5-year Cumulative Incidence Of Relapse Research Articles

Clinical networking results in continuous improvement of the outcome of patients with acute promyelocytic leukemia.

The introduction of all-trans retinoic acid (ATRA) combined with anthracyclines has significantly improved the outcomes for patients with acute promyelocytic leukemia (APL), and this strategy remains the standard of care in countries where arsenic trioxide is not affordable. However, data from national registries and real-world databases indicate that low- and middle-income countries (LMIC) still face disappointing results, mainly due to high induction mortality and suboptimal management of complications. The American Society of Hematology established the International Consortium on Acute Leukemias (ICAL) to address this challenge through international clinical networking. Here, we present the findings from the ICAPL study involving 806 patients with APL recruited in Brazil, Chile, Paraguay, Peru, and Uruguay. The induction mortality rate has decreased to 14.6% compared to the pre-ICAL rate of 32%. Multivariable logistic regression analysis revealed as factors associated with induction death: age ≥ 40 years, ECOG = 3, high-risk status based on the PETHEMA/GIMEMA classification, albumin level ≤ 3.5 g/dL, bcr3 PML/RARA isoform, the interval between presenting symptoms to diagnosis exceeding 48 hours, and the occurrence of central nervous system and pulmonary bleeding. With a median follow-up of 53 months, the estimated 4-year overall survival (OS) rate is 81%, the 4-year disease-free survival (DFS) rate is 80%, and the 4-year cumulative incidence of relapse (CIR) rate is 15%. These results parallel those observed in studies conducted in high-income countries, highlighting the long-term effectiveness of developing clinical networks to improve clinical care and infrastructure in LMIC.

Allogeneic haematopoietic stem cell transplantation might overcome the poor prognosis of adolescents and adult patients with T-lineage acute lymphoblastic leukaemia and CDKN2 deletion.

This study delves into the clinical implications of cyclin-dependent kinase inhibitor 2 (CDKN2) deletion in adult T-lineage acute lymphoblastic leukemia (T-ALL). Among 241 patients included in this study, 57 had CDKN2 deletion and 184 had CDKN2 wild-type (WT), and 165 underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and 76 did not undergo allo-HSCT. CDKN2 deletion correlated with higher white blood cell count, more high-risk diseases, and complex karyotype. The 5-year overall survival (OS) was 36.8% and 58.2% (P < 0.001), 5-year disease-free survival (DFS) was 47.1% and 59.3% (P = 0.018), and 5-year cumulative incidence of relapse (CIR) was 33.7% and 22.3% (P = 0.019) in patients with CDKN2 deletion and WT, respectively. Multivariate analysis identified CDKN2 deletion as an independent adverse prognostic factor for OS (HR 2.11, P = 0.003). In the CDKN2 deletion subgroup, landmark analysis showed that the 5-year OS was 56.7% and 19% (P = 0.002) for patients who underwent allo-HSCT and those who did not, respectively. And multivariate analysis confirmed the beneficial role of allo-HSCT in OS (HR 0.23, P < 0.001). In conclusion, CDKN2 deletion was associated with a poor prognosis in adult T-ALL, and allo-HSCT might be beneficial for this population.

Total body irradiation versus thiotepa/busulfan-based conditioning regimens for myeloablative allogeneic stem cell transplantation in adults with acute lymphoblastic leukemia.

Total body irradiation (TBI)-based conditioning regimens are generally recommended for allogeneic HSCT (allo-HSCT) in patients with acute lymphoblastic leukemia (ALL). Recent evidence suggests that modern chemotherapy-based regimens may be as effective. This multicenter retrospective study compared the clinical outcomes of myeloablative allo-HSCT with thiotepa, busulfan, and cyclophosphamide/fludarabine (TTB) to TBI-based conditioning. Between 2002 to 2018, 63 and 114 patients received TTB- and TBI-based conditioning regimens, respectively. The 5-year cumulative incidence of relapse was lower in the TBI cohort compared to the TTB cohort (30% [95% CI, 22-38] versus 47% [95% CI, 36-59]; P = 0.03). Multivariate analysis identified T-ALL, Ph-negative B-ALL, and measurable residual disease associated with a higher relapse risk. The 5-year cumulative incidence of non-relapsed mortality (NRM) was significantly lower with TTB (12% [95% CI, 5-20]) compared to TBI (25% [95% CI, 18-33]) (P = 0.001). Multivariate analysis found TBI conditioning, older age, and advanced stages of ALL at transplantation associated with a higher NRM. No statistical difference was seen in overall survival (49% [95% CI, 40-58] and 46% [95% CI, 35-60]) in the TBI and TTB groups, respectively; P = 0.9). The study suggests that TTB-based conditioning may be a promising option for ALL patients undergoing allo-HSCT, as it resulted in similar OS and lower NRM than TBI-based conditioning.

Improved Outcome of Allogeneic Transplantation in Older Patients Treated for Myeloid Malignancies Using Post-Transplantation Cyclophosphamide and Reduced Duration of Immune Suppression

BackgroundAllogeneic stem cell transplantation (alloSCT) offers curative potential for older patients with myeloid malignancies. We evaluated the efficacy and safety of alloSCT using post-transplantation cyclophosphamide (PTCy) in combination with a very short duration of immune suppression (IS) in this population. MethodsWe retrospectively analyzed 92 consecutive patients aged 65 years and older who underwent an alloSCT for myeloid malignancies between February 2018 and December 2022 at our institution. Data on patient characteristics, treatment modalities, and outcomes were collected. ResultsNinety-two patients received an alloSCT with PTCy-based GVHD prophylaxis. The majority had minimal comorbidities and were diagnosed with acute myeloid leukemia (AML). Patients mostly received conditioning regimens with low to intermediate TCI scores. In 43% of patients, IS could be permanently stopped at day +90, resulting in a median time of IS of 2.93 months in high-risk patients. At a median follow-up of 21.3 months, the 1- and 2-year overall survival rates were 89% and 87%, respectively. Relapse-free survival rates were 88% and 84% at 1 and 2 years, respectively. The 1- and 2-year cumulative incidences of relapse were 8% and 13%, while transplant-related mortality (TRM) estimates were 9% at both time points. Acute GVHD grade 3-4 occurred in 7% within the first 180 days and severe chronic GVHD in 6% of patients. This all resulted in a 1- and 2-year graft versus host and relapse free survival (GRFS) of 74% and 70%, respectively. ConclusionAlloSCT using PTCy in combination with a short duration of IS in older patients with myeloid malignancies demonstrates favorable survival outcomes due to low relapse rates and a low TRM. The low incidence of relapse and acceptable rates of graft-versus-host disease suggest the efficacy and safety of this approach. Further studies are warranted to validate these findings and optimize transplant strategies for older patients with myeloid malignancies.

Integration of measurable residual disease by WT1 gene expression and flow cytometry identifies pediatric patients with high risk of relapse in acute myeloid leukemia.

Molecular testing plays a pivotal role in monitoring measurable residual disease (MRD) in acute myeloid leukemia (AML), aiding in the refinement of risk stratification and treatment guidance. Wilms tumor gene 1 (WT1) is frequently upregulated in pediatric AML and serves as a potential molecular marker for MRD. This study aimed to evaluate WT1 predictive value as an MRD marker and its impact on disease prognosis. Quantification of WT1 expression levels was analyzed using the standardized European Leukemia Network real-time quantitative polymerase chain reaction assay (qRT-PCR) among a cohort of 146 pediatric AML patients. Post-induction I and intensification I, MRD response by WT1 was assessed. Patients achieving a ≥2 log reduction in WT1MRD were categorized as good responders, while those failing to reach this threshold were classified as poor responders. At diagnosis, WT1 overexpression was observed in 112 out of 146 (76.7%) patients. Significantly high levels were found in patients with M4- FAB subtype (p=0.018) and core binding fusion transcript (CBF) (RUNX1::RUNX1T1, p=0.018, CBFB::MYH11, p=0.016). Following induction treatment, good responders exhibited a reduced risk of relapse (2-year cumulative incidence of relapse [CIR] 7.9% vs 33.2%, p=0.008). Conversely, poor responders' post-intensification I showed significantly lower overall survival (OS) (51% vs 93.2%, p<0.001), event-free survival (EFS) (33.3% vs 82.6%, p<0.001), and higher CIR (66.6% vs 10.6%, p<0.001) at 24 months compared to good responders. Even after adjusting for potential confounders, it remained an independent adverse prognostic factor for OS (p=0.04) and EFS (p=0.008). High concordance rates between WT1-based MRD response and molecular MRD were observed in CBF patients. Furthermore, failure to achieve either a 3-log reduction by RT-PCR or a 2-log reduction by WT1 indicated a high risk of relapse. Combining MFC-based and WT1-based MRD results among the intermediate-risk group identified patients with unfavorable prognosis (positive predictive value [PPV] 100%, negative predictive value [NPV] 85%, and accuracy 87.5%). WT1MRD response post-intensification I serves as an independent prognostic factor for survival in pediatric AML. Integration of WT1 and MFC-based MRD results enhances the reliability of MRD-based prognostic stratification, particularly in patients lacking specific leukemic markers, thereby influencing treatment strategies.

Allogeneic hematopoietic cell transplantation for older patients with AML with active disease. A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Older adults with acute myeloid leukemia (AML) refractory to initial or reinduction chemotherapy have a dismal prognosis if they do not undergo hematopoietic stem-cell transplantation (HCT). However, data assessing HCT outcomes from different donors are scarce. We evaluated results from a retrospective analysis on patients aged ≥70 years, with AML not in remission who received an allogeneic HCT from HLA-matched sibling donor (MSD), HLA-10/10 matched unrelated donor (MUD), or T-cell replete haploidentical (Haplo) donor, from 2010 to 2021, reported to the ALWP-EBMT database. A total of 360 patients (median age 72 years, range 70-79) were included in the analysis. Median follow-up for the entire population was 35.5 months. Donors were MSD (n = 58), 10/10 HLA-MUD (n = 228), and Haplo (n = 74). A total of 213 (59.2%) patients were primary induction failures, while 147 (40.8%) were in first or subsequent relapse. Graft source was peripheral blood in 92% of the patients. Patients transplanted from Haplo donors more frequently received marrow grafts (p < 0.01) and presented the combination female donor to male recipient (p < 0.01). The overall 2-year rates of overall survival (OS) and leukemia-free survival (LFS) were: 62.4% (95% CI 47.2-74.3) and 47.6% (95% CI 33.1-60.8) for MSD, 43% (95% CI 35.8-49.9), and 37.5% (95% CI 30.7-44.4) for MUD, and 25.9% (95% CI 15.8-37.2), and 26.5% (95% CI 16.3-37.8) for recipients of Haplo transplants. The 2-year cumulative incidence of relapse (RI) was slightly lower for Haplo recipients at 29.6% (95% CI 19-40.9), for MUD it was 30.2% (95% CI 23.9-36.7), and for MSD 34.9% (95% CI 22-48.2); counterbalanced by a higher incidence of non-relapse mortality (NRM) of 43.9% (95% CI 31.6-55.6) for Haplo recipients, 32.2% (95% CI 26-33.1) for MUD and 17.5% (95% CI 8.4-29.3) for MSD. Graft-versus-host disease (GVHD-free, relapse-free survival (GRFS) was 35.3% (95% CI 22.3-48.5) for MSD, 29.6% (95% CI 23.2-36.2) for MUD, and 19.2% (95% CI 10.7-29.6) for Haplo patients. In the multivariate model, compared to the referent group of MSD recipients, the risk of NRM was higher among patients transplanted from Haplo donors ([hazard ratio] HR 5.1, 95% CI 2.23-11.61, p < 0.001) and MUD (HR 3.21, 95% CI 1.48-0.6.94, p = 0.003). Furthermore, both Haplo and MUD were associated with inferior OS, (HR 3.6, 95% CI 1.98-0.6.56, p < 0.001, and HR 2.3, 95% CI 1.37-0.3.88, p = 0.002, respectively), and LFS (HR 2.24, 95% CI 1.31-0.3.84, p = 0.003, and HR 1.64, 95% CI 1.04-0.2.60, p = 0.034, respectively). Patients transplanted from Haplo donors were also associated with worse GFRS (HR 1.72, 95% CI 1.07-2.77, p:0.025) compared with MSD patients. Older adult AML patients with active disease transplanted from MSD experienced prolonged OS and LFS compared to 10/10 MUD and Haplo due to lower NRM. Prospective clinical trials are warranted.

Long-term outcomes and renal responses following autologous hematopoietic stem cell transplantation for light chain deposition disease: a retrospective study on behalf of the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.

There is little long-term outcome data on the efficacy of autologous hematopoietic stem cell transplantation (ASCT) in light chain deposition disease (LCDD). We identified 51 LCDD patients in the EBMT registry who had undergone upfront ASCT between 1995 and 2021. The median serum creatinine was 280 μmol/L and 45% required renal replacement therapy (RRT) at time of transplant. The melphalan dose was 100mg/m2 in 23%, 140mg/m2 in 55% and 200 mg/m2 in 21%. The rate of very good partial response or better improved from 41% pre-transplant to 66% at Day +100 post-ASCT. In RRT-independent patients, there was a modest improvement in renal function within the first 3 months; the median eGFR increased from 44 to 51 ml/min/1.73 m2. There was no further change between 3 and 12 months post- ASCT. No patient who was RRT-independent at ASCT became RRT dependent by Day + 100 post-ASCT. Median follow-up post-ASCT was 84 months (IQR: 46-122). At 6-years post ASCT, overall survival (OS) was 88% (95% CI: 78-98%) and PFS was 44% (95% CI: 28-60%). The 2-year cumulative incidence of relapse and non-relapse mortality (NRM) was 17% (95% CI: 6-27%) and 2% (95% CI: 0-6%), respectively. The cumulative incidence of renal transplantation at 4 years after ASCT was 27% (95% CI 13-41) with renal transplantation performed between 6.3 and 52.9 months post-ASCT (median 24.7 months). ASCT represents a feasible option for LCDD patients even if RRT dependent at time of transplant. Outcomes are favourable with low NRM and good long-term OS.

Long-term outcomes after haploidentical stem cell transplantation for hematologic malignancies

AbstractThe introduction of posttransplant cyclophosphamide (PTCy)–based graft-versus-host disease (GVHD) prophylaxis lead to significant improvements in haploidentical stem cell transplantation (haplo-SCT) outcomes over the past decade. We retrospectively assessed long-term outcomes of patients who had their first haplo-SCT between February 2009 and March 2019. Long-term survivors were defined as patients who were alive and disease-free at 2 years after transplant. Three hundred thirty-five patients with a median age of 48 years (range, 18-72) were identified. Of these, 142 patients were disease-free and alive at 2 years after transplant. The 4-year progression-free survival (PFS) and overall survival (OS) for all study patients were 42% and 47%, respectively. With a median follow-up of 52 months for the long-term survivor group, the 4-year PFS and OS were 94% and 96%, respectively. The 4-year cumulative incidence of relapse and non-relapse mortality (NRM) were 2.9% and 3.3%, respectively. Age ≥55 years was the only predictive factor in multivariate analysis for inferior PFS (hazard ratio [HR], 3.41; 95% confidence interval [CI], 1.21-9.60; P = .020) and OS (HR, 3.31; 95% CI, 1.08-10.18; P = .037). Thirteen patients (9%) died in the long-term survivor group, only 2 of whom died of relapsed disease. Secondary primary malignancy was the most frequent cause of NRM (n = 4), followed by infection (n = 2). For haplo-SCT with PTCy–based GVHD prophylaxis, our findings suggest an excellent long-term survival for patients who were disease-free and alive at 2 years after transplant. Late relapses were rare, and age was the only predictive factor for long-term outcomes.

The value of minimal residual disease and IKZF1 deletion for predicting prognosis in adult patients with B-cell acute lymphoblastic leukemia

Objective: To reassess the prognostic value of minimal residual disease (MRD) and IKZF1 gene deletions in adults with B-cell acute lymphoblastic leukemia (B-ALL) who received pediatric-specific chemotherapy regimens during the Nanfang Hospital PDT-ALL-2016 trial. Methods: We retrospectively analyzed the prognosis of 149 adult patients with B-ALL who were admitted to Nanfang Hospital from January 2016 to September 2020. Prognostic factors were identified using Cox regression models. Results: The complete remission rate was 93.2% in 149 patients, with a 5-year overall survival (OS) rate of (54.3±5.0) % and a cumulative incidence of relapse (CIR) of (47.5±5.2) %. The Cox regression analysis revealed that MRD positivity at day 45 (MRD(3)) after induction therapy was independently associated with relapse risk (HR=2.535, 95%CI 1.122-5.728, P=0.025). Deletion of IKZF1 gene was independently associated with mortality risk (HR=1.869, 95%CI 1.034-3.379, P=0.039). Based on MRD(3) and IKZF1 gene status, we categorized adult patients with B-ALL into the low-risk (MRD(3)-negative and IKZF1 gene deletion-negative) and high-risk (MRD(3)-positive and/or IKZF1 gene wild type) groups. The 5-year OS and CIR rates were (45.5±6.0) % vs (69.4±8.6) % (P<0.001) and (61.6±8.3) % vs (25.5±6.5) % (P<0.001), respectively, in the high-risk and low-risk groups, respectively. The multivariate analysis showed that the high-risk group was an independent risk factor for OS (HR=3.937, 95%CI 1.975-7.850, P<0.001) and CIR (HR=4.037, 95%CI 2.095-7.778, P<0.001) . Conclusion: The combined use of MRD and IKZF1 gene in prognostic stratification can improve clinical outcome prediction in adult patients with B-ALL, helping to guide their treatment.

Nilotinib with or without cytarabine for Philadelphia-positive acute lymphoblastic leukemia

AbstractWe previously demonstrated that a reduced-intensity chemotherapy schedule can safely replace hyper-CVAD (cyclophosphamide-vincristine-adriamycin-dexamethasone) cycle 1 when combined with imatinib in adults with Philadelphia-positive acute lymphoblastic leukemia. In the present randomized GRAAPH-2014 trial, we used nilotinib and addressed the omission of cytarabine (Ara-C) in consolidation. The primary objective was the major molecular response (MMR) rate measured by BCR::ABL1 quantification after cycle 4 (end of consolidation). All patients were eligible for allogeneic stem cell transplant (SCT), whereas those in MMR could receive autologous SCT, followed by 2-year imatinib maintenance in both cases. After the enrollment of 156 of 265 planed patients, the data and safety monitoring board decided to hold the randomization because of an excess of relapse in the investigational arm. Among the 155 evaluable patients, 77 received Ara-C during consolidation (arm A) and 78 did not (arm B). Overall, 133 patients (85%) underwent SCT, 93 allogeneic and 40 autologous. The noninferiority end point regarding MMR was reached with 71.1% (arm A) and 77.2% (arm B) of patients reaching MMR. However, the 4-year cumulative incidence of relapse was higher in arm B compared with arm A (31.3% [95% confidence interval {CI}, 21.1%-41.9%] vs 13.2% [95% CI, 6.7%-21.9%]; P = .017), which translated to a lower relapse-free survival. With a median follow-up of 3.8 years, 4-year overall survival was 79.0% (95% CI, 70.6%-89.3%) in arm A vs 73.4% (95% CI, 63.9%-84.4%) in arm B (P = .35). Despite a noninferior rate of MMR, more relapses were observed when ARA-C was omitted without impact on survival. ClinicalTrials.gov ID, NCT02611492.

Open-Label Randomized Controlled Study of Ciprofloxacin vs Rifaximin as Neutropenia Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplantation

Loss of microbiota diversity has been clearly associated with poor outcomes in the allogeneic hematopoietic stem cell transplantation setting. However, the choice of the optimal antibiotic prophylaxis during the pre-engraftment phase remains unclear. We designed a prospective randomized study to compare our standard-of-care neutropenia prophylaxis (ciprofloxacin) with rifaximin. We enrolled 38 consecutive adult patients who underwent allogeneic hematopoietic stem cell transplantation setting and were randomly assigned to receive ciprofloxacin (20 patients) or rifaximin (18 patients) at day -1. Pretransplant and transplant characteristics did not differ between groups. Cumulative incidence (CI) of acute graft-vs-host disease grade II to IV and moderate/severe chronic graft-vs-host disease was similar in both groups. With a median follow-up of 13.2 months (range, 6.8-30.2) in surviving patients, the 1-year CI of relapse was 20.8% in ciprofloxacin vs 17.8% in rifaximin (P = .616). Importantly, the 1-year CI of treatment-related mortality was significantly reduced in the ciprofloxacin group (10.2% vs 27.8%, P = .032), leading to higher 1-year overall survival (88.9% vs 74.6%, P = .038). In Cox-regression multivariate analysis, antibiotic prophylaxis remained the only predictor of overall survival, independently of donor type, disease risk index, and moderate/severe chronic graft-vs-host disease. Further studies are needed to assess the effects on microbiota diversity and confirm these outcomes.

Comparison of long-term outcomes between imatinib and dasatinib prophylaxis after allogeneic stem cell transplantation in patients with Philadelphia-positive acute lymphoblastic leukemia: A multicenter retrospective study.

Although the prognosis of Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) has improved with the introduction of tyrosine kinase inhibitors (TKIs) and stem cell transplantation, prevention of relapse after transplantation remains a concern. The aim of this study was to compare the impact of TKI prophylaxis with imatinib and dasatinib on long-term outcomes after transplantation. Patients with Ph+ALL who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at first complete remission (CR1) and received TKI prophylaxis after allo-HSCT were included in this retrospective analysis. Two cohorts were established based on the choice of TKI prophylaxis: the imatinib (Ima) and dasatinib (Das) cohorts. The survival and safety outcomes of these cohorts were compared. Ninety-one patients in the Ima cohort and 50 in the Das cohort were included. After a median follow-up of 50.6months, the 5-year cumulative incidence of relapse, nonrelapse mortality rate, and overall survival in the Ima and Das cohorts were 16.1% and 12.5%, 5.2% and 9.8%, and 86.5% and 77.6%, respectively, with no statistical differences. The cumulative incidence of mild chronic graft-versus-host disease was higher in the Das cohort. The most common adverse event was neutropenia (64.7% vs. 69.5%). The Das cohort had a higher incidence of gastrointestinal bleeding (25.5% vs. 2.3%) and gastrointestinal reaction (48.9% vs. 31.4%) than the Ima cohort. The proportion of patients treated on schedule was significantly lower in the Das cohort than in the Ima cohort, and drug intolerance was the main reason for protocol violation. For patients with Ph+ALL undergoing allo-HSCT in CR1, imatinib prophylaxis achieved long-term outcomes similar to those of dasatinib.

Continuous PEGasparaginase Dosing Reduces Hypersensitivity Reactions in Pediatric ALL: A Dutch Childhood Oncology Group ALL11 Randomized Trial.

The primary objective of this randomized study was to determine whether a continuous dosing schedule (without the asparaginase-free interval) would result in less hypersensitivity reactions to PEGasparaginase (PEGasp) compared with the standard noncontinuous dosing schedule. Eight hundred eighteen patients (age 1-18 years) with ALL were enrolled in the Dutch Childhood Oncology Group-ALL11 protocol and received PEGasp. Three hundred twelve patients stratified in the medium-risk arm were randomly assigned to receive 14 individualized PEGasp doses once every two weeks in either a noncontinuous or continuous schedule after the first three doses in induction (EudraCT: 2012-000067-25). Hypersensitivity reactions were defined as allergies, allergic-like reactions, and silent inactivation. Secondary end points were other asparaginase-related toxicities, asparaginase activity and antibody levels, and outcome. During induction, 27 of 818 patients (3.3%) experienced hypersensitivity reactions. After random assignment, 4 of 155 (2.6%) in the continuous treatment arm versus 17 of 157 (10.8%) patients in the noncontinuous treatment arm had hypersensitivity reactions (P < .01), of which two (1.3%) versus 13 (8.3%) were inactivating reactions (P < .01). The occurrence of inactivating hypersensitivity reactions was seven times lower in the continuous arm (odds ratio, 0.15 [0.032-0.653]). In addition, antibody levels were significantly lower in the continuous arm (P < .01). With exception of a lower incidence of increased amylase in the continuous arm, there were no significant differences in total number of asparaginase-associated toxicities between arms. However, the timing of the toxicities was associated with the timing of the asparaginase administrations. No difference in 5-year cumulative incidence of relapse, death, or disease-free survival was found between both treatment arms. A continuous dosing schedule of PEGasp is an effective approach to prevent antibody formation and inactivating hypersensitivity reactions. The continuous PEGasp schedule did not increase toxicity and did not affect the efficacy of the therapy.

Clinical analysis of 14 patients aged ≤ 50 years with high-risk multiple myeloma treated with allogeneic hematopoietic stem cell transplantation

Objective: To evaluate the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in young patients with high-risk multiple myeloma (HRMM) and analyzed the factors affecting patient prognosis. Methods: In this retrospective study, we analyzed the clinical data of 14 patients with HRMM with cytogenetic abnormalities or high-risk biological factors who underwent allo-HSCT at the Hematopoietic Stem Cell Transplantation Center of the Institute of Hematology & Blood Diseases Hospital between November 2016 and November 2022. Results: There were seven males and seven females included in the study, with a median age of 39.5 (31-50) years at the time of allo-HSCT. The median number of treatment lines before transplantation was 2 (1-6) . Before allo-HSCT, 42.9% (6/14) of the patients did not achieve complete remission, while 35.7% (5/14) of the patients achieved measurable residual disease positivity. After transplantation, all patients were evaluated for their treatment response, and the overall response rate was 100% (14/14) . All 14 patients successfully underwent allo-HSCT, with median engraftment times for neutrophils and platelets of 11 (10-14) days and 13 (9-103) days, respectively. Acute grade Ⅱ-Ⅳ graft-versus-host disease (GVHD) occurred in five patients (35.7%) , and two patients (14.3%) developed moderate-to-severe chronic GVHD. The median follow-up time after allo-HSCT was 18.93 (4.10-72.53) months, with an expected 2-year transplant-related mortality rate of 7.1% (95% CI 0%-21.1%) and an expected 2-year overall survival rate of 92.9% (95% CI 80.3%-100.0%) . Moreover, the expected 1-year and 2-year progression-free survival rates were 92.9% (95% CI 80.3%-100.0%) and 66.0% (95% CI 39.4%-100.0%) , respectively, and the 2-year cumulative incidence of relapse was 28.9% (95% CI 0%-56.7%) . Upfront allo-HSCT following complete remission after induced therapy and the presence of chronic GVHD might be favorable prognostic factors. Conclusion: allo-HSCT is an effective treatment for improving the prognosis of young patients with HRMM.

Outcome of High-Dose Chemotherapy Followed by Autologous Stem Cell Transplantation in Relapsed/Refractory Hodgkin Lymphoma after Different Numbers of Salvage Regimens.

The introduction of novel drugs (PD-1 inhibitors and/or brentuximab vedotin) into salvage regimens has improved the response rate and the outcome of patients with relapsed/refractory Hodgkin lymphoma. However, the impact of new drugs on the outcome has not been adequately investigated so far. We retrospectively analyzed 42 consecutive patients treated at our institution with high-dose chemotherapy/autologous stem cell transplantation after either one standard chemotherapy represented by BEGEV (n = 28) or >1 salvage therapy (ST) comprising novel drugs (n = 14). With a median follow-up of 24 months, the 2-year cumulative incidence of relapse was similar between the two cohorts: 26% for 1 ST and 18% for >1 ST (p = 0.822). Consistently, overall survival and progression-free survival did not differ among the two groups: 3-year overall survival was 91% and 89% (p = 0.731), respectively, and 3-year progression-free survival was 74% and 83% (p = 0.822) for only one and more than one salvage regimens, respectively. Of note, the post-transplant side effects and engraftment rates were similar between the 1 ST and >1 ST cohorts. In conclusion, consolidation with high-dose chemotherapy/autologous stem cell transplantation is a safe and curative option, even for patients achieving disease response after more than one rescue line of therapy.

Prognostic risk signature in patients with acute myeloid leukemia treated with hypomethylating agents and venetoclax

AbstractHypomethylating agents (HMAs) and venetoclax (Ven) represent the standard of care for patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. However, the European LeukemiaNet (ELN) risk classifications have been validated for patients treated with intensive therapy. In this study, we validate a recently proposed new molecular prognostic risk signature (mPRS) for patients with AML treated with HMAs and Ven. This classification allocated patients to favorable, intermediate (N/KRAS or FLT3–internal tandem duplication mutations), and lower (TP53 mutations) benefit groups. We retrospectively analyzed 159 patients treated with HMA and Ven. The mPRS classification allocated 74 (47%), 31 (19%), and 54 (34%) patients to the higher, intermediate, and lower-benefit groups, respectively. The overall response rate was 71% (86%, 54%, and 59% in the higher, intermediate, and lower-benefit groups, respectively). The median overall survival (OS) and event-free survival (EFS) times were 30 and 19 months, respectively, in the higher-benefit group; 12 and 8 months in the intermediate-benefit group; and 5 and 4 months in the lower-benefit group (P < .001). The C-index for OS and EFS was higher when stratifying patients according to mPRS classification than with the ELN 2022 classification. The 2-year cumulative incidence of relapse was 35%, 70%, and 60% in the higher, intermediate, and lower-benefit groups, respectively (P = .005). The mPRS classification accurately segregated groups of patients with AML treated with HMA plus Ven. In these patients, N/KRAS and TP53 mutations appear to negatively affect outcomes; therefore, new treatment approaches are warranted.

Comparison of Two Venetoclax-Based Regimens As Salvage Therapies Bridged to Allogeneic Hematopoietic Cell Transplantation in Patients with Relapsed/Refractory Acute Myeloid Leukemia

Introduction ： Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for relapsed or refractory acute myeloid leukemia (R/R-AML) patients. However, it is not clear about appropriate salvage therapy bridged to allo-HSCT for R/R-AML patients. In this study, we compared the outcomes of R/R-AML patients treated with venetoclax plus hypomethylating agents (VEN-HMA) regimen or venetoclax plus azacitidine and homoharringtonine (VAH) regimen as salvage therapies bridged to allo-HSCT. Methods ： A total of 105 R/R-AML patients treated with VEN-HMA regimen or VAH regimen bridged to allo-HSCT between September 2018 and February 2023 were enrolled. The outcomes including survival, relapse and NRM after allo-HSCT were analyzed in two groups. Results ： Forty-four patients were treated with VEN-HMA regimen, and 61 with VAH regimen. Seventy-four patients had primary refractory AML and 31 relapsed AML, including 19 relapsed after chemotherapy and 12 relapsed after allo-HSCT. Thirty-one (70.5%) patients achieved composite complete remission (CRc) in VEN-HMA group including 20 (45.5%) with minimal residual disease (MRD) negative, as well as 52 (85.2%) with CRc including 40 (65.6%) with MRD negative in VAH group (P=0.09). Twenty-five (56.8%) patients were stratified with adverse risk in VEN-HMA group and 45 (73.8%) in VAH group according to the 2022 European Leukemia Net (ELN) classification (P=0.07). The 2-year overall survival (OS) and event-free survival (EFS) in VAH group were higher (78.4% vs 58.7%, P=0.03; 68.3% vs 38.7%, P=0.003), as well as 2-year cumulative incidence of relapse (CIR) was lower than VEN-HMA group (23.2% vs 42.4%, P=0.04). Among patients with CRc, the 2-year OS, EFS and CIR was 67.5%, 48.9% and 37.0% in VEN-HMA group, as well as 82.5%, 72.5% and 23.6% in VAH group (P=0.15, 0.05 and 0.24). Among patients with MRD negative, the 2-year OS, EFS and CIR was 75.5%, 55.5% and 31.6% in VEN-HMA group, as well as 90.8%, 80.0% and 17.5% in VAH group (P=0.15, 0.10 and 0.28). Among patients with adverse risk, the 2-year OS and EFS in VAH group were higher (79.3% vs 47.7%, P=0.01; 70.9% vs 24.1%, P=0.0002), as well as 2-year CIR was lower than VEN-HMA group (17.4% vs 45.8%, P=0.01). Non-relapse mortality (NRM) was similar between VEN-HMA group and VAH group (18.9% vs 8.5%, P=0.12). Conclusion ： VAH regimen is an effective salvage therapy bridged to allo-HSCT for R/R-AML patients compared with VEN-HMA regimen. Keywords ： Venetoclax, Azacitidine, Homoharringtonine, Relapsed/Refractory AML, Allogeneic Hematopoietic Cell Transplantation.

Outcomes after Hematopoietic Cell Transplantation for T-Lineage Acute Lymphoblastic Leukemia and Lymphoma: A Cooperative Study from the Adult Acute Lymphoblastic Leukemia Working Group and the Adult Malignant Lymphoma Working Group of the Japanese Society for Transplantation and Cellular Therapy

Background: T-lineage acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LBL) arise from immature precursor T cells and are currently considered a single disease entity according to the World Health Organization Classification. Patients with T-ALL or T-LBL typically receive ALL-type intensive chemotherapy if applicable, and those with high-risk features or relapsed disease undergo hematopoietic cell transplantation (HCT). Although autologous HCT for T-ALL is uncommon, it remains a choice in the general practice of T-LBL, resulting in different donor selection strategies for these diseases. However, there is limited data on outcomes for these patients. Methods: We analyzed nationwide registry data (Transplant Registry of Unified Management Program Japan, TRUMP) from 2000 to 2017 to evaluate outcomes after the first HCT and identify prognostic factors among p with T-ALL/T-LBL. Five patients who underwent autologous HCT for T-ALL were excluded from the analysis. Overall and disease-free survival (OS and DFS) were assessed using the Kaplan-Meier method with the log-rank test. Univariate and multivariate analyses were performed to identify the potential prognostic factors. The Cox proportional hazards method was used for the multivariate analysis to assess OS, whereas Gray's test and the Fine-Gray model were used to determine the cumulative incidence of relapse (CIR) considering competing risks such as relapse and non-relapse mortality (NRM). Results: A total of 1345 patients (T-ALL, n=808; T-LBL, n=537) were included in the database. The median follow-up period of survivors was 4.5 (interquartile range, 2.0-7.7) years. The median age at HCT was 32 (range, 16-70) years. The OS and DFS at 4 years after HCT were comparable between T-ALL and T-LBL (OS 51.7% vs. 52.0%, p = 0.494; DFS 48.3% vs. 45.4%, p = 0.066). However, higher NRM and lower CIR were observed in T-ALL compared with T-LBL (4-year NRM 21.8% vs. 14.5%, p = 0.002; 4-year CIR 29.9% vs. 40.1%, p &amp;lt; 0.001). In T-LBL, patients who received allogeneic HCT (allogeneic LBL, n = 402) had significantly worse survival than those who received autologous HCT (autologous LBL, n = 135) (4-year OS 47.4% vs. 66.2%, p &amp;lt; 0.001; 4-year DFS 47.4% vs. 66.2%, p &amp;lt; 0.001), with significantly worse NRM and comparable CIR (4-year NRM 18.0 vs 3.8%, p &amp;lt; 0.001; 4-year CIR 39.6% vs. 41.6%, p = 0.875). Compared with the allogeneic ALL or allogeneic LBL groups, the autologous LBL group had a significantly older age at HCT (the respective median age was 31 years [range, 16-70], 33 [16-86], and 49 [16-76]; p &amp;lt; 0.001). The allogeneic LBL group had a lower rate of first complete remission (CR1) and a higher rate of non-CR at SCT (CR1/non-CR: allogeneic ALL, 57.1%/30.4%; allogeneic LBL, 37.6%/47.0%; autologous LBL, 57.8%/31.1%; p &amp;lt; 0.001). Among patients in CR1 at HCT, OS and DFS were comparable among the allogeneic ALL (n = 461), allogeneic LBL (n = 151), and autologous LBL (n = 78) groups (Fig. 1, 4-year OS 69.3% vs. 72.6% vs. 76.7%, respectively, p = 0.389; 4-year DFS 64.9% vs. 65.5% vs. 67.1%, respectively, p = 0.830). However, the NRM was lower in the autologous LBL group (4-year NRM 16.6% vs. 8.3% vs. 0.0%, respectively, p &amp;lt; 0.001), and the CIR was lower in the allogeneic ALL group (4-year CIR 18.9% vs. 26.3% vs. 32.9%, respectively, p = 0.004). Among patients without CR at SCT, outcomes were comparable between allogeneic ALL (n = 246), allogeneic LBL (n = 189), and autologous LBL groups (n = 42) (4-year OS 18.4%, 24.6%, vs 36.9%, respectively, p = 0.347; 4-year DFS 17.4%, 21.9%, vs 23.6%, respectively, p = 0.818; 4-year NRM 29.8%, 28.0%, vs 12.7%, respectively, p = 0.107; 4-year CIR 52.8%, 50.2%, vs 63.7%, respectively, p = 0.347). In T-ALL, multivariate analysis identified age ≥ 41 years, male sex, PS ≥ 2, disease status other than CR1, HLA disparity ≥ 2 loci, myeloablative conditioning (MAC) without total body irradiation (TBI), and HCT before 2010 as factors associated with poor OS (Table 1, Upper). In T-LBL, PS ≥ 2, non-CR at HCT, MAC without TBI, use of anti-thymocyte globulin, and multiple treatment regimens before HCT were significant factors for poor OS (Table 1, Lower). Donor type did not affect OS. Conclusion: This largest-ever retrospective study shows comparable OS after HCT for T-ALL or T-LBL. Active disease, PS ≥ 2, and non-TBI MAC were potent poor prognostic factors. In T-LBL, autologous HCT can be a suitable option, which should be confirmed in further prospective studies.

A Single Center Retrospective Study on the Efficacy of Haploidentical Hematopoietic Stem Cell Transplantation in Patients with Myeloid Neoplasms over 50 Years Old

Objective: This study aims to evaluate the efficacy and safety of haploidentical hematopoietic stem cell transplantation in patients with myeloid neoplasms over 50 years old, and to compare the differences in survival, recurrence, and adverse reactions between patients aged 50-55 and over 55 years old. Methods: The patients with myeloid neoplasms over 50 years old who received haploidentical hematopoietic stem cell transplantation from November 2016 to December 2021 in the Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University, School of Medicine were enrolled. According to the age at the time of transplantation, patients were divided into Group A (50-55 years old) and Group B (≥ 55 years old). The differences in Overall survival (OS), progression free survival (PFS), non-relapse mortality (NRM), cumulative incidence of relapse (CIR), incidence of graft versus host disease (GVHD), and infection rate between the two groups were analyzed. Results: A total of 163 patients (group A, n=77; group B, n=86) were enrolled, including 112 cases of acute myeloid leukemia (AML), 39 cases of myelodysplastic neoplasms (MDS), 4 cases of chronic myeloid monocyte leukemia (CMML), 3 cases of primary myelofibrosis (MF), and 5 cases of chronic myeloid leukemia (CML). There were no statistically significant differences in baseline data between the two groups, including follow-up time, disease categories, HCT-CI score, remission status of AML patients, minimal residual lesion (MRD) level of AML patients, and IPSS-R score of MDS patients. However, more patients in Group A received myeloablative (MAC) conditioning than patients in Group B (92.2% vs 50%, P=0.000). The median follow-up time was 741 (7-2377) days. The overall 2-year OS is 73.0% ± 3.5%, 2-year PFS is 71.3% ± 3.6%, 2-year NRM is12.23%（7.65%-17.93%）, and 2-year CIR is 17.20%（11.64%-23.69%）. All patients in group A achieved hematopoietic reconstitution except one patient died of graft failure, while 5 patients of group B died of graft failure(P=0.126). Neutrophils and platelet reconstruction in Group B was slightly longer than in Group A. The neutrophils reconstruction occurred at a median of 12 (8-20) day and 13 (9-25) day, respectively (P=0.007), and platelet reconstruction occurred at a median of 12 (9-28) day and 13 (8-37) day, respectively (P=0.055). The 2-year OS of Group A and Group B was 76.6% ± 4.8% and 69.0 ± 5.1%, respectively (P=0.199); The 2-year PFS was 76.2% ± 4.9% and 66.9 ± 5.1%, respectively (P=0.236); The 2-year NRM was 9.16% (4.00% -16.96%) and 18.61% (11.18% -27.51%), respectively (P=0.094); The 2-year CIR was similar, with 14.66% (7.74% -23.67%) and 19.16% (11.48% -28.33%), respectively (P=0.782). Interestingly, there was a difference in NRM between patients receiving reduced-intensity (RIC) and MAC conditioning in Group B, which was 10.2% (3.69% -20.61%) and 25.58% (13.64% -39.34%), respectively (P=0.043), while there was no difference in CIR, which was 17.31% (7.88% -29.80%) and 18.90% (8.71% -32.06%), respectively (P=0.933). It is suggested that in older patients, the strength of conditioning regimen has a greater impact on NMR. The incidence of grade 3-4 aGVHD within 100 days in all patients was 11.84% (7.31% -17.56%), and the incidence of 2-year intensive cGVHD was 8.19% (4.58% -13.14%). The incidence of grade 3-4 aGVHD within 100 days was similar between the two groups, with 9.46% (4.13% -17.46%) and 14.10% (7.46% -22.81%) (P=0.368), respectively. The 2-year intensive cGVHD was 8.07% (3.26% -15.72%) and 8.28% (3.62% -15.42%) (P=0.890), with similar incidence rates. The incidence of bacterial septicemia, pneumonia, invasive fungal infection, herpes virus and other infections were similar in both groups. Univariate and multivariate analysis both showed that 50-55 years old was an independent protective factor of OS (2.384 (1070-5.312), P=0.034) and GRFS (2.683 (1.181-6.094), P=0.018) in AML patients. Conclusion: Haploidentical hematopoietic stem cell transplantation is an effective and safe treatment for myeloid neoplasms over the age of 50. Compared with patients aged 50 to 55 years old, patients with myeloid neoplasms aged over 55 years old had similar efficacy and safety. The impact of MAC and RIC pretreatment on the prognosis of patients at different ages may be different. This retrospective study is limited in number and needs more cases and prospective cohort study to further verify.

Effect of Early Cytomegalovirus Reactivation on Relapse in Adult Patients with Myelodysplastic Syndromes after Allogeneic Hematopoietic Stem Cell Transplantation: A Registry Study from the Japan Society for Transplantation and Cellular Therapy (JSTCT)

Background Cytomegalovirus reactivation (CMVR) is a well-known complication contributing to morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Previous studies have demonstrated that CMVR is associated with poor clinical outcomes following HSCT. However, some studies have shown that CMVR following HSCT may have a recurrence-suppressing effect on hematological diseases, including acute myeloid leukemia and acute lymphoblastic leukemia. Conversely, data on the relevance between CMVR and relapse in patients with myelodysplastic syndromes (MDS) following HSCT remain limited and inconclusive. This nationwide retrospective study aimed to examine the association between CMVR and MDS relapse following HSCT. Methods This study was conducted by the Adult Myelodysplastic Syndromes Working Group of the Japan Society for Transplantation and Cellular Therapy (JSTCT). Clinical data were collected by the JSTCT and the Japanese Data Center for Hematopoietic Cell Transplantation employing the Transplant Registry Unified Management Program (TRUMP). Overall, 1,082 patients aged ≥16 years who were diagnosed with de novo MDS, underwent initial allogeneic HSCT between 2010 and 2018, and survived until 100 days post-transplant without disease relapse were examined. Patients who received cord blood transplantation, in vivo T-cell depletion, and prophylactic anti-CMV treatment were excluded. CMVR was defined as the initiation of CMV preemptive or definitive therapy within 100 days post-transplant. Patients underwent pp65 antigenemia monitoring commencing at the time of neutrophil engraftment after HSCT. Preemptive therapy was typically instituted upon the detection of a minimum of 2 CMV pp65 antigen-positive cells per 50,000 white blood cells. In analysis, CMVR and acute/chronic graft-versus-host disease (GVHD) were evaluated as time dependent covariates. This retrospective study was approved by the Data Management Committee of the JSTCT and the ethics committee of the Ehime University School of Medicine. Results Of the 1,082 patients, 622 (57.5%) experienced CMVR. The median time from HSCT to the onset of CMVR was 46 (range, 4-97) days. In contrast, reactivation beyond 100 days after HSCT was observed in 20 patients (1.8%). End-organ disease due to CMV infection was detected in 79 (7.3%) patients with a median of 61 (range, 19-385) days. CMV infections included enteritis (n = 65), retinitis (n = 5), pneumonitis (n = 4), hepatitis (n = 3), and others (n = 3). Of the whole cohort, the 5-year cumulative incidence of relapse (CIR), non-relapse mortality (NRM), disease-free survival, and overall survival (OS) were 15.6%, 26.7%, 57.7%, and 60.5%, respectively. The OS of patients with CMVR was significantly lower than that of patients without CMVR (P = 0.047). A total of 423 patients died at the time of analysis, and no difference in the cause of death was found between patients with and without CMVR. Then, the effect of CMVR on relapse after HSCT was analyzed by patient, disease, and transplant characteristics. Interestingly, in patients with &amp;lt;5% bone marrow blast count at the time of HSCT, CMVR was significantly associated with a lower CIR (5-year CIR, 7.6% vs. 16.4%; P = 0.002). On the contrary, no difference in the CIR was found between patients with and without CMVR in the group with ≥5% bone marrow blast count (5-year CIR, 19.4% vs. 18.0%; P = 0.72). Moreover, the OS of patients with CMVR was significantly lower than that of patients without CMVR in the group with ≥5% bone marrow blast count (P = 0.009). However, the OS of patients with &amp;lt;5% bone marrow blast count was similar between with and without CMVR (P = 0.82). In the multivariate analysis, CMVR was significantly associated with a lower CIR in the group with &amp;lt;5% bone marrow blast count (hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.23-0.70; P = 0.001). Furthermore, in the analysis excluding patients with grade II-IV acute GVHD, CMVR was similarly associated with a lower CIR in the group with &amp;lt;5% bone marrow blast count (HR, 0.38; 95% CI, 0.18-0.80; P = 0.011). Conclusion This study presents that CMVR may have different effects on MDS relapse depending on the bone marrow blast count at the time of HSCT. Although more studies are needed to understand the underlying mechanisms of this association, these findings may serve as a basis for devising effective CMV prophylaxis after HSCT.