In this month’s Pharmacy SIG Literature Update: ATG in allogeneic HCT for AML and MDS, importance of day +11 methotrexate, ide-cel versus standard regimens in relapsed and refractory multiple myeloma, recommendations for COVID vaccinations, 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

**Dytfeld D, Wrobel T, Jamroziak K. Carfilzomib, lenalidomide, and dexamethasone or lenalidomide alone as maintenance therapy after autologous stem-cell transplantation in patients with multiple myeloma (ATLAS): interim analysis of a randomized, open-label, phase 3 trial. Lancet Oncol 2023;24:139-150. https://doi.org/10.1016/S1470-2045(22)00738-0.  PMID: 36642080

• Interim analysis of a randomized, open-label, multicenter, phase 3 trial aimed to compare the efficacy and safety of maintenance therapy with carfilzomib, lenalidomide, and dexamethasone versus  lenalidomide  alone  in  patients  with  newly  diagnosed  multiple  myeloma  (MM)  after autologous stem-cell transplantation (auto-SCT).
• Between June 10, 2016, and Oct 21, 2020, 180 patients were randomly assigned to receive either carfilzomib, lenalidomide, and dexamethasone (n=93) or lenalidomide alone (n=87; intention-to- treat population). The median age of patients was 59·0 years (IQR 49·0–63·0).
• Participants were aged 18 years or older with newly diagnosed MM, completed any type of induction and had stable disease or better, auto-SCT within 100 days, initiated induction 12 months before enrolment, and an Eastern Cooperative Oncology Group performance status of 0 or 1.
• Patients were randomly assigned (1:1) to receive up to 36 cycles of carfilzomib, lenalidomide, and dexamethasone (28-day cycles of carfilzomib 20 mg/m2 administered intravenously in cycle one on days 1 and 2 then 36 mg/m2 on days 1, 2, 8, 9, 15, and 16 in cycles one to four and 36 mg/m2 on days 1, 2, 15, and 16 from cycle five up to 36 [per protocol]; lenalidomide 25 mg administered orally on days 1–21; and dexamethasone 20 mg administered orally on days 1, 8, 15, and 22) or lenalidomide alone (10 mg administered orally for the first three cycles and then at the best tolerated dose [≤15 mg for 28 days in 28-day cycles]) until disease progression or unacceptable toxicity as maintenance therapy. After 36 cycles, patients in both treatment groups received lenalidomide maintenance.
• After median follow-up of 33·8 months (IQR 20·9–42·9), median progression-free survival was 59·1 months (95% CI 54·8–not estimable) in the carfilzomib, lenalidomide, and dexamethasone group (CLD-grp) versus 41·4 months (33·2–65·4) in the lenalidomide group (L-grp) (hazard ratio 0·51 [95% CI 0·31–0·86]; p=0·012). The most common grade 3 and 4 adverse events were neutropenia (44 [48%] in the CLD-grp vs 52 [60%] in the L-grp), thrombocytopenia (12 [13%] vs six [7%]), and lower respiratory tract infections (seven [8%] vs one [1%]). Serious adverse events were reported in 28 (30%) patients in the CLD-grp and 19 (22%) in the L-grp.
• In conclusion, the interim analysis provides support for considering carfilzomib, lenalidomide, and dexamethasone therapy in patients with newly diagnosed MM who completed any induction regimen followed by auto-SCT. The treatment regimen and outcomes require further confirmation with a longer follow-up of this ongoing trial (NCT02659293).

Allogeneic/Haploidentical Stem Cell Transplantation

**White J, Elemary M, Linn SM, et al. A multicenter, retrospective study evaluating clinical outcomes of ruxolitinib therapy in heavily pretreated chronic GVHD patients with steroid failure. Transplant Cell Ther. 2023;29:e1-120.e9. https://www.astctjournal.org/action/showPdf?pii=S2666-6367%2822%2901797-3. PMID: 36460202.

• Multicenter, retrospective observational study to evaluate the efficacy of ruxolitinib in cGVHD patients who have failed any previous systemic therapy for cGVHD. REACH3 evaluated ruxolitinib in the second-line, but in real-world practice, ruxolitinib is used in more heavily pretreated patients.
• 115 heavily pretreated patients with steroid-refractory or steroid-dependent cGVHD across 5 transplantation centers were included. Sixty percent of patients had severe cGVHD, and 82% received ruxolitinib as fourth line treatment or beyond. Median follow-up was 13 months. Most patients (49.6%) started at 10 mg BID or 5 mg BID (47.8%). Dose was increased to 10 mg BID or higher in 68.5% of patients.
• ORR was 48.6%, 54.9%, and 48.5% at 3, 6, and 12 months, respectively. Patients with severe cGVHD showed a lower response rate of 37.5% compared to those with mild/moderate cGVHD (77.5%) at 6 months (p < 0.001).
• Clinical benefit (ORR with steroid reduction) was observed in 58.7%, 64.8%, and 60.6% at 3, 6, and 12 months, respectively. Clinical benefit was lower in patients with severe cGVHD (50%) compared to those with mild/moderate cGVHD (80%) at 6 months (p = 0.003). Approximately 33% of patients were able to discontinue prednisone at 12 months, and 63.8% were able to taper to a daily dose of < 0.1 mg/kg at 12 months.
• 10.4% of patients completed therapy with good response, and 33.4% stopped because of treatment failure. Duration of response in those who successfully completed therapy was 14 months vs. 5 months in those who discontinued due to treatment failure. FFS was 64.6% at 12 months. Pre-transplant HSCT-CI > 3 was associated with a high risk of failure because of increasing risk of non-relapse mortality.
• Authors conclude that ruxolitinib is an efficacious option for cGVHD in a heavily pretreated real- world population.

**Nakamura N, Wada F, Kondo T, et al. Significance of omitting day 11 mini-dose methotrexate for GVHD prophylaxis after unrelated bone marrow transplantation. Transplant Cell Ther. 2023;29:119.e1- 119.e7. https://www.astctjournal.org/action/showPdf?pii=S2666-6367%2822%2901771-7. PMID: 36372357.

• Retrospective, single-center study to compare the outcomes between day 11 MTX omitted (n =72) vs. full-dose MTX (n = 63) in unrelated bone marrow transplants from July 2006 to December 2019. HLA-matched donor transplants received tacrolimus + mini-MTX (5 mg/m2 on Day 1, 3, 6, and 11), and HLA-mismatched donor transplants additionally received MMF. Median follow-up was 4.69 years and 4.86 years in the MTX-omitted and full-dose groups, respectively.
• Baseline characteristics were similar between groups.  MTX tended to be omitted in patients who received melphalan. Alternative GVHD prophylaxis methods were not used for any patients in the MTX-omitted group.
• 4-year OS in the omitted vs. full-dose was 56.2% vs. 63.2% (p = 0.11) and 4-year RFS was 49.8% vs. 59.95% (p = 0.01), respectively. 100-day NRM was 3.2% vs. 5.1% (p = 0.48) and 1-year NRM was 28.7% vs. 20.0% (p = 0.40), respectively.
• Incidence of grade III-IV acute GVHD was 18.2% vs. 7.4% in the MTX omitted vs. full dose HLA- matched groups (p = 0.21) and 22.2% vs. 9.8% in the HLA-mismatched group (p = 0.17). In the multivariate analysis, risk was significantly higher in the MTX-omitted group in both cohorts (HLA-matched = HR 2.45, p = 0.03; HLA-mismatched = HR 2.40, p = 0.04).
• Incidence of extensive cGVHD at 2 years was 40.9% vs. 33.3% in the MTX omitted vs. full dose HLA-matched groups (p = 0.34) and 44.4% vs. 16.2% in the HLA-mismatched group (p = 0.05). In the multivariate analysis, risk was significantly higher in the MTX-omitted group in both cohorts (HLA-matched = HR 2.12, p = 0.04; HLA-mismatched = HR 2.37, p = 0.04).
• Neutrophil engraftment rate was similar between the two groups.
• Authors conclude that omission of Day 11 MTX tended to reduce the risks of mucosal damage and bacterial infection, but elevated the risk of severe acute and chronic GVHD.

**Dertschnig S, Gergely P, Finke J et al. Mocravimod, a selective sphingosine-1-phosphate receptor modulator, in allogeneic hematopoietic stem cell transplantation for malignancy. Transplant Cell Ther. 2023;29:41.e1-41.e.9. https://www.astctjournal.org/action/showPdf?pii=S2666-6367%2822%2901741- 9. PMID: 36343893.

• Mocravimod (KRP203) is an oral sphingosine-1-phosphate receptor (S1PR) modulator that blocks the signal required by T cells to egress from lymph nodes and other lymphoid organs while maintaining T cell effector function.
• Two-part, single- and 2-arm randomized, open-label trial to evaluate the safety, tolerability, and pharmacokinetics of mocravimod 1 mg or 3 mg PO daily from Day -10 to 100 on top of SOC GVHD ppx (cyclosporine-MTX or tacrolimus-MTX) in MMUD, MUD, or MRD donor allo-HSCT with myeloablative conditioning.
• 23 patients were enrolled from 2013 to 2017. 10 were recruited to the mocravimod 3 mg + cyclosporine arm (Mo3CsA), 6 were randomized to mocravimod 1 mg + cyclosporine (Mo1CsA), and 7 were randomized to the mocravimod 3 mg + tacrolimus (Mo3Tac) arm.
• Bradycardia was reported in 2 patients, but did not require dose adjustment or discontinuation. Drug was discontinued in two patients for macular edema, which resolved upon discontinuation. Five other patients discontinued the drug for AEs suspected to be mocravimod-related: pleural effusion, macular and retinal ischemia, blepharitis, dyspnea, weight gain, and capillary leak syndrome. Mildly elevated LFTs are typical with most S1PR modulators, but were not observed in this study.
• All patients engrafted neutrophils, and 20 of 22 patients engrafted PLTs. Median times were comparable to those previously reported. 21.7% of patients developed grade 3-4 aGVHD, 56.5% of patients developed moderate cGVHD, 43.5% of patients relapsed (median 757 days).
• Authors conclude that mocravimod is safe and supports a large study to investigate its efficacy.

**Arcuri LJ, Kerbauy MN, Kerbaur LN, et al. ATG in HLA-matched, peripheral blood, hematopoietic cell transplantation in acute myeloid leukemia and myelodysplastic syndrome: a secondary analysis of CIBMTR database. Transplant Cell Ther. 2023;29(1):40.e1-10.e4. https://www.astctjournal.org/action/showPdf?pii=S2666-6367%2822%2901630-X. PMID: 36174936.

• Retrospective analysis of CIBMTR data for to compare patients > 40 years with AML or MDS undergoing first PBSC MRD or MUD HSCT with ATG to those without ATG. ATG dose was not available.
• 1007 patients who received ATG and 3313 patients who received no ATG from 2008 to 2017 were included with a median follow-up of 7.0 years. MUDs and male donors were more common in the ATG group (77.3% vs. 43.2% and 43.9% vs. 36.5%, respectively). MAC regimens were more common in the no ATG group (51.6% vs. 40.7%).
• OS did not differ between the two groups (HR 1.09, p = 0.06), however relapse rate was higher in the ATG group (HR 1.29, p < 0.001) and NRM was lower in the ATG group (HR 0.84, p = 0.03). Relapse rate was higher in RIC or NMA conditioning and OS was also poorer in these groups.
• Grade 2-4 aGVHD was significantly lower with ATG (HR = 0.77, p < 0.001), but not grade 3-4 aGVHD (HR 0.85, p = 0.11). Both cGVHD and moderate/severe cGVHD were lower with ATG (HR 0.54, p < 0.001; HR 0.45, p < 0.001, respectively).
• Authors conclude that ATG can mitigate more severe forms of cGVHD without impairing OS in patients receiving a matched PBSC HSCT with myeloablative conditioning.

*Peter-Martin B, Sascha D, Herve F. Retrospective analysis of hematopoietic cell transplantation for blastic plasmacytoid dendritic cell neoplasm: conditioning intensity matters. Leukemia 2023; 37(2):465- 472. https://doi.org/10.1038/s41375-022-01782-z. PMID: 36550212

• Retrospective analysis among blastic plasmacytoid dendritic cell neoplasia (BPDCN) investigating the individual contributions of conditioning and graft-versus-tumor (GVT) effects to successful hematopoietic cell transplantation (HCT).
• Study analyzed data of 162 adult patients who underwent a first HCT (allogeneic 146, autologous 16) between 2009 and 2017, and were registered with the EBMT. The primary objective was to assess the efficacy of alloHCT and autoHCT in BPDCN by determining progression-free survival (PFS), overall survival (OS), and incidence of relapse (IR) 1 and 2 years after HCT.
• Median age was 57 (range 20–73) years, and disease status at HCT was first complete remission (CR1) in 78%. Among patients receiving allogeneic HCT (alloHCT), myeloablative conditioning (MAC), reduced intensity conditioning (RIC) and in-vivo T-cell depletion (TCD) were used in 54%, 46%, and 59% respectively. Among alloHCT, total body irradiation (TBI) was the conditioning backbone in 61% of MAC and 26% of RIC transplants (p < 0.001), while all expect one received TBI based conditioning regimens in autoHCT patients.
• With a median follow-up of 16 months (interquartile range 4–43), overall survival (OS), progression free survival (PFS), incidence of relapse (IR), and non-relapse mortality (NRM) at two years after alloHCT were 64% (95% CI 55–74%), 62% (95% CI 53–71%), 17% (95% CI 10–25%), and 24% (95% CI 16–33%); and 70% (95% CI 47–100%), 66% (95% CI 43–100%), 25% (95% CI 5–52%) and 9% (95% CI 0–36%) after autoHCT, respectively.
• Overall, among alloHCT recipients, MAC with TBI significantly improved OS and PFS, independently of CR1, age, Karnofsky index and TCD. Accordingly, MAC (ideally based on TBI) should be preferred for alloHCT recipients with BPDCN. In patients who are not eligible for MAC alloHCT, autoHCT could be considered.

*Etra A, Capellini A, Alousi A, et al. Effective treatment of low-risk acute GVHD with itacitinib monotherapy.  Blood 2023;141:481-9.  https://doi.org/10.1182/blood.2022017442 PMID: 36095841

• This was a phase 2 multicenter study of patients with low-risk GVHD deemed very likely to respond to systemic corticosteroids (SCS) using validated clinical and biomarker staging criteria. Definitions of low-risk GVHD included those considered to be Minnesota standard risk for clinical criteria and Ann Arbor 1 for biomarker criteria.
• Patients received 28 days of itacitinib 200 mg daily and patients found to be responding could receive a second 28-day cycle. Outcomes were compared to 140 matched control patient treated with SCS.
• A total of 70 patients received itacitinib. More patients responded to itacitinib with a 7 day period compared with matched controls (81% vs 66%), and response rates were found to be high for both groups (89% vs. 86% for itacitinib and controls, respectively).
• There were fewer serious infections with itacitinib within 90 days of treatment (27% vs. 42% for those treated with itacitinib vs. controls). Cytopenias of grade 3 or higher were similar between groups with the exception of leukopenia which was less severe with itacitinib vs controls (16% vs. 31%).
• No significant differences between groups were found at 1 year for non-relapse mortality, relapse, or cGVHD.
• Authors conclude that itacitinib monotherapy is safe and effective as an alternative treatment to systemic corticosteroids among patients with low-risk GVHD though further investigation is warranted.

Supportive Care

**Jabr R, Khatri A, Anderson D, et al. Early administration of SARS-CoV-2 monoclonal antibody reduces the risk of mortality in hematologic malignancy and hematopoietic cell transplant patients with COVID- 19. Transpl Infect Dis 2023; 25(1) https://doi.org/10.1111/tid.14006. PMID: 36704987

• A retrospective, an uncontrolled cohort of 59 HM/HSCT patients with COVID-19 who received either casirivimab-imdevimab or bamlanivimab from November 21, 2020, to September 30, 2021,during the alpha and delta variant SARS-CoV-2 waves in Miami, Florida. Outcomes measured were mortality, hospital admission, and infusion reaction to SARS-CoV-2-specific mAbs.
• Nearly half of these patients (25/59, 42%) had received cellular therapy; comprising 14/59 (24%) allogeneic HSCT, 9/59 (15%) autologous HSCT, and 2/59 (3%) chimeric antigen receptor T-cell (CAR-T) therapy. There was a relatively even mix of different HM groups, including 22/59 (37%) with lymphoma and 12/59 (20%) with MDS/AML. In those patients (46/59, 78%) who received early treatment of mild COVID-19 as outpatients with either Mab.
• Among the 25 patients who had HCT before COVID-19, the median time in days to COVID-19 diagnosis from allogeneic and autologous HCT was 609 (IQR: 335–1025) and 412 (IQR: 185–804), respectively. The median time from COVID-19 symptom onset to SARS-CoV-2-specific mAb administration was 4 (IQR: 3–6) days.
• Among patients who received SARS-CoV-2-specific mAbs as outpatients, only four (9%) visited the emergency department at days 10, 11, 15, and 35 after SARS-CoV-2-specific mAb administration. None required hospital administration.
• Among the hospitalized patients, five (38%) were admitted to the hospital with neutropenic fever, four (31%) were already hospitalized for transplantation and cellular therapy, three (23%) were admitted for monitoring of COVID-19 symptoms, and one (8%) was admitted with acute kidney injury. Three hospitalized patients died. Two due to COVID-19 infection.
• In conclusion, in this retrospective study use of mAb in outpatients had low rates of progression and lower mortality rates among high risk patients. However, mortality risk among hospitalized patients were substantial. Further studies needed to evaluate us of mAb therapy to treat COVID- 19 especially in transplant patients.

*Patel C, Pasciolla M, Abramova R, et al. Pre-hematopoietic stem cell transplantation rituximab for Epstein-Barr virus in post-lymphoproliferative disorder prophylaxis in alemtuzumab recipients.

Transplant Cell Ther. 2023;29:132.e1-132.e5. https://www.astctjournal.org/action/showPdf?pii=S2666- 6367%2822%2901738-9. PMID: 36334653.

• Single-center, retrospective, pre-post analysis to evaluate the cumulative incidence of EBV reactivation and EBV-PTLD in recipients of allo-HSCT and in vivo T-cell depletion with alemtuzumab who received pre-HSCT rituximab compared to patients who did not.
• 86 consecutive patients from January 2019 to May 2021 were reviewed. Patients who received rituximab 375 mg/m2 within 6 months before HSCT were included in the rituximab cohort (most patients received rituximab at a median of 14 days before transplantation). Patients with a MRD donor received 30 mg of alemtuzumab vs. 60 mg in those with a MUD donor.
• Day +180 EBV reactivation was 53% vs. 0 in patients without rituximab exposure vs. those with pre-HSCT rituximab exposure (p < 0.0001). Similarly, 6 patients without rituximab vs. no patients with rituximab developed PTLD at 1 year (p = 0.02). 4 of these cases were biopsy- proven, and all six patients received rituximab treatment. Median time to diagnosis of EBV- PTLD was 126 days.
• There was no difference in neutrophil engraftment (13 days each), incidence of infections, or acute GVHD at day +180. Patients who received rituximab demonstrated a slightly slower PLT engraftment (16 days vs. 15 days, p = 0.04).
• Authors conclude that pre-HSCT administration of rituximab in patients receiving T-cell depletion with alemtuzumab was associated with a significant decrease in the risk for EBV reactivation and EBV-PTLD without increasing aGVHD or infection rates.

*Khawaja F, Papanicolaou G, Dadwal S, et al. Frequently asked questions on coronavirus disease 2019 vaccination for hematopoietic cell transplantation and chimeric antigen receptor T-cell recipients from the American Society for Transplantation and Cellular Therapy and the American Society of Hematology. https://www.astctjournal.org/action/showPdf?pii=S2666-6367%2822%2901705-5. Transplant Cell Ther. 2023;29:10-18. PMID: 36273782.

• When is the recommend time to administer COVID vaccines to auto-HSCT, allo-HSCT, and CAR-T recipients?
  • 3 months
• What is the currently recommended vaccination schedule for HSCT or CAR-T patients?
  • Primary series
    • Pfizer: 1st dose (3 weeks) → 2nd dose (8 weeks) → 3rd dose
    • Modern: 1st dose (4 weeks) → 2nd dose (4 weeks) → 3rd dose
  • Bivalent Booster
    • 3 months after completing primary series
• Should we revaccinate HSCT or CAR-T patients regardless of pre-transplant vaccination status?
  • Yes
• If a patient develops COVID in before a scheduled vaccine does, when can vaccination continue?
  • As soon as symptoms have resolved and isolation precautions are discontinued.
• What are the clotting risks associated with the COVID vaccine?
  • 1 in 100,000 recipients of the AstraZeneca vaccine developed atypical clotting.
  • Cases of serious VTE events were reported with the Johnson & Johnson/Janssen vaccine, but not clearly linked to the vaccine.
  • mRNA vaccines are preferred over adenoviral-vector vaccines due to their lower risk of VTE.
• Is it safe to combine routine post-transplant vaccines with COVID vaccines?
  • Yes
• Should HSCT or CAR-T candidates/donors receive COVID vaccination prior to receiving treatment?
  • No
• What is the role of serologic testing after COVID vaccination?
  • Not recommended

CAR-T/Cellular Therapy

***Rodriguez‑Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med 2023;388:1002-14. https://doi.org/10.1056/nejmoa2213614 PMID: 36762851