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1.
Reduced-intensity conditioning hematopoietic stem cell transplantation for chronic lymphocytic leukemia and Richter's transformation
Lahoud, O. B., Devlin, S. M., Maloy, M. A., Roeker, L. E., Dahi, P. B., Ponce, D. M., Gyurkocza, B., Koehne, G., Young, J. W., Castro-Malaspina, H. R., et al
Blood advances. 2021;5(14):2879-2889
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Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) may potentially cure patients with chronic lymphocytic leukemia (CLL) and Richter's transformation (CLL-RT) or CLL without RT, but the impact of novel agents on HSCT is unclear. CLL-RT patients have a grave prognosis, and their outcomes after HSCT are uncertain. We conducted a retrospective analysis of all 58 CLL patients, including 23 CLL-RT patients, who underwent reduced intensity conditioning (RIC) HSCT at Memorial Sloan Kettering Cancer Center (New York, NY) between September 2006 and April 2017. With a median follow-up of 68 months (range, 24-147 months), 5-year progression-free survival (PFS) was 40% (95% confidence interval [CI], 28%-56%), and overall survival (OS) was 58% (95% CI, 48%-74%). The 1-year graft-versus-host disease/relapse-free survival (GRFS) was 38% (95% CI, 25%-50%). Patients with CLL-RT and CLL patients without RT had comparable outcomes. In both cohorts, treatment-sensitive response and ≤3 previous lines of therapy produced superior PFS and OS. Outcomes were agnostic to adverse cytogenetic and molecular features. Novel agents did not have a negative impact on HSCT outcomes. Total body irradiation (TBI)-containing RIC yielded inferior PFS, OS, and GRFS. CLL-RT patients older than age 55 years who had an HSCT Comorbidity Index score of ≥2 demonstrated inferior OS. This study, which is the largest series of RIC-HSCT for patients with CLL-RT, provides evidence supporting RIC-HSCT in early remission courses for patients with CLL-RT and poor-risk CLL patients. TBI-containing RIC should be considered with caution.
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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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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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Reduced intensity conditioning regimens including alkylating chemotherapy do not alter survival outcomes after allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia compared to low-intensity non-myeloablative conditioning
Andersen, N. S., Bornhauser, M., Gramatzki, M., Dreger, P., Vitek, A., Karas, M., Michallet, M., Moreno, C., van Gelder, M., Henseler, A., et al
Journal of cancer research and clinical oncology. 2019
Abstract
PURPOSE The optimal dose intensity for conditioning prior to allogeneic hematopoietic stem cell transplantation (alloHSCT) for chronic lymphocytic leukemia (CLL) is unknown. METHODS We retrospectively compared outcomes of patients who received a first alloHCST after non-myeloablative (NMA) and reduced intensity conditioning (RIC). Data of 432 patients with a median age of 55 years were included, of which 86 patients underwent NMA and 346 RIC. RESULTS The median follow-up after alloHSCT was 4.3 years. Compared to the RIC group, more NMA patients had purine-analog-sensitive disease, were in complete remission and received matched related donor transplantation. After RIC, the probabilities for 5-year OS, EFS, CIR, and NRM were 46%, 38%, 28%, and 35% and after NMA the respective probabilities were 52%, 43%, 25%, and 32%. In multivariate analysis, remission status prior to conditioning but not RIC versus NMA conditioning had a significant impact on CIR, EFS, and OS. CONCLUSION Presumed higher anti-leukemic activity of RIC versus NMA conditioning did not translate into better outcomes after alloHSCT, but better remission status prior to conditioning did. Effective pathway inhibitor-based salvage therapies combined with NMA conditioning might thus represent the most attractive contemporary approach for alloHSCT for patients with CLL.
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Rituximab-based allogeneic transplant for chronic lymphocytic leukemia with comparison to historical experience
Shadman, M., Maloney, D. G., Storer, B., Sandmaier, B. M., Chauncey, T. R., Smedegaard Andersen, N., Niederwieser, D., Shizuru, J., Bruno, B., Pulsipher, M. A., et al
Bone marrow transplantation. 2019
Abstract
Relapse of chronic lymphocytic leukemia (CLL) after allogeneic hematopoietic cell transplantation (HCT) remains a clinical challenge. We studied in a phase II trial whether the addition of peri-transplant rituximab would reduce the relapse risk compared with historical controls (n = 157). Patients (n = 55) received fludarabine and low-dose total body irradiation combined with rituximab on days -3, + 10, + 24, + 36. Relapse rate at 3 years was significantly lower among rituximab-treated patients versus controls (17% versus 31%; P = 0.04). Overall survival (OS), progression-free survival (PFS) and nonrelapse mortality (NRM) were statistically similar: (53% versus 50%; P = 0.8), (44% versus 42%; P = 0.63), and (38% versus 28%; P = 0.2), respectively. In multivariate analysis, rituximab treatment was associated with lower relapse rates both in the overall cohort [hazard ratio (HR): 0.34, P = 0.006] and in patients with high-risk cytogenetics (HR: 0.21, P = 0.0003). Patients with no comorbidities who received rituximab conditioning had an OS rate of 100% and 75% at 1 and 3 years, respectively, with no NRM. Peri-transplant rituximab reduced relapse rates regardless of high-risk cytogenetics. HCT is associated with minimal NRM in patients without comorbidities and is a viable option for patients with high-risk CLL. Clinical trial information: NCT00867529.
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Ofatumumab plus high dose methylprednisolone followed by ofatumumab plus alemtuzumab to achieve maximal cytoreduction prior to allogeneic transplantation for 17p deleted or TP53 mutated chronic lymphocytic leukemia
Davids, M. S., Kim, H. T., Yu, L., De Maeyer, G., McDonough, M., Vartanov, A. R., Langey, R., Fernandes, S. M., Hellman, J. M., Francoeur, K., et al
Leukemia & lymphoma. 2018;:1-4
Abstract
We hypothesized that ofatumumab with sequential methylprednisolone - alemtuzumab would be an effective and tolerable regimen for patients with high-risk chronic lymphocytic leukemia (CLL) with TP53 dysfunction. Thirty CLL patients with TP53 dysfunction (15 treatment naive (TN), 15 relapsed/refractory (R/R)) were enrolled in this phase II study. Therapy included ofatumumab with methylprednisolone for 2-4 monthly cycles, then ofatumumab with alemtuzumab for 4-24 weeks, then allogeneic transplantation or maintenance. The rate of overall response, complete response, marrow minimal residual disease (MRD) negativity, 3-year progression-free survival and overall survival were 80, 13, 80, 53, and 66%, respectively, in TN patients and 68, 0, 54, 25, and 53%, respectively, in R/R patients. Notable grade 3/4 toxicities included neutropenia and infection in 43 and 40% of patients, respectively. At median follow-up of 45 months, 13 patients died, and 10 patients are alive posttransplant. Overall, we observed high rates of MRD-negativity and acceptable tolerability in high-risk CLL.
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Reduced intensity is preferred over myeloablative conditioning allogeneic HCT in chronic lymphocytic leukemia whenever indicated: A systematic review/meta-analysis
Kharfan-Dabaja, M. A., Moukalled, N., Reljic, T., El-Asmar, J., Kumar, A.
Hematology/Oncology & Stem Cell Therapy. 2017
Abstract
Despite availability of new and more effective therapies for chronic lymphocytic leukemia, presently this disease remains incurable unless eligible patients are offered an allogeneic hematopoietic cell transplant. Recent published clinical practice recommendations on behalf of the American Society for Blood and Marrow Transplantation relegated the role of for allogeneic hematopoietic cell transplantation to later stages of the disease. To our knowledge, no randomized controlled trial has been performed to date comparing myeloablative versus reduced intensity conditioning regimens in chronic lymphocytic leukemia patients eligible for the procedure. We performed a systematic review/meta-analysis to assess the efficacy of allogeneic hematopoietic cell transplantation when using myeloablative or reduced intensity conditioning regimens. We report the results in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Based on lower non-relapse mortality and slightly better overall survival rates, reduced intensity conditioning regimens appear to be the most desirable choice whenever the procedure is indicated for this disease. It appears highly unlikely that a RCT will be ever performed comparing reduced intensity vs. myeloablative allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia. In the absence of such a study, results of this systematic review/meta-analysis represent the best available evidence supporting this recommendation whenever indicated in patients with chronic lymphocytic leukemia.
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Bendamustine added to allogeneic conditioning improves long-term outcomes in patients with CLL
Khouri, I. F., Sui, D., Jabbour, E. J., Samuels, B. I., Turturro, F., Alatrash, G., Anderlini, P., Ahmed, S., Oran, B., Ciurea, S. O., et al
Bone Marrow Transplantation. 2017;52(1):28-33
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Abstract
Bendamustine has shown a favorable safety profile when included in chemotherapy regimens for several types of lymphoma, including CLL. This study investigated the long-term effect of adding bendamustine to a conditioning regimen on survival, rate of engraftment, immune recovery and GvHD after allogeneic stem cell transplantation (alloSCT) in CLL patients. These outcomes were compared with the fludarabine, cyclophosphamide and rituximab (FCR) conditioning regimen. We reviewed the data for 89 CLL patients treated on three trials at our institution. Twenty-six (29%) patients received bendamustine, fludarabine and rituximab (BFR) and 63 (71%) received FCR. Patient characteristics were similar in both groups. Ten (38%) BFR-treated patients vs only two (3%) FCR-treated patients did not experience severe neutropenia (P=<0.001). The 3-year overall survival estimates for the BFR and FCR groups were 82 and 51% (P=0.03), and the 3-year PFS estimates were 63% and 27% (P=0.001), respectively. The 2-year treatment-related mortality was 8 and 23% and the incidence of grade 3 or 4 GvHD was 4% and 10%, respectively. This study is the first to report that addition of bendamustine to alloSCT conditioning for CLL patients is associated with improved survival and lower mortality, myelosuppression, and GvHD.
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Prognostic factors to predict outcome of reduced intensity allogeneic haematopoietic cell transplantation for chronic lymphocytic leukemia
Jindra, P., Raida, L., Lysak, D., Karas, M., Papajik, T., Jungova, A., Mohammadova, L., Houdova, L.
Neoplasma. 2016;63(4):595-600
Abstract
Despite advances in immunochemotherapy CLL remains an incurable disease.. Allogeneic haematopoietic cell transplantation (HCT) has proven curative potential with ability to overcome adverse prognostic factors, however due to its toxicity it is generally perceived as the last option. We performed retrospective study to explore the outcomes and possible determinants of survival in the unselected consecutive cohort of 68 CLL patients (median age 59 years) receiving reduced intensity HCT as a part of salvage therapy in 2 Czech centers. The median interval from diagnosis to HCT was 69 months with median 3 of prior regimens, all patients were refractory to purine analogues. 49% of patients were transplanted with advanced (i.e. refractory or progressive disease or CR/PR>3), 38% had high risk cytogenetics. With median follow-up of 35 months the 3-year Kaplan-Meier survival probability for OS and PFS were 39% and 26%, respectively. Altogether 18 patients (26%) have relapsed or progressed. During the follow-up 41 patients died, 32 (78%) of transplant related factors (NRM), the others of relapse or disease progression.Univariate analysis failed to identify any clinical and pre- or post-transplant variables having clear prognostic significance for OS or PFS. The marginal OS advantage favoring HCT performed recently was detected (3-year OS: 31% for HCT until 2006 and 47% thereafter, p=0.0923). In multivariable hazards model only the female donors were associated with shorter OS (HR 2.278, p=0.016) whereas transplanted T-cell> 2.75x108/kg predicted inferior PFS(HR 1.957, p=0.035). No prognostic impact of donor type, age of donor and recipient, HLA mismatch, disease status pre-HCT, number of previous therapy lines, interval from dg. to HCT and number of transplanted hematopoietic cells was found. Our findings support the conclusion that alloHCT is able to overcome well known negative cytogenetic prognostic factors and that preferring male to female donors could be beneficial.
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Allogeneic hematopoietic stem cell transplant with reduced-intensity conditioning for chronic lymphocytic leukemia in Sweden: does donor T-cell engraftment 3 months after transplant predict survival?
Machaczka, M., Johansson, J. E., Remberger, M., Hallbook, H., Malm, C., Lazarevic, VLj, Wahlin, A., Omar, H., Juliusson, G., Kimby, E., et al
Leukemia & Lymphoma. 2012;53(9):1699-705
Abstract
Thirty-eight adult patients with chronic lymphocytic leukemia (CLL) underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplant (allo-SCT) in Sweden between 1999 and 2007. The cumulative incidences of acute graft-versus-host disease (GVHD) grades II-IV and chronic GVHD were 29% and 47%, respectively. Rates of non-relapse mortality, progression-free survival (PFS) and overall survival (OS) were 18%, 47% and 74% at 1 year, and 21%, 25% and 45% at 5 years, respectively. T-cell chimerism after transplant was measured in 31 out of 34 patients (91%) surviving beyond day +100. Seventeen patients achieved >90% donor T-cell engraftment at 3 months after allo-SCT and, compared with the 12 patients with <90% donor T-cell engraftment, they showed favorable PFS at 1 year (82% vs. 33%, p =0.002) and better long-term PFS and OS (p =0.002 and 0.046, respectively). Donor T-cell engraftment of >90% at 3 months after RIC allo-SCT for CLL seems to predict favorable short-term and long-term outcome.