Nonmyeloablative Conditioning

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Brenda M Sandmaier - One of the best experts on this subject based on the ideXlab platform.

  • HLA-Haploidentical Hematopoietic Cell Transplantation for Treatment of Nonmalignant Diseases Using Nonmyeloablative Conditioning and Post-Transplant Cyclophosphamide.
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2020
    Co-Authors: Kanwaldeep K. Mallhi, Troy R Torgerson, Paul A Carpenter, K S Baker, Meera A. Srikanthan, Kelsey K. Baker, Haydar Frangoul, Aleksandra Petrovic, Amy E Geddis, Brenda M Sandmaier
    Abstract:

    Abstract Allogeneic hematopoietic cell transplant (HCT) is often the only curative therapy for patients with nonmalignant diseases; however, many patients do not have an HLA-matched donor. Historically, poor survival has been seen after HLA-haploidentical HCT because of poor immune reconstitution, increased infections, graft-versus-host disease (GVHD), and graft failure. Encouraging results have been reported using a Nonmyeloablative T cell–replete HLA-haploidentical transplant approach in patients with hematologic malignancies. Here we report the outcomes of 23 patients with various nonmalignant diseases using a similar approach. Patients received HLA-haploidentical bone marrow (n = 17) or granulocyte colony-stimulating factor–mobilized peripheral blood stem cell (n = 6) grafts after Conditioning with cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, and 2 or 4 Gy total body irradiation. Postgrafting immunosuppression consisted of cyclophosphamide, mycophenolate mofetil, tacrolimus, ± sirolimus. Median patient age at HCT was 10.8 years. Day 100 transplant-related mortality (TRM) was 0%. Two patients died at later time points, 1 from intracranial hemorrhage/disseminated fungal infection in the setting of graft failure and 1 from infection/GVHD. The estimated probabilities of grades II to IV and III to IV acute GVHD at day 100 and 2-year National Institutes of Health consensus chronic GVHD were 78%, 26%, and 42%, respectively. With a median follow-up of 2.5 years, the 2-year overall and event-free rates of survival were 91% and 78%, respectively. These results are encouraging and demonstrate favorable disease-specific lineage engraftment with low TRM in patients with nonmalignant diseases using Nonmyeloablative Conditioning followed by T cell–replete HLA-haploidentical grafts. However, additional strategies are needed for GVHD prevention to make this a viable treatment approach for patients with nonmalignant diseases.

  • Thymic Recovery After Allogeneic Hematopoietic Cell Transplantation with Nonmyeloablative Conditioning Might Be Limited to Patients Younger Than 60 Years of Age.
    Blood, 2009
    Co-Authors: Emilie Castermans, Evelyne Willems, Laurence Seidel, Stéphanie Humblet-baron, Muriel Hannon, Rémi Cheynier, Stephanie Corbier, André Gothot, Vincent Geenen, Brenda M Sandmaier
    Abstract:

    Abstract 1149 Poster Board I-171 Background Nonmyeloablative Conditioning followed by allogeneic hematopoietic cell transplantation (HCT) has been increasingly used as treatment for elderly patients with hematologic malignancies. It has been suspected that T cell reconstitution would be impaired in elderly patients given Nonmyeloablative Conditioning because of age-related thymic atrophy. Here, we investigated long term lymphocyte reconstitution and thymic function in 80 patients given allogeneic peripheral blood stem cells (PBSC) after Nonmyeloablative Conditioning. Patients and Methods Median age at transplant was 57 years (range 10-71). Conditioning regimen consisted of 2 Gy total body irradiation (TBI) with (n=46) or without (n=20) added fludarabine, 4 Gy TBI with fludarabine (n=6), or cyclophosphamide plus fludarabine (n=8). Thirty-three of the 80 patients received grafts from HLA-matched related donors, 22 from HLA-matched unrelated donors, and 25 from HLA-mismatched related or unrelated donors. PBSC were unmanipulated in 56 patients, CD8-depleted in 19 others, and CD34-selected in the remaining 5 patients. GVHD prophylaxis consisted of mycophenolate mofetil and cyclosporine or tacrolimus. Immune recovery was assessed between 1 and 8.5 years after HCT by signal-joint T-cell receptor excision circle (sjTREC) quantification (221 samples), and flow cytometry. Further, in order to demonstrate a potential thymic recovery, sjTREC level changes from day 100 to days 365 and 730 were also assessed by using Wilcoxon signed rank tests. Results There was a close correlation between sjTREC levels and naive CD4+ T cells (defined as CD4+CD45RA+) counts (P 60 (n=22; P=0.3 and P=0.3, respectively) ([Figure 1][1]). Similarly, naive CD4 T cell counts increased from day 100 to 1 and 2 years after transplantation in patients ≤50 (n=23; P=0.01 and P=0.3, respectively), and in those 51-60 years of age (n=35; P=0.5 and P 60 (n=22; P=0.9 and P=1.0, respectively). In multivariate analyses, older patient age (P

  • What Is the Role for Donor Natural Killer Cells after Nonmyeloablative Conditioning
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2009
    Co-Authors: Frederic Baron, Brenda M Sandmaier, Thomas R Chauncey, David G. Maloney, Ted Gooley, Effie W Petersdorf, Mari Malkki, Rainer Storb
    Abstract:

    We investigated the impacts of the tempo of early (days 14, 28, and 42) donor T cell and natural killer (NK) cell engraftment, missing recipient killer cell immunoglobulin-like receptor (KIR) ligands, and numbers of donor inhibitory and activating KIR genes on hematopoietic cell transplantation (HCT) outcomes in 282 patients with hematologic malignancies given Nonmyeloablative Conditioning. Modeling chimerism levels as a continuous linear variable, we found that high early donor T cell chimerism was significantly associated with acute graft-versus-host disease (aGVHD) (P = .01), whereas high donor NK cell chimerism levels had no such association (P = .38). Conversely, high donor NK cell chimerism levels were significantly associated with low relapse risk (P = .0009), whereas no significant association was seen with high donor T cell chimerism (P = .10). The qualitative associations between donor T cell and NK cell chimerism levels and GVHD and relapse did not change after adjustment for the presence of recipient KIR ligands or numbers of donor inhibitory or activating KIR genes. Our data indicate that prompt engraftment of donor NK cells correlated with lessened risks of relapse, but not with GVHD, whereas the converse was true for T cells.

  • Allogeneic Hematopoietic Cell Transplantation (HCT) after Nonmyeloablative Conditioning for Patients (pts) Aged ≥60 Years.
    Blood, 2008
    Co-Authors: Mohamed L Sorror, Barry E Storer, Brenda M Sandmaier, Thomas R Chauncey, David G. Maloney, Edward Agura, Richard T. Maziarz, J. Shizuru, Georg Franke, Firoozeh Sahebi
    Abstract:

    Median ages of pts with most hematological malignancies are beyond 60 years. The advent of Nonmyeloablative Conditioning regimens has extended the use of allogeneic HCT to these older pts. Here, we retrospectively investigated outcomes among 280 pts aged ≥60 years, given HCT between 1998 and 2006. Results were broken down in 3 age groups 60–64 (n=166), 65–69 (n=90), and ≥70 (n=24) years old, respectively. Pts aged ≥70 years had less preceding chemotherapy, less often failed autologous HCT, more often had related grafts, and had higher comorbidity scores compared to pts in the other two age groups (table 1). Acute leukemias were more frequent and lymphoma/multiple myeloma were less frequent among pts aged ≥70 years old, resulting in higher risk for relapse (Table 1). After HCT, non-relapse mortality, relapse, and progression free survivals at 5-years for all pts were 26%, 41%, and 32% respectively. Five-year Kaplan Meier rate of overall survival was 35%, of those 12% vs. 23% were with vs. without chronic GVHD requiring immunosuppressive therapy, respectively. There were no statistically significant differences in outcomes among the three age groups except for more infections and days of hospitalization among pts aged 65–69 years compared to the other two age groups (Table 2). In multivariate analyses of risk factors, high HCT-comorbidity index (1–2 and ≥3) independently predicted higher NRM (HR: 2.84 and 3.0, respectively, p =0.01) and, not surprisingly, previously defined high relapse risk predicted relapse (HR: 2.17, p =0.06); both predicted worse OS ( p =0.005 and p =0.0009, respectively) and PFS ( p =0.01 and p =0.02, respectively). Pts given unrelated grafts did as well as recipients of related grafts. In conclusion, Nonmyeloablative allogeneic HCT can be curative among pts older than 60 years with resolution of chronic GVHD among a majority of pts. Comorbidities and relapse risk rather than age should be used for benefit-risk assessment. Continued enrollment of elderly pts in prospective studies including unrelated donors is warranted. Table 1: Pt characteristics Table 2: Outcomes per age groups

  • allogeneic hematopoietic cell transplantation hct after Nonmyeloablative Conditioning for patients pts aged 60 years
    Blood, 2008
    Co-Authors: Mohamed L Sorror, Barry E Storer, Brenda M Sandmaier, Thomas R Chauncey, David G. Maloney, Edward Agura, Richard T. Maziarz, J. Shizuru, Georg Franke, Firoozeh Sahebi
    Abstract:

    Median ages of pts with most hematological malignancies are beyond 60 years. The advent of Nonmyeloablative Conditioning regimens has extended the use of allogeneic HCT to these older pts. Here, we retrospectively investigated outcomes among 280 pts aged ≥60 years, given HCT between 1998 and 2006. Results were broken down in 3 age groups 60–64 (n=166), 65–69 (n=90), and ≥70 (n=24) years old, respectively. Pts aged ≥70 years had less preceding chemotherapy, less often failed autologous HCT, more often had related grafts, and had higher comorbidity scores compared to pts in the other two age groups (table 1). Acute leukemias were more frequent and lymphoma/multiple myeloma were less frequent among pts aged ≥70 years old, resulting in higher risk for relapse (Table 1). After HCT, non-relapse mortality, relapse, and progression free survivals at 5-years for all pts were 26%, 41%, and 32% respectively. Five-year Kaplan Meier rate of overall survival was 35%, of those 12% vs. 23% were with vs. without chronic GVHD requiring immunosuppressive therapy, respectively. There were no statistically significant differences in outcomes among the three age groups except for more infections and days of hospitalization among pts aged 65–69 years compared to the other two age groups (Table 2). In multivariate analyses of risk factors, high HCT-comorbidity index (1–2 and ≥3) independently predicted higher NRM (HR: 2.84 and 3.0, respectively, p =0.01) and, not surprisingly, previously defined high relapse risk predicted relapse (HR: 2.17, p =0.06); both predicted worse OS ( p =0.005 and p =0.0009, respectively) and PFS ( p =0.01 and p =0.02, respectively). Pts given unrelated grafts did as well as recipients of related grafts. In conclusion, Nonmyeloablative allogeneic HCT can be curative among pts older than 60 years with resolution of chronic GVHD among a majority of pts. Comorbidities and relapse risk rather than age should be used for benefit-risk assessment. Continued enrollment of elderly pts in prospective studies including unrelated donors is warranted. Table 1: Pt characteristics Table 2: Outcomes per age groups

Frederic Baron - One of the best experts on this subject based on the ideXlab platform.

  • kinetics of il 7 and il 15 levels after allogeneic peripheral blood stem cell transplantation following Nonmyeloablative Conditioning
    PLOS ONE, 2013
    Co-Authors: Muriel De Bock, Laurence Seidel, Yves Beguin, Muriel Hannon, André Gothot, Marianne Fillet, Marie-paule Merville, Frederic Baron
    Abstract:

    Background We analysed kinetics of IL-7 and IL-15 levels in 70 patients given peripheral blood stem cells after Nonmyeloablative Conditioning. Methods EDTA-anticoagulated plasma and serum samples were obtained before Conditioning and about once per week after transplantation until day 100. Samples were aliquoted and stored at −80°C within 3 hours after collection until measurement of cytokines. IL-7 and IL-15 levels were measured by ELISAs. Results Median IL-7 plasma levels remained below 6 pg/L throughout the first 100 days, although IL-7 plasma levels were significantly higher on days 7 (5.1 pg/mL, P = 0.002), 14 (5.2 pg/mL, P<0.001), and 28 (5.1 pg/mL, P = 0.03) (but not thereafter) than before transplantation (median value of 3.8 pg/mL). Median IL-15 serum levels were significantly higher on days 7 (12.5 pg/mL, P<0.001), 14 (10.5 pg/mL, P<0.001), and 28 (6.2 pg/mL, P<0.001) than before transplantation (median value of 2.4 pg/mL). Importantly, IL-7 and IL-15 levels on days 7 or 14 after transplantation did not predict grade II–IV acute GVHD. Conclusions These data suggest that IL-7 and IL-15 levels remain relatively low after Nonmyeloablative transplantation, and that IL-7 and IL-15 levels early after Nonmyeloablative transplantation do not predict for acute GVHD.

  • Kinetics of IL-7 and IL-15 Levels after Allogeneic Peripheral Blood Stem Cell Transplantation following Nonmyeloablative Conditioning
    PloS one, 2013
    Co-Authors: Muriel De Bock, Laurence Seidel, Yves Beguin, Muriel Hannon, André Gothot, Marianne Fillet, Marie-paule Merville, Frederic Baron
    Abstract:

    Background We analysed kinetics of IL-7 and IL-15 levels in 70 patients given peripheral blood stem cells after Nonmyeloablative Conditioning. Methods EDTA-anticoagulated plasma and serum samples were obtained before Conditioning and about once per week after transplantation until day 100. Samples were aliquoted and stored at −80°C within 3 hours after collection until measurement of cytokines. IL-7 and IL-15 levels were measured by ELISAs. Results Median IL-7 plasma levels remained below 6 pg/L throughout the first 100 days, although IL-7 plasma levels were significantly higher on days 7 (5.1 pg/mL, P = 0.002), 14 (5.2 pg/mL, P

  • Elevations of tumor necrosis factor receptor 1 at day 7 and acute graft-versus-host disease after allogeneic hematopoietic cell transplantation with Nonmyeloablative Conditioning
    Bone marrow transplantation, 2010
    Co-Authors: Evelyne Willems, Laurence Seidel, Yves Beguin, Stéphanie Humblet-baron, Olivier Dengis, Frederic Baron
    Abstract:

    Acute GVHD has remained a significant cause of nonrelapse mortality after allogeneic hematopoietic cell transplantation (HCT) with Nonmyeloablative Conditioning. The role of TNF-α in the biology of acute GVHD after Nonmyeloablative Conditioning has not been studied thus far. Here, we measured TNF receptor 1 (TNFR1) as a surrogate marker for TNF-α in 106 patients before the start of the Conditioning regimen (baseline) and 7 days after allogeneic HCT with Nonmyeloablative Conditioning. The Nonmyeloablative regimen consisted of 2 Gy TBI alone (n=15), 2 Gy TBI plus fludarabine 90 mg/m2 (n=73), or 4 Gy TBI plus fludarabine 90 mg/m2 (n=18). TNFR1 levels increased significantly from baseline to day 7 after Nonmyeloablative HCT (P

  • Elevations of Tumor Necrosis Factor-Receptor-1 at Day 7 and Acute Graft-Versus-Host Disease After Allogeneic Hematopietic Cell Transplantation with Nonmyeloablative Conditioning.
    Blood, 2009
    Co-Authors: Stéphanie Humblet-baron, Evelyne Willems, Laurence Seidel, Yves Beguin, Olivier Dengis, Frederic Baron
    Abstract:

    Abstract 2269 Poster Board II-246 Background. Acute graft-versus-host disease (GVHD) has remained a significant cause of nonrelapse mortality after allogeneic hematopoietic cell transplantation (HCT) with Nonmyeloablative Conditioning. The role of tumor necrosis factor-alpha (TNF-α) in the biology of acute GVHD following Nonmyeloablative Conditioning has not been studied thus far. Here, we measured TNF receptor 1 (TNFR1) as a surrogate marker for TNF-α in 106 patients before the start of the Conditioning regimen (baseline) and 7 days after allogeneic HCT following Nonmyeloablative Conditioning. Patients and Methods. The Nonmyeloablative regimen consisted of 2 Gy total body irradiation (TBI) alone (n=15), 2 Gy TBI plus fludarabine 90 mg/m 2 (n=18). Postgrafting immunosuppression combined mycophenolate mofetil (MMF) with a calcineurin inhibitor for all patients. Blood samples were prospectively collected before the start of the Conditioning regimen, then on days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, 91, and 98 after HCT, and then generally once every 2 weeks up to day 180. The serum component of each blood sample was separated and frozen for later analysis on the day of sample acquisition. TNFR1 serum concentration was retrospectively assessed using a cytokine enzyme-linked immunoabsorbent assay (R&D, Minneapolis, MN) according to the manufacturer9s protocol. Results. TNFR1 levels increased significantly from baseline to day 7 after Nonmyeloablative HCT ( P P =0.01). Median time for diagnosis of grade II-IV acute GVHD was 38 (range, 4-341) days, with only 1 patient experiencing acute GVHD before day 7. In a multivariate Cox model, high TNFR1 day 7/baseline ratio (modeled as a continuous linear variable) was the only factor statistically significantly associated with a higher risk of grade II-IV (HR 2.2, P=0.01) and grade III-IV (HR 2.9, P=0.007) acute GVHD. There was also a suggestion for an association between a high incidence of grade II-IV acute GVHD and HLA-disparity between donor and recipient, older patient age, and female donor to male recipient, although these factors did not reach statistically significance perhaps because of the relatively small number of patients analyzed. Interestingly, day 7 TNFR1 levels were not statistically significantly associated grade II-IV acute GVHD (P=0.07), suggesting that TNFR1 day 7/baseline ratio predicts better for acute GVHD than TNFR1 day 7 alone. To further analyze the role of TNF in acute GVHD after Nonmyeloablative Conditioning, we compared TNFR1 levels at onset of acute GVHD (median, day 38) in a subgroup of 20 patients with grade II-IV acute GVHD, versus TNFR1 levels around day 38 after HCT in a subgroup of 20 patients who never experienced grade II-IV acute GVHD. TNFR1 levels were significantly higher in patients with grade II-IV acute GVHD than in those without (median 7,119 versus 3,140 pg/mL, P =0.001). One- and three-year overall survival rates were 65% and 45%, respectively. In multivariate analysis, unrelated donor (P=0.01), high disease risk (P=0.05), and higher patient age (P=0.03) were each associated with a higher risk of mortality, while TNFR1 day 7/baseline ratio (modeled as a continuous linear variable) was not (P=0.75). Conclusions. Our data suggest that Nonmyeloablative Conditioning induces the generation of TNF-α, and that the magnitude of TNF-α generation depends on the Conditioning intensity (2 Gy versus 4 Gy TBI). Further, assessment of TNFR1 levels before and on day 7 after Nonmyeloablative HCT provided useful information on subsequent risk of experiencing acute GVHD. Note: SHB and EW contributed equally to the work. Disclosures: No relevant conflicts of interest to declare.

  • Comparison of thrombotic microangiopathy after allogeneic hematopoietic cell transplantation with high-dose or Nonmyeloablative Conditioning.
    Bone marrow transplantation, 2009
    Co-Authors: Evelyne Willems, Frederic Baron, Laurence Seidel, Pascale Frere, Georges Fillet, Yves Beguin
    Abstract:

    Comparison of thrombotic microangiopathy after allogeneic hematopoietic cell transplantation with high-dose or Nonmyeloablative Conditioning

Michael B Maris - One of the best experts on this subject based on the ideXlab platform.

  • comparison of outcomes of hla matched related unrelated or hla haploidentical related hematopoietic cell transplantation following Nonmyeloablative Conditioning for relapsed or refractory hodgkin lymphoma
    Biology of Blood and Marrow Transplantation, 2008
    Co-Authors: Lauri Burroughs, Barry E Storer, Brenda M Sandmaier, Michael B Maris, Leo Luznik, Paul V Odonnell, Heather J Symons, Richard J Jones, Richard F Ambinder, Karl G Blume
    Abstract:

    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.

  • five year follow up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after Nonmyeloablative Conditioning
    Journal of Clinical Oncology, 2008
    Co-Authors: Mohamed L Sorror, Barry E Storer, Brenda M Sandmaier, Michael B Maris, Thomas R Chauncey, Edward Agura, Michael A Pulsipher, Richard T. Maziarz, J. Shizuru, Peter A. Mcsweeney
    Abstract:

    Purpose We reported encouraging early results of allogeneic hematopoietic cell transplantation (HCT) after Nonmyeloablative Conditioning in 64 patients who had advanced chronic lymphocytic leukemia (CLL). Here, we have extended the follow-up to a median of 5 years and have included data on an additional 18 patients. Patients and Methods Eighty-two patients, age 42 to 72 years, who had fludarabine-refractory CLL were conditioned with 2 Gy total-body irradiation alone or combined with fludarabine followed by HCT from related (n 52) or unrelated (n 30) donors. Results Complete remission (CR) and partial remission were achieved in 55% and 15% of patients, respectively. Higher CR rates were noted after unrelated HCT (67% v 48%). The 5-year incidences of nonrelapse mortality (NRM), progression/relapse, overall survival, and progression-free survival were 23%, 38%, 50%, and 39%, respectively. Among 25 patients initially reported in CR, 8% relapsed and 8% died as a result of NRM, whereas 84% have remained alive and in CR. Among 14 responding patients who were tested and who had molecular eradication of their disease, two died as a result of NRM, two relapsed, and 10 have remained negative. At 5 years, 76% of living patients were entirely well, whereas 24% continued to receive immunosuppression for chronic graft-versus-host disease; the median performance status in each group was 100% and 90%, respectively. Lymphadenopathy 5 cm, but not cytogenetic abnormalities at HCT, predicted relapse. In a risk-stratification model, patients who had lymphadenopathy less than 5 cm and no comorbidities had a 5-year OS of 71%. Conclusion Nonmyeloablative HCT resulted in a median survival of 5 years for patients who had fludarabinerefractory CLL with sustained remissions and in the continued resolution of chronic graft-versushost disease in surviving patients. J Clin Oncol 26:4912-4920. © 2008 by American Society of Clinical Oncology

  • comparison of allogeneic hematopoietic cell transplantation hct after Nonmyeloablative Conditioning with hla matched related mrd unrelated urd and related haploidentical haplo donors for relapsed or refractory hodgkin lymphoma hl
    Blood, 2007
    Co-Authors: Lauri Burroughs, Barry E Storer, Brenda M Sandmaier, Michael B Maris, Dietger Niederwieser, Leo Luznik, Heather J Symons, Karl G Blume, Paul Odonnell, Benedetto Bruno
    Abstract:

    We evaluated the utility of allogeneic HCT using Nonmyeloablative Conditioning as a potential treatment option for 79 patients (pts) with HL who were ineligible for high dose conventional allogeneic HCT and compared outcome based on donor cell source (MRD n=34, URD n=24, Haplo n=21). Conditioning consisted of 2 Gy TBI alone (n=15, MRD) or combined with either 90 mg/m 2 (MRD n=19, all URD) or 150 mg/m 2 (all Haplo) fludarabine. All haplo recipients also received cyclophosphamide pre (29 mg/kg) and post (50 or 100 mg/kg) HCT. GVHD prophylaxis consisted of mycophenolate mofetil and a calcineurin inhibitor. Pts were heavily pretreated with a median number of 5 (range, 2–10) prior regimens. Most pts failed prior autologous HCT (91%) and radiation therapy (86%). There were no graft rejections. The incidences of acute grades III–IV and extensive chronic GVHD were 15%/47% (MRD), 8%/60% (URD), and 10%/31% (Haplo). There were no statistically significant differences in the ability to discontinue immunosuppression based on donor cell sources. With a median follow up of 20 (range, 4–91) months for living pts; the 18 month overall survivals (OS), progression free survivals (PFS), and incidences of relapse/progressive disease (PD) were 47%, 20%, and 55% (MRD), 74%, 27%, and 65% (URD), and 71%, 60%, and 35% (Haplo), respectively. Nonrelapse mortalities (NRM) were significantly lower for URD (HR 0.16; p=0.03) and Haplo (HR 0.13; p=0.02) recipients compared to MRD recipients. There were also significantly decreased risks of relapse for Haplo recipients compared to MRD (HR 0.35; p=0.03) and URD (HR 0.36; p=0.02) recipients. These data suggest that salvage allogeneic HCT using Nonmyeloablative Conditioning provides anti-tumor activity in pts with very advanced disease; however, Rel/PD continue to be major problems regardless of stem cell source. Importantly, alternative donor sources are a viable option particularly for those pts who may have a limited window of opportunity to proceed to HCT.

  • relapse risk in patients with malignant diseases given allogeneic hematopoietic cell transplantation after Nonmyeloablative Conditioning
    Blood, 2007
    Co-Authors: Christoph Kahl, Barry E Storer, Brenda M Sandmaier, Michael B Maris, Marco Mielcarek, Karl G Blume, Dietger Niederwieser
    Abstract:

    Allogeneic hematopoietic cell transplantation (HCT) after Nonmyeloablative Conditioning for hematologic malignancies depends on graft-versus-tumor effects for eradication of cancer. Here, we estimated relapse risks according to disease characteristics. Between 1997 and 2006, 834 consecutive patients (median age, 55 years; range, 5-74 years) received related (n = 498) or unrelated (n = 336) HCT after 2 Gy total body irradiation alone (n = 171) or combined with fludarabine (90 mg/m2; n = 663). Relapse rates per patient year (PY) at risk, corrected for follow-up and competing nonrelapse mortality, were calculated for 29 different diseases and stages. The overall relapse rate per PY was 0.36. Patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) in remission (CR), low-grade or mantle cell non-Hodgkin lymphoma (NHL) (CR + partial remission [PR]), and high-grade NHL-CR had the lowest rates (0.00-0.24; low risk). In contrast, patients with advanced myeloid and lymphoid malignancies had rates of more than 0.52 (high risk). Patients with lymphoproliferative diseases not in CR (except Hodgkin lymphoma and high-grade NHL) and myeloid malignancies in CR had rates of 0.26-0.37 (standard risk). In conclusion, patients with low-grade lymphoproliferative disorders experienced the lowest relapse rates, whereas patients with advanced myeloid and lymphoid malignancies had high relapse rates after Nonmyeloablative HCT. The latter might benefit from cytoreductive treatment before HCT.

  • Extended mycophenolate mofetil and shortened cyclosporine failed to reduce graft-versus-host disease after unrelated hematopoietic cell transplantation with Nonmyeloablative Conditioning.
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2007
    Co-Authors: Frederic Baron, Barry E Storer, Brenda M Sandmaier, Michael B Maris, Effie W Petersdorf, Amelia Langston, Thoralf Lange, Wolfgang Bethge, Richard T. Maziarz, Peter A. Mcsweeney
    Abstract:

    Abstract We previously reported data from 103 patients with hematologic malignancies (median age 54 years) who received peripheral blood stem cell (PBSC) grafts from HLA-matched unrelated donors after Nonmyeloablative Conditioning and were given postgrafting immunosuppression consisting of mycophenolate mofetil (MMF; administered from day 0 until day +40 with taper through day +96) and cyclosporine (CSP; given from day −3 to day +100, with taper through day 180) (historical patients). The incidences of grade II-IV acute and extensive chronic graft-versus-host disease (aGVHD, cGVHD) were 52% and 49%, respectively, and the 1-year probabilities of relapse, nonrelapse mortality (NRM), and progression-free survival (PFS) were 26%, 18%, and 56%, respectively. Here, we treated 71 patients with hematologic malignancies (median age 56 years) with unrelated PBSC grafts and investigated whether postgrafting immunosuppression with an extended course of MMF, given at full dosing until day +150 and then tapered through day +180, and a shortened course of CSP, through day +80, would promote tolerance induction and reduce the incidence of GVHD (current patients). We observed 77% grade II-IV aGVHD and 45% extensive cGVHD ( P = .03, and P = .43, respectively, in current compared to historical patients). The 1-year probabilities of relapse, NRM, and PFS were 23%, 29%, and 47%, respectively ( P = .89, P = .02, and P = .08 compared to the historical patients). We conclude that postgrafting immunosuppression with extended MMF and shortened CSP failed to decrease the incidence of GVHD among unrelated PBSC recipients given Nonmyeloablative Conditioning.

Barry E Storer - One of the best experts on this subject based on the ideXlab platform.

  • allogeneic hematopoietic cell transplantation hct after Nonmyeloablative Conditioning for patients pts aged 60 years
    Blood, 2008
    Co-Authors: Mohamed L Sorror, Barry E Storer, Brenda M Sandmaier, Thomas R Chauncey, David G. Maloney, Edward Agura, Richard T. Maziarz, J. Shizuru, Georg Franke, Firoozeh Sahebi
    Abstract:

    Median ages of pts with most hematological malignancies are beyond 60 years. The advent of Nonmyeloablative Conditioning regimens has extended the use of allogeneic HCT to these older pts. Here, we retrospectively investigated outcomes among 280 pts aged ≥60 years, given HCT between 1998 and 2006. Results were broken down in 3 age groups 60–64 (n=166), 65–69 (n=90), and ≥70 (n=24) years old, respectively. Pts aged ≥70 years had less preceding chemotherapy, less often failed autologous HCT, more often had related grafts, and had higher comorbidity scores compared to pts in the other two age groups (table 1). Acute leukemias were more frequent and lymphoma/multiple myeloma were less frequent among pts aged ≥70 years old, resulting in higher risk for relapse (Table 1). After HCT, non-relapse mortality, relapse, and progression free survivals at 5-years for all pts were 26%, 41%, and 32% respectively. Five-year Kaplan Meier rate of overall survival was 35%, of those 12% vs. 23% were with vs. without chronic GVHD requiring immunosuppressive therapy, respectively. There were no statistically significant differences in outcomes among the three age groups except for more infections and days of hospitalization among pts aged 65–69 years compared to the other two age groups (Table 2). In multivariate analyses of risk factors, high HCT-comorbidity index (1–2 and ≥3) independently predicted higher NRM (HR: 2.84 and 3.0, respectively, p =0.01) and, not surprisingly, previously defined high relapse risk predicted relapse (HR: 2.17, p =0.06); both predicted worse OS ( p =0.005 and p =0.0009, respectively) and PFS ( p =0.01 and p =0.02, respectively). Pts given unrelated grafts did as well as recipients of related grafts. In conclusion, Nonmyeloablative allogeneic HCT can be curative among pts older than 60 years with resolution of chronic GVHD among a majority of pts. Comorbidities and relapse risk rather than age should be used for benefit-risk assessment. Continued enrollment of elderly pts in prospective studies including unrelated donors is warranted. Table 1: Pt characteristics Table 2: Outcomes per age groups

  • Allogeneic Hematopoietic Cell Transplantation (HCT) after Nonmyeloablative Conditioning for Patients (pts) Aged ≥60 Years.
    Blood, 2008
    Co-Authors: Mohamed L Sorror, Barry E Storer, Brenda M Sandmaier, Thomas R Chauncey, David G. Maloney, Edward Agura, Richard T. Maziarz, J. Shizuru, Georg Franke, Firoozeh Sahebi
    Abstract:

    Median ages of pts with most hematological malignancies are beyond 60 years. The advent of Nonmyeloablative Conditioning regimens has extended the use of allogeneic HCT to these older pts. Here, we retrospectively investigated outcomes among 280 pts aged ≥60 years, given HCT between 1998 and 2006. Results were broken down in 3 age groups 60–64 (n=166), 65–69 (n=90), and ≥70 (n=24) years old, respectively. Pts aged ≥70 years had less preceding chemotherapy, less often failed autologous HCT, more often had related grafts, and had higher comorbidity scores compared to pts in the other two age groups (table 1). Acute leukemias were more frequent and lymphoma/multiple myeloma were less frequent among pts aged ≥70 years old, resulting in higher risk for relapse (Table 1). After HCT, non-relapse mortality, relapse, and progression free survivals at 5-years for all pts were 26%, 41%, and 32% respectively. Five-year Kaplan Meier rate of overall survival was 35%, of those 12% vs. 23% were with vs. without chronic GVHD requiring immunosuppressive therapy, respectively. There were no statistically significant differences in outcomes among the three age groups except for more infections and days of hospitalization among pts aged 65–69 years compared to the other two age groups (Table 2). In multivariate analyses of risk factors, high HCT-comorbidity index (1–2 and ≥3) independently predicted higher NRM (HR: 2.84 and 3.0, respectively, p =0.01) and, not surprisingly, previously defined high relapse risk predicted relapse (HR: 2.17, p =0.06); both predicted worse OS ( p =0.005 and p =0.0009, respectively) and PFS ( p =0.01 and p =0.02, respectively). Pts given unrelated grafts did as well as recipients of related grafts. In conclusion, Nonmyeloablative allogeneic HCT can be curative among pts older than 60 years with resolution of chronic GVHD among a majority of pts. Comorbidities and relapse risk rather than age should be used for benefit-risk assessment. Continued enrollment of elderly pts in prospective studies including unrelated donors is warranted. Table 1: Pt characteristics Table 2: Outcomes per age groups

  • comparison of outcomes of hla matched related unrelated or hla haploidentical related hematopoietic cell transplantation following Nonmyeloablative Conditioning for relapsed or refractory hodgkin lymphoma
    Biology of Blood and Marrow Transplantation, 2008
    Co-Authors: Lauri Burroughs, Barry E Storer, Brenda M Sandmaier, Michael B Maris, Leo Luznik, Paul V Odonnell, Heather J Symons, Richard J Jones, Richard F Ambinder, Karl G Blume
    Abstract:

    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.

  • five year follow up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after Nonmyeloablative Conditioning
    Journal of Clinical Oncology, 2008
    Co-Authors: Mohamed L Sorror, Barry E Storer, Brenda M Sandmaier, Michael B Maris, Thomas R Chauncey, Edward Agura, Michael A Pulsipher, Richard T. Maziarz, J. Shizuru, Peter A. Mcsweeney
    Abstract:

    Purpose We reported encouraging early results of allogeneic hematopoietic cell transplantation (HCT) after Nonmyeloablative Conditioning in 64 patients who had advanced chronic lymphocytic leukemia (CLL). Here, we have extended the follow-up to a median of 5 years and have included data on an additional 18 patients. Patients and Methods Eighty-two patients, age 42 to 72 years, who had fludarabine-refractory CLL were conditioned with 2 Gy total-body irradiation alone or combined with fludarabine followed by HCT from related (n 52) or unrelated (n 30) donors. Results Complete remission (CR) and partial remission were achieved in 55% and 15% of patients, respectively. Higher CR rates were noted after unrelated HCT (67% v 48%). The 5-year incidences of nonrelapse mortality (NRM), progression/relapse, overall survival, and progression-free survival were 23%, 38%, 50%, and 39%, respectively. Among 25 patients initially reported in CR, 8% relapsed and 8% died as a result of NRM, whereas 84% have remained alive and in CR. Among 14 responding patients who were tested and who had molecular eradication of their disease, two died as a result of NRM, two relapsed, and 10 have remained negative. At 5 years, 76% of living patients were entirely well, whereas 24% continued to receive immunosuppression for chronic graft-versus-host disease; the median performance status in each group was 100% and 90%, respectively. Lymphadenopathy 5 cm, but not cytogenetic abnormalities at HCT, predicted relapse. In a risk-stratification model, patients who had lymphadenopathy less than 5 cm and no comorbidities had a 5-year OS of 71%. Conclusion Nonmyeloablative HCT resulted in a median survival of 5 years for patients who had fludarabinerefractory CLL with sustained remissions and in the continued resolution of chronic graft-versushost disease in surviving patients. J Clin Oncol 26:4912-4920. © 2008 by American Society of Clinical Oncology

  • comparison of allogeneic hematopoietic cell transplantation hct after Nonmyeloablative Conditioning with hla matched related mrd unrelated urd and related haploidentical haplo donors for relapsed or refractory hodgkin lymphoma hl
    Blood, 2007
    Co-Authors: Lauri Burroughs, Barry E Storer, Brenda M Sandmaier, Michael B Maris, Dietger Niederwieser, Leo Luznik, Heather J Symons, Karl G Blume, Paul Odonnell, Benedetto Bruno
    Abstract:

    We evaluated the utility of allogeneic HCT using Nonmyeloablative Conditioning as a potential treatment option for 79 patients (pts) with HL who were ineligible for high dose conventional allogeneic HCT and compared outcome based on donor cell source (MRD n=34, URD n=24, Haplo n=21). Conditioning consisted of 2 Gy TBI alone (n=15, MRD) or combined with either 90 mg/m 2 (MRD n=19, all URD) or 150 mg/m 2 (all Haplo) fludarabine. All haplo recipients also received cyclophosphamide pre (29 mg/kg) and post (50 or 100 mg/kg) HCT. GVHD prophylaxis consisted of mycophenolate mofetil and a calcineurin inhibitor. Pts were heavily pretreated with a median number of 5 (range, 2–10) prior regimens. Most pts failed prior autologous HCT (91%) and radiation therapy (86%). There were no graft rejections. The incidences of acute grades III–IV and extensive chronic GVHD were 15%/47% (MRD), 8%/60% (URD), and 10%/31% (Haplo). There were no statistically significant differences in the ability to discontinue immunosuppression based on donor cell sources. With a median follow up of 20 (range, 4–91) months for living pts; the 18 month overall survivals (OS), progression free survivals (PFS), and incidences of relapse/progressive disease (PD) were 47%, 20%, and 55% (MRD), 74%, 27%, and 65% (URD), and 71%, 60%, and 35% (Haplo), respectively. Nonrelapse mortalities (NRM) were significantly lower for URD (HR 0.16; p=0.03) and Haplo (HR 0.13; p=0.02) recipients compared to MRD recipients. There were also significantly decreased risks of relapse for Haplo recipients compared to MRD (HR 0.35; p=0.03) and URD (HR 0.36; p=0.02) recipients. These data suggest that salvage allogeneic HCT using Nonmyeloablative Conditioning provides anti-tumor activity in pts with very advanced disease; however, Rel/PD continue to be major problems regardless of stem cell source. Importantly, alternative donor sources are a viable option particularly for those pts who may have a limited window of opportunity to proceed to HCT.

Thomas R Chauncey - One of the best experts on this subject based on the ideXlab platform.

  • What Is the Role for Donor Natural Killer Cells after Nonmyeloablative Conditioning
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2009
    Co-Authors: Frederic Baron, Brenda M Sandmaier, Thomas R Chauncey, David G. Maloney, Ted Gooley, Effie W Petersdorf, Mari Malkki, Rainer Storb
    Abstract:

    We investigated the impacts of the tempo of early (days 14, 28, and 42) donor T cell and natural killer (NK) cell engraftment, missing recipient killer cell immunoglobulin-like receptor (KIR) ligands, and numbers of donor inhibitory and activating KIR genes on hematopoietic cell transplantation (HCT) outcomes in 282 patients with hematologic malignancies given Nonmyeloablative Conditioning. Modeling chimerism levels as a continuous linear variable, we found that high early donor T cell chimerism was significantly associated with acute graft-versus-host disease (aGVHD) (P = .01), whereas high donor NK cell chimerism levels had no such association (P = .38). Conversely, high donor NK cell chimerism levels were significantly associated with low relapse risk (P = .0009), whereas no significant association was seen with high donor T cell chimerism (P = .10). The qualitative associations between donor T cell and NK cell chimerism levels and GVHD and relapse did not change after adjustment for the presence of recipient KIR ligands or numbers of donor inhibitory or activating KIR genes. Our data indicate that prompt engraftment of donor NK cells correlated with lessened risks of relapse, but not with GVHD, whereas the converse was true for T cells.

  • Allogeneic Hematopoietic Cell Transplantation (HCT) after Nonmyeloablative Conditioning for Patients (pts) Aged ≥60 Years.
    Blood, 2008
    Co-Authors: Mohamed L Sorror, Barry E Storer, Brenda M Sandmaier, Thomas R Chauncey, David G. Maloney, Edward Agura, Richard T. Maziarz, J. Shizuru, Georg Franke, Firoozeh Sahebi
    Abstract:

    Median ages of pts with most hematological malignancies are beyond 60 years. The advent of Nonmyeloablative Conditioning regimens has extended the use of allogeneic HCT to these older pts. Here, we retrospectively investigated outcomes among 280 pts aged ≥60 years, given HCT between 1998 and 2006. Results were broken down in 3 age groups 60–64 (n=166), 65–69 (n=90), and ≥70 (n=24) years old, respectively. Pts aged ≥70 years had less preceding chemotherapy, less often failed autologous HCT, more often had related grafts, and had higher comorbidity scores compared to pts in the other two age groups (table 1). Acute leukemias were more frequent and lymphoma/multiple myeloma were less frequent among pts aged ≥70 years old, resulting in higher risk for relapse (Table 1). After HCT, non-relapse mortality, relapse, and progression free survivals at 5-years for all pts were 26%, 41%, and 32% respectively. Five-year Kaplan Meier rate of overall survival was 35%, of those 12% vs. 23% were with vs. without chronic GVHD requiring immunosuppressive therapy, respectively. There were no statistically significant differences in outcomes among the three age groups except for more infections and days of hospitalization among pts aged 65–69 years compared to the other two age groups (Table 2). In multivariate analyses of risk factors, high HCT-comorbidity index (1–2 and ≥3) independently predicted higher NRM (HR: 2.84 and 3.0, respectively, p =0.01) and, not surprisingly, previously defined high relapse risk predicted relapse (HR: 2.17, p =0.06); both predicted worse OS ( p =0.005 and p =0.0009, respectively) and PFS ( p =0.01 and p =0.02, respectively). Pts given unrelated grafts did as well as recipients of related grafts. In conclusion, Nonmyeloablative allogeneic HCT can be curative among pts older than 60 years with resolution of chronic GVHD among a majority of pts. Comorbidities and relapse risk rather than age should be used for benefit-risk assessment. Continued enrollment of elderly pts in prospective studies including unrelated donors is warranted. Table 1: Pt characteristics Table 2: Outcomes per age groups

  • allogeneic hematopoietic cell transplantation hct after Nonmyeloablative Conditioning for patients pts aged 60 years
    Blood, 2008
    Co-Authors: Mohamed L Sorror, Barry E Storer, Brenda M Sandmaier, Thomas R Chauncey, David G. Maloney, Edward Agura, Richard T. Maziarz, J. Shizuru, Georg Franke, Firoozeh Sahebi
    Abstract:

    Median ages of pts with most hematological malignancies are beyond 60 years. The advent of Nonmyeloablative Conditioning regimens has extended the use of allogeneic HCT to these older pts. Here, we retrospectively investigated outcomes among 280 pts aged ≥60 years, given HCT between 1998 and 2006. Results were broken down in 3 age groups 60–64 (n=166), 65–69 (n=90), and ≥70 (n=24) years old, respectively. Pts aged ≥70 years had less preceding chemotherapy, less often failed autologous HCT, more often had related grafts, and had higher comorbidity scores compared to pts in the other two age groups (table 1). Acute leukemias were more frequent and lymphoma/multiple myeloma were less frequent among pts aged ≥70 years old, resulting in higher risk for relapse (Table 1). After HCT, non-relapse mortality, relapse, and progression free survivals at 5-years for all pts were 26%, 41%, and 32% respectively. Five-year Kaplan Meier rate of overall survival was 35%, of those 12% vs. 23% were with vs. without chronic GVHD requiring immunosuppressive therapy, respectively. There were no statistically significant differences in outcomes among the three age groups except for more infections and days of hospitalization among pts aged 65–69 years compared to the other two age groups (Table 2). In multivariate analyses of risk factors, high HCT-comorbidity index (1–2 and ≥3) independently predicted higher NRM (HR: 2.84 and 3.0, respectively, p =0.01) and, not surprisingly, previously defined high relapse risk predicted relapse (HR: 2.17, p =0.06); both predicted worse OS ( p =0.005 and p =0.0009, respectively) and PFS ( p =0.01 and p =0.02, respectively). Pts given unrelated grafts did as well as recipients of related grafts. In conclusion, Nonmyeloablative allogeneic HCT can be curative among pts older than 60 years with resolution of chronic GVHD among a majority of pts. Comorbidities and relapse risk rather than age should be used for benefit-risk assessment. Continued enrollment of elderly pts in prospective studies including unrelated donors is warranted. Table 1: Pt characteristics Table 2: Outcomes per age groups

  • five year follow up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after Nonmyeloablative Conditioning
    Journal of Clinical Oncology, 2008
    Co-Authors: Mohamed L Sorror, Barry E Storer, Brenda M Sandmaier, Michael B Maris, Thomas R Chauncey, Edward Agura, Michael A Pulsipher, Richard T. Maziarz, J. Shizuru, Peter A. Mcsweeney
    Abstract:

    Purpose We reported encouraging early results of allogeneic hematopoietic cell transplantation (HCT) after Nonmyeloablative Conditioning in 64 patients who had advanced chronic lymphocytic leukemia (CLL). Here, we have extended the follow-up to a median of 5 years and have included data on an additional 18 patients. Patients and Methods Eighty-two patients, age 42 to 72 years, who had fludarabine-refractory CLL were conditioned with 2 Gy total-body irradiation alone or combined with fludarabine followed by HCT from related (n 52) or unrelated (n 30) donors. Results Complete remission (CR) and partial remission were achieved in 55% and 15% of patients, respectively. Higher CR rates were noted after unrelated HCT (67% v 48%). The 5-year incidences of nonrelapse mortality (NRM), progression/relapse, overall survival, and progression-free survival were 23%, 38%, 50%, and 39%, respectively. Among 25 patients initially reported in CR, 8% relapsed and 8% died as a result of NRM, whereas 84% have remained alive and in CR. Among 14 responding patients who were tested and who had molecular eradication of their disease, two died as a result of NRM, two relapsed, and 10 have remained negative. At 5 years, 76% of living patients were entirely well, whereas 24% continued to receive immunosuppression for chronic graft-versus-host disease; the median performance status in each group was 100% and 90%, respectively. Lymphadenopathy 5 cm, but not cytogenetic abnormalities at HCT, predicted relapse. In a risk-stratification model, patients who had lymphadenopathy less than 5 cm and no comorbidities had a 5-year OS of 71%. Conclusion Nonmyeloablative HCT resulted in a median survival of 5 years for patients who had fludarabinerefractory CLL with sustained remissions and in the continued resolution of chronic graft-versushost disease in surviving patients. J Clin Oncol 26:4912-4920. © 2008 by American Society of Clinical Oncology

  • Allogeneic Hematopoietic Cell Transplantation (HCT) after Nonmyeloablative Conditioning for Relapsed or Refractory Follicular Lymphoma.
    Blood, 2005
    Co-Authors: Michael B Maris, Barry E Storer, Brenda M Sandmaier, Thomas R Chauncey, Edward Agura, Stephen J. Forman, Richard T. Maziarz, James C. Wade, J. Shizuru, Christoph Kahl
    Abstract:

    Forty-five patients (pts) with relapsed or chemotherapy refractory low-grade lymphomas were treated with HLA-matched related (n=22) and unrelated (n=23) HCT after Nonmyeloablative Conditioning using 2 Gy total body irradiation with or without fludarabine. Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil. Lymphoma histologies included follicular (n=38), small lymphocytic (n=5), and marginal zone (n=2). Seven pts had prior intermediate-grade lymphoma transformation. The median pt age was 54 (range 34–67) years and median time from diagnosis to allogeneic HCT was 4.3 (0.5–18.5) years. Twelve pts had failed and 3 received cytoreductive autologous HCT before Nonmyeloablative HCT. Disease status at time of Nonmyeloablative HCT included complete remission (CR, n=16), partial remission (PR, n=12), refractory (n=11) and untested relapse (n=6). Prognostic scoring at the time of HCT using the Follicular Lymphoma International Prognostic Index (FLIPI) identified 25 low-risk and 19 intermediate-risk pts and using the International Prognostic Index (IPI) identified 26 low-risk, 13 low-intermediate risk, and 5 intermediate-high risk pts. There were insufficient data to score 1 pt by the FLIPI or by the IPI. All pts received G-CSF mobilzed peripheral blood mononuclear cells. Six of the 23 unrelated donor graft recipients had human leukocyte antigen (HLA) mismatches: one at a single allele, 4 at a single antigen, and one at an antigen and an allele. The median follow up after nonmyeloblative HCT was 23.8 (range 2– 44.9) months. One pt experienced non-fatal graft rejection of a single antigen mismatched unrelated graft. The cumulative probabilities (CP) of acute grades II-IV, III-IV and chronic GVHD were 60%, 18%, and 51%, respectively. Responses [CR (n=14) and PR (n=6)] were seen in 20 of 28 (71%) pts with measurable disease at HCT while 3 had stable and 3 progressive disease, and 2 were not evaluable due to early nonrelapse death. None of the 20 pts who responded and 3 of the 17 transplanted in CR had disease relapse. At 2 years, the CPs of overall relapse/progression, and non-relapse mortality were 15% and 34%, respectively. The 2-year Kaplan-Meier estimates of overall and progression free survival were 58% and 51%, respectively. Higher IPI and FLIPI scores modeled as continuous variables were independently associated with worse PFS (HR 1.55, p=0.05 and HR 1.35, p=0.10 respectively). Use of a HLA mismatched unrelated donor was associated with a trend for worse OS and PFS (HR 3.0, p=0.08 for both). Allogeneic HCT after Nonmyeloablative Conditioning is a promising salvage strategy for pts with relapsed and refractory indolent lymphoma. The high response and low relapse rates with this approach suggest that relapsed indolent lymphomas are susceptible to graft-versus-tumor responses.

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