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1.
Reduced intensity conditioning for acute myeloid leukemia using melphalan- vs busulfan-based regimens: a CIBMTR report
Zhou, Z., Nath, R., Cerny, J., Wang, H. L., Zhang, M. J., Abdel-Azim, H., Agrawal, V., Ahmed, G., Al-Homsi, A. S., Aljurf, M., et al
Blood advances. 2020;4(13):3180-3190
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Editor's Choice
Abstract
There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.
PICO Summary
Population
Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 (n=1413)
Intervention
Fludarabine/busulfan reduced intensity conditioning regimen (FB, n=791)
Comparison
Fludarabine/melphalan reduced intensity conditioning regimen (FM, n=622)
Outcome
Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82), but was marginally superior beyond 3 months (HR = 0.87). LFS was better with FM compared with FB (HR = 0.89). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85). Long-term relapse was lower with FM (HR = 0.65). Analysis restricted to patients with CR showed comparable results.
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2.
Reduced Toxicity Conditioning for Non-Malignant Hematopoietic Cell Transplants
Contreras, C. F., Long-Boyle, J. R., Shimano, K. A., Melton, A., Kharbanda, S., Dara, J., Higham, C., Huang, J. N., Cowan, M. J., Dvorak, C. C.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
Allogeneic hematopoietic cell transplantation (HCT) for children with non-malignant disorders is challenged by potential drug-related toxicities and poor engraftment. This retrospective analysis expands on our single pediatric medical center experience with targeted busulfan, fludarabine, and intravenous (IV) alemtuzumab as a low-toxicity regimen to achieve sustained donor engraftment. Sixty-two patients received this regimen for their first HCT for a non-malignant disorder between 2004 and 2018. Donors were matched sibling in 27%, 8/8 HLA allele-matched unrelated in 50%, and 7/8 HLA allele-mismatched in 23% (some of whom received additional immunoablation with thiotepa or clofarabine). Five patients experienced graft failure for a cumulative incidence of 8.4% (95% CI, 1-16%). In engrafted patients, the median donor chimerism in whole blood and CD3, CD14/15, and CD19 subsets at 1-year were 96%, 90%, 99%, and 99%, respectively. Only one patient received donor lymphocyte infusions (DLIs) for poor chimerism. Two patients died following disease progression despite 100% donor chimerism. The 3-year cumulative incidence of treatment-related mortality was 10% (95% CI, 2-17%). Overall survival and event-free-survival at 3-years were 87% (95% CI, 78-95%) and 80% (95% CI, 70-90%), respectively. The 6-month cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 7% (95% CI, 3-13%), while the 3-year cumulative incidence of chronic GVHD was 5% (95% CI, 0-11%). These results suggest that use of targeted busulfan, fludarabine and IV alemtuzumab offers a well-tolerated option for children with non-malignant disorders to achieve sustained engraftment with a low incidence of GVHD.
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Long-term results of reduced-intensity conditioning allogeneic hematopoietic cell transplantation for older patients with acute myeloid leukemia: a retrospective analysis of 10-year follow-up data
Yanada, M., Fukuda, T., Tanaka, M., Ota, S., Toya, T., Mori, T., Uchida, N., Ozawa, Y., Nakamae, H., Kanda, Y., et al
Bone marrow transplantation. 2020
Abstract
The long-term outcomes of allogeneic hematopoietic cell transplantation (HCT) with reduced-intensity conditioning (RIC) remain inconclusive. To address this issue, we conducted a nationwide registry-based study of patients with acute myeloid leukemia (AML) age 50 years or older who underwent allogeneic HCT in complete remission using RIC (n = 284) or myeloablative conditioning (MAC, n = 190) between 2002 and 2007. The median follow-up period for surviving patients was 10.1 years for RIC recipients and 10.4 years for MAC recipients. The 10-year probabilities of overall survival, relapse, and non-relapse mortality were 36.4%, 30.0%, and 35.7% for RIC recipients, and 39.8%, 26.3%, and 35.5% for MAC recipients, respectively. Multivariate analysis revealed that the conditioning intensity did not affect overall mortality (P = 0.184), relapse (P = 0.904), or non-relapse mortality (P = 0.387). For the 218 patients qualifying for propensity score-matched pairing (109 pairs), RIC was found to be associated with similar survival (P = 0.095) and relapse (P = 0.467), and significantly lower non-relapse mortality (P = 0.046) compared with MAC. Our results confirm the long-term efficacy of RIC allogeneic HCT for older patients with AML and mitigate concerns over an increase in late relapse.
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Reduced-intensity stem cell transplantation for acute myeloid leukemia with fludarabine-based conditioning with intravenous busulfan versus melphalan
Yamashita, T., Takami, A., Uchida, N., Fukuda, T., Eto, T., Shiratori, S., Ota, S., Akasaka, T., Miyakoshi, S., Kondo, T., et al
Bone marrow transplantation. 2020
Abstract
Reduced-intensity conditioning (RIC) has been facilitating allogeneic hematopoietic cell transplantation (allo-HCT) for patients originally considered ineligible for HCT with myeloablative conditioning. Fludarabine (Flu) with reduced doses of busulfan (Bu) (Flu + Bu) and Flu with reduced doses of melphalan (Mel) (Flu + Mel) are widely used RIC regimens for acute myeloid leukemia (AML). A nationwide retrospective study comparing clinical outcomes of adult patients with AML receiving first allo-HCT after RIC between 2001 and 2010 was performed. Cumulative incidences of relapse were not significantly different among the Flu + ivBu-based (FBiv), Flu + poBu-based (FBpo), and Flu + Mel-based (FM) groups (p = 0.29). Non-relapse mortality (NRM) was significantly lower in patients receiving FBiv compared with FBpo (p = 0.003) and FM (p < 0.001). On multivariate analysis, there was no significant difference in overall survival, but FM was associated with a significantly lower risk of relapse (hazard ratio (HR) = 0.65, 95% confidence interval (CI): 0.50-0.85, p = 0.002), higher NRM (HR = 1.60, 95% CI: 1.10-2.33, p = 0.013) and better leukemia-free survival (HR = 0.77, 95% CI: 0.63-0.95, p = 0.015) compared with FBiv. These results suggest that Flu + Mel has a more intense disease control potential and Flu + ivBu is less toxic than the other. Both RIC regimens provide similar survival outcomes and are effective and useful regimens for patients with AML who received allo-HCT.
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Impact of type of reduced-intensity conditioning regimen on the outcomes of allogeneic haematopoietic cell transplantation in classical Hodgkin lymphoma
Ahmed, S., Ghosh, N., Ahn, K. W., Khanal, M., Litovich, C., Mussetti, A., Chhabra, S., Cairo, M., Mei, M., William, B., et al
British journal of haematology. 2020
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Editor's Choice
Abstract
Reduced-intensity conditioning (RIC) allogeneic haematopoietic cell transplantation (allo-HCT) is a curative option for select relapsed/refractory Hodgkin lymphoma (HL) patients; however, there are sparse data to support superiority of any particular conditioning regimen. We analyzed 492 adult patients undergoing human leucocyte antigen (HLA)-matched sibling or unrelated donor allo-HCT for HL between 2008 and 2016, utilizing RIC with either fludarabine/busulfan (Flu/Bu), fludarabine/melphalan (Flu/Mel140) or fludarabine/cyclophosphamide (Flu/Cy). Multivariable regression analysis was performed using a significance level of <0.01. There were no significant differences between regimens in risk for non-relapse mortality (NRM) (P = 0.54), relapse/progression (P = 0.02) or progression-free survival (PFS) (P = 0.14). Flu/Cy conditioning was associated with decreased risk of mortality in the first 11 months after allo-HCT (HR = 0.28; 95% CI = 0.10-0.73; P = 0.009), but beyond 11 months post allo-HCT it was associated with a significantly higher risk of mortality, (HR = 2.46; 95% CI = 0.1.32-4.61; P = 0.005). Four-year adjusted overall survival (OS) was similar across regimens at 62% for Flu/Bu, 59% for Flu/Mel140 and 55% for Flu/Cy (P = 0.64), respectively. These data confirm the choice of RIC for allo-HCT in HL does not influence risk of relapse, NRM or PFS. Although no OS benefit was seen between Flu/Bu and Flu/Mel 140; Flu/Cy was associated with a significantly higher risk of mortality beyond 11 months from allo-HCT (possibly due to late NRM events).
PICO Summary
Population
Adult patients undergoing human leucocyte antigen (HLA)-matched sibling or unrelated donor allo-HCT for Hodgkin lymphoma (n=492)
Intervention
Reduced intensity conditioning with fludarabine/busulfan (Flu/Bu, n=102) or fludarabine/melphalan (Flu/Mel140, n=318)
Comparison
Reduced intensity conditioning with fludarabine/cyclophosphamide (Flu/Cy, n=72).
Outcome
There were no significant differences between regimens in risk for non-relapse mortality (NRM), relapse/progression or progression-free survival (PFS). Flu/Cy conditioning was associated with decreased risk of mortality in the first 11 months after allo-HCT (HR = 0.28), but beyond 11 months post allo-HCT it was associated with a significantly higher risk of mortality, (HR = 2.46). Four-year adjusted overall survival (OS) was similar across regimens at 62% for Flu/Bu, 59% for Flu/Mel140 and 55% for Flu/Cy, respectively. These data confirm the choice of RIC for allo-HCT in HL does not influence risk of relapse, NRM or PFS. Although no OS benefit was seen between Flu/Bu and Flu/Mel 140; Flu/Cy was associated with a significantly higher risk of mortality beyond 11 months from allo-HCT (possibly due to late NRM events).
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Predictors of increased melphalan exposure correlate with overall survival, nonrelapse mortality, and toxicities in patients undergoing reduced-intensity allogeneic stem cell transplantation with fludarabine and melphalan
Sweiss, K., Calip, G. S., Holden, J., Lewkowski, P., Mialik, I., Johnson, J., Galvin, J. P., Rondelli, D., Patel, P.
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2020;:1078155220927436
Abstract
The reduced-intensity conditioning regimen, fludarabine and melphalan 140 mg/m(2) (FM140), is widely adopted in practice. Pharmacokinetic studies report 10-fold interpatient variability in melphalan exposure. We identified low hemoglobin (Hb) and/or creatinine clearance (CrCl), determinants of melphalan pharmacokinetic, as strong predictors of outcomes after high-dose melphalan and autologous transplant. We hypothesized that these variables could predict for outcomes after FM140. Overall survival was shorter in patients with a lower Hb (113 vs. 2536 days; p = 0.004), due to an increased rate of nonrelapse mortality (NRM) (p = 0.0005). Overall survival was also worse in patients with lower CrCl (75 vs. 317 days; p = 0.003), with a significantly worse nonrelapse mortality (p = 0.0023). In a multivariate analysis, a higher Hb and CrCl predicted for better overall survival (p = 0.017). In patients with a lower Hb, the median duration of hospitalization (p = 0.02) and the mean duration of diarrhea (p = 0.008) were longer. In patients with a lower CrCl, the median duration of hospitalization (p = 0.06) and the mean duration of diarrhea (p = 0.0009) longer, and the rate of infection was higher (p = 0.02). We show for the first time that Hb and CrCl represent important determinants of outcomes after FM140, suggesting that pharmacokinetic-directed dosing may be beneficial in achieving optimal outcomes.
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Reduced-intensity versus myeloablative conditioning in cord blood transplantation for AML (40-60 years) across highly mismatched HLA barriers - On behalf of Eurocord and the Cellular Therapy & Immunobiology Working Party (CTIWP) of EBMT
Sheth, V., Volt, F., Sanz, J., Clement, L., Cornelissen, J., Blaise, D., Sierra, J., Michallet, M., Saccardi, R., Rocha, V., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
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Editor's Choice
Abstract
The use of myeloablative conditioning (MAC) in umbilical cord blood transplantation (UCBT) has been associated with high non-relapse mortality (NRM) in patients >40 years, especially those having a high HLA disparity, thus limiting wider applications. We hypothesized that the NRM advantage of reduced intensity conditioning (RIC) and higher GVL associated with greater HLA disparities would expand its use for patients (40-60 years) without compromising efficacy, and compared outcomes between RIC versus MAC regimens. 288 patients aged 40 to 60 years, with de novo AML, receiving UCBT with at least 2 HLA mismatches with RIC (n=166) or MAC (n=122) regimens were included. As compared to RIC, the MAC cohort included relatively younger patients, having received more single UCBT, with lower total nucleated cell counts, and more in vivo T-cell depletion. Median time to neutrophil engraftment, infections (bacterial, viral and fungal), as well as grade II-IV acute and chronic graft-versus-host disease were similar in both groups. In the multivariate analysis, overall survival (HR-0.98, p=0.9), NRM (HR-0.68, p=0.2) and relapse (HR- 1.24, p=0.5) were not different between RIC and MAC. Refractory disease was associated with worse survival. Outcomes of UBCT for patients 40-60 years having =2 HLA mismatches are comparable after RIC or MAC regimen.
PICO Summary
Population
Patients with de novo AML aged 40 to 60 years (n=288)
Intervention
Cord blood transplantation with at least 2 mismatches, and reduced intensity conditioning (RIC, n=166)
Comparison
Cord blood transplantation with at least 2 mismatches, and myeloablative conditioning (MAC, n=122)
Outcome
As compared to RIC, the MAC cohort included relatively younger patients. Median time to neutrophil engraftment, infections (bacterial, viral and fungal), as well as grade II-IV acute and chronic graft-versus-host disease were similar in both groups. In the multivariate analysis, overall survival (HR-0.98), NRM (HR-0.68) and relapse (HR- 1.24) were not different between RIC and MAC. Refractory disease was associated with worse survival.
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Autologous hematopoietic stem cell transplantation with reduced-intensity conditioning regimens in refractory Takayasu arteritis: a retrospective multicenter case-series from the Autoimmune Diseases Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT)
Laurent, C., Marjanovic, Z., Ricard, L., Henes, J., Dulery, R., Badoglio, M., Farge, D., Snowden, J. A., Moraes, D., Dias, J., et al
Bone marrow transplantation. 2020
Abstract
Autologous hematopoietic stem cell transplantation (AHSCT) has emerged as a promising treatment option in severely affected and refractory patients with autoimmune diseases. This is a retrospective survey of patients reported to the EBMT registry between 1998 and 2019, who received AHSCT for TAK. Data from six patients treated with AHSCT for refractory TAK have been identified, five were female (83%), median age 25 (9-39) years. All patients were pretreated with a median of 6 (4-8) lines of therapy, including steroids (six patients), methotrexate (five patients), cyclophosphamide, mycophenolate mofetil or infliximab (four patients), tocilizumab or etanercept (two patients). Conditioning included cyclophosphamide and rabbit anti-thymocyte globulin in all patients. At 6 months post transplantation, remission was obtained in all cases, which persisted at 12 months in five cases. Four patients reactivated TAK at a median time of 27 (7-52) months after AHSCT, and three resumed disease-modifying therapy. At last follow-up, all patients were alive, two patients were in remission (off-therapy), two patients improved compared with baseline, and two patients were in complete and partial remission, respectively, under immunosuppressive treatment. This retrospective case-series demonstrates that AHSCT has the potential to provide significant clinical responses in TAK patients, but large prospective trials are necessary to confirm these preliminary data.
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Sequential allogeneic hematopoietic stem cell transplantation for active refractory/relapsed myeloid malignancies: results of a reduced-intensity conditioning preceded by clofarabine and cytosine arabinoside, a retrospective study on behalf of the SFGM-TC
Le Bourgeois, A., Labopin, M., Marcais, A., de Latour, R. P., Blaise, D., Chantepie, S., N'Guyen, S., Maillard, N., Forcade, E., Yakoub-Agha, I., et al
Annals of hematology. 2020
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Editor's Choice
Abstract
Allogeneic stem cell transplantation (allo-SCT) represents the most beneficial treatment for patients with active relapsed/refractory (R/R) hematologic malignancies. Recently, sequential regimens combining debulking chemotherapy followed by reduced-intensity conditioning (RIC) have shown encouraging results for these patients. In this retrospective study, we report the extended results of a sequential regimen of clofarabine, cytosine arabinoside, and RIC in 131 adults with active R/R myeloid disease at transplant. Conditioning consisted of clofarabine (30 mg/m(2)/day) and cytosine arabinoside (1 g/m(2)/day) for 5 days, followed, after a rest of 3 days, by an RIC combining cyclophosphamide (60 mg/kg) for 1 day, iv busulfan (3.2 mg/kg/day) for 2 days, and anti-thymocyte globulin (2.5 mg/kg/day) for 2 days. Between 2007 and 2016, 131 patients (males n = 75, median age: 52.6 years) were identified from the SFGM-TC registry. There were 111 acute myeloid leukemia (AML) patients and 20 cases with myelodysplastic or myeloproliferative syndrome. Status at transplant was known for all but 4 patients and was primary refractory (n = 81) and 1st or 2nd relapse (n = 46). All patients received allo-SCT from a matched donor (sibling n = 64, unrelated n = 67). Engraftment was observed in 105/122 (86%) evaluable cases and 63% of the patients achieved complete remission (CR) after transplant. The 1-year overall survival, disease-free survival, relapse incidence, non-relapse mortality, and graft-versus-host disease-free/relapse-free survival were 39.2%, 28.1%, 41.0%, 30.8%, and 22.2%, respectively. This study confirms that this sequential clofarabine-based regimen provides a high CR rate in this critical population, although relapse remains a matter of concern.
PICO Summary
Population
Adults with active relapsed/refractory (R/R) myeloid disease at transplant (n=131)
Intervention
Clofarabine, cytosine arabinoside regimen, followed by reduced intensity conditioning and matched donor allogeneic transplantation
Comparison
None
Outcome
Engraftment was observed in 105/122 (86%) evaluable cases and 63% of the patients achieved complete remission (CR) after transplant. The 1-year overall survival, disease-free survival, relapse incidence, non-relapse mortality, and graft-versus-host disease-free/relapse-free survival were 39.2%, 28.1%, 41.0%, 30.8%, and 22.2%, respectively.
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Outcomes of Older Patients with NPM1 Mutated and FLT3-ITD Negative Acute Myeloid Leukemia Receiving Allogeneic Transplantation
Jentzsch, M., Grimm, J., Bill, M., Goldmann, K., Schulz, J., Niederwieser, D., Platzbecker, U., Schwind, S.
HemaSphere. 2020;4(1):e326
