Grafapex (treosulfan)

Harnessing molecular technologies, clinical expertise, patient-centered decision-making, and innovative pharmaceutical strategies offers an exciting opportunity to shape a transformative and curative treatment framework. Here, we provide a contemporary review on HCT for MDS and MF, highlighting up-to-date insights into disease biology, standard of care, and recommendations, as well as open avenues.

He underwent allo-HCT with stable disease burden using a specifically-designed RIC regimen containing treosulfan (at 50% reduced dosing), fludarabine, and rabbit anti-thymocyte globulin. The graft versus host disease (GVHD) prophylaxis contained reduced-dose post-transplant cyclophosphamide (PTCy dose reduction of 50%) with mycophenolate mofetil and cyclosporine...This case demonstrates the safety and feasibility of haploidentical-HCT using a treosulfan-based reduced-intensity conditioning (RIC) regimen and modified PTCy-based GVHD prophylaxis in DKC. Disease relapse in this patient underscores the impact of pretransplant disease burden on relapse free survival in DKC patients with MDS/AML who are not eligible for myeloablative conditioning.

P=N/A, N=70, Recruiting, Fondazione IRCCS Policlinico San Matteo di Pavia

P2, N=40, Active, not recruiting, Fred Hutchinson Cancer Center | Recruiting --> Active, not recruiting

P2, N=60, Recruiting, Fred Hutchinson Cancer Center | Trial completion date: Dec 2026 --> Jan 2028 | Trial primary completion date: Dec 2024 --> Feb 2026

P2/3, N=50, Recruiting, Federal Research Institute of Pediatric Hematology, Oncology and Immunology

Combination of treosulfan and fludarabine decreased MSLN-CAR T cells anti-tumor killing in normoxia but not hypoxia. In conclusion, treosulfan and fludarabine killed MSLN + ovarian cancer cells without altering MSLN-CAR T cells functions (at low cytostatics concentration) even in hypoxic conditions, and our data support the use of treosulfan and fludarabine as conditioning drugs prior to MSLN-CAR T cell therapy.

P=N/A, N=144, Recruiting, Rigshospitalet, Denmark | Not yet recruiting --> Recruiting | Trial primary completion date: Dec 2026 --> Dec 2025

P1, N=36, Recruiting, medac GmbH | Not yet recruiting --> Recruiting

All patients received myeloablative conditioning based on treosulfan or total body irradiation (TBI). Non-relapse mortality was 5%, the cumulative incidence of relapse or progression at five years was 27%, five-year event-free survival was 67%, and 5-year overall survival was 78%. Thus, our data support that allogeneic αβ T-cell-depleted HSCT can provide long-term overall survival of children with high-risk mature T-cell lymphomas.

P2, N=40, Recruiting, Fred Hutchinson Cancer Center

Pts receiving TBI-based regimen were more likely to develop VOD compared to those receiving Treosulfan (10 to 14 g/m2) or Busulfan ev (9...After defibrotide treatment, the CEC levels increased in the first week, while they progressively decreased during the VOD treatment (T6 and T7, -50,7% and -71,5%, respectively)...We show that CECs can be considered reliable marker of endothelial damage in alloSCT pts, highlighting the impact of previous treatments, the conditioning regimen, and allo-SCT itself. Increased CEC level may be helpful to confirm VOD diagnosis, as well as their monitoring may be useful to evaluate the response to the treatment for VOD.

P2, N=60, Recruiting, Fred Hutchinson Cancer Center | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2023 --> Dec 2024

Conditioning consisted of ATG 1,5 mg/kg from day -13 to day -10, Treosulfan 12gr/sqm from -9 to –7, Fludarabine 30 mg/sqm from -6 to -2 and Thiotepa 5 mg/Kg on days -5 and -4. CMV IgG positive patients received prophylaxis with Ganciclovir during conditioning. All patients received Ambisome for fungal prophylaxis...Conclusions. The infusion of abT/CD19-depleted graft is a sure and effective option for heavely pretreated patients affected by HL R/R resulting into rapid donor hematopoietic engraftment and early expansion of donor-derived γδT lymphocytes, without life-threatening infectious complications and very low incidence of GVHD.

CR = complete remission, MRD = measurable residual disease, MAC = myeloablative conditioning, RIC = reduced intensity conditioning, PTCy = post transplat cyclophosphamide, GvHD = graft versus host disease Patient characteristics are reported in Table 1.14 patients received sorafenib as post HCT maintenance, 5 patients as pre-emptive therapy and 1 patient for hematologic relapse. The median time of sorafenib initiation from HCT was 118 days (range 49-904) and median 20 patients Sex (M/F) 10 / 10 Median age at HCT– years (range) 51 (41-75) Mutational status at diagnosis NPM1+/FLT3-ITD+ FLT3-ITD+ 12 20 Disease status at transplant CR1 CR2 CR MRD+ Advanced disease 9 3 4 4 Conditioning Treosulfan MAC Treosulfan RIC 15 5 GvHD prophylaxis PTCy + Rapamycin based 20 Donor Matched related donor Mismatched related donor Matched unrelated donor Cord Blood 5 5 7 3 279 Published only treatment duration was 698 days (range 3-1431)...Our real-life practice confirms that sorafenib is well-tolerated and contributes to sustained long-lasting CR of FLT3-ITD+ AML after allogeneic HCT. In particular, sorafenib should be considered a feasible and effective therapeutic option as maintenance drug in the post-transplant setting.

P2, N=106, Completed, medac GmbH | Active, not recruiting --> Completed

P1, N=36, Not yet recruiting, medac GmbH | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Nov 2024 --> Aug 2025

Total body irradiation (TBI) + VP16 was administered to 42 and 50 pts in the HYPO and BCRABL groups, respectively, while 18 HYPO and 30 BCRABL pts received non-TBI conditioning (busulfan or treosulfan + fludarabine and thiotepa, as per study protocol)...Notably, 24 out of 143 pts (17%) with HYPO/BCRABL received immunotherapy before HSCT (blinatumomab, inotuzumab ozogamicin, and/or CAR-T cells)... Children receiving HSCT for treatment of BCP-ALL with either hypodiploidy or bcr-abl1 fusion showed outcomes comparable to BCP-ALL pts without these genetic lesions. CIR and EFS reached plateaus beyond 3 y post-HSCT, indicating that approximately two-thirds of these pts can be cured by HSCT with low rates of treatment-related mortality. Pts with BCRABL achieved favorable outcomes without the need for long-term or lifelong TKI therapy.

All patients received myeloablative conditioning, either TBI-based (n=30) or 24 treosulfan-based (n=24), with either cyclophosphamide (n=47) or etoposide (n=7) as a second agent. Conclusion Our data suggest that adding vedolizumab and abatacept to the PTCy-based GVHD prophylaxis backbone is well tolerated and may reduce the incidence of gut GVHD among children with acute leukemia grafted from haploidentical donors. This approach can be further developed to reduce exposure to calcineurin inhibitors and deploy additional anti-leukemia effectors after HSCT.

Only pts with contraindications for TBI received chemo-conditioning, which consisted of i.v. busulfan, cyclophosphamide and etoposide. In the FORUM trial pts >4y of age were randomized to receive either TBI- or chemo-based conditioning regimens; pts 2 y of age at HSCT (94%, n=2024). TBI-based conditioning was applied in 64% (n=1429), while 34% (n=722) of pts received chemo-conditioning.

In the Treo group, 68% of patients received treosulfan at a dose ≥36 g/m and 54% of patients received a second alkylator (thiotepa or melphalan). Leukemia-free survival, overall survival, and GVHD-free, relapse-free survival was 65% versus 68% (P = 0.6), 73% versus 76% (P = 0.5), and 54% versus 53% (P = 0.8) in TBF versus Treo, respectively. In conclusion, we did not find a significant difference between the 2 conditioning in the present study; Treo and TBF represent 2 valid alternative regimens for haplo-HSCT with PTCy for AML in remission.

Patients received fludarabine (Flu), thiotepa (Thio), and either busulfan (Bu) or treosulfan (Treo) before HSCT. In conclusion, both chemo-conditioning regimens were well tolerated and NRM was low. However, relapse was the major cause of treatment failure.

This study suggests that Treo/Flu conditioning may be an alternative to Bu/Flu regimen in elderly patients with high-risk who are not suitable for standard conditioning.

Tebentafusp is a relatively new licenced therapy option for HLA-A 02:01 positive advanced uveal melanoma. We conclude that gemcitabine and treosulfan treatment can delay tumour progression. Adjustments to the treatment dose are necessary in case of adverse events under therapy. Further investigations are needed to show which patients benefit from initial dose reduction in the treatment.

TCRαβ-SCT from mismatched family or unrelated donors, using a chemotherapy only regimen, is a safe alternative donor salvage transplant strategy for second HSCT in patients without a suitably matched donor.

Furthermore, conditioning regimen was the only independent predictor of LFS, OS, and GVHD-free/relapse-free survival. Therefore, our real-world multicenter study suggests that FT14 is associated with better outcomes in primary refractory/relapsed AML.

P1/2, N=38, Recruiting, Heinrich-Heine University, Duesseldorf | Not yet recruiting --> Recruiting

However, female patients had a significantly higher AUC (p = 0.007) and peak value (p = 0.001), and the higher values were associated with longer hospitalizations. (4) Treatment consolidation with TreoMel HDCT demonstrated a promising efficacy and safety profile in our cohort of MM patients and deserves further investigation in prospective studies.

The number of donor cells in patients conditioned with Busulfan or Treosulfan based myeloablation were similar to TBI based conditioning; donor cells averaged 6.8% of microglial cells. Our work represents the largest study characterizing bone marrow-derived macrophages in post-transplant patients. The efficiency of engraftment observed in our study warrants future research on microglial replacement as a therapeutic option for disorders of the central nervous system.

Univariate analysis by age group demonstrated a higher NRM exclusively in patients ≥55 years of age treated with FluTBI compared to FluTreo (27.6% vs. 5.8%, p = 0.02), while a similarly low NRM was observed in patients <55 years in both groups (6.0% vs. 4.7%, p = ns). We conclude that both conditioning regimens are effective and safe, but FluTBI may better be reserved for younger patients below the age of 55 years.

All pts presented unfavorable karyotype and received intensive treatment which included cytarabine and an anthracycline (daunorubicin or idarubicin)...All pts underwent allo-HSCT, receiving myeloablative conditioning (treosulfan, fludarabine) and GVHD prophylaxis with post-HSCT cyclophosphamide, Mycophenolate Mofetil, Tacrolimus... In our cohort 3 pts died of AML relapse, 2 pts died for transplant related mortality and 1 pt is alive in continuous CR of AML. The results obtained are in line with pts with AML with known high-risk features such as Tp53, RUNX1 and unfavorable karyotypes. The previous history of PARPi exposure in association with platinum-based chemotherapy in pts with OC did not clearly impact on allo-HSCT outcomes and should not be considered as a prohibitive factor for intensive treatment and allo-HSCT.

Such a difference was even more pronounced in patients who relapsed post SCT after conditioning with Treosulfan compared to TBI based regimen (Figure1). Patients who relapsed > 6 months from HSCT have an excellent prognosis with only a single Tisa-cel infusion and no further consolidation. Early loss of CAR-T cells may be a reflection of inferior T-cell effector function, i.e. sub- potent starting material for CAR-T manufacturing, early after HSCT. These findings may become relevant for further clinical decision making.

P2, N=120, Recruiting, University Hospital Inselspital, Berne | Not yet recruiting --> Recruiting

Re-induction therapy before SCT was heterogeneous, including ALK-inhibitors, brentuximab vedotin, vinblastine, and chemotherapy...The conditioning regimen was Treosulfan/Fludarabin/Thiotepa in 21 and TBI-based in 4 patients... The outcomes after allogeneic SCT were comparable with previous reports with mainly TBI-based conditioning, indicating that TBI can be replaced by reduced-toxicity conditioning in CNS-negative relapse patients. The observations of possibly inferior outcomes in younger patients after SCT and of improved outcomes for children transplanted from unrelated donors warrant further investigation.

P2, N=80, Recruiting, Fred Hutchinson Cancer Center | Trial completion date: Dec 2024 --> Apr 2027 | Trial primary completion date: Mar 2024 --> Oct 2026

P1/2, N=38, Not yet recruiting, Heinrich-Heine University, Duesseldorf

P2, N=80, Recruiting, Fred Hutchinson Cancer Center | Not yet recruiting --> Recruiting

P=N/A, N=144, Not yet recruiting, Rigshospitalet, Denmark | Trial completion date: Dec 2022 --> Dec 2026 | Trial primary completion date: Dec 2022 --> Dec 2026

P1, N=36, Not yet recruiting, medac GmbH | Initiation date: Oct 2022 --> May 2023

Background: Treosulfan, in combination with fludarabine, is increasingly used as part of pre-HSCT conditioning for malignant and non-malignant disorders in children. This large, multicentre, multi-disease cohort shows that treosulfan based conditioning offers good overall and event-free survival in children that require HSCT for a variety of conditions. The addition of thiotepa does not affect overall survival or TRM.