In this month’s Pharmacy SIG Literature Update: pre-transplant conditioning for AML/MDS with fludarabine and once daily IV busulfan ± clofarabine in alloHCT, acute and delayed cytopenias following CAR-T cell therapy, letermovir discontinuation at day 100 after allogeneic stem cell transplant is associated with increased CMV-related mortality 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

*Dahi PB, Lin A, Scordo M, et al. Evaluation of melphalan exposure in lymphoma patients undergoing BEAM and autologous hematopoietic cell transplantation. Transplant Cell Ther 2022; 28: 485.e1-e6; https://doi.org/10.1016/j.jtct.2022.05.003

• Pharmacokinetic (PK) analysis of melphalan exposure in patients with lymphoma undergoing BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning (n = 105) and autoHCT at Memorial Sloan Kettering Cancer Center to assess the correlation of melphalan exposure with HCT outcomes
• PK blood samples were obtained serially up to 150 minutes after completion of the infusion. Non-compartmental and 2 compartment population PK model was developed and used for individual PK analysis
• A significant range (5.5 fold) of PK variability was observed in melphalan exposure. From the non-compartmental analysis, the estimated median melphalan AUC was 8.1 mg x hr/L (range 3.5 to 20 mg x hr/L). The median melphalan AUC determined by the population-PK model was 8.9 mg x hr/L (range 4.1 to 23 mg x hr/L). These two results were highly correlated (r = 0.97), especially at lower-level exposures. A higher melphalan exposure (> 8.1 mg x hr/L by non- compartmental analysis or > 8.9 mg x hr/L by population PK-model) was correlated to a significant increased incidence of grade > 3 metabolic toxicity when analyzed either as a binary variable or a continuous variable. No other toxicities differed significantly by melphalan exposure level, including oral/gastrointestinal toxicity 
• PFS and OS probability at 12 and 24 months in high-grade lymphomas did not statistically differ based on median melphalan exposure. In patients with T-cell lymphoma, lower than the median melphalan exposure correlated to an improved probability of PFS at 12 and 24 months and OS but this  did not reach statistical significance (p = .06)
• This PK analysis of melphalan exposure suggests that a melphalan AUC of 8 mg x hr/L as a potential target in BEAM chemotherapy. Higher exposure was found to correlate to the incidence of metabolic toxicities, but did not with other toxicities including mucositis or with survival outcomes. The value of PK directed dosing of melphalan is unclear with BEAM chemotherapy and larger prospective studies are needed to evaluate the role of PK-directed melphalan dosing in this setting

Allogeneic stem cell transplantation

**Andersson BS, Thall PF, Ma J, et al. A randomized phase III study of pre-transplant conditioning for AML/MDS with fludarabine and once daily IV busulfan ± clofarabine in allogeneic stem cell transplantation. Bone Marrow Transplant. 2022;57(8):1295-1303. doi:10.1038/s41409-022-01705-7 https://pubmed.ncbi.nlm.nih.gov/35610308/

• Randomized, phase 3 study in AML and MDS patients who received alloHCT to compare transplant outcomes between patients who received fludarabine-busulfan (Flu-Bu) versus fludarabine+clofarabine-busulfan (FCB) between December 2011 and September 2015
• A total of 250 patients were included in the study; 120 in the FCB arm and 130 in the Flu-Bu arm. Median age at transplant was 51 years (range, 8–70) and 86% of patients had poor or intermediate-risk cytogenetics
• For FCB (fludarabine 10 mg/m2 IV, clofarabine 30 mg/m2 IV and busulfan on days -6 through - 3). Target AUC for busulfan was 6000 µMol-min/day for patients up to age 60 years and 4000 µMol-min for patients of ages 61–70 years. Flu-Bu consisted of fludarabine 40 mg/m2 IV followed by the same targeted busulfan dose described above on days -6 to -3
• Median PFS was 39 months (95%CI: 21-not reached) for FCB and 28 months (95%CI: 10-not reached) for Flu-Bu. Median OS was not reached for FCB and was 54 months (95%CI: 15-not reached) for Flu-Bu. GRFS was 9.7 months (95%CI: 7.8–15.8) for FCB, and 9.1 months (95%CI: 6.9–11.1) for the Flu-Bu group (p = 0.896). Patients of age ≤ 60 years not in CR (NCR) had 3-year relapse incidence [RI] of 34% for those receiving FCB versus. 56% for those receiving Flu-Bu (p = 0.037). Older patients (age > 60 yrs) in NCR receiving FCB had 3-year RI of 10.0% vs. 56.0% for those receiving Flu-Bu (p = 0.003). At day 100, NRM rate at day 100 was 5.0% and 2.3% for FCB and Flu-Bu, respectively
• Mucositis and elevated bilirubin were similar between the FCB and Flu-Bu group. There were no cases of VOD/SOS after Flu-Bu, while three cases were encountered after FCB. There was a higher incidence of serious post-transplant infections after FCB, with six patients dying of bacterial infections versus one after Flu-Bu
• Authors conclude that conditioning with FCB did not improve PFS or OS, but improved disease control in NCR patients with an acceptable toxicity profile

*Duque-Afonso J, Finke J, Labopin M, et al. Comparison of fludarabine-melphalan and fludarabine- treosulfan as conditioning prior to allogeneic hematopoietic cell transplantation-a registry study on behalf of the EBMT Acute Leukemia Working Party. Bone Marrow Transplant. 2022;57(8):1269-1276. https://pubmed.ncbi.nlm.nih.gov/35568756/

• Multicenter study using data registries from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) in adult patients at least 18 years of age with AML in CR undergoing alloHCT was conducted between January 2008 and December 2018 to compare transplant outcomes between patients who received fludarabine/melphalan 140 mg/m2 (FluMel) and fludarabine/treosulfan 42 g/m2 (FluTreo).
• 1,427 patients were included of which 1,005 received FluMel and 422 received FluTreo. Median patient age was 58.2 years. Patients in the FluTreo group were associated with high-risk characteristics for relapse as secondary AML (14.3% vs 23.9%, p < 0.0001) and adverse risk cytogenetics (10% vs 15.4%, p = 0.019). However, more patients in the FluTreo group were transplanted in CR1 compared with FluMel group (75.4% vs. 81.8%, p = 0.009)
• At 3 years, the cumulative incidence of relapse was lower in the FluMel group compared to the FluTreo group (32.4% vs. 40.5%, p = 0.001). There was a corresponding lower NRM in the FluTreo group (25.7% vs. 20.2%, p = 0.06). No differences were found by conditioning in patient age subgroups (<55 years ≥ 55 years) regarding outcomes and graft versus host disease incidence. There was a similar 3-year overall survival (OS) (54% vs 51.2%, p value 0.49) for patients conditioned with FluMel and FluTreo, respectively
• Authors conclude that both conditioning protocols with an intermediate TCI score (FluMel and FluTreo) showed similar outcomes regarding OS

*Xu L, Lu Y, Hu S, et al. Unmanipulated haploidentical HCT with radiation-free conditioning in Fanconi anaemia: a retrospective analysis from the Chinese Blood and Marrow Transplantation Registry Group. Br J Haematol. 2022 Aug 21. doi: 10.1111/bjh.18408. https://pubmed.ncbi.nlm.nih.gov/35989315/

• Retrospective analysis of 56 patients with FA across 11 centers in China between 2013-2021, median age 8.5 (range 2-37) years and median duration from FA diagnosis to HCT of 23 (range 1-108) months
• Conditioning consisted of Flu-Cy (48.2%), Bu-Flu-Cy (41.1%), or Bu-Flu (10.7%); one patient received alemtuzumab for in vivo t-cell depletion while all others received rabbit antithymocyte globulin. The most common GVHD prophylaxis was CSA + MMF + MTX (62.5%) or TAC + MMF + MTX (23.2%)
• With median follow-up 2.4 (range 0.2-5.8) years, mean cumulative incidence for 30-day neutrophil engraftment was 96.4% and 100-day platelet engraftment was 85.5% with mean OS of 80.9% (SD 5.5%) and EFS 79.3% (SD 5.6%)
• The mean incidence of aGvHD Grade II–IV and Grade III–IV were 55.4% (SD 0.45%) and 42.9% (SD 0.45%) respectively, with mean cumulative incidence of 3-year cGvHD 34.7% (SD 0.86%) and moderate-to-severe cGvHD 9.0% (SD 0.19%). No secondary malignancies were observed
• In patients with intrinsic DNA repair defects from FA with hypersensitivity to radiotherapy and alkylating agents, unmanipulated haplo-HCT with radiation-free conditioning regimens had favorable engraftment and survival outcomes although with notably high rates of GVHD

*Liang EC, Craig J, Torelli S, et al. Allogeneic Hematopoietic Cell Transplantation for Adult Acute Lymphoblastic Leukemia in the Modern Era. Transplant Cell Ther. 2022;28(8):490-495. https://pubmed.ncbi.nlm.nih.gov/35584783/

• Retrospective, single center study of adult ALL patients who received first alloHCT between 2008-2019 (n = 285)
  • Stratified into 2 cohorts based on year of HCT: 2008 to 2013 (earlier era; n = 119) vs. 2014 to 2019 (later era; n = 166)
• Higher proportion of Hispanic patients (38% vs. 21%; absolute standardized difference [ASD] 0.68), HCT-comorbidity index ≥ 3 (31% vs. 18%; ASD 0.32), use of non-HLA matched donors (38% vs. 24%; ASD 0.68) and UCB (16% vs. 0%; ASD 0.68) in the later era. Pre-HCT MRD rates were similar in both groups, but lower proportion of patients underwent HCT with active disease in later era (4% vs. 16%; ASD 0.41)
• In unadjusted analyses, OS improved across eras, with 2-year estimates for the later and earlier eras of 73% (95% CI, 66%-80%) vs. 55% (95% CI, 46%-64%), respectively. Multivariable analysis confirmed this association between later era and OS (HR 0.52; 95% CI, 0.34-0.78)
• Among patients relapsing after HCT (25% in later era and 33% in earlier era), the use of novel immunotherapies (such as blinatumomab, inotuzumab and CART) increased in the later era (44% vs. 3%), as did median OS after post-HCT relapse (16 months vs. 8 months; P < 0.001)
• Authors conclude that in recent years, access to HCT for ALL patients from racial and ethnic minority groups has improved as well as OS after HCT for adult ALL. The use of novel targeted immunotherapies has significantly improved outcomes in patients who relapse after HCT

Graft-versus-host disease

*Salas MQ, Charry P, Pedraza A, et al. PTCY and Tacrolimus for GVHD Prevention for Older Adults Undergoing HLA-Matched Sibling and Unrelated Donor AlloHCT. Transplant Cell Ther.

2022;28(8):489.e1-489.e9. https://pubmed.ncbi.nlm.nih.gov/35577323/

• Retrospective, single-center study comparing outcomes of PTCY-tacrolimus (PTCY-TK) prophylaxis and conventional GVHD prophylaxis (without PTCy) in patients aged ≥ 50 years undergoing first alloHCT between January 2014 and February 2021 (n = 161)
  • PTCY-TK arm (n = 88) vs. other GVHD prophylaxis regimens (n = 73) which included calcineurin inhibitors with standard doses of MTX, MMF or sirolimus.
• Overall median age was 60 years, 70.8% patients underwent RIC alloHCT and 54.7% received PTCY-TK for GVHD prophylaxis
• Baseline characteristics were balanced between the 2 cohorts, except for the proportion of males (63.6% vs. 45.2%; P = 0.026) and patients receiving unrelated donor grafts (93.3% vs. 42.4%; P < 0.001) that were higher in the PTCY-TK arm. Additionally, median age for donors were lower in the PTCY-TK arm (33 vs. 48 years, P < 0.001).
• Time to neutrophil and platelet engraftment was longer in the PTCY-TK group (20 vs. 16 days and 19 vs. 11 days, respectively; P < 0.001).
• Multivariate analysis showed that PTCY-TK reduced the probability of grade II-IV aGVHD (HR 0.32; P = 0.014), any grade cGVHD (HR 0.43; P = 0.018), and of moderate/severe cGVHD (HR 0.10; P = 0.001). At 2 years, the OS (65.4% vs. 65.6%; P = 0.472), RFS (58.4% vs. 58.8%; P = 0.758), NRM (17.4% vs. 13.7%; P = 0.967), and cumulative incidence of relapse rates (24.2% vs. 27.5%; P = 0.712) were comparable between both cohorts whereas GRFS was higher in the PTCY-TK group (50.2% vs. 21.8%; P < 0.001).
• Authors conclude that in patients aged ≥ 50 years, PTCY-TK was safe and more effective than non-PTCY containing GVHD prophylaxis, even with the use of matched and mismatched unrelated donors, and resulted in comparable relapse rates and better GRFS.

CAR-T cell therapy

*Brudno JN, Natrakul D, Lam N, et al. Acute and delayed cytopenias following CAR-T cell therapy: an investigation of risk factors and mechanisms. Leukemia & Lymphoma 2022; 63:8: 1849-60. https://pubmed.ncbi.nlm.nih.gov/35389319/

• Prolonged myelosuppression after CAR T-cell therapy is common and poorly understood. A retrospective analysis of 43 patients was conducted to investigate factors contributing to CAR T- cell-related cytopenias (35 were evaluable).
• Time to hematologic recovery (THR) was defined as number of days after CAR T-cell infusion for recovery to hemoglobin ≥ 8.0 g/dL, platelets ≥ 50.0 k/µL, and neutrophil count ≥ 1.0 k/µL without transfusions or growth factors for 7 days
• Baseline % bone marrow malignancy involvement correlated with TTHR (p = 0.0447)
• Grades 3-4 CRS had longer TTHR than those with grades 0-2 CRS (p = 0.0479)
• Patients with prolonged or delayed cytopenias after anti-BCMA CAR T-cells had a higher percentage of CAR+ cells in bone marrow aspirates at 2 months after CAR-T infusion s (n = 10; p

= 0.0159).

• No factors were identified which were significantly associated with development of delayed cytopenias across clinical trials
• Cytopenias generally recovered over a period of weeks after initiation of eltrombopag ± corticosteroids. The authors do allow that is unclear whether these therapies caused recovery or whether recovery occurred spontaneously over time

Supportive Care

*Sidana S, Dueck AC, Thanarajasingam G, et al. Longitudinal Patient Reported Outcomes with CAR-T Cell Therapy Versus Autologous and Allogeneic Stem Cell Transplant. Transplant Cell Ther. 2022;28(8):473-

482. https://pubmed.ncbi.nlm.nih.gov/35550440/

• Prospective, longitudinal, observational single-center study comparing longitudinal patient- reported outcomes in patients with hematological malignancies after CAR-T cell therapy (n = 34) to cohorts undergoing autoHCT (n = 33) and alloHCT (n = 37)
• Primary endpoint was change in quality of life (QoL). Secondary endpoints were patient- reported adverse events (PRO-AEs) as measured by the Patient-Reported Outcomes version of the CTCAE and cognitive function (NeuroQoLv2 questionnaire). Time profile of PRO-AEs was evaluated using longitudinal analysis, Toxicity over Time (ToxT)
• Patients completed questionnaires at baseline, week 2 after CART and monthly for 6 months
• Baseline QoL and performance status was similar across groups although all groups had short- term decline that gradually returned to baseline. The decline in overall QoL, physical and functional well-being was significantly less with CART vs. HCT groups and returned to baseline faster
• Patients in the alloHCT group reported the greatest symptom burden, greater decrease in performance status, largest short-term decline in QoL and slowest recovery
• Authors conclude that this study provides comprehensive patient-reported data over 6 months after CART therapy and may serve as a guide for patient education, symptom management, and future studies in CART therapy to improve the overall patient experience

Infectious Diseases

*Little JS, Shapiro RM, Aleissa MM, et al. Invasive Yeast Infection after Haploidentical Donor Hematopoietic Cell Transplantation Associated with Cytokine Release Syndrome. Transplant Cell Ther. 2022;28(8):508.e1-508.e8. https://pubmed.ncbi.nlm.nih.gov/35526780/

• Retrospective, single-center study evaluating incidence and risk factors for invasive fungal disease (IFD) in patients aged ≥ 18 years undergoing haploHCT between May 2011 and May 2021 (n = 205)
• Median age was 57 years, 59% were male, and AML was the most common underlying diagnosis. Most patients received RIC vs. MAC (75% vs. 25%)
• Twenty-nine patients (14%) developed IFD following haploHCT. Invasive yeast infection (IYIs) in the first 30 days and 1 year after haploHCT occurred in 13 and 19 patients, respectively, with a cumulative incidence of 6.3% (95% CI, 2.9% to 9.6%) and 9.3% (95% CI, 5.2% to 13.2%). Candida albicans was the most frequently isolated yeast species (n = 7), and majority of yeast isolates (17 of 20; 85%) were fluconazole-susceptible
• Incidence of IYI in the first 30 days after haploHCT was 10% in the 110 patients (54%) who developed CRS following graft infusion and 21% in the 29 patients (14%) who received tocilizumab for more severe CRS
• On multivariable analysis, AML (HR 6.24; 95% CI, 1.66 to 23.37; P = 0.007) and CRS (HR 4.65; 95% CI, 1.00 to 21.58; P = 0.049) were associated with an increased risk of early IYI after haploHCT
• Authors conclude that while CRS may be a risk factor for IYI, further studies are needed to determine the impact of CRS on immune reconstitution and development of other infections after haploHCT. Based on these findings, patients who develop CRS especially those requiring tocilizumab treatment may benefit from targeted antifungal prophylaxis.

*Liu LW, Yn A, Gao F, et al.. Transplant Letermovir discontinuation at day 100 after allogeneic stem cell transplant is associated with increased CMV-related mortality Cell Ther 2022; 28: 510.e1-e9; https://doi.org/10.1016/j.jtct.2022.05.020

• Single-center, retrospective, comparative cohort of 524 patients from Jan 2016 to Jun 2019 to analyze letermovir use for CMV prophylaxis to examine outcomes beyond 24 weeks of alloHCT and identify factors that may warrant extended duration of letermovir use.
• The study investigated clinical outcomes between pre- and post-letermovir eras. Letermovir prophylaxis was initiated in January of 2018 and was given orally at a dose of 480 mg once daily starting at day 10 and continued until day 100 post-transplant.
• The primary endpoint was the incidence of clinically significant CMV infection (csCMVi) by day

180.  The csCMVi was defined as CMV viremia or CMV disease that was treated with antivirals.

• Of the 524 alloSCT recipients, 333 transplants included a CMV seropositive donor or recipient and 149 recipients received letermovir. The median follow-up period for survivors was 27.3 months (range 6.4 to 52.5 months). Letermovir was used for a median duration of 90 days (range 8 to 309 days) and was used beyond 90 days in 73 patients.
• The primary endpoint of csCMVi at day 180 was 19.5% with letermovir and 39.1% without (p <

.0001). Letermovir use was associated with decreased incidence of csCMVi in the overall population, the CMV D+/R+, and the CMV D-/R+ cohorts. However, a rapid rise in csCMVi incidence in the letermovir group was seen in these three cohorts after month 4. A multivariate analysis of CMV-related mortality demonstrated benefit with letermovir use in day 0 to 99 (HR 0.40, p = .04) and worsening during from day 180 to 365 (HR 3.19, p = .01] after letermovir is stopped. On landmark analysis, a day 100 IgG level under 400 mg/dL was associated with increased csCMVi incidence.

• This retrospective, single-center study demonstrated that discontinuation of letermovir at day 100 leads to increased incidence of late CMV reactivation and CMV-related mortality. Total mortality benefit of letermovir noted at 3 months disappeared at 6 months. The results suggest that letermovir use in CMV seropositive recipients may need to be extended. Serum IgG levels < 400 mg/dL at day 100 was identified as a risk factor with increased late CMV reactivation.