Impact of High-Risk Cytogenetics and Achievement of
Molecular Remission on Long-Term Freedom from Disease
after Autologous
e
Allogeneic Tandem Transplantation in
Patients with Multiple Myeloma
Nicolaus Kröger
1,
*
, Anita Badbaran
1
, Tatjana Zabelina
1
, Francis Ayuk
1
,
Christine Wolschke
1
, Haefaa Alchalby
1
, Evgeny Klyuchnikov
1
,
Djordje Atanackovic
2
, Georgia Schilling
2
, Timon Hansen
2
, Sabine Schwarz
1
,
Marion Heinzelmann
1
, Silke Zeschke
1
, Ulrike Bacher
1
, Thomas Stübig
1
,
Boris Fehse
1
, Axel R. Zander
1
1Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 2Department of Hematology/Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Article history: Received 1 August 2012 Accepted 11 October 2012 Key Words: Unrelated donor Graft-versus-host disease ASO primer
Plasma cell chimerism
a b s t r a c t
Within a prospective protocol, the incidence and impact of achievement of molecular remission (mCR) and high-risk cytogenetics was investigated in 73 patients with multiple myeloma (MM) after autologous (auto) eallogeneic (allo) tandem stem cell transplantation (SCT). After induction chemotherapy, patients received melphalan 200 mg/m2before undergoing auto-SCT, followed 3 months later by melphalan 140 mg/m2and fludarabine 180 mg/m2 before allo-SCT. Sixteen patients had high-risk cytogenetic features, defined by positive FISH for del(17p13) and/or t(4;14). Overall, 66% of the patients achieved CR or near-CR, and 41% achieved mCR, which was sustained negative (at least 4 consecutive samples negative) in 15 patients (21%), with no significant difference in incidence between the patients with high-risk cytogenetics and others (P¼.70). After a median follow-up of 6 years, overall 5-year progression-free survival was 29%, with no significant difference between del 17p13/t(4;14)-harboring patients and others (24% versus 30%;P¼.70). The 5-year progression-free survival differed substantially according to the achieved remission: 17% for partial remission, 41% for CR, 57% for mCR, and 85% for sustained mCR. These results suggest that autoeallo tandem SCT may overcome the negative prognostic effect of del(17p13) and/or t(4;14) and that achievement of molecular remission resulted in long-term freedom from disease.
Ó2013 Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation.
INTRODUCTION
Multiple myeloma (MM) is considered an incurable
disease, but in some patients long-term survival can be
achieved after high-dose chemotherapy followed by
autolo-gous (auto) or allogeneic (allo) stem cell transplantation
(SCT). Several previous studies have suggested longer
survival in those patients who achieve complete remission
(CR),
especially
after
high-dose
chemotherapy
[1,2].
Compared with other treatment modalities for MM, allo-SCT
induces a high rate of clinical complete response.
Approxi-mately 50% of patients with CR also achieve CR at the
molecular level (mCR)
[3,4]. Only those patients who achieve
mCR have a high probability of long-term freedom from
disease and cure
[5].
Standard myeloablative conditioning has been associated
with high treatment-related morbidity and mortality. The
advent of reduced-intensity conditioning (RIC) and the use of
auto
e
allo tandem SCT approaches has broadened the use of
allo-SCT in patients with MM; however, the results of
prospective trials are controversial
[6-13]. Patients harboring
del(17p) or t(4;14) are considered to have worse prognoses
[14-17]. In the present study, we investigated within
a prospective protocol the incidence and impact of mCR and
of high-risk cytogenetic features, de
fi
ned as detection of
del(17p13) and t(4;14) by FISH, on long-term outcomes after
auto
e
allo tandem SCT in patients with MM.
PATIENTS AND METHODS Patients
Between April 2000 and October 10, 2008, 73 patients with advanced stage II/III MM were included in the study. The major inclusion criteria were MM stage II/III and age 18-65 years. Induction therapy was not part of the protocol and consisted of idarubicin/dexamethason or vincristine/ adriamycin and dexamethasone and, in more recent years, bortezomib/ dexamethason. Stem cell mobilization was performed with granulocyte colony-stimulating factor (10mg/kg) from the steady state. Before auto-grafting, 3% of the patients were in CR, 59% were in partial remission (PR), 19% had minor response or no change, and 19% had progressive disease. A minimum dose of 2.0106/kg CD34þcells was required for auto-SCT. The
conditioning regimen for auto-SCT consisted of melphalan 200 mg/m2in
divided doses given over 2 days. After an interval of 2-3 months, the patients received an RIC regimen consisting of melphalan 140 mg/m2,fludarabine 180 mg/m2, and antithymocyte globulin (ATG-Fresenius; Fresenius, Grä-felfing, Germany) at a dose of 10 mg/kg for recipients of related donor grafts and 20 mg/kg for recipients of unrelated donor grafts on days -3, -2, and -1, followed by allo-SCT. Twenty-three patients received a graft from an HLA-identical sibling, and 25 patients each received a graft from a matched or mismatched unrelated donor.
Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine A and a short course of methotrexate. Additional donor lymphocyte infu-sions (DLIs) were allowed in cases of incomplete chimerism or persistent disease by day 120 after discontinuation of immunosuppressive therapy. FISH analysis was performed in 63 patients and revealed del 13q14 in 43 patients, t4;14 in 8 patients, and del 17q13 in 8 patients. Patient
American Society for Blood
ASBMT
and Marrow Transplantation
This trial was registered inClinicalTrials.gov(registration NCT 00781170).
Financial disclosure:See Acknowledgments on page 403.
*Correspondence and reprint requests: Prof Dr Med Nicolaus Kröger, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany.
E-mail address:nkroeger@uke.uni-hamburg.de(N. Kröger).
1083-8791/$esee front matterÓ2013 Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation.
characteristics are summarized inTable 1. The median patient age was 49 years (range, 28-64 years). One patient who experienced severe side effects from melphalan after auto-SCT received treosulfan (310 mg/m2) instead of melphalan before allo-SCT. The median time from auto-SCT to allo-SCT was 110 days (range, 39-228 days). Fifteen patients received DLI according to the protocol due to mixed chimerism or residual disease after discon-tinuation of immunosuppressive therapy. Preliminary results of this study have been reported previously[6], and those patients are included in the present cohort with longer follow-up.
All patients provided informed consent, and the study was approved by the local Ethics Committee and health authorities. The study has been registered inClinicalTrials.gov(NCT 00781170).
Response Criteria
The criteria for remission were based on modified European Group for Blood and Marrow Transplant (EBMT) criteria[18]. CR was defined as the absence of detectable monoclonal immunoglobulin in serum and urine, negative immunofixation, and<5% plasma cells in marrow aspirate. PR was defined as at least a 75% reduction in monoclonal immunoglobulin in serum or 90% light chains in 24-hour urine. Near-CR was defined as absence of visible monoclonal paraprotein in electrophoresis but positive immunofi x-ation in serum or urine. mCR was defined as at least 2 negative PCR results with ASO primer or at least 2findings of 99.9% donor chimerism of CD138-selected plasma cells by sensitive PCR from bone marrow samples, as described below.
Sustained minimal residual disease (MRD) negativity was defined by at least 4 consecutive negative molecular results by either ASO primer or plasma cell chimerism. Mixed molecular remission was defined as detection of negative molecular markers on at least 2 occasions, but with intermittent positivity as determined by ASO primer or plasma cell chimerism. Positive MRD was defined as never or only once negativity for ASO primer or plasma cell chimerism. Bone marrow samples for detection of MRD were obtained from patients with CR or near CR (defined as normal electrophoresis but positive immunofixation) in 3- to 6-month intervals during thefirst 3 years after therapy, usually starting between dayþ100 and dayþ180 after allo-SCT.
Molecular Remission Testing
In 37 of 48 patients with CR or near-CR, MRD could be monitored by patient-specific primers (n ¼ 15) or by highly sensitive plasma cell
chimerism (n¼22). In 5 patients, only 1 MRD measurement was available, and those patients were excluded from the MRD subanalysis. Myeloma-specific primers were generated as described elsewhere[19]. In brief, after enrichment of CD138þcells (MACS, Miltenyi, Bergisch Gladbach, Germany), RNA of plasma cells was isolated and transcripted into cDNA. DNA was prepared after a preliminary lysis of erythrocytes and centrifugation from approximately 1-5105bone marrow cells using the QIAampDNA DNA
Blood Mini Kit (Qiagen, Hilden, Germany). Four sets of VH consensus forward primers and one common reverse JH primer were used for IgH sequence identification. Amplification products were electrophoresed on 2% agarose gels with ethidium bromide and visualized. Clonal PCR products were excised and purified with a DNA gel extraction kit (Qiagen). Purified PCR fragments were sequenced directly using a Big Dye Terminator Kit and an ABI Prism Model 377 sequencer (Life Technologies, Carlsbad, CA). The relevant VH family and JH consensus primers were used as sequencing primers. Vh, Dh, and Jh regions; N nucleotides; and other individual features of IgH gene were identified using the IMGT database (http://www.imgt. cines.fr/) and IgBLAST (http://www.ncbi.nlm.nih.gov/igblast/).
Tumor-specific primers for nested PCR and as forward and reverse primers for TaqMan were designed using Primer Express (Life Technologies). Nested PCR was performed in 2 rounds of amplification, with PCR "enrich-ment" with relevant VH family and JH consensus primers followed by the second round with a pair of tumor-specific primers. Parallel analysis of the
HCKgene was performed for amplification control.
Determination of plasma cell chimerism was performed as described previously[20]. In brief, plasma cells were obtained using CD138 microbe-ads and MiniMACS columns (Miltenyi Biotec), according to the manufac-turer’s instructions. The genetic markers were selected following Alizadeh et al.[21], including S01A, S01B, S07A, S07B, S08A, S08B, S11A, and, in cases of a male recipient and female donor, theDFFRYgene from the Y chromo-some, as described by Fehse et al.[22]. The reported sensitivity of this method is 1:1000 cells, 1:100,000 cells for chromosome-specific PCR. Quantitative PCR was performed using TaqMan technology on an ABI Prism 7700 sequencer (Life Technologies). Sensitivity of plasma cell chimerism was assessed by experiments using bone marrow samples from healthy male donors and dilution experiments using healthy female donor cells. These experiments revealed a sensitivity of 104using real-time PCR and
single nucleotide polymorphisms, 105using Y-chromosome PCR, and 105
using nested PCR with patient-specific primers.
To determine the relative specificity threshold of donor plasma cell chimerism for identifying MRD after allo-SCT, the percentage of donor plasma cell chimerism was compared with immunofixation and in some cases with nested PCR of patient-specific primers. For this study, plasma cell chimerism was used in those patients in whom generation of specific primers was not feasible. In some patients, both methods were available and showed good correlation of results, but patient-specific primers were used for thefinal analysis in these patients.
Statistical Methods
Study endpoints were overall survival (OS), progression-free survival (PFS), transplantation-related mortality (TRM), and incidence of relapse.
Table 1 Patient Characteristics (n¼73) Characteristic Value Sex, n Female 29 Male 44 Donor, n HLA-identical sibling 23 Unrelated 50 Matched 25 Mismatched 25
Disease status before allo-SCT, n
CR 4 PR 57 mCR 5 Stable disease 3 Progressive disease 4 Del 13q14, n Positive 43 Negative 20 Unknown 10 t(4;14), n 8 Del 17p13, n 8
Age, years, median (range) 49 (28-64) Stem cell source, n
Peripheral blood 70
Bone marrow 3
Follow-up, years, median (range) 72 (30-131) Interval between auto-SCT and allo-SCT, days,
median (range)
110 (39-228) Remission status after induction therapy, n (%)
CR 2 (3) PR 43 (59) mCR 12 (16) No change 2 (3) Progressive disease 14 (19) Table 2 Results Parameter Value
Primary graft failure, n 1 Time to ANC>1.0109/L, days, median (range) 15 (11-27)
Time to platelets>20109/L, days, median (range) 17 (9-122)
Acute GVHD, n (%) None 31 (43) Grade I 12 (17) Grade II 20 (27) Grade III 9 (12) Grade IV 1 (1) Response CR/near-CR, n (%) 48 (66) mCR, n 30 Sustained negative 15 Mixed 15 PR, n (%) 15 (21) Progressive disease, n (%) 2 (3) Not evaluated, n (%) 8 (11) 5-year PFS, % 29 (17-41) 5-year OS, % 54 (42-66) Cumulative incidence of relapse at 5 years, % 42 (30-54) Cumulative incidence of TRM at 1 year, % 23 (13-33)
Patient characteristics are expressed as median and range for continuous variables and as frequency for categorical variables. Categorical data were compared using thec2test or the Fisher exact test. Survival curves were estimated by the Kaplan-Meier method. The log-rank test was used to estimate the incidence of TRM and relapse, to account for competing risks. For TRM, relapse was the competing event and for relapse, TRM was the competing event. Gray’s test was used to compare cumulative incidence curves. Calculations were performed with SPSS version 15 (SPSS, Inc., Chi-cago, IL), and the competing-risk analyses were done using ACCorD (V. Gebski, National Health and Medical Research Council Clinical Trials Centre, Camperdown, Australia).
RESULTS
Engraftment
One graft failure was observed. The median time to
leukocyte and platelet engraftment was 15 days (range, 11-27
days) and 17 days (range, 9-122 days), respectively (Table 2).
TRM
The cumulative incidence of 1-year TRM was 23% (95% CI,
13%-33%). This incidence was identical in HLA-identical
sibling graft recipients (22%) and matched unrelated donor
graft recipients (20%) and slightly, but not signi
fi
cantly,
higher in mismatched unrelated donor graft recipients (32%;
P
¼
.40).
Response
A total of 44 patients (60%) achieved CR according to
EBMT criteria with negative immuno
fi
xation, 6% achieved
near-CR, and 21% achieved PR. In addition, 3% had
progres-sive disease, and 11% were not evaluable for determination of
remission. mCR was observed in 30 patients; in 15 of these
patients, the molecular markers were sustained negative,
and in the other 15 patients, the molecular markers were
only mixed negative as described above, resulting in an
overall mCR rate of 41% and a sustained mCR rate of 21%. The
mCR rate was 50% in patients with del 17p/t(4;14) and 40% in
those without del 17p/t(4;14) (P
¼
.50). Sustained mCR was
seen in 6 patients with del 17p and/or t(4;14) and in 9
patients without del 17p/t(4;14) (P
¼
.70) (Table 3).
Table 3Results According to CR or mCR
CR versus PR PValue mCR versus Others PValue Sustained mCR versus Mixed mCR PValue 5-year PFS 41% (95% CI, 25-57) versus
17% (95% CI, 0-34) (4 years) .008 57% (95% CI, 37-77) versus 26% (95% CI, 10-42) (3 years) <.001 85% (95% CI, 65-100) versus 31% (95% CI, 7-55) .003 5-year OS 74% (95% CI, 60-88) versus
38% (95% CI, 15-61) .03 89% (95% CI, 77-100) versus 39% (95% CI, 19-59) <.001 91% (95% CI, 73-100) versus 87% (95% CI, 69-100) .06 5-year relapse 45% (95% CI, 29-61) versus
56% (95% CI, 31-81) (4 years) .44 36% (95% CI, 18-54) versus 55% (95% CI, 34-76) .06 7% (95% CI, 0-21) versus 63% (95% CI, 35-91) .002 Included patients n=73 nCR/CR after allografting n=48 Molecular markers available n=37 [ASO n=15 PCC n=22] Sustained molecular remission n=10*
Molecular remission after allograft
n=22
No molecular remission n=15
Sustained molecular remission after DLI
n=5† Molecular remission after DLI n=8 <nCR after allografting n=25 No molecular markers available n=11 DLI n=15
Figure 1.mCR after AutoeAllo Tandem SCT in MM. ASO indicates allele-specific oligonucleotide; PCC, plasma cell chimerism.*Five patients with high-risk
The study protocol allowed DLI in patients with persistent
disease after discontinuation of immunosuppressive therapy.
A total of 15 patients received DLI, 8 of whom achieved mCR
(mixed in 3 and sustained in 5). In 3 of these responding
patients, mCR was associated with the development of GVHD
(Table 3
and
Figure 1).
Figure 2
shows the occurrence of mCR,
along with the dates of DLI and relapse.
PFS
At a median follow-up of 6 years, overall 5-year PFS was
29% (95% CI, 17%-41%). PFS at 5 years did not differ between
patients with del 17p/t(4;14) and those without del 17p/
t(4;14) (24% versus 30%;
P
¼
.70). Patients who achieved CR
after transplantation had a better 5-year PFS compared with
patients with only PR (41% versus 17%;
P
¼
.008). Within
the group that achieved CR according to EBMT criteria, 3-year
PFS was signi
fi
cantly better in the patients who achieved
mCR compared with those who did not (57% versus 26%:
P
.001). However, in the group of patients who achieved mCR,
those with sustained negative mCR had a 5-year PFS of 85%,
versus 31% for those with mixed mCR (P
¼
.003) (Table 3).
The 5-year OS for the entire study population was 54%
(95% CI, 42%-66%). Donor source, HLA mismatch, or
remis-sion before transplantation did not in
fl
uence OS. Patients
who achieved CR according to EBMT criteria had an
improved 5-year OS compared with those who achieved only
PR (74% versus 38%;
P
¼
.03). Patients who achieved mCR
had a better 5-year OS than those who did not (89% versus
39%;
P
<
.001). There was also a trend toward improved OS
in patients with sustained mCR versus those with mixed
mCR (91% versus 87%;
P
¼
.06). The 5-year OS did not differ
among recipients of grafts from HLA-identical siblings,
matched donors, or mismatched donors (65% versus 40%
versus 51%, respectively;
P
¼
.30) (Figure 3A and B).
Relapse
The cumulative incidence of relapse at 5 years was 42%
(95% CI, 30%-54%) and was not in
fl
uenced by the presence of
del 17p or t(4;14) (40% versus 52%;
P
¼
.10). Patients with
mCR exhibited a trend toward a lower incidence of relapse
(36% versus 55%;
P
¼
.06). Patients with sustained mCR had
a relapse incidence of only 7% (95% CI, 0-21%) at 5 years,
Figure 2.Achievement of mCR after autoeallo tandem SCT. Patients 1-15 achieved a mixed mCR; patients 15-30, a sustained mCR. REZ, relapse;B, MRD-negative;compared with 63% in those with mixed mCR (P
¼
.005)
(Figures 1
and
4).
DISCUSSION
The achievement of CR is now considered a major factor
for prolonged event-free survival and OS in patients with
MM who receive standard chemotherapy or high-dose
chemotherapy followed by auto-SCT or allo-SCT
[23].
Furthermore, duration of CR in the sense of sustained CR is
a major factor for long-term survival after auto-SCT
[24].
mCR is rarely observed after auto-SCT
[3,4], but can be
ach-ieved in some patients by posttransplantation consolidation
or maintenance therapy
[25]. After standard myeloablative
conditioning followed by allo-SCT, approximately 50% of the
patients who achieve CR will also achieve mCR
[3,4], but this
treatment approach is associated with high
treatment-related morbidity and TRM
[26,27]. The introduction of RIC
has broadened the application of allografting in MM, owing
to the reduced treatment-related morbidity and TRM. Some
randomized studies using an auto
e
allo tandem SCT
approach have suggested a bene
fi
t for OS
[9-13,28].
The incidence and outcome of mCR after RIC have not
been previously studied in a large cohort of patients
[29].
Here we report that 66% of patients achieved CR and 41%
achieved mCR according to EBMT criteria with RIC auto
e
allo
tandem SCT. Sustained mCR, de
fi
ned as 4 consecutive
MRD-negative bone marrow samples, was achieved in 21% of
patients. Those with sustained mCR had a signi
fi
cantly better
5-year PFS than those who achieved only mixed mCR or no
mCR (85% versus 31% versus 17%, respectively), supporting
previously published results on mCR after standard
mye-loablative conditioning
[5]. Our 21% rate of sustained mCR
after RIC is somewhat lower than the reported 50% after
myeloablative conditioning
[3,4], possibly related to
meth-odological differences and the stringent de
fi
nition of
“
sus-tained
”
mCR in our study. Of note, PFS increased according to
the depth of remission, from 41% for CR to 57% in mCR and
85% in sustained mCR. Furthermore, only those patients with
sustained mCR, de
fi
ned as 4 consecutive negative samples,
are at very low risk of relapse at 5 years (7%), whereas those
with mixed mCR have only a delayed onset of relapse, but
identical cumulative incidence at 5 years (Figure 2).
The International Myeloma Working Group recently
introduced a stringent de
fi
nition of CR
[30], but comparative
studies have shown no further bene
fi
t from adding the free
light chain ratio to the standard EBMT de
fi
nition of CR
[31,32]. The most sensitive methods are molecular methods,
especially the use allelic-speci
fi
c primers based on IgH
rearrangement, with a sensitivity up to 10
6[3,4,5,25].
Shortcomings of this approach include the time-consuming
procedure,
generation
of
individual
patient-speci
fi
c
primers, and a success rate of
<
75%. Owing to
pretreat-ment with induction chemotherapy, we were able to
generate patient-speci
fi
c primers in only 45% of our patients.
To overcome this limitation, we used a highly sensitive
plasma cell chimerism with a sensitivity of 10
5, which has
the advantage of being less time-consuming
[20]. Among the
disadvantages of this approach are the low speci
fi
city and its
applicability only after allo-SCT. Whereas complete donor
plasma cell chimerism is closely correlated with speci
fi
city of
patient-speci
fi
c primers, in cases of mixed plasma cell
chimerism, this method does not allow differentiation
between residual healthy and malignant plasma cells. Other
investigators have used multicolor
fl
ow cytometry to detect
MRD, which is readily applicable but has a lower sensitivity,
w
10
4, compared with molecular methods
[32,33].
No clear characteristics were identi
fi
ed in those patients
who achieved sustained mCR. Interestingly, long-lasting
mCR was seen in patients harboring del 17p13 or t(4;14)
Figure 3.OS (A) and PFS (B) after autoeallo tandem SCT according toachievement of mCR.
Figure 4.Cumulative incidence of relapse after autoeallo tandem SCT according to achievement of mCR.
and in patients who were refractory at time of
trans-plantation (Table 4).
Patients with del 17p and/or t(4;14) and those without
these high-risk cytogenetic features had similar rates of mCR
and relapse, as well as similar PFS, suggesting that these
negative prognostic factors may be overcome by an upfront
auto
e
allo tandem SCT approach. Previous studies in patients
with more advanced disease have shown a negative impact
of del 17p, but not of t(4;14), after allo-SCT
[34,35]. More
recently, the Société Française de Greffe de Moelle et de
Thérapie Cellulaire reported no difference in outcomes
between patients with or without del 17p and/or t(4;14) after
allo-SCT
[36]. Interestingly, no difference in outcomes was
seen between recipients of HLA-identical sibling grafts and
recipients of unrelated donor grafts, which is important
because unrelated SCT as part of an auto
e
allo tandem
approach has been reported only rarely
[37].
Of note, 5 of 15 patients who received DLI because of
persistent disease achieved sustained mCR. This
fi
nding
supports strategies to target mCR by posttransplantation
therapies for those who did not achieve mCR from the
transplantation
itself.
To
improve
results,
post-transplantation strategies including, for instance, DLI or
novel immunomodulating drugs, such as thalidomide,
lena-lidomide, and bortezomib, can be used to upgrade CR to
mCR, as reported recently
[38,39]. The present study
underscores the importance of the depth of remission and
demonstrates that achievement of mCR is associated with
long-term freedom from disease and potential cure of MM
and, even more important, that this can be achieved in
patients with high-risk cytogenetics, de
fi
ned by del 17p and/
or t(4;14).
ACKNOWLEDGMENTS
Financial disclosure:
The authors have nothing to disclose.
Authorship statement:
Nicolaus Kröger designed the study,
analyzed data, and wrote the manuscript. Anita Badbaran,
Sabine Schwarz and Silke Zeschke performed ASO primer
and plasma cell chimerism analyses. Tatjana Zabelina
per-formed statistical analysis. Francis Ayuk, Christine Wolschke,
Haefaa Alchalby, Evgeny Klyuchnikov, Djordje Atanackovic,
Thomas Stübig, Marion Heinzelmann, Ulrike Bacher, and
Axel R. Zander included patients into the study, evaluated
results, and wrote the manuscript. Georgia Schilling and
Timon Hansen performed FISH analyses. Boris Fehse
super-vised ASO primer and plasma cell chimerism analyses.
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Table 4
Characteristics of Patients Who Achieved Sustained mCR
Type Sex Donor Cytogenetics (by FISH) Status after Induction
Status before Allo-SCT
GVHD after SCT DLI for MRD
Status at Follow-up IgG kappa Male MUD del 13q14, t(4;14) CR CR Ø Yes Relapse after 7 years; alive
9 yearsþ
Light chain/plasma cell leukemia
Female MUD del 13q14, t(14;16) PR PD Ø No Alive, mCR, 8 yearsþ
IgA kappa Male MUD del 13q14; del 17p13, t(4;14)
PR PR Chronic GVHD No Dead, chronic GVHD, 5 years in mCR
IgA lambda Female MUD t(4;14), del 13q14 PR PR Ø Yes Alive, mCR, 7 yearsþ
IgG kappa Male MUD del 13q14 PR PR Ø No Alive, mCR, 6.5 yearsþ
IgA lambdaþ
extramedullary
Male Related Not done PR PR Ø No Alive, mCR, 6.5 yearsþ
Light chain kappa Male MUD Normal PR PR Chronic GVHD No Alive, mCR 6 yearsþ
IgA lambda Female Related del17p13/ del 13q14 PR CR ChronicGVHD No Relapse after 3.5 years; alive 4.5 yearsþ
IgG lambdaþ
extramedullary
Male MUD Not done PR PR Ø Yes Alive, mCR, 9.5 yearsþ
IgG kappa Female MUD del 13q14 PR PR Ø No Alive, mCR, 4.5 yearsþ
IgG kappa Male Related Unknown PR PR Ø No Alive, mCR, 11.5 yearsþ
IgG kappa Male Related Normal PR PR Ø Yes Alive, mCR, 10.5 yearsþ
IgG kappa Male MUD Not done PR PR Chronic GVHD Yes Alive, mCR, 11yearsþ
IgG kappa Male Related del17p13 PR PR Acute GVHD grade II
No Alive, mCR, 4.5 yearsþ
Light chain kappa Male MUD del 13q14, del 17p13 PD PR Ø No Alive, mCR, 4.5 yearsþ
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