Cell Transplantation In Older Patients Research Articles

Conditioning with Treosulfan and Fludarabine followed by Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies

In this prospective study 60 patients of median age 46 (range: 5-60 years), with acute myelogenous leukemia (AML; n= 44), acute lymphoblastic leukemia (ALL; n = 3), or myelodysplastic syndrome (MDS; n = 13) were conditioned for allogeneic hematopoietic cell transplantation with a treosulfan/fludarabine (Flu) combination. Most patients were considered at high risk for relapse or nonrelapse mortality (NRM). Patients received intravenous treosulfan, 12 g/m(2)/day (n = 5) or 14 g/m(2)/day (n = 55) on days -6 to -4, and Flu (30 mg/m(2)/day) on days -6 to -2, followed by infusion of marrow (n = 7) or peripheral blood stem cells (n = 53) from HLA-identical siblings (n = 30) or unrelated donors (n = 30). All patients engrafted. NRM was 5% at day 100, and 8% at 2 years. With a median follow-up of 22 months, the 2-year relapse-free survival (RFS) for all patients was 58% and 88% for patients without high-risk cytogenetics. The 2-year cumulative incidence of relapse was 33% (15% for patients with MDS, 34% for AML in first remission, 50% for AML or ALL beyond first remission and 63% for AML in refractory relapse). Thus, a treosulfan/Flu regimen was well tolerated and yielded encouraging survival and disease control with minimal NRM. Further trials are warranted to compare treosulfan/Flu to other widely used regimens, and to study the impact of using this regimen in more narrowly defined groups of patients.

Effect of Age on Outcome of Reduced-Intensity Hematopoietic Cell Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission or With Myelodysplastic Syndrome

PURPOSE Acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) primarily afflict older individuals. Hematopoietic cell transplantation (HCT) is generally not offered because of concerns of excess morbidity and mortality. Reduced-intensity conditioning (RIC) regimens allow increased use of allogeneic HCT for older patients. To define prognostic factors impacting long-term outcomes of RIC regimens in patients older than age 40 years with AML in first complete remission or MDS and to determine the impact of age, we analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR). PATIENTS AND METHODS We reviewed data reported to the CIBMTR (1995 to 2005) on 1,080 patients undergoing RIC HCT. Outcomes analyzed included neutrophil recovery, incidence of acute or chronic graft-versus-host disease (GVHD), nonrelapse mortality (NRM), relapse, disease-free survival (DFS), and overall survival (OS). RESULTS Univariate analyses demonstrated no age group differences in NRM, grade 2 to 4 acute GVHD, chronic GVHD, or relapse. Patients age 40 to 54, 55 to 59, 60 to 64, and > or = 65 years had 2-year survival rates as follows: 44% (95% CI, 37% to 52%), 50% (95% CI, 41% to 59%), 34% (95% CI, 25% to 43%), and 36% (95% CI, 24% to 49%), respectively, for patients with AML (P = .06); and 42% (95% CI, 35% to 49%), 35% (95% CI, 27% to 43%), 45% (95% CI, 36% to 54%), and 38% (95% CI, 25% to 51%), respectively, for patients with MDS (P = .37). Multivariate analysis revealed no significant impact of age on NRM, relapse, DFS, or OS (all P > .3). Greater HLA disparity adversely affected 2-year NRM, DFS, and OS. Unfavorable cytogenetics adversely impacted relapse, DFS, and OS. Better pre-HCT performance status predicted improved 2-year OS. CONCLUSION With these similar outcomes observed in older patients, we conclude that older age alone should not be considered a contraindication to HCT.

Reduced-intensity conditioning allogeneic stem cell transplantation for older adults: is it the standard of care?

We reviewed reduced-intensity hematopoietic cell transplantation for older patients in the context of recently published studies. Most studies describe applicability of reduced-intensity transplantation to older patients with overall survival rates that compare favorably to chemotherapy alone, though relapse and graft-versus-host disease remain complicating factors. Though transplant recipients likely represent a highly selected population, current studies do not demonstrate an upper age for transplantation and suggest that myeloablative regimens may be considered in older patients with limited comorbidities. Avenues being pursued to improve transplant outcomes include natural killer cell immunotherapy and regulatory T-cell modulation. Until prospective studies show otherwise, transplant conditioning intensity for the older patient should be based on individual patient and disease characteristics. Enrollment into clinical trials is paramount in efforts to reduce transplant-related mortality and improve outcomes.

Low-Dose Total Body Irradiation and Fludarabine Conditioning for HLA Class I-Mismatched Donor Stem Cell Transplantation and Immunologic Recovery in Patients with Hematologic Malignancies: A Multicenter Trial

HLA-mismatched grafts are a viable alternative source for patients without HLA-matched donors receiving ablative hematopoietic cell transplantation (HCT), although their use in reduced intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning HCT has been not well established. Here, we extended HCT to recipients of HLA class I-mismatched grafts to investigate whether NMA conditioning can establish stable donor engraftment. Fifty-nine patients were conditioned with fludarabine (Flu) 90 mg/m(2) and 2 Gy total body irradiation (TBI), followed by immunosuppression with cyclosporine (CsA) 5.0 mg/kg twice a day and mycophenolate mofetil (MMF) 15 mg/kg 3 times a day for transplantation of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSCs) from related (n = 5) or unrelated donors (n = 54) with 1 antigen +/- 1 allele HLA class I mismatch or 2 HLA class I allele mismatches. Sustained donor engraftment was observed in 95% of the evaluable patients. The incidence of grade II-IV acute and extensive chronic graft-versus-host disease (aGVHD, cGVHD) was 69% and 41%, respectively. The cumulative probability of nonrelapse mortality (NRM) was 47% at 2 years. Two-year overall and progression-free survival (OS, PFS) was 29% and 28%, respectively. NMA conditioning with Flu and low-dose TBI, followed by HCT using HLA class I-mismatched donors leads to successful engraftment and long-term survival; however, the high incidence of aGVHD and NRM needs to be addressed by alternate GVHD prophylaxis regimens.

Non-Myeloablative Hematopoietic Stem Cell Transplantation in Older Patients with AML and MDS: Results from the Center for International Blood and Marrow Transplant Research (CIBMTR)

Background: AML and MDS disproportionately affect older-aged individuals. Hematopoietic cell transplantation (HCT) is the best established curative therapy but is generally not offered due to concerns about toxicity and poor outcome. Reduced-intensity conditioning (RIC) regimens have been developed to allow allografting in older patients; however, there is a paucity of data to support transplantation in patients over 65 years of age.Purpose: To better study age as a predictor of outcome, we retrospectively analyzed data reported to the CIBMTR from 1995–2005 among patients receiving RIC HCT for MDS (551 patients) and AML (565 patients) in first complete remission (CR).Patient and Methods: Outcomes analyzed for both disease groups included transplant-related mortality (TRM), engraftment, incidence of acute and chronic graft-versus-host disease (GVHD), leukemia-free (LFS) and overall survival (OS). Patients were stratified according to age cohorts for comparison: 40–54, 54–59, 60–64 and ≥65 years.Results: Clinical characteristics were well matched across age cohorts but notably, most AML patients presented with de novo disease (P=0.001) and received their allograft from a matched related donor (MRD) (P=0.001) with 51% of patients ≥65 years having a MRD. MDS patients more often had unrelated donors (URD), especially in the older cohorts (73% for ≥ 65 years); but donor type was not significantly different between groups. Most patients received peripheral blood (PB) allografts (76–97%), fludarabine-containing regimens for conditioning and cyclosporine-containing regimens for GVHD prophylaxis. Univariate analysis demonstrated no statistically significant differences in TRM across age cohorts and no overall difference in occurrence of acute (31–35% at 100 days) or chronic GVHD (36–53% at 2 years). Relapse rates were similar across all age groups (29–39% at 3 years) (Table). Multivariate analysis revealed no statistically significant impact of age on TRM, relapse, LFS, or OS (all p > 0.4). Disease and status at transplant were significant risk factors for OS/LFS at 1 year while affecting TRM/relapse at 2 years. Performance status and HLA disparity were also significant at 2 years for nearly all outcomes.Conclusion: 1. The outcomes for older adults undergoing allogeneic HCT are not significantly different than for younger adults, even after adjusting for multiple risk factors; 2. Age by itself should not be the limiting factor for proceeding to allogeneic HCT in older patients with AML or MDS; 3. Continued participation in clinical trials should be encouraged to explore strategies that could improve treatment outcome.Univariate probabilities of patients age ≥40 years receiving allogeneic HCT for AML/MDS in first complete remission reported to the CIBMTR, 1995–2005.N40–54N55–60N60–64N>65AMLTRM22015013263100 days11 (7–16)%6 (3–10)%13 (8–20)%10 (4–18)%1 year20 (15–26)%18 (12–24)%24 (17–33)%30 (19–42)%Relapse1 year27 (21–33)%34 (26–42)%31 (23–40)%22 (12–33)%3 years32 (26–39)%35 (27–43)%39 (30–49)%33 (21–46)%LFS1 year53 (46–60)%49 (41–58)%44 (35–53)%48 (36–61)%3 years43 (36–51)%41 (32–50)%27 (19–37)%34 (22–47)%OS100 days84 (78–88)%92 (87–96)%83 (76–89)%89 (80–95)%1 year59 (52–65)%60 (52–68)%51 (42–60)%51 (39–64)%3 years45 (40–54)%47 (42–59)%30 (25–43)%36(24–49)%Follow-up (months)37 (2–110)25 (1–87)36 (3–96)29 (3–59)MDSTRM21915012755100 days17 (13–23)%17 (11–23)%14 (9–21)%19 (9–30)%1 year31 (24–37)%33 (25–41)%32 (24–41)%34 (22–47)%Relapse1 year26 (20–32)%27 (20–35)%26 (18–34)%25 (14–37)%3 years29 (23–35)%29 (22–37)%31 (23–40)% higher33 (20–47)%LFS1 year43 (36–50)%40 (32–49)%43 (34–51)%42 (29–56)%3 years36 (29–43)%27 (–2035)%29 (21–39)%23 (12–38)%OS100 days77 (71–82)%77 (70–83)%81 (74–87)%76 (64–87)%1 year50 (43–56)%46 (38–54)%53 (44–62)%48 (35–61)%3 years39 (32–46)%29 (22–37)%30 (21–40)%29 (17–43)%Follow-up (months)36 (2–86)40 (3–86)35 (3–68)36 (3–85)

Comparison of Outcomes of HLA-Matched Related, Unrelated, or HLA-Haploidentical Related Hematopoietic Cell Transplantation following Nonmyeloablative Conditioning for Relapsed or Refractory Hodgkin Lymphoma

We compared the outcome of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) for patients with relapsed or refractory Hodgkin lymphoma (HL) based on donor cell source. Ninety patients with HL were treated with nonmyeloablative conditioning followed by HCT from HLA-matched related, n=38, unrelated, n=24, or HLA-haploidentical related, n=28 donors. Patients were heavily pretreated with a median of 5 regimens and most patients had failed autologous HCT (92%) and local radiation therapy (83%). With a median follow-up of 25 months, 2-year overall survivals, progression-free survivals (OS)/(PFS), and incidences of relapsed/progressive disease were 53%, 23%, and 56% (HLA-matched related), 58%, 29%, and 63% (unrelated), and 58%, 51%, and 40% (HLA-haploidentical related), respectively. Nonrelapse mortality (NRM) was significantly lower for HLA-haploidentical related (P=.02) recipients compared to HLA-matched related recipients. There were also significantly decreased risks of relapse for HLA-haploidentical related recipients compared to HLA-matched related (P=.01) and unrelated (P=.03) recipients. The incidences of acute grades III-IV and extensive chronic graft-versus-host disease (aGVHD, cGVHD) were 16%/50% (HLA-matched related), 8%/63% (unrelated), and 11%/35% (HLA-haploidentical related). These data suggested that salvage allogeneic HCT using nonmyeloablative conditioning provided antitumor activity in patients with advanced HL; however, disease relapse/progression continued to be major problems. Importantly, alternative donor stem cell sources are a viable option.

Predictive factors for outcomes after reduced intensity conditioning hematopoietic stem cell transplantation for hematological malignancies: a 10-year retrospective analysis from the Société Française de Greffe de Moelle et de Thérapie Cellulaire

This retrospective study analyzed the impact of demographic and transplantation variables on outcomes of 1108 patients who have undergone allogeneic hematopoietic stem cell transplantation after reduced intensity conditioning (RIC HSCT) for hematological malignancies and were reported to the Société Française de Greffe de Moelle et de Thérapie Cellulaire registry between November 1994 and December 2004. Only 442 patients (40%) were in complete remission (CR) at time of transplantation. Peripheral blood stem cells were used in the majority of patients (n = 878; 79%), 255 patients received fludarabine and low-dose total body irradiation, while 465 patients (42%) fludarabine and busulfan with rabbit anti-thymocyte globulins (ATG). The impact of demographic and transplant variables was studied on overall (OS) and event-free survival (EFS) in univariate and multivariate analysis. With a median follow-up of 21 months, 3-year probability of OS and EFS was 42% and 30%, respectively, and treatment-related mortality was 15% at 2 years. The multivariate analysis showed a significant negative impact on OS and EFS of the absence of CR status before transplantation; conditioning regimen, including >10 mg/kg ATG; and minor ABO incompatibility. In conclusion, this study highlights the major impact on RIC HSCT outcome of disease status before transplantation, ATG dose and ABO incompatibility.

Treatment of acute myeloid leukemia in older patients

Acute myeloid leukemia carries a dismal prognosis in patients over 60 years of age and, despite many clinical trials of both novel and conventional agents, there has been no significant improvement in overall survival during the last 30 years. Combinations of anthracyclines and cytarabine remain the cornerstone of therapy and produce complete remission in 45–55% of older patients, with a median survival of only 8–12 months. These statistics become even worse in patients over 70 years and those with unfavorable cytogenetics and/or poor performance status. Deciding which older acute myeloid leukemia patients would benefit from intensive chemotherapy is difficult and efforts are underway to improve existing risk-assessment tools. Many new agents are under development, including signal transduction inhibitors, farnesyl transferase inhibitors, antibodies and novel chemotherapeutics. To date, small-molecule inhibitors and targeted therapies have had limited single-agent efficacy and have required combination with chemotherapy. The role of hematopoietic stem cell transplantation in older patients is under investigation. All patients over 60 years of age with acute myeloid leukemia should be encouraged to participate in a clinical trial if possible.

Measures of Morbidity: Functional Assessment and Cytokines

With the increasing use of progenitor cell transplantation in older patients defining predictors of outcomes in this patient population will be important to guarantee the appropriate use of this procedure. Comorbidity assessments are not sufficiently sensitive in determining outcomes, functional assessment tools such as those used in rehabilitation medicine could be useful not only in predicting outcomes, but as another dimension of quality of life. These tools have rarely been used in the setting of hematopoietic progenitor cell transplantation. In this session we will review current trends in predicting transplant outcomes, the use of functional assesment tools in predicting morbidity post medical interventions, as well as potential strategies of improving functional status using growth hormone agonists.

Overcoming T cell–mediated rejection of bone marrow allografts by T-regulatory cells: Synergism with veto cells and rapamycin

Recently, we have shown that anti-third-party cytotoxic T lymphocytes (CTLs) depleted of alloreactivity against the host are endowed with marked veto activity and can facilitate bone marrow (BM) allografting without graft-versus-host disease. We also demonstrated synergism between rapamycin (RAPA) and the veto cells. CD4(+)CD25(+) T-regulatory (Treg) cells are suppressor cells that can enhance alloengraftment. We investigated whether donor Tregs would be synergistic with veto CTLs and RAPA in augmenting alloengraftment or, conversely, would suppress veto CTL effects. Lethally irradiated C3H mice were transplanted at day 2 after irradiation with Balb-nude BM. Graft rejection was induced by purified host-type T cells infused 1 day prior to BMT. The addition of Tregs led to moderate enhancement of engraftment. RAPA at different doses was synergistic with Tregs. The addition of veto CTLs to Tregs enabled reducing the effective RAPA dose fourfold. Combining all three agents was necessary to overcome rejection at low-dose RAPA. Chimerism analysis at 5 to 9 months revealed a significant presence of host-type cells coexisting with the predominant donor T cells, suggesting that tolerance had been attained. The synergistic effects between Tregs, veto CTLs, and RAPA offer an attractive approach for facilitating alloengraftment.

Autologous hematopoietic stem cell transplantation for older patients with relapsed non-Hodgkin's lymphoma

To evaluate autologous stem cell transplant (ASCT) in older patients with intermediate grade non-Hodgkin's lymphoma (NHL), the Mayo Clinic Rochester BMT database was reviewed for all patients 60 years of age and older who received ASCT for NHL between September 1995 and February 2003. Factors evaluated included treatment-related mortality (TRM), event-free survival (EFS) and overall survival (OS). Ninety-three patients were identified, including twenty-four (26%) over the age of 70 years. Treatment-related mortality (5.4%) was not significantly different when compared to a younger cohort (2.2%). At a median follow-up of 14 months (0.6-87.6 months), the estimated median survival is 25 months (95% confidence interval (CI) 12-38) in the older group compared to 56 months (95% CI 37-75) (P=0.037) in the younger group. The estimated 4-year EFS was 38% for the older group compared to 42% in the younger cohort (P=0.1). By multivariate analysis, the only factor found to influence survival in the older group was age-adjusted International Prognostic Index at relapse, 0-1 better than 2-3 (P=0.03). Autologous stem-cell transplant can be safely performed in patients 60 years or older with chemotherapy sensitive relapsed or first partial remission NHL. The outcome may not be different from that of younger patients in terms of TRM and EFS.

Unrelated Cord Blood Transplantation Using a Reduced-Intensity Conditioning Regimen without Total Body Irradiation in Two Patients with Multiple Myeloma

Reduced-intensity unrelated cord blood transplantation was performed on two patients (a 55- year-old woman and a 52- year-old man) with multiple myeloma that had progressed after high-dose chemotherapy (melphalan : 200 mg/m 2 ) with autologous stem cell transplantation support. The conditioning regimen consisted of fludarabine (180 mg/m 2 ) and busulfan (8 mg/kg) without total body irradiation. Tacrolimus was administered as a graft-versus-host disease prophylaxis. The engraftments were rapid (day +17 in patient 1 and day +26 in patient 2). Regimen-related toxicity was tolerable and acute graft-versushost disease (grade I) appeared only in patient 2. Complete donor chimerism continued following the treatment and no disease progression was observed in the succeeding 12 months. These results demonstrate the feasibility and effectiveness of reducedintensity cord blood transplantation after autologous stem cell transplantation in older patients.

Nonablative stem cell transplantation for older patients with acute leukemias and myelodysplastic syndromes

High-dose chemoradiotherapy with allogeneic bone marrow or peripheral blood stem cell transplantation (SCT) is a potentially curative treatment for advanced or poor-prognosis hematological malignancies. This procedure was initially considered as a means to deliver supralethal doses of chemotherapy and radiation for the eradication of the malignancy, but it has subsequently become apparent that much of the therapeutic benefit of SCT relates to an associated immune-mediated graft-versus-leukemia (GVL) effect. Additionally, due to the increased risk of morbidity and graft-versus-host disease (GVHD) that occurs with advanced age, the use of standard myeloablative preparative regimens with allogeneic progenitor cell transplantation has been generally limited to younger patients in good medical condition. However, most patients with hematologic malignancies are older and therefore the overall impact of allografting is relatively small. Thus despite resulting in high rates of long term disease control, allografting is only performed in a small fraction of patients, either because of lack of a suitable donor or the high risk of toxicity due to age or the general medical condition. Therefore strategies aimed at improving the safety and tolerability of allografting to allow for its more frequent application in older patients are necessary. Semin Hematol 39:57-62. Copyright © 2002 by W.B. Saunders Company.

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

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. (Blood. 2001;97:3390-3400)