Acute myeloid leukemia (AML) is both more common and with more biologically aggressive phenotype in the elderly. Allogenic stem cell transplantation (allo-SCT) is the best treatment option in fit ...patients. Either HLA-matched unrelated donor (MUD) or haploidentical (Haplo) donor are possible alternative for patients in need.
We retrospectively compared non-T-cell-depleted Haplo (n = 250) to 10/10 MUD (n = 2589) in AML patients ≥ 60 years.
Median follow-up was 23 months. Disease status at transplant differs significantly between the two groups (p < 10
). Reduced intensity conditioning (RIC) was administrated to 73 and 77% of Haplo and MUD, respectively (p = 0.23). Stem cell source was the bone marrow (BM) in 52% of the Haplo and 6% of MUD (p < 10
). Anti-thymocyte globulin (ATG) was most frequently used in MUD (p < 10
) while post-Tx cyclophosphamide (PT-Cy) was given in 62% of Haplo. Engraftment was achieved in 90% of the Haplo vs 97% of MUD (p < 10
). In multivariate analysis, no significant difference was found between Haplo and MUD for acute (a)graft versus host disease (GVHD) grade II-IV, relapse incidence (RI), non-relapse mortality (NRM), leukemia free survival (LFS), graft-versus-host-free-relapse free survival (GRFS), and overall survival (OS). Extensive chronic (c)GVHD was significantly higher for MUD as compared to Haplo (HR 2, p = 0.01, 95% CI 1.17-3.47). A propensity score analysis confirmed the higher risk of extensive cGVHD for MUD without differences for other outcomes.
Allo-SCT from both Haplo and MUD are valid option for AML patients ≥ 60 years of age with similar results. Transplantation from MUD was associated with higher extensive cGVHD. Our findings suggest that Haplo is a suitable and attractive graft source for patients≥ 60 with AML in need of allo-SCT.
Toxicity-reduced conditioning is being used for allogeneic stem cell transplantation in older and/or comorbid patients. We report on the treatment of 133 patients (median age: 55.6 years 23-73 years) ...with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS; n = 81), myeloproliferative syndromes (MPS; n = 20), and lymphoid malignancies (n = 32) using conditioning with FBM: fludarabine (5 × 30 mg/m2), 1,3-bis(2-chloroethyl)-1-nitrosourea (or carmustine, BCNU; 2 × 200 mg/m2), and melphalan (140 mg/m2). Patients 55 years or older received fludarabine with reduced BCNU (2 ×150 mg/m2) and melphalan (110 mg/m2). After engraftment, chimerism analyses revealed complete donor hematopoiesis in 95.7% of patients. With a median follow-up of 58.5 months, 3- and 5-year overall survival (OS) was 53.0% and 46.1%, event-free survival (EFS) was 46.4% and 41.9%. No significant differences in OS and EFS were evident considering disease status (early vs advanced), patient age (<55 vs≥55 years), or donor type (related vs unrelated) in univariate and multivariate analyses. The cumulative 5-year incidence of death due to relapse was 20.1%. Nonrelapse mortality (NRM) after 100 days and 1 year was 15.8% and 26.3%. Among patients with AML/MDS, advanced cases (n = 64, including 61 with active disease) showed an OS of 44.6% and 42.4% after 3 and 5 years, respectively. Therefore, FBM conditioning combines effective disease control with low NRM.
The
JAK2 V617F
mutation can be detected with a high frequency in patients with myeloproliferative neoplasms (MPN). MPN treatment efficiency can be assessed by
JAK2 V617F
quantification. Real-time ...quantitative PCR (qPCR) is widely used for
JAK2 V617F
quantification. Emerging alternative technologies like digital droplet PCR (ddPCR) have been described to overcome inherent qPCR limitations. The purpose of this study was to evaluate the utility of ddPCR for
JAK2 V617F
quantification in patient samples with MPN. Sensitivity and specificity were established by using DNA artificial mixtures. In addition, 101 samples from 59 patients were evaluated for
JAK2 V617F
mutation. Limit of detection was 0.01 % for both qPCR and ddPCR. The
JAK2 V617F
mutation was detected in 43 out of 59 patients by both PCR platforms. However, in 14 % of the samples,
JAK2 V617F
mutation was detected only with ddPCR. This 14 % of discrepant samples were from patients shortly after allogeneic stem cell transplantation. Percentage of
JAK2 V617F
mutation measured by qPCR and ddPCR in clinical samples showed a high degree of correlation (Spearman
r
: 0.9637
p
< 0.001) and an excellent agreement assessed by Bland-Altman analysis. In conclusion, ddPCR is a suitable, precise, and sensitive method for quantification of the
JAK 2 V617F
mutation.
Background Older primary central nervous system lymphoma (PCNSL) patients have an inferior prognosis compared to younger patients because available evidence on best treatment is scarce and treatment ...delivery is challenging due to comorbidities and reduced performance status. High-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) after high-dose methotrexate (MTX)-based immuno-chemotherapy has become an increasingly used treatment approach in eligible elderly PCNSL patients with promising feasibility and efficacy, but has not been compared with conventional chemotherapy approaches. In addition, eligibility for HCT-ASCT in elderly PCNSL is not well defined. Geriatric assessment (GA) may be helpful in selecting patients for the best individual treatment choice, but no standardized GA exists to date. A randomized controlled trial, incorporating a GA and comparing age-adapted HCT-ASCT treatment with conventional chemotherapy is needed. Methods This open-label, multicenter, randomized phase III trial with two parallel arms will recruit 310 patients with newly diagnosed PCNSL > 65 years of age in 40 centers in Germany and Austria. The primary objective is to demonstrate that intensified chemotherapy followed by consolidating HCT-ASCT is superior to conventional chemotherapy with rituximab, MTX, procarbazine (R-MP) followed by maintenance with procarbazine in terms of progression free survival (PFS). Secondary endpoints include overall survival (OS), event free survival (EFS), (neuro-)toxicity and quality of life (QoL). GA will be conducted at specific time points during the course of the study. All patients will be treated with a pre-phase rituximab-MTX (R-MTX) cycle followed by re-assessment of transplant eligibility. Patients judged transplant eligible will be randomized (1:1). Patients in arm A will be treated with 3 cycles of R-MP followed by maintenance therapy with procarbazine for 6 months. Patients in arm B will be treated with 2 cycles of MARTA (R-MTX/AraC) followed by busulfan- and thiotepa-based HCT-ASCT. Discussion The best treatment strategy for elderly PCNSL patients remains unknown. Treatments range from palliative to curative but more toxic therapies, and there is no standardized measure to select patients for the right treatment. This randomized controlled trial will create evidence for the best treatment strategy with the focus on developing a standardized GA to help define eligibility for an intensive treatment approach. Trial registration German clinical trials registry DRKS00024085 registered March 29, 2023. Keywords: Primary central nervous system lymphoma (PCNSL), High-dose chemotherapy (HCT), Autologous stem cell transplantation (ASCT), Elderly patients, Transplant eligibility
Previously, we demonstrated that the addition of anti-human-T-lymphocyte immunoglobulin (ATLG) to standard ciclosporin and methotrexate prophylaxis reduced graft-versus-host disease (GvHD) in adult ...patients treated with allogeneic haemopoietic cell transplantation from matched unrelated donors without negatively affecting relapse and survival. Since reports on long-term results from randomised trials testing anti-thymocyte globulin are scarce, we performed an extended follow-up of the trial.
Between May 26, 2003, and Feb 8, 2007, 202 patients with haematological malignancies were centrally randomly assigned using computer-generated centre-stratified block randomisation to receive ciclosporin and methotrexate with or without ATLG. 201 patients who underwent transplantation with peripheral blood (n=164; 82%) or bone marrow (n=37; 18%) grafts after myeloablative conditioning were included in the full analysis set, and were analysed according to their randomly assigned treatment (ATLG n=103, non-ATLG n=98). We assessced chronic GvHD, non-relapse mortality, relapse, relapse mortality, disease-free survival, overall survival, severe GvHD-free (acute GvHD III-IV, and extensive chronic GvHD) and relapse-free survival, and time under immunosuppressive therapy after long-term follow-up. The trial is registered with the German Clinical Trials Register (DRKS00000002), ClinicalTrials.gov (NCT00655343), and EudraCT (2004-000232-91).
Median follow-up was 8·6 years (IQR 8·0-9·3). Only patients at risk for chronic GvHD (ie, patients who were alive and without a second transplant at 100 days) were included in the analyses of chronic GvHD (90 patients in the ATLG group, 80 patients in the non-ATLG group). At 8 years, the incidence of extensive chronic GvHD was 14% (95% CI 8-29) in the ATLG group versus 52% (42-64) in the non-ATLG group (adjusted hazard ratio HR 0·18, 95% CI 0·09-0·34; p<0·0001). Non-relapse mortality was 21% (95% CI 14-30) versus 34% (26-45; adjusted HR 0·66, 95% CI 0·38-1·16; p=0·15), incidence of relapse was 35% (95% CI 27-46) versus 30% (22-41; adjusted HR 1·17, 95% CI 0·71-1·93; p=0·54), relapse mortality was 31% (95% CI 23-41) versus 29% (21-40; adjusted HR 1·03, 95% CI 0·61-1·76; p=0·90), disease-free survival was 44% (95% CI 35-54) versus 36% (27-46) (adjusted HR 0·91, 95% CI 0·63-1·31; p=0·60), overall survival was 49% (95% CI 39-59) versus 37% (27-47; adjusted HR 0·82, 95% CI 0·56-1·20; p=0·31), and severe GvHD-free and relapse-free survival was 34% (25-43) versus 13% (7-21) (adjusted HR 0·55, 95% CI 0·39-0·76; p=0·0003). The probability of being alive and free of immunosuppressive therapy was 47% (95% 37-57) in the ATLG group and 11% (5-18) in the non-ATLG group at 8 years.
ATLG in addition to standard ciclosporin and methotrexate as GvHD prophylaxis improves severe GvHD-free and relapse-free survival in the long term. The use of ATLG in unrelated donor transplantation after myeloablative conditioning substantially increases the probability of surviving free of immunosuppressive therapy, and thus reduces the risk associated with long-term immunosuppression.
Neovii Biotech.
High-dose chemotherapy followed by autologous stem cell transplantation has been shown to be feasible and highly effective in newly diagnosed primary central nervous system lymphoma. In this ...retrospective multicenter study, we investigated prognosis and baseline risk factors in patients with primary central nervous system lymphoma who underwent this treatment approach. We retrospectively analyzed 105 immunocompetent patients with primary central nervous system lymphoma who underwent high-dose chemotherapy followed by autologous stem cell transplantation with or without whole brain radiotherapy as first-line consolidation treated at 12 German centers between 1997 and 2011. We estimated survival rates and investigated the impact of age, performance status, serum lactate dehydrogenase level, and deep brain involvement on overall and progression-free survival. Patients were additionally categorized into three prognostic groups according to the Memorial Sloan Kettering Cancer Center prognostic model. After a median follow up of 47 months, median progression-free survival and overall survival was reached after 85 and 121 months; 2- and 5-year survival rates were 82% and 79%, respectively. The Memorial Sloan Kettering Cancer Center prognostic model did not predict survival. Only age revealed some evidence of prognostic relevance. Overall response rate was 95%; of those patients with progressive disease before high-dose chemotherapy, 7 of 20 achieved ongoing complete remission after therapy without whole brain radiation therapy. Transplantation-associated mortality was 2.8%. High-dose chemotherapy followed by autologous stem cell transplantation is a highly effective and safe treatment modality for selected primary central nervous system lymphoma patients. Superiority compared to standard chemotherapy still warrants further investigation.
High-dose methotrexate-based chemotherapy is standard for primary CNS lymphoma, but most patients relapse. High-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) is supposed to ...overcome the blood-brain barrier and eliminate residual disease in the CNS. We aimed to investigate the safety and efficacy of HCT-ASCT in patients with newly diagnosed primary CNS lymphoma.
In this prospective, single-arm, phase 2 trial, we recruited patients aged 18-65 years with newly diagnosed primary CNS lymphoma and immunocompetence, with no limitation on clinical performance status, from 15 hospitals in Germany. Patients received five courses of intravenous rituximab 375 mg/m(2) (7 days before first high-dose methotrexate course and then every 10 days) and four courses of intravenous high-dose methotrexate 8000 mg/m(2) (every 10 days) and then two courses of intravenous rituximab 375 mg/m(2) (day 1), cytarabine 3 g/m(2) (days 2 and 3), and thiotepa 40 mg/m(2) (day 3). 3 weeks after the last course, patients commenced intravenous HCT-ASCT (rituximab 375 mg/m(2) day 1, carmustine 400 mg/m(2) day 2, thiotepa 2 × 5 mg/kg days 3 and 4, and infusion of stem cells day 7), irrespective of response status after induction. We restricted radiotherapy to patients without complete response after HCT-ASCT. The primary endpoint was complete response at day 30 after HCT-ASCT in all registered eligible patients who received at least 1 day of study treatment. This trial is registered at ClinicalTrials.gov, number NCT00647049.
Between Jan 18, 2007, and May 23, 2011, we recruited 81 patients, of whom two (2%) were excluded, therefore we included 79 (98%) patients in the analysis. All patients started induction treatment; 73 (92%) commenced HCT-ASCT. 61 (77·2% 95% CI 66·1-86·6) patients achieved a complete response. During induction treatment, the most common grade 3 toxicity was anaemia (37 47%) and the most common grade 4 toxicity was thrombocytopenia (50 63%). During HCT-ASCT, the most common grade 3 toxicity was fever (50 68% of 73) and the most common grade 4 toxicity was leucopenia (68 93% of 73). We recorded four (5%) treatment-related deaths (three 4% during induction and one 1% 4 weeks after HCT-ASCT).
HCT-ASCT with thiotepa and carmustine is an effective treatment option in young patients with newly diagnosed primary CNS lymphoma, but further comparative studies are needed.
University Hospital Freiburg and Amgen.
Primary induction failure (PIF) in acute myeloid leukemia (AML) patients is associated with poor outcome, with allogeneic hematopoietic stem cell transplantation (HCT) being the sole curative ...therapeutic option. Here, we retrospectively evaluated long-term outcomes of 220 AML patients undergoing allogeneic HCT after PIF who never achieved remission, and identified clinical and molecular risk factors associated with treatment response and ultimate prognosis. In this high-risk population, disease-free survival was 25.2% after 5 years and 18.7% after 10 years, while overall survival rates were 29.8% and 21.6% after 5 and 10 years of HCT, respectively. 10-year non-relapse mortality was 32.5%, and 48.8% of patients showed disease relapse within 10 years after allogeneic HCT. Adverse molecular risk features determined at initial diagnosis, poor performance status at the time of allogeneic HCT, and long diagnosis-to-HCT intervals were associated with unfavorable prognosis. Collectively, our data suggests that immediate allogeneic HCT after PIF offers long-term survival and cure in a substantial subset of cases and that high-risk AML patients who never achieved complete response during induction might benefit from early donor search.
To improve outcome for older patients with poor-prognosis myeloid malignancies by using allogeneic hematopoietic stem-cell transplantation (alloHSCT) from unrelated and sibling donors after ...reduced-intensity conditioning (RIC).
Nineteen older patients (median age, 64 years; range, 60 to 70 years) with active myeloid malignancies were treated with an RIC regimen that was based on fludarabine, melphalan, and carmustine followed by alloHSCT from matched unrelated (n = 12) or sibling donors (n = 7). Before transplantation, patients had a median of 50% bone marrow blasts (range, 0% to 70%). Graft-versus-host-disease (GvHD) prophylaxis consisted of cyclosporine and mycophenolate mofetil or methotrexate. Eleven of 12 patients with an unrelated donor also received anti-T-lymphocyte globulin (ATG).
Engraftment was successful for all 19 patients. Seventeen assessable patients achieved complete response (CR). Four patients experienced relapse; three achieved CR again after donor lymphocyte infusion (n = 1) or a second alloHSCT (n = 2). Six patients died as a result of relapse (n = 2), GvHD-associated complications (n = 2), or fungal infections (n = 2), resulting in a 1-year nonrelapse mortality rate of 22%. With a median follow-up of 825 days (range, 595 to 1,028 days), 13 of 19 patients are alive, resulting in a 1-year survival rate of 68% (95% confidence interval, 48% to 89%).
In older patients with untreated poor-prognosis leukemia, this RIC regimen combined with alloHSCT sufficiently reduces the leukemic burden, resulting in a high CR rate. When ATG is added, matched unrelated donor transplantation can be performed safely in older patients. For these patients, early transplantation after diagnosis offers a fair chance of cure.
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