131I-Anti-CD45 Antibody Plus Fludarabine, Low-Dose Total Body Irradiation and Peripheral Blood Stem Cell Infusion for Elderly Patients with Advanced Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 397-397 ◽  
Author(s):  
John M. Pagel ◽  
Frederick R. Appelbaum ◽  
Brenda M. Sandmaier ◽  
Joseph G. Rajendran ◽  
Ted Gooley ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Elderly Patients ◽  
Total Body Irradiation ◽  
Peripheral Blood ◽  
Low Dose ◽  
High Dose ◽  
Post Transplant ◽  
Total Body ◽  
Reduced Intensity

Abstract The poor survival of elderly patients with advanced AML or high-risk MDS following conventional chemotherapy, as well as their poor tolerance for high-dose regimens used in conventional myeloablative hematopoietic cell transplantation (HCT) demands innovative therapeutic approaches. Recent success achieving stable donor chimerism following infusion of allogeneic peripheral blood stem cells (PBSC) after reduced intensity (non-myeloablative) conditioning regimens affords an opportunity to safely induce a graft-vs-leukemia (GVL) effect with minimal acute morbidity. GVL effects, however, appear to be most potent in patients with low tumor burdens at the time of transplantation. We have therefore conducted a Phase I clinical trial of targeted hematopoietic irradiation delivered by an 131I-labeled anti-CD45 antibody (BC8) to determine the feasibility, safety and efficacy of this approach toward reducing the burden of disease before an established non-myeloablative regimen. In this dose escalation study designed to estimate the maximum tolerated dose of 131I-BC8 antibody that can be combined with fludarabine (FLU) and low dose total body irradiation (TBI), 33 patients over 50 years of age with advanced AML or high-risk MDS (> 5% blasts) were treated with 246 to 932 mCi 131I delivering an estimated 5.2 to 45.9 (mean 27.5) Gy to bone marrow, 17.3 to 155 (mean 81.2) Gy to spleen, and 12–24 Gy to the liver (dose-limiting organ). Patients then received FLU (30 mg/m2 daily for 3 days), 2 Gy TBI, and HLA-matched related (n = 10) or unrelated (n = 23) PBSC grafts with graft-vs-host disease prophylaxis provided by cyclosporine and mycophenolate mofetil. The median age of patients was 61 (50–71) years. Twenty-four patients had AML, with 6 (13%) patients in second or third complete remission, 2 (4%) with primary refractory disease, and 16 (35%) in relapse. Nine (20%) patients had MDS with >5% blasts. Treatment with the 131I-BC8 Ab/FLU/TBI regimen produced a remission in all patients, and all had 100% donor CD3+ and CD33+ cell engraftment by day 28 post-transplant. The absolute neutrophil count surpassed 500/uL at a median of 14 (range, 10–19) days, and the self-sustained platelet count surpassed 20,000/uL at a median of 17 days (range, 15–43). Eighteen patients (55%) are surviving disease-free 2 to 16 months (median 9.5 months) post-transplant. In 9 (27%) patients, the disease relapsed 3 to 38 months after HCT. The day-100 non-relapse mortality was 12%. This study demonstrates that at least an average of 27 Gy of targeted radiotherapy can be delivered to bone marrow and an average of 81 Gy to the spleen, in addition to a standard reduced intensity transplant regimen, without a marked increase in day 100 mortality. Whether this approach will reduce post-transplant relapse rates for older patients with high-risk AML/MDS remains to be determined.

Comparative Single-Institute Analysis of Cord Blood Transplantation from Unrelated Donors with Unrelated Bone Marrow or Related Peripheral Blood Stem-Cell Transplants in Elderly Patients with Hematologic Diseases after Reduced Intensity-Conditioning Regimen.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2011-2011
Author(s):  
Naoyuki Uchida ◽  
Atsushi Wake ◽  
Kazuhiro Masuoka ◽  
Kazuya Ishiwata ◽  
Masanori Tsuji ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Elderly Patients ◽  
Cord Blood ◽  
Peripheral Blood ◽  
Cord Blood Transplantation ◽  
Long Term Outcome ◽  
Post Transplant ◽  
Unrelated Donors ◽  
Reduced Intensity

Abstract Although cord blood (CB) transplantation with reduced-intensity (RI) conditioning (RICBT) has been widely applied to those who lack available related or unrelated donors and are not eligible for conventional conditioning, indication of RICBT to elderly patients relative to other stem-cell sources is still controversial due to higher early mortality post-transplant and undefined long-term outcome. Since there has been not much data available regarding this issue, we retrospectively reviewed patients aged 55 and older who underwent RI allogeneic stem-cell transplantation at our institute from Nov. 2000 to Dec. 2006 consecutively. The study includes 121 recipients of CB (n=42), unrelated bone marrow (UBM, n=41), and related mobilized peripheral blood (RPB, n=38) for AML / MDS (n=66), ALL (n=11), CML (n=4), ML (n=31), MF (n=3), and AA (n=6). The median age for CB, UBM, and RPB recipients were 61 (range 56–69), 60 (55–70), and 60 (55–66), respectively. CB recipients had more serologically HLA-mismatched grafts (98% vs. 24% vs. 5%, P < .05), were conditioned more frequently with melphalan (90% vs. 34% vs. 32%, P < .05) and with total body irradiation (88% vs. 71% vs. 16%, P < .05), used more tacrolimus (100% vs. 71% vs. 18%, P < .05) and less methotrexate (0% vs. 76% vs. 74%, P < .05) for GVHD prophylaxis, had shorter duration of donor search (median 41 days (14–151) vs. 166 (93–345) vs. 130 (41–311), P < .05), and were transplanted more recently (2005–2006: 71% vs. 56% vs. 37%, P < .05). CB recipients tended to have high-risk disease status (76%) relative to UBM (59%) and RPB (66%) recipients, although not statistically significant. Other characteristics such as sex, diagnosis, and body weight were balanced among three groups. Median follow-up time of survivors was 554 days (25–1132), 667 days (315–1794), and 703 days (57–2214) for CB, UBM, and RPB recipients, respectively. CB recipients tended to show slower neutrophil recovery (median 19 days (12–36) vs. 16 (10–27) vs. 13 days (10–21)), and lower rate of myeloid engraftment (86% vs. 90% vs. 100%), although not statistically significant. The incidence of grades II–IV acute GVHD among evaluable CB recipients (61%) was lower than that of UBM (83%, P < .05) and comparable to that of RPB recipients (50%). The incidences of chronic GVHD for evaluable CB, UBM, and RPB recipients were 45%, 71%, and 71%, respectively (N.S.). The disease-free survival and overall survival (OS) at 2 years post-transplant were 23+/–7% and 33+/–8% for CB, 42+/–8% and 47+/–8% for UBM, and 35+/–9% and 40+/–9% for RPB recipients, respectively (N.S.). Within those who had standard risk diseases, 2-year OS were 67+/–15.7%, 48+/–13%, and 59+/–14% for CB (n=10), UBM (n=17), and RPB (n=13) recipients, respectively (N.S.). These data suggest that CB could be a viable stem-cell source for elderly patients as UBM or RPB, not just expanding opportunity of transplant. A larger-sized, randomized study is needed to further define the position of CB for this population of patients.

Allogeneic Transplantation in Elderly Patients with AML and MDS Comparing Reduced-Intensity Conditioning with Flamsa-Busulfan Versus Fludarabine/BCNU/Melphalan

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5839-5839
Author(s):  
Nicole Engel ◽  
Wolfgang Hill ◽  
Susanne Fritsch ◽  
Dusan Prevalsek ◽  
Anna-Katharina Zoellner ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Acute Toxicity ◽  
Elderly Patients ◽  
Umbilical Cord Blood ◽  
Peripheral Blood ◽  
Allogeneic Transplantation ◽  
Reduced Intensity Conditioning ◽  
Conditioning Regimens ◽  
Reduced Intensity

Abstract By reducing treatment intensity allogeneic hematopoietic stem cell transplantation (allo-HSCT) has become feasible for elderly patients. Different reduced-intensity conditioning (RIC) regimens are available, but there is little consensus about the optimal preparative regimen to use, in particular with regard to the outcomes counterbalancing the aim of feasibility and tolerability with higher rates of relapse. Here, we retrospectively evaluate the outcome of sequential therapy employing RIC with fludarabine 30 mg/m2, cytarabine 2g/m2 and amsacrine 100 mg/m2 for 4 days (FLAMSA; Schmid C et al. JCO 2005) followed by busulfan 10 x 0.8 mg/kg (FLAMSA-Bu) compared to RIC utilizing fludarabine 5 x 30 mg/m2, carmustine (BCNU) 2 x 150 mg/m2 and melphalan 110 mg/m2 (FBM; Marks R et al. Blood 2008) in elderly patients treated consecutively at our institution between July 2005 and October 2012. We analyzed the course of 114 patients (pts) with acute myeloid leukemia (AML; n=99) or myelodysplasia (MDS; n=15) aged ≥ 59 years with 59 pts aged ≥ 66 years who were treated with either FLAMSA-Bu (n=66; n=24 ≥ 66 years) or FBM (n=48; n=35 ≥ 66 years). All patients received sero-therapy with anti-thymocyteglobuline (ATG). Median patient age was 66 years for the entire cohort (68 years FBM; 64 years FLAMSA-Bu). 36 patients (75%) of the FBM and 42 patients (63 %) of the FLAMSA-Bu group suffered from high risk disease defined as relapsed or refractory AML or refractory anemia with excess of blasts in transformation (RAEB-T). The hematopoietic cell transplantation comorbidity index (HCT-CI) was higher for the patients of the FBM group than for the FLAMSA-Bu group with 26 (54 %) versus (vs) 24 patients (36 %) scoring ≥ 2 (p 0.085). Graft source after conditioning with FBM/FLAMSA-Bu was bone marrow (1/2), G-CSF mobilized peripheral blood stem cells (40/62) and double-umbilical cord-blood (7/1). In 23 pts (20 %) HLA-matched related and in 91 pts (80 %) HLA-matched unrelated donor transplantation was performed. Engraftment failure was observed in 1 patient after FLAMSA-Bu, while engraftment was achieved in all evaluable patients of the FBM group in a median of 23 days vs 18 days after FLAMSA-Bu (p 0.003), while 7 pts with double-umbilical cord-blood transplantation where included in the FBM group vs 1 pt in the FLAMSA-Bu group. Non-hematological treatment-related acute toxicity ≥ CTC III (gastrointestinal, hepatic, cardiovascular, renal, centralnervous system) occurred in 12/48 pts (25 %) after FBM and in 18/66 pts (27 %) after FLAMSA-Bu. Incidence of severe acute (III-IV) and chronic GvHD was 22.9 %/16.6 % for FBM vs 18.2 %/19.7 % for FLAMSA-Bu, respectively. After conditioning with FBM 2/48 pts vs 9/66 pts after FLAMSA-Bu were diagnosed with a secondary malignancy (p 0.08). Non-relapse mortality (NRM) after 12 months was 26.8 % for FBM versus 25.2 % for the FLAMSA-Bu group. Incidence of relapse after FBM vs FLAMSA-Bu conditioning was 22.9 % vs 15.2 % after 1 year and 31.3 % vs 16.7 % after 2 years. Occurrence of relapse was significantly related to an incomplete or mixed chimerism (donor cells ≤ 95 % in peripheral blood and/or bone marrow) at day +30 (p 0.001). After a median follow up of 31.4 months (range 4.4-97.5) estimated overall survival (OS) and relapse-free survival (RFS) after 2 years was 55.4 % and 51.4 % for the FBM vs 58 % and 56.7 % for the FLAMSA-Bu group, respectively. Analyzing different subgroups, FBM conditioning might be favorable for pts aged ≥ 66 years when suffering from high risk AML (n=26): Within this group 1-year OS after FBM vs FLAMSA-Bu was 71.4 % vs 66.7 % (p 0.58) and 1-year RFS was 71.4 % vs 58.3 % (p 0.59), respectively. Notably, for pts at highest risk (aged ≥ 66 years and suffering from secondary or therapy-related AML; n=24) the benefit of FBM conditioning becomes more pronounced: 1-year OS after FBM vs FLAMSA-Bu was 62.5 % vs 37.5 % (p 0.26) and 1-year RFS 54.2 % vs 37.5 % (p 0.17). Both conditioning regimens are feasible, and provide similar rates of acute toxicity, NRM and GvHD. There might be evidence for a benefit of conditioning with FBM for the subgroup of “the oldest patients at highest risk”. Taking into account that there is an increasing group of ‘medically fit’ elderly patients in the field of allogeneic transplantation, prospective clinical trials are needed to investigate different conditioning regimens considering their special requirements. Disclosures No relevant conflicts of interest to declare.

Final Results of a Phase II Danish Trial Testing Low Dose Total Body Irradiation Following Six Bi-Weekly RCHOP-14 Plus 2 Extra Rituximab in Elderly High risk Patients with Aggressive CD20+ Diffuse Large B-Cell Lymphoma (DLBCL).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1013-1013
Author(s):  
Akmal Safwat ◽  
Lena Specht ◽  
Flemming Hansen ◽  
Mads Hansen ◽  
Jesper Jurlander ◽  
...  
Keyword(s):  
High Risk ◽  
Elderly Patients ◽  
Phase Ii ◽  
Total Body Irradiation ◽  
Low Dose ◽  
B Cell Lymphoma ◽  
Observation Time ◽  
Phase Iii ◽  
Total Body

Abstract Background: To further improve the results achieved by adding Rituximab (R) and shortening chemotherapy interval in elderly patients, an effective but relatively non-toxic treatment modality is needed. We tested therefore the addition of low dose total body irradiation (LTBI) of 1,6 Gy given after chemo-immunotherapy. Methods: A multicenter, phase II trial including patients >60 yrs with stage II-IV, CD20-positive DLBCL was performed between 2003 and 2007. Patients received 6x R-CHOP-14 + 2x R alone followed by LTBI given as 2 courses of 4 daily fractions of 0,2 Gy separated by 2 weeks of rest. Radiotherapy to sites of bulky (>7.5 cm) disease was given according to the local guidelines of the participating centres. Results: Forty two patients were included. Observation time ranged from 3 to 47 months with median follow up of 24 months. The median age was 67 years; 62% had stage III or IV; 48% had B symptoms and 36% had bulky (> 7.5 cm) disease; 50% had ECOG score ≥ 1; 76% had elevated LDH and 57% had IPI of >2. Twenty four patients (57%) achieved a CR or CRu at the end of chemotherapy, while 12 (28.5%) were in PR. One of the 12 PR patients refused LTBI. Of the remaining 11 PR patients who received LTBI, 8 (82%) achieved CR in the first follow up after LTBI while the remaining 3 patients had initially stable disease but progressed shortly after. One patient (2%) progressed under chemotherapy while seven patients (17%) relapsed after achieving CR. Six of these refractory/relapsed cases presented with IPI ≥ 3. The 3-yr event-free and progression-free survival values were 64.8% (SE: 8.7%) and 73.5% (SE: 8.9%), respectively, while the 3-yr overall survival was 85.4% (SE: 5.5%). There were 3 toxic deaths (7.1%) due to sepsis occurring during chemotherapy. Ninteen of 235 cycles of CHOP (8%) were given at reduced dose levels in 3 patients (7%), while 3 cycles (1.3%) were delayed but given at 100% dose level. None of the 305 injections of Rituximab were dose reduced. Only one of 31 patients (3%) got his second LTBI cycle at 75% of the planned dose because of thrombocytopenia. CTC Gr 3–4 neutropenia occurred following 50 of 250 R-CHOP-14 cycles (20%). CTC Gr. 3–4 thrombocytopenia was seen in 8 pts (22%) following LTBI. Conclusions: Despite the high risk profile of the patient cohort enrolled in this trial, the 3-yr outcome values match the results of the best performing recent phase III clinical trials designed for elderly patients with DLBCL. Adding LTBI to 6 cycles of R-CHOP-14 was well tolerated and effective in converting the majority of PRs into CRs. Therefore, it may provide survival benefit and should be tested in a randomised setting.

Leukemia following low-dose total body irradiation and chemotherapy for non-Hodgkin's lymphoma.

1996 ◽  
Vol 14 (2) ◽  
pp. 565-571 ◽  
Author(s):  
L B Travis ◽  
J Weeks ◽  
R E Curtis ◽  
J T Chaffey ◽  
M Stovall ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Total Body Irradiation ◽  
Hodgkin’S Lymphoma ◽  
Low Dose ◽  
Alkylating Agents ◽  
Salvage Treatment ◽  
Hodgkin's Lymphoma ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Total Body

PURPOSE Low-dose total body irradiation (TBI) is used to treat non-Hodgkin's lymphoma (NHL) and several other malignancies. Large volumes of bone marrow and other tissue receive considerable exposure, but few studies have quantified late carcinogenic sequelae. PATIENTS AND METHODS A cohort of 61 2-year survivors of NHL treated initially with low-dose TBI was monitored for second cancer occurrence. Data on primary and subsequent therapy were collected, and cumulative dose of radiation to active bone marrow (ABM) (median, 5.2 Gy) was reconstructed. RESULTS Thirteen second primary cancers occurred. Four patients developed acute nonlymphocytic leukemia (ANLL), which represents a relative risk (RR) of 117 (95% confidence interval [CI], 31.5 to 300) compared with population rates. A fifth patient was diagnosed with myelodysplastic syndrome (MDS). All five patients with secondary hematologic malignancies subsequently received salvage treatment, with either alkylating agents alone (n = 1) or combined modality therapy (CMT) (n = 4). Overall, eight solid tumors were observed (RR = 2.0; 95% CI, 0.9 to 4.0). The 15-year cumulative risks of all second cancers and secondary ANLL were 37% and 17%, respectively. CONCLUSIONS Despite the small number of subjects, a considerable risk of leukemia was observed among patients treated with low-dose TBI in combination with CMT including alkylating agents. Based on these results, approximately eight to nine excess ANLLs might be expected to occur among 100 NHL patients treated with low-dose TBI and salvage treatment and followed-up for 15 years.

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