In this month’s Pharmacy SIG Literature Update: post-transplant cyclophosphamide for prevention of acute graft versus host disease, recommendations for the management of COVID-19 in patients with hematological malignancies or HCT, ASTCT clinical practice recommendations for transplantation and cellular therapies in 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

Autologous stem cell transplantation

*Martin P, Cohen JB, Wang M, et al. Treatment outcomes and roles of transplantation and maintenance rituximab in patients with previously untreated mantle cell lymphoma: results from large real-world cohorts. J Clin Oncol. 2022 Jun 28;JCO2102698. https://pubmed.ncbi.nlm.nih.gov/35763708/

• Retrospective data from 4,216 adult patients with mantle cell lymphoma from 2011-2021 from 280 community oncology clinics across the US were evaluated for treatment patterns and outcomes. The efficacy findings with ASCT and maintenance rituximab (MR) were validated by an independent cohort of 1,168 patients from 12 academic centers
• MR-eligible (alive without disease progression after 8 months of first-line BR or 6 months first-line R- CHOP) and ASCT-eligible (age < 65 years alive without disease progression 6 months after first-line treatment) patients were primary groups analyzed
• Of 962 patients considered ASCT-eligible, 282 (29.3%) received ASCT; no significant association between ASCT and rwTTNT (95% CI, 0.68 – 1.03; p= 0.1) or OS (95% CI 0.63 – 1.18, p= 0.4) was found
• Among MR-eligible patients, MR after BR vs BR alone had longer rwTTNT (95% CI 1.61 – 2.38; p< 0.01) and OS (95% CI 1.19 – 1.92; p<0.001). Amongst the validation cohort, 3-year PFS (74.2% vs 48.5%) & OS (91.9% vs 73.2%) rates were higher in the validation cohort amongst MR-eligible patients
• Study affirms lower ASCT utilization in community setting and complements existing data on mixed outcomes of ASCT, highlighting need for ongoing prospective research on efficacy of consolidative ASCT

Allogeneic stem cell transplantation

*Tachibana T, Kondo T, Uchida N, et al. The Clinical Significance of BCR-ABL1 Mutations in Patients With Philadelphia Chromosome-Positive Chronic Myeloid Leukemia Who Underwent Allogeneic Hematopoietic Cell Transplantation. Transplant Cell Ther. 2022;28(6):321.e1-321.e8. https://pubmed.ncbi.nlm.nih.gov/35296447/

• Nationwide retrospective study from Japanese transplant registry database of adult CML patients who underwent first alloHCT between 2006-2016 (n = 315)
  • Point mutations were detected in 152 patients (T315I mutation [n = 101] and non-T315I [n = 51]) vs. no mutation in 163 patients
• With a median follow-up period was 38 months (range, 2-114 months), 3-year OS was significantly lower in the BCR-ABL1 mutation group than in no-mutation group (53% vs. 71%, respectively; P = 0.002) which was validated in a multivariate analysis (HR 1.5; 95% CI, 1.02-2.2; P = 0.038)
• OS in the non-T315I group was significantly worse than that in the no-mutation group (HR 1.69; 95% CI, 1.0-2.8; P = 0.035)
• Authors concluded that mortality risk was significantly higher in the patients with BCR-ABL1 group than those without

*Kurosawa S, Shimomura Y, Itonaga H, et al. Myeloablative Versus Reduced-Intensity Conditioning With Fludarabine/Busulfan for Myelodysplastic Syndrome: A Propensity Score-Matched Analysis. Transplant Cell Ther. 2022;28(6):323.e1-323.e9. https://pubmed.ncbi.nlm.nih.gov/35296446/

• Nationwide retrospective study from Japanese transplant registry database of de novo MDS patients aged ≥ 16 years who underwent first alloHCT between 2006-2018
  • Received Flu/Bu4 (n = 202) or Flu/Bu2 conditioning (n = 202) and matched by PS

·    Primary endpoint: 3-year OS was 44.8% (95% CI, 37.1–52.1%) and 46.9% (95% CI, 39.2–54.2%) in the Flu/Bu4 and Flu/Bu2 groups, respectively (P = 0.67)

• Secondary endpoints for Flu/Bu4 vs. Flu/Bu2

o  3-year GRFS: 28.8% (95% CI, 22.2–35.7%) vs. 33% (95% CI, 26.2–40.0%), respectively (P =

0.36).

• 3-year cumulative incidence rates of relapse: 28.9% (95% CI, 22.6–35.6%) vs. 30% (95% CI, 23.6–36.6%), respectively (P = 0.47)
• 3-year cumulative incidence rates of NRM: 28.2% (95% CI, 21.7–35.0%) vs. 27.1% (95% CI, 20.6–33.9%), respectively (P = 0.6)
• 100-day cumulative incidence rate of grade II–IV aGVHD: 41.7% (95% CI, 34.8%–48.4%) vs. 29.3% (95% CI, 23.2%-35.7%), respectively (P = 0.012)
• Subgroup analysis of age, HCT-CI, cytogenetic risk, disease status at alloHCT, stem cell source, and donor group did not show any differences in OS, RFS, relapse and NRM
• Authors concluded that there were no significant differences in OS between Flu/bu4 and Flu/Bu2 although this study population was highly selected by PS matching. More prospective studies are needed to determine optimal intensity of conditioning regimens in MDS patients

*Kaito S, Kurosawa S, Najima Y, et al. Allogeneic Hematopoietic Stem Cell Transplantation for Adult Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia in Second Complete Remission. Transplant Cell Ther. 2022;28(6):326.e1-326.e10. https://pubmed.ncbi.nlm.nih.gov/35306218/

• Nationwide retrospective study from Japanese transplant registry database of Ph-negative B-ALL patients aged ≥16 years who underwent first alloHCT between 2003-2017 (n = 2390)
  • Underwent alloHCT in CR2 (n = 382) vs. CR1 (n = 1375)
• Median age of patients who received alloHCT in CR2 was significantly younger than CR1 (32 vs. 40 years, respectively; P <0.001), and time from diagnosis to alloHCT was significantly longer with CR2 vs. CR1 (median 30 vs. 6 months; P <0.001). There were also significantly fewer related donors (28% vs. 34.7%, respectively; P=0.001) and more UCBT (29.3% vs. 20.3%, respectively; P=0.001) in CR2 vs CR1
• CR2 group had a significantly lower 3-year OS (51.8% vs. 68.1%, respectively; P <0.001) and a higher 3-year relapse rate (34.2% vs. 17.6%, respectively; P <0.001) compared to CR1
• In a multivariate analysis among CR2 patients, time from diagnosis to allo-HCT (≤2 years) was a significant factor for OS (HR 1.87; 95% CI, 1.36-2.56; P <0.001), DFS (HR 1.79; 95% CI, 1.34-2.41; P <0.001), GRFS (HR 1.69; 95% CI, 1.31-2.18; P <0.001), and relapse (HR 1.88; 95% CI, 1.32-2.68; P <0.001) whereas age at alloHCT (≥ 30 years) was a significant factor for OS (HR 2.1; 95% CI, 1.46-3.02; P <0.001) DFS (HR 2; 95% CI, 1.43-2.78; P <0.001), GRFS (HR 1.73; 95% CI, 1.31-2.29; P

<0.001), and NRM (HR 2.68; 95% CI, 1.6-4.51; P <0.001)

• Authors concluded that survival outcomes of alloHCT in adult Ph-neg B-ALL pts in CR2 were inferior to those in CR1 mainly due to higher relapse rate. Further studies are needed on outcomes of alloHCT after achieving CR2 with novel drugs.

Graft-versus-host disease

**Broers AEC, de Jong CN, Bakunina K, et al. Posttransplant Cyclophosphamide for Prevention of Graft- versus-Host Disease: results of the prospective randomized HOVON-96 Trial. Blood Adv. 2022 June 14; 6 (11): 3378-3385. https://pubmed.ncbi.nlm.nih.gov/35143644

• Prospective, randomized, multicenter, phase 3 trial to study whether post-transplant cyclophosphamide (PT-Cy) combined with a short course of CSA would result in a reduction of severe GVHD and improvement of GVHD-free, relapse-free survival (GRFS) as compared with combination of CSA and mycophenolic acid (MPA) after NMA match-related and unrelated peripheral blood alloHCT
• 151 adult patients with high-risk hematological malignancy and having a matched related or at least 8/8 HLA-matched unrelated donor were randomized and allocated in a 1:2 ratio to CSA/MPA (n=52) or PT-Cy/CSA (n=99)
  • PT-Cy/CSA arm: PT-Cy 50 mg/kg IV on days +3 and +4 and CSA day + 5 onward aiming for trough levels 250-350 µg/L; if no GVHD, CSA was discontinued on day +70 without tapering
• GVHD and Survival Outcomes: 6-month cumulative incidence of grade 2 to 4 aGVHD was 48% in CSA/MPA vs 30% in PT-Cy/CSA (HR, 0.48; 95% CI, 0.29-0.82; P = 0.007); 2-year cumulative incidence of extensive cGVHD was 48% vs 16% (HR, 0.36; 95% CI, 0.21-0.64; P < 0.001); 1-year

estimate of GRFS was 21% (11% to 32%) vs 45% (35% to 55%), P < 0.001. With a median follow- up of 56.4 months, relapse incidence, PFS, and OS were not significantly different between the 2 arms

• Toxicities: 42% in CSA/MPA arm experienced at least 1 CTCAE grade 3 to 5 AE within 6 months vs 61% in PT-Cy/CSA; CTCAE grade 3 to 5 infections were 21% vs 41%; CMV reactivation was similar, but 1 patient developed CMV disease in PT-Cy/CSA arm
• Authors concluded that PT-Cy combined with a short course of CSA after NMA matched alloHCT significantly improves GRFS due to significant reduction in severe acute and chronic GVHD

CAR-T cell therapy

*Qi Y, Zhao M, Hu Y, and et al. Efficacy and Safety of CD19-specific CAR T cell-based therapy in B-cell Acute Lymphoblastic Leukemia Patients with CNSL. Blood. 2022 Jun 9;139(23):3376-3386. https://Pubmed.ncbi.nlm.nih.gov/35338773

• Phase 2, open-label, single-arm, multi-center clinical trial in China of 48 R/R B-cell ALL patients with CNSL who received CD19-directed or combined CD19 and CD22 CAR T-cell infusion
• After leukapheresis, CNS-directed bridging therapy was administered to patients with high disease burden; CNS reassessment was required before CAR-T-cell infusion. All patients received fludarabine 30 mg/m2 IV (days -5 to -3) and cyclophosphamide 750 mg/m2 IV (day -5) as lymphodepletion chemotherapy
• Baseline characteristics: Median age was 31 years with 33.3% ≥ 40 years old; median of 4 prior therapies; 20.8% had prior alloHCT; 75% had BM and CNS involvement while 25% had isolated CNS disease; 64.6% had poor-risk cytogenetics; 8.3% had primary refractory disease; and 62.5% had CNS-3 before infusion
• Response and survival outcomes: CR/CRi within BM was 87.5% with a remission rate of 85.4% in CNSL; response rates were higher in those patients who received bridging therapy (96.3% vs 71.4%, p = 0.034). With a median follow-up of 11.5 months, median EFS was 8.7 months and median OS was 16 months; cumulative incidences of relapse in BM and CNS were 31.1% and 11.3% at 12 months
• Toxicities: any grade and grade > 3 CRS occurred in 89.6% and 18.8% of patients, respectively. Any grade and grade 3/4 ICANS occurred in 37.5% and 22.9% of patients, respectively
• Authors concluded that CD19-specific CAR T cell-based therapy can induce similar response rates in BM and CNS disease, with an acceptable safety profile under intensive management. It is a potential therapy option for a cohort of previously excluded patients with CNSL with otherwise poor prognosis

*Gauthier J, Gazeau N, Hirayama AV, et al. Impact of CD19 CAR T-cell Product Type on Outcomes in Relapsed or Refractory Aggressive B-NHL. Blood. 2022 Jun 30; 139 (26): 3722-3731. https://pubmed.ncbi.nlm.nih.gov/35439295

• Retrospective clinical trial evaluating independent impact on outcomes in 129 patients with R/R aggressive B-NHL treated with commercially available CD19 CAR T-cell therapy (axicel or tisacel) or the investigational product JCAR014.

• Baseline characteristics: axicel (n= 68, 53% ), tisacel (n = 31, 24% ), JCAR014 (n=30, 23%); median age was similar between all 3 groups (62 yrs, 64 yrs, and 60 yrs); more non-DLBCL histologies in JCAR014 (23% vs 6% and 3%, p =0.004); higher percentage of patients received bridging therapy with axicel and tisacel vs JCAR014 (p < 0.001); prior line of therapies was higher with JCAR014 (median of 4 vs 3, p = 0.004); and median time from leukapheresis to CAR T-cell infusion in axicel, tisacel, and JCAR014 was 27, 40, and 17 days (p < 0.001)
• After adjustment for age, HCT-CI, LDH, largest lesion diameter, and ALC, CAR T-cell product type remained associated with outcomes in multivariable models
  • JCAR014 had lower CRS severity compared to axicel (adjusted odds ratio [aOR], 0.19; 95% CI, 0.08-0.46, p < 0.001); trend toward lower CRS severity with tisacel compared to axicel (aOR, 0.47; 95% CI, 0.21-1.06, p = 0.07)

o  Tisacel (aOR, 0.17; 95% CI, 0.06-0.48, p <0.001) and JCAR014 (aOR, 0.17; 95% CI, 0.06-

0.47, p <0.001) were associated with lower ICANS severity compared to axicel

• Lower odds of CR were predicted with tisacel (aOR, 0.23; 95% CI, 0.06-0.78; p = 0.02) and JCAR014 (aOR, 0.21; 95% CI, 0.06-0.73; p = 0.01) compared to axicel; sensitivity analysis with PET and CT response criteria suggested higher efficacy of axicel over JCAR014, the impact of tisacel vs axicel became undetermined; however, imaging assessments were not consistent between groups due to insurance policies and institutions
• The impact of age on CRS and ICANS was undetermined. Higher pre-leukapheresis LDH, largest lesion diameter, and lower ALC were independently associated with lower odds of CR
• Authors concluded that CD19 CAR T-cell product type independently impacts toxicity and efficacy in R/R aggressive B-NHL patients.

*Shargian L, Raanani P, Yeshurun M, et al. Chimeric antigen receptor T-cell therapy is superior to standard of care as second-line therapy for large B-cell lymphoma: A systematic review and meta- analysis. Br J Haematol. 2022 Jun 28. doi: 10.1111/bjh.18335. https://pubmed.ncbi.nlm.nih.gov/35765220/

• Meta-analysis of 3 trials (ZUMA-7, BELINDA, and TRANSFORM) with 865 subjects receiving axicabtagene ciloleucel, tisagenlecleucel, or lisocabtagene maraleucel as second-line R/R LBCL therapy vs high-dose salvage chemotherapy followed by ASCT
• Primary outcomes were significantly improved with CAR-T vs SOC, with OS (HR 0.77, 95% CI 0.60– 0.98, I2 = 29%) and EFS (HR 0.57, 95% CI 0.49–0.68, I2 = 94%) both superior though EFS advantage was not significant among non-GCB subjects
• CAR-T therapy was also associated with better ORR (RR 1.55, 95% CI 1.12–2.13; I2 = 85%, p= 0.001) and CR (RR 1.49, 95% CI 1.09–2.05; I2 = 72%, p=0.03) vs SOC salvage + ASCT. The risk of any Grade III or IV toxicity was similar (RR 1.03, 95% CI 0.93–1.14; I2 = 74%) between the two groups. Grade III–IV neutropenia was higher with CAR-T (61 % vs 42%, RR 1.41, 95% CI 1.06–1.90; I2 = 79%), but incidence of febrile neutropenia (9% vs 26%, RR 0.33, 95% CI 0.13–0.88; I2 = 85%) and grade III-IV thrombocytopenia were both significantly lower (29% vs 55%, RR 0.52, 95% CI 0.28–0.95; I2 = 92%)
• Short follow-up time, high heterogeneity (particularly from BELINDA), and differences in EFS definition are main limitations, but pooled analysis suggests CAR-T has significant survival advantages without vs SOC salvage chemotherapy followed by ASCT for R/R LBCL

Infectious disease/supportive care

**Cesaro S, Ljungman P, Mikulska M, et al. Recommendations for the management of COVID-19 in patients with haematological malignancies or haematopoietic cell transplantation, from the 2021 European Conference on Infections in Leukaemia (ECIL 9). Leukemia. 2022;36:1467-1480. https://pubmed.ncbi.nlm.nih.gov/35488021/

• Severity and outcomes of COVID-19 are worse in HM patients compared to the general population. Patients with lymphoproliferative disorders (i.e., NHL, CLL, MM) have a high prevalence of COVID-19. Higher mortality rate has been observed in patients with acute leukemia and high-risk MDS. Within HM subsets, higher risk for mortality includes older age, cardiovascular and metabolic comorbidities, and active malignancy
• Diagnosis: Molecular NAT assays should be used for diagnosis of SARS-CoV-2, utilizing nasopharyngeal or naso-oropharyngeal swabs
  • Decision to defer treatment should be based on results of molecular assays
  • Ct-value > 30 is associated with low/absent risk of transmission
  • Antibody assays and RNA detection in the blood are not recommended for diagnosing acute infections
• Treatment for HM: Not recommended to defer chemotherapy in asymptomatic SARS-CoV-2 HM patients or stop JAK2-inhibitors and TKI/BTKi therapy
  • Patients receiving cellular therapy (HCT, CAR-T) positive for SARS-CoV-2 and persistently shedding virus should have therapy deferred, regardless of the absence of symptoms
  • G-CSF should be used strictly within recommended indications due to risk of worse COVID-19 outcomes
• Vaccination & Prevention: Patients should complete the full vaccination series, including 3rd and 4th  doses according to national guidelines. Patients vaccinated before or during treatment should have antibody titers reassessed 6 months after treatment completion for need for revaccination. Antibody titers can be assessed for response 3-5 weeks after the last vaccine dose
  • In HCT patients, vaccination or re-vaccination should be initiated at least 6 months after transplant, but an assessment should be made regarding the risk for worsening/eliciting GVHD in allogeneic HCTs
  • Pre-exposure prophylaxis with long-acting anti-SARS-CoV-2 mAbs is recommended in patients not immunized
  • No specific recommendations are made for vaccination of stem cell donors, other than for the protection of the donor.
• Treatment for SARS-CoV-2: Patients with mild COVID-19 can be treated with the following: anti- SARS-CoV-2 mAbs, convalescent plasma (in the absence of mAbs), inhaled IFN b-1a, molnupiravir, remdesivir, ritonavir/nirmatrelvir, or colchicine (in the absence of other options).
  • Dexamethasone is not recommended in mild COVID-19. For moderate or severe COVID- 19 patients can receive remdesivir, or if they are seronegative, anti-SARS-CoV-2 mAbs, or convalescent plasma. Dexamethasone can also be used and if clinical worsening despite dexamethasone and COVID-19-related inflammation, can consider anti-IL-6, anti-IL1, or JAK-inhibitor.

**Seydoux C, Battegay R, Joerg H, et al. Impact of busulfan pharmacokinetics on outcome in adult patients receiving an allogeneic hematopoietic cell transplantation. Bone Marrow Transplantation 2022;57:903-910. PMID: 35361896

• Busulfan (Bu) exhibits variable interpersonal pharmacokinetics (PK) and the role of PK-targeted dosing has not been fully elucidated
• This was a single-center retrospective study of patients with myeloid malignancies (AML, MDS, MPN, CML) who received a busulfan-based preparative regimen prior to alloHCT and for whom PK monitoring data was available
• The primary endpoints were the relationship between Bu dose and the proportion of patients reaching target AUC as well as toxicity. Secondary endpoints included long-term outcomes such as cGVHD, NRM, relapse, GVHD-free-relapse-free survival, PS, cause of death, and potential impact on dosing strategy with respect to adverse drug effects
• Patients received busulfan as either four-times-daily infusions of 0.8 mg/kg (Bu-4) or a single daily infusion of 3.2 mg/kg (Bu-1). Target AUC values were 900-1350 µmol/L*min for Bu-4 and 4680-5848 µmol/L*min for Bu-1. Dose adjustments of 25% were made when the Bu-AUC was ± 25% of the Bu-AUC target
• A total of 658 patients received alloHCT between 2013 and 2020, of whom 376 received Bu- based conditioning and 300 met inclusion criteria. Among these, 253 received Bu-4, and 47 received Bu-1. AUC target was reached in 46% of patients (40% were classified as low AUC and 14% as high AUC)
• Viral and fungal infections were more common among those in the high AUC group (20% vs 8%; p=0.01, and 37% vs 17%; p=0.03)
• Those receiving Bu-1 were more likely to be in the low AUC group compared with those receiving Bu-4 (66% vs 36%; p< 0.01) and also had higher reported rates of mucositis
• At 2-years, NRM and risk of death were higher in the high-AUC group compared with others. Cumulative incidence of relapse and rates of GVHD were not significantly different. Authors determined that the optimal AUC cut-off of busulfan associated with low NRM was 969

µmol/L*min and conclude that low-AUC Bu appears beneficial with respect to NRM and survival

**Dhakal B, Shah N, Kansagra A, et al. ASTCT clinical practice recommendations for transplantation and cellular therapies in multiple myeloma. Transplant Cell Ther 2022; 28: 284-293. https://doi.org/10.1016/j.jtct.2022.03.019

• A clinical practice guideline developed by an ASTCT coordinated assembled panel of 35 members with content expertise in MM, cellular therapy and transplantation along with two community-based practice physicians and an independent methodologist with expertise in systematic reviews, meta-analysis, and the RAND-modified Delphi method
• The panel endorsed continued use of autologous HCT consolidation for patients with NDMM as a standard-of-care option, whereas in the front line allogeneic HCT and CAR-T were not recommended outside the setting of a clinical trial
• For patients not undergoing autologous HCT upfront, the panel recommended its used in first relapse
• Lenalidomide as a single agent was recommended for maintenance especially for standard risk patients