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Blood, Vol. 93 No. 5 (March 1), 1999:
pp. 1534-1539
Autografting With Philadelphia Chromosome-Negative Mobilized
Hematopoietic Progenitor Cells in Chronic Myelogenous Leukemia
By
Angelo M. Carella,
Enrica Lerma,
Maria T. Corsetti,
Anna Dejana,
Palmina Basta,
Franca Vassallo,
Monica Abate,
Monica Soracco,
Federica Benvenuto,
Osvaldo Figari,
Marina Podestà,
Giovanna Piaggio,
Raimondo Ferrara,
Mario Sessarego,
Caterina Parodi,
Michele Pizzuti,
Alessandra Rubagotti,
Domenico Occhini, and
Francesco Frassoni
From the Hematology/ABMT Unit, Department of Hematology, Ospedale San
Martino, Genoa; Biostatistic Unit, Department of Oncology, National
Cancer Institute, University of Genoa; Internal Medicine I, DIMI,
University of Genoa; Cytogenetics, Ospedale San Martino, Genoa; and the
Division of Hematology, Potenza, Italy.
 |
ABSTRACT |
Intensive chemotherapy given in early chronic phase of chronic
myelogenous leukemia (CML) has resulted in high numbers of circulating
Philadelphia (Ph) chromosome-negative hematopoietic progenitor cells
(HPC). We have autografted 30 consecutive patients with CML in chronic
phase with HPC collected in this way to facilitate restoration of
Ph-negative hematopoiesis in bone marrow after high-dose therapy.
Hematopoietic recovery to greater than 0.5 ×109/L
neutrophils and to greater than 25 × 109/L platelets
occurred in all patients, a median of 13 (range, 9 to 32) days and 16 (range, 6 to 106) days postautograft, respectively. Regenerating marrow
cells were Ph-negative in 16 (53%) patients and greater than 66%
Ph-negative in 10 (33%) patients. Twenty-eight patients are alive 6 to
76 months (median, 24 months) after autografting. Three patients have
developed blast crisis from which 2 have died. Eight patients are in
complete cytogenetic remission at a median of 20 (range, 6 to 44)
months with a median ratio BCR-ABL/ABL of 0.002 (range, <0.001 to
0.01). Eight patients are in major cytogenetic remission at a median of
22 (range, 6 to 48) months. No patient died as a consequence of the
treatment. All patients had some degree of stomatitis that was severe
in 15 (50%) patients. Gastrointestinal and hepatic toxicities were
observed in about one fourth of patients. Thus, autografting with
Ph-negative mobilized HPC can result in prolonged restoration of
Ph-negative hematopoiesis for some patients with CML; moreover, most
autograft recipients report normal or near normal activity levels,
suggesting that this procedure need not to be associated either with
prolonged convalescence or with chronic debility.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
CHRONIC MYELOGENOUS leukemia (CML) is a
malignant disease of hematopoietic stem cells. Conventional treatment
with chemotherapy controls signs of disease but neither postpones onset of acute phase nor prolongs survival. Except for MD
Anderson,1 interferon- can offer significant cytogenetic
remission in 9% to 19% rates.2-4 Transplantation with
stem cells obtained from either related or unrelated donors can result
in prolonged disease-free survival, and it is curative in many
patients.5-7 Unfortunately, donor stem-cell transplants may
be offered to only a minority of CML patients. In these last years,
several investigators have observed that diploid hematopoietic
progenitor cells (HPC) coexist with their malignant counterparts in the
marrow of some patients with CML,8-13 observations that led
to clinical trials testing autografting after high-dose
chemoradiotherapy regimens.14-20
Beginning in July 1989, our group initiated a pilot study with
intensive chemotherapy to induce aplasia followed by leukaphereses of
peripheral blood HPC, in an attempt to verify whether residual diploid
cells have, in the repopulating phase, a proliferative advantage over
Philadelphia (Ph) chromosome-positive cells and if they could be
collected in quantities suitable for autografting applications. These
studies showed that it was possible to collect diploid cells also in
patients with advanced phases of disease cytogenetically refractory to
interferon therapy.21 In a subsequent study, we confirmed
that patients treated early in chronic phase with chemotherapy had a
higher number of diploid cells than patients in the more advanced phase
of disease.22
Here we present the results from 30 consecutive patients autografted
with Ph-negative or prevalently Ph-negative ( 34% Ph-positive) HPC
during their chronic phase of CML.
| |
PATIENTS AND METHODS |
Patients with Ph-positive CML who were less than 65 years old,
ineligible for allogeneic stem-cell transplantation, and in morphologic
chronic phase entered this study. All patients had previously received
only hydroxyurea to reduce white blood cells less than or
equal to 20 × 109/L. The first cohort of patients
(n = 11) were mobilized with the ICE protocol consisting
of idarubicin 8 mg/m2/d intravenously for 5 days;
cytarabine (ARA-C) 800 mg/m2 by 2-hour infusion for 5 days;
and etoposide 150 mg/m2/d by 2-hour infusion for 3 days.
Subsequently, 19 patients were given a mini-ICE protocol (the same
three drugs at the same doses but idarubicin and ARA-C were given for 3 days only). Beginning 8 days after the end of the chemotherapy,
recombinant human granulocyte colony-stimulating factor (rhG-CSF) was
administered daily at a dosage of 5 µg/kg until the total neutrophil
count was more than 1.0 × 109/L for 3 consecutive days.
Leukaphereses were performed using CS 3000 PLUS machine (Baxter,
Deerfield, IL) or Dideco Excel (Milan, Italy), generally
starting on the first day that the white blood cell count exceeded 0.8 × 109/L and the concentration of CD34+ cells
was at least 5/µL on peripheral blood. The next leukapheresis was
usually performed when the white blood cell count had surpassed 109/L and the circulating CD34+ cells were more
than 10/µL. The collections were continued until the total number of
CD34+ cells collected was at least 2 × 106/kg. Each leukapheresis product was analyzed
cytogenetically and for CD34+ and colony-forming
unit-granulocyte-macrophage (CFU-GM) numbers. The total leukapheresis
product for each patient was frozen using a Planner R-203 (SACI, Milan,
Italy). Between June 1992 and April 1998, 40 candidates had their
peripheral blood HPC treated with mobilization procedure, but 10 of
them could not be autografted because of high level of Ph-positive
cells in the leukapheretic product (6 patients), very low level of
CD34+ cells (<1 × 106/kg; 3 patients),
and matched unrelated donor (MUD) transplant in the last 1 patient.
Patients.
The 30 patients were aged 22 to 62 years (median 46 years) at the time
of autografting (Table 1). All patients
were in first chronic phase. The treatment was approved by the local
ethical committee, and patients gave informed consent before entry into the study.
High-dose therapy.
Patients were treated with one of the two intensive therapy regimens.
The median time from diagnosis and autograft was 6 months (range, 3 to
30 months). Four patients received autograft over 11 months after
diagnosis. Two of them decided to wait for research of MUD, and in the
meantime they were treated with hydroxyurea. MUD research was negative;
therefore, they were autografted at 14 months from diagnosis. The other
2 patients did not agree to receive autograft so early, and they were
given only hydroxyurea. After 17 and 30 months they underwent autografting.
Six patients received idarubicin (50 mg intravenously in single dose
over 3 hours) on day  11; etoposide (800 mg/m2 as a
2-hour infusion) on days 8/7; and total body irradiation (850 cGy
in single dose) on day 2. Peripheral HPC were reinfused on day 0. The subsequent 24 patients received busulfan alone at 4 mg/kg/d orally
for 4 consecutive days (total 16 mg/kg). A loading dose of 600 mg oral
phenytoin was administered 1 day before the start of chemotherapy, and
phenytoin was continued at a dose of 100 mg/d for 5 days to prevent
epileptic seizures. All patients received hydration with urine
alkalinization, allopurinol, and ranitidine. Peripheral HPC were
reinfused 5 days after the end of chemotherapy.
Supportive care.
Patients were managed in conventional rooms (without high-efficiency
particulate air filtration) and given intravenous antibiotics and
amphotericin B, irradiated blood products, and intravenous nutrition as indicated.
Assessment for autografting.
Marrow samples were taken at regular intervals after autografting for
morphologic and cytogenetic analyses. BCR-ABL/ABL ratio was performed
after autografting and during the follow-up only on patients resulting
Ph-negative.
Definition of response.
Hematologic remission was defined as the absence of morphologic
evidence of CML in the blood and marrow. Cytogenetic remission was
defined as the presence of 100% (complete) or 66% to 99% (major) Ph-negative metaphases in Giemsa-banded preparations from 24- to
48-hour marrow cultures. BCR-ABL/ABL ratio was evaluated for assessing
the BCR-ABL transcript and BCR-ABL/ABL ratio on marrow cells during the
follow-up as described.23
Treatment after autografting.
Therapy with interferon- 2a or 2b was begun earlier after
engraftment and given at 3 M/U daily for 5 days per week for 8 weeks
together with interleukin-2 (IL-2) at 2 × 106 daily for 5 days every 9 weeks. This course was repeated for 3 times, and after
that the patient received interferon therapy alone.
Statistical methods.
Actuarial curves were estimated according to the Kaplan and Meier
method.24 Surviving patients were censored on the last day
of follow-up.
| |
RESULTS |
Composition of the autograft.
The number of CD34+ cells infused ranged from 1.06 to 74.5 × 106/kg (median, 4.04) and the number of CFU-GM from
0.11 to 108 × 104/kg (median, 19.2). Twenty-two patients
were reinfused with Ph-negative cells only and 14 (64%) achieved
marrow cytogenetic remission postgraft. Six patients were infused with
less than 34% Ph-positive cells and 2 (33%) of them achieved marrow
cytogenetic remission postautograft. The last 2 patients were reinfused
with greater than 34% Ph-positive cells, and they achieved 10% and
95% Ph-positive cells postautograft. No correlation is possible
considering the very few patients reinfused with Ph-positive greater
than 34%.
Hematopoietic recovery.
Recovery of neutrophils to greater than 0.5 × 109/L
occurred at a median of 13 (range, 9 to 32) days and recovery of
platelets to greater than or equal to 25 × 109/L at a
median of 16 (range, 6 to 106) days. During the first 2 months
following hematopoietic recovery after autografting, cytogenetic
analysis showed complete remission in marrow cells in 16 (53%) of the
30 patients and major remission in 10 (33%) patients (Table 1). Four
patients showed Ph-positive cells greater than 34% of marrow cells. In
8 patients, platelets recovery greater than 50 × 109/L
did not occur during the first 8 weeks after autografting. In 1 patient
this recovery occurred after 15 weeks. After this time, in all cases
engraftment was achieved and there were no cases of late cytopenia.
Toxicity.
All patients had some degree of stomatitis, which was severe in 15 patients (Table 2).
Gastrointestinal and hepatic toxicities were observed in
about one fourth of patients. No other major toxicities were
encountered.25 Specifically, no patient had busulfan-related pulmonary toxicity, hepatic veno-occlusive disease, or
epileptic seizures.
| |
OUTCOME |
Two patients died of myeloid blastic transformation at 18 and 29 months
after autografting. Twenty-eight patients are alive 6 to 76 months
(median, 24 months) after autografting, with an actuarial survival of
87% (95% confidential limit [CL]: 54 to 97). Eight of
these maintain complete cytogenetic remission at a median of 20 (range,
6 to 44) months after autografting. The median ratio BCR-ABL/ABL was of
0.002 (range, <0.001 to 0.01). Between 3 and 17 months (median 5 months), Ph-positive cells became detectable in 8 of the 16 patients
who achieved complete cytogenetic remission (Fig
2). These 8 patients are now in major
cytogenetic remission at a median of 22 (range, 6 to 48) months. All
patients (Ph-negative and Ph-positive) remain on interferon-
therapy. The status of each patient on the last day of follow-up is
shown in Table 1. Survival plot after autografting is shown in Fig 1.
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| Fig 1.
Actuarial survival after autografting. Patients who
remain in complete ( ) or in major ( ) cytogenetic remission are
indicated.
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| Fig 2.
Time to recurrence of greater than 1% Ph-positive cells
after infusion of mobilized Ph-negative cells in 16 patients in whom
complete cytogenetic remission was achieved.
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| |
DISCUSSION |
The general rationale for autografting in first chronic phase is that a
reduction in the target population of leukemic stem cells available for
secondary mutational events will delay emergence of a blast-phase
subclone and thereby prolong survival. The fact that Ph-positive cells
subsequently became detectable is not surprising in view of experience
with syngeneic transplants and evidence that immune effectors cells in
allografting can make an important contribution to the prevention of
disease recurrence after allografting. Most of the published experience
in autografting for CML in chronic phase has involved the infusion of
Ph-positive cells obtained from untreated patients at
diagnosis.14,16,20,26 Although significant decreases in the
percentage of Ph-positive marrow metaphases posttransplant have been
noted in many patients, only a minority of patients have shown less
than 25% Ph-positive cells, and only exceptional cases were completely
Ph-negative early or at greater than or equal to 1 year
posttransplantation.14,16 Several investigators suggest
that total survival may be extended in autografted patients compared
with historic controls, particularly in those who show some Ph-negative
cells after grafting.14,16,27,28 However, it
has been noted that a significant percentage of such patients may
require repeated autografts because of early or late graft
failure.14
There is limited experience to date using Ph-negative cells in an
attempt to increase the curative potential of autografting in CML.
Approaches to obtaining such cells have involved the use of repeated
courses of intensive chemotherapy,29 in vitro
purging,12,15,17,31-37 or long-term
culture8,10,18 and in vivo
purging.21,22,30,31,46-48
A total of 40 patients were treated with intensive chemotherapy and
G-CSF. Of these, 10 patients could not be autografted because 1 patient
underwent MUD, 6 patients collected highly contaminated Ph-positive
cells, and the last 3 patients achieved a very low level of
CD34+ cells (<1 × 106/kg).
In this report we have analyzed the results achieved in 30 consecutive
patients autografted with Ph-negative or prevalently Ph-negative cells
combined with adequate number of HPC. It was shown that the restoration
of normal hematopoiesis was achieved in the majority of patients,
suggesting that the chance of graft failure is minimized with cells
mobilized with this procedure. The speed of hematopoietic recovery was
consistent with an autograft-derived origin of predominantly diploid
cells. No patient died as a consequence of the treatment. The majority
of patients had stomatitis, which was severe in 50% of them, and only
a minority of patients encountered some degree of hepatic and
gastrointestinal toxicities. Specifically, no patient had
busulfan-related pulmonary toxicity, hepatic veno-occlusive disease, or
epileptic seizures. Thus, we can reasonably agree with the London data
that the use of busulfan produces results at least as good as those
achieved with total body irradiation (TBI)-containing
regimens.38 There has been predominantly Ph-negative hematopoiesis in the majority of our patients for months postgrafting, and with the exception of 3 patients evolved in blastic crisis, there
have been no hematologic relapses to date. The median follow-up postautograft was 24 (range, 6 to 76) months, and the actuarial survival at 3.5 years postautograft was 87% (95% CL: 54 to 97). Finally, most autograft recipients report normal or near-normal activity levels, suggesting that this procedure need not be associated either with prolonged convalescence or with chronic debility.
All autografted patients received postgraft immunobiological therapy
with rhIL-2 and interferon- in the attempt to delay the blastic
evolution. Combination therapies of rhIL-2 and interferon- have been
shown to function synergistically in augmenting cytolytic activity in
mice, both in vitro and in vivo.39-45 Both rhIL-2 and interferon- were able to increase the suppressed natural killer cytolytic activity of lymphocytes isolated from CML
patients.43,44 Recently, the efficacy of this combination
has been confirmed in chronic and advanced phases of CML.45
In conclusion, our data suggest that early transplantation with
mobilized Ph-negative or prevalently Ph-negative is a technique worth
developing further. Because it is well tolerated, it can increase the
age for investigative treatment for CML; 23% of the 30 patients we
have autografted were between 52 and 62 years of age. Taken together,
the results achieved by our group suggest that this approach, when
applied in early chronic phase, is able to restore and to maintain
major or complete cytogenetic response in greater than 50% of the
initial population. This percentage seems to be superior to that
obtained with interferon therapy alone; however, such a small series
cannot be compared with the results of large-scale trials. Randomized
trials are needed to evaluate our procedure versus interferon- ± low-dose ARA-C. This approach is being investigated in three randomized
trials under way in Germany, the United States/United Kingdom (ECOG-MRC
CML trial), and European Group for Blood and Marrow Transplantation.
| |
ACKNOWLEDGMENT |
We thank Mara Capurro for manuscript preparation.
| |
FOOTNOTES |
Submitted July 20, 1998; accepted October 22, 1998.
Supported by Associazione Italiana Ricerca contro il Cancro (AIRC), 1998.
Address reprint request to Angelo M. Carella, MD,
Hematology/ABMT Unit, Via Acerbi, 10/22, 16148 Genoa, Italy; e-mail:
amcarella{at}smartino.ge.it.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
| |
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Abstract
Introduction