Pharmacy SIG Literature Update: Impact of anti-T-lymphocyte globulin dosing on GVHD in MUD SC

In this month’s Pharmacy SIG Literature Update: Impact of anti-T-lymphocyte globulin dosing on GVHD in MUD SCT, impact of MRD status before alloHCT on outcomes in secondary AML, low-dose post- transplant cyclophosphamide with low-dose antithymocyte globulin for prevention of GVHD in MUD SCT 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

*Ho M, Moscvin M, Low SK, et al. Risk factors for the development of orthostatic hypotension during autologous stem cell transplant in patients with multiple myeloma. Leuk Lymphoma 2022; 63(10):2403- 2412. https://doi.org/10.1080/10428194.2022.2084729

  • Single-center, retrospective analysis of 171 MM patients admitted between June 2012 and April 2014 for first ASCT to identify the incidence, time of onset, risk and protective factors, and prognostic implications of orthostatic hypotension (OH) in the peri-transplant period following ASCT
  • All patients had orthostatic vital signs routinely checked three times per week and patients who developed orthostatic presyncope/syncope also had orthostatic vital sign check as clinically indicated
  • Notable baseline demographic characteristics included a median age of 60 years (range 23-74), 48% female, 91% Caucasian race, 77% with baseline peripheral neuropathy, 26% receiving gabapentin therapy, 11% with DM, and 46% on at least one antihypertensive medication
  • A total of 110 patients (64%) developed OH during the course of admission with 29% having symptomatic OH. The median time to OH onset was 7 days (95% CI; 5.5, 8.5). The development of OH did not impact the median time to discharge and did not have an impact on the overall OS or PFS
  • The multivariable analysis found that > 0.5% weight loss/day (RR: 2.7; 95% CI: 1.1, 7; p = 0.038), white race (RR: 5.9; 95% CI: 1.3, 26.5; p = 0.023), treatment with gabapentin (RR: 4.5; 95% CI:1.5, 13.2; p = 0.006), and therapy with at least one antihypertensive medication (RR: 3.1; 95% CI: 1.3, 7.4; p = 0.012) significantly increased the risk of developing peri-transplant OH
  • This trial confirmed the results of other trials that demonstrated a substantial incidence of symptomatic hypotension in MM patients in the peri-transplant period following ASCT. The trial also demonstrated the importance of fluid management, monitoring concomitant medication use and the need to closely monitor for OH during the peri-transplant period

*Porrata LF, Inwards DJ, Ansell SM, et al. Impact of autograft-absolute lymphocyte count on survival in double/triple hit lymphomas post-autologous stem cell transplantation. Leuk Lymphoma 2022; https://doi.org/10.1080/10428194.2022.2064988

  • Single-center, retrospective analysis of autograft-absolute lymphocyte count (A-ALC) as a prognostic factor for OS and PFS in double/triple hit (DHL/THL) lymphoma patients undergoing autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT)
  • A prior phase 3 study from this center (Mayo Clinic) demonstrated A-ALC as a prognostic factor for lymphoma patients undergoing APBHSCT but did not evaluate outcomes in DHL/THL patients
  • The patient population consisted of 77 adults with DHL/THL who received APBHSCT between January 2012 and December 2020 following a BEAM (carmustine, etoposide, cytarabine, melphalan) conditioning regimen. An A-ALC cell infusion containing 0.5 x 109 cells/kg was chosen as a cutoff to evaluate for prognosis. Numerous other relevant prognostic factors were also evaluated. There were 40 patients that received cell infusions with an A-ALC > 0.5 x 109 cells/kg and 37 patients with cell infusions with an A-ALC < 0.5 x 109 cells/kg. The two study groups were balanced except for LDH and IPI which were statistically higher in the low A-ALC group.
  • In a multivariate analysis, A-ALC > 0.5 x 109 cells/kg and being transplanted in CR1 versus CR/PR from second-line therapy were identified as independent predictors for OS and PFS. The 5-year OS rates for the A-ALC > 0.5 x 109 cells/kg group was 73% (95% CI: 52-87%) versus 18% (95% CI: 7-39%) for the A-ALC group < 0.5 x 109 cells/kg group. The 5-year PFS for the A-ALC > 0.5 x 109 cells/kg group was 73% (95% CI: 59-85%) and for the A-ALC group < 0.5 x 109 cells/kg group was 13% (95% CI: 5-33%). In a combined analysis of categorical groups, the patients in the high A- ALC group transplanted in CR1 had the best prognosis for OS and PFS and patients in the low A- ALC group transplanted in CR/PR after second-line therapy had the worse prognosis for OS and PFS.
  • This retrospective analysis was a confirmatory study of the role of A-ALC on OS and PFS prognosis following APBHSCT in the DHL/THL population. External validity of the results are limited by retrospective study design, small patient population and imbalance in LDH and IPI in the two study populations.

*Puckrin R, Chua N, Shafey M and Stewart DA. Improving the outcomes of secondary CNS lymphoma with high-dose thiotepa, busulfan, melphalan, rituximab conditioning and autotransplant. Leuk Lymphoma 2022; 63(10):2444-2452. https://doi.org/10.1080/10428194.2022.2068005

  • Retrospective, multicenter study included 62 consecutive patients > 18 years old with aggressive large B cell lymphoma (LBCL) and secondary central nervous system lymphoma (SCNSL) intended for transplant with high-dose methotrexate (HD-MTX)-based induction followed by high-dose thiotepa, busulfan, melphalan, rituximab (TBMR) conditioning and ASCT between 2011 and 2020
  • Patients with chemosensitive disease proceeded to high-dose TBMR conditioning (rituximab 375 mg/m2 IV on day -7, 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 IV on day -1 and autologous PBSC infusion
  • Median age was 58 years (range 20–75) and 52 (84%) patients had ECOG performance status >1 at diagnosis of SCNSL. Fifty-two (84%) patients completed induction and proceeded to TBMR/ ASCT.  At median follow-up  of 5.7 years, 5-year progression-free and overall survival rates for 62 patients intended for transplant were 53% (95% CI 39–65%) and 65% (95% CI 51–76%) and 62% (95% CI 45–74%) and 73% (95% CI 57–84%) for the 52 patients who underwent TBMR/ASCT, respectively
  • Nearly all patients who underwent TBMR/ASCT developed expected toxicities of HDT including pancytopenia, nausea, mucositis, and febrile neutropenia. There were no cases of hepatic sinusoidal obstruction syndrome. There were 3 treatment-related death (peri-transplant infections (n = 2) and therapy-related AML occurring 1.5 years after TBMR/ASCT (n = 1)). Among the 40 long-term survivors of TBMR/ASCT, most recovered without neurologic sequela and there were no cases of progressive or severe neurotoxicity or dementia
  • In conclusion, despite a historically poor prognosis, HD-MTX-based induction followed by TBMR/ASCT has the potential to achieve long-term survival in a substantial proportion of patients with SCNSL

*Gertz MA, Warsame R, Muchtar E et al. Lack of a caregiver is associated with shorter survival in myeloma patients undergoing autologous stem cell transplantation. Leuk Lymphoma 2022; 63(10):2422- 2427. https://doi.org/10.1080/10428194.2022.2074993

  • Single institute retrospective study to determine whether lack of caregiver is associated with poor outcomes in myeloma patients undergoing ASCT. Inability to provide caregiver during transplant was used as a surrogate for lack of a robust social network, inadequate family support or social isolation
  • Study included patients with MM undergoing ASCT from 1/1/2000 – 12/31/2009. There were 2103 patients who received outpatient transplant had support of full-time caregiver or chaperone while 41 patients received inpatient transplant due to lack of caregiver
  • The median OS of those transplanted inpatient was 57.8 months compared to 95.3 months for those patients transplanted as an outpatient (p = 0.0008). Progression free survival was not different between the 2 groups and the curves did not diverge until approximately one year following SCT. The discrepancy between PFS and OS suggests a continued impact of lack of caregivers well beyond transplantation
  • In conclusion, patients who are unable to have a caregiver chaperone them through an outpatient stem cell transplant for multiple myeloma have shortened survival unrelated to the biology of the myeloma

*Savage KJ, Horwitz SM, Advani R, et al. Role of stem cell transplant in CD30+ PTCL following frontline brentuximab vedotin plus CHP or CHOP in ECHELON-2. Blood Adv. 2022 Oct 11;6(19):5550-5555. doi: 10.1182/bloodadvances.2020003971. https://pubmed.ncbi.nlm.nih.gov/35470385/

  • Exploratory sub-analysis of 38 consolidative SCT (36 autologous, 2 allogeneic) within the double- dummy, placebo-controlled, active-comparator ECHELON-2 study for patients in CR after frontline PTCL; median PFS follow-up was 47.57 months (95% CI, 41.89-48.16)
  • Across all patients who achieved CR following A+CHP (114/177, 64%), those undergoing SCT had lower risk of PFS events with HR 0.36 (95% CI, 0.17-0.77). Estimated 3-year PFS in patients who underwent SCT was 80.4% vs 54.9% in patients who did not and at 5 years estimated PFS was 65.3% vs 46.4% respectively
  • Of the patients on the CHOP arm (99/177), there was a nonsignificant trend favoring consolidative SCT vs those who did not: HR, 0.63 (95% CI, 0.32-1.24). The estimated 3-year PFS in those who had SCT was 67.2% vs 54.1% in patients who did not and at 5 years the estimated PFS was 48.9% vs 50.9%, respectively
  • Among those for whom positive intent to transplant was indicated, patients who underwent SCT had no difference in adverse event profile vs those who did not undergo SCT
  • Authors concluded that the analysis suggests that consolidative SCT should still be considered even with superior frontline therapy using A+CHP in CD30+ PTCL patients, although the utility of consolidative SCT remains unanswered

Allogeneic stem cell transplantation

*Biavasco F, Ihorst G, Wasch R, et al. Therapy response of glucocorticoid-refractory acute GVHD of the lower intestinal tract. Bone Marrow Transplant. 2022; 57(10):1500-1506. https://pubmed.ncbi.nlm.nih.gov/35768570/

  • Cross-sectional single-center cohort analysis of 144 adults who developed GI GVHD. There was a higher number of males (62.5%) and a median age of 59 years. 63% of patients received a HCT for acute leukemia
  • The most common type of donor was a MUD (45.1%), followed by MRD (25.7%) and MMUD (19.9%). Haploidentical HCT accounted for 9.7%
  • 59% of patients had severe (grade III-IV) GI GVHD at onset, and 8.3% of patients developed severe GI GVHD during the course
  • 82 patients (57%) were found to have steroid-refractory (SR) GI GVHD. Of these, 77 patients received a second-line therapy, most commonly ruxolitinib (74%), followed by extracorporeal photopheresis (6.5%), and everolimus (6.5%)
  • Of those receiving second-line therapy, 59.8% achieved a response, with 27 (35.1%) having a CR. In ruxolitinib specifically, the OR rate was 64.9% with a CR rate of 38.6%
  • Response rates decreased with each subsequent line, with CR rates for third and fourth line of 25.8% and 25%, respectively. No patient had a CR after fifth-line therapy
  • OS was higher in patients with steroid-sensitive GVHD compared to SR-GVHD. The median OS in the steroid-sensitive group was not reached, and the median OS in the SR-GVHD group was 11.9 months (p=0.016). Patients who had a CR at day 28 had a higher OS than those who did not (median OS not reached vs 42.6 months for PR and 8.2 months for non-responders; p=0.04)

*Nagler A, Labopin M, Cornelissen JJ, et al. Outcome of human umbilical cord blood stem cell transplantation (CBT) for acute myeloid leukemia in patients achieving first complete remission after one versus two induction courses: A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2022; 57(10):1514- 1519. https://pubmed.ncbi.nlm.nih.gov/35773347/

  • Retrospective, multi-center comparison of patients receiving a cord blood transplant in CR1 after first induction (1I; N=243) or second induction (2I; N=82)
  • There was no difference in conditioning between the two arms, with most patients receiving MAC (43% in 1I and 37% in 2I; p=0.31). The most common conditioning was fludarabine/busulfan (31% in 1I and 18% in 2I; p=0.086). 62% in 1I and 76% in 2I received TBI (p=0.086)
  • The most common GVHD prophylaxis was CSA and MMF (76% in 1I and 83% in 2I)
  • Grades II-IV aGVHD at day 180 was similar in both the 1I and 2I groups (38% and 36%, respectively; p=0.81) as well as grades III-IV aGVHD (12% and 9%, respectively; p=0.41). cGVHD at 2-years was 23% in 1I and 27% in 2I (p=0.65)
  • On both univariate and multivariate analysis, there was no difference in NRM, relapse rate, OS, and GRFS between the two groups

*Massoud R, Klyuchnikov E, Gagelmann N, et al. Impact of anti-T-lymphocyte globulin dosing on GVHD and immune reconstitution in matched unrelated myeloablative peripheral blood SCT. Bone Marrow Transplant. 2022; 57(10):1548-1555. https://pubmed.ncbi.nlm.nih.gov/35831408/

  • Retrospective, single-center review comparing 30 mg/kg of ATG (ATG-30; N=73) and 60 mg/kg of ATG (ATG-60; N=216)
  • No difference in baseline characteristics between arms except for a higher median donor age in the ATG-60 group (32 vs 26; p=0.022) and more patients receiving CNI plus MMF in the ATG-60 group (94% vs 85%; p=0.044) compared to ATG-30 group. More patients in the ATG-60 group had CR (85% vs 67%) but less patients in the ATG-60 group had progressive disease (6% vs 24%; p=0.001)
  • The median time to neutrophil engraftment was higher in the ATG-60 group (12 vs 11 days; p=0.009). The median time to platelet engraftment was also higher in the ATG-60 group compared to ATG-30 (16 vs 14 days; p=0.002)
  • There was a higher cumulative incidence of infections before day 100 in the ATG-60 group (75% vs 67%; p=0.002), with a higher incidence of EBV reactivation in this arm as well (41% vs 21%; p=0.049). Incidence of CMV reactivation or infection-related mortality was similar between the two groups
  • Grade IV aGVHD was higher with ATG-30 compared to ATG-60 (8% vs 0.5%; p=0.0002). On univariate analysis, there was no difference in any grade cGVHD between the two groups
  • There was no difference in OS, PFS, or NRM between the two groups. On multivariate analysis, negative recipient CMV serology, female donor, SCT chronology > 1, and active disease at time of HCT were associated with decreased DFS whereas older age, female donor, and negative recipient CMV serology were associated with worse NRM
  • There was a faster reconstitution of naïve B-cells and gamma-T cells at Day +30 with ATG-30 (p=0.045), but values at Day +100 and +180 were comparable between groups. Reconstitution of naïve helper T-cell, NK-cell, and naïve B-cells at day +180 was also faster with ATG-30 (p<0.0001)

**Maffini E, Labopin M, Beelen DW, et al. Measurable residual disease (MRD) status before allogeneic hematopoietic cell transplantation impact on secondary acute myeloid leukemia outcome. A study from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2022; 57(10):1556-1563. https://pubmed.ncbi.nlm.nih.gov/35835997/

  • Multicenter, retrospective analysis of 318 adults with secondary AML (sAML) who received alloHCT in CR1. At the time of HCT, 208 (65%) were MRD-negative (MRD(-)) and 110 (35%) were MRD(+). Baseline characteristics were similar between arms with most patients receiving unrelated donor transplants, peripheral blood stem cells, and RIC
  • There was a trend towards worse survival in those with adverse risk cytogenetics (LFS: HR 1.7; p=0.029) and increased age (OS: HR 1.27; p=0.009)
  • There were no differences in NRM, relapse rates, LFS, GRFS, or OS between patients who were MRD(+) and MRD(-)
  • Grafts from unrelated donors had increased toxicities, which was reflected in the NRM (HR 2.51; p=0.02). Adverse cytogenetics and KPS <90 were associated with decreased LFS. Relapse rates were increased with KPS <90 and AML secondary to MDS vs AML secondary to other causes

**Zu Y, Li Z, Gui R, et al. Low-dose post-transplant cyclophosphamide with low-dose antithymocyte globulin for prevention of graft-versus-host disease in first complete remission undergoing 10/10 HLA- matched unrelated donor peripheral blood stem cell transplants: A multicenter, randomized controlled trial. Bone Marrow Transplant. 2022; 57(10):1573-1580. https://pubmed.ncbi.nlm.nih.gov/35840747/

  • Multicenter, randomized trial evaluating 104 patients with hematologic malignancies who received 10/10 MUD-PBSCT in CR1
    • Randomized to low-dose PTCy 20 mg/kg on days +3 and +4 and low-dose ATG 6 mg/kg (N=53) or standard dose ATG 10 mg/kg (N=51) alone.
  • Conditioning consisted of fludarabine, busulfan, cytarabine ± TBI for those with lymphoid malignancies. All patients received CSA and MMF, and standard dose group also received MTX. All patients received G-CSF starting on day +5
  • Median time to neutrophil engraftment (12 vs 13 days; p=0.001) and median time to platelet engraftment (12 vs 14 days; p=0.002) was shorter with low-dose compared to standard dose, respectively. There was no difference in chimerism at day +30 between the two arms (98.1% vs 94.1%; p=0.289)
  • The 2-year cumulative incidence of relapse and median time to relapse were similar between low-dose and standard dose. NRM at 2 years was lower with low-dose (13.2% vs 34.5%; p=0.049)
  • The 2-year OS (79.1% vs 63.6%; p=0.142) and DFS (77% vs 61.6%; p=0.236) were similar between low-dose and standard-dose whereas 2-year GRFS was higher with low-dose (67.3% vs 42.3%; p=0.032)
  • The 100-day cumulative incidence of grade II-IV aGVHD was lower in the low-dose group (24.5% vs 47.1%; p=0.017). There was no difference in grades III-IV aGVHD and no late onset aGVHD. The 2-year incidence of cGVHD was lower in the low-dose group (14.1% vs 33.3%; p=0.013), although there was no difference in rates of severe cGVHD between the groups
  • CMV reactivation was similar between groups. 2-year EBV reactivation (15.1% vs 60.8%; p=0.000) and incidence of pulmonary infections (35.8% vs 58.5%; p=0.019) were lower in the low-dose group compared to standard-dose, respectively

**Winters AC, Bosma G, Abbott D, et al. Outcomes are similar after allogeneic hematopoietic stem cell transplant for newly diagnosed acute myeloid leukemia patients who received venetoclax + azacitidine versus intensive chemotherapy. Transplant Cell Ther. 2022;28(10):694.e1-694.e9. https://pubmed.ncbi.nlm.nih.gov/35902048/

  • Retrospective, single-institution analysis of 169 patients with AML between 2010-2020 receiving SCT in CR1 after IC or venetoclax/azacitidine (ven/aza)
  • Of patients assessed, 140 received IC and 29 aza/ven. Cohorts differed in age (55.5 yr IC vs 65 yr ven/aza), the ven/aza group was more likely to be in a MLFS at SCT, less likely to receive MAC conditioning, and more patients in the ven/aza group received post-SCT maintenance
  • At median follow up (24.6 mo IC vs 14.3 mo ven/aza), there was no difference in RFS (66.1% IC vs 73.2% ven/aza) or OS (74.7% IC vs 76.3% ven/aza) at 12 months. GRFS did not differ significantly between groups and cumulative incidences of relapse, transplantation-related mortality, grade 2-4 aGVHD, and any cGVHD were comparable between cohorts
  • Similar survival outcomes were observed when cohorts were separately compared for age 65 years and older as well as age less than 65 years. Pre-SCT minimal residual disease was predictive of post-SCT outcomes in the IC group, but not the ven/aza group
  • Authors felt their findings in addition to existing data support the consideration of ven/aza as remission induction therapy in adult AML patients proceeding to allo-SCT, including non-elderly and “fit” patients

**Mehta RS, Saliba RM, Rondon G, et al. Post-transplantation cyclophosphamide versus tacrolimus and methotrexate graft-versus-host disease prophylaxis for HLA-matched donor transplantation. Transplant Cell Ther. 2022;28(10):685.e1-695.e10. https://pubmed.ncbi.nlm.nih.gov/35902049/

  • Retrospective, single-center study of adults who underwent first SCT with MSD or MUD and received PTCy-based or Tac/MTX-based GVHD prophylaxis. The Tac/MTX group in the MUD cohort also received ATG
  • MUD cohort: Of 552 patients, 306 in Tac/MTX/ATG group and 246 in PTCy group. Cohorts differed in age (54 yr in Tac/MTX/ATG vs 61 yr in PTCy, p<.001), number of myeloid malignancies (59% Tac/MTX/ATG vs 90% PTCy, p<.001), and PBSC graft (64% Tac/MTX/ATG vs 77% PTCy, p=.001). Groups were otherwise similar
    • Grade II-IV aGVHD at day 180 differed at 42% Tac/MTX/ATG vs 52% PTCy (p=.03) but was similar for grade III-IV aGVHD and SR/SD-aGVHD. The 3-year CI of cGVHD and systemic therapy-requiring cGVHD were similar
    • NRM at 3-yr was 23% in Tac/MTX/ATG vs 13% in PTCy (p=.002), but rate of relapse was similar. PFS (48% vs 57%, p=.01), OS (55% vs 61%, p=.05), and GRFS (37% vs 47%, p=.01) at 3 years were all lower in the Tac/MTX/ATG group compared to the PTCy group, respectively. Infection was leading cause of NRM in both groups, and deaths related to acute or chronic GVHD accounted for 20% of NRM deaths in the Tac/MTX/ATG group versus 40% in PTCy group
    • Significantly lower incidence of bacterial infections in the Tac/MTX/ATG group (44%) than the PTCy group (53%) (p=.01), but higher incidence of viral infections (59% vs 46%, respectively; p<.001)
  • MSD cohort: Of 412 patients, 272 received Tac/MTX and 140 received PTCy. Cohorts differed in age (54 yr Tac/MTX vs 60 yr PTCy, p<.001), number of myeloid malignancies (64% Tac/MTX vs 85% PTCy, p<.001), and MAC conditioning (63% Tac/MTX vs 74% PTCy, p=.02). Almost all patients received PBSC and groups were similar in baseline DRI and HCT-CI.
    • Grade II-IV aGVHD, grade III-IV aGVHD and SR/SD-aGVHD rates were similar between groups. The 3-year CI of cGVHD (37% vs 19%, p<.001) and systemic therapy-requiring cGVHD (29% vs 10%, p<.001) was significantly higher in the Tac/MTX group compared to the PTCy group
    • NRM and rate of relapse was similar between groups. PFS (54% vs 57%, p=.3) and OS (61% vs 65%, p=.2) were similar between Tac/MTX versus PTCY, respectively, but differed in GRFS (29% vs 47%, p<.001). GVHD contributed to over half of NRM in Tac/MTX group (34% acute, 17% chronic) and was less in the PTCy group (31% acute). Infections were 26% of NRM in the Tac/MTX group and 31% in the PTCY group
    • Significantly lower incidence of bacterial infections in the Tac/MTX group (40%) than the PTCy group (54%) (p=.005), and viral and fungal infections were similar
  • Authors concluded their data support the use of PTCy-based GVHD prophylaxis in both MSD (versus Tac/MTX) and MUD (versus Tac/MTX/ATG). PTCy was associated with a lower risk of viral infections, viral infection-related deaths, lower NRM, better PFS and GRFS in the MUD cohort, and lower risk of therapy-requiring cGVHD, lower NRM (in those without F-to-M), and improved GRFS in the MSD cohort

*Ruggeri A, Galimard JE, Labopin M, et al. Comparison of outcomes after unrelated double-unit cord blood and haploidentical peripheral blood stem cell transplantation in adults with acute myeloid leukemia. Transplant Cell Ther. 2022;28(10):710.e1-710.e10. https://pubmed.ncbi.nlm.nih.gov/35830930/

  • Multicenter, retrospective review of adults with de novo AML who underwent allo-SCT while in CR1 or CR2 and received double-unit unrelated UCB or related haploidentical PBSCs. All patients undergoing haplo-SCT received PTCy as GVHD prophylaxis in combination with CNIs and MMF
  • A total of 709 patients underwent Haplo-PTCy (n=544) or dUCBT (n=165). Median duration of follow-up was shorter in the Haplo-PTCY group (2.5 yr vs 4.3 mo, p<.001), Haplo-PTCy transplantations were performed more recently (p<.001), Haplo-PTCy recipients more often had a positive CMV serology (p=.003) and were more likely to receive MAC conditioning (p<.001). RIC regimens were used more frequently in the dUCBT group (74% vs 16%)
  • The 2-year probability of LFS (59% Haplo-PTCY vs 56% dUCBT) and OS (64% Haplo-PTCY vs 59% dUCBT) was not significantly different between groups. Infection and GVHD were the most common causes of SCT-related death in both groups. Risk of relapse was not statistically different between treatment groups, but risk was increased with poor cytogenetics. NRM was not different between groups, but weas higher in patients in CR2 and an older age at time of transplant
  • The CI of day 60 neutrophil engraftment and day 180 platelet engraftment was similar between groups with longer time to engraftment of both cell lines in the dUCBT group. More patients in the Haplo-PTCy group (n=25) experienced graft failure than the dUCBT group (n=9), and of these 23 died within 90 days post HCT
  • MVA showed no significant differences between groups in grade II-IV aGVHD (HR, 1.31; p=.18) and grade III-IV aGVHD (HR, 1.17; p=.56). In MVA for cGVHD at 2 years, there was not a significant difference in risk between groups (HR, 0.86; p=.48)
  • In conclusion, with the accumulating experience and longer follow-up data, PTCy-based haploidentical donor PBSC transplantation is now considered a valid option for transplantation- eligible patients without an available HLA-matched donor. Compared with dUCBT, Haplo-PTCY using PBSCs showed similar outcomes in adult AML patients in remission

Infectious Diseases

**Kimura M, Ferreira VH, Kothari S, et al. Safety and immunogenicity after a three-dose SARS-CoV-2 vaccine schedule in allogeneic stem cell transplant recipients. Transplant Cell Ther. 2022;28(10):p706.e1- 706.e7. https://pubmed.ncbi.nlm.nih.gov/35914727/

  • Prospective, single-center study of 122 allo-SCT recipients who received a 3-dose schedule of SARS-CoV-2 vaccine to assess cell-mediated and humoral immunogenicity
  • Of 122 patients, 72 (60.7%) received 3 doses of SARS-CoV-2, 66 (54.1%) were in their first year post-SCT, and 58 (47.5%) were on IMS at enrollment. The majority of patients had a MUD SCT (44.3%), followed by MRD SCT (27.9%) and haplo-SCT (24.6%). Median intervals between transplantation date and date of first, second, and third dose were 185 days (IQR = 115-524), 249 days (IQR = 160-681), and 459 days (IQR = 294-883)
  • Of 95 patients included in immunogenicity analysis, 64 received a third vaccine dose. The median antibody titer after the third dose was significantly higher than the first and second dose (P<.0001). A positive response was observed in 57 (89.1%) patients and immunogenicity was suboptimal in 12 (18.8%) patients. Chronic kidney disease (p=.04), haplo-SCT (p=.01), and median lymphocyte count (p=.03) at third dose were all significantly associated with suboptimal antibody response after third vaccine dose
  • Most patients experienced local tenderness (>60%) and fatigue (≥ 14%) and there were no grade 4 adverse events apart from one patient who developed Guillan-Barre syndrome. There were 23 episodes (23/301 doses, 7.6%) of new-onset or worsening GVHD in 22 patients, and only 4 of these episodes occurred after the third dose. Seven patients developed SARS-CoV-2, 6 were after the third vaccine dose, and none required hospitalization
  • In conclusion, the 3-dose SARS-CoV-2 vaccine schedule provided immunity associated with a low risk of GVHD and other adverse effects. This prospective cohort showed that the third dose of SARS-CoV-2 vaccine in allo-SCT recipients promoted better humoral and cellar immune responses than after the initial series without increasing the risk of GVHD or severe adverse effects

Pediatric stem cell transplantation

  • Untreated donor-specific HLA antibodies are associated with graft failure and poor survival after haploidentical transplantation with post-transplantation cyclophosphamide in pediatric patients with nonmalignant disorders. Transplant Cell Ther 2022;28:698.e1-698.e11. PMID: 35882362
    • Donor specific antibodies (DSAs) are a known risk factor for graft failure in adult patients undergoing haplo-SCT with PTCy GVHD prophylaxis however their role in pediatric haplo-SCT for non-malignant disorders is not well understood
    • This was a retrospective evaluation of 59 pediatric (age </= 21) patients who received haplo-SCT with GVHD prophylaxis consisting of PTCy along with CSA and MTX for a non-malignant disorder. The primary endpoints were neutrophil and platelet engraftment and graft failure. Secondary endpoints included event-free survival (EFS) and overall survival (OS)
    • All patients received a marrow product and the majority (91.5%) received fludarabine-based conditioning. The two most common transplant indications were Fanconi anemia (n=33) and aplastic anemia (n=11). Eleven patients had true positive DSAs (mean fluorescence intensity > 1000), 4 of whom received desensitization therapy with rituximab x 1 dose and plasmapheresis x 3 sessions.  The remaining 7 received no therapy
    • All patients with treated DSAs achieved donor engraftment. In a multivariate analysis, untreated DSAs were associated with a significant increase in lower incidence of neutrophil recovery (SHR 0.15; 95% CI 0.03-0.63, P=.001) increased likelihood of graft failure (Sub- distribution HR 20.57; 95% CI 6.57-64.43, P<.001), inferior EFS (HR 10.09; 95% CI 3.37-30.22, P<.001), and inferior OS (HR 5.56; 95% CI 1.92-16.12, P=.002)
    • Positivity for DSAs predicted adverse OS prior to day +365 whether or not those DSAs had been treated
    • Authors conclude that presence of DSAs is an independent predictor for poor outcomes following haplo-SCT with PTCy for non-malignant disorders.  Further, DSA-positive donors should be avoided. However, if this is not possible, desensitization therapy should be utilized to increase the likelihood of favorable patient outcomes


A-CHP: brentuximab, cyclophosphamide, doxorubicin, and prednisone

ICANS: immune effector cell-associated neurotoxicity syndrome

AE: adverse events

IMS: immunosuppression

Axi-cel: axicabtagene ciloleucel

MAC: myeloablative chemotherapy

alloHCT: allogeneic hematopoietic cell transplant

MDS: myelodysplastic syndrome

aGVHD: acute graft versus host disease

MLFS: morphologic leukemia-free state

ALL: acute lymphoblastic leukemia

MM: multiple myeloma

AML: acute myeloid leukemia

MMF: mycophenolate mofetil

ASCT: autologous stem cell

MMUD: mismatched unrelated donor

ATG: anti-thymocyte globulin

MRD: matched related donor

cGVHD: chronic graft versus host disease

MSD: matched sibling donor

CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone

MUD: matched unrelated donor

CMV: cytomegalovirus

MTX: methotrexate

CNI: calcineurin inhibitor

NMA: non-myeloablative

CNS: central nervous system

NRM: non-relapse mortality

CR: complete response

ORR: overall response rate

CRS: cytokine release syndrome

OS: overall survival

CSA: cyclosporine

PBSC: peripheral blood stem cell

DOR: duration of response

PFS: progression-free survival

DRI: disease risk index

PTCy: post-transplant cyclophosphamide

dUCB: double UCB

PTCL: peripheral T-cell lymphoma

ECOG: Eastern Cooperative Oncology Group

RFS: relapse-free survival

EFS: event free survival

RI: relapse incidence

GRFS: GVHD-free relapse-free survival

RIC: reduced intensity conditioning

Haplo: haploidentical

SCT: stem cell transplant

HCT: hematopoietic cell transplant

TAC: tacrolimus

HCT-CI: hematopoietic stem cell transplantation comorbidity index

UCB: unit cord blood

HLA: human leukocyte antigen

URD: unrelated donor

IC: intensive chemotherapy


GVHD: graft-versus-host disease



ASTCT Pharmacy SIG Research Working Committee:

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

Tags: SIG update, SIG, MRD, myeloma, AlloHCT, GVHD, transplantation, Cellular therapy, Survival, hematopoietic, clinical, Clinical Research, researchers, Autologous, allogeneic stem cell transplantation, graft-versus-host

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