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HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies

Michael B. Maris, Dietger Niederwieser, Brenda M. Sandmaier, Barry Storer, Monic Stuart, David Maloney, Effie Petersdorf, Peter McSweeney, Michael Pulsipher, Ann Woolfrey, Thomas Chauncey, Ed Agura, Shelly Heimfeld, John Slattery, Ute Hegenbart, Claudio Anasetti, Karl Blume and Rainer Storb

Article Figures & Data

Figures

  • Figure 1.

    Median percentage donor chimerism among nucleated marrow cells and peripheral blood granulocytes and T cells among evaluable patients. There were 77 patients studied at day 28, 68 on day 56, 60 on day 84, 44 on day 180, 29 on day 365, and 15 on day 540 (A). ♦ indicates granulocytes; ▴, marrow mononuclear cells; and ▪, T cells (CD3+). Median percentage donor chimerism among peripheral blood T cells in recipients given G-PBMCs versus those given marrow (B).

  • Figure 2.

    Cumulative probabilities. Cumulative probabilities of grade II, III, and IV acute GVHD (A) and chronic extensive GVHD (B) are shown.

  • Figure 3.

    Kaplan-Meier product estimates of survival and progression-free survival for all 89 patients.

  • Figure 4.

    Kaplan-Meier product estimates of survival for patients with B-cell malignancies, chronic myeloid leukemia, acute leukemia, or myelodysplastic/myeloproliferative syndromes.

  • Figure 5.

    Kaplan-Meier product estimates of progression-free survival of patients given G-PBMCs (n = 71) or marrow grafts (n = 18).

  • Figure 6.

    Kaplan-Meier progression-free survival for patients with B-cell malignancies, chronic myeloid leukemia, acute leukemia, or myelodysplastic/myeloproliferative syndromes.

Tables

  • Table 1.

    Patient and disease characteristics

    MarrowG-PBMCOverall
    Patient no. 18 71 89
    Median age, y 52.5 53 53
    Median no. of preceding therapies (range) 4 (0-12) 4 (0-11) 4 (0-12)
    Median follow-up after HCT, d 425 390 390
    Preceding auto/allo HCT 4/2 19/2 23/4
    Median no. CD34 cells × 106/kg (range) 2.1 (0.21-4.1) 7.0 (1.26-28) 5.72 (0.21-28)
    Median no. CD3 × 108/kg 0.3 2.6 2.33
    Donor HLA match, no. of patients
        10 allele match 15 54 69
        1 class l allele mismatch 3 13* 16
    Diagnosis and status at HCT, no. of patients
    AML/ALL, total 4 13 17
        CR1 2 6 8
        CR2 2 2 4
        More than CR3 0 4 4
        Rel/ref/IF 0 1 1
    MDS, total 4 17 21
        RA 1 3 4
        RAEB 1 2 3
        RAEB-T 0 3 3
        AML CR1/CR2 0/0 2/1 3
        AML Rel/ref 0/2 2/1 2/3
        CMML PR/ref/IF 0/0/0 1/1/1 1/1/1
    CML, total 4 10 14
        CP/AP/BP 2/1/1 6/1/0 8/2/1
        CP-2 0 3 3
    MPS, total 2 5 7
        ET 0 2 2
        AMM-transformation 2 1 3
        NOS 0 2 2
    Indolent/high-grade NHL, total 3 10 13
        CR 3 0 2 2
        PR 1 2 3
        Ref/rel 0/2 4/2 4/4
    CLL, total 0 5 5
        CR 0 1 1
        FLU refractory 0 4 4
    HD, total 0 4 4
        PR 0 2 2
        Rel 0 2 2
    MM, total 0 7 7
        PR/ref 0 4/3 4/3
    Waldenstroms, total 1 0 1
    • G-PBMC indicates granulocyte colony-stimulating factor—mobilized peripheral blood mononuclear cells; HCT, hematopoietic cell transplantation; auto, autologous; allo, allogeneic; AML, acute myeloid leukemia; ALL, acute lymphocytic leukemia; CR, complete remission; rel, relapsed; ref, refractory; IF, induction failure; MDS, myelodysplastic syndromes; RA, refractory anemia; RAEB, refractory anemia with excess blasts; RAEB-T, refractory anemia with excess blasts in transformation; CMML, chronic myelomonocytic leukemia; PR, partial remission; CML, chronic myelogenous leukemia; CP, chronic phase; AP, accelerated phase; BP, blast phase; MPS, myeloproliferative syndromes; ET, essential thrombocytosis; AMM transformation, agnogeneic myeloid metaplasia in transformation; NOS, not otherwise specified; NHL, non-Hodgkin lymphoma; CLL, chronic lymphoid leukemia; FLU, fludarabine; HD, Hodgkin disease; and MM, multiple myeloma.

    • * One patient mismatched at 3 class l alleles.

  • Table 2.

    Multivariate analysis of risk factors for rejection

    Hazard ratio (95% CI)P
    Hematopoietic cell source
        G-PBMC, n = 71 1.0 .003
        Marrow, n = 18 4.7 (1.8-12)
    Preceding chemotherapy
        No, n = 24 1.0 .003
        Yes, n = 65 0.2 (0.1-0.6)
    • CI indicates confidence interval. All other abbreviations are explained in Table 1. Factors considered included diagnosis, hematopoietic cell source, disease type, CD34 dose, CD3 dose, patient sex, donor sex, sex mismatch, HLA class I mismatch, preceding transfusion, preceding chemotherapy, and prior autologous transplant.

  • Table 3.

    Incidence of grade III and IV toxicities (n = 89)

    Grade, no. episodes (% of patients)
    IIIIV
    Cardiac 23 (26) 1 (1)
    Pulmonary 7 (8) 11 (12)
    Hepatic 11 (12) 5 (6)
    Neurologic 7 (8) 2 (2)
    Gastrointestinal 6 (7) 1 (1)
    Renal 1 (1) 4 (4)
    Hemorrhage 4 (4) 1 (1)
  • Table 4.

    Multivariate analysis of risk factors risk factors for survival (n = 87)*

    Hazard ratio (95% CI)P
    CD3 dose
        More than or equal to median, n = 37 1.0 .0006
        Less than median, n = 37 2.8 (1.4-5.5)
        Unknown, n = 12 5.6 (2.1-15)
    Risk group
        Low, n = 18 1.0 .04
        High, n = 69 2.8 (1.0-8.1)
    Donor sex
        Female, n = 54 1.0 .01
        Male, n = 33 2.1 (1.0-4.4)
    Preceding transfusion
        No, n = 16 1.0 .003
        Yes, n = 70 3.4 (1.0-12)
    Marrow blasts at HCT
        Less than or equal to 5%, n = 70 1.0 .002
        More than 5%, n = 16 3.3 (1.6-6.6)
    • Abbreviations are explained in Table 1.

    • * Patients who died prior to day 28 were excluded.

    • CD3 cell enumeration did not take place.

  • Table 5.

    Multivariate analysis of risk factors for progression-free survival (n = 89)

    Hazard ratio (95% CI)P
    Blasts at HCT <.0001
        Less than or equal to 5% blast cells, n = 73 1.0
        More than 5%, n = 16 4.5 (2.4-8.4)
    Hematopoietic cell source
        G-PBMC, n = 71 1.0 .006
        Marrow, n = 18 2.5 (1.4-4.7)
    • Abbreviations are explained in Table 1.