Docstoc

Begin manual factors comparison of two preparative anemi

Document Sample
Begin manual factors comparison of two preparative  anemi Powered By Docstoc
					               From www.bloodjournal.org by on January 14, 2011. For personal use only.




                                          1996 87: 51-58


Allogeneic marrow transplantation for refractory anemia: a
comparison of two preparative regimens and analysis of prognostic
factors
JE Anderson, FR Appelbaum, G Schoch, T Gooley, C Anasetti, WI Bensinger, E Bryant, CD
Buckner, TR Chauncey, RA Clift, K Doney, M Flowers, JA Hansen, PJ Martin, DC Matthews, JE
Sanders, H Shulman, KM Sullivan, RP Witherspoon and R Storb




Information about reproducing this article in parts or in its entirety may be found online at:
http://bloodjournal.hematologylibrary.org/misc/rights.dtl#repub_requests

Information about ordering reprints may be found online at:
http://bloodjournal.hematologylibrary.org/misc/rights.dtl#reprints

Information about subscriptions and ASH membership may be found online at:
http://bloodjournal.hematologylibrary.org/subscriptions/index.dtl




Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published
weekly by the American Society of Hematology, 2021 L St, NW, Suite
900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights
reserved .
                        From www.bloodjournal.org by on January 14, 2011. For personal use only.

 Allogeneic Marrow Transplantation for Refractory Anemia: A Comparison
      of Two Preparative Regimens and Analysis of Prognostic Factors
 By Jeanne E. Anderson, Frederick R. Appelbaum, Gary Schoch, Ted Gooley, Claudio Anasetti, William I. Bensinger,
       Eileen Bryant, C. Dean Buckner, Thomas R. Chauncey, Reginald A. Clift, Kristine Doney, Mary Flowers,
     John A. Hansen, Paul J. Martin, Dana C. Matthews, Jean E. Sanders, Howard Shulman, Keith M. Sullivan,
                                     Robert P. Witherspoon, and Rainer Storb

From 1990 to 1993 we performed a prospective study of            with improved survival: younger age, shorter disease dura-
busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) in          tion, lower neutrophilcount pretransplant, and lower hema-
30 patients with refractory anemia (RA) undergoing related       tocrit pretransplant. We also found that 15 patients 40 to 55
(n = 17) or unrelated (n = 13) donor marrow transplantation.     years of age had a 46% 3-year actuarial DFS and 26 patients
Nineteen patients survive disease free (63% 3-year actuarial     receiving unrelated or mismatched ralated donor marrow
disease-free survival [DFSI) and no patient ralapsed. These      had a 50% 3-year actuarial DFS. We conclude that there does
resultswere comparedto those of 38 historicalcontrolswith        not appear to be any significantdflerence in outcome based
RA treated with cyclophosphamide and total body irradia-         on preparative regimen in this patient population. In addi-
tion, of whom 22 are disease-free survivors and 1 relapsed.      tion, allogeneic bone marrow transplantation may be a rea-
After correcting for significant variables between the two       sonable approach to therapy of RA early after diagnosis.
treatment groups, we found no statisticallysignificantdiffer-    However, whether early intervention with transplantation
ence in outcome based on preparative regimen. Combining          prolongs survival over that expected without transplanta-
data from these 68 patients plus 2 additional patients with      tion cannot be ascertained with certainty from available
RA treated before 1993 with busulfan and cyclophospha-           data.
mide, we identified four variables independently associated      0 1996 by The American Society of Hematology.



T    HE MYELODYSPLASTIC syndrome (MDS) com-
       prises a group of clonal hematopoietic disorders with
a multistep pathogenesis. The neoplastic clone has a prolifer-
                                                                                   PATIENTS AND METHODS
                                                                     Between November 1990 and December 1993, all patients with
                                                                 RA with or without ringed sideroblasts (as defined by standard crite-
ative advantage over normal stem cells which results in dys-     rial') or aplastic anemia with a clonal cytogenetic abnormality re-
functional hematopoiesis and, as genetic lesions accumulate,     ferred to the Fred Hutchinson Cancer Research Center or affiliated
progressive peripheral cytopenias and frequent evolution to      hospitals for allogeneic bone marrow (BM) transplantation were
acute myeloid leukemia (AML).' Although the natural his-         enrolled on a single phase I1 treatment protocol to study BU-CY as
tory of MDS is variable, up to 50% of patients die from          the preparative regimen. Patients with aplastic anemia and a clonal
cytopenic complications and another 20% to 30% transform         cytogenetic abnormality were considered to have hypoplastic MDS,
to AML and die of progressive disease or complications of        a subcategory of RA." Two patients who were enrolled on this
                                                                 protocol were not included in this analysis because subsequent mor-
induction ~hemotherapy.'.~   Allogeneic marrow transplanta-
                                                                 phology review showed a diagnosis of myeloproliferative disorder
tion, although limited in applicability because of patient age   in one and AML in the other. No patient had a history of more
and donor availability, is currently the only curative treat-    advanced MDS or of A M L nor had any patient received AML-type
ment for MDS. We and others have reported approximately          induction chemotherapy. Evaluation in Seattle immediately before
40% long-term disease-free survival (DFS) in patients with       the start of the preparative regimen included complete blood count,
MDS receiving this treatment!-" In studies using cyclophos-      BM aspirate and biopsy, chromosomal analysis of BM cells, and
phamide (CY) and total body irradiation (TBI) the prepar-
                                                 as              human leukocyte antigen (HLA) typing of donor and recipient. Clini-
ative regimen, we found a significant difference in relapse      cal characteristics of the 30 patients with RA are described in Table
rate based on disease                   Patients with less ad-    1.
vanced disease (ie, refractoq anemia [RA]) had a 4% 5-year           All patients received BU 1 mgkg orally every 6 hours for a
actuarial relapse rate compared to 49% among patients with       total of 16 doses (total dose 16 mg/kg) followed by CY 60 mgkg
advanced disease (ie, RA with excess blasts, RA with excess      intravenously every day for 2 days (total dose 120 m a g ) . Phenytoin
blasts in transformation, or chronic myelomonocytic leuke-       was administered for seizure prophylaxis during BU administration.
mia).4
   Because the primary cause for treatment failure among            From the Clinical Research Division, Fred Hutchinson Cancer
patients with RA prepared with CY-TI31 was nonrelapse            Research Center, Seattle; and the Seattle Veterans Administration
mortality, we performed a prospective, phase I1 study to         Medical Center, Seattle, WA.
determine if the use of a busulfan (BU)-CY preparative regi-        Submitted February 21, 1995; accepted August 17, 1995.
men could reduce nonrelapse mortality without increasing            Supported by Grants No. CA18029, CA18221, HL36444, from the
the uniquely low risk of relapse. In this report we analyze      National Cancer Institute and the National Heart, Lung and Blood
the outcome of this prospective study and compare it with        Institute, National Institutes of Health.
our previous experience using the CY-TBI regimen. R e -            Address reprint requests to Jeanne E. Anderson, MO, Fred Hutch-
                                                                 inson Cancer Research Center. 1124 Columbia St, M-385, Seattle,
viously published studies on marrow transplantation for
                                                                 WA 98104.
MDS were not of sufficient size to evaluate the effect of
                                                                    The publication costs of this article were defrayed in part by page
pretransplant characteristics on outcome specifically for pa-    charge payment. This article must therefore be hereby marked
tients with RA. Therefore, the second objective of this report   "advertisement" in accordance with 18 U.S.C. section 1734 solely to
was to use data from the entire group of patients with RA        indicate this fact.
to determine prognostic variables associated with survival          0 1996 by The American Society o Hematology.
                                                                                                          f
after transplantation.                                             0006-4971/96/8701 -OO38$3.00/0

Blood, Vol 87, No 1 (January 1). 1996 pp 51-58                                                                                      51
                         From www.bloodjournal.org by on January 14, 2011. For personal use only.

52                                                                                                                                ANDERSON ET AL


 Table 1. Clinical and Transplantation Characteristics of 30 Patients     Table 2. Comparison of Patients Treated With BU-CY and CY-TBI
                         Treated With BU-CY                                                                           ~~




                                                                                                                     BU-CY*        CY-TBI     PValue
 No. of patients                                30                      No. of patients                              28            38
 Median age, yr (range)                         29 (5-53)
                                                                        Median age (yr)                              29            28        1.1
Sex                                             18 males, 12 females
 Median disease duration, mo (range)                                    Median disease duration (mo)                 10            11        >.1
                                                 8 (2-108)
Disease etiology (no. of patients)                                      Peripheral blood counts at time of
   Idiopathic                                   25                          transplant
   Prior cytotoxic therapy for                                            Median white blood cell count,
     Hodgkin's disease                                                       cells x 109/L                                 2.4      2.4      >.l
     Multiple myeloma                                                     Median neutrophil count, cells
   Benzene and other chemical exposure                                       x 107~                                        0.67     0.73     >.l
   History of aplastic anemia
                                                                          Median platelet count, cells x
Prior treatment for MDS (no. of patients)
  None
                                                                             1O ~ / L                                31            16          ,0069
                                                 3
  Transfusions only                              8                        Median hematocrit, %                       25            27        >.l
  Transfusions and other treatment              15                      Marrow cellularity at time of
  Other                                          4                          transplant
Disease morphology at time of transplant                                  Below normal, %                            46            55        >.1
        (no. of patients)                                               Marrow fibrosis present at time of
  RA                                            25                          transplant, %                                  7       16        >.l
  RA with ringed sideroblasts                    3                      Disease morphology at time of
  Aplastic anemia with clonal cytogenetic
                                                                            transplant
       abnormality                               2
                                                                          Aplastic anemia, %                               7       26          .046
Peripheral blood counts at time of
       transplant                                                       Disease etiology
  Median white blood cell count, lo9 cells/L                              Prior cytotoxic therapy, %                       4        3        >.l
       (range)                                   2.40 (0.90-5.05)       Normal karyotype at time of
  Median neutrophil count, lo9 cells/L                                      transplant, %                            39            50        1.1
       (range)                                  0.67 (0.21-3.96)        Positive patient cytomegalovirus
  Median platelet count, lo9 cells/L (range)   29 (6-231)                   serology, %                              75            76        >.1
  Median hematocrit, % (range)                 25 (15-34)               Unrelated or HLA mismatched
Marrow cellularity at time of transplant
                                                                            related donor, %                         46            29        >.I
       (no. of patients)
  Acellular                                      1                        * Patients who had contraindications to the use of TBI are excluded
  Hypocellular                                  12                      from this comparative analysis.
  Normocellular                                 10
  Hypercellular                                  7
Marrow fibrosis at time of transplant                                   Marrow source and type of graft-versus-host disease (GVHD) pro-
       (no. of patients)
                                                                        phyla xi^'^.'^ used are shown in Table 1. Informed consent was ob-
  None                                         28
  Grade 1
                                                                        tained from all patients or their guardian before initiating therapy.
                                                0
  Grade 2                                       1                          Between December 1981 and November 1990, 40 patients with
  Grade 3                                        1                      RA who met the same criteria as described above underwent alloge-
  Grade 4                                        0                      neic transplantation. Details of these patients were reported e ~ l i e r . 4 . ~
Cytogenetic evaluation at time of transplant                            Two patients were prepared with BU-CY because of contraindica-
       (no. of patients)                                                tions to TBI and 38 patients were prepared with CY (37 patients,
  Normal                                        11                       120 mgkg; 1 patient, 150 mgkg) and TBI (33 patients, 12 Gy; 4
  Monosomy 7 2 complex (3or more)                                       patients, 13.2 Gy; 1 patient, 14 Cy)."' The 38 patients who received
       abnormalities                            8                       CY-TBIserved as historical controls and were compared with 28
  Trisomy 8 only                                3
  Deletion 5q- only
                                                                        of the 30 patients who received BU-CY between 1990 and 1993
                                                3
  Other chromosomal abnormalities               5                       (Table 2). Two of the 30 patients in the current BU-CY study were
Patient cytomegalovirus serology                                        excluded from the comparative analysis because they had received
       (no. of patients)                                                chest irradiation for a prior malignancy and were not eligible to
  Positive                                     22                       receive TBI.
  Negative                                      8                          The methods of time-to-event analysis were used with date of
Marrow source (no. of patients)                                         last contact before November 1994 for patients remaining at risk.I6
  Genotypically HLA identical sibling          16                       Actuarial survival, DFS, relapse, and nonrelapse mortality curves
  HLA-B mismatched sibling                      1                       were calculated by the method of Kaplan and Meier.I6 Relapse was
  HLA-A, B. DR matched unrelated donor         10
                                                                        defined as either recurrence of a previously present cytogenetic ab-
  HLA "minor" mismatched unrelated
       donor*                                   3                                                      %
                                                                        normality, presence of ~ 5 marrow blasts, or return of morphologic
GVHD prophylaxis                                                        dysplasia. BM examination was routinely performed approximately
  Cyclosporine and methotrexatet               26                       28 days, 80 days, and 1 year after transplantation and when clinically
  FK506 and methotrexate*                       3                       indicated. Chimerism studies were performed in the majority of sex-
  Cyclosporine and corticosteroids               1                      mismatched transplants by conventional cytogenetics or fluorescence
     "Minor" mismatch was defined as an HLA mismatch in the DRBl        in situ hybridization with a Y-chromosome-specific DNA probe
locus or within a cross-reactive group of the A or B locus.             using techniques previously described." In sex-matched transplants
  t See reference 14 for details.                                       performed after 1990, chimerism was assessed with the use of ampli-
  *See reference 15 for details.                                        fied variable number tandem repeat (VNTR) DNA markers. Loci
                           From www.bloodjournal.org by on January 14, 2011. For personal use only.

MARROW TRANSPLANTATION FOR REFRACTORY ANEMIA                                                                                             53




                                                             0.6    -I+--

                                                                          r
                                                                         I
   Fig 1. DFS (-1 and nonrelapse mortality (-----I for                  I
30 Datienta wlth RA tmeted with BU and CY and                   0                       I                1                1               1

allo&neic marrow transplantetion between 1990                       0                  1                2                 3              4
and 1993. Tick marks r e p m o n t patients alive in con-
tinuous complete remission.                                                                 Years after Transplantation


analyzed included ApoB, DlS80, and 33.6. If no informative mark-              plant after conditioning with busulfan, cyclophosphamide,
ers were identified at these loci, then additional loci were tested,          and antithymocyte globulin and has stable donor engraftment
including SE-33, 33.1, and YNZ22. Sample preparation and DNA                  3 years later. All surviving patients have normal peripheral
amplification were performed as described by Scharf et al." Ampli-            blood counts except for the patient recovering from cytomeg-
fied products were analyzed by polyacrylamide gel electrophoresis             alovirus infection, the patient recovering from bleeding
and silver staining.Ig Univariate comparisons between the current
patients and historical controls were made using Wilcoxon's rank
                                                                              esophageal varices, and 1 patient on azathioprine for chronic
sum for continuous variables (age, disease duration, and peripheral           GVHD.
blood counts), the chi-squared test for discrete variables, and the log          Of the 16 recipients of HLA-identical sibling marrow, 12
rank test for time-to-event variables.I6 Multivariate analysis was            survive (3-year actuarial DFS 74%), 2 died of GVHD, 1
performed using a stepwise, step-up proportional hazards Cox re-              died of veno-occlusive disease of the liver, and 1 died of
gression model using a chi-square P value of .05 as the upper limit           idiopathic pneumonia syndrome. Seven HLA-identical sib-
for entry into the model.16No adjustment for multiple comparisons             ling marrow recipients developed acute grades 11-IV GVHD
was made in calculating P values.                                             and 3 developed chronic GVHD. Of the 13 recipients of
                                                                              unrelated donor marrow, 7 survive (3-year actuarial DFS
                               RESULTS
                                                                              54%), 5 died of GVHD and related complications, and 1
   Outcome using BU-CY. Nineteen of 30 patients survive                       died of GVHD and veno-occlusive disease of the liver. All
without cytogenetic or morphologic evidence of relapse be-                    but one of the patients undergoing unrelated donor trans-
tween 0.8 and 3.8 years after transplantation (median 2.1                     plantation developed acute grades 11-IV GVHD and 7 devel-
years). Eleven patients died of nonrelapse causes between                     oped chronic GVHD. The one patient who received an HLA-
22 days and 1.3 years after transplantation (median 56 days)                  B mismatched sibling graft died of acute GVHD.
and none relapsed. The 3-year actuarial DFS and nonrelapse                       Comparison of BU-CY and CY-TBI. Among the 38 his-
mortality rates were 63% and 37%, respectively (Fig 1). The                   torical control patients treated with CY-TBI, 1 patient re-
median Karnofsky performance status of the survivors is                       lapsed, 15 died of nonrelapse causes, and the remaining
 100% (range 30 to 100). Three patients have a performance                    22 survive disease-free.",5In univariate analysis, the 3-year
status of less than 80%: 1 has bleeding esophageal varices                    actuarial DFS rates were similar for the CY-TBI group and
possibly due to liver GVHD, 1 has chronic GVHD and is                         the BU-CY group (60% v 63%, P = .9) (Fig 2). Similarly,
recovering from cytomegalovirus enteritis, and 1 is oxygen-                   there were no differences in the 3-year actuarial relapse (4%
dependent because of bronchiolitis obliterans associated with                 v 0%, P = .6) and nonrelapse mortality (37% v 37%, P =
chronic GVHD.                                                                 .9) rates between the two groups. Because the comparison
   All patients had evidence of marrow engraftment, as docu-                  between the two groups was not done in a prospective, con-
mented by neutrophil recovery to greater than 0.5 X lo9                       trolled fashion, we adjusted for the potential confounding
cellsk. One patient with a monosomy 7 cytogenetic abnor-                      variables listed in Table 2 (excluding disease etiology vari-
mality who received an HLA-B and DRB 1 mismatched unre-                       able because of the small number of patients with secondary
lated transplant developed graft failure 2 months after trans-                MDS) in Cox regression models. After adjusting for combi-
plantation. This female patient transiently had 7% blasts in                  nations of these variables that were either statistically sig-
the marrow while on granulocyte colony-stimulating factor,                    nificantly associated or suggestive of being associated with
but all metaphase cells examined by cytogenetics were of                      outcome, the preparative regimen variable was not statisti-
male (donor) origin. Because she had no dysplastic features                   cally significantly associated with outcome.
or recurrent cytogenetic abnormality she was not considered                      Predictive variables for survival after transplantation for
to have relapsed. She successfully received a second trans-                   RA. Using a multivariate model we analyzed the relation-
                              From www.bloodjournal.org by on January 14, 2011. For personal use only.

54                                                                                                                                      ANDERSON ET AL




                                             Disease-Free Survival
           0.6                                   -*-+-          - - - - -t-t----t-t-t-f--+



                                                                                                           Fig 2. DFS and relapse after allogeneic marrow
                                             Relapse                                                    transplantation for 28 patient. with RA treated with
            0                                                                                           BU and CY 1-1 and for 38 patient. with RA treated
                               I             1              I            1           I             I    with CY and TBI (-----I. Pationts in whom the use of
                 0            2        4          6        8                        10            12    irradiation was contraindlcated are excluded from
                                                                                                        this comparison. Tick marks repre6ont patients alive
                                     Years after Transplantation                                        in continuous complete remission.



ship between pretransplant characteristics and posttransplant                               After adjusting for neutrophil count, increasing patient
survival. Because the preparative regimen did not appear                                 age was associated with an increased risk of death after
to affect outcome, data from all 70 patients with RA who                                 transplantation. The 3-year actuarial survival was 78% for
underwent allogeneic transplantation after preparation with                              20 patients less than 20 years of age, 58% for 20 patients
either BU-CY or CY-TBI between 1981 and 1993 were                                        20 to 29 years of age, 47% for 15 patients 30 to 39 years
included in this model. Table 3 summarizes the results of a                              of age, and 46% for 15 patients 40 years of age or older
step-wise Cox regression using the variables listed in Table                             (Fig 3). The third independent predictive variable in the
2. To avoid overfitting the model because only 28 events                                 Cox regression was disease duration. The 3-year actuarial
occurred, only 4 variables were allowed to enter the model.                              survival was 65% for patients transplanted within the first
   A higher neutrophil count before transplantation was asso-                            year after diagnosis (n = 40) compared with 50% for patients
ciated with an increased risk of death. The 3-year actuarial                             receiving transplants 1 or more years after diagnosis (n =
survival was 23% for 13 patients with a neutrophil count 2                               30) and 30% for patients receiving transplants 5 or more
1.5 X lo9 cellsn compared to 72% for 32 patients with a                                  years after diagnosis (n = 10) (Fig 4). The final variable
neutrophil count 0.5 to 1.5 X lo9 cellsn and 60% for 25                                  independently associated with survival after adjusting for
patients with a neutrophil count < 0.5 X lo9cellsL. Among                                neutrophil count, age, and disease duration was hematocrit.
the 13 patients with normal neutrophil counts, the median                                A higher hematocrit before transplantation was associated
age was 3 1 years and the median disease duration 17 months.                             with an increased risk of death: the 3-year actuarial survival
Two had received prior cytotoxic therapy, none had received                              was 68% for 35 patients with hematocrit < 27% and 48%
hematopoietic growth factors, and 8 received marrow from                                 for 35 patients with hematocrit z 27%. Among the patients
either unrelated or mismatched related donors. Five died of                              in the former group, 4 had never been transfused and 3 had
GVHD, 2 of infection, 2 of multi-organ failure, and 1 of                                 been treated with erythropoietin; in the latter group, 8 had
hemorrhage.                                                                              never been transfused and none had received erythropoietin.
                                                                                            Additional variables that were not significant in the multi-
                                                                                         variate analysis, but may be of clinical interest, include dis-
 Table 3. Multivariate Cox Regression Analysis of Survival for 70                        ease etiology, morphologic subtype, and karyotype. In the
                        Patients W~ RA                                                   univariate analysis survival was lower among the 5 patients
       ~         ~~       ~          ~

                                                                                         whose disease was caused by prior cytotoxic therapy com-
                      Univariate    Entry        Multivariate      Relative Risk"
     Covariate         PValue       SteD          PValue             (95% Cl)            pared with the remaining patients (20%v 63% 3-year actuar-
                                                                                         ial survival, P .052). The 12 patients with an aplastic marrow
Neutrophil count        ,0049            1         ,0161                1.654
                                                                                         and clonal cytogenetic abnormality had a similar survival
  (cells x iOg/L)t                                                 (1.098-2.491)
Age (decade)            ,0062            2          ,0068               1.529
                                                                                         compared to the remaining patients with dysmorphic features
                                                                   ( 1.124-2.080)
                                                                                         classic for refractory anemia (59% v 60% 3-year actuarial
Disease duration        ,0162            3          .0063               1.133            survival, P = .96). The distinction between normal and ab-
  (yr)                                                             (1.036-1.240)         normal karyotype had no effect on survival (54% v 63% 3-
Hematocrit (%)t         ,0075            4          .0192               1.089            year actuarial survival, P = .23). Among patients with clonal
                                                                   (1.014-1.170)         abnormalities, 8 of 16 patients with monosomy 7 or complex
    The relative risk is the increased risk of dying after transplantation               cytogenetic abnormality (defined as 3 or more abnormali-
per unit of measurement of the covariate. The 95% confidence inter-                      ties), 4 of 5 patients with trisomy 8 as the sole abnormality,
vals are included.                                                                       all 4 patients with partial or complete deletion of the short
  t Obtained just before the start of the preparative regimen.                           arm of chromosome 5 as the sole abnormality, and 10 of 14
                             From www.bloodjournal.org by on January 14, 2011. For personal use only.

MARROW TRANSPLANTATION FOR REFRACTORY ANEMIA                                                                                                         55




                                                                       -
                                                                       !
                                                                             -$;
                                                                                                    I     I "I                       ,       I   I   I1




                                                          %
                                                               0.6-
                                                                       :
                                                                       . 'it+
                                                                       i               -tf+t-   - - - - - - - -20---*- (n=20)
                                                                                                                        - -4
                                                                                                                   29 years

                                                         .-
                                                         -                                              ........+       -
                                                         c

                                                         a                                                            30 39 years (n=15)
                                                         2     0.4-
                                                                                                                                 I
                                                         2                                       I
                                                         n                                                            > 39 years (n=15)
                                                               0.2 -


    Fig 3. Survival after allogeneic marrow trans-                 0               I            I                 I         I            I           I




of the remaining patients with clonal cytogenetic abnormali-                   transplant (all of whom are surviving). One patient was ini-
ties (primarily patients with other single abnormalities) are                  tially a complete chimera by in situ hybridization, but
surviving.                                                                     subsequently relapsed clinically and by conventional cytoge-
   Evidence for long-term donor engraftment. Chimerism                         netics, as previously described:
studies of marrow or peripheral blood cells were performed
                                                                                                                 DISCUSSION
in 25 patients who survived more than 100 days after trans-
plantation, using VNTR studies in 12 patients undergoing                          Previous phase I1 studies suggesting that the BU-CY regi-
sex-matched transplants (1 of whom received CY-TBI and                         men was active in myeloid malignancies and associated with
the remaining BU-CY) and karyotype analysis in 13 patients                     low toxicity'' formed the rationale for our prospective phase
undergoing sex-mismatched transplants (6 of whom received                      I1 study. In our study, we found that the 3-year actuarial
CY-TBI and the remaining BU-CY). VNTR analysis re-                             DFS after BU-CY and allogeneic marrow transplantation
vealed donor engraftment in 1 1 patients between 9 and 39                      for 30 patients with RA was 63%. Two other studies using
months posttransplant (10 of whom are surviving). In 1 pa-                     busulfan-containing regimens without TBI reported a similar
tient 20% of granulocytes were of host origin at l year                        outcome for patients with MDS without excess blasts (9 of
posttransplant and 5% at 26 months posttransplant. This pa-                    16 disease-free s~rvivors).~" our nonrandomized, retro-
                                                                                                              In
tient, who did not have a cytogenetic abnormality pretrans-                    spective comparison to the CY-TBI regimen, we found that
plant, currently has normal peripheral blood counts. Karyo-                    the BU-CY regimen appeared to result in no statistically
type analysis showed complete donor engraftment in 12                          significant difference in DFS, relapse, or nonrelapse mortal-
patients (4 by conventional cytogenetics and 8 by fluores-                     ity. Our findings are consistent with a recently completed
cence in situ hybridization) between 6 and 36 months post-                     prospective, randomized study at our institution comparing


        1


     0.8
                                          Less than 1 year
     0.6
                                                - - - - - +-- 4 +- - -ti-
                                                                 -
                                          1 year and greater

P
a            ....................    +...+

            1
                                          5 years and greater

     Om2
      0 :                I            I           I            I           I              I        Fig 4. Survival after allogeneic marrow trans-
         0              2            4           6            8            10            12     plantation for 70 patients with RA based on diseaso
                                                                                                duration. Tick marks represent patients alive in con-
                                    Years after Transplantation                                 tinuous complete remission.
                       From www.bloodjournal.org by on January 14, 2011. For personal use only.

56                                                                                                            ANDERSON ET AL


BU-CY with CY-TBI among patients with chronic myeloid             31 patients with MDS with and without excess blasts trans-
leukemia in chronic phase, in which survival, relapse, and        planted with unrelated donor marrow.26The only other report
nonrelapse mortality were similar between the two treatment       describing a relatively large number of patients (n = 32)
groups.2’ However, other prospective, randomized studies          with h4DS undergoing unrelated donor transplantation found
comparing BU-CY with CY-TBI have concluded CY-TBI                 a less favorable actuarial DFS of 18% at 2 years.27If future
yields superior results.”~23  Results from our current retro-     studies uphold our more favorable results, then marrow
spective comparison do not help identify any subgroup of          transplantation for RA using such alternative donors should
RA patients who might do better with one regimen or the           not be viewed as a treatment of last resort.
other. However, based on previous experience gained in pa-           The toxicity of marrow transplantation may cause an un-
tients receiving transplants for lymphoma, patients with a        derstandable reluctance to refer patients for this procedure.
history of prior chest irradiation for a prior malignancy         However, the overall long-term DFS of over 60%, and our
should receive a chemotherapy-only based regimen.                 previous finding of reduced relapse among patients with RA
   A stepwise multivariate regression combining data from         compared to patients with more advanced disease:’      warrants
all 70 patients with RA treated at our institution showed that    consideration for early transplantation among patients who
younger age, shorter disease duration, lower pretransplant        have never progressed beyond RA. Additionally, although
neutrophil count, and lower pretransplant hematocrit were         the finding of reduced survival with increasing age suggests
significantly associated with improved survival. In a previ-      caution in transplanting older patients with RA, the 3-year
ous multivariate analysis that included both patients with        DFS of 46% for the 15 patients aged 40 to 55 also suggests
and without excess blasts, we also found that younger age         such patients should be considered for this procedure.
and shorter disease duration were associated with improved           In absence of historical or concurrent control patients, we
survival and reduced nonrelapse mortality.’ The finding of        are unable to determine if allogeneic marrow transplantation
improved survival with younger age is consistent with virtu-      for RA prolongs survival compared with nontransplant ther-
ally every previous study of allogeneic marrow transplanta-       apy. Therefore, it is difficult to give specific guidelines for
tion for hematologic maligniancies. The finding of improved       the most appropriate timing of transplantation for RA and
survival with shorter disease duration is consistent with pre-    the most appropriate patient selection criteria. Some patients
vious studies in chronic myeloid le~kemia.”.~’     The shorter    with RA, in particular, those without significant cytopenias
survival in patients with a higher neutrophil count and a         or those with the 5q- syndrome, may have an indolent
higher hematocrit is not readily explained. Among the pa-         course and a median survival of 5 or more               Several
tients with the highest neutrophil counts (21.5 cells X lo9/      scoring systems have been developed to help determine an
L) and the shortest survival, the disease duration was longer     individual patient’s prognosis. Patients whose single adverse
and the use of mismatched or unrelated donors was higher          feature is a platelet count less than 100,000, a hemoglobin
than among the remaining patients, features that may have         less than 9 g/dL, or the presence of complex cytogenetic
contributed to their worse outcome. Increased hematocrit          abnormalities have a median survival of 3 years or less,
before transplantation may reflect a clinical decision to main-   regardless of marrow blasts per~entage.’~.~’     Therefore, al-
tain a higher oxygen-carrying capacity because of other med-      though the concept of transplantation should be at least dis-
ical conditions or reflect a greater total number of units        cussed with all patients, we would recommend that trans-
transfused, both of which could contribute to increased mor-      plantation be considered for patients with RA less than age
tality after transplantation. However, data on the total num-     56 with an HLA-matched related or unrelated donor if any
ber of red blood cell transfusions and presence of iron over-     one of these adverse prognostic features is present at diagno-
load were not routinely obtained before transplantation and       sis. Other patients could be observed closely and offered
could not be entered into the current analysis. Patients who      marrow transplantation when one of these features develops.
had an aplastic marrow with a cytogenetic abnormality were           The risk of relapse after allogeneic marrow transplantation
often referred to our institution immediately after diagnosis     for hematologic malignancies ranges from 13% for patients
and with minimal prior treatment or transfusions. These clin-     with chronic myeloid leukemia in chronic phase” to 70%
ical features may have contributed to the finding that lower      for patients with relapsed acute leukemia.32In contrast, re-
blood counts were associated with lower risk of death. Cur-       sults from this study suggest that the risk of relapse for
rently, data are insufficient to conclude that pretransplant      patients with MDS who have never progressed beyond RA
management of patients’ cytopenias should be altered. Fu-         is extremely low (1 of 70 patients in this study). In addition,
ture studies on patients with MDS undergoing allogeneic           the chimerism data on 25 of our long-term survivors, docu-
transplantation which analyze the variables potentially asso-     menting persistent donor engraftment in 23 patients, also
ciated with outcome will be necessary to confirm or refute        support this low rate of clinically evident relapse. Data from
our findings.                                                     five other smaller studies of transplantation for MDS which
   In our study, the use of mismatched or unrelated donor         reported RA patients separately report only 1 of 37 patients
marrow was not associated with a statistically significantly                                    ~ , ~ very ~ ~
                                                                  to have r e l a ~ s e d . ~ , The , ’ ~ ~low relapse rate noted
worse outcome. The 3-year actuarial DFS was 50% for these         in these reports and in our current study suggests that the
patients (8 of 16 unrelated marrow recipients and 5 of 10         neoplastic stem cell clone has not yet developed mechanisms
mismatched related marrow recipients survive) compared            of resistance to the myeloablative regimen andor that any
with 64% for the remaining patients. We have previously           remaining clonal cells can be eliminated by the allogeneic
reported a similar actuarial DFS rate (46% at 3 years) for        graft-versus-tumor effect.
                         From www.bloodjournal.org by on January 14, 2011. For personal use only.

MARROW TRANSPLANTATION FOR REFRACTORY ANEMIA                                                                                             57


   In summary, we report that nearly two thirds of patients           Bensinger W, Buckner CD, Clift R, Doney K, Farewell V, Hansen
less than 56 years of age with RA appear to be cured of               J, Hill R, Lum L, Martin P, McGuffin R, Sanders J, Stewart P,
their disease after marrow transplantation from a related or          Sullivan K, Witherspoon RP,Yee G, Thomas ED: Methotrexate and
unrelated donor. We conclude that there is no apparent dif-           cyclosporine compared with cyclosporine alone for prophylaxis of
                                                                      acute graft-versus-host disease after marrow transplantation for leu-
ference between the two preparative regimens. Future studies          kemia. N Engl J Med 314:729, 1986
concentrating on judiciously reducing the intensity of the                15. Nash RA, Etzioni R, Storb R, Furlong T, Gooley T, Anasetti
preparative regimen in an attempt to decrease toxicity with-          C, Appelbaum F, Doney K, Martin P, Sullivan K, van der Jagt R,
out increasing relapse are worthy of further investigation.           Witherspoon R, Jusko WJ, Zager RA, Deeg HJ: Tacrolimus (FK506)
                                                                      alone or in combination with methotrexate or methylprednisolone
                          REFERENCES                                  for the prevention of graft-versus-host disease after marrow trans-
   1. Jacobs A: Genetic lesions in preleukaemia. Leukemia 5:277,      plantation from HLA-matched siblings: A single center study. Blood
1991                                                                  85:3746, 1995
   2. Ganser A, Hoelzer D: Clinical course of myelodysplastic syn-        16. Fisher LD, Van Belle G: Biostatistics: Methodology for the
dromes. Hematol Oncol Clin North Am 6:607, 1992                       Health Sciences. New York, NY, Wiley, 1993
   3. Sanz GF, Sanz MA, Vallespi T, Canizo MC, Torrabadella M,            17. Durnam DM, Anders KR, Fisher L, O’Quigley J, Bryant EM,
Garcia S, Irriguible D, San Miguel J F Two regression models and      Thomas ED: Analysis of the origin of marrow cells in BMT recipi-
a scoring system for predicting survival and planning treatment in    ents using a Y chromosome specific in situ hybridization assay.
myelodysplastic syndromes: A multivariate analysis of prognostic      Blood 74:2220, 1989
factors in 370 patients. Blood 74:395, 1989                               18. Scharf SJ, Smith AG, Hansen JA, Mcfarland C, Erlich HA:
   4. Anderson JE, Appelbaum FR, Storb R: An update on alloge-        Quantitative determiniation of bone marrow transplant engraftment
neic marrow transplantation for myelodysplastic syndrome. Leuk        using fluorescent polymerase chain reaction primers for human iden-
Lymphoma 17:95, 1995                                                  tity. Blood 85:1954, 1995
   5. Anderson JE, Appelbaum FR, Fisher LD, Schoch G, Shulman             19. Budowle B, Chakraborty R, Giusti AM, Eisenberg AJ, Allen
H, Anasetti C, Bensinger W ,Bryant E, Buckner CD, Doney K,
                             I                                        RC: Analysis of the VNTR locus D E 8 0 by the PCR followed by
Martin PJ, Sanders JE, Sullivan KM, Thomas ED, Witherspoon RP,        high-resolution PAGE. Am J Hum Genet 48:137, 1991
Hansen JA, Storb R: Allogeneic bone marrow transplantation for 93        20. Tutschka PJ, Copelan EA, Kapoor N: Replacing total body
patients with myelodysplastic syndrome. Blood 82:677, 1993            irradiation with busulfan as conditioning of patients with leukemia
   6. Ratanatharathom V, Karanes C, Uberti J, Lum LG, de Planque      for allogeneic marrow transplantation. Transplant Proc 21 :2952,
MM, Schultz KR, Cronin S, Dan ME, Mohamed A, Hussein M,                1989
Sensenbrenner LL: Busulfan-based regimens and allogeneic bone            21. Clift RA, Buckner CD, Thomas ED, Bensinger WI, Bowden
marrow transplantation in patients with myelodysplastic syndromes.    R, Bryant E, Deeg HJ, Doney KC, Fisher LD, Hansen JA, Martin
Blood 81:2194, 1993                                                   P, McDonald GB, Sanders JE,Schoch G, Singer J, Storb R, Sullivan
   7. Nevi11 TJ, Shepherd JD, Reece DE, Barnett MJ, Nantel SH,        KM, Witherspoon RP, Appelbaum FR: Marrow transplantation for
Klingemann HG, Phillips GL: Treatment of myelodysplastic syn-         chronic myeloid leukemia. A randomized study comparing cyclo-
drome with busulfan-cyclophosphamide conditioning followed by         phosphamide and total body irradiation with busulfan and cyclophos-
allogeneic BMT. Bone Marrow Transplant 10:445, 1992                   phamide. Blood 84:2036, 1994
   8. Sutton L, Leblond V, L e Maignan C, Jouet JP, Keuntz M,            22. Ringden 0, Ruutu T, Remberger M, Nikoskelainen J, Volin
Gluckman E, Blaise D, Marit G, Attal M, Troussard X, Bordigoni        L, Vindelov L, Parkkali T, Lenhoff S, Sallerfors B, Ljungman P,
P, Cahn JY, Ribaud P Bone marrow transplantation for myelodys-        Mellander L, Jacobsen N: A randomized trial comparing busulfan
plastic syndrome and secondary leukemia: Outcome of 86 patients.      with total body irradiation as conditioning in allogeneic marrow
Bone Marrow Transplant 7:39, 1991 (suppl 2)                           transplant recipients with leukemia: A report from the Nordic Bone
   9. DeWitte T, Zwaan F, Hermans J, Vemant J, Kolb H, Vossen         Marrow Transplantation Group. Blood 83:2723, 1994
J, Lonnqvist B, Beelen D, Ferrant A, Gmur J, Liu Yin J, Troussard        23. Blaise D, Maraninchi D, Archimbaud E, Reiffers J, Devergie
X, Cahn J, Van Lint M, Gratwohl A: Allogeneic bone marrow             A, Jouet JP, Milpied N, Attal M, Michallet M, Ifrah N, Kuentz M,
transplantation for secondary leukaemia and myelodysplastic syn-      Dauriac C, Bordigoni P, Gratecos N, Guilhot F, Guyotat D, Gouver-
drome: A survey by the Leukaemia Working Party of the European        net J, Gluckman E: Allogeneic bone marrow transplantation for acute
Bone Marrow Transplantation Group (EBMTG). Br J Haematol              myeloid leukemia in first remission: A randomized trial of a busul-
74:151, 1990                                                          fan-cytoxan versus cytoxan-total body irradiation as preparative regi-
   10. Longmore G, Guinan EC, Weinstein HJ, Gelber RD, Rappe-         men: A report from the Groupe d’Etudes de la Greffe de Moelle
port JM, Antin JH: Bone marrow transplantation for myelodysplasia     Osseuse. Blood 79:2578, 1992
and secondary acute nonlymphoblastic leukemia. J Clin Oncol              24. Goldman JM, Szydlo R, Horowitz MM, Gale RP, Ash RC,
8:1707, 1990                                                          Atkinson K, Dicke KA, Gluckman E, Herzig RH,Marmont A, Ma-
   11. O’Donnell MR, Nademanee AP, Snyder DS, Schimdt GM,             saoka T, McGlave PB, Messner H, O’Reilly RJ, Reiffers J, Rimm
Parker PM, Bierman PJ, Fahey JL, Stein AS, Krance RA, Stock           AA, Speck B, Veum-Stone JA, Wingard JR, Zwaan FE, Bortin
AD, Forman SJ, Blume KG: Bone marrow transplantation for myelo-       MM: Choice of pretransplant treatment and timing of transplants for
dysplastic and myeloproliferative syndromes. J Clin Oncol 5: 1822,    chronic myelogenous leukemia in chronic phase. Blood 82:2235,
1987                                                                  1993
   12. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton             25. Thomas ED, Clift RA: Indications for marrow transplantation
DAG, Gralnick HR, Sultan C: Proposals for the classification of the   in chronic myelogenous leukemia. Blood 732361, 1989
myelodysplastic syndromes. Br J Haematol 5 1:189, 1982                   26. Anderson JE, Anasetti C, Appelbaum FR, Hansen JA, Storb
   13. Appelbaum FR, Barral J, Storb R, Ramberg R, Doney K,           R: Allogeneic marrow transplantation for myelodysplastic syndrome
Sale GE, Thomas ED: Clonal cytogenetic abnormalities in patients      using unrelated donors. Leuk Res 18:26, 1994 (suppl)
with otherwise typical aplastic anemia. Exp Hematol 15:1134, 1987        27. Kernan NA, Bartsch G, Ash RC, Beatty PG, Champlin R,
   14. Storb R, Deeg HJ, Whitehead J, Appelbaum F, Beatty P,          Filipovich A, Gajewski J, Hansen JA, Henslee-Downey J, McCul-
                         From www.bloodjournal.org by on January 14, 2011. For personal use only.

58                                                                                                                     ANDERSON ET AL


lough J, McGlave P, Perkins HA, Phillips GL, Sanders J, Stroncek        Wattel E, Bauters F, Fenaux P: Cytogenetic analysis has strong
D, Thomas ED, Blume KG: Analysis of 462 transplantations from           independent prognostic value in de novo myelodysplastic syndromes
unrelated donors facilitated by the National Marrow Donor Program.      and can be incorporated in a new scoring system: A report on 408
N Engl J Med 328593, 1993                                               cases. Leukemia 7:1315, 1993
   28. Mufti GJ: A guide to risk assessment in the primary myelo-          32. Clift RA, Buckner CD, Appelbaum FR, Schoch G, Petersen
dysplastic syndrome. Hematol Oncol Clin North Am 6587, 1992             FB, Bensinger WE, Sanders J, Sullivan KM, Storb R, Singer 3,
  29. Goasguen E,      Garand R, Bizet M, Bremond JL, Gardais J,        Hansen JA, Thomas ED: Allogeneic marrow transplantation during
Callat MP, Accard F, Chaperon J: Prognostic factors of myelodys-        untreated first relapse of acute myeloid leukemia. J Clin Oncol
plastic syndromes-A simplified 3-D scoring system. Leuk Res             10:1723, 1992
14:255, 1990                                                               33. Castro-Malaspina H, Childs B, Gillio A, Papadopoulos E,
   30. Aul C, Gattermann N, Hey11 A, Germing U, Derigs G, Schnei-       Boulad F, Young J, Small T, MacKinnon S, Keman N, Collins N,
der W: Primary myelodysplastic syndromes: Analysis of prognostic        Reyes B, O’Reilly RI: Improved disease-free survival in patients
factors in 235 patients and proposals for an improved scoring system.   with low risk (< 5% marrow blasts) myelodysplastic syndromes
Leukemia 652, 1992                                                      treated with HLA-identical sibling-derived T-cell depleted (SBA-E-)
   31. Morel P, Hebbar M, h i JL, Duhamel A, Preudhomme C,              marrow transplants. Blood 84:518a, 1994 (abstr, suppl 1)

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:2
posted:1/15/2011
language:English
pages:9