In this month’s Pharmacy SIG Literature Update: Haploidentical vs. MUD allogeneic transplants for lymphomas, harmonizing definitions of diagnostic criteria for TA-TMA, use of a risk-based strategy for letermovir prophylaxis, 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

*Ekberg S, Smedby KE, Albertsson-Lindblad A, et al. Late effectsin patients with mantle cell lymphoma treatedwith or without autologous stem cell transplantation. Blood Adv. 2023;7(5):866-874. PMID: 35973196

• Swedish population-based matched cohort study to describe the late effects among MCL patients treated between 2000 and 2014 with or without HD-ASCT in relation to population comparators without MCL.
• Six hundred twenty MCL patients and 6,200 matched comparators were evaluated. Forty percent (n=247) of MCL patients received HD-ASCT within one year of diagnosis and were significantly younger, with fewer comorbidities and a higher level of education compared to patients without HD-ASCT.
• Compared with the general population, MCL patients had a two-fold increased incidence of outpatient visits (IRR: 2; 95% CI 1.8-2.2) and seven to eight-fold increased rate of inpatient visits (IRR: 7.2; 95% CI 6.3-8.3) and hospital length of stay (IRR: 8.3; 95% CI: 6.8-10.1). Patients with MCL also suffered from high relative risks of blood disorders as well as infectious and respiratory complications.
• Two patients died from ASCT within 60 days after transplant. After accounting for baseline differences between the groups, the 5-year cumulative probability of MCL-specific death was not  different in  patients treated with and without ASCT.
• The diagnosis of MCL led to higher healthcare utilization and increased rates of blood,  infectious and respiratory disorders regardless of whether patients received ASCT. Further efforts are warranted to identify more efficacious treatment options and reduce MCL-related late effects.

*Lin M, Wu X, Zhang L, et al. Fotemustine, etoposide, cytarabine, and cyclophosphamide (FEAC) conditioning regimenfor autologous stem cell transplantation in lymphoma. Leuk Lymphoma. 2023;64(3):605-612. PMID: 36657436.

• Retrospective review of 76 lymphoma patients undergoing autologous stem cell transplant after FEAC conditioning.
• The FEAC regimen was formulated with fotemustine replacing carmustine due to pulmonary toxicity, and cyclophosphamide replacing melphalan due to drug shortage.
• Seventy-five (of 76) patients successfully engrafted at a median time of 11 days (6-21 days) and 13 days (8-24 days) for neutrophils and platelets respectively. The 2-year PFS rate was 69.1%  and 2 year OS rate was 84.2%.
• One patient died of severe pulmonary infections, which gives a transplant-related mortality of 1.3%. Toxicities included 89.5% of patients having varying degrees of GI toxicity, 39.5% of patients developing febrile neutropenia, and 15.8% developing transaminitis.
• FEAC conditioning has acceptable toxicity and efficacy, making it a feasible alternative to BEAM for autologous stem cell transplant.

Allogeneic/Haploidentical Stem Cell  Transplantation

*** Mussetti A, Kanate AS, Wang T, et al. Haploidentical Versus Matched Unrelated Donor Transplants Using Post-Transplantation Cyclophosphamide for Lymphomas. Transplantation and cellular therapy. 2023;29(3):184.e1 184.e9. PMID: 36577482

• Retrospective study of 2,140 adult patients with HL (28%) or NHL (72%) who received a haplo- HCT or MUD-HCT reported to either CIBMTR or EBMT. Recipients of haplo-HCT were mismatched at 2 or more HLA loci, whereas MUD allogeneic transplants were matched at the allele level at HLA-A, -B, -C, and -DRB1 (8/8). GVHD prophylaxis in both groups included PTCy- based regimens, most commonly in combination with calcineurin inhibitor + MMF. Both peripheral blood and bone marrow grafts as well as myeloablative and non- myeloablative/reduced intensity conditioning   were included.
• 2-year OS rates were 63% haplo-HCT and 73% MUD allo-HCT  (p=0.007)
• 2-year NRM was 21% haplo-HCT vs. 15% MUD allo-HCT (p=0.024), progression/relapse incidence  at 2-years was 27% haplo-HCT vs. 22% MUD allo-HCT (p=0.213), PFS 2-year PFS was 53% haplo- HCT vs. 63% MUD allo-HCT (p=0.004), neutrophil recovery: day-28 neutrophil recovery 90% haplo-HCT vs. 93% MUD allo-HCT (P<0.001), and platelet recovery: day-28 platelet recovery 54% haplo-HCT vs. 86% MUD allo-HCT (p<0.001), 100-day acute GVHD 33% haplo-HCT vs. 24% MUD allo-HCT (p=0.004) and 1-year chronic GVHD 24% haplo-HCT vs.  17% MUD  allo-HCT
• There wasa slower rate of platelet engraftment in haplo-HCT vs. MUD allo-HCT (P<0.001) but similar rates for neutrophil recovery (p=0.025). Platelet recovery was negatively associated with chemo resistant disease status, HCT-CI score ≥2, time from diagnosis to transplant of 6-12 months and recipient age ≥ 40. Neutrophil recovery was negatively associated by sex- mismatched transplants from female donor  to male recipient and recipient age ≥ 6.
• Authors conclude that a MUD allo-HCT that is available in a timely fashion should be considered over a haploidentical donor  when using  PTCy based GVHD prophylaxis

**Schoettler ML, Carreras ME, Cho B, et al. 162 - Harmonizing Definitions for Diagnostic Criteria and Prognostic Assessment of Transplant Associated Thrombotic Microangiopathy: A Report on Behalf of the European Society for Blood and Marrow Transplantation (EBMT), American Society for Transplantation and Cellular Therapy (ASTCT), Asia-Pacific Blood and Marrow Transplantation Group (APBMT) and the Center for International Blood and Marrow Transplant Research(CIBMTR). Transplantation and cellular therapy. 2023;29(2):S130-S131.  PMID: 36442770

• A consensus panel of internationally recognized transplant-associated thrombotic microangiopathy (TA-TMA) experts convened and developed guidance to harmonize and facilitate the identification of TA-TMA across populations diverse in race, ethnicity, age, disease indications, and transplantation characteristics. The goal is to allow for a better understanding of the incidence, risk factors, and outcomes and allows the interpretation of the impact of TA- TMA-directed therapy.
• TA-TMA diagnosis was agreed to be based on findings of a renal biopsy, intestinal biopsy, or clinically using the modified Jodele criteria. These criteria do not rely on the presence of organ dysfunction or on a single diagnostic criterion allowing for an earlier   diagnosis.
• High risk TA-TMA patients should be enrolled in a clinical trial. Poor prognostic features include elevatedsC5b-9, random urine protein-to-creatinine ratio ≥1 mg/mg, organ dysfunction, LDH ≥2 times the ULN, concurrent grade II-IV acute GVHD, or concurrent infections (bacterial or viral). Absence of these features is considered standard risk and patients can be observed closely.
• All allogeneic HCT recipients and children undergoing autologous HCT for neuroblastoma should be regularly screened for TA-TMA until day 100 post-transplantation and thereafter in the presence of comorbidities, particularly GVHD and infections.
• Authors conclude that standardizing the diagnosis of TA-TMA and the enrollment of patients in TA-TMA directed clinical trials is warranted to understand its impact on organ function and survival, particularly in patients with highly comorbid complications, such as GVHD and infection.

**Sachi Singhal, Salwa S. Saadeh, Urshila Durani et al. Allogeneic Hematopoietic Stem Cell Transplantationin the Outpatient Setting: The Mayo Clinic Experience. Transplantation and Cellular Therapy 2023;29:183.e1-183.e6. PMID: 36584940

• Single-center retrospective chart review of 856 patients who underwent outpatient alloHCT spanning 17 years with 265 transplants performed from 2000-2008 and 592 from 2009-2017. 96% of transplants were for malignant causes and almost similar rates of transplants received MAC vs. RIC/NMA regimens.
• Rates of non-routine hospital admissions was 66% within 100 days (a diagnosis of AML > MM, MPN, ALL > CLL for admission). CLL patients were significantly less likely to be admitted compared to AML (OR = 0.44, P < .01). MM, MPN, AML had increased odds of admission.
• Median time to engraftment (defined as absolute neutrophil count >500) was 17 days (IQR = 14- 20). Mean days to engraftment was 19.9 days. There was no difference in admission based on time to engraftment. Higher HCT-CI sore was a significant  predictor of  admission (OR = 3.40, P < .03).

• Causes of inpatient admission include mostly for infection, GI toxicity and pain. Median length of stay was 6 days vs 30 days for inpatient alloHCT per existing literature, and in-hospital mortality rate was 5%.
• Authors conclude that outpatient management of alloHCT had a favorable outcomes and safety profile.

**Sourisseau M, Faure E, Béhal H, et al. The promising efficacy of a risk-based letermovir use strategyin CMV-positive allogeneic hematopoietic cell recipients. Blood Adv. 2023;7(5):856-865. PMID: 36350752

• Single center study of 316 CMV positive, alloHCT patients to determine the efficacy of a  risk-based letermovir utilization strategy.
• Patients were evaluatedbased on the date of transplantation: 186 patients during period 1 (2015-2017) when letermovir was not available, and 130 alloHCT recipients during period 2 (2018-2021) when letermovir was administered based on a CMV risk score. For patients at low risk of clinically significant CMV infection (csCMVi), letermovir was initiated only if corticosteroids were used prior to day 100.
• Approximately 50% of patients were low-risk and high-risk for csCMVi in both periods. Baseline characteristicswere comparable except for fewer haploidentical donors in period 2. Among low- risk patients, 18 of 63 patients in period 2 received letermovir and resulted in a significantly lower incidence of csCMVi compared with period 1 by week 14, week 24, and one-year post transplant (p=0.03). Systematic use of letermovir in high-risk patients led to significantly lower incidence of  csCMVi in period 2 versus period 1 (p<0.001) at all time points.
• Incidence of CMV disease, OS, PFS, CIR and NRM was not significantly different across the two periods, regardless of  CMV risk status.
• Thirty-six patientsoverall (13 low-risk and 23 high-risk) developed late csCMVi (>week 14). The incidence of late csCMVi was not significantly different between both periods among low-risk and high-risk patients.
• Authors concluded that CMV positive alloHCT patients benefited from a risk-based strategy that maintained efficacy in high-risk patients while sparing letermovir use in low-risk patients who   did not require corticosteroids prior to day 100.
• Swobada R, Labopin M, Giebel S, et a. Total body irradiation plus fludarabine versus busulfan plus fludarabine as a myeloablative conditioning  for adults withacute myeloid leukemia treatedwith  allogeneic hematopoietic cell transplantation. A study on behalf of the Acute Leukemia Working Partyof the EBMT. Bone Marrow Transplantation (2023)  58:282–287.  PMID: 36460819
• Retrospective, multicenter registryanalysis by the Acute Leukemia Working Party of the EBMT comparing outcomes between two MA conditioning regimens in adult patients with AML in CR1 or CR2 receiving alloHCT from HLA MRD or URD from peripheral or bone marrow source, excluding those  with ex vivo  T-cell depleted grafts.
  • FluTBI12 (fludarabine + TBI 12 Gy of heterogeneous delivery schedule) vs. FB4 (fludarabine + IV busulfan  12.8mg/kg x 4 days).
• For each patient who received FluTBII12 (n=109), two patients who received FB4 (n=213) were selected using exact and propensity-score matchedcriteria of age, donor and recipient sex, donor type, cell source, cytogenetic risk, disease status, performance status, and use of in vivo T-cell depletion.
• Baseline demographics were well matched with standardizedmean difference estimatesof less than 5% for all matchedparameters, including AML cytogenetic risk categories. There was a higher percentage of CMV seropositive recipients in the FB4 cohort (78% vs 58%, p 0.0004). The median age of both cohorts was 41 years with 78% in CR1 and 78% received URD transplants with the majority (97%) via a peripheral blood source.
• There was no difference in the primary endpoint of leukemia-free survival (LFS) 65.2% vs 59.8%, HR 1.1 95% CI 0.73-1.67; p=0.64) or in any secondary endpoint including OS, relapse incidence, NRM, grade II-IV aGVHD, cGVHD, or GRFS (all p- values > 0.1).
• The authors concluded neither regimen was superior and suggested the choice of conditioning regimen be based on patient specific factors as well as experience of transplant center and availability of TBI. Limitations of this study include the retrospective design, the lack of full molecular characteristics of AML and MRD status before transplantation, the heterogeneous methods of TBI delivery, lack of therapy-related toxicity data, and the lack of busulfan pharmacokinetic AUC targets, if utilized.

*Lin C, DiCioccio RA, Haykal T, et al. A Phase I Trial of SYK Inhibition with Fostamatinib in the Prevention and Treatment of Chronic  Graft-Versus-Host Disease. Transplantation and cellular  therapy. 2023;29(3):179.e1-179.e10.  PMID: 36577483

• Phase I prospective, open label, single center study including adult patients who underwent alloHCT and received fostamatinib for prophylaxis  (n=5) or treatment for cGVHD  (n=14).
• Patients received 1 of 3 dose levels: 100 mg daily, 150 mg daily, and 100 mg twice a day and was started between 80 and 150 days after HCT and continued until 1 year after HCT.
• Patients who received the highest dose level of 100 mg twice a day experienced at least a partial response compared to no response at the lower dose level. The median time to response was 2 months (range, 0.5-4.8) and 60% of responses occurred within the first 3 months of therapy. The median duration of response  was 19.3 months (range, 1.2-34.1).
• At 3-year follow up: cancer relapse (n=0) while on fostamatinib treatment, recurrent malignancy (n=1).
  • In the prophylaxis arm (n=5), 1 patient (20%) developed cGVHD while on fostamatinib.
  • In the treatment arm, ORR: 77%, with a CR: 31%, 12-month failure-free survival was 69%, steroid dose reduction was possible by a median of 80% with 73% maintaining lower steroids dose at 1-year compared to baseline and B-cell reconstitution was not significantly impacted after allogeneic HCT.
• Treatment related AE: Grade 2 HTN (47%), URI (21%), fatigue (16%), dry eyes (16%), elevated AST/ALT (11%) and VTE (5%). Grade 3 AE: HTN (11%), hyperglycemia (16%) and VTE (5%) and no grade 4 AE.
• Authors conclude that fostamatinib has a manageable safety profile and early efficacy data warranting further studies to confirm these findings.

*Godfrey J, Liu H, Yu J, et al. Pembrolizumab for the treatment of disease relapse after allogeneic hematopoietic stem cell transplantation. Blood Adv. 2023;7(6):963-970.
PMID: 35973200

• Single center, prospective, pilot study to investigate the safety and efficacy of fixed dose pembrolizumab 200 mg IV every 3 weeks (maximum  two years) for the treatment of relapsed disease after alloSCT in patients with mature B-cell malignancies, MDS and AML. Patients were required to be at least 90 days post-transplant, off all immunosuppression for a minimum of two weeks and no history of grade 3 or  4 aGVHD or any cGVHD.
• Twelve patients were enrolled, all of whom received reduced intensity alloHCT using fludarabine and melphalan with GVHD prophylaxis regimens including alemtuzumabplus tacrolimus for matched related donor transplants (n=7) and ATG, tacrolimus and MMF for umbilical cord blood transplants (n=5). Five patients had a history of grade 1 or 2 aGVHD. All patients were treated with at least one cycle of pembrolizumab.
• Dose limiting toxicities were reported in three patients: grade 3 to 4 pneumonitis (n=2) and grade 3 hyperthyroidism (n=1) which resolved with pembrolizumab discontinuation and corticosteroids. Five patients experienced any grade of immune-related adverse events. Pembrolizumab was discontinued in all patients at the time of data cut off.
• Efficacy was assessable in nine patients. Two patients achieved a CR, two patients had stable disease and five patients experienced PD. Both patients with complete responses had PD-L1 gene-amplified lymphomas (DLBCL and cHL) and strong PD-L1 expression on pretreatment biopsies.
• The median PFS  and OS were 2.9 months and 23.3 months, respectively.
• Pembrolizumab is a feasible treatment option for disease relapse after alloHCT. However, the clinical benefit may be limited to lymphoid malignancies and further investigation is needed to identify biomarkers to facilitate careful patient selection and minimize the risk of developing immune-related adverse events.

CAR-T Therapy

***Laetsch TW, Maude SL, Rives S, et al. Three-Year Update of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial. J Clin Oncol. 2023;41(9):1664-1669. PMID: 36399695

• ELIANA was a phase II, open-label, multicenter, global study of tisagenlecleucel (tisa-cel) in 79 young adult patients with relapsed/refractory B-ALL.
• ORR was 82% (65/79; 95% CI, 72 to 90), median EFS was 24 months, and median OS was not reached, with a median follow-up of 38.8 months.
• Among 32 responders who received no subsequent therapy while in complete remission (i.e. allogeneic transplant), the estimated RFS rate was 81% (95% CI, 62 to 91) at 24 months and 76% (95% CI, 56 to 88) at 36 months.
• Safety profile was consistent with previous published reports and no new adverse events or treatment related mortality were observed.
• These findings demonstrate favorable long-term safety and suggest tisa-cel as a curative treatment option for heavily pretreated pediatric and young  adult  patients with R/R B-ALL.

**Wang T, Tang Y, Cai J, et al. Coadministration of CD19- and CD22-Directed Chimeric Antigen Receptor T-Cell Therapyin Childhood B-Cell Acute Lymphoblastic Leukemia: A Single-Arm, Multicenter, Phase II Trial. J Clin Oncol. 2023;41(9):1670-1683. PMID: 36346962

• Open label, phase II, multicenter clinical trial of administration of CD19 and CD22 autologous CAR-T coadministration in a 1:1 ratio in patients aged ≤ 20 years with refractory disease or high- risk  hematologic or extramedullary B-acute lymphoblastic leukemia.
• Out of 194 patients with refractory leukemia or  isolated or combined  hematologic relapse (of 225 evaluable patients), CR was achieved in 192patients(99.0% CI 97.5 to 100), with a 12 month EFS of 73.5% (95% CI, 67.3 to 80.3) and OS of 87.7% (95% CI, 82.9 to 92.9).
• Consolidative transplant was performed in 24 of the 37 patients with KMT2A-rearrangedor ZNF384-rearranged ALL and in 54 patients due to parental request. Patients who received transplant had better 12-month EFS than those who did not (85% vs. 69.2%; P =   0.03).
• CRS developed in 88% of patients was grade >3 in 28.4% patients, and fatal in one patient. Neurotoxicity occurred in 20.9%, was grade >3 in 4.0% patients, and fatal in two patients.
• CD19-/CD22-CAR T-cell therapy achieved relatively durable remission in children with relapsed or refractory B-acute lymphoblastic leukemia, including those with isolated or combined extramedullary relapse.

**Van Le H, Van Naarden Braun K, Nowakowski GS, et al. Use of a real-world synthetic control arm for direct comparison of lisocabtagene maraleucel and conventional therapy in relapsed/refractorylarge B- cell lymphoma.  Leuk Lymphoma. 2023;64(3):573-585.  PMID: 36755418.

• A real-world population was used as a synthetic comparator for the single-arm TRANSCEND NHL 001 study in patients with relapsed/refractorylarge B-cell lymphoma receiving lisocabtagene maraleucel (liso-cel) after two or more lines of previous therapy compared with conventional therapy.
• Primary data source for conventional therapy arm was patient-level data from the NDS-NHL-001 study,  a global, multicenter, retrospective, observational study  evaluating real world outcomes of R/R LBCL diagnosed between January 2003 and September 2018. The inclusion and exclusion criteria from TRANSCEND were applied to create a propensity-matched cohort.
• Efficacy outcomes significantly favored liso-cel, including ORR (74% vs 39%; p<0.0001) and median OS (23.5 vs 6.8 months; p < 0.0001).
• Results demonstrated a statistically significant benefit of liso-cel in patients with third or later line R/R LBCL relative to conventional therapy. Safety endpoints were not assessed.

Supportive Care

*Lehrnbecher T, Robinson PD, Ammann RA, et al. Guideline for the Management of Fever and Neutropenia in Pediatric Patients With Cancer and Hematopoietic Cell Transplantation Recipients: 2023 Update. J Clin  Oncol. 2023;41(9):1774-1785. PMID: 36689694.

• Systematic review of relevant randomized controlled trials published since 2017 CPG update with 10 new RCTs identified in addition to the 69 RCTs identified in previous FN    CPGs
• Recommendations or statements were approved if at least 80% of panel members were in agreement.
• Changes from the 2017 CPG:
  • Discontinuation of empiric antibacterial therapyin clinically well and afebrile patients with low-risk FN if blood cultures remain negative at 48 hours despite no evidence of marrow recovery (previously recommended at 72 hours).
  • Pre-emptive antifungal therapy for invasive fungal disease in high-risk patients not receiving anti-mold prophylaxis.  The panel created a good practice statement to initiate FN CPG-consistent empiric antibacterial therapy as soon as possible in clinically unstable febrile patients.
    
    

ASTCT Pharmacy SIG Research Working Committee:

Amber Clemmons, Jennifer Collins, Aaron Cumpston, Arpita Gandhi, Alycia Hatashima, Haval Norman, Thomas Hughes, Jitesh Kawedia, Kaily Kurzweil, Andrew Lin, Dennis Marjoncu, Cameron Ninos, Mary Nauffal, Jonathan Ptachcinski, Julianna Roddy, Justin  Tossey, Sorana Ursu, Abhijna Vithal Yergolkar

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