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 Previous Article | Table of Contents
Blood, Vol. 94 No. 11 (December 1), 1999:
pp. 3960-3962
CORRESPONDENCE
Long-Term Follow-up of a Randomized Study Comparing
Cyclophosphamide and Total Body Irradiation With Busulfan and
Cyclophosphamide for Patients Receiving Allogeneic Marrow Transplants
During Chronic Phase of Chronic Myeloid Leukemia
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LETTER |
To the Editor:
In September 1994 we reported the results of a randomized trial
comparing 2 regimens to condition patients with chronic myeloid leukemia (CML) in chronic phase (CP) for allogeneic marrow
transplantation.1 Patients were treated between October
1988 and November 1992 and received marrow from HLA-identical siblings.
Sixty-nine patients were treated with 120 mg/kg of cyclophosphamide and
6 daily exposures each of 200 cGy of total body irradiation (TBI), and
73 patients received 16 mg/kg of oral busulfan over 4 days followed by
120 mg/kg of cyclophosphamide (BU-CY). The 2 regimens had similar survival and relapse probabilities. The BU-CY regimen was better tolerated than the CY-TBI regimen. The median duration of follow-up in
this study is now more than 7 years, and we report these outcomes updated to July 1, 1998.
Patients treated with the CY-TBI regimen (N = 69).
In the initial report, 29 patients had developed chronic
graft-versus-host disease (GVHD) and 6 of these had died of causes not
associated with relapse. Since then, 2 more of these patients have died
of causes not associated with relapse and 2 additional patients (both
of whom survive) have developed clinical extensive chronic GVHD.
In the initial report, 15 patients had cytogenetic relapse and none of
these had died. The relapse was transient in 5 instances and these
patients still survive in continuing remission without treatment. Of
the 10 patients with persistent relapse, 3 have died in relapse, 4 are
in cytogenetic remission after treatment with interferon (IFN)
(polymerase chain reaction [PCR] status is positive in 2, negative in
1, and unknown in 1), and 3 are in continuing cytogenetic relapse
despite IFN therapy. Since publication of the initial report, 6 patients have developed cytogenetic relapse between 2 and 6 years after
transplant; 2 of these patients have died in relapse and 4 are being
treated but remain in relapse.
In the initial report, 14 patients had died (4 during the first 100 days). Since then, 8 more patients have died; 5 (between 2 and 9 years
after transplant) after relapse, 1 of myocardial infarction at 4 years,
and 2 of chronic GVHD disease at 5 years.
Patients treated with the BU-CY regimen (N = 73).
In the initial report, 30 patients had developed chronic GVHD and 4 of
these had died of causes not associated with relapse. Since then, none
of these patients has died and 1 more patient (who survives) has
developed clinical extensive chronic GVHD.
In the initial report, 10 patients had cytogenetic relapse and none of
these had died. The relapse was transient in 3 instances and these
patients still survive in continuing cytogenetic (and PCR) remission
without treatment. Of the 7 patients with persistent relapse, 3 had
died at the time of the original report and 1 additional patient has
died at 7 years after transplant and 3 patients are in cytogenetic (and
PCR) remission (1 after treatment with interferon). Since publication
of the initial report, 6 patients have developed cytogenetic relapse
between 21/2 and 81/2 years after transplant, and all of
these patients survive. Two patients were recently diagnosed and remain
in relapse untreated, 2 are in cytogenetic (and PCR) remission after
donor lymphocyte infusion (DLI), and 2 are in cytogenetic remission (1 PCR-negative and 1 PCR-positive) after IFN treatment.
In the initial report, 15 patients had died (3 during the first 100 days). Since then, 2 more patients have died, 1 after relapse (at 7 years after transplant) and 1 of colon carcinoma at 81/2 years
after transplant.
Survival estimates.
Figure 1 shows the 9 year Kaplan-Meier
probabilities of survival (0.73 for BU-CY and 0.65 for CY-TBI,
P = not significant [NS]) and the cumulative incidences of
relapse (0.19 for BU-CY and 0.22 for CY-TBI, P = NS). Figure
2 shows the Kaplan-Meier probabilities of
event-free survival (0.55 for BU-CY and 0.48 for CY-TBI,
P = NS) and the cumulative incidences of nonrelapse mortality
(0.20 for BU-CY and 0.25 for CY-TBI, P = NS). Table 1 describes the current status of survivors
in each study group.
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| Fig 1.
Kaplan-Meier estimates of survival and cumulative
incidence of relapse for patients conditioned for HLA-identical marrow
transplantation with the BU-CY and CY-TBI regimens. Endpoints were
calculated as in the original report.1 Results are updated
to July 1999.
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| Fig 2.
Kaplan-Meier estimates of surviving event-free (relapse
and death were identified as events) and of dying from causes other
than relapse for patients conditioned for HLA-identical marrow
transplantation with the BU-CY and CY-TBI regimens. Endpoints were
calculated as in the original report.1 Results are updated
to July 1999.
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Discussion.
Since publication of the original report, there have been 2 other
reports of randomized studies comparing the BU-CY and TBI regimens in
patients with CML in CP.2,3 The study by the Nordic Bone
Marrow Transplantation group2 included patients with
advanced stages of acute and chronic leukemia, and only 28% had CML in
CP. Patients treated with busulfan had more early toxicity, which
resulted in increased transplant-related mortality and worse survival in patients with advanced disease, but this was not the case
for patients with early disease. A recent update of this study4 concluded that late toxic effects (including chronic GVHD and obstructive bronchiolitis) were more common after treatment with busulfan compared with TBI, but the report did not discriminate between patients with early or advanced disease with respect to these
toxicities. Transplant-related mortality and survival were worse in
patients with advanced disease who received busulfan. In patients with
early disease there was no difference in outcome with the 2 conditioning regimens. The study from the French Society of Bone Marrow
Grafts3 was limited to patients with CML in CP. It was
concluded that BU is an acceptable alternative to TBI for patients with
CML in first chronic phase receiving bone marrow transplantation from
HLA-identical sibling donors. Both regimens caused similar
transplant-related mortality. The antileukemic efficacy of the BU-CY
regimen was either similar to or possibly better than that of the
CY-TBI regimen.
The results from our updated analysis with a median follow-up of 7.7 years support our original conclusions. For patients with CML in CP,
BU-CY is better tolerated than CY-TBI as a preparative regimen for
marrow transplantation from an HLA-identical sibling. The 2 regimens have comparable efficacy against CML and similar risks
of mortality from causes other than relapse.
R.A. Clift
J. Radich
F.R. Appelbaum
P. Martin
M.E.D. Flowers
H.J. Deeg
R. Storb
E.D. Thomas
Seattle Marrow Transplant
Team
Seattle, WA
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REFERENCES |
1.
Clift RA, Buckner CD, Thomas ED, Bensinger WI, Bowden R, Bryant E, Deeg HJ, Doney KC, Fisher LD, Hansen JA, Martin P, McDonald GB, Sanders JE, Schoch G, Singer J, Storb R, Sullivan KM, Witherspoon RP, Appelbaum FR:
Marrow transplantation for chronic myeloid leukemia: A randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide.
Blood
84:2036, 1994[Abstract/Free Full Text]
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Ringdén O, Ruutu T, Remberger M, Nikoskelainen J, Volin L, Vindelov L, Parkkali T, Lenhoff S, Sallerfors B, Ljungman P, Mellander L, Jacobsen N, for the Nordic Bone Marrow Transplantation Group:
A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia: a report from the Nordic bone marrow transplantation group.
Blood
83:2723, 1994[Abstract/Free Full Text]
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Devergie A, Blaise D, Attal M, Tigaud JD, Jouet JP, Vernant JP, Bordigoni P, Ifrah N, Dauriac C, Cahn JY, Lioure B, Troussard X, Reiffers N, Gratecos N, Milpied N, Belanger D, Guyotat D, Tilly H, Michallet M, Gluckman E, for the French Society of Bone Marrow Graft (SFGM):
Allogeneic bone marrow transplantation for chronic myeloid leukemia in first chronic phase: A randomized trial of busulfan-cytoxan versus cytoxan-total body irradiation as preparative regimen: A report from the French Society of Bone Marrow Graft (SFGM).
Blood
85:2263, 1995[Abstract/Free Full Text]
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Ringdén O, Remberger M, Ruutu T, Nikoskelainen J, Volin L, Vindelov L, Parkkali T, Lenhoff S, Sallerfors B, Mellander L, Ljungman P, Jacobsen N:
Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation: Long-term results of a randomized trial in allogeneic marrow recipients with leukemia.
Blood
93:2196, 1999[Abstract/Free Full Text]
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