Allogeneic Bone Marrow Transplant for Multiple Myeloma

Full text

1997 89: 2610
N. H. Russell, G. Miflin, C. Stainer, J. G. Mc Quaker, N. Bienz, A. P. Haynes and E. M. Bessell
Allogeneic Bone Marrow Transplant for Multiple Myeloma
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CORRESPONDENCE
Allogeneic Bone Marrow Transplant for Multiple Myeloma
To the Editor: in CR from influenza A pneumonitis at 5 months posttransplant and
1 patient, who failed to achieve a CR posttransplant, eventually died
from progressive disease. This patient was transplanted 32 months
In a detailed analysis of 80 patients with multiple myeloma (MM) from diagnosis and had received 2 previous chemotherapy regimens.
undergoing allogeneic bone marrow tranplantation Bensinger et al
1
She was also the only patient to receive cyclophosphamide and TBI
concluded that future studies of this treatment modality in MM conditioning therapy.
should focus on the use of less toxic conditioning regimens applied From these results we would suggest that fractionated TBI and
earlier in the course of the disease. We would support these conclu- melphalan is a well tolerated conditioning regimen for patients with
sions based on our own analysis of a smaller group of 13 patients MM. The dose of melphalan used in our series (110 mg/m
2
) is lower
undergoing allogeneic transplantation in Nottingham since 1990. than is conventionally used with TBI in autologous PBSCT for MM
Patient characteristics are shown in Table 1. As can be seen, the (140 mg/m
2
).
2
This lower dose melphalan was chosen in an attempt
majority of patients were tranplanted early in their disease, 6 patients to reduce regimen related toxicity and to minimize mortality in a
in first response and 7 in second response. The median time to predominantly older group of patients with a disease characterized
tranplantation was 19 months and of the 6 patients transplanted in by a high transplant related mortality (TRM).
3
The high rate of CR
first response, all were transplanted within 18 months of diagnosis. (10 out of 11 patients) and relatively low probability of day 100
The first patient received conditioning with fractionated total body nonrelapse mortality (15%) compared to other studies
1,3
would sug-
irradiation (TBI) (12 Gy in 6 fractions) and cyclophosphamide (120 gest that this is an effective and relatively nontoxic antimyeloma
mg/kg), with all subsequent patients receiving fractionated TBI and conditioning regimen. The group of patients reported here were gen-
melphalan (110 mg/m
2
). In addition, in the week before admission, erally transplanted earlier in their disease than the patients reported
patients received additional top up radiotherapy to sites of major by Bensinger et al
1
and no patient had received more than 2 lines
bone disease if evident on skeletal survey. All patients received of conventional therapy before proceeding to transplant. Thus the
cyclosporin and a short course of methotrexate (15 mg/m
2
on day high response rate, low relapse rate, and low TRM may also reflect
/
1 and 10 mg/m
2
on day
/
3,
/
6, and
/
11) for prevention of graft- this. The EBMT experience has also shown that patients transplanted
versus-host disease (GVHD). Twelve patients were transplanted following just 1 line of chemotherapy have a superior CR rate and
from HLA-identical sibling donors; however, 1 patient in second overall survival compared with patients transplanted with more ad-
response was transplanted from a 1 HLA-B mismatched sister. vanced disease.
4
Finally, the results reported here and elsewhere,
1,3
Twelve patients received bone marrow (BM) and 1 patient was which suggest that some patients with MM undergoing allogeneic
transplanted with granulocyte colony-stimulating factor mobilized bone marrow transplant may be cured of their disease, means that
peripheral blood stem cells. Of the 13 patients transplanted 11 were we continue to evaluate allogeneic transplantation in preference to
evaluable posttranplant of whom 10 achieved a complete remission autologous PBSCT for all newly diagnosed MM patients
õ
50 years
(CR) defined as a normal BM aspirate and trephine biopsy with with poor prognostic features who have a fully matched sibling
a complete absence of monoclonal protein in blood or urine by donor.
immunofixation. No patient has relapsed and currently 9 are surviv-
ing, disease-free, ranging from 7 to 70 months posttransplant. Of
the 6 patients tranplanted in first response, all within 18 months of
diagnosis, 5 are in CR. The overall disease-free survival for all
patients transplanted is shown in Fig 1. Four patients have died, 3
from transplant related causes. Of these, 2 patients died before day
100, 1 from acute GVHD (grade IV), and 1 from multiorgan failure;
both patients were transplanted in second response. No other patient
developed more than grade I acute GVHD. One further patient died
Table 1. Patient Characteristics (n Å13)
Median age (range) at transplantation 49 yr (44-47)
Sex (M:F) 6:7
Stage at diagnosis
I1
II 3*
III 9†
No. of previous lines of treatment
16
27
Median time (range) from diagnosis to transplant 19 mo (5-53)
* One patient had systemic amyloidosis complicating myeloma.
Fig 1. Event-free survival of 13 patients transplanted with MM.
† One patient had plasma cell leukemia with a peripheral blood
plasma cell count of 72 110
9
/L at presentation.
2610
Blood,
Vol 89, No 7 (April 1), 1997: pp 2610-2617
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CORRESPONDENCE 2611
N. H. Russell bone marrow transplantation for multiple myeloma. An analysis of
risk factors on outcome. Blood 88:2787, 1996
G. Miflin 2. Jagannath S, Barlogie B, Dicke K, Alexanian R, Zagars G,
C. Stainer Cheson B, Lemaistre FC, Smallwood L, Pruitt K, Dixon DO: Autolo-
J. G. M
C
Quaker gous bone marrow transplantation in multiple myeloma: Identifica-
N. Bienz tion of prognostic factors. Blood 76:1860, 1990
A. P. Haynes 3. Gahton G, Ture S, Ljungman P, Belanger C, Brandt L, Cavo
E. M. Bessell M, Facon T, Granena A, Gratwohl A, Lowenberg B, Nikoskelainen
Department of Haematology and J, Reiffers J, Samson D, Selby P, Volin L: for the European Group
Department of Clinical Oncology for Blood and Marrow Transplantation: Allogeneic bone marrow
Nottingham City Hospital transplantation in multiple myeloma. N Engl J Med 325:1267, 1991
Nottingham, UK 4. Gahrton G, Ture S, Ljungman P, Blade J, Brandt L, Cavo M,
Facon T, Gratwohl A, Hagenbeek A, Jacobs P, De Laurenzi A, Van
REFERENCES
Lint M, Michallet N, Nikoskelainen J, Reiffers J, Samson D, Verdonck
1. Bensinger WI, Buckner CD, Anasetti C, Clift R, Storb R, L, De Witt T, Volin L: Prognostic factors in allogeneic bone marrow
transplantation for multiple myeloma. J Clin Oncol 13:1312, 1995Barnett T, Chauncey T, Shulman H, Appelbaum FR: Allogeneic
Can Ferritin Provide Iron for Hemoglobin Synthesis?
To the Editor: of erythroid cells on Tf-bound Fe. Interestingly, in 1962 Bessis and
Breton-Gorius themselves reviewed critically their original hypothe-
We have read with great interest a recent report by Gelvan et al
1
sis, and did not exclude the possibility that the phenomenon of
attempting to resurrect an old idea that immature erythroid cells ‘‘rhopheocytosis’’ takes place in the opposite direction, ie, ‘‘the
obtain iron (Fe) from ferritin. We wish to comment on one single and erythroblast imparts the ferritin to the reticular cell.’’
14
extremely important issue in this report, viz, that Fe from internalized Ferritin is not only an improbable source of Fe for the erythroid
ferritin can be used for hemoglobin synthesis. We believe that neither cells, but it is also an unlikely mediator involved in intracellular
the results of previous studies nor experiments presented by Gelvan translocation of Fe for heme synthesis. Although ferritin has been
et al
1
provide adequate evidence supporting this claim. postulated to act as an intermediate for heme synthesis in erythroid
In 1957 Bessis and Breton-Gorius
2
presented electron micrographs cells,
15,16
several studies failed to show that
59
Fe from
59
Fe-ferritin
depicting erythroblastic islands in the bone marrow, in which a could be incorporated into hemoglobin.
17,18
When heme synthesis
central reticulum cell (‘‘nurse cell’’) was surrounded by a ring of was inhibited in erythroid cells incubated with
59
Fe-transferrin, very
erythroblasts. In the region of contact between these cells the authors little
19,20
or no
21 59
Fe accumulates in ferritin. More importantly, when
observed ferritin and proposed that it was transferred from the reticu- heme synthesis is restored in these cells, no
59
Fe in ferritin was used
lum cell to the erythroblasts by a form of micropinocytosis termed for heme synthesis.
20
These findings concur with observations that
‘‘rhopheocytosis’’ (for review see ref 3). Somewhat later, Jandl, the intracellular Fe release from ferritin may require its catabolism,
22
Katz, and coworkers
4,5
showed that immature erythroid cells take and suggests limited availability of ferritin Fe for metabolic pur-
up Fe from plasma Fe-binding protein, transferrin (Tf), and sug- poses.
gested the existence of a membrane-bound Tf receptor which may The evidence from previous studies showing that Tf and not ferri-
be involved in Fe uptake. The many studies and discussions that tin is the Fe donor for hemoglobin synthesis must now be considered
followed have led to a general consensus that Tf, not ferritin, is with the recent investigation by Gelvan et al.
1
In this latter study
the source of Fe for hemoglobin synthesis, and this view has been the authors have incubated erythroid precursors with
59
Fe-labeled
supported by the following evidence. First, under normal conditions ferritin for 21 hours, at which time they detected some
59
Fe in the
all plasma Fe is associated with Tf, and ferrokinetic studies have cells and in heme. Unfortunately, a number of technical flaws prevent
provided clear evidence that all Fe used for hemoglobin synthesis the conclusion that
59
Fe found in heme comes from
59
Fe in the
passes through the plasma.
6
Hence, if the reticulum cell ferritin was ferritin core. To prepare
59
Fe-labeled ferritin, Gelvan and associates
the source of hemoglobin Fe, these cells would have to acquire it have exposed apoferritin to a mixture of 5%
59
Fe(III) (as
59
FeCl
3
)
from Tf. However, virtually no Fe enters the reticuloendothelial and 95%
56
Fe(II) in an oxygenated buffer at pH 7.0. It is essential
system from plasma Tf.
7
Second, it should also be pointed out that to point out that apoferritin shells can be loaded with Fe(II), whereas
plasma ferritin has a very low Fe content, and no ferrokinetic evi- attempts to load Fe(III) into the core have failed.
23
In their study,
dence supports its role in Fe transport.
7
Third, a specific relationship Gelvan et al probably presumed that
59
Fe(III), in the presence of a
between Tf and erythroid cells is documented by in vitro studies large excess of unlabeled Fe(II), would be converted to
59
Fe(II).
showing that this molecule is the only physiologically relevant Fe However, in the absence of Fe-binding ligands such a conversion
complex capable of providing Fe for hemoglobin synthesis.
8
Fourth, has been shown to occur only at an extremely low pH (
õ
1.0, ref
normally developing erythroid cells take up 26 mg Fe/d from plasma 24). From method description
1
it is not apparent what ligand was
Tf,
7
a rate that matches almost perfectly with the daily production present in the MOPS buffer that would stabilize both Fe(II) and
of hemoglobin (
Ç
6.2 g). The final and most convincing evidence Fe(III) in aqueous solution at pH 7.0 to allow electron self-exchange
of an absolute requirement for Tf by erythroid cells comes from between the two redox states of Fe to occur. MOPS buffers are
observations that both humans and mice with hereditary atransferri- sometimes supplemented with EDTA (although this is not specified
nemia have severe hypochromic microcytic anemias.
9-11
Further- in ref 1) which, however, has almost 11 orders of magnitude higher
more, when compared with wild-type animals, hypotransferrinemic formation constant for Fe(III) than for Fe(II).
25
Hence, under aerobic
mice show an extremely restricted uptake of
59
Fe by the erythron.
12,13
conditions the Fe(II)-EDTA complex should be rapidly oxidized to
Fe(III)-EDTA complex, but no reduction of
59
Fe(III)-EDTA wouldCollectively, the above studies document the stringent dependency
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