scispace - formally typeset

Journal ArticleDOI

The role of hematopoietic stem cell transplantation in chronic myeloid leukemia

27 Mar 2015-Annals of Hematology (Springer Berlin Heidelberg)-Vol. 94, Iss: 2, pp 177-186

TL;DR: A more balanced appraisal of HSCT for individual patients should include disease risk, transplant risk, and macroeconomic aspects and should be integrated into the treatment algorithms from diagnosis and be considered very early at first TKI failure for patients with high disease but low transplant risk.
Abstract: Allogeneic hematopoietic stem cell transplantation (HSCT) is currently recommended as 2nd or 3rd line therapy for patients with chronic myeloid leukemia (CML) in first chronic phase or as salvage for patients with very advanced disease. As a consequence, numbers of HSCT in chronic phase have dropped significantly since the introduction of tyrosine kinase inhibitors (TKI), numbers of transplants in advanced disease to a lesser extent. These current recommendations consider primarily disease risk, defined as failure of TKI therapy; they might need to be adapted. We propose a more balanced appraisal of HSCT for individual patients which should include disease risk, transplant risk, and macroeconomic aspects. HSCT should be integrated into the treatment algorithms from diagnosis and be considered very early at first TKI failure for patients with high disease but low transplant risk. For patients with very advanced disease and high transplant risk in contrast, HSCT might only be recommended in a restricted research setting.
Topics: Hematopoietic stem cell transplantation (58%), Transplantation (54%), Myeloid leukemia (51%), Leukemia (51%)

Content maybe subject to copyright    Report

REVIEW ARTICLE
The role of hematopoietic stem cell transplantation in chronic
myeloid leukemia
Alois Gratwohl & Helen Baldomero & Jakob Passweg
Received: 15 July 2014 / Accepted: 7 December 2014
#
Springer-Verlag Berlin Heidelberg 2015
Abstract Allogeneic hematopoietic stem cell transplantation
(HSCT) is currently recommended as 2nd or 3rd line therapy
for patients with chronic myeloid leukemia (CML) in first
chronic phase or as salvage for patients with very advanced
disease. As a consequen ce, numbers of HSCT in chronic
phase have dropped significantly since the introduction of
tyrosine kinase inhibitors (TKI), numbers of transplants in
advanced disease to a lesser extent. These current recommen-
dations consider primarily disease risk, defined as failure of
TKI therapy; they might need to be adapted. We propose a
more balanced appraisal of HSCT for individual patients
which should include disease risk, transplant risk, and macro-
economic aspects. HSCT should be integrated into the treat-
ment algorithms from diagnosis and be considered very early
at first TKI failure for patients with high disease but low trans-
plant risk. For patients with very advanced disease and high
transplant risk in contrast, HSCT might only be recommended
in a restricted research setting.
Keywords Chronic myeloid leukemia
.
Hematopoietic stem
cell transplantation
.
Allogeneic
.
Autologous
.
Risk
assessment
Introduction
Chronic myeloid leukemia (CML) has seen unprecedented
changes over the last decade. The introduction of tyrosine
kinase inhibitors (TKI) has changed the outlook for patients
with this previously uniformly fatal disease. The ease of ap-
plication, the rapid response, and the mostly excellent tolera-
bility by the patients has focused interest on targeted drug
therapy [17]. Hematopoietic stem cell transplantation
(HSCT) has lost its former importance as the only curative
therapy [812]. This is reflected by the numbers of publica-
tions in medical journals or by the numbers of presentation on
the topic at scientific or promotional meetings. If any, it is
considered by many as tool of last resort when everything else
has failed. This phenomenon is not restricted to CML. Ease of
application and improved response to modern drug therapy
has almost halted HSCT for multiple myeloma and limited
HSCT to selected patients [13, 14]. Still, HSCT is the most
powerful intervention; it holds the potential for cure and
outcome has dramatically improved over the last years [15,
16]. It might be good to look at the past and to reconsider the
current status and the potential role of HSCT in the treatment
algorithm of CML today.
Evolution of HSCT for CML
Historical perspective: the role model of CML for HSCT
The first report of a successful HSCT from a syngeneic donor
to a patient with CML dramatically changed the concept on
how to look at CML. For the first time, it became possible to
achieve a Ph state, to eradicate the malignant BCR/ABL
clone, and to reverse the previously inexorable course of the
disease [17]. The concept was rapidly taken up and extended
to HSCT from an HLA-identical sibling donor. It did coincide
with the introduction of cyclosporine A as novel and most
powerful tool for the prevention of graft-versus-host disease
(GvHD) and the concept of HSCT in first complete remission
of acute leukemia; hence, it was introduced in patients with
CML early in their disease, in first chronic phase [810, 18].
A. Gratwohl (*)
:
H. Baldomero
:
J. Passweg
Hematology, University Hospital, Dittingerstrasse 4,
4053 Basel, Switzerland
e-mail: alois.gratwohl@unibas.ch
Ann Hematol (2015) 94(Suppl 2):S177S186
DOI 10.1007/s00277-015-2313-3

The first allogeneic HSCT for CML was reported to the Eu-
ropean Group for Blood and Marrow Transplantation
(EBMT) database in 1975 from France, soon to be followed
in 1978 by a patient from Switzerland and by 10 patients in
1979 from France, Italy, and the UK (personal communica-
tion; EBMT database, Leiden NL). The concept proved to be
right and CML became soon the most frequent indication for
an allogeneic HSCT in Europe and worldwide (Fig. 1)[11,
19]. Of note, as of June 2014, 3 of these 12 patients were
reported to be alive at plus 35 years, one as lost to follow-up.
CML played a role model for HSCT in general in
many aspects. CML did provide the first example for
risk assessment with the EBMT risk score (see below)
[ 20 22]. It became clear that disease stage was more
important than bulk of the disease. Splenectomy, consid-
ered initially as essential showed no advantage, nor did
splenic irradiation [23]. CM L was the first disease to
demonstrate a consistent graft-versus-leukemia effect.
Relapse risk was highest after T cell depletion in CML
compared to other diseases, in contrast, donor lympho-
cyte infusion (DLI) proved to be the most powerful tool
in CML. CML paved the way for reduced intensity con-
ditioning, specifically with the additional role of preemp-
tive DLI [2426]. Last but not least, in no other disease
became the impact of macroeconomic factors on use of
HSCT as clear as in CML. Rates of HSCT for CML
dropped already in the year 2000, 2 years before the
release of imatinib in high income countries, illustrating
how expectations drive m edical decision making. They
remained at a stable level in middle and low income
countries whe re costs of drug therapy became higher
than costs for a transplant [11, 19, 2730].
CML showed a s well a r ole model for autologous
HSCT. It was introduced in Europe early on, almost si-
multaneously with allogeneic HSCT. The first patient
was reported to the EBMT database in 1979 from
France, to be followed by 4 patients in 1980, from
France as well. None of them stayed alive. The concept
was clear, restore chronic phase in patients with ad-
vanced disease throu gh stem cel ls obtai ned in early
phase. Pilot studies proved to be promising and led to
the design of several multicenter prospective randomized
trials in Europe [31, 32]. None was completed; the intro-
duction of the TKI ended these trials prematurely and the
answer about the potential role of autologous HSCT re-
mains open. At least, a retrospective meta-analysis of six
multicentre trials in Europe and the US showed no ad-
vantage of such a procedure compared to concurrent
drug treatment [33]. Numbers of autologous HSCT al-
most vanished away since 2006 [11](Fig.1).
Current status in 2014
Data from the EBMT activity survey report a total of 377
allogeneic HSCT for CML in 2012, 167 in early phase of
the disease, 210 in advanced phase from 35 countries, and 8
autologous HSCT, 5 in early disease, 3 in advanced phase.
Their distribution over disease stage, donor type, and stem cell
source is illustrated in Table 1. Compared to previous years,
total numbers remained stable.
Allogeneic HSCT were performed in 35 countries. There
were significant differences in transplant rates (numbers of
HSCT per 10 million inhabitants) between reporting countries
(Fig. 2). They ranged from none to more than 10 in Belgium,
Estonia, Finland, Sweden, and Switzerland.
0
200
400
600
800
1000
1200
90 92 94 96 98 00 02 04 06 08 10 12
H
S
C
T
Year
CML early allo
CML advanced allo
0
50
100
150
200
250
H
S
C
T
Year
CML early auto
CML advanced auto
a
b
90 92 94 96 98 00 02 04 06 08 10 12
Fig. 1 Evolution of HSCT in Europe from 1990 to 2012. The graph
illustrates i ncrease and decrease of absolute numbers of allogeneic
(Fig. 1a) and autologous (Fig. 1b) HSCT in Europe over time. In blue
early disease (first chronic phase), in green advanced disease stage at time
of HSCT (accelerated phase or blast crisis). a Evolution of allogeneic
HSCT. b Evolution of autologous HSCT
S178 Ann Hematol (2015) 94(Suppl 2):S177S186

Outcome of HSCT for CML
Factors associated with outcome
HSCT has been and still is associated with significant early
and late transplant-related mortality. In the early days, mortal-
ity appeared erratic, with some young patients dying, others
surviving. In the mid-eighties of last century, it became appar-
ent that outcome was related to specific pretransplant criteria,
independent of transplant technology. This was especially im-
portant for patients with CML who faced the difficult decision
to make, an early transplant with the significant risk for
immediate mortality versus t he risk of blastic transforma-
tion with minimal chances for rescue with HSCT. The
EBMT risk score, based on five pretransplant factors
didpermitarapidassessmentonascalefrom0VII at
the physicians desk and gained rapid acceptance
(Table 2). The risk score was validated in several inde-
pendent cohorts and proved to be valid, with some minor
modifications, for all acquired hematological disorders
and for autologous HSCT as well [ 2022].
The difficulty in risk assessment lies in the fact that
some factors such as disease stage have congruent im-
pact on the two key endpoints, transplant-related mor-
tality and relapse, hence affect overall survival uniform-
ly in the same direction; others have discordant effects.
Thenetresultmightthendependonthesumofall
other risk factors. T cell depletion reduces the risk of
graft-versus- host disease bu t i ncreases the risk of re-
lapse. The net benefit on overall survival will differ
between patients transplanted in early disease compared
to those transplanted in advanced disease stage. Re-
duced intensity might be of benefit in an older patient
with comorbidities but early disease; it might be of no
benefit in the same patient with no comorbidities but
advanced disease (Table 3)[2022].
As a general concept, risk factors act additively but not in a
symmetrical way. A negative CMV serostatus might further
improve outlook for a low-risk patient but will have no addi-
tional beneficial effect in a high-risk patient; in contrast, a
reduced Karnofsky score might be of minimal impact in a
low-risk patient but deleterious in a high-risk patient. Hence,
the general statement that the probability of survival after an
allogeneic HSCT for CML at 5 years is 60 % is of limited
value; it might range from more than 90 % to less than 5 %. As
we will see below, integration of all elements, including mac-
roeconomic factors of patients location, should impact on
choice of transplant technique and the final decision to pro-
ceed with HSCT or to abstain from it [3439].
Impact of pretransplant treatment
Most patients will have pretreatment for their CML be-
fore HSCT. Earlier studies indicated a higher transplant-
related mortality in patients pretreated with busulfan
compared to hydroxyurea and in patients given interfer-
on alpha up to the day of the transplant. Today, all
patients will have had TKI before their transplant. There
are clear indications that no type of TKI given before or
after the transplant has a deleterious effect on outcome
after HSCT; in one study, results appeared even better
for patients with TKI prior to HSCT. In contrast, type
of response to TKI therapy will impact on post trans-
plant outcome with a good outcome for patients intol-
erant to TKI but with a higher likelihood of worse out-
come for those who failed T KI therapy before HSCT
[34, 4045].
Impact of HSCT methodology
Despite now 30 years of experience, the best condition-
ing regime n an d the be st gr a ft - ver s us - hos t di s eas e pr e-
vention method remains to be defined. No other condi-
tioning has been documented to arrive at better long term
overall survival than cyclophosphamide and total body
irradiation or the combination of busulfan and cyclo-
phosphamide, no other graft-versus-host disease preven-
tionmethodthanthecombination of cyclosporine and
short methotrexate [ 8]. Reduced intensity conditioning
has extended application of HSCT to elderly patients or
to those with comorbidities [26]. In a large observational
retrospective study by the CIBMTR, it showed a better
overall survival in elderly patients compared to non-
myeloablative cond itioning; no compa rison was made
Table 1 HSCT for CML in Europe 2013 (preliminary data)
Allogeneic HSCT Autologous HSCT Total
Donor type Stem cell source Total Total
Syngeneic Family Unrelated BM PB CB
cP 0 60 80 34 102 4 140 0 140
Not cP 0 78 117 32 157 6 195 3 198
Total 0 138 197 66 259 10 335 3 338
Ann Hematol (2015) 94(Suppl 2):S177S186 S179

with standard conditioning [42]. Bone marrow as stem
cell source appears to be of advantage in early low-risk
disease, peripheral blood in advanced disease [46, 47].
Of general importance to note, there are no indications
that impact of transplant technology in CML differs from
that in any other disease treated with HSCT [8, 15, 48].
Fig. 2 Transplant rates in Europe 1999 and 2012. The figure depicts
number of HSCT per 10 million inhabitants and illustrates the decrease
in transplant rates for CML over time, in contrast to the transplant rates for
all indications in general. It depicts as well the vast heterogeneity between
countries. a Transplant rates for CML in 1999. b Transplant rates for
CML in 2012. a Transplant rates for all allogeneic indications in 1999.
a Transplant rates for all allogeneic indications in 2012
S180 Ann Hematol (2015) 94(Suppl 2):S177S186

Graft-versus-hostgraft-versus-leukemia effects
There is no doubt about the astonishing graft-versus-
leukemia effects observed in CML as documented by
the powerful effects of DLI [25, 43]. Complete and
lasting molecular remissions can be obtained with even
one infusion of cells, some without any signs of graft-
versus-host disease. Many attempts have been made to
exploit this effect better; so far, no study has proven to
separate graft-versus-host from graft-versus-leukemia
Fig. 2 (continued)
Ann Hematol (2015) 94(Suppl 2):S177S186 S181

Citations
More filters

Journal ArticleDOI
TL;DR: Current treatment options are combined in a concluding strategy for the management of BC, and the best prognosis is observed in patients that achieve a 2nd CP.
Abstract: Tyrosine kinase inhibitors (TKI) have moderately improved survival in BC, but a median survival of less than 1 year is still unsatisfactory. This article reviews the various tests required for diagnosis of BC, features at diagnosis, treatment modalities (intensive chemotherapy, TKI, allo-SCT and a selection of investigational agents), options of prevention and predictors of progression. The best prognosis is observed in patients that achieve a 2nd CP. Allo-SCT probably further improves prognosis of patients in 2nd CP. The choice of TKI should be directed by the mutation profile of the patient. BC can be prevented. A careful analysis of risk factors for progression may help. Current treatment options are combined in a concluding strategy for the management of BC.

43 citations


Cites background from "The role of hematopoietic stem cell..."

  • ...As a consequence of these findings, more CML patients are now transplanted in second chronic or advanced phases than in first CP [67]....

    [...]


Journal ArticleDOI
Jakob Passweg1, Helen Baldomero2, Peter Bader3, Chiara Bonini4  +12 moreInstitutions (9)
TL;DR: Drug development data show different effects on HSCT use; highly effective drugs may replace HSCT, whereas other drugs may improve the patient’s condition to allow for HSCT.
Abstract: Hematopoietic stem cell transplantation (HSCT) is used with increasing frequency in Europe with 40 000 transplants reported in 2014. Transplant-related mortality remains high in allogeneic HSCT (10–20%); high-dose chemotherapy is toxic and demanding for patients. Drug development is accelerating and with limited toxicity of some targeted drugs may replace HSCT, whereas others may function as a ‘bridge to transplant’. We analyzed HSCT reported to the activity survey for selected diseases in which major advances in drug development have been made. Tyrosine kinase inhibitors markedly changed the number of allogeneic HSCT in early CML. In myelodysplastic syndromes, hypomethylating agents show no effect on HSCT activity and Janus kinase inhibitors for myeloproliferative neoplasm appear to have only a temporary effect. For CLL autologous HSCT decreased after publication of trials showing improved PFS but no overall survival advantage and allogeneic rates are dropping after the introduction of Bruton kinase and PI3K Inhibitors. Whether these are ‘game changers’ as was imatinib for CML requires additional follow-up. For myeloma, proteasome inhibitors and new immunomodulatory drugs do not appear to impact transplant rates. Drug development data show different effects on HSCT use; highly effective drugs may replace HSCT, whereas other drugs may improve the patient’s condition to allow for HSCT.

37 citations


Journal ArticleDOI
Yuhui Wang1, Nan Wu1, Duo Liu1, Yan Jin1Institutions (1)
01 Oct 2017-Current Genomics
TL;DR: The history of fusion genes, mechanisms of formation, and treatments against specific fusion genes in leukemia are reviewed to benefit patients with leukemia by providing more diagnostic markers and therapies in the future.
Abstract: Introduction Since the first fusion gene was discovered decades ago, a considerable number of fusion genes have been detected in leukemia. The majority of them are generated through chromosomal rearrangement or abnormal transcription. With the development of techniques, high-throughput sequencing method makes it possible to detect fusion genes systematically in multiple human cancers. Owing to their biological significance and tumor-specific expression, some of the fusion genes are attractive diagnostic tools and therapeutic targets. Tyrosine kinase inhibitors (TKI) targeting BCR-ABL1 fusions have been widely used to treat CML. The combination of ATRA and ATO targeting PML-RARA fusions has proven to be effective in acute promyelocytic leukemia (APL). Moreover, therapy with high dose cytarabine (HDAC) has significantly improved the prognosis of core binding factor (CBF) acute myeloid leukemia (AML) patients. Therefore, studies on fusion genes may benefit patients with leukemia by providing more diagnostic markers and therapies in the future. Conclusion The presented review focuses on the history of fusion genes, mechanisms of formation, and treatments against specific fusion genes in leukemia.

21 citations


Cites background from "The role of hematopoietic stem cell..."

  • ...Since the advent of TKIs, HSCT is now recommended as second line or even third line therapy for CML patients, restricted to those who have failed multiple TKIs, or whom with very advanced disease [36, 37]....

    [...]


Journal ArticleDOI
TL;DR: Cancer risk relative to the general population was elevated for those transplanted for lymphoma, some leukemia subtypes, and severe aplastic anemia, recipients who developed chronic graft-versus-host disease (cGVHD) and irrespective of radiation-based conditioning or stem cell source.
Abstract: We quantified the risk of second cancer and late mortality in a population-based Australian cohort of 3273 adult (≥15 years) allogeneic hematopoietic stem cell transplant recipients (1992 to 2007). Most recipients received nonradiation-based conditioning and a peripheral blood graft from a matched related donor. Using record linkage with death and cancer registries, 79 second cancers were identified a median of 3.5 years after transplantation. The competing-risk adjusted cumulative incidence of second cancers was 3.35% (95% CI, 2.59 to 4.24) at 10 years, and the cancer risk relative to the matched general population was 2.10 (95% CI, 1.65 to 2.56). We observed an excess risk of melanoma and lip, tongue, esophagus, and soft tissue cancers. Cancer risk relative to the general population was elevated for those transplanted for lymphoma, some leukemia subtypes, and severe aplastic anemia, recipients who developed chronic graft-versus-host disease (cGVHD) and irrespective of radiation-based conditioning or stem cell source. In those alive 2 years after transplantation (n = 1463), the cumulative incidence of late mortality was 22.2% (95% CI, 19.7 to 24.9) at 10 years, and the risk of death relative to the matched general population was 13.8 (95% CI, 12.2 to 15.6). In multivariable modeling, risk of late death was reduced for females compared with males and those transplanted for chronic myeloid leukemia compared with acute myeloid leukemia; risk was increased for recipients with discordant sex donors, cGVHD, those undergoing second transplants, and disease relapse. Adults undergoing allogeneic transplantation have unique cancer and mortality risk profiles that continue to warrant prevention and surveillance activities targeted at high-risk subgroups.

18 citations


Cites background from "The role of hematopoietic stem cell..."

  • ...Significant efforts are underway to optimize allograft regimens, identify the determinants and mechanisms of relapse, and develop risk-adapted protocols before and after transplantation [34-37]....

    [...]


Journal ArticleDOI
TL;DR: The number of chronic myeloid leukemia (CML) patients in Germany is expected to increase further until at least 2040–2050 with a maximum of more than 20,000 CML patients as the most probable scenario.
Abstract: Purpose Due to prolonged survival, there will be many more chronic myeloid leukemia (CML) patients alive in the future. The aims of this work were to estimate the current prevalence of CML by using routine data and to project future patient numbers in Germany.

9 citations


Cites background from "The role of hematopoietic stem cell..."

  • ...Since introducing tyrosine kinase inhibitors (TKIs) into the treatment for chronic myeloid leukemia (CML) at the beginning of the twenty-first century, patients’ survival rates have increased remarkably (Bjorkholm 2008; Hehlmann 2015; Kantarjian et al. 2012)....

    [...]

  • ...At present, just about 1.5 % of the patients with CML die per year when treated with TKIs, leading thus to a rise in the prevalence of CML. Additionally, due to the aging of society, an increase in the raw incidence of CML is expected, since the age-specific incidence of CML is highest in the elderly (Hoffmann et al. 2015; Hoglund et al. 2013)....

    [...]

  • ...Admittedly, generics will be introduced in the market but, simultaneously, second-generation TKIs that are considerably more expensive than imatinib have gained additional market shares....

    [...]

  • ...Since the popularity of SCTs has been decreasing rapidly with the advent of TKIs (Gratwohl et al. 2015), playing only a minor role today, we considered it appropriate to leave this aside....

    [...]


References
More filters

Journal ArticleDOI
TL;DR: Imatinib was superior to interferon alfa plus low-dose cytarabine as first-line therapy in newly diagnosed chronic-phase CML and was better tolerated than combination therapy.
Abstract: Background Imatinib, a selective inhibitor of the BCR-ABL tyrosine kinase, produces high response rates in patients with chronic-phase chronic myeloid leukemia (CML) who have had no response to interferon alfa. We compared the efficacy of imatinib with that of interferon alfa combined with low-dose cytarabine in newly diagnosed chronic-phase CML. Methods We randomly assigned 1106 patients to receive imatinib (553 patients) or interferon alfa plus low-dose cytarabine (553 patients). Crossover to the alternative group was allowed if stringent criteria defining treatment failure or intolerance were met. Patients were evaluated for hematologic and cytogenetic responses, toxic effects, and rates of progression. Results After a median follow-up of 19 months, the estimated rate of a major cytogenetic response (0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome) at 18 months was 87.1 percent (95 percent confidence interval, 84.1 to 90.0) in the imatinib group and 34.7 percent (95 perce...

3,256 citations


Journal ArticleDOI
Edward A. Copelan1Institutions (1)
Abstract: Hematopoietic stem-cell transplantation, which is used to treat both malignant and nonmalignant conditions, was first conceived more than 50 years ago, but problems associated with transplanting a nonsolid organ and modulating the immune response had to be solved before the procedure could be used clinically. This review summarizes background information about hematopoietic stem-cell transplantation and discusses the current role of the procedure.

1,929 citations


"The role of hematopoietic stem cell..." refers background or result in this paper

  • ...The net detrimental effects of graftversus-host reactions still outweigh the benefits [8]....

    [...]

  • ...No other conditioning has been documented to arrive at better long term overall survival than cyclophosphamide and total body irradiation or the combination of busulfan and cyclophosphamide, no other graft-versus-host disease prevention method than the combination of cyclosporine and short methotrexate [8]....

    [...]

  • ...Of general importance to note, there are no indications that impact of transplant technology in CML differs from that in any other disease treated with HSCT [8, 15, 48]....

    [...]


Journal ArticleDOI
08 Aug 2013-Blood
TL;DR: Optimal responders to chronic myeloid leukemia treatment should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved.
Abstract: Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors, mandate regular updating of concepts and management. A European LeukemiaNet expert panel reviewed prior and new studies to update recommendations made in 2009. We recommend as initial treatment imatinib, nilotinib, or dasatinib. Response is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels ≤10% at 3 months, 10% at 6 months and >1% from 12 months onward define failure, mandating a change in treatment. Similarly, partial cytogenetic response (PCyR) at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no CyR (Philadelphia chromosome–positive [Ph+] >95%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months onward define failure. Between optimal and failure, there is an intermediate warning zone requiring more frequent monitoring. Similar definitions are provided for response to second-line therapy. Specific recommendations are made for patients in the accelerated and blastic phases, and for allogeneic stem cell transplantation. Optimal responders should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved.

1,522 citations


Journal ArticleDOI
15 Dec 1990-Blood
TL;DR: Three patients with hematologic relapse after bone marrow transplantation for chronic myelogenous leukemia were treated with interferon alpha and transfusion of viable donor buffy coat and had complete hematological and cytogenetic remission, which persisted 32 to 91 weeks after treatment, an example of adoptive immunotherapy without cytoreductive chemotherapy or radiotherapy in human chimeras.
Abstract: Three patients with hematologic relapse after bone marrow transplantation for chronic myelogenous leukemia were treated with interferon alpha and transfusion of viable donor buffy coat. All had complete hematologic and cytogenetic remission, which persisted 32 to 91 weeks after treatment. In two patients graft-versus-host disease developed and was treated by immunosuppression. These results are an example of adoptive immunotherapy without cytoreductive chemotherapy or radiotherapy in human chimeras.

1,384 citations


Journal ArticleDOI
Ted Gooley1, Jason W. Chien1, Jason W. Chien2, Steven A. Pergam1  +19 moreInstitutions (2)
TL;DR: A substantial reduction in the hazard of death related to allogeneic hematopoietic-cell transplantation, as well as increased long-term survival, over the past decade is found.
Abstract: BACKGROUND Over the past decade, advances have been made in the care of patients undergoing transplantation. We conducted a study to determine whether these advances have improved the outcomes of transplantation. METHODS We analyzed overall mortality, mortality not preceded by relapse, recurrent malignant conditions, and the frequency and severity of major complications of transplantation, including graft-versus-host disease (GVHD) and hepatic, renal, pulmonary, and infectious complications, among 1418 patients who received their first allogeneic transplants at our center in Seattle in the period from 1993 through 1997 and among 1148 patients who received their first allogeneic transplants in the period from 2003 through 2007. Components of the Pretransplant Assessment of Mortality (PAM) score were used in regression models to adjust for the severity of illness at the time of transplantation. RESULTS In the 2003-2007 period, as compared with the 1993-1997 period, we observed significant decreases in mortality not preceded by relapse, both at day 200 (by 60%) and overall (by 52%), the rate of relapse or progression of a malignant condition (by 21%), and overall mortality (by 41%), after adjustment for components of the PAM score. The results were similar when the analyses were limited to patients who received myeloablative conditioning therapy. We also found significant decreases in the risk of severe GVHD; disease caused by viral, bacterial, and fungal infections; and damage to the liver, kidneys, and lungs. CONCLUSIONS We found a substantial reduction in the hazard of death related to allogeneic hematopoietic-cell transplantation, as well as increased long-term survival, over the past decade. Improved outcomes appear to be related to reductions in organ damage, infection, and severe acute GVHD. (Funded by the National Institutes of Health.).

1,163 citations


"The role of hematopoietic stem cell..." refers background or result in this paper

  • ...Still, HSCT is the most powerful intervention; it holds the potential for “cure” and outcome has dramatically improved over the last years [15, 16]....

    [...]

  • ...Of general importance to note, there are no indications that impact of transplant technology in CML differs from that in any other disease treated with HSCT [8, 15, 48]....

    [...]


Performance
Metrics
No. of citations received by the Paper in previous years
YearCitations
20214
20201
20174
20165