971 Unrelated Bone Marrow Transplantation for Children with Chronic Myeloid Leukemia (CML): A
Report from the Japan Marrow Donor Program (JMDP)
Saturday, December 6, 2008
Hall A (Moscone Center)
Poster Board I-76
Hideki Muramatsu1*, Seiji Kojima1*, Ayami Yoshimi2*, Yoshiko Atsuta2*, Chikako Tono3*, Koji Kato4, Yoshihisa
Nagatoshi5*, Masami Inoue6*, Kazutoshi Koike7*, Takakazu Kawase8*, Keisei Kawa6* and Hiroyuki Shimada9*
1Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
2Department of Hematopoietic Stem Cell Transplantation Data Management, Nagoya University School of
Medicine, Nagoya, Japan
3Department of Pediatrics, Aomori Rosai Hospital, Aomori, Japan
4Division of Pediatric Hematology/Oncology, Children's Medical Center, Japanese Red Cross Nagoya First
Hospital, Nagoya, Japan
5Section of Pediatrics, National Kyushu Cancer Center, Fukuoka, Japan
6Department of Hematology/Oncology, Osaka Medical Center and Research Institute for Maternal and Child
Health, Osaka, Japan
7Department of Pediatrics, Ibaraki Children's Hospital, Ibaraki, Japan
8Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
9Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
Background: Chronic myeloid leukemia (CML) is a rare disease in children and accounts for
approximately 2% to 3% of all childhood leukemia. Despite of introduction of tyrosine kinase inhibitors, allogeneic
hematopoietic stem cell transplantation is still the only proven curative treatment for patients with CML. Few
studies have specifically addressed transplantation outcomes in childhood CML.
Patients and Methods: We analyzed the clinical data of 125 children (81 boys and 44 girls) with CML
undergoing unrelated bone marrow transplantation (UBMT) through the Japan Marrow Donor Program (JMDP)
between 1993 and 2006 (median observation period, 95 months). The recipients’ median age at transplantation
was 14 years (range, 1 - 19 years). The disease phases at conditioning were chronic phase (CP) 1 (n=88), CP2
(n=12), CP3 (n=1), accelerated phase (n=11) and blastic crisis (n=13). The median interval from diagnosis to
BMT was 14 months (range, 2 - 111 months). 95 (76%) patients received interferon-alpha (IFN-alpha), and 17
(14%) received imatinib mesylate (IM) before BMT. 96 (77%) patients received total body irradiation (TBI)
containing a conditioning regimen, and 29 (23%) received a non-TBI regimen. Cyclosporine A (CSA)-based graft-
versus-host disease (GVHD) prophylaxis was used for 81 (65%) patients, and tacrolimus based prophylaxis was
used for 43 (34%) patients. One patient received methotrexate only for GVHD prophylaxis. HLA matching data
based on high-resolution DNA typing for HLA-A, -B, -Cw, -DRB1 and -DQB1 alleles were available in 99 (79%)
patients; 41 of 99 (41%) patients were “fully matched (10/10)”. The median infused cell number was 314×106/kg
(range, 27 - 880×106/kg).
Results: Five-year overall survival (OS) and leukemia-free survival probabilities were 59.3% ± 4.5% and
55.5% ± 4.5%, respectively. Grade II to IV acute GVHD occurred in 50 (40%) patients, and chronic GVHD
occurred in 51 (41%) patients. Six (5%) patients did not achieve engraftment. In multivariate models for OS,
disease phase (advanced phase/CP1) (p=0.008, RR 2.431 (1.261-4.689)), infused cell number (<314×106/kg/
≥314×106/kg) (p=0.004, RR 2.917 (1.404-6.060)), HLA-A allele mismatch (p=0.001, RR 4.076 (1.798-9.236)),
and age at transplantation (≥15/ <15 years) (p=0.031, RR 2.236 (1.076-4.651)) were independent risk factors.
For transplant-related mortality (TRM), disease phase (advanced phase/CP1) (p=0.021, RR 2.341 (1.137-
4.820)) and infused cell number (<314×106/kg/ ≥314×106/kg) (p=0.001, RR 3.792 (1.686-8.529)) were
significant risk factors. HLA-B, -Cw, -DRB1, and -DQB1 allele mismatch were not significant risk factors for OS
and TRM on univariate and multivariate analyses. Subgroup analyses of CP1 patients (n=88) showed that
cytogenetic response (with or without major cytogenetic response) at BMT was a strong risk factor for OS (5-year
OS: 91.4% ± 6.0% vs 53.4% ± 8.1%, p=0.001). For the 29 patients who achieved major cytogenetic response at
BMT, the probability of OS was not statistically different between patients treated with IM (n=15) and those
treated with IFN-alpha (n=14) before BMT (p=0.722).
Conclusions: Disease phase, infused cell number, HLA-A allele mismatch, patient age and cytogenetic
response at transplantation were important risk factors for transplant outcomes. This is one of the largest cohorts
studied to date, and the results provide important information to assess the indications and to improve the
outcomes of children with CML undergoing UBMT.
2123 Favorable Outcome of Chronic Myeloid Leukemia Patients Treated with Imatinib Vs Early
Allogeneic Stem Cell Transplantation
Sunday, December 7, 2008
Hall A (Moscone Center)
Poster Board II-217
Joerg Hasford1*, Michael Lauseker2*, Insa Gathmann3*, Markus Pfirrmann, PhD1*, Richard A. Larson, MD4,
François Guilhot5, Stephen G O'Brien6*, Brian J. Druker7, Ruediger Hehlmann8, Andreas Hochhaus, MD9, For
the IRIS Study Group10* and For the German CML Study Group11*
1IBE, München, Germany
2IBE Munich, München, Germany
3Novartis Pharma AG, Basel, Switzerland
4University of Chicago, Chicago, IL
5Clinical Investigational Centre INSERM 802, CHU Poitiers, Poitiers, France
6University of Newcastle, Newcastle, United Kingdom
7Oregon Health & Science University Cancer Institute, Portland, OR
8Dept. of Hematology/Oncology, University of Heidelberg, Mannheim, Germany
9Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany
10Oregon Health & Science University Cancer Institute
11Medical Faculty Mannheim, University Heidelberg, Mannheim, Germany
Background: Early allogeneic stem cell transplantation has been considered the only curative treatment for CML.
The advent of imatinib provided a new chance to suppress long-lastingly the disease without risk of early deaths.
As there is no randomized trial comparing transplantation with imatinib therapy, we compared the outcome
between transplanted and imatinib-treated patients of two randomized trials. Data base: We used the survival
data of patients randomly allocated to imatinib in the IRIS trial (Druker et al. N Engl J Med 2006;355:2408) and
compared them with the genetically randomized transplanted (matched related donors) patients of the German
CML III and IIIA studies (Hehlmann et al. Blood;109:4686). Methods: Applying uniform inclusion criteria for age
(18–55 yrs at diagnosis) to generate comparable samples, survival time was determined according to the
intention-to-treat principle and after stratification for the Euro and EBMT scores using Kaplan-Meier curves.
Information about Sokal and Euro score was missing for 123 and 128 patients from the IRIS trial and for 4 resp. 6
patients from the German CML III/IIIA studies. Results: 377 CML patients in chronic phase treated with imatinib
and 285 patients with early allogeneic stem cell transplantation were analyzed. In the imatinib arm of the IRIS trial,
42 patients had been transplanted and 12 patients have died subsequently. Five-year-survival in this subgroup
of 377 younger patients of the IRIS trial was 94.7%. The patients’ characteristics of the two groups were
comparable (CML III/IIIA vs IRIS), median age: 38 vs 44 yrs., female sex: 40% vs 39%, Sokal Score low 49.8% vs
58.3%, intermediate 30.2% vs 25.2%, high risk 19.9% vs 16.5%; Euro Score low 62.7% vs 58.6%, intermediate
31.5% vs 34.9%, high risk 5.7% vs 6.4%. Median observation time was 75 months for transplanted patients and
61 months for imatinib-treated patients. Patients of both groups have not yet reached median survival times. Five-
year survival rates were 94.7 % (all imatinib treated patients) and 71.1 % (all transplanted patients). In all
prognostic strata, irrespective of the prognostic score used, five-year-survival with imatinib was evidently superior
compared to transplantation: Euro score: low risk 97.8% vs 78.3%, intermediate risk 93.6% vs 58.9%, EBMT
score 0-2: 94.7% vs 78.8%, EBMT score 3-4: 94.7% vs 52.2%. There were just 5 transplanted patients with an
EBMT score >4. Neither the censoring of the 42 transplanted patients of the IRIS trial affected the results nor the
in- or exclusion of the 12 subsequent deaths. Conclusions: We could not identify any subgroup of patients with
CML who clearly showed a benefit from early transplantation compared to treatment with imatinib, given an
observation time of 5–6 years.
2120 Stem Cell Transplant (SCT) for Patients (pts) with Chronic Myeloid Leukemia (CML) Resistant to
Tyrosine Kinase Inhibitors (TKI) with BCR-ABL Kinase Domain (KD) Mutation T315I
Sunday, December 7, 2008
Hall A (Moscone Center)
Poster Board II-214
Nikolai Velev1*, Jorge Cortes1, Richard Champlin2, Hagop M. Kantarjian1, Gabriela Rondon2, Sergio Giralt2,
Gautam Borthakur1 and Marcos De Lima2
1Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center,
Houston, TX
Background: Resistance to TKI therapy is associated with development of KD mutations in approximately 50-60%
of pts. Although many imatinib-resistant mutations respond well to second generation TKI, T315I is insensitive to
all currently available TKI (imatinib, dasatinib, nilotinib) in vitro and in the clinic. SCT is frequently recommended
for these pts but there is no available data about the efficacy of SCT in such pts. Aims: To investigate the
efficacy and safety of SCT for patients with TKI-resistant CML with a T315I mutation. Methods: We reviewed the
outcome of all pts with T315I that have received a SCT at MD Anderson Cancer Center. Results: Seven pts
received 8 transplants. Their median age was 44 years (yrs) (range, 26 to 64 yrs). The median time from
diagnosis to SCT was 42 months (mo) (range, 9-160 mo). All pts had become resistant to with imatinib; 5
received dasatinib and 1 nilotinib after imatinib failure, and 6 pts received other additional therapy prior to SCT.
At the time of SCT 2 pts were in chronic phase (CP), both in partial cytogenetic response; 2 in accelerated (AP)
with active disease; and 3 in second or greater CP from lymphoid blast phase (BP) (1 in minor cytogenetic
response, 2 major molecular response, 1 complete molecular response –CMR-). Six transplants were from
matched unrelated donors and 2 from cord blood. Best response after SCT was CCyR in 3 (2 AP, 1 BP), CMR in
4 (2 CP, 2 BP), and 1 unknown (died early). After a median follow-up of 11 months from SCT, 4 pts are alive; the
2 transplanted in CP are alive after 11 and 42 months after SCT and in CMR; 1 pt transplanted in AP has a
sustained CCyR 20 mo after SCT with persistent T315I representing 94% of transcripts by pyrosequencing; and
1 in BP has a CMR sustained 6 mo after a second SCT (relapsed 5 months after first SCT) 3 pts have died: 1 AP
and 2 BP, all with relapse. Conclusion: SCT appears to be an effective strategy for pts with CML with T315I,
although longer follow up is needed. Results are significantly better when pts are transplanted in CP. Thus, SCT
should be considered in pts with resistance to TKI once T315I is identified, ideally in CP.
970 Allogeneic Myeloablative Hematopoietic Stem Cell Transplantation for Chronic Myelogenous
Leukemia in the Imatinib Era
Saturday, December 6, 2008
Hall A (Moscone Center)
Poster Board I-75
Jiri Pavlu1*, Matthias Klammer1*, Ian Gabriel1*, Richard Szydlo1*, Eduardo Olavarria1*, Dragana Milojkovic1*,
Andrea Kew2, Katy Rezvani1*, Francesco Dazzi1*, David Marin1, John Goldman1* and Jane Apperley1*
1Department of Hematology, Imperial College London, Hammersmith Hospital, London, United Kingdom
2Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is no longer the first treatment option for patients
with chronic myelogenous leukemia (CML) but there is a considerable debate about its use as a second line
therapy. When used in this indication the second-generation tyrosine kinase inhibitors (2G-TKI) induce complete
cytogenetic responses (CCyR) in 40-50% of patients in chronic phase but those without CCyR are unlikely to
benefit in long term. It is therefore important to identify groups of patients with a good outcome after
transplantation so that this may be offered as second line therapy where appropriate. The outcome of allo-SCT
has improved over time so we restricted our analysis to the most recent 8 years to coincide with the introduction
of imatinib into clinical practice. 131 patients received myeloablative transplants from January 2000 till December
2007. 67 patients were transplanted in chronic phase (14 in second and 2 in third chronic phase), 46 in
accelerated phase and 2 in blastic phase. Forty-nine patients received imatinib at some point prior to
transplantation and 30 of these experienced failure of imatinib therapy (as defined by European LeukemiaNet
criteria). Conditioning consisted of cyclophosphamide and total body irradiation for 51 recipients of sibling stem
cells. In addition in vivo T cell depletion with anti CD52 antibody (Campath 1H) was used for 80 unrelated donor
transplants. The median age of the patients was 33.4 (15 to 56) years and the median disease duration at
transplant was 13 (2 to 105) months.
The probability of overall survival (OS) at 3 and 5 years was 64.8% and 62.6% respectively. We confirmed the
prognostic value of the EBMT risk assessment score (Gratwohl) and pre-transplant level of the C-reactive protein
(CRP) and developed a combined additive pre-transplant scoring system based on these predictive factors
(EBMT risk assessment score plus 0 for CRP <2 mg/L, 1 for CRP from 2 to 10 mg/L, and 2 for CRP >10 mg/L).
This identified 5 prognostic groups (Figure 1) with 3yr probabilities of survival of 92.6% (N= 27, score 0-1), 86.2%
(N=29, score 2), 58.2% (N=29, score 3), 47.5% (N=20, score 4) and 30.8% (N=26, score 5 or more). The patients
who failed imatinib (N=30) had significantly higher prognostic scores on the above described pre-transplant
scoring system compared to the rest of patients transplanted (p=0.001). However, in a multivariate analysis
adjusted for prognostic scores, their OS was significantly better (p=0.032).
The OS in the best prognostic group is comparable with that of unselected patients treated with imatinib and it is
possible that their long-term survival might be better. Allogeneic transplantation is unlikely to be preferred as the
first line therapy even in selected patients due to its higher early mortality but our data support its use as second
line therapy in patients in chronic phase who failed imatinib and have poor pre-2G-TKI predictive factors for
CCyR as determined previously at our institution (namely Sokal risk score at diagnosis, the best cytogenetic
response obtained on imatinib, G-CSF requirement during imatinib therapy and time from detection of imatinib
failure to onset of 2G-TKI therapy) but achieved good score on the pre-transplant scoring system. It should also
be used for those whose disease is more advanced where the 2G-TKI do not offer durable remissions.
973 Results of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Advanced Chronic
Myeloid Leukemia (CML) Patients (pts) Who Failed Tyrosine Kinase Inhibitors (TKIs) after Developing
BCR-ABL Kinase Domain (KD) Mutations
Saturday, December 6, 2008
Hall A (Moscone Center)
Poster Board I-78
Elias Jabbour1, Jorge Cortes1*, Leandro de Padua Silva2*, Marcos De Lima2*, Dan Jones3*, Susan O'Brien1*,
Gabriela Rondon2*, Uday Popat2*, Sergio Giralt2*, Hagop Kantarjian1* and Richard Champlin2*
1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Stem Cell Transplantation & Cell Therapy, The University of Texas MD Anderson Cancer Center,
Houston, TX
3Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
Background: HSCT is curative for many pts with CML, and may be effective after imatinib failure. Resistance to
TKI therapy is often associated with point mutations in the BCR-ABL KD. Aims: We assessed the efficacy of
HSCT in pts with CML post TKI therapy failure, and who had BCR-ABL KD sequencing. Patients and methods:
Forty-seven pts with CML (chronic phase [CP]=34, accelerated phase [AP]=9, blast phase [BP] =4) had KD
sequencing. Patient and treatment-related characteristics are described in the table. Graft-versus-host disease
(GVHD) prophylaxis consisted of tacrolimus and mini-methotrexate. Results: Nineteen pts (40%) harbored 20
different KD mutations; one pt harbored 2 different mutations. P-loop mutations were detected in 9 (45%) pts; the
most common mutations were E255K and T315I detected in 4 pts, each. Table 1 describes pts characteristics.
Forty-five pts (96%) engrafted within 12 days (range, 5-20). Both patients with primary graft failure received cord
blood transplantation. There was no significant early regimen-related toxicity. Acute (GVHD) was observed in 28
(62%) pts (Grade I in 13, Grade II/III in 12, Grade IV in 3). Chronic GVHD was observed in 21 (47%) pts
(extensive in 9). Chimerism studies at day 30 post HSCT were 100% of donor type in 27 (60%) and mixed in 18
(40%). Forty-one pts (91%) responded: 31 achieved a major molecular remission (complete in 30) and 11(24%)
achieved a complete cytogenetic response only. Three pts harboring E255K did not respond. After a median
follow-up of 22 months (range, 5-53) from HSCT, 31 (66%) pts were alive; 16 patients died, 10 of disease
progression, 3 of GVHD, two of uncontrollable infection, and one of unknown cause. Sixteen pts relapsed (8 of
them with mutations) after a median of 8 months (range, 1-44) from HSCT. The estimated 2-year survival was
63%. Table 2 summarizes outcome by phase at HSCT and mutation status. Conclusion: HSCT is an important
salvage option for pts with or without BCR-ABL KD mutations who develop resistance to TKI therapy. Outcomes
were primarily determined by disease stage, and pts with mutations were more likely to have advanced CML at
transplant, suggesting that they should be allografted once the mutation is identified after TKI failure. Table 1.
Patients characteristics
Total
N=47
Mutant BCR-ABL
N=19
Non Mutant BCR-ABL
N=28
Age (years ; range))
43 (19-64)
43 (19-63)
43 (22-64)
Median time from diagnosis to HSCT (mos, range)
54 (6-170)
75 (6-117)
43 (7-170)
Best Response to imatinib
CHR (%)
20 (43)
10 (53)
10 (36)
MCyR (%)
17 (36)
6 (32)
11 (39)
CCyR (%)
15 (32)
5 (26)
10 (36)
Failure to 2nd TKI (%)
29 (62)
16 (84)
13 (46)
Ablative regimen (%)
9 (19)
5 (26)
4 (14)
Match related ASCT (%)
23 (49)
11 (58)
12 (43)
Stage at ASCT
CP (%)
16 (34)
4 (21)
12 (43)
AP (%)
12 (26)
4 (21)
8 (28)
BP (%)
9 (19)
6 (32)
3 (11)
2nd CP (%)
10 (21)
5 (26)
5 (18)
Table 2. Outcomes
N (%)
Mutant BCR-ABL (N=19)
Non Mutant BCR-BL (N=28)
Stage @ ASCT
CP
4 (21)
Advanced phases*
15 (79)
CP
12 (43)
Advanced phases*
16 (57)
Best Response
MMR
4 (100)
7 (46)
9 (75)
11 (61)
CCyR
_
5 (33)
1 (8)
5 (30)
Relapse
1 (25)
4 (27)
1 (10)
7 (44)
Median (mos)
4
15 (3-45)
9
5 (3-20)
Alive in CR
2 (50)
5 (33)
8 (80)
8 (50)
Median (mos, range)
27+ (13+-40+)
19+ (9+-25+)
28+ (12+-53+)
21+ (6+-48+)
Death in CR
1 (25)
3 (20)
1 (10)
1 (6)
*Accelerated, blastic, and second chronic phases.
ASCT=allogeneic stem cell transplantation; MMR=major molecular response; CCyR=complete cytogenetic
response; CR=complete response
979 Long-Term Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Patients (pts)
with Advanced Chronic Myeloid Leukemia (CML) Post Imatinib Failure
Saturday, December 6, 2008
Hall A (Moscone Center)
Poster Board I-84
Elias Jabbour1, Marcos De Lima2*, Leandro de Padua Silva2, Sergio Giralt2*, Jorge Cortes1*, Muzaffar
Qazilbash2*, Gabriela Rondon2*, Stefan Ciurea2*, Roy Jones2*, Yago Nieto2*, Martin Korbling2*, Daniel
Couriel2*, Hagop Kantarjian1* and Richard Champlin2*
1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Stem Cell Transplantation & Cell Therapy, The University of Texas MD Anderson Cancer Center,
Houston, TX
Allogeneic HSCT is a potentially curative treatment for pts with CML, and is effective after imatinib failure. We
assessed the long-term results of HSCT in 92 consecutive pts with CML that had failed imatinib. Herein are the
results of this review. Preparative regimens were reduced-intensity intravenous (IV) busulfan (Bu)-fludarabine
(Flu) in 40 pts, IV Bu-cyclophosphamide in 39, Flu-melphalan in 6, and total body irradiation (TBI) based
regimens in 7. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and mini-methotrexate 5
mg/m2. Donors were matched related in 49 (53%) and matched unrelated in 43 (47%). Prior to HSCT, 43 (47%)
pts received imatinib therapy after interferon failure and 49 (53%) as frontline therapy. At the start of imatinib
therapy, 48 (52%) pts were in chronic phase (CP), 23 (25%) in accelerated phase (AP), and 21 (23%) in blastic
phase (BP). Median time on imatinib before HSCT was 15 months (range, 2-50). Best response to standard-dose
imatinib was complete cytogenetic response (CCyR) in 32 (35%), partial (PCyR) in 10 (11%), minor (mCyR) in 10
(11%), and complete hematologic response (CHR) in 25 (27%). Median age at HSCT was 43 years (range, 14-
69). At HSCT, 30 pts were in CP (33%), 27 in AP (29%), 17 in BP (18%), and 18 in second CP (20%). Pts were
followed for a median of 48 months (range 4-93) from HSCT. All but 2 pts engrafted within a median of 12 days
(range, 5-20). Acute GVHD was observed in 42 (46%) pts (Grade I in 15, Grade II/III in 19, Grade IV in 8). Chronic
GVHD was observed in 35 pts (extensive in 20). Chimerism studies at day 30 post HSCT were available in 81 pts
and were 100% of donor type in 61 (75%) and mixed in 20 (25%). Seventy-nine pts (86%) responded (100% for
pts in CP, 93% for pts in AP, 94% for pts in 2nd CP, 41% for pts in BP). Sixty-three pts achieved a major
molecular response (MMR), complete (CMR) in 60; 16 achieved a CCyR only. Of the 30 pts in CP that
responded, 2 (7%; both achieved a CMR) relapsed, 9 and 24 months post HSCT. Of the 25 pts in AP who
responded, 8 (32%: 6 CMR, 2 CCyR) relapsed after a median of 13 months (range, 2-51) post HSCT. Of the 17
pts in 2nd CP who responded, 6 (35%; 2 CMR, 4 CCyR) relapsed. Of the 7 pts in BP who responded, 4 (57%; 4
CMR) relapsed after a median of 16 months (range, 3-45) post HSCT. At the last follow-up, 49 (53%) pts were
alive and 43 (47%) died. Causes of death included progressive disease in 29, GVHD in 6, infections in 5, diffuse
alveolar hemorrhage in 2, and unknown cause in 1.One and 2-year survival rates were 65% and 54%. The
median survival for pts in BP, 2nd CP, and AP were, 4, 14, and 72 months, respectively. The median survival for
pts in CP has not been reached. The estimated 1- and 4-year survival by disease stage is as follows : BP, 24%
and 12%; 2nd CP, 67% and 49%; AP, 67% and 62%; CP 87% and 74%, respectively. In conclusion, HSCT
remains an effective salvage strategy post imatinib failure, and disease stage at HSCT remains the stronger
prognostic factor.
Response to allogeneic HSCT (MMR, major molecular response; CMR, complete molecular response; CCyR,
complete cytogenetic response)
CP
AP
2nd CP
BP
N
30
27
18
17
MMR (%)
83
70
67
41
CMR (%)
77
67
67
41
CCyR (%)
100
93
95
41
Relapse rate (%)
7
32
35
57
Median survival (mos)
NR
72
14
4
1- and 4-year survival (%)
87 & 74
67 &
2154 Novel Tyrosine Kinase Inhibitor Therapy Before Allogeneic Stem Cell Transplantation in Patients
with Chronic Myeloid Leukemia
Sunday, December 7, 2008
Hall A (Moscone Center)
Poster Board II-248
Leandro de Padua Silva1, Jorge Cortes1*, Elias Jabbour2, Sergio Giralt1*, Partow Kebriaei1*, Susan O'Brien2*,
Amin Alousi1*, Muzaffar Qazilbash1*, Gabriela Rondon1*, Farhad Ravandi1*, Rachel Ribeiro1*, Chitra Hosing1*,
Hagop Kantarjian2*, Richard Champlin1* and Marcos De Lima1*
1Department of Stem Cell Transplantation & Cell Therapy, The University of Texas MD Anderson Cancer Center,
Houston, TX
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Background: A significant proportion of patients undergoing allogeneic hematopoietic stem cell transplantation
(HSCT) for CML will have received a novel tyrosine kinase inhibitor (NTKI) after failing imatinib mesylate. It is
unclear, however, if these drug will influence HSCT outcomes by changing the toxicity profile of transplantation.
Aims: To describe outcomes of patients that received a NTKI prior to HSCT. Methods: We retrospectively
analyzed the outcome of 30 patients (pts) with CML [8 chronic phase (CP), 9 accelerated phase (AP), and 13 in
blastic phase (BP)] that were so treated. All pts failed imatinib, and then received a second TKI {dasatinib (n=14),
nilotinib (n=13), bosutinib (n=3)}, or a third TKI {dasatinib (n=2), nilotinib (n=1), or INNO-406 (n=1)} prior to
HSCT. Preparative regimens were intravenous busulfan-based in 24 pts and fludarabine and melphalan in 6.
Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and mini-methotrexate 5 mg/m2 on days 1,
3, 6, and 11 after HSCT. Donors were match related (MRD) in 12, match unrelated (MUD) in 14, haplo-identical in
1, 1-antigen mismatched related in 1, and unrelated cord blood in 2 cases. Results: Median age at HSCT was 42
years (range, 22-63). The median time on NTKI treatment was 27 weeks (range, 2-86), and the median time from
the end of NTKI therapy to HSCT was 10 weeks (range, 1-32). At the time of start of second TKI, 8 were in CP, 9
in AP, and 13 in BP. At the time of start of 3rd TKI, 2 were in AP, and 2 in BP. Twenty-one pts (70%) responded
to 2nd TKI; this included: 2 partial hematologic response (PHR; 1 AP, 1 BP), 5 complete hematologic response
(CHR; 2 CP, 3 BP), 5 minor cytogenetic response (minor cytogenetic response (mCyR): 1 CP, 2 AP, 2 BP), 2
partial cytogenetic response (PCyR; 1 CP, 1 AP), and 7 complete cytogenetic response (CCyR; 2 CP, 2 AP, 3
BP). Two pts responded to third TKI: 1 PHR and 1 CCyR. Eight of the responders (38%) maintained their
response till the HSCT. At the time of HSCT, 9 pts were in CP, 8 were in second CP, 6 were in AP, and 7 in BP.
Twenty-eight pts (93%) engrafted neutrophils within a median of 12 days (range, 5-20). Both pts with primary
graft failure received cord blood transplants: one was rescued with autologous stem cells and the second
received a haplo-identical transplant. Two pts had secondary graft failure 2 and 6 months from the first HSCT,
respectively, and were rescued with a related 1-antigen mismatched donor transplant and same MUD transplant,
respectively. Acute GVHD was observed in 19 pts (Grade I in 11, Grade II/III in 6, Grade IV in 2). Chronic GVHD
was observed in 10 pts (extensive in 5). Of the 28 evaluable pts for response, 5 achieved a complete cytogenetic
response (CCyR), 20 achieved a complete molecular response (CMR); 3 did not respond and had disease
progression by day 30 post HSCT. Eight (4 CCyR, 4 CMR) patients relapsed within a median of 4 months (range,
3-7) from HSCT. After a median follow-up of 20 months (range, 5-44), 17 patients were alive: 12 in CMR, 2 in
CCyR, and 3 with active disease; 13 patients died (2 and 8 within 3 and 12 mos post HSCT, respectively), 8 of
disease progression, 4 of GVHD, and one of uncontrollable infection. The estimated 2-year survival was 51%.
Conclusion: Previous treatment with NTKI did not increase early transplant-related morbidity/mortality in this
preliminary experience. These drugs may “downstage’ CML prior to HSCT, and this effect may be beneficial.
Further follow-up and larger number of patients will be necessary to expand these observations.
3264 Late Mortality and Relapse Following HLA-Identical Sibling Donor Marrow Transplantation for
Chronic Myeloid Leukemia
Monday, December 8, 2008
Hall A (Moscone Center)
Poster Board III-346
Edward Copelan1, Pamela Crilley, DO2*, Jeffrey Szer3, Anthony J. Dodds, FRACP, FRCPA4, Dustin E.
Stevenson, DO5*, Gary Phillips6*, Patrick Elder7*, Ian Nivison-Smith4*, Belinda Avalos8, Sam Penza6*, David
Topolsky2*, R. Sobecks1, Matt Kalaycio1 and Brian J. Bolwell, MD1
1Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
2Division of Hematology/Oncology, Drexel University College of Medicine, Philadelphia, PA
3Clinical Haematology & BMT Service, The Royal Melbourne Hospital, Parkville, Australia
4St. Vincent's Hospital Sydney Ltd., Sydney, NSW, Australia
5Hematology - Medical Oncology, Lackland Air Force Base, Lackland AFB, TX
6Hematology/Oncology, The Ohio State Univ., Columbus, OH
7Division of Hematology/Oncology, Ohio State University, Columbus, OH
8Medicine, Division of Hematology/Oncology, Heart and Lung Research Institute, The Ohio State University,
Columbus, OH
We studied the incidence and reasons for late failure following allogeneic transplantation for chronic myeloid
leukemia (CML). Three-hundred thirty-five adult patients (median age 37, 229 chronic, 62 accelerated, 44 blastic
phase) who underwent allogeneic marrow transplantation from HLA identical siblings at 7 institutions from 1984 –
1995 following preparation with busulfan and cyclophosphamide (BuCy2), the most commonly used regimen in
this circumstance. Cyclosporine or tacrolimus-based regimens were used to prevent graft-versus-host-disease
(GVHD). Median follow-up of surviving patients exceeded 14 years. Of 182 patients alive and free of leukemia at
3 years, 77.0% (95% CI: 65 to 83.6%) survive at 18 years and 61.9% (95% CI: 52.1 – 70.3%) survive without
relapse. Twenty-seven (42.2%) of the 64 total relapses occurred beyond 3 years. Death occurred less frequently
(P<.001) and the interval from relapse to death was longer (P=.01) in patients who relapsed late compared to
those who relapsed early. The hazard rate for relapse fell rapidly from year 1 through 5, then remained low but
constant through year 15. The cumulative incidence of late (beyond 3 years) relapse for patients alive and free
of disease at 3 years was 22.8%.. The cumulative incidence of non-relapse mortality was 18.1% for those alive
and leukemia-free at 3 years and in the 36 patients who died beyond 3 years, the primary cause of death was
chronic GVHD in 11, relapse in 7, new malignancy in 6, organ failure in 6 (pulmonary in 4) and infection in 2.
Multivariate analysis demonstrated that advanced disease stage (HR 2.75, P=.001) and older age (HR 1.39, P = .
032) were associated with diminished LFS of patients alive and free of disease at 3 years. Overall survival was
also adversely influenced by older age (HR 3.86, P < .001) and advanced stage (HR 1.54, P=.024). Advanced
disease phase was associated with a higher incidence of late relapse (HR ≥ 2.50, P=.039) and late NRM (HR
3.18, P=.008). Acute GVHD and short interval from diagnosis to transplant influenced early, but not late failure.
Chronic GVHD was associated with lower incidence of late relapse (HR=.30, P=.002) but did not significantly
influence survival or LFS. Overall, nearly 2 of every 5 patients alive and free of leukemia at 3 years died or
relapsed over the subsequent 15 years. No plateau in LFS was seen.
155 Influence of Myeloablative Conditioning Regimens on Outcomes after Single Unrelated Cord
Blood Transplantation for Adults with Leukemia : An Analysis on Behalf of Eurocord-EBMT-Netcord
Monday, December 8, 2008: 8:30 AM
Gateway Ballroom 104 - South (Moscone Center)
Samir Kanaan Nabhan, MD1*, Vanderson Rocha, MD1*, William Arcese, MD2, Anne Sirvent, MD3*, Irina Ionescu,
MD1*, Renata Bizzetto, MD1*, Karim Boudjedir, MD1*, Wagnara Chaves, MD1*, Andrée-Laure Herr, MD1*, Eliane
Gluckman, MD1 and Guillermo Sanz, MD, PhD4
1Eurocord, Paris, France
2Dept. of Hematology and Transplant, University of Rome 'Tor Vergata', Rome, Italy
3Hôpital de l'Archet 1, Nice, France
4Dept. of Hematology, Hospital Universitario La Fe, Valencia, Spain
Cyclophosphamide (CY) associated to high dose total body irradiation (TBI) or busulfan (BU) is the gold standard
of myeloablative conditioning regimen (MAC) in allogeneic hematopoietic stem cell transplantation (HSCT). In
unrelated transplants, anti-T cell serotherapy (ATG/ALG) is often added as immunosuppressive drug. Recently,
new drugs such as fludarabine (FLU) or thiotepa (TT) have also shown their value in conditioning regimen.
However, no MAC has shown to be significantly superior to the conventional TBICY or BUCY. Unrelated cord
blood transplantation (UCBT) has been increasingly used in adult patients lacking a HLA-matched donor, but the
impact of MAC in this setting is unknown.
In order to do so, we analyzed 226 patients who underwent single UCBT after MAC for leukemia [acute
lymphoblastic leukemia (n=80), acute myeloid leukemia (n=86), myelodysplasia (n=33), chronic myeloid leukemia
(n=27)]. According to IBMTR classification, 60% of patients had early- or intermediate-risk disease status at
transplantation. All patients were transplanted from January 2000 to February 2008 in Europe. Median age was
33 years (18-60) and median follow-up was 21 months (2-96). UCB grafts had ≥ 2 HLA incompatibilities in 62% of
cases; median nucleated cell dose infused was 2.5 x 107/kg. Ninety-three percent of patients received ATG/ALG
before day 0. Three groups of MAC were observed: group 1- TBICY or BUCY (n=82; 36%), group 2- CY+TT
(mostly associated to BU) (n=73; 32%) and group 3- FLU based regimens (mostly associated to intravenous BU
9.6 mg/kg and TT 10 mg/kg) (n=71; 31%). Graft-versus-host disease (GVHD) prophylaxis consisted of
cyclosporine and corticosteroids in 77% of patients.
Patients-, disease- and transplant-related factors were compared among the 3 conditioning groups. All 3 groups
showed the same frequency of diagnosis and status of the disease at transplantation. Group 1 (TBICY or BUCY)
, included a higher number of patients with negative CMV serology, transplanted before 2004, ≥ 2 HLA disparity
and higher number of infused cells compared to group 2 and/or group 3. There was no statistical difference of
those characteristics between group 2 and 3. Cumulative incidence of 60 day-neutrophil recovery (>500/mm3),
180 day-platelet recovery (>20000/mm3), 100 day-acute GVHD, 100 day non-relapse mortality (NRM) and
relapse at 2 years were 80±3%, 52±3%, 24±3%, 28±3% and 24±4%, respectively. Two-year disease-free
survival (DFS) was 37%±5 for patients transplanted in remission and 22±5% for those in more advanced phase
(p=0.001). The association of groups of MAC and outcomes are shown in the table below. In a center effect
adjusted multivariate analysis, among other variables such as CMV recipient serology, disease status and HLA
disparity, groups 2 and 3 confirmed an increased incidence of neutrophil recovery [hazard ratio (HR)=0.44 (95%
CI 0.32-0.60)] and platelets recovery [HR=0.52 (95% CI 0.34-0.79)]. However, none of the conditioning regimens
were associated with acute GVHD, 100-day NRM or DFS.
Conclusion: these findings support the use of fludarabine and/or thiotepa based MAC as a strategy to improve
neutrophil/platelet recovery after single UCBT in patients with leukemia. Further prospective randomized trials
should be performed to address this issue.
Conditioning regimens
Neutrophil recovery (day+60)
Platelets recovery
(day+180)
aGVHD
(II-IV)
(day +100)
NRM
(day +100)
DFS
(2 years)
Group 1 - TBICY or BUCY (n=82)
71±5%
39±5%
17±4%
28±5%
28±6
Group 2 - CY+TT (± BU or TBI) (n=73)
78±5%
53±6%
37±6%
38±6%
29±5
Group 3 - FLU (+ BU + TT) (n=71)
92±4%
66±6%
18±5%
17±4%
35±7
P (overall)
<0.001
0.003
0.001
0.021
0.400
448 Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in the Imatinib-Era: High Survival Rate
Following Allogeneic HSCT after Imatinib Failure: Results of the German CML Study IV
Monday, December 8, 2008: 2:15 PM
2009-2011-2022-2024 - West (Moscone Center)
Susanne Saussele, MD1*, Michael Lauseker2*, Alois Gratwohl, MD3, Dominik Heim, MD3*, Dietrich Wilhelm
Beelen, MD4*, Hartmut Döhner, MD5, Rainer Schwerdtfeger, MD6, Anthony D. Ho, MD7*, Hans-Jochem Kolb,
MD8*, Markus Pfirrmann, PhD2*, Martin C. Müller, MD1*, Armin Leitner, MD1*, Ulrike Proetel, MD1*, Elena
Kovalevskaya, MD1*, Claudia Haferlach, MD9*, Brigitte Schlegelberger, MD10, Joerg Hasford, MD2*, Andreas
Hochhaus, MD1 and Ruediger Hehlmann, MD1
1Medical Faculty Mannheim, University Heidelberg, Mannheim, Germany
2IBE University, München, Germany
3University Hospital, Basel, Switzerland
4BMT Unit, University, Essen, Germany
5University, Ulm, Germany
6German Diagnostic Clinic, Wiesbaden, Germany
7Medical Faculty, University, Heidelberg, Germany
8Department of Medicine, University, München
9MLL Leukemia Laboratory, München, Germany
10Inst. of Cell & Molecular Pathology, MHH, Hannover, Germany
Allogeneic HSCT remains an important option for patients with chronic myeloid leukemia (CML) who failed
imatinib. Focus has been on second line tyrosine kinase inhibitors (TKI). Little is known on the outcome of HSCT
for such patients. In July 2002, the German CML-Study Group activated a prospective randomized trial
comparing different imatinib based strategies in chronic phase CML (CP). Elective early HSCT was considered
for patients (pts) with EBMT score 0–1 for those with high disease risk, and after imatinib failure. By the end of
July 2008, 1197 pts were randomized. In 80 (6,5 %) pts HSCT was documented. 52 pts were male (65%), 23 were
high risk pts (28%) according to the Euro score. Median age at diagnosis was 37 years (yrs) (range 16-62),
median time to HSCT was 12.6 months (mo, range 3.5-54 mo). EBMT score was 0-1 in 8 (10%), 2 in 10 (12%), 3-
4 in 44 (55%) and 5 in 18 pts (23%). Median follow-up after HSCT was 19 mo (range 0-59). Cumulative
response rates prior to HSCT were 68% for complete hematologic response, 23% for complete cytogenetic
responses, and 9% for major molecular responses. Based on the indication for HSCT three groups were defined:
i) early HSCT (n= 19, 23%; low EBMT score (n=9), high risk pts (n=7), patient request (n=3); ii) HSCT after
imatinib failure or intolerance in first CP (n=34, 43%) and iii) HSCT in second CP or higher, accelerated phase or
blast crisis (n=27, 34%). 14 pts died, 10 deaths were transplantation related, 4 CML related. Two pts with a
molecular relapse were successfully treated with donor lymphocyte infusion in combination with TKI. Overall
survival rate at two yrs for group one was 87.8%, for group two 93.8%, and for group three 49.5%. By EBMT
score, survival rates were 100% for risk score 0-2, 82.2% for risk score 3-4, and 43.5% for risk score 5. Data
from this prospective controlled cohort study clearly show that HSCT remains an attractive and important rescue
therapy for CML patients with imatinib failure or intolerance, particularly for those with a low EBMT risk score.
HSCT in 1st CP
HSCT in advanced phases
early HSCT
HSCT for failure and intolerance in 1st CP
Total
n
19
34
53
27
Euro score
high
6
8
14
9
intermediate
3
12
15
7
low
10
14
24
11
% male
63
56
60
78
Median age (range)
35 (16-56)
38 (21-56)
37(16-56)
37 (18-62)
Median time to HSCT (Range) (months)
8.5 (4.8-23.6)
17,5 (5.0 – 53.7)
12.6 (4.8 – 53.7)
12.0 (3.5-54.1)
EBMT score
0-1
5
3
8
0
2
5
4
9
1
3-4
9
26
35
9
>=5
0
1
1
17
Best response
CHR
11/18
28/34
39/52
14/26
CCyR
3/17
10/33
13/50
4/22
MMR
2/17
3/31
5/48
2/19
Response at HSCT
BC
0
0
0
24
AP
0
0
0
3
CP
19
34
53
0
HR
11
19
30
0
Ccyr
2
2
4
0
MMR
0
0
0
0
Transplant source
Sibling
10
10
20
9
Unrelated
9
24
33
18
Conditioning therapy
standard
14
21
35
17
reduced
3
6
9
4
other
2
7
9
6
Source
PB
13
26
39
22
BM
6
8
14
5
Dead
2
2
4
10
TRM
2
2
4
6
CML
0
0
0
4
Probability of survival at 2 years after HSCT
87.8%
93.8%
91.4%
49.5%