Risk assessment in haematopoietic stem cell transplantation: Conditioning

doi:10.1016/j.beha.2006.09.004

Best Practice & Research Clinical Haematology

Volume 20, Issue 2, June 2007, Pages 295-310

https://doi.org/10.1016/j.beha.2006.09.004 Get rights and content

After the introduction of cyclophosphamide and total body irradiation in the 1970s, a variety of conditioning regimens has been developed. However, none has proven to be superior. Fractionation of the irradiation results in less toxic side-effects, but the total dose has to be increased to obtain similar immunosuppressive effects. Data from randomized trials indicate that among patients with myeloid leukaemia, busulfan in combination with cyclophosphamide results in similar outcome, while a regimen containing total body irradiation is probably still the best for patients with acute lymphoblastic leukaemia. Busulfan treatment can be optimized by targeted steady-state concentration or with the use of intravenous preparations. Intensified regimens decrease the relapse incidence, but because of a higher mortality from transplant-related causes survival is unchanged. Reduced-intensity conditioning can reduce transplant-related mortality and offer otherwise ineligible patients a potentially curative treatment. Long-term results are unknown.

Section snippets

Total body irradiation

Because of its immunosuppressive properties, activity against a wide range of malignant disorders, even in chemoresistant diseases, and penetration of sanctuary sites such as the central nervous system and testicles, total body irradiation (TBI) has been an important part of the conditioning for malignant disorders for the last 35 years.⁴ However, there are concerns about late adverse effects such as secondary malignancies. Both radiation from dual opposing ⁶⁰Co sources and linear accelerators

Cyclophosphamide

The alkylating agent cyclophosphamide (CY) is strongly immunosuppressive and also an effective anti-neoplastic agent, but is not marrow-ablative. Dose-limiting toxicity is haemorrhagic myocarditis. When used as a single agent, the maximum tolerated dose is approximately 200 mg/kg, and infusion of HSCs has no impact on survival.¹³ Following animal studies it was shown that CY can be substituted for TBI in the conditioning.¹⁴

CY 50 mg/kg/day for 4 successive days is one of the most common

Chemotherapy-based high-dose regimens

A wide range of high-dose chemotherapy regimens has been developed. Different mechanisms have driven this research. To decrease the incidence of relapse, disease-specific chemotherapy regimens were developed. In small children, attempts have been made to avoid detrimental effects from irradiation on growth and central nervous system development.²⁷ Furthermore, chemotherapy regimens may avoid or diminish late complications from irradiation such as second malignancies, cataract, and sterility.28,

Radioimmunotherapy

Replacing, or augmenting, the external-beam TBI with more selective irradiation of the bone marrow might reduce the risk of relapse while causing only limited toxicity to non-target organs. A variety of antibodies (anti-CD20, anti-CD33, anti-CD45, and anti-CD66) have been labelled with different β-emitters (¹³¹I, ⁹⁰Y and ¹⁸⁸Re).⁵² Dose-escalation and distribution studies have been performed, and clinical trials with radioimmunotherapy in combination with both conventional myeloablative

Reduced intensity conditioning

The curative effect of allo-HSCT is partly mediated by the graft-versus-tumour (GVT) effect from immunocompetent cells originating from the graft. Evidence of this GVT effect was first seen in animal studies and later in clinical trials.54, *55 Patients with graft-versus-host disease (GVHD) have a reduced incidence of relapse, whereas recipients of syngeneic, or T-cell-depleted grafts, have a higher risk of relapse.⁵⁶ The ultimate proof of the potent GVT effect is the reinduction of remission

Individualization

A common trend in recent years is the individualization of the transplant procedure. With a variety of conditioning regimens, stem-cell sources and methods of GVHD prevention, the complexity has increased substantially. Conditioning regimen depends on both the disease and the age and co-morbidity of the patient. Patients with high risks for TRM and a low risk for relapse should probably receive a different conditioning regimen from patients with low risk for TRM and a high relapse risk. Some

Summary

The conditioning given before allo-HSCT has evolved from a standard maximized radiochemotherapy into an individualized treatment. Depending on disease, age, co-morbidity, previous treatment, stem-cell source and type of donor, the composition of the conditioning may vary considerably. However, the number of prospective randomized trials comparing different conditioning regimens is low. A conventional myeloablative preparative regimen is still the gold standard for eligible patients. BUCY

References (79)

E.D. Thomas et al.
Marrow transplantation for acute nonlymphoblastic leukemia in first remission using fractionated or single-dose irradiation
International Journal of Radiation Oncology, Biology, Physics
(1982)
R.A. Clift et al.
Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: A randomized trial of two irradiation regimens
Blood
(1990)
R.A. Clift et al.
Allogeneic marrow transplantation in patients with chronic myeloid leukemia in the chronic phase: a randomized trial of two irradiation regimens
Blood
(1991)
R. Storb et al.
Cyclophosphamide combined with antithymocyte globulin in preparation for allogeneic marrow transplants in patients with aplastic anemia
Blood
(1994)
K.G. Blume et al.
Total body irradiation and high-dose etoposide: a new preparatory regimen for bone marrow transplantation in patients with advanced hematologic malignancies
Blood
(1987)
P.F. Coccia et al.
High-dose cytosine arabinoside and fractionated total-body irradiation: an improved preparative regimen for bone marrow transplantation of children with acute lymphoblastic leukemia in remission
Blood
(1988)
D.I. Marks et al.
A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission
Biology of Blood and Marrow Transplantation
(2006)
T.R. Spitzer et al.
Etoposide in combination with cyclophosphamide and total body irradiation or busulfan as conditioning for marrow transplantation in adults and children
International Journal of Radiation Oncology, Biology, Physics
(1994)
G. Socie et al.
Nonmalignant late effects after allogeneic stem cell transplantation
Blood
(2003)
P.J. Tutschka et al.
Bone marrow transplantation for leukemia following a new busulfan and cyclophosphamide regimen
Blood
(1987)

D. Blaise et al.

Allogeneic bone marrow transplantation for acute myeloid leukemia in first remission: a randomized trial of a busulfan-cytoxan versus cytoxan-total body irradiation as preparative regimen: a report from the Groupe d'Etudes de la Greffe de Moelle Osseuse

Blood

(1992)

A. Devergie et al.

Allogeneic bone marrow transplantation for chronic myeloid leukemia in first chronic phase: a randomized trial of busulfan-cytoxan versus cytoxan body irradiation as preparative regimen: a report from the French Society of Bone Marrow Graft (SFGM)

Blood

(1995)

R.A. Clift et al.

Marrow transplantation for chronic myeloid leukemia: a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide

Blood

(1994)

O. Ringdén et al.

A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia: a report from the Nordic Bone Marrow Transplantation Group

Blood

(1994)

G. Socie et al.

Busulfan plus cyclophosphamide compared with total-body irradiation plus cyclophosphamide before marrow transplantation for myeloid leukemia: long-term follow-up of 4 randomized studies

Blood

(2001)

K.G. Blume et al.

A prospective randomized comparison of total body irradiation-etoposide versus busulfan-cyclophosphamide as preparatory regimens for bone marrow transplantation in patients with leukemia who were not in first remission: a Southwest Oncology Group study

Blood

(1993)

J.T. Slattery et al.

Marrow transplantation for chronic myeloid leukemia: the influence of plasma busulfan levels on the outcome of transplantation

Blood

(1997)

L.B. Grochow et al.

Busulfan disposition in children

Blood

(1990)

B.S. Andersson et al.

Acute safety and pharmacokinetics of intravenous busulfan when used with oral busulfan and cyclophosphamide as pretransplantation conditioning therapy: a phase I study

Biology of Blood and Marrow Transplantation

(2000)

A. Kashyap et al.

Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality

Biology of Blood and Marrow Transplantation

(2002)

J.G. Jurcic et al.

Targeted alpha particle immunotherapy for myeloid leukemia

Blood

(2002)

M.M. Horowitz et al.

Graft-versus-leukemia reactions after bone marrow transplantation

Blood

(1990)

R. Storb et al.

Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation

Blood

(1997)

P.A. McSweeney et al.

Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects

Blood

(2001)

E. Holler et al.

Increased serum levels of tumor necrosis factor a precede major complications of bone marrow transplantation

Blood

(1990)

P.D. Kottaridis et al.

In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation

Blood

(2000)

F. Baron et al.

Kinetics of engraftment in patients with hematologic malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning

Blood

(2004)

D. Niederwieser et al.

Allogeneic hematopoietic cell transplantation (HCT) following reduced-intensity conditioning in patients with acute leukemias

Critical Reviews in Oncology/Hematology

(2005)

A.Y. Ho et al.

Reduced-intensity allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome and acute myeloid leukemia with multilineage dysplasia using fludarabine, busulphan, and alemtuzumab (FBC) conditioning

Blood

(2004)

L. Barkholt et al.

Allogeneic haematopoietic stem cell transplantation for metastatic renal carcinoma in Europe

Annals of Oncology

(2006)

M.L. Sorror et al.

Comparing morbidity and mortality of HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: influence of pretransplantation comorbidities

Blood

(2004)

R. Diaconescu et al.

Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors

Blood

(2004)

E.P. Alyea et al.

Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age

Blood

(2005)

F.B. Petersen et al.

Marrow transplantation following escalating doses of fractionated total body irradiation and cyclophosphamide–a phase I trial

International Journal of Radiation Oncology, Biology, Physics

(1992)

S. Slavin et al.

Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases

Blood

(1998)

L.O. Jacobson et al.

Effect of spleen protection on mortality following x-irradiation

The Journal of Laboratory and Clinical Medicine

(1949)

J.M. Main et al.

Successful skin homografts after the administration of high dosage X radiation and homologous bone marrow

Journal of the National Cancer Institute

(1955)

E.D. Thomas et al.

Supralethal whole body irradiation and isologous marrow transplantation in man

The Journal of Clinical Investigation

(1959)

E.D. Thomas et al.

Bone-marrow transplantation. Parts I and II

The New England Journal of Medicine

(1975)

Cited by (34)

The mythological chimera and new era of relapse prediction post-transplant
2023, Blood Reviews
Citation Excerpt :
Multiple factors are associated with relapse post allo-HCT. While the shift from myeloablative conditioning (MAC) to reduced intensity conditioning (RIC) regimens has reduced transplant related mortality and expanded transplant as an option for adult patients >60 years or with comorbidities, it is, in general, also associated with a greater risk of relapse [27–30]. Several studies have shown that chronic GVHD is associated with a lower risk of relapse in leukemia [31,32].
Allogeneic hemopoietic stem cell transplantation is the treatment of choice for high-risk or relapsed acute leukemia. However, unfortunately, relapse post-transplant continues to be the most common cause of treatment failure with 20–80% of patients relapsing based on disease risk and status at transplant.
Advances in molecular profiling of different hematological malignancies have enabled us to monitor low level disease before and after transplant and develop a more personalized approach to the management of these disease including early detection post-transplant. While, in general, detectable disease by morphology remains the gold standard to diagnosing relapse, multiple approaches have allowed detection of cancer cells earlier, using peripheral blood-based methods with sensitivities as high as 1:10⁶, together called minimal/measurable residual disease (MRD) detection. However, a in significant number of patients with acute leukemia where no such molecular markers exist it remains challenging to detect early relapse. In such patients who receive transplantation, chimerism monitoring remains the only option. An increase in mixed chimerism in post allogeneic HCT patients has been correlated with relapse in multiple studies. However, chimerism monitoring, while commonly accepted as a tool for assessing engraftment, has not been routinely used for relapse detection, at least in part because of the lack of standardized, high sensitivity, reliable methods for chimerism detection.
In this paper, we review the various methods employed for MRD and chimerism detection post-transplant and discuss future trends in MRD and chimerism monitoring from the viewpoint of the practicing transplant physician.
Viral infection in hematopoietic stem cell transplantation: an International Society for Cell & Gene Therapy Stem Cell Engineering Committee review on the role of cellular therapy in prevention and treatment
2022, Cytotherapy
Citation Excerpt :
Allogeneic hematopoietic stem cell transplant (HSCT) is a potentially curative therapy for many patients with malignant and non-malignant blood disorders. [1] However, the morbidity and mortality related to disease relapse, regimen-related toxicity, graft-versus-host disease (GVHD) and opportunistic infections limit the success of HSCT in these applications.[2–4] Central to the paradigm of HSCT is the immunosuppression required to allow engraftment of donor cells within the host, and to prevent GVHD due to the alloreactive donor cells attacking the host tissues.
Despite recent advances in the field of HSCT, viral infections remain a frequent causeof morbidity and mortality among HSCT recipients. Adoptive transfer of viral specific T cells has been successfully used both as prophylaxis and treatment of viral infections in immunocompromised HSCT recipients. Increasingly, precise risk stratification of HSCT recipients with infectious complications should incorporate not only pretransplant clinical criteria, but milestones of immune reconstitution as well. These factors can better identify those at highest risk of morbidity and mortality and identify a population of HSCT recipients in whom adoptive therapy with viral specific T cells should be considered for either prophylaxis or second line treatment early after inadequate response to first line antiviral therapy. Broadening these approaches to improve outcomes for transplant recipients in countries with limited resources is a major challenge. While the principles of risk stratification can be applied, early detection of viral reactivation as well as treatment is challenging in regions where commercial PCR assays and antiviral agents are not readily available.
Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis
2016, The Lancet Haematology
Intravenous busulfan combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic haemopoietic cell transplantation (HCT). The best method to estimate busulfan exposure and optimum exposure in children or young adults remains unclear. We therefore assessed three approaches to estimate intravenous busulfan exposure (expressed as cumulative area under the curve [AUC]) and associated busulfan AUC with clinical outcomes in children or young adults undergoing allogeneic HCT.
In this retrospective analysis, patients from 15 centres in the Netherlands, USA, Canada, Switzerland, UK, Italy, Germany, and Australia who received a busulfan-based conditioning regimen between March 18, 2001, and Feb 12, 2015, were included. Cumulative AUC was calculated by numerical integration using non-linear mixed effect modelling (AUC_NONMEM), non-compartmental analysis (AUC from 0 to infinity [AUC_0-∞] and to the next dose [AUC_0-τ]), and by individual centres using various approaches (AUC_centre). The main outcome of interest was event-free survival. Other outcomes of interest were graft failure or relapse, or both; transplantation-related mortality; acute toxicity (veno-occlusive disease or acute graft versus-host disease [GvHD]); chronic GvHD; overall survival; and chronic-GvHD-free event-free survival. We used propensity-score-adjusted Cox proportional hazard models, Weibull models, and Fine-Gray competing risk regressions for statistical analyses.
790 patients were enrolled, 674 of whom were included: 274 (41%) with malignant and 400 (59%) with non-malignant disease. Median age was 4·5 years (IQR 1·4–10·7). The median busulfan AUC_NONMEM was 74·4 mg × h/L (95% CI 31·1–104·6), which correlated with the standardised method AUC_0–∞ (r²=0·74), but the latter correlated poorly with AUC_centre (r²=0·35). Estimated 2-year event-free survival was 69·7% (95% CI 66·2–73·0). Event-free survival at 2 years was 77·0% (95% CI 72·1–82·9) in the 257 patients with an optimum intravenous busulfan AUC of 78–101 mg × h/L compared with 66·1% (60·9–71·4) in the 235 patients at the low historical target of 58–86 mg × h/L and 49·5% (29·2–66·0) in the 44 patients with a high (>101 mg × h/L) busulfan AUC (p=0·011). Compared with the low AUC group, graft failure or relapse occurred less frequently in the optimum AUC group (hazard ratio [HR] 0·57, 95% CI 0·39–0·84; p=0·0041). Acute toxicity (HR 1·69, 1·12–2·57; p=0·013) and transplantation-related mortality (2·99, 1·82–4·92; p<0·0001) were significantly higher in the high AUC group (>101 mg × h/L) than in the low AUC group (<78 mg × h/L), independent of indication; no difference was noted between AUC groups for chronic GvHD (<78 mg × h/L vs ≥78 mg × h/L, HR 1·30, 95% CI 0·73–2·33; p=0·37).
Improved clinical outcomes are likely to be achieved by targeting the busulfan AUC to 78–101 mg × h/L using a new validated pharmacokinetic model for all indications.
Research Allocation Program and the UCSF Helen Friller Family Comprehensive Cancer Center and the Mt Zion Health Fund of the University of California, San Francisco.
Comparison of outcomes of idarubicin intensified TBI-CY and traditional TBI-CY conditioning regimen for high-risk acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation: A single center experience
2015, Leukemia Research
Citation Excerpt :
Etoposide (VP-16), thiotepa and Ara-C have been proposed with CY plus TBI in intensified regimens [8–11]. However until now, the satisfying conditioning regimens for high-risk ALL patients are still controversial [1,12–13]. Idarubicin (IDA, 4-demethoxydaunorubicin) has shown more excellent anti-leukemia effect for acute myelocytic leukemia (AML) and ALL patients than conventional anthracyclines [14].
High-risk acute lymphoblastic leukemia (ALL) carries a very poor prognosis, even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Exploring novel conditioning regimen to more effectively eliminate leukemic clone while not alter transplant-related mortality (TRM) has become focus of attention. We retrospectively evaluated outcomes of 87 high-risk ALL patients undergoing allo-HSCT: 47 patients received idarubicin (IDA) intensified TBI–CY and 40 patients received traditional TBI–CY regimen. In IDA intensified group, patients received TBI (8 Gy) on day-8, IDA of 15 mg/m²/d from day-6 to -5, followed by CY (60 mg/kg/d) on day-3 to -2. The cumulative incidence of relapse was significantly lower in IDA intensified group compared with TBI–CY group (P = 0.018). Oropharyngeal mucositis was observed more frequent in IDA intensified group (P = 0.013), while not followed by increased TRM. Very high-risk ALL patients benefit from IDA intensified regimen with only two of eight patients in no remission (NR) pre-transplantation and two of twelve ph⁺ALL patients relapsed after transplantation. After a median follow-up for all survivors of 21 months (range, 12–53 months), 2-year estimated OS and DFS was 66.2% vs 45.3% (P = 0.031) and 62.5% vs 43.5% (P = 0.044), respectively. In conclusion, IDA intensified TBI–CY regimen may reduce relapse while not increasing TRM, providing better survival for high-risk ALL patients undergoing allo-HSCT.
Targeting the hematopoietic system for the treatment of Alzheimer's disease
2011, Brain, Behavior, and Immunity
Alzheimer’s disease (AD) is the most prevalent cause of dementia in humans. This disease is characterized by the presence of amyloid beta (Ab) deposits in the parenchyma (also known as amyloid plaques or senile plaques) and in the cerebral vasculature. Though Ab formation and deposits are strongly correlated with cognitive impairment, the mechanisms responsible for the synaptic dysfunctions and loss of neurons in AD remain largely unknown. Many studies have provided evidence that microglial cells are attracted to amyloid deposits both in human samples and in rodent transgenic models that develop this disease. We have recently found that blood-derived microglia and not their resident counterparts have the ability to eliminate amyloid deposits by a cell-specific phagocytic mechanism. These bone marrow-derived microglia have consequently a great therapeutic potential for AD patients. Molecular strategies aiming to improve their recruitment could lead to a new powerful tool for the elimination of toxic Ab and improve cognitive functions. However, numerous limitations have to be taken into consideration before recommending such a cellular therapy and these are discussed in the present review.
Cyclophosphamide plus total body irradiation compared with busulfan plus cyclophosphamide as a conditioning regimen prior to hematopoietic stem cell transplantation in patients with leukemia: A systematic review and meta-analysis
2011, Hematology/ Oncology and Stem Cell Therapy
Cyclophosphamide plus total body irradiation (CYTBI) and oral busulfan plus cyclophosphamide (BUCY) are commonly used conditioning regimens prior to allogeneic hematopoietic stem cell transplantation (HSCT) in patients with leukemia. However, there is conflicting data on the superiority of one regimen over the other. Our aim was to critically appraise and synthesize available evidence regarding the efficacy and safety of CYTBI compared to BUCY as a conditioning regimen.
Systematic review and meta-analysis of randomized, controlled trials (RCTs) comparing BUCY with CYTBI.
We did a systematic search of the indexed medical literature using appropriate keywords to identify potentially relevant articles. The primary outcome of interest was efficacy measured by overall survival (OS) and disease-free survival (DFS). Acute and late toxicity were secondary endpoints. Meta-analysis was attempted only on RCTs. A relative risk or risk ratio (RR) and 95% confidence interval (CI) was calculated for each outcome in the meta-analysis.
Fifteen non-randomized comparative studies involving 6280 patients were included in a narrative review without attempting a pooled analysis, in view of the potential for significant bias. Outcome data from seven RCTs involving 730 patients randomly assigned to either CYTBI or BUCY was pooled using meta-analytic methods. CYTBI was associated with a modest but non-significant reduction in all cause mortality (RR = 0.82, 95%CL: 0.64–1.05; P = .12) and relapse of leukemia (RR = 0.89, 95%CI: 0.72–1.10; P = .28). Transplant-related mortality (TRM) was significantly lesser with CYTBI compared to oral BUCY (RR-0.53, 95%CI: 0.31-0.90; P = .02). The cumulative incidence of major complications was not significantly different between the two regimens, but specific complications varied according to the conditioning regimen. TBi-based regimens were associated with more severe late effects on growth and development in children.
This analysis represents the largest comparative analyses of CYTBI with BUCY as a conditioning regimen prior to HSCT in the indexed medical literature. Conditioning regimen and disease (type and setting) can significantly affect outcomes. TRM is significantly lesser with CYTBI, but this does not translate into a significant survival benefit. There remain valid concerns regarding the late effects of TBI, particularly in children. Although not overly superior, the weight of evidence favors CYTBI over BUCY as a first choice-conditioning regimen in patients with leukemia.

View all citing articles on Scopus

View full text

11Risk assessment in haematopoietic stem cell transplantation: Conditioning

Section snippets

Total body irradiation

Cyclophosphamide

Chemotherapy-based high-dose regimens

Radioimmunotherapy

Reduced intensity conditioning

Individualization

Summary

International Journal of Radiation Oncology, Biology, Physics

Blood

Blood

Blood

Blood

Blood

Biology of Blood and Marrow Transplantation

International Journal of Radiation Oncology, Biology, Physics

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Biology of Blood and Marrow Transplantation

Biology of Blood and Marrow Transplantation

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Critical Reviews in Oncology/Hematology

Blood

Annals of Oncology

Blood

Blood

Blood

International Journal of Radiation Oncology, Biology, Physics

Blood

Effect of spleen protection on mortality following x-irradiation

The Journal of Laboratory and Clinical Medicine

Successful skin homografts after the administration of high dosage X radiation and homologous bone marrow

Journal of the National Cancer Institute

Supralethal whole body irradiation and isologous marrow transplantation in man

The Journal of Clinical Investigation

Bone-marrow transplantation. Parts I and II

The New England Journal of Medicine

11
Risk assessment in haematopoietic stem cell transplantation: Conditioning