Karl G Blume

Publications (38)298.31 Total impact

• Article: Related and unrelated nonmyeloablative hematopoietic stem cell transplantation for malignant diseases

  George E. Georges, Michael Maris, Brenda M. Sandmaier, David G. Maloney, LyleFeinstein, Dietger Niederweiser, Judith A. Shizuru, Peter A. McSweeney, Thomas R. Chauncey, Edward Agura, Marie-Trse Little, Firoozeh Sahebi, Ute Hegenbart, Michael A. Pulsipher, Benedetto Bruno, Stephen Forman, Ann E. Woolfrey, Jerald P. Radich, Karl G. Blume, Rainer Storb
  [show abstract] [hide abstract]
  ABSTRACT: Patients with advanced hematological malignancies ineligible for conventional myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) due to advanced age or medical contraindications were enrolled in a multi-center study to investigate the safety and efficacy of nonmyeloablative HSCT using a 2 Gy total body irradiation (TBI)-based regimen. A total of 192 patients (median age 55) were treated with HLA-matched sibling peripheral blood stem cell (PBSC) grafts, and 63 patients (median age 53) received a 10 of 10 HLA-antigen matched unrelated donor (URD) HSCT (PBSC graft, n=48; marrow graft, n=15). Diagnoses included multiple myeloma (n=61), myelodysplastic syndrome (n=55), chronic myeloid leukemia (n=31), non-Hodgkin lymphoma (n=31), acute myeloid leukemia (n=28), chronic lymphocytic leukemia (n=24), Hodgkin Disease (n=14). The conditioning regimen was fludarabine 30 mg/m2/d × 3 days and 2 Gy TBI. Ninety-five related HSCT patients received 2 Gy TBI without fludarabine. Postgrafting immunosuppression was combined mycophenolate mofetil and cyclosporine. Transplants were well tolerated with a median of 0 days of hospitalization in the first 60 days for eligible patients. For related HSCT recipients, median follow-up was 289 (100–1188) days. Nonfatal graft rejection occurred in 6.8%. Of those with sustained engraftment, graft-versus-host disease (GVHD) occurred in 49% (33% grade II, 11% grade III, 5% grade IV). Day-100 non-relapse mortality was 6%. Overall, 59% (114/192) of patients were alive. The relapse/disease progression mortality was 18%, and non-relapse mortality was 22%. The projected 2-year survival and progression-free survival were 50% and 40%. For the URD HSCT recipients, median follow-up was 190 (100–468) days. Graft rejection occurred in 27% (17/63) of patients, mostly in recipients of marrow grafts (9/15). Acute GVHD occurred in 63% (50% grade II, 13% grade III) of 46 engrafted patients. Chronic GVHD requiring therapy occurred in 50% of patients. Of the 63 URD HSCT patients, 54% were alive, 37% in CR, 3% PR, and 14% with disease progression or relapse. Related and unrelated nonmyeloablative HSCT is feasible and potentially curative in patients with advanced hematological malignancies who have no other treatment options.
  International Journal of Hematology 04/2012; 76:184-189. · 1.27 Impact Factor
• Article: Long-term outcomes among older patients following nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation for advanced hematologic malignancies.

  Mohamed L Sorror, Brenda M Sandmaier, Barry E Storer, Georg N Franke, Ginna G Laport, Thomas R Chauncey, Edward Agura, Richard T Maziarz, Amelia Langston, Parameswaran Hari, [......], Finn Bo Petersen, Lars Vindeløv, Peter A McSweeney, Kai Hübel, Marco Mielcarek, George E Georges, Dietger Niederwieser, Karl G Blume, David G Maloney, Rainer Storb
  [show abstract] [hide abstract]
  ABSTRACT: A minimally toxic nonmyeloablative regimen was developed for allogeneic hematopoietic cell transplantation (HCT) to treat patients with advanced hematologic malignancies who are older or have comorbid conditions. To describe outcomes of patients 60 years or older after receiving minimally toxic nonmyeloablative allogeneic HCT. From 1998 to 2008, 372 patients aged 60 to 75 years were enrolled in prospective clinical HCT trials at 18 collaborating institutions using conditioning with low-dose total body irradiation alone or combined with fludarabine, 90 mg/m(2), before related (n = 184) or unrelated (n = 188) donor transplants. Postgrafting immunosuppression included mycophenolate mofetil and a calcineurin inhibitor. Overall and progression-free survival were estimated by Kaplan-Meier method. Cumulative incidence estimates were calculated for acute and chronic graft-vs-host disease, toxicities, achievement of full donor chimerism, complete remission, relapse, and nonrelapse mortality. Hazard ratios (HRs) were estimated from Cox regression models. Overall, 5-year cumulative incidences of nonrelapse mortality and relapse were 27% (95% CI, 22%-32%) and 41% (95% CI, 36%-46%), respectively, leading to 5-year overall and progression-free survival of 35% (95% CI, 30%-40%) and 32% (95% CI, 27%-37%), respectively. These outcomes were not statistically significantly different when stratified by age groups. Furthermore, increasing age was not associated with increases in acute or chronic graft-vs-host disease or organ toxicities. In multivariate models, HCT-specific comorbidity index scores of 1 to 2 (HR, 1.58 [95% CI, 1.08-2.31]) and 3 or greater (HR, 1.97 [95% CI, 1.38-2.80]) were associated with worse survival compared with an HCT-specific comorbidity index score of 0 (P = .003 overall). Similarly, standard relapse risk (HR, 1.67 [95% CI, 1.10-2.54]) and high relapse risk (HR, 2.22 [95% CI, 1.43-3.43]) were associated with worse survival compared with low relapse risk (P < .001 overall). Among patients aged 60 to 75 years treated with nonmyeloablative allogeneic HCT, 5-year overall and progression-free survivals were 35% and 32%, respectively.
  JAMA The Journal of the American Medical Association 11/2011; 306(17):1874-83. · 30.03 Impact Factor
• Article: Long-term outcome of patients with metastatic breast cancer treated with high-dose chemotherapy and transplantation of purified autologous hematopoietic stem cells.

  Antonia M S Müller, Holbrook E K Kohrt, Steven Cha, Ginna Laport, Jared Klein, Alice E Guardino, Laura J Johnston, Keith E Stockerl-Goldstein, Elie Hanania, Christopher Juttner, Karl G Blume, Robert S Negrin, Irving L Weissman, Judith A Shizuru
  [show abstract] [hide abstract]
  ABSTRACT: Metastatic breast cancer remains a major treatment challenge. The use of high-dose chemotherapy (HDCT) with rescue by autologous mobilized peripheral blood (MPB) is controversial, in part because of contamination of MPB by circulating tumor cells. CD34(+)Thy-1(+) selected hematopoietic stem cells (HSC) represent a graft source with a greater than 250,000-fold reduction in cancer cells. Here, we present the long-term outcome of a pilot study to determine feasibility and engraftment using HDCT and purified HSC in patients with metastatic breast cancer. Twenty-two patients who had been treated with standard chemotherapy were enrolled into a phase I/II trial between December 1996 and February 1998, and underwent HDCT followed by rescue with CD34(+)Thy-1(+) HSC isolated from autologous MPB. More than 12 years after the end of the study, 23% (5 of 22) of HSC recipients are alive, and 18% (4 of 22) are free of recurrence with normal hematopoietic function. Median progression-free survival (PFS) was 16 months, and median overall survival (OS) was 60 months. Retrospective comparison with 74 patients transplanted between February 1995 and June 1999 with the identical HDCT regimen but rescue with unmanipulated MPB indicated that 9% of patients are alive, and 7% are without disease. Median PFS was 10 months, and median OS was 28 months. In conclusion, cancer-depleted HSC following HDCT resulted in better than expected 12- to 14-year PFS and OS in a cohort of metastatic breast cancer patients. These data prompt us to look once again at purified HSC transplantation in a protocol powered to test for efficacy in advanced-stage breast cancer patients.
  Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2011; 18(1):125-33. · 3.15 Impact Factor
• Article: Phase I/II trial of GN-BVC, a gemcitabine and vinorelbine-containing conditioning regimen for autologous hematopoietic cell transplantation in recurrent and refractory hodgkin lymphoma.

  Sally Arai, Renee Letsinger, Ruby M Wong, Laura J Johnston, Ginna G Laport, Robert Lowsky, David B Miklos, Judith A Shizuru, Wen-Kai Weng, Philip W Lavori, Karl G Blume, Robert S Negrin, Sandra J Horning
  [show abstract] [hide abstract]
  ABSTRACT: Autologous hematopoietic cell transplantation with augmented BCNU regimens is effective treatment for recurrent or refractory Hodgkin lymphoma (HL); however, BCNU-related toxicity and disease recurrence remain challenges. We designed a conditioning regimen with gemcitabine in combination with vinorelbine in an effort to reduce the BCNU dose and toxicity without compromising efficacy. In this phase I/II dose escalation study, the gemcitabine maximum tolerated dose (MTD) was determined at 1250 mg/m(2), and a total of 92 patients were treated at this dose to establish safety and efficacy. The primary endpoint was the incidence of BCNU-related toxicity. Secondary endpoints included 2-year freedom from progression (FFP), event-free survival (EFS), and overall survival (OS). Sixty-eight patients (74%) had 1 or more previously defined adverse risk factors for transplant (stage IV at relapse, B symptoms at relapse, greater than minimal disease pretransplant). The incidence of BCNU-related toxicity was 15% (95% confidence interval, 9%-24%). Only 2% of patients had a documented reduction in diffusing capacity of 20% or greater. With a median follow-up of 29 months, the FFP at 2 years was 71% and the OS at 2 years was 83%. Two-year FFP was 96%, 72%, 67%, and 14% for patients with 0 (n = 24), 1 (n = 37), 2 (n = 23), or 3 (n = 8) risk factors, respectively. Regression analysis identified PET status pretransplant and B symptoms at relapse as significant prognostic factors for FFP. This new transplant regimen for HL resulted in decreased BCNU toxicity with encouraging FFP and OS. A prospective, risk-modeled comparison of this new combination with other conditioning regimens is warranted.
  Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 02/2010; 16(8):1145-54. · 3.15 Impact Factor
• Article: TLI and ATG conditioning with low risk of graft-versus-host disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from related and unrelated donors.

  Holbrook E Kohrt, Brit B Turnbull, Kartoosh Heydari, Judith A Shizuru, Ginna G Laport, David B Miklos, Laura J Johnston, Sally Arai, Wen-Kai Weng, Richard T Hoppe, Philip W Lavori, Karl G Blume, Robert S Negrin, Samuel Strober, Robert Lowsky
  [show abstract] [hide abstract]
  ABSTRACT: A hematopoietic cell transplantation regimen was adapted from a preclinical model that used reduced-intensity conditioning (RIC) and protected against graft-versus-host disease (GVHD) by skewing residual host T-cell subsets to favor regulatory natural killer T cells. One hundred eleven patients with lymphoid (64) and myeloid (47) malignancies received RIC using total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) followed by the infusion of granulocyte colony-stimulating factor-mobilized grafts. Included were 34 patients at least 60 years of age, 32 patients at high risk of lymphoma relapse after disease recurrence following prior autologous transplantation, and 51 patients at high risk of developing GVHD due to lack of a fully human leukocyte antigen (HLA)-matched related donor. Durable chimerism was achieved in 97% of patients. Cumulative probabilities of acute GVHD (grades II-IV) were 2 and 10% of patients receiving related and unrelated donor grafts. Nonrelapse mortality (NRM) at 1 year was less than 4%. Cumulative incidence of chronic GVHD was 27%. The 36-month probability of overall and event-free survival was 60% and 40%, respectively. Disease status at start of conditioning and the level of chimerism achieved after transplantation significantly impacted clinical outcome. The high incidence of sustained remission among patients with active disease at time of transplantation suggests retained graft-versus-tumor reactions. Active trial registration currently at clinicaltrials.gov under IDs of NCT00185640 and NCT00186615.
  Blood 06/2009; 114(5):1099-109. · 9.90 Impact Factor
• Article: Comparison of outcomes of HLA-matched related, unrelated, or HLA-haploidentical related hematopoietic cell transplantation following nonmyeloablative conditioning for relapsed or refractory Hodgkin lymphoma.

  Lauri M Burroughs, Paul V O'Donnell, Brenda M Sandmaier, Barry E Storer, Leo Luznik, Heather J Symons, Richard J Jones, Richard F Ambinder, Michael B Maris, Karl G Blume, Dietger W Niederwieser, Benedetto Bruno, Richard T Maziarz, Michael A Pulsipher, Finn B Petersen, Rainer Storb, Ephraim J Fuchs, David G Maloney
  [show abstract] [hide abstract]
  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.
  Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 12/2008; 14(11):1279-87. · 3.15 Impact Factor
• Article: Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning.

  Mohamed L Sorror, Barry E Storer, Brenda M Sandmaier, Michael Maris, Judith Shizuru, Richard Maziarz, Edward Agura, Thomas R Chauncey, Michael A Pulsipher, Peter A McSweeney, James C Wade, Benedetto Bruno, Amelia Langston, Jerald Radich, Dietger Niederwieser, Karl G Blume, Rainer Storb, David G Maloney
  [show abstract] [hide abstract]
  ABSTRACT: 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. 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. 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 > or = 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%. Nonmyeloablative HCT resulted in a median survival of 5 years for patients who had fludarabine-refractory CLL with sustained remissions and in the continued resolution of chronic graft-versus-host disease in surviving patients.
  Journal of Clinical Oncology 09/2008; 26(30):4912-20. · 18.37 Impact Factor
• Article: Long-term remission of Philadelphia chromosome-positive acute lymphoblastic leukemia after allogeneic hematopoietic cell transplantation from matched sibling donors: a 20-year experience with the fractionated total body irradiation-etoposide regimen.

  Ginna G Laport, Joseph C Alvarnas, Joycelynne M Palmer, David S Snyder, Marilyn L Slovak, Athena M Cherry, Ruby M Wong, Robert S Negrin, Karl G Blume, Stephen J Forman
  [show abstract] [hide abstract]
  ABSTRACT: Allogeneic hematopoietic cell transplantation (HCT) is the only known curative modality for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL). Sixty-seven patients with HLA-matched sibling donors received fractionated total body irradiation (FTBI) and high-dose VP16, whereas 11 patients received FTBI/VP16/cyclophosphamide, and 1 patient received FTBI/VP16/busulfan. The median age was 36 years. At the time of HCT, 49 patients (62%) were in first complete remission (CR1) and 30 patients (38%) were beyond CR1 (> CR1). The median follow-up was 75 months (range, 14-245 months). The 10-year overall survival for the CR1 and beyond CR1 patients was 54% and 29% (P = .01), respectively, and event-free survival was 48% and 26% (P = .02), respectively. There was no significant difference in relapse incidence (28% vs 41%, P = .28), but nonrelapse mortality was significantly higher in the beyond CR1 patients, (31% vs 54%, P = .03, respectively). By univariate analysis, factors affecting event-free and overall survival were white blood cell count at diagnosis (< 30 x 10(9)/L vs > 30 x 10(9)/L) and disease status (CR1 vs > CR1). The median time to relapse for CR1 and for beyond CR1 patients was 12 months and 9 months, respectively. Our results indicate that FTBI/VP16 with or without cyclophosphamide confers long-term survival in Ph(+) ALL patients and that disease status at the time of HCT is an important predictor of outcome.
  Blood 08/2008; 112(3):903-9. · 9.90 Impact Factor
• Article: Reduced-intensity conditioning followed by allogeneic hematopoietic cell transplantation for adult patients with myelodysplastic syndrome and myeloproliferative disorders.

  Ginna G Laport, Brenda M Sandmaier, Barry E Storer, Bart L Scott, Monic J Stuart, Thoralf Lange, Michael B Maris, Edward D Agura, Thomas R Chauncey, Ruby M Wong, Stephen J Forman, Finn B Petersen, James C Wade, Elliot Epner, Benedetto Bruno, Wolfgang A Bethge, Peter T Curtin, David G Maloney, Karl G Blume, Rainer F Storb
  [show abstract] [hide abstract]
  ABSTRACT: Allogeneic hematopoietic cell transplantation (HCT) is the only curative strategy for patients with myelodysplastic syndrome (MDS) and myeloproliferative disorders (MPD). We report the results of 148 patients (median age = 59 years old) with de novo MDS (n = 40), acute myelogenous leukemia (AML) after antecedent MDS/MPD (n = 49), treatment-related MDS (t-MDS) (n = 25), MPD (n = 27), and chronic myelomonocytic leukemia (CMML) (n = 7) who underwent allogeneic HCT using a conditioning regimen of low-dose total body irradiation (TBI) alone (200 cGy) on day 0 (n = 5) or with the addition of fludarabine (Flu) 30 mg/m(2)/day on days -4 to -2 (n = 143). Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil (MMF). Seventy-five patients (51%) received an allograft from a matched related donor (MRD), and 73 patients (49%) were recipients of unrelated donor (URD) grafts. There was no significant difference in the incidence of acute (gr II-IV) and chronic extensive graft-versus-host disease (aGVHD, cGVHD) between the recipients of related and unrelated donor grafts. By day +28, 75% of patients demonstrated mixed T cell chimerism. Graft rejection was seen in 15% of patients. With a median follow-up of 47 (range: 6-89) months, the 3-year relapse-free survival (RFS) and overall survival (OS) are both 27% for all patients, with a relapse incidence of 41%. The 3-year RFS for the patients with de novo MDS, AML after antecedent MDS/MPD, t-MDS, MPD, and CMML were 22%, 20%, 29%, 37%, and 43%, respectively, and the 3-year OS was 20%, 23%, 27%, 43%, and 43%, respectively. The 3-year nonrelapse mortality (NRM) was 32%. Factors associated with a lower risk of relapse were the development of extensive cGVHD and having a low risk or intermediate-1 risk International Prognostic Score for the de novo MDS patients. Nonmyeloablative HCT confers remissions in patients who otherwise were not eligible for conventional HCT but for whom relapse is the leading cause of treatment failure.
  Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2008; 14(2):246-55. · 3.15 Impact Factor
• Article: Relapse risk in patients with malignant diseases given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning.

  Christoph Kahl, Barry E Storer, Brenda M Sandmaier, Marco Mielcarek, Michael B Maris, Karl G Blume, Dietger Niederwieser, Thomas R Chauncey, Stephen J Forman, Edward Agura, [......], Benedetto Bruno, Amelia Langston, Michael A Pulsipher, Peter A McSweeney, James C Wade, Elliot Epner, Finn Bo Petersen, Wolfgang A Bethge, David G Maloney, Rainer Storb
  [show abstract] [hide abstract]
  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/m(2); 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.
  Blood 11/2007; 110(7):2744-8. · 9.90 Impact Factor
• Chapter: Allogeneic Hematopoietic Cell Transplantation for Adult Patients With Acute Myeloid Leukemia

  Keith E. Stockerl‐Goldstein, Karl G. Blume
  10/2007: pages 1025 - 1039; , ISBN: 9780470987070
• Article: High-dose carmustine, etoposide, and cyclophosphamide followed by allogeneic hematopoietic cell transplantation for non-Hodgkin lymphoma.

  Lisa Y Law, Sandra J Horning, Ruby M Wong, Laura J Johnston, Ginna G Laport, Robert Lowsky, Judith A Shizuru, Karl G Blume, Robert S Negrin, Keith E Stockerl-Goldstein
  [show abstract] [hide abstract]
  ABSTRACT: Allogeneic hematopoietic cell transplantation (HCT) has been shown to be curative in a group of patients with aggressive non-Hodgkin lymphoma (NHL). A previous study has demonstrated equivalent outcomes with a conditioning regimen based on total body irradiation and another not based on total body irradiation with preparative therapy using cyclophosphamide, carmustine, and etoposide (CBV) in autologous HCT. We investigated the safety and efficacy of using CBV in an allogeneic setting. Patients were required to have relapsed or be at high risk for subsequent relapse of NHL. All patients had a fully HLA-matched sibling donor. Patients received carmustine (15 mg/kg), etoposide (60 mg/kg), and cyclophosphamide (100 mg/kg) on days -6, -4, and -2, respectively, followed by allogeneic HCT. All patients were treated with cyclosporine and methylprednisolone as prophylaxis for graft-versus-host disease (GVHD). Thirty-one patients (median age, 46 years) who were felt to be inappropriate candidates for autologous transplantation were enrolled. Each subject had a median of 3 previous chemotherapy regimens. All patients engrafted. Fifteen of 31 patients are alive. Median follow-up time was 11.5 months (range, .4-126). There were 8 deaths due to relapse. Nonrelapse mortality (n = 8) included infection (n = 3), GVHD (n = 2), diffuse alveolar hemorrhage (n = 1), veno-occlusive disease in the setting of concurrent acute GVHD of the liver (n = 1), and leukoencephalopathy (n = 1). Probabilities of event-free survival and overall survival were, respectively, 44% (95% confidence interval, 26%-62%) and 51% (33%-69%) at 1 year and 44% (26%-62%) and 47% (29%-65%) at 5 years. Probability of relapse was 33% (15%-51%) at 1 year and 5 years. Probability of nonrelapse mortality was 31% (13%-49%) at 1 year and 5 years. Incidences were 29% for acute GVHD and 39% for chronic GVHD. None of the 12 patients who developed chronic GVHD has disease recurrence. Patients who had required >3 previous chemotherapy regimens before HCT had an increased probability of relapse. CBV is an effective preparative regimen for patients with aggressive NHL who undergo allogeneic HCT.
  Biology of Blood and Marrow Transplantation 07/2006; 12(7):703-11. · 3.87 Impact Factor
• Article: Unrelated donor granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell transplantation after nonmyeloablative conditioning: the effect of postgrafting mycophenolate mofetil dosing.

  Michael B Maris, Brenda M Sandmaier, Barry E Storer, David G Maloney, Judith A Shizuru, Edward Agura, Constanze Kliem, Michael Pulsipher, Richard T Maziarz, Peter A McSweeney, James Wade, Amelia A Langston, Thomas R Chauncey, Benedetto Bruno, Karl G Blume, Rainer Storb
  [show abstract] [hide abstract]
  ABSTRACT: We previously reported results in 71 patients with advanced hematologic malignancies given HLA-matched unrelated granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell (G-PBMC) grafts after fludarabine 90 mg/m(2), 2 Gy of total body irradiation, and postgrafting mycophenolate mofetil (MMF) 15 mg/kg twice daily and cyclosporine 6.25 mg/kg twice daily orally. Graft rejection was 15%; the cumulative probability of acute graft-versus-host disease (GVHD) was 52%. According to MMF pharmacokinetic studies, which showed a short half-life of its active metabolite, mycophenolic acid, we increased MMF dosing from 15 mg/kg twice daily to 15 mg/kg 3 times daily to increase immunosuppression and reduce the incidence of both graft rejection and acute GVHD. Among 103 patients so treated, graft rejection occurred in 5%, whereas acute GVHD remained at 53%. Outcomes were compared with results of previous G-PBMC recipients given MMF twice daily. Infection rates were slightly higher with MMF 3 times daily than with MMF twice daily. Nevertheless, 2-year nonrelapse mortality and overall and progression-free survivals were similar for MMF 3-times-daily and twice-daily patients (19%, 58%, and 49% versus 20%, 48%, and 37%, respectively). Nonmyeloablative conditioning with postgrafting cyclosporine and MMF given 3 times daily allowed 95% durable engraftment of unrelated donor G-PBMC grafts.
  Biology of Blood and Marrow Transplantation 05/2006; 12(4):454-65. · 3.87 Impact Factor
• Source

  Available from: ufl.edu

  Article: A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission.

  David I Marks, Stephen J Forman, Karl G Blume, Waleska S Pérez, Daniel J Weisdorf, Armand Keating, Robert Peter Gale, Mitchell S Cairo, Edward A Copelan, John T Horan, Hillard M Lazarus, Mark R Litzow, Philip L McCarthy, Kirk R Schultz, David D Smith, Michael E Trigg, Mei-Jie Zhang, Mary M Horowitz
  [show abstract] [hide abstract]
  ABSTRACT: We compared the outcomes of 298 patients with acute lymphoblastic leukemia in first or second complete remission (CR1 or CR2) receiving HLA-matched sibling allografts after cyclophosphamide and total body irradiation (Cy-TBI) conditioning with 204 patients receiving etoposide and TBI. Consequently, 4 groups were compared: Cy-TBI <13 Gy (n = 217), Cy-TBI > or =13 Gy (n = 81), etoposide-TBI <13 Gy (n = 53), and etoposide-TBI > or =13 Gy (n = 151). Analyses of relapse, leukemia-free survival (LFS), and survival were performed separately for CR1 and CR2 transplantations. Transplant-related mortality did not differ by conditioning regimen. In CR1, there were also no significant differences in relapse, LFS, or survival by conditioning regimen. In CR2, these outcomes differed among conditioning groups. In comparison with Cy-TBI <13 Gy, the risks of relapse, treatment failure (inverse of LFS), and mortality tended to be lower with etoposide (regardless of TBI dose) or with TBI doses > or =13 Gy. For both CR1 and CR2 transplantations, causes of death were similar among the groups; disease recurrence accounted for 47% of deaths. We conclude that for HLA-identical sibling allografts for acute lymphoblastic leukemia in CR2, there is an advantage in substituting etoposide for Cy or, when Cy is used, in increasing the TBI dose to > or =13 Gy.
  Biology of Blood and Marrow Transplantation 04/2006; 12(4):438-53. · 3.87 Impact Factor
• Article: Nonmyeloablative Hematopoietic Cell Transplantation

  LYLE FEINSTEIN, BRENDA SANDMAIER, DAVID MALONEY, PETER A. McSWEENEY, MICHAEL MARIS, CHRISTOPHER FLOWERS, JERRY RADICH, MARIE-TÉRÈSE LITTLE, RICHARD A. NASH, THOMAS CHAUNCEY, ANN WOOLFREY, GEORGE GEORGES, HANS-PETER KIEM, JAN M. ZAUCHA, KARL G. BLUME, JUDITH SHIZURU, DIETGER NIEDERWIESER, RAINER STORB
  [show abstract] [hide abstract]
  ABSTRACT: Conventional allografting produces considerable regimen-related toxicities that generally limit this treatment to patients younger than 55 years and in otherwise good medical condition. T cell-mediated graft-versus-tumor (GVT) effects are known to play an important role in the elimination of malignant disease after allotransplants. A minimally myelosuppressive regimen that relies on immunosuppression for allogeneic engraftment was developed to reduce toxicities while optimizing GVT effects. Pre-transplant total-body irradiation (200 cGy) followed by post-transplant immunosuppression with cyclosporine (CSP) and mycophenolate mofetil (MMF) permitted human leukocyte antigen (HLA)-matched sibling donor hematopoietic cell engraftment in 82% of patients (n= 55) without prior high-dose therapy. The addition of fludarabine (90 mg/m2) facilitated engraftment in all 28 subsequent patients. Overall, fatal progression of underlying disease occurred in 20% of patients after transplant. Non-relapse mortality occurred in 11% of patients. Toxicities were low. Grade 2–4 acute graft-versus-host disease (GVHD) associated with primary engraftment developed in 47% of patients, and was readily controlled in all but two patients. Donor lymphocyte infusions (DLI) were not very effective at converting a low degree of mixed donor/host chimerism to full donor chimerism; however, the addition of fludarabine reduced the need for DLI. With a median follow-up of 244 days, 68% of patients were alive, with 42% of patients in complete remission, including molecular remissions. Remissions occurred gradually over periods of weeks to a year. If long-term efficacy is demonstrated, such a strategy would expand treatment options for patients who would otherwise be excluded from conventional allografting.
  Annals of the New York Academy of Sciences 01/2006; 938(1):328 - 339. · 3.15 Impact Factor
• Article: Protective conditioning for acute graft-versus-host disease.

  Robert Lowsky, Tsuyoshi Takahashi, Yin Ping Liu, Sussan Dejbakhsh-Jones, F Carl Grumet, Judith A Shizuru, Ginna G Laport, Keith E Stockerl-Goldstein, Laura J Johnston, Richard T Hoppe, Daniel A Bloch, Karl G Blume, Robert S Negrin, Samuel Strober
  [show abstract] [hide abstract]
  ABSTRACT: Conditioning with total lymphoid irradiation plus antithymocyte serum protects mice against acute graft-versus-host disease (GVHD) after hematopoietic-cell transplantation. We tested this strategy in humans. Thirty-seven patients with lymphoid malignant diseases or acute leukemia underwent an experimental conditioning regimen with 10 doses of total lymphoid irradiation (80 cGy each) plus antithymocyte globulin, followed by an infusion of HLA-matched peripheral-blood mononuclear cells from related or unrelated donors who received granulocyte colony-stimulating factor. Of the 37 transplant recipients, only 2 had acute GVHD after hematopoietic-cell transplantation. Potent antitumor effects in patients with lymphoid malignant diseases were shown by the change from partial to complete remission. In the transplant recipients who underwent conditioning with total lymphoid irradiation and antithymocyte globulin, the fraction of donor CD4+ T cells that produced interleukin-4 after in vitro stimulation increased by a factor of five, and the proliferative response to alloantigens in vitro was reduced, as compared with normal control subjects and control subjects who underwent conditioning with a single dose of total-body irradiation (200 cGy). A regimen of total lymphoid irradiation plus antithymocyte globulin decreases the incidence of acute GVHD and allows graft antitumor activity in patients with lymphoid malignant diseases or acute leukemia treated with hematopoietic-cell transplantation.
  New England Journal of Medicine 10/2005; 353(13):1321-31. · 53.30 Impact Factor
• Article: A phase I/II study of mycophenolate mofetil in combination with cyclosporine for prophylaxis of acute graft-versus-host disease after myeloablative conditioning and allogeneic hematopoietic cell transplantation.

  Richard A Nash, Laura Johnston, Pablo Parker, Jeannine S McCune, Barry Storer, John T Slattery, Terry Furlong, Claudio Anasetti, Frederick R Appelbaum, Michele E Lloid, H Joachim Deeg, Hans-Peter Kiem, Paul J Martin, Mark M Schubert, Robert P Witherspoon, Stephen J Forman, Karl G Blume, Rainer Storb
  [show abstract] [hide abstract]
  ABSTRACT: Abstract In a phase I/II study, the combination of cyclosporine (CSP) and mycophenolate mofetil (MMF) was investigated as graft-versus-host disease (GVHD) prophylaxis after myeloablative conditioning and hematopoietic cell transplantation from an HLA-matched sibling donor. In phase I, 3 groups, each with 10 or 11 patients, received MMF (15 mg/kg) from day 0 to day 27 at decreasing dose intervals of every 12, 8, and 6 hours to determine a safe and effective total daily dose. At the 45 mg/kg/d dosage level, 4 of 11 patients developed only grade II GVHD, and a concentration at steady state of mycophenolic acid (the active moiety of MMF) consistent with a therapeutic range described for solid-organ transplantation was achieved. There was a suggestion of increased toxicity without improved efficacy at the 60 mg/kg/d dosage level. Accordingly, the 45 mg/kg/d dosage was therefore selected for phase II, and another 15 patients were added to this group from the phase I study (n=26). The concentrations at steady state for this dosage at days 0, 6, 13, 20, and 27 were 2.73, 3.02, 3.20, 2.62, and 2.64 microg/mL, respectively. No toxicities were attributed to MMF at this dose. The median time to engraftment after hematopoietic cell transplantation was 15 days (range, 10-20 days). The incidence of acute GVHD was 62%, which was comparable to a group of historical controls receiving CSP and methotrexate (MTX) for GVHD prophylaxis. Although a significant improvement in the prevention of GVHD was not suggested, compared with CSP and MTX, MMF in combination with CSP could be considered in cases in which MTX is contraindicated.
  Biology of Blood and Marrow Transplantation 08/2005; 11(7):495-505. · 3.87 Impact Factor
• Article: Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia.

  Mohamed L Sorror, Michael B Maris, Brenda M Sandmaier, Barry E Storer, Monic J Stuart, Ute Hegenbart, Edward Agura, Thomas R Chauncey, Jose Leis, Michael Pulsipher, Peter McSweeney, Jerald P Radich, Christopher Bredeson, Benedetto Bruno, Amelia Langston, Michael R Loken, Haifa Al-Ali, Karl G Blume, Rainer Storb, David G Maloney
  [show abstract] [hide abstract]
  ABSTRACT: Patients with chemotherapy-refractory chronic lymphocytic leukemia (CLL) have a short life expectancy. The aim of this study was to analyze the outcome of patients with advanced CLL when treated with nonmyeloablative conditioning and hematopoietic cell transplantation (HCT). Sixty-four patients diagnosed with advanced CLL were treated with nonmyeloablative conditioning (2 Gy total-body irradiation with [n = 53] or without [n = 11] fludarabine) and HCT from related (n = 44) or unrelated (n = 20) donors. An adapted form of the Charlson comorbidity index was used to assess pretransplantation comorbidities. Sixty-one of 64 patients had sustained engraftment, whereas three patients rejected their grafts. The incidences of grades 2, 3, and 4 acute and chronic graft-versus-host disease were 39%, 14%, 2%, and 50%, respectively. Three patients who underwent transplantation in complete remission (CR) remained in CR. The overall response rate among 61 patients with measurable disease was 67% (50% CR), whereas 5% had stable disease. All patients with morphologic CR who were tested by polymerase chain reaction (n = 11) achieved negative molecular results, and one of these patients subsequently experienced disease relapse. The 2-year incidence of relapse/progression was 26%, whereas the 2-year relapse and nonrelapse mortalities were 18% and 22%, respectively. Two-year rates of overall and disease-free survivals were 60% and 52%, respectively. Unrelated HCT resulted in higher CR and lower relapse rates than related HCT, suggesting more effective graft-versus-leukemia activity. CLL is susceptible to graft-versus-leukemia effects, and allogeneic HCT after nonmyeloablative conditioning might prolong median survival for patients with advanced CLL.
  Journal of Clinical Oncology 07/2005; 23(16):3819-29. · 18.37 Impact Factor
• Article: Prognostic relevance of 'early-onset' graft-versus-host disease following non-myeloablative haematopoietic cell transplantation.

  Marco Mielcarek, Lauri Burroughs, Wendy Leisenring, Razvan Diaconescu, Paul J Martin, Brenda M Sandmaier, David G Maloney, Michael B Maris, Thomas R Chauncey, Judith A Shizuru, Karl G Blume, Ute Hegenbart, Dietger Niederwieser, Stephen Forman, Benedetto Bruno, Ann Woolfrey, Rainer Storb
  [show abstract] [hide abstract]
  ABSTRACT: We retrospectively analysed outcomes among 395 patients with haematologic malignancies who underwent non-myeloablative haematopoietic cell transplantation (HCT) from human leucocyte antigen (HLA)-matched related (n = 297) or unrelated donors (n = 98) in order to identify a possible correlation between the time of onset of graft-versus-host disease (GVHD) and survival. The non-myeloablative regimen consisted of 2 Gy total body irradiation with or without fludarabine, followed by postgrafting immunosuppression with mycophenolate mofetil and cyclosporine. The cumulative incidences of grades II-IV acute GVHD and extensive chronic GVHD were 45% and 47%, respectively, with related donors, and 68% and 68%, respectively, with unrelated donors. High-dose corticosteroid treatment for acute or chronic GVHD was started at a median of 79 (range, 8-799) days and 30 (range, 5-333) days after transplantation from related and unrelated donors respectively. With related donors, the cumulative incidence of non-relapse mortality among patients with GVHD was 55% at 4 years when prednisone was started before day 50 (n = 72), compared with 29% when treatment was started after day 50 (n = 115) (P < 0.001). With unrelated donors, time to onset of treatment for GVHD was not associated with survival. Patients with early-onset GVHD after non-myeloablative HCT from HLA-identical related donors might benefit from intensified primary immunosuppressive treatment.
  British Journal of Haematology 05/2005; 129(3):381-91. · 4.94 Impact Factor
• Article: Randomized trial of allogeneic related bone marrow transplantation versus peripheral blood stem cell transplantation for chronic myeloid leukemia.

  Vivian G Oehler, Jerald P Radich, Barry Storer, Karl G Blume, Thomas Chauncey, Reginald Clift, David S Snyder, Stephen J Forman, Mary E D Flowers, Paul Martin, Katherine A Guthrie, Robert S Negrin, Frederick R Appelbaum, William Bensinger
  [show abstract] [hide abstract]
  ABSTRACT: Seventy-two chronic myeloid leukemia patients were enrolled as part of a larger randomized trial at 3 centers between March 1996 and July 2001 to undergo either HLA-matched related allogeneic bone marrow (BM) or filgrastim (granulocyte colony-stimulating factor)-mobilized peripheral blood stem cell (PBSC) transplantation. Forty patients received BM, and 32 patients received PBSCs. There was no statistically significant difference in the incidence of acute or chronic graft-versus-host disease (GVHD), overall survival, disease-free survival, or non-relapse-related mortality between patients receiving BM or PBSC transplants. The cumulative incidence of grade II to IV acute GVHD was 49% in BM and 55% in PBSC recipients ( P = .48). The cumulative incidence of clinical extensive chronic GVHD was 50% in BM and 59% in PBSC recipients ( P = .46). Among 62 chronic phase chronic myeloid leukemia patients, there was no significant difference in overall survival (87% versus 81%; P = .59), disease-free survival (80% versus 81%; P = .61), or non-relapse-related mortality (13% versus 19%; P = .60) by cell source (BM versus PBSCs). Among chronic phase patients, however, there was a trend toward a higher cumulative incidence of relapse at 3 years in BM recipients (7% versus 0%; P = .10) and a higher cumulative incidence of chronic GVHD in PBSC recipients (59% versus 40%; P = .11). The trend toward a higher relapse incidence in BM recipients persisted with a longer follow-up.
  Biology of Blood and Marrow Transplantation 03/2005; 11(2):85-92. · 3.87 Impact Factor