Nonmyeloablative Allogeneic Stem-Cell Transplantation for Hematologic Malignancies: A Systematic Review

Benjamin Djulbegovic, MD, PhD, Jerome Seidenfeld, PhD, Claudia Bonnell, BSN, MLS, Ambuj Kumar, MD, MPH

Cancer Control. 2003;10(1)

Methods

We searched the MEDLINE computer database for reports from 1995 through June 2002 using the following search terms: (nonmyeloablat* OR "transplant lite" OR "mini-transplant" OR "mini-allograft*" OR graft-vs-host disease (mh)) AND explode hematologic neoplasms (mh) AND human. Similar terms were used to search the EMBASE database. Computer searches were supplemented by manual reviews of bibliographies of selected references, reviews of meeting abstracts from key hematology/oncology meetings, and reviews of Current Contents, an electronic resource that provides access to bibliographic research information.

A flow diagram of our search results and selection process is shown in Figure 2. We initially identified 308 studies for potential retrieval. After further review, we excluded 283 studies, including review articles containing no primary data, abstracts that were later available as full reports, duplicate studies, reports on nonhematologic malignancies, studies on T-cell depletion and donor-lymphocyte infusion, reports on discussions at conferences about NM-allo-SCT, and reports involving fewer than 5 patients. Data were extracted from the remaining 25 studies, which included 23 published as full reports, one abstract, and one letter.

(Enlarge Image)

Flow diagram showing identification of the papers for inclusion in the systematic review.

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No significant relationship exists between the authors and the companies/organizations whose products or services may be referenced in this article.

Cite this: Nonmyeloablative Allogeneic Stem-Cell Transplantation for Hematologic Malignancies: A Systematic Review - Medscape - Jan 01, 2003.

Table 1. Benefits and Harms of "Standard" Allo-SCT in Hematologic Malignancies: Data From the International Bone Marrow Transplant Registry
Disease	Benefits		Harms
Disease	5-Year Survival	Comments	100-Day Mortality	Comments
ALL	30-50%	Depending on the type of donor (HLA-identical sibling vs unrelated donor) and time of transplant (CR1, CR2+)	14-38%	Depending on timing of transplant (CR1, CR+, others)
AML	30-60%	Depending on the type of donor (HLA-identical sibling vs unrelated donor) and time of transplant (CR1, CR2+)	13-38%	Depending on timing of transplant (CR1, CR+, others); HLA-identical sibling, 1-year TRM for early leukemia: 21%; for intermediate: 24%; for advanced leukemia: 36%
CLL	38-46%	Depending on age at transplant (<45 yrs vs >45 yrs) (HLA-identical sibling only)		Currently not reported by/available from IBMTR
CML	37-67%	Depending on type of the donor and timing of transplant	15-29%	Depending on the phase of the disease (chronic, accelerated, blast crisis)
Hodgkin's disease		Currently not reported by/available from IBMTR		Currently not reported by/available from IBMTR
MDS	20-55%	Depending on the phase of the disease (RAEB/RAEB-t vs RA/RARS)	25%
Myeloma	32% (at 4 years)	From Alyea and Anderson ^[4]; currently not reported by/available from IBMTR	10-56%	From Alyea and Anderson ^[4]; currently not reported by/available from IBMTR
NHL		Currently not reported by/available from IBMTR		Currently not reported by/available from IBMTR

Table 2. NM-Allo-SCT: Summary of Published Evidence*
Disease	No. of Patients
ALL	59
AML	105
CLL	27
CML	114
HD	37
NHL	124
MDS	32
MM	105
Total	603^¶

Appendix 1A: NM-Allo-SCT in Hematologic Malignancies: Demographics and Patient Characteristics
Study	Disease	No. of Patients	Sex	Median Age (range)	Comorbid Conditions	Regimen	Study Design	HLA Type	Comments
Giralt^[17] 1997 (updated 2001^[15])	AML/MDS	43	52 F, 34 M	52 (22-70) (56% older than 50 yrs)	NR	Flu/Ida or CDA/AraC or Flu/Mel 140 or 180	Prospective cohort/case series without historical control	HLA-compatible siblings (n=39) or 1-antigen mismatched siblings (n=7); HLA (6/6) MUD (n=40); not specified according to disease	All considered poor candidates for conventional allo-transplant; median of 3 previous treatments (range 0-8)
	CML	27
	HD	4
	NHL	9				2CDA/AraC (not used after 1997)
	ALL	3				2CDA/AraC (not used after 1997)
Carella^[24] 1998	CML	2	1 F, 1 M	52 (50-55)	NR	Flu/Cy	Prospective cohort/case series without historical control	HLA-matched siblings
	HD	4	2 F, 2 M	30 (22-36)
	NHL	2	1 F, 1 M	33 (24-43)
	MDS (RAEB)	1	1 F	57
Kelemen^[11] 1998	CML	19	NA	Not reported individually (21-51)	NR	DBM/AraC/Cy	Prospective cohort/case series, no historical control	HLA-identical siblings (n=19)	8 patients under age 30
Khouri^[16] 1998	CLL	8	8 M	59 (51-71)	Yes	Flu/Cy/cisplatin/ cytarabine	Prospective cohort/case series, no historical control	HLA-identical siblings	13 patients older than age 50, 2 had elevated ALT levels 2° due to alcohol-induced liver toxicity, 1 had hepatitis C infections
Khouri^[16] 1998	NHL (4 patients with Richter's syndrome)	7	3 F, 4 M	52 (45-58)	Yes	Flu/Cy or cisplatin/Flu/cytarabine	Prospective cohort/case series, no historical control	HLA-identical siblings
Slavin^[8] 1998	ALL	2	2 M	49 (12-46)	NR	Flu/Bu/anti-T-lymphocyte globulin	Prospective cohort/case series without historical control	Matched related donors (n=2)	Included data on patients with nonhematologic malignancies but abstracted data only on those with hematologic malignancies
	AML	8	6 F, 2 M	26 (1-51)				Matched related donors (n=8)
	CML	8	1 F, 7 M	37 (2-56)				Matched related donors (n=8)
	NHL	2	2 M	49 (37-61)				Matched related donors (n=2)
	MDS	1	1 M	41				Matched related donor
	MM	1	1 M	51				Matched related donor
Childs^[22] 1999	CML	4	1 F, 3 M	59 (28-68)	NR	Cy/Flu	Prospective cohort/case series without historical control	Not specified according to disease; HLA identical (n=14) or single HLA locus mismatched sibling (n=1)	Included data on patients with nonhematologic malignancies but abstracted data only on those with hematologic malignancies
	NHL	1	1 F	55l
	MDS	2	2 M	59 (58-60)
	MM (EMP)	1	1 F	34
Garban^[26] 1999 abstract (updated 2001^[13])	MM	12	NR	53.5 (45-61)	PS ≤ 2	Bu/ATG/Flu	Prospective cohort/case series without control group	HLA-identical sibling
Giralt^[14] 1999 abstract	MM	18	NR	50 (46-61)	NR	Flu/Mel	Prospective cohort/case series without control group	HLA-identical sibling (n=13); MUD (n=5)
Sykes^[12] 1999	NHL	5	NR	32 (20-51)	No	Cy/ATG/TI	Prospective cohort/case series without historical control	Haploidentical-related donor sharing at least one HLA A, B or D allele on the mismatched haplotype
Bornhauser^[29] 2000	ALL	1	1 F	52	Yes	Bu/Flu	Prospective cohort/case series with no control	HLA-matched sibling
	AML	10	2 F, 8 M	53 (38-65)
	CLL	3	1 F, 2 M	41 (33-46)
	CML	4	1 F, 3 M	51 (25-61)
	HD	2	2 M	36 (35-37)
	NHL	1	1 F	59
Gomez- Almaguer^[25] 2000 (updated Ruiz- Arguelles 2001^[37])	AML	6	6 F, 9 M	43 (14-52)	NR	Bu/Cy/Flu	Prospective cohort/case series, no historical control	HLA-identical sibling	21 patients transplanted in outpatient setting, 1 with thalassemia (excluded from this analysis)
	MDS	1		39
	CML	8		45 (24-61)
McSweeney^[7] 1999 (updated 2001^[5])	AML	11	4 F, 7 M	57 (36-63)	Yes	Low-dose TBI (n=44), 1 patient received Flu (30 mg/m²) in addition to low-dose TBI (which is now the standard treatment and appeared to reduce increased incidence of the graft failure seen with low-dose TBI only)	Prospective cohort/case series without control group	HLA-identical sibling	53% transplanted as outpatients; general eligibility criteria included those with "relative contraindication to standard allo-SCT" such as age >50 years (>60 for CML); CLL/NHL had to fail at least frontline treatment and MM had to be stage II/III (n=2) with chemo-resistant acute leukemia and aspergillosis (n=1) after induction chemotherapy
	CML	9	2 F, 7 M	(40-71)	No
	CLL	8	1 F, 7 M	(46-67)	No
	NHL	1	1 F	53	No
	HD	4	2 F, 2 M	45 (31-61)	No
	ALL	1	1 M	60	Yes
	MM	8	4 F, 4 M	56 (46-63)	No
	MDS	1	1 M	43 (36-72)	Yes
	WF	2	2 M	55 (52-58)	No
Nagler^[28] 2000	NHL	19	4 F, 15 M	41 (13-62)	NR	Low-intensity Flu	Prospective cohort/case series, no historical control	HLA-matched sibling
Nagler^[28] 2000	HD	4	4 M	31 (17-53)	NR	Low-intensity Flu	Prospective cohort/case series, no historical control	HLA-matched sibling
Spitzer^[27] 2000	ALL	1	NE	40	NR	Cy/ATG/TI	Prospective cohort/case series, no control group	HLA genotypic ally (n=20) or phenotypic ally (n=1) matched donor transplant
	AML	3		38 (27-44)
	HD	4		33 (27-55)
	NHL	11		45 (22-62)
	CLL	2		53 (50-55)
Elmaagacli^[9] 2001	ALL	2	3 F, 6 M	NE	Yes	Bu/Flu/ATG	Prospective cohort series with historical controls	HLA-matched genotypic ally (n=7); partially HLA identical (n=2)	Included data on myeloablative conditioning regimens but only data on nonmyeloablative regimens are included in this table; age and gender not reported separately by disease
	AML	1
	CML	6
Lee^[30] 2001	NHL	6	1 F, 5 M	31 (22-56)	Yes	Bu/Flu/ATG/ methylprednisone	Prospective cohort/case studies without historical controls	NR
Lee^[30] 2001	HD	1	1 M	53	Yes	Bu/Flu/ATG/ methylprednisone	Prospective cohort/case studies without historical controls	NR
Michallet^[20] 2001	ALL	25	NR	NR	Yes	Flu/Bu/ATG Ida/Flu/AraC OAT/LG	Retrospective case series analysis	All HLA-identical sibling; 1 HLA-identical unrelated donor but not reported according to disease category	Conditioning regimens and HLA types not reported separately by disease; 3 patients with solid tumors excluded from abstracting and analysis; data extracted on evaluable patients
	MDS	9
	NHL	13
	MM	11
	HD	3
	CLL	3
	CML	12
Mohty^[31] 2001	NHL	3	1 F, 2 M	42 (26-47)	Yes	Bu/Flu	Prospective cohort/case studies without historical control	HLA-matched genotypic ally (n=10); partially HLA identical (n=1)	One each of NHL, HD and CLL also received ATG as part of conditioning regimen
	HD	1	1 M	40
	CLL	1	1 M	49
	MM	6	3 F, 3 M	54 (47-62)
Chakraverty^[33] 2002	MM	12	5 F, 7 M	47 (34-52)	Yes	CAMPATH1H/Flu/Mel	Prospective cohort study without historical controls	Not specified according to disease; all patients had MUD transplant	Low-and high-grade lymphoma grouped as NHL
	NHL	15	5 F, 10 M	39 (18-56)
	CML	5	2 F, 3 M	48 (36-53)
	AML	6	4 F, 2 M	49 (30-55)
	ALL	2	1 F, 1 M	22 (18-27)
	HD	5	3 F, 2 M	31 (22-38)
	CLL (T-PLL)	1	1 F	50
	CMML	1	1 M	62
Corradini^[19] 2002	AML	5	17 F, 28 M	NE	Yes	Thiotepa/Cy/Flu	Prospective cohort study without historical controls	Not specified by disease; HLA-identical (n=42) or single HLA locus mismatched (n=3) sibling	Indolent and high-grade lymphoma grouped as NHL
	MDS	6
	ALL	1
	NHL	24
	HD	4
	MM	5
Schlenk^[34] 2002	AML	9	3 F, 6 M	61 (30-64)	Yes	Flu/Cy/Ida/etoposide	Prospective cohort study without historical control	All HLA-identical sibling (n=11)
	ALL	1	1 M	57
	CML	1	1 M	62
Nagler^[21] 2001	CML	7	1 F, 6 M	17 (12-48)	Yes	Flu/Bu/ATG	Prospective cohort study without historical controls	MUD (n=16)
	AML	4	2 F, 2 M	21 (18-27)
	ALL	4	4 M	10 (8-17)
	NHL	1	1 M	13
Pawson^[18] 2001	AML	7	5 F, 2 M	32 (24-48)	Yes	FLAG (n=2) FLAG-Ida (n=4) FLAG-X (n=1)	Prospective cohort/case series with no historical control	Full HLA-matched (n=13), 1-antigen-mismatched (n=1)
	ALL	5	5 M	18 (9-31)		FLAG-Ida (n=4) FLAG-X (n=1)
	MDS/(RAEB-t)	2	2 F	40 (38-42)		FLAG-Ida
Badros^[10] 2002	MM	31	13 F, 18 M	56 (38-69)	Yes	Mel/TBI/Flu	Prospective cohort/case studies with historical controls	HLA-matched sibling (n=25); MUD (n=6)	Conditioning regimen for HLA-matched transplant differed from MUD transplant
Baron^[32] 2002	ALL	1	1 M	25	No	Flu/TBI	Prospective cohort/case studies with no historical control	MUD, identical	Patients eligible for NM-allo-SCT if older than age 55 (n=4), had concurrent medical conditions (n=0), failed previous autograft (n=4), or had multiple factors (n=3); 2 with RCC excluded from abstraction; MUD or not heavily pretreated patients received TBI/Flu; Flu/Cyused if previously given ≥ 12 Gy TBI
	AML	1	1 F	57 TBI		HLA-matched sibling
	CLL	1	1 F	61		TBI		HLA-matched sibling
	CML	2	1 F, 1 M	60 (58-62)		TBI (n=1) Flu/TBI (n=1)		HLA-matched sibling
	HD	1	1 M	22		TBI		HLA-matched sibling

Appendix 1C: NM-Allo-SCT in Hematologic Malignancies: Harms
Reference	Disease	Transplant-Related Mortality	Acute GVHD	Chronic GVHD	Veno-Occlusive Disease	Relapse	Other Toxicity (Grade III-IV) and Comments
Giralt^[17] 1997 (updated 2001^[15])	AML	43% (16/43)	49% (95% CI 38-60)	68% ± 9% (21/46)	NR	27% (23/86)	Nonrelapse mortality at 2 yrs was ~45%
	MDS	43% (16/43)	60% (34/76)	NE		NE
	CML	25% (7/27)	NE
	HD	75% (3/4)
	NHL	78% (7/9)
	ALL	67% (2/3)
Carella^[24] 1998	CML	0% (0/2)	50% (1/2)	NR	NR	NR	No severe procedure-related toxicity
	HD	25% (1/4)	50% (2/4)
	NHL	0% (0/2)	0% (0/2)
	MDS (RAEB)	0% (0/1)	0% (0/1)
Kelemen^[11] 1998	CML	11% (2/19)	11% (2/18)	67% (12/18)	0% (0/18)	33% (6/18)	6% (1/18); not explicitly stated but estimated from Table 1 and comments in the text
Khouri^[16] 1998	CLL	38% (3/8)	NE	13% (1/8)	NR	NE	Toxicity NE; acute GVHD occurred after initial transplantation in 5 patients; not specified according to disease
Khouri^[16] 1998	NHL	43% (3/7)	14% (1/7)	13% (1/8)	NR	NE
Slavin^[8] 1998	ALL	0% (0/2)	NE	50% (1/2)	NE	50% (1/2)	Differences noted in reporting on GVHD between text and Table 3; data extracted from Table 3
	AML	25% (2/8)	38% (3/8)	13% (1/8)		13% (1/8)
	CML	25% (2/8)	50% (4/8)	13% (1/8)		0% (0/8)
	NHL	0% (0/2)	NE	50% (1/2)		0% (0/2)
	MDS	0% (0/1)	NE	NS		0% (0/1)
	MM	0% (0/1)	NE	NS		0% (0/1)
Childs^[22] 1999	CML	NE	50% (2/4)	25% (1/4)	0% (0/4)	0% (0/4)	2 patients died of transplant-related causes (1 had melanoma)
	NHL		100% (1/1)	0% (0/1)	0% (0/1)	0% (0/1)
	MDS		50% (1/2)	0% (1/2)	50% (1/2)	0% (0/2)
	MM		0% (0/1)	0% (0/1)	0% (0/1)	100% (1/1)
Garban^[26] 1999 (updated 2001^[13])	MM	17% (2/12)	50% (6/12)	58% (7/12) (2 extensive)	NR	8% (1/12)	5 of 11 patients developed CMV infection (1 died of CMV encephalitis)
Giralt^[14] 1999	MM	47% (8/17)	52% (9/17)	18% (3/17)	NR	NR
Sykes^[12] 1999	NHL	40% (2/5)	100% (5/5)	0% (1/5)	NR	20% (1/5)
Bornhauser^[29] 2000	ALL	NE	100% (1/1)	0% (0/1)	NE	NE	100% (1/1)
	AML	10% (1/10)	40% (4/10)	50% (5/10)		30% (3/10)	10% (1/10)
	CLL	NE	67% (2/3)	33% (1/3)		0% (0/3)	33% (1/3)
	CML		75% (3/4)	25% (1/4)		50% (2/4)	0% (0/4)
	HD		50% (1/2)	0% (0/2)		100% (2/2)	50% (1/2)
	NHL		100% (1/1)	0% (0/1)		NE	0% (0/1)
Gomez- Almaguer^[25] 2000 (updated Ruiz- Arguelles, 2001^[37])	ALL	NE	30% (3/10)	29% (2/7)	NE	60% (3/5)	TRM was 12% (3/25) for all patients; each died of acute GVHD
	AML		0% (0/6)	0% (0/5)		50% (2/4)
	CML		62% (5/8)	63% (5/8)		75% (3/4)
	MDS		100% (1/1)	100% (1/1)		0% (0/1)
McSweeney^[7] 2000 (updated 2001^[5])	AML	0% (0/11)	36% (4/11)	45% (5/11)	NR	% (1/11)	Toxicity was mild; none experienced mucositis, severe nausea and vomiting, pulmonary toxicity, cardiac toxicity, hemorrhagic cystitis, or new-onset alopecia; 3 of 45 patients (7%) died
	CML	0% (0/9)	67% (6/9)	44% (4/9)		0% (0/9)
	CLL	13% (1/8)	63% (5/8)	75% (6/8)		0% (0/8)
	NHL	100% (1/1)	100% (1/1)	NR		0% (0/1)
	ALL	0% (0/1)	100% (1/1)	0% (0/1)		0% (0/1)
	MM	13% (1/8)	50% (4/8)	17% (1/6)		13% (1/8)
	HD	0% (0/4)	75% (3/4)	50% (2/4)		0% (0/4)
	MDS	0% (0/1)	0% (0/1)	NR		0% (0/1)
	WM	0% (0/2)	50% (1/2)	100% (2/2) 1 extensive		0% (0/2) stable disease
Nagler^[28] 2000	NHL	NE	NE	NE	0% (0/19)	NE	7 patients died (4 of grade III-IV GVHD and severe infections, 2 of bacterial sepsis, 1 of pulmonary failure)
Nagler^[28] 2000	HD	NE	NE	NE	0% (0/4)	NE
Spitzer^[27] 2000	ALL	0% (0/1)	0% (0/1)	NE	NE	NE	NE
	AML	33% (1/3)	67% (2/3)
	CLL	0% (0/2)	100% (2/2)
	HD	0% (0/4)	100% (4/4)
	NHL	9% (1/11)	36% (4/11)	9% (1/11)
Elmaagacli^[9] 2001	ALL	NE	NE	NE	NE	NE	NE
	AML
	CML
Lee^[30] 2001	NHL	100% (6/6)	50% (3/6)	17% (1/6)	NR	NE	NR
Lee^[30] 2001	HD	100% (1/1)	100% (1/1)	100% (1/1)	NR	NE	NR
Michallet^[20] 2001	ALL	96% (24/25)	24% (6/25)	24% (6/25)	NR	16% (4/25)	NE
	MDS	44% (4/9)	44% (4/9)	22% (2/9)		11% (1/9)
	NHL	54% (7/13)	62% (8/13)	8% (1/13)		0% (0/13)
	MM	55% (6/11)	72% (8/11)	27% (3/11)		37% (4/11)
	HD	17% (2/12)	42% (5/12)	42% (5/12)		0% (0/12)
	CLL	67% (2/3)	67% (2/3)	0% (0/3)		0% (0/3)
	CML	0% (0/3)	33% (1/3)	33% (1/3)		0% (0/3)
Mohty^[31] 2001	NHL	67% (2/3)	0% (0/3)	NR	0% (0/3)	NR	All patients survived beyond day 30 and maintained good oral intake throughout the procedure
	HD	100% (1/1)	100% (1/1)		0% (0/1)
	CLL	100% (1/1)	100% (1/1)		0% (0/1)
	MM	33% (2/6)	100% (6/6)		0% (0/6)
Chakraverty^[33] 2002	MM	17% (2/12)	50% (6/12)	0% (0/12)	0% (0/12)	8% (1/12)	NR
	NHL	47% (6/15)	27% (4/15)	0% (0/15)	0% (0/15)	0% (0/15)
	CML	0% (0/5)	60% (3/5)	20% (1/5)	0% (0/5)	0% (0/5)
	AML	17% (1/6)	33% (2/6)	17% (1/6)	0% (0/6)	17% (1/6)
	ALL	50% (1/2)	0% (0/2)	0% (0/2)	0% (0/2)	0% (0/2)
	HD	20% (1/5)	40% (2/5)	20% (1/5)	0% (0/5)	20% (1/5)
	T-PLL (CLL)	0% (0/1)	0% (0/1)	0% (0/1)	0% (0/1)	100% (1/1)
	CMML	0% (0/1)	0% (0/1)	0% (0/1)	0% (0/1)	0% (0/1)
Corradini^[19] 2002	AML	NE	40% (2/5)	40% (2/5)	NR	NE	NR
	MDS		83% (5/6)	17% (1/6)
	ALL		100% (1/1)	0% (0/1)
	NHL		75% (18/24)	42% (10/24)
	HD		50% (2/4)	75% (3/4)
	MM		80% (4/5)	40% (2/5)
Schlenk^[34] 2002	AML	4% (4/9)	22% (2/9)	0% (0/9)	NR	44% (4/9)	11% (1/9)
	ALL	0% (0/1)	0% (0/1)	0% (0/1)		100% (1/1)	0% (0/1)
	CML	100% (1/1)	100% (1/1)	100% (1/1)		100% (1/1)	0% (0/1)
Nagler^[21] 2001	CML	67% (2/7)	86% (6/7)	0% (0/7)	NR	0% (0/7)	14% (1/7)
	AML	25% (1/4)	100% (4/4)	0% (0/4)		25% (1/4)	25% (1/4)
	ALL	25% (1/4)	100% (4/4)	0% (0/4)		50% (2/4)	0% (0/4)
	NHL	0% (0/1)	100% (1/1)	0% (0/1)		0% (0/1)	0% (0/1)
Pawson^[18] 2001	AML	NE	29% (2/7)	0% (0/7)	NR	NE	Relapse not reported by disease but 10 of 14 patients relapsed
	ALL		60% (3/5)	60% (3/5)
	MDS (RAEB-t)		50% (1/2)	50% (1/2)
Badros^[10] 2002	MM	10% (3/31)	58% (18/31)	32% (10/31)	0% (0/31)	0% (0/31)	TRM in mini-allograft group was 10% (3/31) vs 29% (27/93) in standard allo-SCT group
Baron^[32] 2002	NHL	20% (1/5)	60% (3/5)	80% (4/5)	NR	NR	NR
	CML	50% (1/2)	0% (0/2)	0% (0/2)
	CLL	100% (1/1)	100% (1/1)	0% (0/1)
	AML	0% (0/1)	0% (0/1)	00% (1/1)
	ALL	100% (1/1)	0% (0/1)	0% (0/1)

Appendix 2: Overview of Published Evidence in Hematologic Malignancies According to Specific Diseases: Indications for Nonmyeloablative Allogeneic Transplant, HLA Status, and Engraftment Outcomes
Author	Comorbid Condition	Reasons for Consideration of NM-allo-SCT vs Standard	HLA	MUD	Graft Failure	Comments
Giralt^[17] 1997 (update 2001^[15])	Concurrent medical conditions were also eligible	Patients considered poor candidates for conventional allotransplant because of age (> 50 yrs) or concurrent medical conditions	HLA-compatible siblings 6/6 (n=39); one-antigen-mismatched siblings 5/6 (n=7)	n=40 (6/6)	n=1 (autologous reconstitution)	All 17 patients who entered remission had 100% donor cells at 1 yr
Carella^[24] 1998	NS (no general contraindication to stem cells transplantation)	First-and second-line therapy without success (HD=4; NHL=2); CML in accelerated phase (n=1); CML in myeloblastic transformation with 70% marrow blasts (n=1); refractory anemia with excess blasts (n=1)	HLA-matched siblings (n=9)	n=0	n=0	Evidence of 100% donor cell engraftment in 6 patients
Kelemen^[11] 1998	NS	NS	HLA-identical siblings (n=19)	n=0	n=0
Khouri^[16] 1998	Patients were eligible if >50 yrs or had other medical problems that would preclude the administration of high dose; elevated ALT secondary to alcohol-induced liver toxicity (n=2); history of active hepatitis C (n=1); performance status of 3 (n=4)	Patients ineligible for high-dose ablative preoperative regimens due to age >50 yrs (n=13) or comorbidities	HLA-identical siblings (n=15)	n=0	n=0
Slavin^[8] 1998	NS	26 patients with standard indications for allogeneic BMT; NS	HLA-matched related donors (n=22)	n=0	n=0
Childs^[22] 1999	NS	Eligibility criteria for hematologic malignancies included disease with a probability of slow progression or in remission in patients >55 yrs	HLA-identical siblings (n=8)	n=0	n=0	One patient rejected transplant with subsequent recovery of autologous hematopoiesis
Garban^[26] 1999 (update 2001^[13])	NS	Poor candidates to conventional allogeneic transplantation with high-risk or relapsing myeloma patients	HLA-identical siblings (n=12)	n=0	n=0
Giralt^[14] 1999	NS	Patients having failed prior auto SCT (n=7)	HLA-identical siblings (n=13)	n=5	n=0	8 patients were <30 yrs of age
Sykes^[12] 1999	Eligibility criteria: chemotherapy-refractory NHL, performance status 2 or less; age 65 yrs or younger, and adequate organ function	Chemotherapy-refractory NHL performance status 2 or less, age 65 yrs or less, and adequate organ function	Haploidentical-related donor sharing at least 1 HLA A, B, or D allele on the mismatch haplotype	n=0	n=0
Bornhauser^[29] 2000	NS according to patients and disease	Patients with reduced performance status or major infectious complications not eligible for standard transplant procedure	HLA-matched siblings (n=21)	n=0	n=0
Gomez- Almaguer^[25] 2000 (update Ruiz- Arguelles 2001^[37])	NS	NS	HLA-identical siblings in all instances 6/6 (n=25)	n=0	n=1	Full chimerism (defined as more than 90% of donor cells on day 30 and afterwards) was seen in 17 patients, outpatients n=21
McSweeney 1999^[7] (update 2001^[5])	Preexisting liver cirrhosis (n=1), coronary artery disease, pulmonary aspergillosis, number of patients not specified	Patients ineligible for conventional HCT because of age or medical contraindications CLL and lymphomas had failed at least front-line therapy (n=NS); resistant acute leukemia (n=3); preexisting liver cirrhosis (n=1) aspergillosis (n=1)	HLA-identical siblings in all instances 6/6 (n=45)	n=0	n=9	53% of eligible patients had entirely outpatient transplants; 9 patients subsequently rejected their grafts (between 2-4 mos); none of these patients died
Nagler^[28] 2000	NS	All patients were very high risk and heavily treated; of the 23 patients, 12 had resistant disease (primary refractory or resistant relapse) and 11 were in third partial relapse at treatment	HLA-matched siblings (n=22)	n=1	n=0
Spitzer^[27] 2000	NS	Chemotherapy-refractory hematologic malignancies	HLA genotypic ally (n=20) or phenotypic ally (n=1) matched-donor transplant	n=0	n=0
Elmaagacli^[9] 2001	NS	To assess the efficacy of NM-allo-SCT vs BMT	HLA sibling (n=7); HLA partially matched family (n=2)	n=0	n=0
Lee^[30] 2001	NS according to patients and disease	To investigate the effectiveness of nonmyeloablative stem-cell transplantation for patients with heavily pretreated refractory lymphoma	NR	NR	NE	HLA type not reported in this study
Michallet^[20] 2001	NS according to treatment and disease	To assess the impact of pre-and post-transplantation factors on the outcome after nonmyeloablative preparative regimens	HLA-identical sibling (n=78)	n=0	NR
Mohty^[31] 2001	NS	NS	HLA-identical sibling (n=11)	n=0	n=0
Chakraverty^[33] 2002	NS	To investigate the effectiveness of reduced-intensity conditioning regimen in patients undergoing transplant from matched unrelated donor	n=0	n=47	NE
Corradini^[19] 2002	NS according to disease	To investigate the effectiveness of reduced-intensity conditioning regimen in patients considered as poor candidates for conventional myeloablative regimens	HLA-identical (n=42) or single HLA locus-mismatched (n=3) siblings	n=0	NE
Schlenk^[34] 2002	NS according to patients and disease	Assess toxicity and feasibility of achieving engraftment of allogenic blood progenitor cells following nonmyeloablative conditioning	HLA-identical sibling (n=11)	n=0	NR
Nagler^[21] 2001	NS	To investigate the feasibility of low intensity conditioning for BMT from matched unrelated donors	n=0	n=16	n=0
Pawson^[18] 2001	NS	To test the use of reduced intensity conditioning regimens to lessen transplant-related morbidity and mortality	Full HLA match (n=13); one-antigen-mismatch (n=1)	n=0	n=0
Badros^[10] 2002	NS	To investigate the feasibility of low-intensity melphalan-based conditioning regimen	HLA-identical siblings (n=25)	n=6	n=0
Baron^[32] 2002	NS	Patients were not eligible for standard SCT	HLA siblings (n=7); HLA sibling one-mismatch (n=2)	n=2	NR

Appendix 3: Conditioning Regimens Used in Studies of Nonmyeloablative Allo-SCT
Study	Conditioning Regimen Doses								Comments
Study	Flu	Bu	CY	ATG	TBI	TI	Mel	Other	Comments
Giralt^[17] 1997	30 mg/m² IV x 4 days							Either Ara-C 2 g/m² or Ia 12 mg/m² x 3 days (IV)	1 patient received melphalan 140 mg/m² once at the end of chemotherapy; 2/15 had grade III/IV toxicity
Giralt^[17] 1997	30 mg/m² x 4 days IV							Ara-C 1 g/m² x 5 days and 2-CDA 12 mg/m² (IV)	7 patients
Carella^[24] 1998	30 mg/m² x 3 days		300 mg/m² x 3 days						No procedure-related deaths
Kelemen^[11] 1998			150 mg/kg IV on days-4,-3,-2					DBM 120 mg/kg p. o. x 3 days, Ara-C IV 60 mg/kg x 3 days	Remarkable reduction in certain transplant-related complication
Khouri^[16] 1998	30 mg/m² IV x 3 days		300 mg/m² IV x 3 days						5 CLL patients
	30 mg/m² IV x 5 days		1000 mg/m² IV x 2 days						4 patients
	30 mg/m² IV x 2 days		1000 mg/m² IV x 2 days					Cisplatin 25 mg/m² IV x 2 days, cytarabine 500 mg/m² x 2 days	4 patients with Richter's syndrome
Slavin^[8] 1998	30 mg/m² IV x 6 days	Oral 4 mg/kg x 2 days		10 mg/kg x 4 days					No procedure-related deaths reported
Childs^[22] 1999	25 mg/m² IV x 5 days		60 mg/kg IV x 2 days
Garban^[26] 1999 abstract	25 mg/m² x 5 days	2 mg/kg x 2 days		2.5 mg/kg					Well-tolerated protocol, no mucositis; x 5 days duration of aplasia <7 days
Giralt^[14] abstract 1999							140 or 180		Flu/mel 140 or 180 was well tolerated with only 1 toxic death from tumor lysis and multiorgan failure
Sykes^[12] 1999			50 mg/kg	30 mg/kg		7 Gy on day-1
Bornhauser^[29] 2000	30 mg/m² IV x 5 days	3.3 mg/kg IV x 3 days							TRM was 12.5%
Gomez- Almaguer^[25] 2000 (update Ruiz- Arguelles 2001^[37])	30 mg/m² IV x 3 days	Oral 4 mg/kg x 2 days	350 mg/m² IV x 3 days						Showed that allogeneic stem cell transplantation can be performed safely on outpatient basis
McSweeney 2000^[7] (update 2001^[5])					Low-dose TBI 2 Gy single fractional day-4				Toxicity was mild, no mucositis, and no nausea; almost no myelosuppression noted
Nagler^[28] 2000	Low-intensity regimen								7 patients died (4 of grade III-IV GVHD and severe infections, 2 of bacterial sepsis, 1 pulmonary failure
Spitzer^[27] 2000			50 mg/kg IV on day-6 or -5 through-3	30 mg/kg x 2 days		7 Gy on day-1
Elmaagacli^[9] 2001	30 mg/m² IV x 4 days	1 mg/kg BW p. o. every 6 hrs over 2 days		10 mg/kg BW for 4 days
Lee^[30] 2001	30 mg/m²/d IV on days -7 to-2	4 mg/kg/d p. o. on days -7 and-6		20 mg/kg/d IV on days-5 to-2				Methylprednisolone 2 mg/kg/d IV on days-5 to-2
Michallet^[20] 2001	Dose varying from 25-30 mg/m²/d for 5 or 6 days	2 to 4 mg/kg/d for 2 days		2.5 mg/kg/d for 3, 4 or 5 days	ALG 5 mg/kg/d for 4 or 5 days combined with TBI in 5 patients			Ida 21 mg/m²/d days, cytarabine 2 g/m²/d for 4 days	3 different types of conditioning regimens were considered: FBT v IFA v ATG/ALG or regimens containing or not containing ATG/ALG: with ATG/ALG (FBT + ATG/ALG) and without ATG/ALG (IFA)
Mohty^[31] 2001	25 mg/m² IV x 5 days	2 mg/kg BW p. o. over 2 days		2.5 mg/kg/d IV for 4 days					ATG was administered to 3 patients only (NHL, HD, and CLL)
Chakraverty^[33] 2002	30 mg/m²/d IV on days-7 and-3						140 mg/m² IV 30 min on day-2	CAMPATH-1H 20 mg/d IV on days-8 to-4
Corradini^[19] 2002	30 mg/m²/d IV on days-4 and -3, 4 hrs after cyclophosphamide administration		30 mg/kg days on -4 and-3					Thiotepa 15 or 10 mg/kg (38 patients); thiotepa 5 mg/kg (7 patients)	Conditioning regimen was generally well tolerated in terms of mucosal or organ toxicity
Schlenk^[34] 2002	25 mg/m²/d on days-7 to-3		200 mg/m²/d on days -7 to-3					Ida 12 mg/m²/d on days-7 to-5; etoposide 250 mg/m²/d on days-4 to-3	1/11 patients developed grade IV mucositis; 3/11 developed fever >38.5°C
Nagler^[21] 2001	30 mg/m²/d IV for 6 days from day 10 to 5	4 mg/kg/d orally for 2 days on days 6 and 5		10 mg/kg/d IV for 4 days from day 4 to 1					Low median age of the patients (17.5 yrs) might have contributed to low toxicity
Pawson^[18] 2001								Liposomal daunorubicin 80 mg/m²/d on days 1-3	Dose for the FLAG regimen not reported; 10 patients received FLAG-Ida, 2 FLAG, and 2 FLAG + liposomal daunorubicin 80 mg/m²/d on days 1-3
Badros^[10] 2002	30 mg/m²/d IV on days-2 and-1				2.5 Gy in 2 fractions on day-2		100 mg/m² IV over 20 min on day 1		Flu and TBI were used only in MUD cases

Table 3. NM-Allo-SCT: Overview of Published Evidence in Hematologic Malignancies*
Benefits
Survival**	75% at 1-4 yrs (n=18) ^[11]
	28% at 2 yrs (n=86, 95% CI, 20-39%) ^[15]
	30% at 2 yrs (n=31) ^[10]
	60% at 58 mos (n=14) ^[18]
	53% at 24 mos (n=45) ^[19]
	75% at 36 mos (n=16) ^[21]
	31% at 2 yrs (n=76) ^[20]
Complete response	44% (215/486)
Harms
Treatment-related	32% (130/406) mortality
Acute GVHD	51% (232/454)
Chronic GVHD	23% (99/435)
Veno-occlusive disease	0.8% (1/37)
Relapse	15% (50/330)

Table 1. Benefits and Harms of "Standard" Allo-SCT in Hematologic Malignancies: Data From the International Bone Marrow Transplant Registry
Disease	Benefits		Harms
Disease	5-Year Survival	Comments	100-Day Mortality	Comments
ALL	30-50%	Depending on the type of donor (HLA-identical sibling vs unrelated donor) and time of transplant (CR1, CR2+)	14-38%	Depending on timing of transplant (CR1, CR+, others)
AML	30-60%	Depending on the type of donor (HLA-identical sibling vs unrelated donor) and time of transplant (CR1, CR2+)	13-38%	Depending on timing of transplant (CR1, CR+, others); HLA-identical sibling, 1-year TRM for early leukemia: 21%; for intermediate: 24%; for advanced leukemia: 36%
CLL	38-46%	Depending on age at transplant (<45 yrs vs >45 yrs) (HLA-identical sibling only)		Currently not reported by/available from IBMTR
CML	37-67%	Depending on type of the donor and timing of transplant	15-29%	Depending on the phase of the disease (chronic, accelerated, blast crisis)
Hodgkin's disease		Currently not reported by/available from IBMTR		Currently not reported by/available from IBMTR
MDS	20-55%	Depending on the phase of the disease (RAEB/RAEB-t vs RA/RARS)	25%
Myeloma	32% (at 4 years)	From Alyea and Anderson ^[4]; currently not reported by/available from IBMTR	10-56%	From Alyea and Anderson ^[4]; currently not reported by/available from IBMTR
NHL		Currently not reported by/available from IBMTR		Currently not reported by/available from IBMTR

Table 3. NM-Allo-SCT: Overview of Published Evidence in Hematologic Malignancies*
Benefits
Survival**	75% at 1-4 yrs (n=18) ^[11]
	28% at 2 yrs (n=86, 95% CI, 20-39%) ^[15]
	30% at 2 yrs (n=31) ^[10]
	60% at 58 mos (n=14) ^[18]
	53% at 24 mos (n=45) ^[19]
	75% at 36 mos (n=16) ^[21]
	31% at 2 yrs (n=76) ^[20]
Complete response	44% (215/486)
Harms
Treatment-related	32% (130/406) mortality
Acute GVHD	51% (232/454)
Chronic GVHD	23% (99/435)
Veno-occlusive disease	0.8% (1/37)
Relapse	15% (50/330)

Table 4. NM-allo-SCT: Overview of Published Evidence in Hematologic Malignancies According to Specific Diseases*
		AML	ALL	CML	MDS	NHL	HD	CLL	MM
Benefits	Survival**	NA at 4 yrs	NA	89% (17/19) at 1 yr	NA	100% (1/1) at 1 yr	NA	NA	33%
Benefits	CR	66% (41/62)	49% (27/55)	58% (42/72)	48% (10/21)	31% (32/103)	41% (16/39)	33% (9/27)	37% (38/103)
Harms	TRM	19% (10/52)	72% (29/40)	20% (13/64)	36% (5/14)	43% (32/75)	26% (9/35)	33% (8/24)	24% (24/98)
	Acute GVHD	36% (25/70)	36% (19/52)	60% (32/53)	54% (12/22)	50% (49/97)	57% (21/37)	68% (13/19)	59% (61/103)
	Chronic GVHD	23% (15/66)	24% (12/50)	29% (15/51)	31% (6/19)	12% (11/91)	41% (13/32)	32% (10/31)	18% (17/95)
	Veno-occlusive Disease	0% (0/6)	0% (0/2)	0% (0/27)	50% (1/2)	0% (0/38)	0% (0/10)	0% (0/2)	0% (0/50)
	Relapse	25% (13/52)	27% (11/40)	18% (12/65)	7% (1/15)	2% (1/41)	11% (3/27)	6.6% (1/15)	10% (8/76)

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