Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects

Blood ◽  
2001 ◽  
Vol 97 (11) ◽  
pp. 3390-3400 ◽  
Author(s):  
Peter A. McSweeney ◽  
Dietger Niederwieser ◽  
Judith A. Shizuru ◽  
Brenda M. Sandmaier ◽  
Arthur J. Molina ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Graft Rejection ◽  
Hematopoietic Cell Transplantation ◽  
Hematologic Malignancies ◽  
Outpatient Setting ◽  
Hematopoietic Cell ◽  
Mixed Chimerism ◽  
High Dose ◽  
Antitumor Effects ◽  
Total Body

Toxicities have limited the use of allogeneic hematopoietic cell transplantation (HCT) to younger, medically fit patients. In a canine HCT model, a combination of postgrafting mycophenolate mofetil (MMF) and cyclosporine (CSP) allowed stable allogeneic engraftment after minimally toxic conditioning with low-dose (200 cGy) total-body irradiation (TBI). These findings, together with the known antitumor effects of donor leukocyte infusions (DLIs), led to the design of this trial. Forty-five patients (median age 56 years) with hematologic malignancies, HLA-identical sibling donors, and relative contraindications to conventional HCT were treated. Immunosuppression involved TBI of 200 cGy before and CSP/MMF after HCT. DLIs were given after HCT for persistent malignancy, mixed chimerism, or both. Regimen toxicities and myelosuppression were mild, allowing 53% of eligible patients to have entirely outpatient transplantations. Nonfatal graft rejection occurred in 20% of patients. Grades II to III acute graft-versus-host disease (GVHD) occurred in 47% of patients with sustained engraftment. With median follow-up of 417 days, survival was 66.7%, nonrelapse mortality 6.7%, and relapse mortality 26.7%. Fifty-three percent of patients with sustained engraftment were in complete remission, including 8 with molecular remissions. This novel allografting approach, based on the use of postgrafting immunosuppression to control graft rejection and GVHD, has dramatically reduced the acute toxicities of allografting. HCT with the induction of potent graft-versus-tumor effects can be performed in previously ineligible patients, largely in an outpatient setting. Future protocol modifications should reduce rejection and GVHD, thereby facilitating studies of allogeneic immunotherapy for a variety of malignancies.

Evaluation of the Toxicity of Total Body Irradation As a Separate Treatment in Preparation for Hematopoietic Cell Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4579-4579
Author(s):  
Sebastian Giebel ◽  
Tomasz Kruzel ◽  
Maria Sadus-Wojciechowska ◽  
Jacek Najda ◽  
Tomasz Czerw ◽  
...  
Keyword(s):  
Adverse Events ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Disease Status ◽  
Hematopoietic Cell ◽  
Cancer Center ◽  
High Dose ◽  
Separate Treatment ◽  
Total Body

Abstract Abstract 4579 BACKGROUND: Myeloablative regimens used for allogeneic or autologous hematopoietic cell transplantation (HCT) may be based on either chemotherapy alone or total body irradiation (TBI). TBI is generally considered highly toxic, however, it is usually combined with high-doses of cyclophosphamide or other cytostatics, which does not allow reliable assessment of its tolerance. In Maria Sklodowska-Curie Cancer Center and Institute of Oncology in Gliwice TBI is used a single treatment in the preparation for the first autologous HCT in patients with multiple myeloma (MM). Second HCT in a tandem procedure is performed after 4 months interval with high-dose melphalan as conditioning. The protocol gives opportunity to separately assess early toxicity of TBI, which is a goal of this study. PATIENTS AND METHODS: The clinical course of 30 patients with MM, aged 58 years (range, 50–66), including 14 men and 16 women was evaluated. The disease status prior to autoHCT was CR (n=9), VGPR (n=7), or PR (n=14). 47% patients were pre-treated with 2 or more lines of chemotherapy and the median number of preceding cycles was 8. TBI was administered at the dose of 12 Gy divided in 3 fractions on days -3, -2, -1. 6 MV X-ray beam was used with lung shielding after 6 Gy and additional irradiation of chest wall using electrons 9–15 MeV to the planned total dose. Peripheral blood was used as a source of stem cells. The incidence of adverse events was assessed using ‘Common Toxicity Criteria v4.03’. RESULTS: Within 100 days follow-up all patients were alive. Median time to neutrophil >0.5 ×10e9/L and platelet >50 ×10e9/L recovery was 12 days (11–21) and 14 days (9–18), respectively. Patients required the median of 1 (0–3) platelet and 0 (0–6) red blood cell transfusions. The median hospital stay since HCT was 16 days (14–21). The most frequent grade 3 or 4 adverse events were infections (43%), including neutropenic fever (23%). Other severe toxicities were rare. In particular no patient experienced hepatic or renal complications (Table 1). CONCLUSION: TBI as a separate treatment is well tolerated and may be safely used for conditioning in a population of patients up to 66 years old. Our observation may potentially be applied to both autologous and allogeneic transplantations. Disclosures: No relevant conflicts of interest to declare.

Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors

Blood ◽  
2004 ◽  
Vol 104 (5) ◽  
pp. 1550-1558 ◽  
Author(s):  
Razvan Diaconescu ◽  
Christopher R. Flowers ◽  
Barry Storer ◽  
Mohamed L. Sorror ◽  
Michael B. Maris ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
High Dose ◽  
Myeloablative Conditioning ◽  
Younger Patients ◽  
Comorbidity Scores ◽  
Related Donor ◽  
Total Body ◽  
Toxicity Criteria

Abstract Nonmyeloablative regimens for allogeneic hematopoietic cell transplantation (HCT) have been developed for patients ineligible for myeloablative conditioning. We compared regimen-related toxicities (RRTs) and nonrelapse mortality (NRM) in 73 nonmyeloablative and 73 myeloablative recipients of HLA-matched related donor HCT, using the National Cancer Institute (NCI) Common Toxicity Criteria. Nonmyeloablative regimens were 2 Gy total body irradiation (TBI), either alone (n = 40) or combined with fludarabine, 30 mg/m2/d for 3 days (n = 33). Posttransplantation immunosuppression included mycophenolate mofetil and cyclosporine. Myeloablative regimens consisted mostly of cyclophosphamide + TBI or busulfan + cyclophosphamide, followed by posttransplantation methotrexate and cyclosporine. Nonmyeloablative patients were at higher risk than ablative patients because of greater age, longer time from diagnosis to HCT, more frequent preceding high-dose HCT, and higher pretransplantation Charlson comorbidity scores. Nevertheless, they experienced significantly less severe toxicities in 7 organs/systems: hematologic, gastrointestinal, hepatic, hemorrhage, infection, metabolic, and pulmonary. This translated into less NRM at day 100 (3% versus 23%, P = 10-4) and 1 year (16% versus 30%, P = .04). In multivariate analysis, the strongest factor predicting lessened RRT and NRM was nonmyeloablative conditioning, whereas high pretransplantation comorbidity scores predicted higher NRM. In conclusion, nonmyeloablative regimens had lower RRT and NRM and could be considered for comparative studies, including younger patients with more favorable Charlson comorbidity scores.

Emerging approaches to improve allogeneic hematopoietic cell transplantation outcomes for non-malignant diseases

Blood ◽  
2021 ◽  
Author(s):  
Zachariah DeFilipp ◽  
Mehrdad Hefazi ◽  
Yi-Bin Chen ◽  
Bruce R. Blazar
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Disease Free Survival ◽  
Hematologic Malignancies ◽  
Current Approach ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Mixed Chimerism ◽  
Malignant Diseases ◽  
Graft Versus Host

Many congenital or acquired non-malignant diseases (NMD) of the hematopoietic system can be potentially cured by allogeneic hematopoietic cell transplantation (HCT) with varying types of donor grafts, degrees of HLA matching, and intensity of conditioning regimens. Unique features that distinguish the use of allogeneic HCT in this population include higher rates of graft failure, immune-mediated cytopenias, and the potential to achieve long-term disease-free survival in a mixed chimerism state. Additionally, in contrast to patients with hematologic malignancies, a priority is to completely avoid graft-versus-host disease in patients with NMD, as there is no theoretical beneficial graft-versus-leukemia effect that can accompany graft-versus-host responses. In this review, we discuss the current approach to each of these clinical issues and how emerging novel therapeutics hold promise to advance transplant care for patients with NMD.

Allogeneic hematopoietic cell transplantation after fludarabine and 2 Gy total body irradiation for relapsed and refractory mantle cell lymphoma

Blood ◽  
2004 ◽  
Vol 104 (12) ◽  
pp. 3535-3542 ◽  
Author(s):  
Michael B. Maris ◽  
Brenda M. Sandmaier ◽  
Barry E. Storer ◽  
Thomas Chauncey ◽  
Monic Jain Stuart ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Transplantation ◽  
Total Body Irradiation ◽  
Hematopoietic Cell Transplantation ◽  
Cell Lymphoma ◽  
Hematopoietic Cell ◽  
High Dose ◽  
Mantle Cell ◽  
Total Body ◽  
Autologous Hct

We carried out HLA-matched related (n = 16) and unrelated (n = 17) hematopoietic cell transplantation (HCT) in 33 patients with relapsed and refractory mantle cell lymphoma after nonmyeloablative conditioning with fludarabine and 2 Gy total body irradiation. Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil. Fourteen patients had failed high-dose autologous HCT. Of the 33 patients studied, 31 had stable engraftment, whereas 2 patients experienced nonfatal graft rejections. The incidences of acute grades II, III, and IV, and chronic graft-versus-host disease (GVHD) were 27%, 17%, 13%, and 64%, respectively. The overall response rate in the 20 patients with measurable disease at the time of HCT was 85% (n = 17; 75% complete remissions [CR] and 10% partial remissions [PR]), whereas 3 patients had progressive disease. Only one of the 17 patients who responded and none of the 13 who received transplants in CR had disease relapse with a median follow-up of 24.6 months. Relapse and nonrelapse mortalities were 9% and 24%, respectively, at 2 years. The Kaplan-Meier probabilities of overall and disease-free survivals at 2 years were 65% and 60%, respectively. Allogeneic HCT after nonmyeloablative conditioning is a promising salvage strategy for patients with relapsed and refractory mantle cell lymphoma. The high response and low relapse rates with this approach suggest that mantle cell lymphoma is susceptible to graft-versus-tumor responses.

scholarly journals Pharmacodynamics of mycophenolate mofetil after nonmyeloablative conditioning and unrelated donor hematopoietic cell transplantation

Blood ◽  
2005 ◽  
Vol 106 (13) ◽  
pp. 4381-4388 ◽  
Author(s):  
Luisa Giaccone ◽  
Jeannine S. McCune ◽  
Michael B. Maris ◽  
Theodore A. Gooley ◽  
Brenda M. Sandmaier ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
T Cell ◽  
Cell Transplantation ◽  
Graft Rejection ◽  
Hematopoietic Cell Transplantation ◽  
Plasma Concentrations ◽  
Hematologic Malignancies ◽  
Immunosuppressive Drug ◽  
Hematopoietic Cell ◽  
Unrelated Donor

The immunosuppressive drug mycophenolate mofetil (MMF) is used after nonmyeloablative hematopoietic cell transplantation (HCT); however, limited pharmacodynamic data are available. We evaluated plasma concentrations of mycophenolic acid (MPA), the active metabolite of MMF, and outcomes in 85 patients with hematologic malignancies conditioned with fludarabine and 2 Gy total body irradiation followed by HLA-matched unrelated-donor HCT and postgrafting cyclosporine and MMF. The first 38 patients received MMF 15 mg/kg twice daily; the next 47 patients received MMF 3 times daily. MPA pharmacokinetics were determined on days 7 and 21. Comparing the twice-daily and 3-times-daily MMF groups, the mean total MPA concentration steady state (Css) was 1.9 and 3.1 μg/mL; the unbound Css was 18 and 36 ng/mL, respectively (P < .001). Sixteen patients with a total MPA Css less than 3 μg/mL had low (< 50%) donor T-cell chimerism (P = .03), and 6 patients with MPA Css less than 2.5 μg/mL had graft rejection. An elevated unbound Css was associated with cytomegalovirus reactivation (P = .03). There were no significant associations between MPA pharmacokinetics and acute graft-versus-host disease (GVHD) or relapse. We conclude that increased MPA Css's predicted higher degrees of donor T-cell chimerism after unrelated donor nonmyeloablative HCT and suggest that targeting MPA Css's greater than 2.5 μg/mL could prevent graft rejection.

Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematological diseases

Blood ◽  
2003 ◽  
Vol 101 (4) ◽  
pp. 1620-1629 ◽  
Author(s):  
Dietger Niederwieser ◽  
Michael Maris ◽  
Judith A. Shizuru ◽  
Effie Petersdorf ◽  
Ute Hegenbart ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Cell Transplantation ◽  
Total Body Irradiation ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
High Dose ◽  
Hematological Diseases ◽  
Donor Chimerism ◽  
Unrelated Donors ◽  
Total Body

Toxicities of high-dose conditioning regimens have limited the use of conventional unrelated donor hematopoietic cell transplantation (HCT) to younger, medically fit patients. Based on preclinical studies, an HCT approach has been developed for elderly or medically infirm patients with HLA-matched or mismatched unrelated donors. In this study, 52 patients with hematological diseases were included. Most (88%) had preceding unsuccessful conventional HCT or refractory/advanced disease. Patients were treated with fludarabine 30 mg/m2/d from days −4 to −2, 2 Gy total body irradiation on day 0, cyclosporine at 6.25 mg/kg twice daily from day −3, and mycophenolate mofetil at 15 mg/kg twice daily from day 0. Durable donor chimerism was attained in 88% of the patients. By day 28, a median of 100% of CD56+ cells were of donor origin. Granulocyte and T-cell donor chimerism increased to medians of 100% on day 56 and day 180 (range, 55%-100%), respectively. Acute GVHD, grade II, was seen in 42% (CI, 29%-56%); grade III in 8% (CI, 0%-15%); and grade IV in 13% (CI, 4%-23%) of patients; it was fatal in 9%. The 100-day transplantation-related mortality was 11%. Complete remissions, including molecular remissions, were seen in 45% of patients with measurable disease before transplantation. Mortality from disease progression was 27% at one year. With a median follow-up of 19 months, 18 of the 52 patients (35%) were alive and 25% were in remission. HCT from HLA-matched or mismatched unrelated donors can be performed with a reduced intensity conditioning regimen in patients ineligible for conventional HCT.

Ablative Allogeneic Hematopoietic Cell Transplantation in Adults 60 Years of Age and Older

2005 ◽  
Vol 23 (15) ◽  
pp. 3439-3446 ◽  
Author(s):  
Herschel Wallen ◽  
Theodore A. Gooley ◽  
H. Joachim Deeg ◽  
John M. Pagel ◽  
Oliver W. Press ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Blast Crisis ◽  
Progression Free Survival ◽  
Hematologic Malignancies ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Allogeneic Hct ◽  
Total Body

Purpose To evaluate outcomes of ablative allogeneic hematopoietic cell transplantation (HCT) in older patients with hematologic malignancies. Patients and Methods We treated 52 patients from 1979 to 2002 with a median age of 62.8 years (range, 60.1 to 67.8 years) using ablative preparative regimens followed by allogeneic HCT from sibling donors. Diagnoses included myelodysplastic syndrome (MDS; n = 35), chronic myeloid leukemia (CML; n = 8), acute myeloid leukemia (AML; n = 6), and other (n = 3). Conditioning regimens included cyclophosphamide (CY) and busulfan (BU) (67%), total-body irradiation and CY (21%), BU-fludarabine (10%), and CY (2%). Results Eighteen (35%) of 52 patients are alive at a median of 4.6 years (range, 0.8 to 9.1 years) after transplantation. Median overall survival (OS) and progression-free survival were 300 and 218 days, respectively. Three-year OS and relapse rates are estimated to be 34% and 24%, respectively. Nonrelapse mortality (NRM) rates at 100 days and 3 years are estimated to be 27% and 43%, respectively. Grade 3 to 4 acute graft-versus-host disease (GVHD) occurred in 20% of patients, and chronic extensive GVHD was described in 53% of patients. Fourteen (40%) of 35 patients with MDS are alive at a median of 2.8 years (range, 0.8 to 8.2 years). Four of six patients with CML in chronic or accelerated phase are alive at a median of 6.9 years (range, 4.1 to 9.1 years) after transplantation. None of the patients with AML, CML in blast crisis, or other diagnoses have survived. Patients who underwent transplantation after 1993 had improved survival. Conclusion These data suggest that allogeneic HCT is feasible in selected patients ≥ 60 years of age, although novel methods to reduce NRM while maintaining efficacy are needed.

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