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1.
Allogeneic hematopoietic cell transplantation for Richter transformation of chronic lymphocytic leukemia: an intention-to-transplant analysis
Puckrin, R., Owen, C., Fontaine, A., Peters, A., Stewart, D., Shafey, M.
Bone marrow transplantation. 2023
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2.
Comparison of Outcomes of Transplant and Nontransplant High-Risk Chronic Lymphocytic Leukemia Patients in the Novel Targeted Therapy Era
Aytan, P., Yeral, M., Gereklioglu, C., Kasar, M., Buyukkurt, N. H., Asma, S., Korur, A., Kozanoglu, I., Ozdogu, H., Boga, C.
Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation. 2021
Abstract
OBJECTIVES Our aim was to compare patients with high-risk chronic lymphocytic leukemia referred to our transplant center who underwent allogeneic stem cell transplant with those who did not receive this treatment. Factors compared included demographics, clinical characteristics, and survival rates in the novel targeted therapy era. MATERIALS AND METHODS All 33 patients with high-risk chronic lymphocytic leukemia who were referred to the hematopoietic stem cell transplant center were enrolled in this retrospective, single-center nonrandomized study. Outcomes of patients who received allogeneic stem cell transplant were compared with those of nontransplant patients. Chemoimmunotherapy and ibrutinib were given when indicated. Factors related to overall and progression-free survival were assessed. RESULTS Thirteen patients underwent allotransplant, and transplant was not done in 20 patients for various reasons. Demographic and clinical features of the transplant and nontransplant groups were similar. The estimated cumulative overall survival was 72.6 ± 15 and 84.3 ± 13 months in the nontransplant and transplant groups, respectively. The 5-year overall and progression-free survival rates in the transplant and nontransplant groups were 57.3%/36.0% and 40%/20.6%, respectively. In the nontransplant group, overall survival of those who used ibrutinib was longer than overall survival in patients in the transplant group who used the same drug, but the difference was not statistically significant. Although not significant, overall survival in patients who did not use ibrutinib was longer in the transplant group than in the nontransplant group. Cox regression analyses showed that transplant, relapse, and Binet stage were independent predictors of overall survival. CONCLUSIONS In patients who do not use ibrutinib, allogeneic stem cell transplant improved survival compared with nontransplant patients. Addition of ibrutinib provided comparable life expectancies, showing that allogeneic stem cell transplant and ibrutinib may have complementary roles. Transplant is still an independent predictor of overall survival.
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3.
Outcomes of patients diagnosed with chronic lymphocytic leukemia after allogeneic hematopoietic stem cell transplantation: Results from a tertiary care center
Mar Linn, S., Vasudevan Nampoothiri, R., Chen, C., Pasic, I., Al-Shaibani, Z., Lam, W., Datt Law, A., Michelis, F. V., Kim, D. D. H., Gerbitz, A., et al
Hematology/oncology and stem cell therapy. 2021
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HCT) is currently the only curative treatment for patients with chronic lymphocytic leukemia (CLL). METHODS We analyzed the outcomes of 93 patients (median age: 52?years) who underwent allo-HCT at our center between 1989 and 2019. RESULTS After a median follow-up of 35?months, relapse was observed in 15.1% (n?=?14) patients. The estimated 2-year non-relapse mortality, relapse-free survival, and overall survival (OS) were 38.1%, 54.2%, and 58.7%, respectively. The ECOG performance status?=?2 (hazard ratio [HR]: 4.1; p?=?.001) and use of total body irradiation (in a myeloablative conditioning regimen; HR: 2.64; p?=?.005) were predictive of poor OS after multivariable analysis. The occurrence of sinusoidal obstruction syndrome/veno-occlusive disease post-transplant was associated with poor survival (p?=?.001). CONCLUSION Although the use of kinase and bcl2 inhibitors may result in a decrease in the number and need of transplants, allo-HCT remains a viable option in selected patients with high-risk CLL and good performance status.
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4.
Allogeneic hematopoietic cell transplantation after prior targeted therapy for high-risk chronic lymphocytic leukemia
Kim, H. T., Shaughnessy, C. J., Rai, S. C., Reynolds, C., Ho, V. T., Cutler, C., Koreth, J., Gooptu, M., Romee, R., Nikiforow, S., et al
Blood advances. 2020;4(17):4113-4123
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Abstract
Allogeneic hematopoietic cell transplantation (alloHCT) can cure previously treated high-risk chronic lymphocytic leukemia (CLL) patients if they are suitable for transplant through the graft-versus-leukemia effect. However, since the emergence of targeted therapies, the role of alloHCT for high-risk CLL is less clear. To address this question, we evaluated 108 high-risk CLL patients who underwent alloHCT from 2010 to 2018. Thirty patients from the period of 2013 to 2018 received targeted therapy prior to alloHCT. The median age for the targeted therapy cohort was 60 years (range, 30-71 years), and 20% and 73% had complete and partial remission, respectively: 76% had del(17p), 46.2% had 5 or more cytogenetic abnormalities, and 78.9% were IGHV unmutated. The median number of prior therapies was 4 (range, 1-9). With a median follow-up time of 36 months (range, 10-72 months), the 3-year overall (OS) and progression-free survival (PFS) were 87% and 69%, respectively. The 3-year cumulative incidence of nonrelapse mortality and relapse was 7% and 24%, respectively. For the control cohort of 78 patients who underwent alloHCT from 2010 to 2014 and received only chemoimmunotherapy prior to transplant, the 3-year OS and PFS were 69% and 58%, respectively. Patients treated with targeted therapy prior to alloHCT had a significantly higher number of circulating T and B cells and a lower ratio of CD4 regulatory T cells to CD4 conventional T cells early after transplant. In summary, despite multiple high-risk features, the clinical outcome of CLL patients who receive targeted therapy prior to transplant is excellent and alloHCT should be offered while the disease is under control.
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Refractory and 17p-deleted chronic lymphocytic leukemia: improving survival with pathway inhibitors and allogeneic stem cell transplantation
Farina, L., Barretta, F., Scarfo, L., Bruno, B., Patriarca, F., Frustaci, A. M., Coscia, M., Salvetti, C., Quaresmini, G., Fanin, R., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
Refractory/early relapsed and 17p deletion/p53 mutation (del(17p)/TP53mut)-positive chronic lymphocytic leukemia (CLL) has been conventionally considered a high-risk disease, potentially eligible for allogeneic stem cell transplantation (alloSCT). In this multicenter retrospective analysis of 157 patients, we compared the outcomes of high-risk CLL treated with alloSCT or B-cell receptor pathway inhibitors (BCRis) or both. Seventy-one patients were treated with BCRis, 67 patients underwent reduced intensity alloSCT, and 19 received alloSCT with BCRis before and/or after transplant. An inverse probability of treatment weighting analyses were performed to compare alloSCT versus no-alloSCT groups: 5-year OS, PFS, and cumulative incidence of NRM and relapse were 40%/60% (p=0.096), 34%/17% (p=0.638), 28%/5% (p=0.016), and 38%/83% (p=0.005), respectively. Patients treated with alloSCT+BCRis showed a 3-year OS of 83%. Three -year OS and NRM by year of alloSCT, including patients treated with BCRis, were 53% and 17% in 2000-2007, 55% and 30% in 2008-2012 and 72% and 18% in 2013-2018. In conclusion, the combination of pathway inhibitors and alloSCT is feasible and may further improve the outcome of high-risk CLL patients.
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Allogeneic stem cell transplantation for chronic lymphocytic leukemia in the era of novel agents
Roeker, L. E., Dreger, P., Brown, J. R., Lahoud, O. B., Eyre, T. A., Brander, D. M., Skarbnik, A., Coombs, C. C., Kim, H. T., Davids, M., et al
Blood advances. 2020;4(16):3977-3989
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Abstract
Although novel agents (NAs) have improved outcomes for patients with chronic lymphocytic leukemia (CLL), a subset will progress through all available NAs. Understanding outcomes for potentially curative modalities including allogeneic hematopoietic stem cell transplantation (alloHCT) following NA therapy is critical while devising treatment sequences aimed at long-term disease control. In this multicenter, retrospective cohort study, we examined 65 patients with CLL who underwent alloHCT following exposure to =1 NA, including baseline disease and transplant characteristics, treatment preceding alloHCT, transplant outcomes, treatment following alloHCT, and survival outcomes. Univariable and multivariable analyses evaluated associations between pre-alloHCT factors and progression-free survival (PFS). Twenty-four-month PFS, overall survival (OS), nonrelapse mortality, and relapse incidence were 63%, 81%, 13%, and 27% among patients transplanted for CLL. Day +100 cumulative incidence of grade III-IV acute graft-vs-host disease (GVHD) was 24%; moderate-severe GVHD developed in 27%. Poor-risk disease characteristics, prior NA exposure, complete vs partial remission, and transplant characteristics were not independently associated with PFS. Hematopoietic cell transplantation-specific comorbidity index independently predicts PFS. PFS and OS were not impacted by having received NAs vs both NAs and chemoimmunotherapy, 1 vs =2 NAs, or ibrutinib vs venetoclax as the line of therapy immediately pre-alloHCT. AlloHCT remains a viable long-term disease control strategy that overcomes adverse CLL characteristics. Prior NAs do not appear to impact the safety of alloHCT, and survival outcomes are similar regardless of number of NAs received, prior chemoimmunotherapy exposure, or NA immediately preceding alloHCT. Decisions about proceeding to alloHCT should consider comorbidities and anticipated response to remaining therapeutic options.
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Efficacy of minimal residual disease driven immune-intervention after allogeneic hematopoietic stem cell transplantation for high-risk chronic lymphocytic leukemia: results of a prospective multicentric trial
Tournilhac, O., Le Garff-Tavernier, M., Nguyen Quoc, S., Forcade, E., Chevallier, P., Legrand-Izadifar, F., Damaj, G. L., Michonneau, D., Tomowiak, C., Borel, C., et al
Haematologica. 2020
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) remains a potentially curative and useful strategy in high-risk relapsing CLL. Minimal Residual Disease (MRD) assessment at 12 months post-HSCT is predictive of relapse. This phase 2 study aimed to achieve M12 MRD negativity (MRDneg) using MRD-driven immune-intervention (Md-PII) algorithm based on serial flow-cytometry blood MRD, involving cyclosporine tapering followed if failure by donor lymphocytes infusions. Patients had high-risk CLL according to 2006 EBMT consensus, in complete or partial response with lymphadenopathy < 5 cm and comorbidity score ≤ 2. Donors were HLA-matched sibling or matched unrelated (10/10). Forty-two enrolled patients with either 17p deletion (front-line, n=11; relapse n=16) or other high-risk relapse (n=15) received reduced intensity-conditioning regimen before HSCT and were submitted to Md-PII. M12-MRDneg status was achieved in 64% versus 14.2% before HSCT. With a median follow-up of 36 months (range, 19-53), 3-year overall survival, non-relapse mortality and cumulative incidence of relapse are 86.9% (95%CI, 70.8-94.4), 9.5% (95%CI, 3.7-23.4) and 29.6% (95%CI, 17.3-47.7). Incidence of 2-year limited and extensive chronic graft versus host disease (cGVHD) is 38% (95%CI, 23-53) and 23% (95%CI, 10-36) including 2 cases post Md-PII. Fifteen patients converted to MRDneg either after CsA withdrawal (n=12) or after cGVHD (n=3). As a time-dependent variable, MRDneg achievement at any time-point correlates with reduced relapse (HR=0.14 [0.04-0.53], p=0.004) and improvement of both progression free (HR=0.18 [0.06-0.6], p<0.005) and overall (HR: 0.18 [0.03-0.98], p=0.047) survival. These data highlight the value of MRD-driven immune-intervention to induce prompt MRD clearance in the therapy of CLL.
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Idelalisib treatment prior to allogeneic stem cell transplantation for patients with chronic lymphocytic leukemia: a report from the EBMT chronic malignancies working party
Schetelig, J., Chevallier, P., van Gelder, M., Hoek, J., Hermine, O., Chakraverty, R., Browne, P., Milpied, N., Malagola, M., Socié, G., et al
Bone marrow transplantation. 2020
Abstract
No studies have been reported so far on bridging treatment with idelalisib for patients with chronic lymphocytic leukemia (CLL) prior to allogeneic hematopoietic cell transplantation (alloHCT). To study potential carry-over effects of idelalisib and to assess the impact of pathway-inhibitor (PI) failure we performed a retrospective EBMT registry-based study. Patients with CLL who had a history of idelalisib treatment and received a first alloHCT between 2015 and 2017 were eligible. Data on 72 patients (median age 58 years) were analyzed. Forty percent of patients had TP53(mut/del) CLL and 64% had failed on at least one PI. No primary graft failure occurred. Cumulative incidences of acute GVHD °II-IV and chronic GVHD were 51% and 39%, respectively. Estimates for 2-year overall survival (OS), progression-free survival (PFS), and cumulative incidences of relapse/progression (CIR) and non-relapse mortality NRM were 59%, 44%, 25%, and 31%. In univariate analysis, drug sensitivity was a strong risk factor. For patients who had failed neither PI treatment nor chemoimmunotherapy (CIT) the corresponding 2-year estimates were 73%, 65%, 15%, and 20%, respectively. In conclusion, idelalisib may be considered as an option for bridging therapy prior to alloHCT. Owing to the high risk for acute GVHD intensified clinical monitoring is warranted.
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Allogeneic hematopoietic cell transplantation for patients with TP53 mutant or deleted chronic lymphocytic leukemia: Results of a prospective observational study
Schetelig, J., Hoek, J., Stilgenbauer, S., Middeke, J. M., Andersen, N. S., Fox, C. P., Lenhoff, S., Volin, L., Shimoni, A., Schroyens, W., et al
Bone marrow transplantation. 2020
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10.
Allogeneic transplantation for high-risk chronic lymphocytic leukemia-a summary of a 16-year experience
Helbig, G., Spalek, A., Wieczorkiewicz-Kabut, A., Markiewicz, M., Kopera, M., Zielinska, P., Wozniczka, K., Kopinska, A., Grygoruk-Wisniowska, I., Koclega, A.
Annals of hematology. 2019
Abstract
In the pathway inhibitor era, the number of allogeneic stem cell transplantation (ASCT) for chronic lymphocytic leukemia (CLL) continues to decrease and this approach should be offered only after careful risk-benefit assessment. Nevertheless, ASCT still remains only curative therapeutic modality for CLL, especially in countries with limited access to novel agents. Thirty patients with CLL at median age of 42 years at diagnosis (range 29-64) underwent ASCT between years 2002 and 2018. Thirteen patients were transplanted in complete remission (CR), ten patients achieved partial response (PR), and seven had stable disease. The median time from diagnosis to transplant was 4 years (range 0.5-12). Twenty-three patients received HLA-matched related donor stem cell grafts, and seven patients received either matched unrelated donor or HLA-mismatched grafts. Reduced intensity conditioning (RIC) and myeloablative regimen (MAC) were used in 24 and 6 patients, respectively. Mortality to day + 100 after transplant was 16% (8% for RIC only). Acute and chronic graft versus host disease (GVHD) developed in 40% and 63% of patients, respectively. Fifteen patients relapsed or progressed after transplant. Thirteen patients (43%) are alive at last follow-up and 10 (77%) remain in clinical CR. Median follow-up for survivors was 6.8 years (range 0.4-15.2). Three-year progression-free and overall survivals were 56% and 60%, respectively. These outcomes were better for patients who received RIC conditioning: 64% and 72%, respectively. CR at transplant was found to have favorable impact on post-allograft survival. RIC should be preferred over MAC. ASCT may remain a valuable option for some CLL patients.