In order to keep readers abreast of the latest developments, the Department of Hematology has launched the "Yimai Monthly" to select the latest research progress in the field of hematological oncology every month. In this issue, we select 5 studies for the benefit of readers.
Data update on a new regimen study for salvage haploid transplantation with failed first haploid hematopoietic stem cell transplant engraftment
Bone Marrow Transplantation（IF：4.8）
PMID：38565964
Implantation failure (GF) is a rare but fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT), with a case fatality rate approaching 100% without salvage therapy. There are no general recommendations on the best treatment for this complication. A second transplant is often recommended to save the patient's life. However, there is currently no standard regimen for conditioning in secondary transplantation, donor selection, graft-versus-host disease (GvHD) prophylaxis, and other variables.
Way:
The study is an extension of a previous clinical trial (NCT03717545). Secondary transplantation regimen: The conditioning regimen is Flu (30 mg/m2/d, intravenous injection) from day - 6 to day - 2; Cy (1000 mg/m2/day, intravenously) was given on days -5 and -4. The primary endpoint of the second transplant is the time to neutrophil engraftment within 28 days after the second transplant.
Outcome:
Thirty patients received salvage transplants. All patients received a myeloablative conditioning regimen, and the majority (93.3%) received Bu/Cy/ATG. Of the 30 patients, 1 died 19 days after the second haplo-HSCT. The median time to neutrophil implantation was 11 (range: 8-24) days in 29 patients and 17.5 (range: 9-140) days for platelet implantation in 22 patients. The 1-year OS rate and LFS rate were 60% and 53.3%, respectively. The cumulative recurrence rate (CIR) and TRM were 6.7% and 33.3%, respectively.
Conclusion:
Previous studies have reported positive outcomes with a second salvage treatment for haplo-HSCT using the new regimen. The study further confirms the advantages of this new protocol in terms of implantation efficacy and survival, suggesting that it may be a viable salvage treatment option for GF in patients with hematologic malignancies after the first allo-HSCT. However, there is currently no standard second transplant protocol. This study is the first time that a unified salvage protocol has been reported after GF transplantation, particularly in haplo-HSCT.
Efficacy and safety outcomes of CD22-targeting CAR-T cell therapy in pediatric and adult patients with B-ALL
Leukemia（IF：11.4）
PMID：38491306
In order to explore the feasibility of NCI's preparation method for CD22-targeting CAR (CD22 CAR) and the safety of CD22 CAR-T therapy in patients with lymphoid malignancies, a phase Ib clinical trial was conducted to explore the efficacy of CD22 CAR-T therapy in children and adults with relapsed/refractory (R/R) B-ALL or B-cell non-Hodgkin lymphoma (NHL). Recently, the research team published data results from the trial for the R/R B-ALL cohort of pediatric and adult patients.
Way:
The lymphodepletion regimen prior to CAR-T cell infusion is as follows: fludarabine (30 mg/m2/day, intravenously on days -5, -4, and -3) and cyclophosphamide (500 mg/m2/day, days -5, -4, -3). The CD22 CAR-T cell infusion dose is 1×106 cells/kg (±20%). If a dose-limiting toxicity (DLT) event is observed, the infusion dose is reduced to 3×105 cells/kg.
Outcome:
The Phase Ib clinical trial resulted in 16 R/R B-ALL patients receiving CAR-T cell transfusions, including 8 adults and 8 children. Among all patients treated with CAR-T (n=16), the median age was 23 (range: 2-62) years, and the median number of prior therapy was 6 (range: 3-8). Thirteen patients (81%) developed cytokine release syndrome (CRS; Grades 1-2, n=12; Grade 3, n=1). Two patients developed immune effector cell-associated neurotoxicity syndrome (ICANS; Grade 1, n=1, grade 4, n=1). Of all patients (n=16), 12 (75%) achieved CR, of which 9 had a negative MRD (flow cytometry results).
Conclusion:
The Phase Ib clinical trial preliminarily confirmed the feasibility of the preparation of CD22-CAR-T therapy, and the efficacy of the therapy in children and adults with B-ALL was significant and the safety was controllable. Although patients with relapsed/refractory B-ALL respond significantly to CD22 CAR-T therapy, their long-term survival is still poor, and new drug development remains a top priority.
MANIFEST研究:pelabresib治疗髓系恶性肿瘤患者安全性和耐受性
Leukemia & Lymphoma（IF：2.6）
PMID：38259250
Pelabresib (CPI-0610) is a BET protein inhibitor currently in clinical development for hematologic malignancies due to its ability to target NF-κB gene expression. The MANIFEST Phase I study evaluated the efficacy of pelabresib in patients with acute leukemia, high-risk myelodysplastic syndrome (MDS), or MDS/myeloproliferative neoplasms (MPNs) (NCT02158858).
Way:
MANIFEST is a phase I, multicenter, open-label, sequential dose-escalation study of 44 patients who received Pelabresib orally at different doses (24-400 mg capsules or 225-275 mg tablets) once daily for 14 days and 7 days off for 1 cycle.
Outcome:
The most common drug-related adverse events were nausea, decreased appetite, and fatigue. The maximum tolerated dose (MTD) is 225 mg once daily. One patient with chronic myelomonocytic leukemia (CMML) was in partial remission. 25.8% of patients with acute myeloid leukemia (AML) and 38.5% of patients with high-risk MDS achieved stable disease. One patient with AML and one patient with CMML obtained peripheral blood reactions.
Conclusion:
In this dose-escalation study in patients with acute leukemia, high-risk MDS, or MDS/MPN, all doses of pelabresib were rapidly absorbed and had a half-life to support daily dosing. The MTD of pelabresib monotherapy was determined to be 225 mg tablets. Pelabresib was generally well tolerated, and no new safety concerns were identified. The efficacy of pelabresib in combination with ruxolitinib is being studied in the MF study development process as well as in the recommended Phase II dose of pelabresib and in the ongoing Phase III trial (NCT04603495).
A real-world study of upfront autologous stem cell transplantation in peripheral T-cell lymphoma patients who achieve complete remission after first-line therapy
British Journal of Haematology（IF：6.5）
PMID：38272453
Long-term outcomes for peripheral T-cell lymphoma (PTCL) remain poor, with a 5-year overall survival (OS) rate of only 30% for most PTCL subtypes (with the exception of ALK-positive anaplastic large cell lymphoma [ALCL]), so autologous hematopoietic stem cell transplantation (ASCT) as first-line consolidation therapy is critical for long-term disease management in transplant-friendly patients, but whether patients with PTCL who are in complete remission (CR) after first-line therapy benefit from ASCT remains controversial. Chinese investigators conducted a retrospective, multicenter study comparing the efficacy of consolidation therapy with or without first-line ASCT in patients with PTCL in the real world.
Way:
A total of 347 patients with PTCL who achieved complete remission after first-line therapy were included in the study. Of these, 257 received consolidation chemotherapy (non-ASCT group) and 90 received ASCT (ASCT group).
Outcome:
Clinical outcomes were similar in both ASCT and non-ASCT groups. The two-year cumulative incidence and recurrence rates of treatment-related mortality (TRM) remained similar between the two groups (1.9 versus 2.0 percent, p=0.985; 24.7 versus 47.1 percent, p=0.021). However, there were significant differences in progression-free survival (PFS) and OS rates between the two groups. In the T-cell lymphoma subgroup, the 2-year PFS rate (73.4% vs. 50.8%, p=0.024) and OS rate (92.1% vs. 73.5%, p=0.021) of patients with ASCT were better than those with non-ASCT. Notably, no significant differences were observed in patients with NK/T-cell lymphoma.
Conclusion:
This real-world data suggests that first-line ASCT is a safe and effective consolidation treatment option for patients with PTCL who have acquired CR, particularly those with T-cell lymphoma.
Patients with multiple myeloma with renal insufficiency at the time of transplantation have a low non-relapse mortality rate and a favorable hematologic and renal response after autologous hematopoietic stem cell transplantation
British Journal of Haematology（IF：6.5）
PMID：37953476
High-dose melphalan combined with autologous hematopoietic stem cell transplantation (ASCT) is widely used in the initial treatment of patients with newly diagnosed multiple myeloma (MM). However, the safety and efficacy of kidney transplantation in patients with renal insufficiency (RI) remains controversial.
Way:
The French investigators followed a prospective cohort of 50 patients with newly diagnosed MM with serum creatinine clearance of <40 mL/min at transplantation in a multicenter multicenter. Patients receive the recommended dose of melphalan 140 mg/m2. The primary endpoint was non-relapse mortality (NRM) at day 100.
Outcome:
One patient died within 100 days of transplantation. The median time for neutrophil engraftment was 12 days and the median time for platelet engraftment was 13 days. NRM was 2% (95% CI: 0.2-9.3) at day 100 and 6% (95% CI: 1.5-15) at 1-year. Sixty-nine percent of patients had improved hematologic responses, from partial response (PR) to very good partial response (VGPR) (10%), from PR to complete response (CR)/strict complete response (sCR) (16%), from VGPR to CR/sCR (39%), and from CR to sCR (2%). The 2-year overall survival (OS) rate was 84 percent, the progression-free survival (PFS) rate was 70 percent, and the cumulative recurrence rate was 20 percent. Renal remission improved in 59% of patients, with optimal renal remission after transplantation being mild (9%), partial (2%), and complete (48%).
Conclusion:
The study observed lower NRM within 100 days of ASCT but better hematologic and renal remission. These encouraging results support the use of ASCT in patients with kidney impairment.
参考文献：[1]Ma, R., Zhu, DP., Zhang, XH. et al. Salvage haploidentical transplantation for graft failure after first haploidentical allogeneic stem cell transplantation: an updated experience. Bone Marrow Transplant (2024). https://doi.org/10.1038/s41409-024-02276-5. [2] Schultz LM, Jeyakumar N, Kramer AM, et al. CD22 CAR T cells demonstrate high response rates and safety in pediatric and adult B-ALL: Phase 1b results. Leukemia. Published online March 15, 2024. doi:10.1038/s41375-024-02220-y. [3] Stein EM, Fathi AT, Harb WA, et al. Results from phase 1 of the MANIFEST clinical trial to evaluate the safety and tolerability of pelabresib in patients with myeloid malignancies. Leuk Lymphoma. 2024 Apr; 65(4):503-510. doi: 10.1080/10428194.2023.2300710. Epub 2024 Jan 23. PMID: 38259250. [4] Yang P, Cai M, Cao Y, et al. Up-front autologous stem cell transplant in peripheral T-cell lymphoma patients achieving complete response after first-line treatment: A multicentre real-world analysis. Br J Haematol. 2024 Apr; 204(4):1414-1421. doi: 10.1111/bjh.19317. Epub 2024 Jan 25. PMID: 38272453. [5] Garderet L, Ouldjeriouat H, Bekadja MA, et al. Low non-relapse mortality and good haematological and renal responses after autologous haematopoietic stem cell transplantation in multiple myeloma patients with renal insufficiency at transplant: A prospective Société Francophone de Greffe de Moelle-Thérapie Cellulaire observational study. Br J Haematol. 2024 Apr; 204(4):1450-1458. doi: 10.1111/bjh.19163. Epub 2023 Nov 12. PMID: 37953476.
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