06.03.22

s Pharmacy SIG Literature Update: PTCy in One-Antigen Mismatched URD HCT (1Ag-MMUD) Vs. HaploHCT in AML and More

In this month’s Pharmacy SIG Literature Update: PTCy in one-antigen mismatched URD HCT (1Ag-MMUD) vs. HaploHCT in AML, conditioning regimen intensity in PTCL, optimal fludarabine lymphodepletion prior to CART 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

Allogeneic stem cell transplantation

**Battipaglia G, Galimard J-E, Labopin, M, et al. Post-transplant cyclophosphamide in one-antigen mismatched unrelated donor transplantation versus haploidentical transplantation in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the EBMT. Bone Marrow Transplant 2022; 57:562-571. https://doi.org/10.1038/s41409-022-01577-x

  • Retrospective, multicenter study utilizing EBMT data to evaluate transplant outcomes among adult AML patients receiving a one-antigen mismatched unrelated donor (1Ag-MMUD) transplant versus HaploHCT utilizing PTCy for GVHD prophylaxis. Transplants were performed between 2009 and 2019.
  • Three cohorts were compared: 1Ag-MMUD receiving PBSC (1Ag-MMUD –PB, n = 155), HaploHCT receiving bone marrow (Haplo-BM, n = 647), and HaploHCT receiving PBSC (Haplo-PB, n = 949)
  • A MAC was used in 54%, 71% and 58% of patients in the 1Ag-MMUD-PB, Haplo-BM, and Haplo-PB, respectively (p< 0.01). A combination of a calcineurin inhibitor and MMF was the most frequently used immunosuppressive across all groups.
  • The multivariate analysis showed that when compared with 1Ag-MMUD, those who underwent Haplo-BM and with Haplo-PB had a higher incidence of NRM (HR 2.28, p < 0.01 and HR 2.65, p<0.01, respectively). No significant differences were found between the groups in terms of relapse incidence. A RIC preparative regimen was independently associated with a higher relapse incidence (HR 1.71, 95% CI 1.34-2.20, p < 0.001. Compared to the 1Ag-MMUD-PB recipients, Haplo recipients experienced lower LFS (Haplo-BM: HR 1.51, p = 0.02, Haplo-PB: HR 1.47, p=0.02) and lower OS (Haplo-BM: HR 1.50, p = 0.04; Haplo-PB: HR 1.51, p = 0.03). Haplo-BM was associated with a lower risk of aGVHD, while no statistical differences were observed between groups for grade II-IV aGVHD and cGVHD. Monthly Literature Update May 2022 2
  • A higher NRM was observed in Haplo transplant recipients resulting in lower LFS and OS compared to 1Ag-MMUD-PB recipients. While multiple variables could have contributed to these differences, this study supports 1Ag-MMUD-PB as a viable option when considering alternative donors. Prospective studies are needed to confirm findings from this retrospective trial.

*Haroon A, Alfraih F, Hanbali A, et al. Allogeneic transplant compared to pediatric-inspired therapy for Philadelphia chromosome-negative adolescent and adult ALL in first complete remission. Bone Marrow Transplant 2022; 57:593-597. https://doi.org/10.1038/s41409-022-01595-9

  • Retrospective, single-center study evaluating the outcomes of adolescent and adult Ph- ALL patients in first remission treated with alloHCT vs. pediatric-inspired chemotherapy regimen. The two cohorts involved patients treated over consecutive time periods (2005-2015 and 2015- 2020). The primary objective was to compare OS, DFS and EFS in both cohorts. Secondary objectives included NRM and relapse rate.
  • The alloHCT (2005-2015, n = 85) were initially treated with an adult-based CALGB 19802 protocol followed by alloHCT in patients with high-risk features and an available MSD after achieving CR1, using PBSC graft with cyclophosphamide and total body irradiation MAC. GVHD prophylaxis consisted of short course MTX and cyclosporine. The pediatric-inspired chemotherapy cohort (2015-2020, n = 72) received a modified version of Children’s Cancer Group (CCG) 1900 protocol. Patients with refractory disease, Burkitt leukemia and Ph+ ALL were excluded from both cohorts.
  • Baseline characteristics were balanced between both groups, however patients in the alloHCT cohort were slightly older (19 years vs 17 years, p = 0.03), had a higher WBC at diagnosis (36 vs 5, p < 0.001) and had a higher number of patients with CNS involvement at diagnosis (13 vs 3, p = 0.02).
  • The five- year OS and DFS favored the chemotherapy arm (80.2% and 71.9%, respectively, p = 0.03) compared to the allo-HCT arm (63.1% and 58.8, respectively, p = NS). No differences between the groups were found for five-year EFS, relapse rate and NRM.
  • The study limitations (single center, low patient numbers, differences in baseline characteristics, and different time periods for the cohorts) prevent definitive conclusions and require further investigation. The difference in OS favoring pediatric based chemotherapy demonstrated in this study are consistent with another single center study published in 2016 (Seftel MD, et al. Am J Hematol 2016; 91:322-329) and suggest that alloHCT in the adolescent and adult ALL population may need to be reserved for relapsed and refractory cases in the era of pediatric based chemotherapy regimens and newer salvage treatment options.

**Murthy HS, Ahn KW, Estrada-Merly N, et al. Outcomes of allogeneic hematopoietic cell transplantation in T cell prolymphocytic leukemia: a contemporary analysis from the Center for International Blood and Marrow Transplant Research. Transplant Cell Ther. 2022 Apr;28(4):187.e1- 187.e10. https://pubmed.ncbi.nlm.nih.gov/35081472/

  • Retrospective study of 266 adult T-PLL patients receiving first alloHCT between 2008-2018 to identify predictors of post-transplantation relapse and survival
  • Median age was 59.1 years and majority were white (87%) in complete remission (56%) with KPS ≥90 (58%). MRD (30%) and 8/8 MUD donors (43%) were most common, as were peripheral blood 3 grafts (89%), reduced-intensity and nonmyeloablative conditioning (70%), and calcineurin-based GVHD prophylaxis (80%). Cord blood and ex vivo T cell-depleted grafts were excluded.
  • Four-year OS, DFS, relapse, and TRM rates were 30.0%, 25.7%, 41.9%, and 32.4%, respectively.
  • In multivariable analyses, inferior OS was associated with receipt of MAC regimen (HR 2.18; p=0.0001), age > 60 years (HR 1.61; p=0.0053), and KPS <90 (HR 1.53; p=0.0073). Receipt of MAC regimen was also associated with increased TRM (HR 3.31; p<.0001), elevated grade II-IV aGVHD incidence (HR 2.94; p=0.0011), and inferior DFS (HR 1.86; p=0.0004) compared to RIC regimens. PTCy-based prophylaxis was predictive of reduced grade II-IV acute (OR 0.26, p=0.0082) and had less chronic GVHD (OR 0.44, p=.0.0645) than calcineurin-based prophylaxis without PTCy. Use of in vivo T cell-depletion had inferior DFS (HR 1.50, p=0.027).
  • The authors concluded that RIC without alemtuzumab or ATG in vivo T-cell depletion before alloHCT was associated with improved long-term survival in T-PLL patients age ≤ 60 years, KPS > 90, or with chemosensitive disease.

*Ruggeri L, Eikema D, Bondanza A, et al. Mother donors improve outcomes after HLA haploidentical transplantation: a study by the Cellular Therapy and Immunobiology Working Party of the European Society for Blood and Marrow Transplantation. Transplant Cell Ther. 2022 Apr;28(4):206.e1-206.e6. https://pubmed.ncbi.nlm.nih.gov/35017118/

  • Retrospective analysis of maternal donors in haploHCT between 1995-2012 to evaluate potential immunologic memory role of exposure to paternal HLA haplotype antigens during pregnancy on the outcome of HCT
  • Eight EBMT centers with 409 patients (102 pediatric, 307 adult) with AML or ALL included, 54.5% in complete remission and at median age 32.6 years. Common conditioning included lethal TBI combined with fludarabine, thiotepa, and ATG (n=168) or chemotherapy-based busulfan or treosulfan and fludarabine and ATG or anti-CD3 (n=146). Maternal donors were used for 96 (23.5%) patients vs other family donors. Ex vivo T cell-depleted transplant was used in 296 (72.7%) patients; 111 (27.3%) patients had unmanipulated transplants by leukapheresis but only included 16 (3.9%) maternal donors. Mycophenolate, sirolimus, and ATG were used as pharmacologic prophylaxis.
  • In multivariable analyses, non-maternal donors were associated with higher relapse incidence (HR 2.16, p= 0.007), worse PFS (HR 1.63, p=0.015), and worse GRFS (HR 1.57, p=0.033) in T cell-depleted HCTs. Non-maternal donors with unmanipulated HCTs had numerically higher relapse incidence (HR 4.15, p=0.06). Incidence of acute and chronic GVHD were similar between maternal and all other family donors (17% vs 15% and 6% vs 6%, respectively), with no differences observed between mother-to-daughter and mother-to-son HCTs.
  • The authors concluded that mothers should be the preferred donor to provide better GFRS without worse GVHD in T cell-depleted haploidentical HSCs for acute leukemia, but limited inclusion of unmanipulated HCT precluded recommending as preferred donors in that setting.

Autologous Stem Cell Transplantation

*Swan D, Hayden PJ, Eikema DJ, et al. Trends in autologous stem cell transplantation for newly diagnosed multiple myeloma: Changing demographics and outcomes in European Society for Blood and Marrow Transplantation centres from 1995 to 2019. Br J Haematol. 2022;197(1):82-96. https://pubmed.ncbi.nlm.nih.gov/35166376/

  • Retrospective EBMT study of all patients undergoing first autoHCT for MM between 1995-2019 (n = 117,711)
  • The number of HCTs has increased sevenfold across study period, with the median age increasing from 55 to 61 years, and there was an increase in percent of patients aged >65 years from 7% to 30%.
  • Use of chemotherapy-based induction with VAD (vincristine, doxorubicin and dexamethasone) fell significantly (80.4% to 1.6%), being largely replaced by bortezomib-based regimens (0% to 82.6%).
  • 2-year CR rate increased from 22% to 42%, 5-year PFS and OS increased from 28% to 31% (p <0.001) and from 52% to 69% (p <0.001), respectively. The overall HCT mortality rate fell from 5.9% to 1.5%.
  • Authors concluded that while ongoing advances in MM treatment may challenge the future role of autoHCT, it still remains central to the MM treatment paradigm at the current time.

Conditioning Regimens

*Puckrin R, Chua N, Shafey M, and et al. Improving the Outcomes of Secondary CNS Lymphoma (SCNSL) with High-Dose Thiotepa, Busulfan, Melphalan, Rituximab Conditioning and Auto Transplant. Leukemia and Lymphoma. 2022 April 22: 1-92. https://pubmed.ncbi.nlm.nih.gov/35459424/. PMID: 35459424.

  • Retrospective, multicenter study including 62 patients with SCNSL intended for transplant with high-dose methotrexate (HD-MTX)-based induction followed by high-dose thiotepa (250 mg/m2 IV on Days -6 and -5), busulfan (3.2 mg/kg IV on Days -4 to -2), melphalan (100 mg/m2 on Day - 1), rituximab (375 mg/m2 on Day -1) (TBMR) conditioning and autoHCT.
  • Baseline characteristics: median age was 58 years (range 20-75) and 52 (84%) patients had ECOG performance status > 1 at diagnosis; 52 (84%) patients completed induction and proceeded to TBMR/AutoHCT.
  • Primary outcomes: Best response post-ASCT was CR in 43 (83%), PR in 6 (12%), stable disease in 1 (2%) and PD in 2 (4%). With a median follow-up of 5.7 yrs., 5- yr PFS and OS were 53% (95% CI 39-65%) and 65% (95% CI 45-74%) for all patients and 62% (95% CI 45-74%) and 73% (95% CI 57- 84%) for those undergoing TBMR/AutoHCT.
  • Patients achieving CR/PR to induction had superior OS (5-year OS 77%, 95% CI 60-88%) compared to patients with SD/PD (5-year OS 31%, 95% CI 11-53), p < 0.0001). AEs were consistent with what would be expected from TBMR conditioning and ASCT.
  • Authors concluded that high-dose TBMR conditioning and autoHCT can achieve long-term survival in approximately 75% of transplanted patients with SCNSL. Outcomes appear favorable for patients with SCNSL at initial diagnosis or with isolated CNS relapse, whereas patients with concurrent CNS-systemic relapse or with progressive disease during induction might benefit from novel therapeutic approaches. Future studies are needed to optimize induction and re- 5 induction so that a greater proportion of patients with older age and comorbidities might benefit from this potentially curable therapy.

**Savani M, Ahn KW, Chen Y, et al. Impact of conditioning regimen intensity on the outcomes of peripheral T-cell lymphoma, anaplastic large cell lymphoma and angioimmunoblastic T-cell lymphoma patients undergoing allogeneic transplant. Br J Haematol. 2022;197(2):212-222. https://pubmed.ncbi.nlm.nih.gov/35106754/

  • Retrospective CIBMTR study of patients between ages of 18-65 years diagnosed with peripheral T-cell lymphoma -NOS, anaplastic large cell lymphoma and angioimmunoblastic T-cell lymphoma, who underwent RIC/NMA (n = 545) vs MAC alloHCT (n = 258) between 2008-2019
  • Significantly more patients in the RIC/NMA cohort had PB grafts (92% vs 87%), history of prior autoHCT (39% vs 16%), HCT-CI ≥ 3 (40% vs 29%) and chemosensitive disease before alloHCT (87% vs 79%) compared to the MAC cohort.
  • On multivariate analysis, there was no difference between groups with regards to OS (HR 1.01; p=0.95), NRM (HR 0.85; p=0.34), risk of progression/relapse (HR 1.29; p=0.07), and PFS (HR 1.14; p=0.23) between the RIC/NMA vs MAC groups.
  • Compared to MAC, RIC/NMA was associated with a significantly lower risk of grade 3-4 aGVHD (HR 0.67; 95% CI 0.46–0.99; p = 0.04). There was a lower risk of grade III-IV aGVHD with RIC/NMA compared to MAC (HR 0.67; p=0.04).
  • Authors concluded that there was no association between conditioning intensity and outcomes after alloHCT for T-cell NHL.

Graft-versus-host disease

*Mirza A, Tandon A, Jenneman D, et al. Outcomes following intolerance to tacrolimus/sirolimus graftversus-host disease prophylaxis for allogeneic hematopoietic cell transplantation. Transplant Cell Ther. 2022 Apr;28(4):185.e1-185.e7. https://pubmed.ncbi.nlm.nih.gov/35017119/

  • Retrospective analysis of 777 adult alloHCT patients receiving combined tacrolimus/sirolimus GVHD prophylaxis between 2009-2018, with intolerance defined as discontinuing either agent due to toxicity before day +100
  • A total of 104 patients experienced intolerance at median 30 days (range 5 to 90 days). Most frequent causes of intolerance were acute kidney injury (n=53, 51%), thrombotic microangiopathy (n=31, 28%), and VOD (n=23, 22%).
  • In multivariate analyses adjusting for disease risk index, comorbidity index, conditioning regimen, and donor type/age, cumulative grade II-IV acute GVHD incidence was 50% for intolerant patients vs 25% for tolerant patients (p< 0.001); 1-year NRM was 47% vs 12% (p<0.001); 2-year OS was 38% vs 69% (p<0.001).
  • Tacrolimus was the prematurely discontinued agent in 84 (81%) of patients, sirolimus in 18 (17%), and both in 2 (2%) patients; dose reduction strategies were not assessed as trough levels were not included in dataset. Offending agent was frequently replaced by mycophenolate mofetil (n=68, 65%), but in some cases stopped with patients continuing on single-drug prophylaxis (n=32, 31%). The GVHD prophylaxis used after intolerance had no significant association with outcomes. 6
  • The authors concluded that tacrolimus/sirolimus intolerance is associated with higher risk of acute GVHD, increased NRM, and worse survival, with current management strategies using alternative agents or continuing on single-drug therapy insufficient to mitigate outcomes

CAR-T cell therapy

*Maziarz RT, Yang H, Liu Q, and et al. Real-World Healthcare Resource Utilization (HRU) and Costs Associated with Tisagenlecleucel (Tisa-cel) and Axicabtagene ciloleucel (Axi-cel) Among Patients with Diffuse Large B-Cell Lymphoma: An analysis of Hospital Data in the United States. Leukemia and Lymphoma. 2022 April 14:1-14. https://pubmed.ncbi.nlm.nih.gov/35422192/. PMID: 35422192.

  • Retrospective, non-interventional cohort study used data acquired from the Premier Healthcare Database (2017 Q1 – 2020 Q1). This study compared real-world non-CAR-T HRU, costs, AE, AE treatments associated with CAR-T therapies, tisa-cel and axi-cel for R/R DLBCL in 119 adult patients.
    • 33 received tisa-cel (74.8% as inpatient infusion) and 86 received axi-cel (100% inpatient)
  • Baseline characteristics: mean ages were 62.3 and 59.8 years for tisa-cel and axi-cel; over half of the patients in both cohorts were male and white. Other baseline characteristics were comparable between groups except depression was higher in the tisa-cel cohort (36.4% vs 18.6%, p =0.04).
  • HRU and cost during the infusion encounter: Tisa-cell was associated with significantly shorter mean inpatient LOS than axi-cel (11.3 days vs 18.3 days); fewer tisa-cel patients transferred to the ICU (9.1% vs 20.9%). Among patients with an ICU stay, mean ICU days were 5.3 vs 8 (tisa-cel vs axi-cel). Post-remission rates within 30 days and 60 days were comparable. Costs were significantly lower for tisa-cel compared with axi-cel during infusion ($27,594.8 vs $51,378.3, p < 0.05)
  • HRU and costs during the entire follow-up period: average length of follow-up was 5 months for tisa-cel and 3.3 months for axi-cel. Despite the longer follow-up for the tisa-cel cohort, a significantly lower proportion had ≥ 1 inpatient admission during the study period vs. the axi-cel cohort (90.9% vs 100%, p < 0.05). Tisa-cel had significantly shorter mean inpatient days (monthly: 3.9 vs. 6.9 days, p = 0.03), but had a significantly higher proportion with ≥ outpatient visits (81.8% vs 52.3%, p < 0.01). Costs were significantly lower for tisa-cel compared with axi-cel during follow up ($28,777.3 vs $46,575.7, p < 0.05).
  • Comparison of AEs and related treatments: AEs and treatment of AEs were not significantly different, but both CRS and neurotoxicity events were numerically higher with axi-cel. Significantly fewer tisa-cel vs axi-cel treated patients used tocilizumab.
  • Authors concluded that patient with R/R DLBCL in a large US hospital database, tisa-cel was associated with fewer inpatient admissions, shorter LOS, and more outpatient visits during the infusion encounter than axi-cel. During follow-up, monthly inpatient LOS was longer for axi-cel vs tis-cel, but tisa-cel was associated with a higher monthly rate of outpatient visits. Non-CART costs were lower for tisa-cel than axi-cel, driven by lower inpatient costs.

**Fabrizio VA, Boelens JJ, Mauguen A, et al. Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy. Blood Adv. 2022;6(7):1961- 1968. https://pubmed.ncbi.nlm.nih.gov/34788386/

  • Multicenter, retrospective analysis in pediatric and young adult patients with R/R ALL receiving standard of care CD19 CAR-T cell therapy, looking at fludarabine exposure in LDC prior to tisagenlecleucel.
  • 152 patients were evaluable with a median age of 12.5 years (range <1-26) and were predominantly Caucasian or Hispanic. Pre-infusion disease burden was high in 50% of patients and undetectable in 28% of patients. The mean time from diagnosis to infusion was 43 months with an average of 3.5 prior lines of therapy.
  • The mean fludarabine dose was 41 mg (range, 11-70 mg) with an estimated mean fludarabine cumulative AUC of 14.4 mg x h/L (SD 1.6; range 11.4-22.4). Fludarabine AUC was found to be higher in non-responders than responders, with a mean of 14.7 mg x h/L and 14.4 mg x h/L, respectively (p=0.046). Optimal fludarabine exposure was determined to be ≥ 13.8 mg x h/L.
  • At a median follow-up of 1.1-yrs., high pre-infusion disease and suboptimal fludarabine exposure were associated with increased risk of relapse (HR, 2.66; p= 0.001 and HR, 2.45; p=0.005). OS was not associated with suboptimal fludarabine exposure. In an analysis of patients with high pre-infusion disease burden, suboptimal fludarabine exposure was associated with reduced OS for all treated patients (HR, 2.27; p=0.03) and for responding patients only (HR, 3.50; p=0.02).
  • Cumulative incidence of a clinically important composite end point (relapse or loss of BCA) was 55.2% at 12 months. Twelve and 24-month survival for the entire cohort were 75.1% and 56.5%, respectively.
  • All grade CRS was 64% and grade ≥ 3 was 22% within the cohort. Neurotoxicity was 24% all grade and 8% grade ≥ 3. No difference was found in the incidence of CRS, neurotoxicity or infections in patients that received sub-optimal or optimal fludarabine dosing.
  • The investigators concluded that optimal fludarabine exposure was found to be ≥ 13.8 mg x h/L and was associated with reduced disease relapse and a clinically relevant composite end point of relapse or loss of BCA. OS was not affected by fludarabine exposure in the entire cohort nor in responding patients only.

Infectious disease/supportive care

*Bognàr T, Bartelink IH, Egberts TCG, et al. Association between the magnitude of intravenous busulfan exposure and development of hepatic veno-occlusive disease in children and young adults undergoing myeloablative allogeneic hematopoietic cell transplantation. Transplant Cell Ther. 2022;28:196-202. https://pubmed.ncbi.nlm.nih.gov/35065280/

  • Observational, multicenter study across 15 centers performed from 2000 to 2015 in pediatric and young adult patients who underwent bulsulfan conditioning to investigate the association between the magnitude of busulfan exposure and the occurrence of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS). VOD/SOS was defined by either modified Seattle or Baltimore Criteria.
  • 697 patients received busulfan, median age 4.7 years (range 0.04 to 30.4 years) and a median body weight of 18 kg (range 2.7 to 117.8 kg). Most frequently used conditioning regimens were busulfan/cyclophosphamide (39.7%), busulfan/fludarabine (28.8%), and busulfan/cyclophosphamide/melphalan (10.5%). 8
  • 12.6% (n = 88) of patients were diagnosed with VOD/SOS. For patients receiving only busulfan (in combination with non-alkylator chemotherapy) as an alkylator, cumulative busulfan exposure (>78 mg x h/L) was associated with increased VOD/SOS risk (12.6% versus 4.7%, OR = 2.95; 95% CI 1.13 to 7.66). Patients who received busulfan in combination with other alkylators (cyclophosphamide, melphalan, or both) busulfan exposure was not associated with a further increase in VOD/SOS risk (15.2% versus 15.4%).
  • The number of alkylators in the conditioning regimen was a strong effect modifier (P < 0.001). Patients who received busulfan in combination with cyclophosphamide and melphalan, the risk of developing VOD/SOS increased fourfold (26.0% versus 7.9%, OR = 4.09; 95% CI 2.02 to 8.30).
  • Authors conclude that that in patients receiving busulfan as the only alkylator, high busulfan AUCwas associated with a threefold higher risk of developing VOD/SOS.

*Kimura SI, Kameda K, Harada K, et al. Risk and predictive factors for candidemia after allogeneic hematopoietic cell transplantation: JSTCT transplant complications working group. Transplant Cell Ther. 2022; 28:209.e1-209.e9. https://pubmed.ncbi.nlm.nih.gov/34995815/

  • Retrospective analysis utilizing data from the Transplant Registry Unified Management Program (data registry managed by the Japanese Society for Transplantation and Cellular Therapy and the Japanese Data Center for Hematopoietic Cell Transplantation) in pediatric and adult patients who underwent their first allogeneic HCT from either HLA MRD, MMRD, MUD, MMUD, or cord blood (CB) donors to evaluate the risk factors for candedemia after allogeneic HCT.
  • 26,236 patients were identified with a median age of 50 years (range, 0-85). Candidemia was observed in 469 patients at a median of 29 days (range, 0-1666 days) after HCT. The most frequently identified Candida species was C. parapsilosis, (32.2%), followed by C. albicans (13.0%) and C. glabrata (12.8%).
  • Increased incidence of candidemia was significantly associated for the following pre-transplant patient factors: age > 40 years (hazard ratio [HR] 1.85), male (HR 1.34), HCT-comorbidity index (HCT-CI 1-2, HR 1.56; HCT-CI ≥ 3, HR 2.21), performance status ≥ 2 (HR 2.01), high-risk disease (HR 1.78) and donor type (MMRD) (HR 1.96), MMUD (HR 2.05), and cord blood (CB) (HR 2.85)
  • For early phase (days 0-40) after HCT, HCT-CI, PS, high-risk disease and CB transplantation together with engraftment and severe acute GVHD significantly affected the development of candidemia. In the late phase (days 41-100), higher HCT-CI, male, and donor type including MMRD, and CB were associated with the occurrence of candidemia together with acute GVHD and disease relapse. In the very late phase (days 101-365), HCT-CI > 3 and high-risk disease significantly affected occurrence of candidemia together with acute and chronic GVHD, and disease relapse.
  • Authors conclude that In addition to well-recognized risk factors, patient factors such as HCT-CI and PS were associated with an increased incidence of candidemia, which suggests that severely ill patients are more likely to develop candidemia. Authors further suggest that azole antifungal 9 prophylaxis instead of echinocandin might be considered in high-risk patients considering the high proportion of C. parapsilosis as a causative pathogen in Japan

*Kambhampati S, Sheng Y, Huang CY, et al. Infectious complications in patients with relapsed refractory multiple myeloma after BCMA CAR T-cell therapy. Blood Adv. 2022;6(7):2045- 2054. https://pubmed.ncbi.nlm.nih.gov/34543400/

  • Single-center, retrospective study looking at infectious complications of patients with MM who received BCMA CAR-T therapy between 2018 and 2020. Institutional standards for infection prophylaxis include G-CSF for ANC < 500 cells/m3 (not before 14 days after CAR T-cell), VZV prophylaxis, antibacterial and antifungal prophylaxis while ANC < 500 cells/m3 , and PCP prophylaxis when CD4 count was < 200 cells/ m3 . Serum IgG concentration was monitored prior to CAR-T and approximately one month after, with infusion of immunoglobulin (400 mg/kg IV) for IgG concentration < 400 mg/dL
  • Included 55 patients with a mean age of 62 years, the majority with IgG-kappa MM (53%), and a median time from diagnosis to CAR-T of 6.8 years (0.6-14.3) after receiving a median of 6 (1-3) prior treatment regimens. Prior treatments included stem cell transplant (89%) and prior McAb (89%) treatment. Within 30 days prior to CAR-T infusion, 24% had an infection and 42% of patients had a serum IgG < 300 prior to LDC. Patients were treated with one of four different BCMA CAR-T products, JCARH125, BB2121, BB21217, or JNJ4528.
  • At median follow-up of 6.0 months there were 47 infection events in 29 patients, with an expected 1.4 infections per patient at 12 months if they remained free of progression or death. Infections were mostly viral (53%) and low severity. Bacterial infections made up 40% of events and fungal 3%. Of the total events, 13% were mild, 79% moderate, 6% severe, and 1% fatal (due to Aspergillus). Median time to onset of infection was 3.9 months, with 53% of events occurring in the first 100 days after CAR-T therapy.
  • No risk factors were identified to have a statistically significant association with incidence of infection. Risk factors that trended towards increased infection risk included > 3 prior lines of therapy, use of bridging chemotherapy, and infection 30 days prior to CAR-T therapy. Tocilizumab use and total dose, dexamethasone use and total dose, and maximum grade CRS or neurotoxicity were not significantly associated with developing high severity infections. Development of infection was not associated with mortality risk when assessed with univariate Cox regression.
  • Despite risk factors for severe immunosuppression, relatively few life-threatening or severe infections occurred, but further larger studies are needed to better characterize the risk factors for and occurrence of infections after BCMA CAR-T.

*Abou-Ismail MY, Fraser R, Allbee-Johnson M, et al. Does recipient body mass index inform donor selection for allogeneic haematopoietic cell transplantation?. Br J Haematol. 2022;197(3):326-338. https://pubmed.ncbi.nlm.nih.gov/35286719/

  • Retrospective CIBMTR study examining the effect of obesity (pre-HCT BMI > 30) on outcomes in adult patients who received alloHCT: haplo (n = 2894), cord (n = 1487) vs MUD (n = 11,801)
  • There were significant differences in baseline characteristics between the two arms, including a high amount of peripheral blood source stem cells in the MUD group compared to haplo group (86% vs 66%; p<0.01). There was also a higher incidence of MAC conditioning in the MUD and 10 cord arms (51% and 49%, respectively) compared to haplo (39%), whereas haplos had more NMA (32%) compared to MUD (14%) and cord (18%); p<0.01.
  • Multivariate analysis showed significant, but non-linear interaction between pre-HCT BMI and donor groups for NRM (p < 0.0001), DFS (p = 0.0002) and OS (p = 0.0002), but not for disease relapse. There was a significantly increased NRM with cords compared to haplos with a BMI of 25-30 (HR 1.66-1.71; p<0.05) as well as with MUDs at a BMI of 25-45 (HR 1.61 – 3.47; p<0.05).
  • Authors concluded that NRM and OS are worse in overweight and obese HCT recipients (BMI ≥ 25), although obesity does not appear to confer a uniform differential mortality risk with one donor group over the other. If matched sibling donor is not available, study supports using BMI in donor selection process for MUD, haplo, and cord.

Abbreviations:

alloHCT: allogeneic hematopoietic cell transplant

AE: adverse events

ALL: acute lymphoblastic leukemia

AML: acute myeloid leukemia

ANC: absolute neutrophil count

ATG: antithymocyte globulin

AUC: area under the curve

autoHCT: autologous hematopoietic cell transplant

Axi-cel: axicabtagene ciloleucel

beti-cel: betibeglogene autoemcel

BCA: B-cell antigen

BCMA: B-cell maturation antigen-directed

BMI: body mass index

BMT: bone marrow transplant

CAR-T: chimeric antigen receptor T-cell

CBU: cord blood unit

CIR: cumulative incidence of relapse

cGVHD: chronic GVHD

CML: chronic myeloid leukemia

CRS: cytokine release syndrome

CSA/MTX: cyclosporine/methotrexate

DFS: disease-free survival

EBMT: European Society for Blood and Marrow Transplantation

EFS: event free survival

GI: gastrointestinal

G-CSF: granulocyte colony-stimulating factor

GRFS: graft-versus-host-disease-free, relapse-free survival

GVHD: graft-versus-host disease

Haplo: haploidentical

HCT: hematopoietic cell transplant

HR: hazard ratio

IgG: immunoglobulin G

KPS: Karnofsky performance status

LDC: lymphodepleting chemotherapy

LFS: leukemia-free survival

MAC: myeloablative conditioning

MM: multiple myeloma

MDS: myelodysplastic syndrome

MRD: matched related donor

MUD: matched unrelated donor

NRM: non-relapse mortality

RIC: reduced-intensity conditioning

OS: overall survival

PBSC: peripheral blood stem cell

PCP: Pneumocystis jirovenci pneumonia 

PTCy: post-transplant cyclophosphamide

TBI: total body irradiation

Tisa-cel: Tisagenlecleucel

T-PLL: T cell prolymphocytic leukemia

VOD: veno-occlusive disease

VZV: varicella zoster virus

ASTCT Pharmacy SIG Research Working Committee:

Arpita Gandhi, Jonathan Ptachcinski, Andrew Lin, Katie Gatwood, Jennifer Collins, Jitesh Kawedia, Dennis Marjoncu, Julianna Roddy, Lily Yan, Thomas Hughes, Sorana Ursu, Haval Normal, Kaily Kurzweil

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