Introduction: Due to the graft versus tumor effect allogeneic stem cell transplantation (allo-SCT) is a curative strategy for hematological malignancies. However, its benefits are offset by ...non-related mortality (NRM) primarily from graft-versus-host-disease (GVHD). In vivo T-cell depletion (TCD) with Anti-T-Lymphocyte globulin (ATLG) can reduce GVHD. Although lower ATLG doses may compromise the immunosuppression effects, higher ATLG doses may offset its benefit by decreasing antiviral and graft-versus-malignancy effect by depletion of donor effector T cells. Even though the use of ATLG in allo-SCT is well established, however, data on optimal ATLG dosing in the setting of matched sibling donor (MSD) -allo-SCT is scarce. Methods: In this retrospective study conducted at the Department of stem cell transplantation, University Medical Center Hamburg Eppendorf (UKE) we aim to compare the transplant outcomes between recipients of 15 mg/Kg vs 30 mg/Kg ATLG as T-cell depletion in Patients undergoing allo-SCT from MRD. Results: In the study, 109 sequential patients (ATLG 15, n=72; ATLG 30, n=37) underwent allo-SCT between the years 2018 and 2022 from MSD for hematological conditions. PBSC was the primary stem cell source in both cohorts (ATLG-15, 99%; ATLG-30, 92%; p=0.08). In the ATLG-15 group, 13% received TBI versus none in the ATLG-30 group (p=0.025). The MAC regimen was utilized in 65% of ATLG-15 patients, compared to 27% in ATLG-30 (p<0.001). The most prevalent disease was AML in ATLG-15 (54%) and PMF in ATLG-30 (54%, p<0.001). More ATLG-15 patients were transplanted in CR (43%) than in ATLG-30 (16%, p=0.02). All ATLG-15 patients had ECOG0-1 status, against 90% in ATLG-30 (p=0.007). The median age at transplant was similar, 58 and 56 years in ATLG-15 and ATLG-30, respectively (p=0.99). All other Patients donor and transplant characteristics were comparable between the two groups. One patient died prior to engraftment and three patients had primary graft failure in the ATLG-15 group, all remaining patients successfully engrafted. The ATLG-15 cohort showed an earlier leukocyte engraftment (median 11 days, range 9-19, p=0.001) and a tendency towards quicker platelet engraftment (median 12 days, range 8-107, p=0.06) compared to the other group's medians of 13 days (range 8-16) and 17 days (range 3-130), respectively. Grade II-IV aGVHD at day 100 was 36% in the ATLG-15 group compared to 23% in the ATLG-30 group (p=0.45). A trend towards lower 2-year moderate/severe cGVHD was observed in the ATLG-15 group (48% vs 36%, p=0.08). The ATLG-15 group showed a trend towards higher 2-year OS (84% vs 72%, p=0.06), however this trend disappeared on multivariate analysis (MVA) (HR 0.853 95%CI 0.319, 2.283; p=0.75) no other factor affected OS on MVA. The 2-year PFS was similar across both groups (ATLG-15, 63%; ATLG-30, 60%; p=0.5). On MVA only TBI had a significant effect on PFS (HR 0.310 95%CI, 0.101, 0.957, p=0.04), none of the other factors significantly affected PFS. There was a trend for Lower NRM in the ATLG-30 group (at 1 Yr, 0% vs 11%, p=0.09), while the two-year relapse incidences were comparable (ATLG-15, 7%; ATLG-30, 14%; p=0.2). Conclusion: Acknowledging the retrospective nature of our study, however our results show that a higher ATLG dose may reduce incidence of chronic GVHD in Patients undergoing allo-SCT from MSD, however our findings should be confirmed in larger prospective studies.
Background The discovery of prognostically informative mutations in patients with primary myelofibrosis (PMF) prompted the development of mutation-enhanced risk scores. Among these mutations, those ...in ASXL1 are invariably associated with adverse outcome, either as single variants or as part of a high-mutation-risk category (HMR) including SRSF2, EZH2, and IDH1/2. Furthermore, it was suggested that ASXL1 mutations show distinct outcomes in PMF and post polycythemia vera / essential thrombocythemia myelofibrosis (PPV/PET MF). Particularly, the ASXL1G646fs* variant was reported to have a strong adverse impact on survival, specifically in patients with PMF. For patients undergoing curative treatment with hematopoietic cell transplantation (HCT), ASXL1 mutations were associated with increased risk for post-transplant mortality and therefore included in transplant-specific risk stratification. However, results on outcomes of different variants have not been reported so far. Patients and Methods We here report characteristics and outcomes of 273 patients with PMF (n=169, 62%) and PPV/PET MF (n=104; 38%) who underwent first HCT. Patients were homogenously treated with reduced-intensity conditioning using busulfan-fludarabine and anti-T-lymphocyte globulin for graft-versus-host disease prophylaxis. Patient samples were collected prior to start of conditioning and analyzed using next-generation sequencing. Primary endpoint was post-transplant overall survival, secondary endpoints were non-relapse mortality and incidence of relapse. Results The median age at the time of HCT was 59 years (range, 29-75). 57% of patients were male and 43% were female, 62% tested positive for cytomegalovirus (CMV). DIPSS at time of HCT was low (1%), intermediate-1 (22%), intermediate-2 (55%), and high (22%). Transfusion-dependency at time of HCT was present in 54% of patients, 50% received Ruxolitinib prior to HCT. Fibrosis grade 2 or higher was detected in 85% of patients. In terms of driver mutation genotype, 10% of patients were triple negative 63% of patients tested positive for JAK2, 22% for CALR, and 6% for MPL. In the total cohort, 24% of patients had a detectable ASXL1 mutation (7% had ASXL1G646fs* and 3% ASXL1R634fs*). There was a significant difference in distribution of mutations according to type of MF, with 83% and 71% of patients with ASXL1G646fs* or ASXL1R634fs* having PMF, while 75% of patients with other ASXL1 mutations had PMF compared with 25% having PPV/PET MF (P=0.04) . ASXL1G646fs* was associated with a tendency towards higher absolute leukocyte counts and lower platelet counts at time of HCT compared with wild-type or other ASXL1 mutations (P=0.10 and 0.07). DIPSS categories did not differ significantly between ASXL1G646fs*, other ASXL1 mutations and wild-type (P=0.66). No difference in co-occurring driver mutations between the groups was detected (P=0.38). Notably, more patients with ASXL1G646fs* had co-occurring mutations in EZH2 (P=0.004) and RUNX1 (P=0.003). In terms of outcomes, ASXL1 mutations showed worse overall survival (P=0.01), with no difference between ASXL1G646fs* and other ASXL1 mutations (P=0.51). 5-year survival was 54% for ASXL1G646fs* 53% for ASXL1 and 74% for the wild-type group. Poorer survival was seen in both PMF and PPV/PET MF (P=0.002 and P=0.03, respectively). Patients with ASXL1G646fs* showed significantly higher rates of early relapse 1 year after HCT, with incidence of 22% compared with 17% for other ASXL1 mutations and 10% for the wild-type group (P<0.001; Figure). Multivariable modelling (including donor type, leukocyte and platelet counts, Karnofsky performance status, and age) confirmed similar outcomes for the ASXL1 groups but higher risk for death compared with wild-type configuration, with hazard ratios of 1.50 for ASXL1G646fs* and 1.62 for other ASXL1 mutations. ASXL1G646fs* was associated with significantly higher risk for relapse (hazard ratio, 1.95). Conclusion ASXL1 mutations showed significantly inferior post-transplant outcomes in both PMF and PPV/PET MF. While the newly identified mutation ASXL1G646fs* was associated with worse outcomes (especially for post-transplant relapse), HCT seems to abrogate the recently suggested onset poorer outcomes for this mutation compared with other ASXL1 mutations.
Background: Allogeneic stem cell transplantation (SCT) is potentially curative therapy for patients with CMML. Data on optimal allo-SCT conditioning in CMML Patients is scarce. Methods: This ...retrospective study from the Department of Stem Cell Transplantation at the University Medical Center Hamburg, Germany, compared allo-SCT outcomes in CMML patients across three conditioning regimes: Thiotepa-Busulfan (TB), Sequential FLAMSA-Busulfan Fludarabine (FLAMSA-FB), and Treosulfan-Fludarabine (Treo-Flu). TB consisted of Thiotapa ( 5mg/Kg; a total dose of 10mg/Kg) on day -6 and -5 and Busulfan (3.2mg/Kg; total dose 6.4mg/Kg or 9.6mg/Kg) on days -4 and -3 or -4 to -2. FLAMSA-FB regimen consists of fludarabine (30 mg/m 2 ; total dose 120 mg/m 2 ), amsacrine (100 mg/m 2 ; total dose 400 mg/m 2 ), and cytarabine (1 g/m 2 ; total dose 4 g/m 2 ) therapy from days -11 to minus -8, followed by a three-day interval without therapy and Busulfan from day -4 to -2 with a total dose of 6.4mg/Kg and Fludarabine on day -4 and -3 (30 mg/m 2, total dose 60mg/m 2 ).Treo-Flu regimen consisted of Treosulfan (12 g/m 2 , total dose 36 mg/m 2 ) on days-6 to -4 and fludarabine (30 mg/m 2 ; total dose 150 mg/m 2 ) on days -6 to -2. Results Sixty-nine consecutive patients with CMML who underwent allo-SCT between the years 2006-2022. Twenty-two received TB, 27 received FLAMSA-FB, and 20 received Treo-Flu conditioning. Transplant sources included matched related donors (MRD, 8 patients), mismatched related donors (MMRD, 8 from TB), matched unrelated donors (MUD, 31), and mismatched unrelated donors (MMUD, 23) with significant group variations (p<0.001). Most Patients received ATLG for GVHD prophylaxis (TB 68%, FLAMSA-FB 93%, Treo-Flu 85%, p=0.08). Regarding CPSS-mol scores, the TB group exhibited a significantly higher proportion of high (46%) and intermediate-2 scores (32%) than FLAMSA-FB (11% high, 7% intermediate-2) and Treo-Flu (40% high, 20% intermediate-2) (p=0.001). One TB patient experienced primary graft failure, but engraftment times were comparable across groups. Although not statistically significant (p=0.07), the TB group showed a trend towards improved 3-year OS rates (84%) compared to FLAMSA-FB (37%) and Treo-Flu (49%). The TB group also displayed significantly higher 3-year PFS rates (79%) compared to FLAMSA-FB and Treo-Flu (both 30%), (p=0.03). (Figure 1) No significant differences were observed in 3-year non-relapse mortality (NRM) across the TB (17%), FLAMSA-FB (30%), and Treo-Flu (26%) groups (p=0.7). Interestingly, no TB patients relapsed at 3 years, contrasting with the FLAMSA-FB (41%) and Treo-Flu groups (43%, p=0.02). Lastly, cumulative incidences of acute GVHD grade II-IV (TB 41%, FLAMSA-FB 35%, Treo-Flu 30%, p=0.75) and all-grade chronic GVHD (TB 50%, FLAMSA-FB 65%, Treo-Flu 40%, p=0.35) were similar across groups. Conclusion Our study suggests that sequential conditioning with FLAMSA-FB does not improve Transplant outcomes in patients undergoing allo-SCT for CMML.
Objective
Allogeneic stem cell transplantation (allo‐SCT) may have a curative potential due to the graft versus lymphoma effect. In this study, we aimed to compare transplant outcomes between ...refractory‐T‐NHL (ref‐NHL) and Chemosensitive‐T‐NHL (CS‐T‐NHL).
Materials and Methods
We retrospectively reviewed the records of 26 ref‐NHL and 29 CS‐T‐NHL consecutive patients who underwent allo‐SCT at our center and compared the transplant outcomes between the groups.
Results
All patients were heavily pretreated with 27% of patients relapsing post‐auto‐SCT and two patients in the ref‐T‐NHL post‐allo‐SCT. Patients were transplanted mainly from unrelated donors. There were no differences in leucocytes and platelet engraftment between the two groups. At 3 years, the relapse incidence was 34% in Ref‐TNHL and 19% in CS‐TNHL (p = .33), with non‐relapse mortality rates of 28% and 22%, respectively (p = .52). Female patients and those with a previous auto‐SCT had lower relapse incidence (p = .045, p = .003). The 3‐year overall survival was 39% in Ref‐TNHL and 56% in CS‐TNHL (p = .15). Trends for improved progression‐free survival (PFS) and graft‐versus‐host disease relapse‐free survival (GRFS) were observed in the CS‐TNHL group (PFS: 60% vs. 30%, p = .075; GRFS: 38% vs. 21%, p = .1).
Conclusion
Acknowledging the retrospective nature of our study, our results indicate that allo‐SCT has a curative potential in patients with T‐NHL even in refractory status.
Introduction
Patients with relapsed/refractory (r/r) AML have in general a dismal prognosis. Allogeneic stem cell transplantation (allo-SCT) provides a curative approach for these patients, however ...the overall survival (OS) remains still low achieving 20-40%. Though post-transplant minimal residual disease (MRD) monitoring has been shown to be predictive for development of post-transplant relapses and lower survival, data focusing on pre-transplant relapsed/refractory AML patients is scarce. In this study, we investigated the impact of achieving MRD negativity on day +100 for relapses and survival for this high risk patients.
Patients and Methods
We analyzed post-transplant outcomes for pre-transplant r/r AML patients depending on their post-transplant MRD status at day +100. The day +100 was chosen concerning the possibility of early post-transplant interventions (e.g. tapering of immunosuppression or administration of donor lymphocytes).
Fifty six consecutive adult patients (≥18 years old) with r/r AML (median age 58, range 20-76; male, n=34, 61%) who underwent allo-SCT (first, n=44, 79%; second, n=12, 21%) between 2015-2020 at the Department for Stem Cell Transplantation at the University Medical Center Hamburg (Germany) were included. The MRD was assessed on day +100 using multiparameter flow cytometry according to “different from normal” strategy.
The patients experienced rather primary refractory disease (64%), secondary/therapy-related AML (55%) and abnormal cytogenetics (59%) at diagnosis. The median pre-transplant blast count was 25% (6-91%). A number of 29 patients (52%) showed blasts in peripheral blood. Myeloablative conditioning was used in 31 (55%) patients, whereas 25 (45%) patients received reduced intensity regimens. A number of 29 patients (52%) received a FLAMSA-based conditioning. Post-transplant donor lymphocyte infusions as well as other treatment were given to 13 (23%) and 17 (30%) patients, respectively.
Results
The median follow up was 20 months (range 4-66). Forty patients (71%) achieved MRD negativity on day +100 and 16 (29%) remained MRD positive. The 2-year OS, LFS, relapses and NRM at 2 years for day +100 MRD negative patients were: 76% (95% CI: 60-87%), 59% (95% CI: 41-75%), 31% (95% CI: 17-50%) and 8% (95% CI: 3-19%), respectively. The 2-year OS, LFS, relapses and NRM at 2 years for day +100 MRD positive patients were: 35% (95% CI: 17-59%, p=p=0.001), 23% (95% CI: 9-46%, p<0.0001), 70% (95% CI: 45-87%, p=0.0002) and 6% (95% CI: 1-28%, p=0.88), respectively.
Several factors were evaluated for possible association with day +100 MRD negativity (Table 1). There were no significant associations. Further, the incidence of acute (grade II-IV) GvHD at 100 days was not significantly different between the day 100 MRD positive und negative patients.
Following factors had impact on post-transplant outcomes in multivariate analysis: presence (no vs yes) of peripheral blasts prior to allograft (OS: HR 0.3, 95% CI: 0.1-0.9, p=0.03; LFS: HR 0.4, 95% CI: 0.1-0.9, p=0.03; relapses: HR 0.4, 95% CI: 0.1-0.99, p=0.048; NRM: HR 0.5, 95% CI: 0.2-1.3, p=0.17), FLAMSA vs other preparative regimens (OS: HR 0.4, 95% CI: 0.1-0.93, p=0.03; LFS: HR 0.4, 95% CI: 0.2-0.98, p=0.04; relapses: HR 0.4, 95% CI: 0.2-1.0, p=0.05; NRM: HR 0.4, 95% CI: 0.2-1.0, p=0.06), and day +100 MRD (negative vs positive) (OS: HR 0.3, 95% CI: 0.1-0.7, p=0.009; LFS: HR 0.2, 95% CI: 0.1-0.6, p=0.001; relapses: HR 0.2, 95% CI: 0.1-0.4, p=0.0001; NRM: HR 0.2, 95% CI: 0.1-0.5, p=0.0006).
Conclusions
Post-transplant MRD detection plays predictive role in pre-transplant r/r AML patients and may help to define possible candidates for early post-transplant interventions.
No relevant conflicts of interest to declare.
Splenomegaly is a hallmark of myelofibrosis (MF), and reports on the impact of spleen size on the outcome of allo-HSCT have been conflicting, possibly due to differences in methods of assessment. We ...retrospectively analysed the impact of spleen volume and length measured by computed tomography on allo-HSCT outcome in 93 patients, 74% of whom had prior ruxolitinib treatment. Median spleen volume and length were 1.58 dm
and 20 cm, respectively. We found a strong correlation between spleen volume and length (Pearson's r = 0.95, p < 0.001), Spearman (rho = 0.96, p < 0.001). After a median follow-up of 41.7 months, 5-year overall and disease-free survival were 66% and 59%, respectively. Spleen size did not impact overall survival or non-relapse mortality. Larger spleen volume and length as continuous variables were associated with slower platelet and leucocyte engraftment and a higher risk of disease relapse in univariate and multivariate analyses. Spleen length measured precisely by imaging is a good surrogate for spleen volume. In the era of JAK inhibitors, larger spleen size reflects advanced disease in MF and is associated with an increased risk of relapse but has no impact on non-relapse mortality and overall survival after allo-HSCT.
Myelofibrosis is one of the Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) characterized by clonal myeloproliferation. Allogeneic hematopoietic stem-cell transplantation is the ...only potentially curative treatment for patients with myelofibrosis. With that, it can resolve fibrosis and lead to complete loss of the clonal burden. More than 90% of myelofibrosis patients harbor driver mutations in one of the 3 genes JAK2, CALR, and MPL, with JAK2 mutations being associated with worse outcomes. We herein report a study to determine whether the persistence of cells with MPN-associated driver mutations in the early period after allogeneic hematopoietic stem-cell transplantation was associated with outcomes. Patient samples for molecular analysis were prospectively collected from peripheral blood at 5 different time points: at start of conditioning prior to stem cell infusion, at days 30, 100, 180, and 1 year after transplantation. We applied quantitative PCR technology to detect individual driver mutations in JAK2, CALR, and MPL (with a high sensitivity of 0.01%). Simulation was applied to explain variances at different time points. Multivariable modelling was employed to determine independent effects. A total of 312 patients receiving first reduced-intensity conditioning transplantation were included. Distribution of driver mutation genotype at time of transplantation was as follows: 67% with JAK2, 19% with CALR, 4% with MPL, and 8% were triple-negative. Conditioning regimen comprised busulfan and fludarabine. Donor platform for transplantation was: matched related (18%), matched unrelated (58%), haploidentical (1%), and mismatched unrelated (23%). Disease risks at time of transplantation were low (1%), intermediate-1 (22%), intermediate-2 (55%), and high (22%). Median follow-up of the total cohort was 6 years. The median allele burden at time of transplantation was significantly (P<0.001) different between driver mutations: 20% (range, 0.1-100%) for JAK2, 44% (range, 3-54%) for CALR, 60% (range, 43-99%) for MPL. CALR and MPL showed earlier mutation clearance after transplantation compared with JAK2 ( Table). Mutation clearance was achieved at day 30 after transplantation in 46% with JAK2, 67% for CALR, and 30% for MPL (P=0.02). At day 100 after transplantation, 66% of JAK2, 75% of CALR, and 100% of MPL showed complete mutation clearance (P=0.09). Complete mutation clearance at day 30 after transplantation was predictive of post-transplantation relapse at 1 year (P=0.009), showing cumulative incidence of relapse of 6% versus 16%. Similar results were seen for complete mutation clearance at day 100 after transplantation, demonstrating cumulative incidence of relapse of 4% versus 24% (P<0.001). Mutation clearance at day 30 and 100 after transplantation explained 80% and 87% of variance of later time points. The effect of mutation clearance on post-transplant relapse was irrespective of driver mutation status ( Figure). 6-year disease-free survival according to mutation type was 52% for JAK2, 63% for CALR, and 80% for MPL (P=0.045). Mutation clearance at day 30 after transplantation was associated with better disease-free survival, irrespective of driver mutation status ( Figure). Moreover, day-30 complete mutation clearance predicted disease-free survival in JAK2, showing rates of 60% for negative versus 47% in JAK2 positive patients (P=0.05). Importantly, achievement of mutation clearance at day 30 after transplantation could also distinguish different risk groups in patients with onset better prognosis harboring CALR/MPL mutations. The 6-year disease-free survival was 76% for patients with mutation clearance versus 59% for CALR/MPL-positive patients(P=0.02) . Multivariate analysis (adjusting for donor type, diagnosis of primary or secondary myelofibrosis, allele burden at time of transplantation, and age) confirmed that patients who had mutation clearance at day 30 after transplantation had lower risk of relapse, better disease-free and overall survival. In conclusion, this is the first study to show that CALR and MPL are associated with earlier mutation clearance after transplantation compared with JAK2. Mutation clearance at day 30 and 100 after transplantation was the best predictor of relapse and disease-free survival, independent of driver mutation status.
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