct 28;S2666-6367(22)01713-4. doi: 10.1016/j.jtct.2022.10.017. https://pubmed.ncbi.nlm.nih.gov/36404519/

• Retrospective multicenter cohort study of 723 adult patients undergoing aHCT with melphalan conditioning between 2016 -2019, with 502 receiving stem cells ≥ 24 hours after melphalan administration and 221 receiving cells < 24 hours after melphalan
• There was no significant difference in baseline demographics between groups
• Timing between melphalan administration and stem cell infusion in the <24 hours cohort was a median 18 hours and a minimum 12 hours
• Median time to neutrophil and platelet engraftment was 12 days and 19 days, respectively, for both cohorts (p = .07 and 0.25, respectively)
• Authors concluded that a 24-hour waiting period between melphalan administration and stem cell infusion might not be necessary, and shorter waiting periods could confer shorter lengths of stay, cost savings, and convenience for transplantation center personnel as well as patients

Allogeneic/haploidentical stem cell transplantation

**Kasudhan KS, Patil AN, Jandial A et al. Post-transplant cyclophosphamide pharmacokinetics and haploidentical hematopoietic cell transplantation outcomes: an exploratory study. Leukemia 2022; 36(11):2679-2685. https://doi.org/10.1080/10428194.2022.2087067

• Exploratory study to determine the relationship between PTCy pharmacokinetics (PK), pharmacogenetics and immune reconstitution and transplant outcomes (aGVHD, cGVHD, GRFS, OS and NRM)
• Data from 30 patients treated on MAC (70%) and RIC (30%) conditioning regimens were included in this study. For PK analysis, samples were collected after PTCy infusion (D+3 and D+4 post-transplant) and inactive metabolite carboxy-ethyl phosphoramide mustard (CEPM) was used as surrogate for hydroxy cyclophosphamide (HCy) exposure. CEPM levels were determined using LC-MS/MS assay and PK parameters were estimated using trapezoidal methods for non- compartmental modeling.
• Single nucleotide polymorphism (SNPs) in CYP2B6*2 (rs8192709), CYP2B6*4 (rs2279343), CYP2B6*6 (rs3745274), CYP2C9*2 (rs1799853), ALDH1A1_2 (-416/-432), ALDH3A1*2 (rs2228100), GSTP1 (rs947894) genes in the recipient genomic DNA were evaluated. Flow cytometry was performed in a subset of the patients at day + 30, +90, and +180 post-HCT. The following immune cell subsets were evaluated by multi-color flow cytometry according to protocols already standardized in our laboratory: CD4, CD8, Treg CD25highCD127low), and NK cells (CD3-CD56þ).
• The median CEPM AUC0–48 was 14.2 (14) mg.hr/L. The incidence of severe cGVHD (73% vs. 11%, p=0.02), and GRFS was significantly inferior in the CEPM AUC0–48 < 14mg.hr/L group (54 days vs. 344 days, p=0.02). There was, however, no difference in grade III-IV aGVHD (38% vs. 14%, p=0.12) and OS (295 days vs. not reached, p = 0.2).
• The median CEPM AUC0–8 was 3.9mg.hr/L (IQR 2.0–7.6). There was good correlation between day +3 CEPM AUC0–8 and total CEPM AUC0–48 (r2  = 0.85, p<0.0001).
• There was no difference in the incidence of SNP of enzymes involved in Cy metabolism (CYP2B*2/4/6, ALDH1A1/3A1, and GSTP1) either individually or combined between the two groups with CEPM AUC0–48 less and more than 14mg.hr/L. There was no difference in the immune reconstitution of T-cells and their subsets CD4, CD8, Treg, and NK-cells at day +30, +90, and +180 post-HCT between the two groups with CEPM AUC0–48 less and more than 14mg.hr/L. The Treg cells at six months were also not significantly different (33 vs. 21/mL, p=0.09).
• The results of this exploratory study need to be confirmed in a larger patient population. A prospective randomized controlled trial of fixed-dose day +3, +4 PTCy versus day +4 dose guided by day +3 CEPM AUC will help us answer if this strategy can improve haplo-HCT outcomes in the future.
   

*Mishra A, Tamari R, DeZern AE, et al. Eprenetapopt plus azacytidine after allogeneic hematopoietic stem-cell transplantation for TP53-mutant acute myeloid leukemia and myelodysplastic syndromes. J Clin Oncol 2022; 40(34):3985-3993. https://doi.org/10.1200/JCO.22.00181

• This Phase II, single-arm, multicenter, open-label trial was conducted at eight academic hospitals in the United States to assess efficacy and safety of Eprenetapopt (first-in-class, small-molecule p53 reactivator) combined with azacytidine as maintenance therapy after HCT.
  •  Eprenetapopt 3.7 grams IV once daily on Days 1-4 and azacitidine 36 mg/m2 IV/SC once daily Days 1-5 in a 28-day cycle; continued until evidence of disease relapse or upon meeting other stopping criteria.
• The  patient  population included transplant  eligible  adult MDS and AML  patients with a   TP53 mutation.
• The primary end points: RFS and TEAE; secondary endpoints: OS, NRM, time to progression, cumulative incidence of relapse (CIR), and incidence of acute and chronic GVHD.
• A total of 33 patients were treatment with maintenance therapy between September 2019 and November 2020. The patient demographics included a median age of 65 (range 40-74), 14 patients with AML and 19 with MDS, and 67% received a reduced intensity conditioning regimen. The median time from HCT to starting therapy was 68 days and the median number of treatment cycles was 7 (range 1-12) with 13 patients (39% ) completing 12 cycles.
• With a median follow-up of 14.5 months, the median RFS was 12.5 months and the 1-year RFS probability was 59.9%. With a median follow-up of 17 months, the median OS was 20.6 months and the 1-year OS probability was 78.8%. The 1-year CIR rate was 38.3% (95% CI, 23.7 – 57.6%) and the 1-year NRM was 3.8% (95% CI, 0.6% - 24.3%). Median time to progression was 15.2 months (95% CI, 8.7 to NE). The median time to relapse for patients with MDS and AML was 9.9 months and not reached, respectively.
• The authors concluded that maintenance therapy with eprenetapopt and azacitidine was well tolerated with encouraging RFS and OS outcomes compared to prior studies in this high-risk population. Future studies of this maintenance therapy regimen may be warranted in a phase 3 randomized trial.
   

*Greinix HT, Ayuk F, Zeiser R. Extracorporeal photopheresis in acute and chronic steroid-refractory graft-versus-host disease: an evolving treatment landscape. Leukemia 2022; 36(11):2558-2566. https://doi.org/10.1038/s41375-022-01701-2

• Review article on recent published studies on the management of acute and chronic steroid- refractory graft-versus-host disease (SR-GVHD). The review primarily focuses on published trials on two treatment approaches for SR-GVHD: the JAK-inhibitor ruxolitinib and extracorporeal photopheresis (ECP). In addition, the article reviews two small trials that have evaluated the combined therapy of ruxolitinib and ECP. The authors promote this combination approach and encourage future prospective trials with this strategy. The review also includes some recent results with ibrutinib, beulumosudil, and a small prospective phase II trial evaluating the combination of ECP and adlesleukin (IL-2).
• Although the title of the review article suggests a focus on ECP therapy in SR-GVHD, the article instead provides a brief review of a variety of treatment strategies in SR-GVHD that have been evaluated in recent years including combination therapy.

Supportive Care

*Selby PR, Warner MS, Peake SL, et al. Optimizing antifungal prophylaxis in allogeneic stem cell transplantation: A cohort study of two different approaches. Transpl Infect Dis. 2022; 24(6):e13988. https://pubmed.ncbi.nlm.nih.gov/36349869/

• Retrospective cohort study to assess tolerability, efficacy and cost of second line antifungal prophylaxis if oral posaconazole is unable to be administered in alloHCT patients. Second-line options included IV voriconazole (N=71) or IV posaconazole (N=71).
• There was a higher incidence of progression to third or fourth line antifungal prophylaxis in the voriconazole arm (38%) compared to the posaconazole arm (1%) (p<0.0001). While the cause of change was numerically higher in the voriconazole arm (72% vs 59%), this was not statistically significant (OR 1.76; 95% CI 0.88-3.46; p=0.16).
• There was no difference in the rate of proven invasive fungal infections (IFI) between the voriconazole and posaconazole arms (3% vs 7%, respectively; p=0.44). Probable infections occurred at a rate of 4% in the voriconazole arm and 1% in the posaconazole arm (p=0.62). Possible IFI occurred in more patients receiving voriconazole compared to posaconazole (28% vs 4%, respectively; OR 8.89; 95% CI 2.67-29.2; p=0.0002), which lead to a subsequent larger number of patients requiring escalation to therapeutic antifungals (37% vs 13%; p=0.001)
• Less patients in the voriconazole arm were within the therapeutic range compared to posaconazole (68% vs 78%, respectively; p=0.0004). Of patients who developed a proven or probable IFI, 64% of azole concentrations were above the lower limit of the therapeutic range.
• Neuropsychiatric events occurred more often in the voriconazole arm compared to the posaconazole arm (49% vs 20%, respectively; OR 3.96; 95% CI 1.87-8.03; p=0.0004). The most common event in this category were visual hallucinations, occurring in 30% in the voriconazole arm and 4% in the posaconazole arm (p<0.0001).

Pediatric stem cell transplantation

*Eichinger A, Poetschger U, Glogova E, et al. Incidence of subsequent malignancies after total body irradiation-based allogeneic HSCT in children with ALL – long-term follow-up from the prospective ALL- SCT 2003 trial. Leukemia 2022; 36(11):2567-2576. https://doi.org/10.1038/s41375-022-01693-z

• Analysis of the incidence, outcome, and risk factors for subsequent malignant neoplasms (SMN) in children prospectively enrolled in the ALL-SCT-BFM 2003 German cooperative group study (2003-2011) and its subsequent extension registry (2011-2013).
• 705 pediatric patients with ALL were analyzed including 411 patients transplanted under the multicenter trial and 294 patients in the extension registry. Patients > 2 years of age and without contraindications for TBI received conditioning of TBI (12 Gy in 6 fractions over 3 days) and etoposide (60 mg/kg; upper total dose of 3600 mg). Patients < 2 years of age and those with contraindications for TBI received conditioning with myeloablative doses of busulfan, cyclophosphamide (120 mg/kg total dose), and etoposide (40 mg/kg total dose).
• For the multivariate analysis, the risk factors evaluated included the use of TBI, age, sex match, donor type, stem cell source, disease recurrence risk at time of HSCT, CMV constellation, and leukemia immunophenotype. The impact of chronic GVHD on the cumulative incidence of SMN was evaluated separately by means of a Fine and Gray model.
• The median follow-up after HSCT was 5.3 years (range: 0.01 -16.4). Most patients were conditioned with TBI and etoposide (n = 558; 79%) while 110 patients (16%) received conditioning with busulfan/cyclophosphamide/etoposide.
• In total, 39 SMN were reported in 33 patients (5%) in the entire study cohort. The 5-,8- and 10- year cumulative incidence of SMN were 0.02 + 0.01, 0.06 + 0.01 and 0.13 + 0.02, respectively. Of the 33 affected patients, 21 (64%) were reported alive at a median follow-up of 5.8 years (0-9.9) after the diagnosis of their first SMN. SMN occurred exclusively in patients who received TBI/etoposide as conditioning and in univariate and multivariate analysis only TBI conditioning versus non-TBI based conditioning emerged as a significant risk factor.
• This study confirms prior studies that have identified TBI as a significant risk factor for SMN. The analysis is unique from the standpoint that it originates from a prospective cooperative group trial with uniform conditioning exclusively in children with ALL.

*Kuhn A, Puttkammer J, Madigan T, et al. Letermovir as cytomegalovirus prophylaxis in a pediatric cohort: a retrospective analysis. Transplant Cell Ther. 2022 Oct 13;S2666-6367(22)01700-6. doi: 10.1016/j.jtct.2022.10.005. https://pubmed.ncbi.nlm.nih.gov/36244677/

• Retrospective chart review describing 9 pediatric patients receiving letermovir prophylaxis for allogeneic HCT between 2020-2022
• Median age was 14 years (range 4-19), 56% were female, and 78% were receiving as primary prophylaxis; the 3 smallest/youngest received 240 mg/day with the other 6 receiving 480 mg/day, a median dose of 10.4 mg/kg across the cohort with a median duration of 182 days
• Letermovir was crushed and administered via nasogastric tube in 4 of 9 patients, despite official labeling against doing so, due to prior literature rationale that there is no specific characteristic predicting manipulation would compromise drug delivery
• One 20-kg 6-year-old female with history of severe aplastic anemia receiving alemtuzumab and second HCT on 240 mg (12 mg/kg) letermovir starting day -2 had low-level CMV viremia by day +32 that responded to switching to valganciclovir, but no other patients experienced CMV reactivation while on letermovir and no clinical CMV disease occurred
• Authors concluded letermovir administration was feasible and well tolerated in pediatric patients though larger prospective studies are warranted, and that it is reasonable to assume crushing the immediate-release letermovir tablet has only nominal effect on pharmacokinetic properties

CART-Cell Therapy

**Oluwole OO, Chen JMH, Chan K, et al. Matching-adjusted indirect comparison of axi-cel and liso-cel in relapsed or refractory large B-cell lymphoma. Leuk Lymphoma. 2022; 63(13):3052-3062. https://pubmed.ncbi.nlm.nih.gov/36048026/

• Match-adjusted indirect comparison of the ZUMA-1 (axicabtagene ciloleucel; axi-cel) and TRANSCEND-NHL-001 (lisocabtagene maraleucel; liso-cel) for the management of relapsed/refractory DLBCL
• After matching between the two trials, there was no difference in ORR (OR 2.18; 95% CI: 0.96- 4.98), CR (OR 1.84; 95% CI: 0.97-3.5), or PR (OR 0.89; 95% CI: 0.4-1.98).
• Compared to liso-cel, axi-cel had an improved OS (HR 0.53; 95% CI: 0.34-0.82) and PFS (HR 0.61; 95% CI: 0.4-0.92).
• Axi-cel had an increased rate of grade 3 or higher CRS (OR 3.64; 95% CI: 1.04-12.76) as well as neurologic events (OR 3.45; 95% CI: 1.65-7.19).
• The authors concluded that axi-cel improved OS compared to liso-cel, though this was accompanied by an increased rate of TEAE
   

*Di Blasi R., Le Gouill S., Bachy E., et al. Outcomes of patients with aggressive B-cell lymphoma after failure of anti-CD19 CAR T-cell therapy: a DESCAR-T analysis. Blood 2022;140:2584-93. PMID: 36122385

• An analysis of 550 patients from the French DESCAR-T registry who received CAR T-Cell therapy for relapsed or refractory aggressive B-cell lymphoma.
• At a median follow-up of 7.9 months, 238 (43.3%) experienced either progression or relapse. At the time of infusion, 66% of patients had progressive disease.
• Failure after CAR T therapy occurred at a median of 2.7 months (range 0.2-21.5). Fifty-four (22.7%) patients failed within 30 days of CAR-T treatment, 102 (42.9%) failed between days 31- 90, and 82 (34.5%) patients failed after day 90.
• The median PFS and OS were 2.8 months and 5.2 months, respectively. The PFS was significantly shorter among patients with failure prior to day 30 versus those with failure after day 30 at 1.7 and 3.0 months, respectively.
• Multivariate analysis found elevated LDH at the time of infusion, failure within 30 days of CAR T- Cell treatment, and high C-reactive protein as predictors of worse OS.
• Authors conclude that the outcomes following failure of CAR T-Cell therapy remain very poor, especially among patients with failure less than 30 days following infusion. Further novel treatment strategies for patients failing CAR T-cell therapy remains an unmet need.
   

**Abramson J., Johnston P., Kamdar M., et al. Health-related quality of life with lisocabtagene maraleucel vs standard of care in relapsed or refractory LBCL. Blood Adv. 2022;13:5969-79. PMID: 9713278

• In the TRANSFORM phase 3 trial, lisocabtagene maraleucel (liso-cel) showed superiority in EFS over standard of care immunochemotherapy when used as a second-line treatment. Liso-cel also demonstrated significant improvements in key secondary end points of CR and PFS.
• This analysis is a presentation of health-related quality of life (HRQOL) results from the TRANSFORM study which included adult patients with refractory or relapsed (</= 12 months after first-line therapy) large B-cell lymphoma (LBCL).
• HRQOL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and assessed 30 total items across domains relating to symptom control, functionality, and global health status/quality of life (QOL).
• The proportion of patients reporting a meaningful improvement in QOL status was higher, and deterioration was lower, among those receiving liso-cel.
• Scores among patients receiving SOC showed meaningful worsening in global health status/QOL scores at 6 months, worsening fatigue scores at day 29 and 6 months, and worsening pain scores at 6 months.  Mean scores for other domains were similar between arms.
• Time to confirmed deterioration also favored liso-cel vs. standard of care in global health/QOL with a median time to deterioration of 19.0 weeks vs not reached in the SOC vs liso-cel arms, respectively. However, there was a trend toward greater risk of deterioration in emotional function among patients receiving liso-cel vs SOC.
• Authors conclude that patients treated with liso-cel had improved HRQOL outcomes including global health status/QOL, cognitive function, and fatigue compared with those receiving SOC treatment.
   

**Strati P, Jallouk AP, Sun R et al. Impact of conditioning chemotherapy on lymphocyte kinetics and outcomes in LBCL patients treated with CAR T-cell therapy. Leukemia 2022; 36(11):2669-2677.  DOI: 10.1038/s41375-022-01704-z

• Retrospective study which analyzed the impact of conditioning chemotherapy (CCT) on lymphocyte count and assessed how its depth of change referred to as delta lymphocyte index (DLIx), relates to clinical outcomes, cytokine levels, and genetic variation in patients with large B-Cell lymphoma (LBCL) receiving CAR T-cell therapy.
• Study included 171 consecutive patients with relapsed or refractory LBCL treated with standard of care axicabtagene ciloleucel (axi-cel), of which 86 (50%) received bridging therapy post- leukapheresis..  Patients received CCT with cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) administered intravenously on days −5, −4 and −3, followed by axi-cel infusion (2 × 106  cells/kg) on day 0.
• DLIx was categorized in quartiles: quartile 1 (median 0.19, range 0.01–0.26), quartile 2 (median 0.41, range 0.27–0.52), quartile 3 (median 0.69, range 0.55–0.79), and quartile 4 (median 1.36, range 0.88–2.75). Their association with survival was analyzed, and quartile 1 selected as low (vs. high) DLIx based on the strongest association with survival outcomes.
• Median DLIx was 0.5 × 109/L (range, 0.01–2.75 × 109/L) and was significantly higher in patients who achieved complete response (p = 0.04). On multivariate analysis, low DLIx was associated only with use of bridging therapy (odds ratio 0.4, 95% CI 0.2–0.8, p = 0.007). Low DLIx was independently associated with shorter progression-free (p = 0.02) and overall survival (p = 0.02).
• DLIx was also associated with genetic variations related to drug metabolism ABCB1, which encodes for P-glycoprotein 1 (also known as multidrug resistance protein 1), and genes involved in macrophage biology such as MISP (coding for mitotic spindle positioning protein ) and CPVL (coding for carboxypeptidase vitellogenic like protein). However, no significant association was observed in our study with genotypic variants of DCK, coding for deoxycytidine kinase, or of CYP2C19 and CYP2B6, coding for cytochrome P450 family members, all of which are also involved in the metabolism of fludarabine and cyclophosphamide.
• DLIx was not associated with cytokine levels, when compared with low DLIx to those with high DLIx, there were no significant differences in mean plasma IL-7 and IL-15 levels on day −5 (p = 0.28 and p = 0.16, respectively), day 0 (p = 0.16 and 0.11, respectively). No significant difference in the delta change in IL-7 and IL-15 levels between these days was observed when comparing the 2 groups (p = 0.43 and p = 0.17, respectively).
• Overall, the impact of CCT on lymphocyte count is affected by use of bridging therapy, but change in lymphocyte count is independently associated with efficacy. Studies aimed at investigating macrophage biology in this setting may suggest strategies to increase the efficacy of CCT and improve outcomes.