|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 6 (March 15), 1999:
pp. 2136-2138
CORRESPONDENCE
Comparative Analysis of Autografting in Chronic
Myelogenous Leukemia: Effect of Priming Regimen and Marrow or Blood
Origin of Stem Cells
 |
LETTER |
To the Editor:
The report of Verfaillie et al1 compares their results to
those of our group in attempting to harvest Philadelphia (Ph) chromosome-negative progenitors from chronic myelogenous leukemia (CML)
patients for use in autologous transplant. This is not a reasonable
comparison, in view of the differences in the patients studies, the
type of drugs for mobilization, and the timing of harvesting. From our
experience in developing this strategy over 9 years in 176 patients, it
is evident that (1) a combination with idarubicin, intermediate-dose
cytarabine, and etoposide (ICE/mini-ICE protocols)2-5 or
modifications of it6,7 is the most effective therapy to
mobilize Ph-negative hematopoietic progenitor cells (HPC). Few patients
received high-dose hydroxyurea on the basis of the above criteria, but
the small number of patients treated does not allow us to state any
definitive conclusions.8 These data have been confirmed
also in advanced highly pretreated patients cytogenetically refractory
to interferon- (IFN-).9 It must be underlined that
ICE is the acronym of idarubicin-containing regimen and not ifosfamide
containing regimen, as wrongly reported by Verfaillie et
al.1 I do not understand the reason why the investigators
decided to use Cy alone or in combination with low doses of
mitoxantrone and cytarabine instead of the most effective mini-ICE or
IDAC protocols. The differences between their results and our results
may be due to the different myeloreductive approaches. It has been
clearly demonstrated that cyclophosphamide is not myeloreductive enough
and poorly effective on leukemic patients; besides, it has been well
demonstrated that the duration of aplasia is not important but rather
the quality of cells killed by the oncolytic drugs.
Perhaps the therapy used by Verfaillie et al1 did not
determine an adequate myeloreduction in the marrow and the growth
factors stimulated the residual leukemic cells instead of the arising
diploid residual HPC. In addition, we deem that very strict criteria
are needed to start the collections. As we recently published, we have
learned in these past few years that the best collections in terms of
CD34+ cells and diploid cells were achieved when the white
blood cell count (WBC) was greater than 0.8 × 109/L
combined with  10/µL CD34+ cells on peripheral blood.
The investigators say that they started their collections when the
absolute WBC was between 500 and 1,000/µL without CD34+
cell control in peripheral blood, but in Table 1, the WBC at the time
of mobilization was incredibly high, ie, 2.9 to 84 × 109/L (median, 7.7 × 109/L; Cy/GM/BM); 2.4 to 27.2 × 109/L (median, 9.8 × 109/L;
MAC/G/PB), and 2.6 to 36.1 × 109/L (median,
4.7 × 109/L; Cy/G/PB). With respect to our experience,
this may be the reason why they obtained such different results from
ours. Only 15 patients received this approach during early chronic
phase, and the short duration and intensity of chemotherapy
administration could have had a negative impact on the type of cells
mobilized in the peripheral blood when they were recovering. Another
difference between our experience and that of Verfaillie et al derives
from the timing of starting the procedure. In our experience, the
median time between diagnosis and HPC mobilization was 2 months, versus 8 months for Verfaillie et al. As is known, the best results have been
reported for HPC mobilization performed as soon as possible after
diagnosis when the WBC reached  20 × 109/L after
hydroxyurea. The explanation for an early approach derives from
biological reports demonstrating that the benign hematopoietic clone
decreases with time, and it is possible that the normal HPC pool has
decreased considerably. The data reported in the report by
Verfaillie et al seem to confirm that an early approach combined with
more intensive therapy (MAC/G/PB) does better in terms of cytogenetic
response than the protocols with cyclophosphamide alone.
In conclusion, our work over these last 9 years with
idarubicin-containing regimens (ICE/mini-ICE) allows us to state that the results with this procedure are as follows: (1) poor in
accelerated/blastic phase, probably because diploid cells are no longer
available in marrow and patients cannot withstand toxic therapy; (2)
compromised by longer hospitalization, less good cell phereses, and
longer recovery in highly pretreated patients with interferon; (3) the high rate of diploid collections is achieved in untreated patients in
the first few weeks from diagnosis and the response is correlated with
Sokal score (excellent results in low and intermediate risk and less
good results in high-risk patients); and (4) ICE or mini-ICE protocols
determine the same Ph-positive HPC collections, but mini-ICE has more
potential benefits because it may be administered in outpatient
facility and is less GI toxic and because shorter hospitalizations were
needed. Diploid cells are most likely in pheresis 1, but at least 2 to
3 phereses are required to collect more than 3 to 4 × 106
CD34+ cells. We have treated 45 patients in the earlier
phase of disease (at a median of 2 months from diagnosis) and not
pretreated with interferon. Thirty-two patients were autografted, and 3 other patients are now receiving the transplant. Ten patients could not
be autografted because of very high number of Ph-positive cells (6 patients), low HPC collected (3 patients), and MUD (1 patient). Thirty
of 32 patients are alive, with 18 patients still Ph-negative (10 patients) or less than 34% Ph-positive (8 patients).
In summary, I deem that no correlation between the study of Verfaillie
et al and our study may be performed. This is due mainly to the fact
that Verfaillie et al treated very few patients in early chronic phase
and with three different protocols. Moreover, other discrepancies
between the two studies arise from mobilization therapy, timing, and
choice of the best day to start the collections.
Angelo
Michele Carella
N.O.A. Hematology/ABMT
Ospedale San
Martino
Genoa, Italy
| |
REFERENCES |
1.
Verfaillie CM, Bhatia R, Steinbuch M, DeFor T, Hirsch B, Miller JS, Weisdorf D, McGlave PB:
Comparative analysis of autografting in chronic myelogenous leukemia: Effects of priming regimen and marrow or blood origin of stem cells.
Blood
92:1820, 1998[Abstract/Free Full Text]
2.
Carella AM, Cunningham I, Lerma E, Dejana A, Benvenuto F, Podestà M, Celesti L, Chimirri F, Abate M, Vassallo F, Figari O, Parodi C, Sessarego M, Valbonesi M, Carlier P, Prencipe E, Gatti AM, van der Berg D, Hoffman R, Frassoni F:
Mobilization and transplantation of Philadelphia-negative peripheral-blood progenitor cell early in chronic myelogenous leukemia.
J Clin Oncol
15:1575, 1997[Abstract]
3.
Carella AM, Lerma E, Celesti L, Dejana A, Panagiotis Z, Corsetti MT, Frassoni F:
Effective mobilization of Philadelphia-chromosome-negative cells in chronic myelogenous leukaemia patients using a less intensive regimen.
Br J Haematol
100:445, 1998[Medline]
[Order article via Infotrieve]
4.
Waller CF, Heinzinger M, Rosenstiel A, Lange W:
Mobilization and transplantation of Philadelphia chromosome-negative peripheral blood progenitor cells in patients with CML.
Br J Haematol
103:227, 1998[Medline]
[Order article via Infotrieve]
5.
Fischer T, Neubauer A, Mohm J, Huhn D, Busemann C, Link H, Arseniev L, Bussing B, Novotny J, Ganser A, Duyster J, Bunjes D, Kreiter S, Aulitzky W, Hehlmann R, Huber C:
Chemotherapy-induced mobilization of karyotypically normal PBSC for autografting in CML.
Bone Marrow Transplant
10:1029, 1998
6.
Kantaryian HM, Talpaz M, Hester J, Feldman E, Korbling M, Liang J, Rios MB, Smith TL, Calvert L, Deisseroth AB:
Collection of peripheral blood diploid cells from chronic myelogenous leukemia patients early in the recovery phase from myelosuppression induced by intensive dose chemotherapy.
J Clin Oncol
13:553, 1995[Abstract/Free Full Text]
7.
Chalmers EA, Franklin IM, Kelsey SM, Ne AC, Clark RE, Sproul AM, Crotty G, Mc Cann SR, Fielding A, Goldstone AH, Hepplestone A, Watson W, Sharp RA, Tansey P:
Treatment of chronic myeloid leukaemia in first chronic phase with idarubicin and cytarabine: Mobilization of Philadelphia-negative peripheral blood stem cells.
Br J Haematol
96:627, 1997[Medline]
[Order article via Infotrieve]
8.
Johnson RJ, Smith GM:
Mobilization and reinfusion of Philadelphia-negative peripheral blood mononuclear cells in chronic myeloid leukaemia with hydroxyurea and G-CSF.
Leuk Lymphoma
27:401, 1997[Medline]
[Order article via Infotrieve]
9.
Carella AM, Simonsson B, Link H, Lennard A, Boogaerts M, Gorin NC, Tomas-Martinez JF, Dabouz-Harrouche F, Gautier L, Badri N:
Mobilization of Philadelphia-negative peripheral blood progenitor cells with chemotherapy and rhU-G-CSF in chronic myelogenous leukemia patients with a poor response to interferon-alpha.
Br J Haematol
101:111, 1998[Medline]
[Order article via Infotrieve]
Response
In general, we agree with the comments from Dr Carella on our study
published in Blood, "Comparative Analysis of Autografting in
Chronic Myelogenous Leukemia: Effect of Priming Regimen and Marrow or
Blood Origin of Stem Cells." In contrast to published studies from
the University of Genoa, most patients studied at the University of
Minnesota were in late chronic phase or accelerated phase at the time
of enrollment, and the time between diagnosis and transplantation was
longer for patients in studies at the University of Minnesota. Better
results seen in studies from the University of Genoa could thus be due
to the fact that patients transplanted earlier after diagnosis may have
a larger population of normal stem cells than patients enrolled at the
University of Minnesota. As pointed out by Dr Carella and in the
Discussion of our report, it is also possible that the longer duration
of chemotherapy or specific agents in the ICE regimen used at the University of Genoa may mobilize more Ph-negative cells, even though we
were unable to demonstrate a significant impact of intensifying the
chemotherapeutic regimen from cyclophosphamide to cyclophosphamide, ARA-C, and mitoxantrone on the Ph status of the graft. We apologize for
the confusion concerning the timing of PBPC collections. Data in Table
1 represent WBC counts before the start of mobilizing chemotherapy,
whereas data provided in Table 2 represent the time of PBPC collections
performed when the ANC is 0.7 and 1.0 × 109/L. In
conclusion, we agree with Dr Carella that differences in patient
selection and, possibly, differences between the chemotherapeutic regimens used at the University of Genoa and the University of Minnesota may explain differences seen in outcome after autologous transplantation with mobilized PBPC in CML. The observation that partial or complete cytogenetic responses obtained in a large number of
patients transplanted either at the University of Minnesota or
University of Genoa are not durable indicates that further tumor
depletion from the graft or additional posttransplant therapy will be
needed to increase durable remissions after autografting for CML.
Catherine Verfaillie
Philip McGlave
Jeffrey S. Miller
Division of Hematology, Oncology and Transplantation
University of Minnesota
Minneapolis, MN
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
|
|
