Introduction: Systemic light chain (AL-) amyloidosis is a rare protein deposition disorder which is caused by a monoclonal plasma cell or B cell disorder with poor prognosis if the heart is severely ...affected. In a retrospective EBMT analysis allogeneic stem cell transplant (allo-SCT) performed from 1991 until 2003 has emerged as an effective treatment but was associated with a high non-relapse-mortality (NRM) (Schönland et al., Blood 2006).
Patients and Methods: We performed a prospective non-interventional study (NIS) within the EBMT using allo-SCT in AL amyloidosis patients. Primary endpoint was efficacy (best hematologic remission (HR) and organ response). Secondary endpoints were acute and chronic Graft-versus-host-disease (GvHD), NRM, non-hematologic toxicity, event-free and overall survival (OS). We selected those centres that had performed any allogeneic HSCT for AL amyloidosis in the past. We approached 24 centres, of which 6 participated. Fourteen patients have been included and were transplanted between 2006 and 2014. Median age at allo-SCT was 50 years (range, 41 - 60). Five patients had cardiac and 10 patients kidney involvement at diagnosis. As underlying hematologic disease one patient had a M. Waldenström, the other 13 patients had a clonal plasma cell dyscrasia. All but one patient were in a good performance status (80-100%) assessed by Karnofsky Index at allo-SCT. Previous chemotherapy included high-dose melphalan (HDM) with autologous stem cell transplantation in 11 patients as well as bortezomib, lenalidomide, melphalan, rituximab and steroids. Disease stages at allo-SCT were as follows: 2 CRs, 1 VGPR, 6 PRs, 3 no responses and 1 with progression. Two patients received myeloablative and 12 reduced intensity conditioning (RIC, TBI 2 Gy / fludarabine in 10 patients, TBI 6 Gy in one patient). Three patients received T cell depletion (2 with ATG, one with Campath). HDM 200 mg/m2 was applied prior to the one syngeneic SCT. Donors were: 8 identical siblings, 1 mismatched relative, 1 syngeneic, 3 matched unrelated donors and 1 mismatched unrelated donor (MMUD). Source of stem cells was peripheral blood in 13 and cord blood in 1 patient, respectively. Time from diagnosis to allo-SCT was 23 months in median (range, 4-61).
Results: All but one patient engrafted. Acute GvHD grade II-IV occurred in 4 patients and chronic GvHD in 9 patients (4 patients with limited and 5 with extensive disease, respectively). NRM occurred in 3 patients (GvHD, infection and suicide). One patient died due to progressive disease. 1- and 2-year-mortality was 14 and 21%, respectively. Best HR after allo-SCT was CR in 9 (64%). Ten patients were alive after an estimated median follow-up of 53 months (figure, continuous line) with an OS plateau beginning at 28 months post allo-SCT of 70%. Four patients relapsed or progressed and 7 patients were alive and relapse-free.
In addition, we updated the 19 AL patients of our published cohort (Schönland et al., Blood 2006). 1- and 2-year-mortality was 42 and 53%, respectively. Five (26%) patients were still alive after a cumulative median follow-up of 208 months, four of these living longer than 10 years after allo-SCT (figure, dashed-line).
Conclusion: Preliminary analysis of our NIS shows that allo-SCT is nowadays feasible and highly effective in selected patients with AL amyloidosis. In opposite to our retrospective analysis we observed a rather low NRM using mostly reduced-intensity conditioning with TBI 2 Gy and fludarabine. Furthermore, both analyses revealed rewarding long-term survival suggesting very good disease control. Therefore, allo-SCT might be a reasonable treatment option in young, medically fit and heavily pretreated patients (e.g. relapse or non-response after HDM).
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Schönland:Prothena: Consultancy; Janssen: Consultancy, Honoraria, Research Funding. Hegenbart:Janssen: Honoraria. Schipperus:Novartis: Consultancy. Garderet:Bristol-Myers Squibb: Consultancy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The standard treatment of anal canal cancer (ACC) is combined chemotherapy and radiation therapy (RT), which is complex because of the shape of the target volumes and the need to minimize the ...irradiation of normal pelvic structures. In this study we compared the dosimetric results of helical tomotherapy (HT) plans with traditional 3D conformal RT (3DRT) plans for the treatment of ACC.
Twelve patients (median age 57 years, range 38-83; F/M 8/4) treated with HT and concurrent chemotherapy for locally advanced ACC were selected. All had histologically confirmed squamous-cell carcinoma. A clinical target volume including the tumor and pelvic and inguinal lymph nodes was treated with HT to a total dose of 36 Gy in 1.8-Gy daily fractions. Then a sequential boost of 23.4 Gy in 1.8-Gy daily fractions (total dose 59.4 Gy) was delivered to the tumor and involved nodes. For all 12 patients, 3DRT plans were generated for comparison. Treatment plans were evaluated by means of standard dose-volume histograms. Dose coverage of the planning target volumes (PTVs), homogeneity index (HI), and mean doses to organs at risk (OARs) were compared.
The coverage of PTV was comparable between the two treatment plans. HI was better in the HT vs. 3DRT plans (1.25 and 3.57, respectively; p<0.0001). HT plans resulted in better sparing of OARs (p<0.0001).
HT showed superior target dose conformality and significant sparing of pelvic structures compared with 3DRT. Further investigation should determine if these dosimetric improvements will improve clinical outcomes regarding locoregional control, survival, and treatment-related acute and late morbidity.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
An HLA-matched sibling has been considered the optimal donor for allogeneic hematopoietic cell transplantation (HSCT). However, several potential transplant recipients may have a haploidentical ...sibling or an offspring who may also serve as donors. In this study, we sought to determine the optimal alternative related donor (haploidentical sibling or an offspring) as compared to an HLA-matched sibling. The primary objective was comparison of chronic graft-versus-host disease (GVHD). Secondary outcomes included acute GVHD, non-relapse mortality (NRM), relapse, treatment failure (relapse or death, inverse of relapse-free survival) and overall mortality. The study population included 4540 donor-recipient pairs (n=218 haploidentical sibling; n=218 offspring; n=4104 HLA-matched sibling) with acute myeloid (n=3617) and acute lymphoblastic (n=923) leukemia transplanted in 2008 to 2015. There were few offspring (n=87) who donated to patients aged 18-54 years and haploidentical siblings (n=61) who donated to patients aged 55-76 years and were excluded from the analysis. Post-transplant cyclophosphamide (PT-Cy) with calcineurin inhibitor (CNI) and mycophenolate was used for GVHD prophylaxis for all haploidentical HSCTs. HLA-matched siblings received CNI-containing GVHD prophylaxis; CNI with methotrexate was the predominant prophylaxis regimen. Patient age was correlated with donor age and donor-recipient relationship. Bone marrow was the predominant graft for haploidentical HSCTs (64%) and peripheral blood (89%) for HLA-matched sibling HSCTs. Younger patients (age 18-54 years) of were more likely to receive reduced intensity conditioning regimens for haploidentical HSCTs compared to HLA-matched sibling HSCTs (22%). Among older patients, conditioning regimen intensity did not differ by donor type. Exploratory analysis confirmed differences in survival by patient age. Therefore, based on differences in survival by patient age, two age groups were created: 18 - 54 years and 55 - 76 years and within each patient age group, donor-recipient relationship and its effect on transplant outcomes were tested using Cox regression models. In addition to the standard Cox regression model, we also performed a matched-pair analysis. Recipients of haploidentical HSCT (cases; n=436) were matched to HLA-matched siblings (controls; n=1707) on age, disease and disease risk index. 88% of patients aged 18-54 years were matched to 4 controls and 96% of patients aged 55-76 years were matched to 4 controls. The median difference in age between cases and controls were 0.08 (range 0-9.9) years for patients aged 18-54 years and 0.05 (0 - 9.5) years for patients aged 55-76 years. The results of multivariate Cox regression and matched-pair analysis are shown in Tables 1, 2. Among patients aged 18-54 years, chronic GVHD risks were lower after haploidentical sibling compared to HLA-matched sibling HSCT. There were no differences in acute GVHD, NRM, relapse, treatment failure or overall mortality. Among patients aged 55-76 years, acute and chronic GVHD risks were lower after offspring compared to HLA-matched sibling HSCT. But risks for NRM, treatment failure and overall mortality were higher after offspring compared to HLA-matched sibling HSCT. The 2-year probabilities of overall survival, adjusted for disease risk index and sex are shown in Figure 1. In summary, chronic GVHD rates were lower after haploidentical HSCT with PT-Cy containing GVHD prophylaxis regimens compared to HLA-matched sibling HSCT for all patients. Whether this can be attributed solely to the GVHD prophylaxis regimen or in part attributed to use of peripheral blood grafts for HLA-matched sibling HSCT must be studied further in a setting in which PT-Cy containing GVHD prophylaxis is used for HLA-matched sibling HSCT. Despite lower chronic GVHD with haploidentical sibling donor HSCT with PT-Cy, NRM and overall survival did not differ by donor type for patients aged 18-54 years. However, for patients aged 55 - 76 years, despite lower chronic GVHD with offspring donor HSCT with PT-Cy, NRM was higher and overall survival was lower compared to HLA-matched sibling HSCT. Definitive proof of these findings would require a prospective randomized trial.
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Ciceri:GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Mohty:Sanofi: Honoraria, Speakers Bureau.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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Secondary acute myeloid leukemia (sAML) includes a heterogeneous group of diseases evolved from myelodysplasia, myeloproliferative disorders (MDS/ MPN), bone marrow failure syndrome or after ...exposure to leukemogenic agents such as chemotherapy and/or radiation therapy for malignant hematological (other malignant hematological diseases) or solid tumors.
Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy but relapse is a frequent cause of failure after HCT occurring in more than 50% of patients. No systematic large analysis of HCT for sAML has evaluated risk factors and outcome based on a prior diagnosis of MDS or MPN. Therefore, the EBMT Acute Leukemia Working Party (ALWP) performed a multicenter retrospective registry study on patients undergoing HCT for sAML following MDS/MPN comparing myeloablative (MAC) to reduced intensity conditioning (RIC). ALWP-EBMT supplemental data forms were used to establish the occurrence of any prior hematological disorder or non-hematological malignancy as well as details of cytogenetic data and therapy.
We studied 811 patients with a previous diagnosis of MDS/ MPD and available cytogenetic data who had received HCT for sAML from an HLA-identical sibling (MRD, n=344 42.4%) or unrelated donor transplant (URD- 9/10 or 10/10) during 2000-16. Median time from diagnosis (sAML) to transplant was 137 days (IQR 94-204). Median age at HCT was 59.57 years (IQR 52-65). sAML with adverse cytogenetics accounted for 269 (33.2%) patients. At the time of HCT, 401 (49.5%) patients were in CR1 and 367 (45.3%) had active disease. Median follow-up of surviving patients was 32 months (IQR, 11-62).
Regimen intensity was assessed by EBMT criteria. MAC regimens were used in 326 (40.2%) patients while 485 (59.8%) received RIC. Older patients were more likely to receive RIC than MAC regimens (p<0.001). Most patients received peripheral blood stem cell grafts (n=731 90.3%; MAC 85.6% vs RIC 93.4%, p<0.001). A total of 534 (67.9%) patients were cytomegalovirus (CMV) seropositive pre-HCT. There were no significant differences in disease characteristics (e.g. disease status at transplant, cytogenetic risk category), donor source, year of transplant or CMV serology status between MAC and RIC cohorts. All patients received a calcineurin inhibitor-based combination as prophylaxis against graft versus host disease (GVHD) and 516 (63%) received in vivo T-cell depletion (rATG 474 (58%).
A total of 667 (95.2%) patients engrafted (MAC 94.5% vs. RIC 95.6%; p=0.596). Acute GVHD (grade II-IV) within 100 days of HCT occurred in 24% (95% CI, 21-27; MAC vs. RIC, p=0.126) and 2-year cumulative incidence of chronic GVHD was 33% (95% CI 30-37; MAC vs. RIC, p=0.150). Three-year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) were 41% (95% CI, 38-45; MAC 37% 31-42 vs. RIC 45% 40-49, p=0.029) and 25% (95% CI, 22-28%, MAC 25% 20-30 vs. RIC 25% 21-29, p=0.959), respectively. The Kaplan-Meier estimate of overall survival (OS) and leukemia free survival (LFS) at 3 years were 40% (95% CI, 37-44; MAC 44% 38-50 vs. RIC 38% 33-43, p=0.041) and 34% (95% CI, 31-38; MAC 38% 33-45 vs. RIC 31% 27-36, p=0.032), respectively (Figure 1).
In multivariate analysis by Cox Regression, a higher RI was seen after RIC regimens (HR 1.72 1.16-2.55; p=0.0063). Patients receiving RIC regimens had a higher risk of chronic GVHD (HR 1.37 1.02-1.84, p=0.0389). Non-relapse mortality (NRM) was equivalent in MAC and RIC groups.MAC regimens were associated with superior OS (HR 1.46, 95% CI 1.1-1.94; p=0.0085) and LFS (HR 1.37, 95% CI 1.02-1.85; p=0.0387). High risk cytogenetics and older age contributed significantly to inferior outcomes.
In summary, this EBMT registry study of HCT for sAML after MDS/MPN is the largest cohort reported. Myeloablative conditioning regimens were associated with a lower relapse risk and superior survival. Given that NRM after HCT has declined in the current era, these data indicate that the outcome of HCT for sAML may be improved by careful patient selection for MAC regimens. Survival may be further enhanced by effective pre-HCT disease control (also associated with decreased NRM) and post-HCT pre-emptive therapy to decrease RI.
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Savani:Jazz Pharmaceuticals: Speakers Bureau. Ciceri:GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Schmid:Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees; MoilMed: Membership on an entity's Board of Directors or advisory committees. Mohty:Sanofi: Honoraria, Speakers Bureau.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Image guided radiotherapy (IGRT) improves patient positioning for treatment delivery at the cost of an additional dose. This work aimed to calculate the effective dose (as an indicator of dose) for ...head & neck (H&N) and breast IGRT treatments by implementing dose calculation models to determine the dose distributions.
The kV dose-models were created for the IGRT systems of Elekta Synergy (XVI) and Varian Clinac (OBI) linear accelerators within Philips Pinnacle TPS. Profiles and depth dose curves were measured in water. The models were validated in a CIRS thorax phantom. The IGRT dose distributions for five H&N and five breast patients were calculated. The effective dose was determined from the dose distributions following ICRP 103 recommendations. Moreover, time-saving approximations were studied in order to propose an alternative way of segmenting the tissues for a clinical implementation of the method.
The effective dose specifically associated with IGRT varied from 1 to 10mSv depending on the protocol. The kV dose-model allowed us to calculate the dose distributions from IGRT for different configurations and patients, and to determine effective dose for IGRT protocols. The clinical implementation of the method was found to reduce time and to introduce a small enough increase of uncertainty in the results to be clinically usable.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract
Purpose
CheckTomo is an independent dose calculation software for tomotherapy. Recently, Accuray (Accuray Inc., Sunnyvale, CA, USA) released an upgrade of its tomotherapy treatment device, ...called Tomo
EDGE
Dynamic Jaws, which improves the quality of treatment plans by enhancing the dose delivery with the help of jaws motion. This study describes the upgrade of CheckTomo to that new feature.
Methods
To account for the varying width and off‐axis shift of dynamic jaws fields, the calculation engine of CheckTomo multiplies the treatment field profile by a penumbral filter and shifts the dose calculation grid. Penumbral filters were obtained by dividing the edge field profiles by that of the corresponding nominal field. They were sampled at widths 1.0, 1.8, and 2.5 cm at isocenter in the edges of the 2.5 and 5 cm treatment field.
Results
The upgrade of CheckTomo was tested on 30 patient treatments planned with dynamic jaws. The gamma pass rate averaged over 10 abdomen plans was 95.9%, with tolerances of 3 mm/3%. For 10 head and neck plans, the mean pass rate was 95.9% for tolerances of 4 mm/4%. Finally, misplacement and overdosage errors were simulated. In each tested cases, the 2 mm/3% gamma pass rate fell below 95% when a 4 mm shift or 3% dose difference was applied.
Conclusions
These results are equivalent to what CheckTomo achieves in static jaws cases. So, in terms of dose calculation accuracy and errors detection, the upgraded version of CheckTomo is as reliable for dynamic jaws plans as the former release was for static cases.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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