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

[Cancer Control 10(1):17-41, 2003. © 2003 H. Lee Moffitt Cancer Center and Research Institute, Inc.]


Table 1. Benefits and Harms of "Standard" Allo-SCT in Hematologic Malignancies: Data From the International Bone Marrow Transplant Registry


DiseaseBenefitsHarms
5-Year SurvivalComments100-Day MortalityComments
ALL30-50%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)
AML30-60%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%
CLL38-46%Depending on age at transplant (<45 yrs vs >45 yrs) (HLA-identical sibling only) Currently not reported by/available from IBMTR
CML37-67%Depending on type of the donor and timing of transplant15-29%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
MDS20-55%Depending on the phase of the disease (RAEB/RAEB-t vs RA/RARS)25% 
Myeloma32% (at 4 years)From Alyea and Anderson [4]; currently not reported by/available from IBMTR10-56%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*


DiseaseNo. of Patients
ALL59
AML105
CLL27
CML114
HD37
NHL124
MDS32
MM105
Total603

*Data from 23 full papers, 1 abstract, and 1 letter. Note that most publications reported on more than one disease.
Includes patients with PLL.
Includes patients with plasma cell leukemia and extramedullary plasmacytoma (n=1). Assumed that the report by Michallet et al [20] included different patients than those described by Garban et al. [26]
Excludes 25 additional patients with unclassified acute leukemia, 2 with Waldenström's macroglobulinemia, and 1 with CMML.

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 response44% (215/486)
Harms
Treatment-related32% (130/406) mortality
Acute GVHD51% (232/454)
Chronic GVHD23% (99/435)
Veno-occlusive disease0.8% (1/37)
Relapse15% (50/330)

*The table represents a compilation of extractable data from 25 different studies that are heterogeneous with respect to population selection, pretransplant conditions, and conditioning regimens. Data should be interpreted with caution.
**Data from individual studies reporting survival beyond 1 yr.

Table 4. NM-allo-SCT: Overview of Published Evidence in Hematologic Malignancies According to Specific Diseases*


 AMLALLCMLMDSNHLHDCLLMM
BenefitsSurvival**NA at 4 yrsNA89% (17/19) at 1 yrNA100% (1/1) at 1 yrNANA33%
CR66% (41/62)49% (27/55)58% (42/72)48% (10/21)31% (32/103)41% (16/39)33% (9/27)37% (38/103)
HarmsTRM19% (10/52)72% (29/40)20% (13/64)36% (5/14)43% (32/75)26% (9/35)33% (8/24)24% (24/98)
Acute GVHD36% (25/70)36% (19/52)60% (32/53)54% (12/22)50% (49/97)57% (21/37)68% (13/19)59% (61/103)
Chronic GVHD23% (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 Disease0% (0/6)0% (0/2)0% (0/27)50% (1/2)0% (0/38)0% (0/10)0% (0/2)0% (0/50)
Relapse25% (13/52)27% (11/40)18% (12/65)7% (1/15)2% (1/41)11% (3/27)6.6% (1/15)10% (8/76)

*This table represents a compilation of extractable data from 25 different studies; there is a considerable heterogeneity among studies reflected in population selection, pretransplant conditions, and variety of conditioning regimens. Caution is needed in interpreting these data since they likely do not reflect an accurate body of evidence in NM-allo-SCT.
**Data on survival from single reports.

Appendix 1A: NM-Allo-SCT in Hematologic Malignancies: Demographics and Patient Characteristics


StudyDiseaseNo. of PatientsSexMedian Age (range)Comorbid ConditionsRegimenStudy DesignHLA TypeComments
Giralt[17]
1997
(updated
2001[15])
AML/MDS4352 F, 34 M52 (22-70) (56% older than 50 yrs)NRFlu/Ida or CDA/AraC or Flu/Mel 140 or 180Prospective cohort/case series without historical controlHLA-compatible siblings (n=39) or 1-antigen mismatched siblings (n=7); HLA (6/6) MUD (n=40); not specified according to diseaseAll considered poor candidates for conventional allo-transplant; median of 3 previous treatments (range 0-8)
CML27
HD4
NHL92CDA/AraC (not used after 1997)
ALL3
Carella[24]
1998
CML21 F, 1 M52 (50-55)NRFlu/CyProspective cohort/case series without historical controlHLA-matched siblings 
HD42 F, 2 M30 (22-36)
NHL21 F, 1 M33 (24-43)
MDS (RAEB)11 F57
Kelemen[11]
1998
CML19NANot reported individually (21-51)NRDBM/AraC/CyProspective cohort/case series, no historical controlHLA-identical siblings (n=19)8 patients under age 30
Khouri[16]
1998
CLL88 M59 (51-71)YesFlu/Cy/cisplatin/
cytarabine
Prospective cohort/case series, no historical controlHLA-identical siblings13 patients older than age 50, 2 had elevated ALT levels 2° due to alcohol-induced liver toxicity, 1 had hepatitis C infections
NHL (4 patients with Richter's syndrome)73 F, 4 M52 (45-58)Flu/Cy or cisplatin/Flu/cytarabine
Slavin[8]
1998
ALL22 M49 (12-46)NRFlu/Bu/anti-T-lymphocyte globulinProspective cohort/case series without historical controlMatched related donors (n=2)Included data on patients with nonhematologic malignancies but abstracted data only on those with hematologic malignancies
AML86 F, 2 M26 (1-51)Matched related donors (n=8)
CML81 F, 7 M37 (2-56)Matched related donors (n=8)
NHL22 M49 (37-61)Matched related donors (n=2)
MDS11 M41Matched related donor
MM11 M51Matched related donor
Childs[22]
1999
CML41 F, 3 M59 (28-68)NRCy/FluProspective cohort/case series without historical controlNot 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
NHL11 F55l
MDS22 M59 (58-60)
MM (EMP)11 F34
Garban[26]
1999
abstract
(updated
2001[13])
MM12NR53.5 (45-61)PS </= 2Bu/ATG/FluProspective cohort/case series without control groupHLA-identical sibling 
Giralt[14]
1999
abstract
MM18NR50 (46-61)NRFlu/MelProspective cohort/case series without control groupHLA-identical sibling (n=13); MUD (n=5) 
Sykes[12]
1999
NHL5NR32 (20-51)NoCy/ATG/TIProspective cohort/case series without historical controlHaploidentical-related donor sharing at least one HLA A, B or D allele on the mismatched haplotype 
Bornhauser[29]
2000
ALL11 F52YesBu/FluProspective cohort/case series with no controlHLA-matched sibling 
AML102 F, 8 M53 (38-65)
CLL31 F, 2 M41 (33-46)
CML41 F, 3 M51 (25-61)
HD22 M36 (35-37)
NHL11 F59
Gomez-
Almaguer[25]
2000
(updated
Ruiz-
Arguelles
2001[37])
AML66 F, 9 M43 (14-52)NRBu/Cy/FluProspective cohort/case series, no historical controlHLA-identical sibling21 patients transplanted in outpatient setting, 1 with thalassemia (excluded from this analysis)
MDS139
CML845 (24-61)
McSweeney[7]
1999
(updated
2001[5])
AML114 F, 7 M57 (36-63)YesLow-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 groupHLA-identical sibling53% 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
CML92 F, 7 M(40-71)No
CLL81 F, 7 M(46-67)No
NHL11 F53No
HD42 F, 2 M45 (31-61)No
ALL11 M60Yes
MM84 F, 4 M56 (46-63)No
MDS11 M43 (36-72)Yes
WF22 M55 (52-58)No
Nagler[28]
2000
NHL194 F, 15 M41 (13-62)NRLow-intensity FluProspective cohort/case series, no historical controlHLA-matched sibling 
HD44 M31 (17-53)
Spitzer[27]
2000
ALL1NE40NRCy/ATG/TIProspective cohort/case series, no control groupHLA genotypic ally (n=20) or phenotypic ally (n=1) matched donor transplant 
AML338 (27-44)
HD433 (27-55)
NHL1145 (22-62)
CLL253 (50-55)
Elmaagacli[9]
2001
ALL23 F, 6 MNEYesBu/Flu/ATGProspective cohort series with historical controlsHLA-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
AML1
CML6
Lee[30]
2001
NHL61 F, 5 M31 (22-56)YesBu/Flu/ATG/
methylprednisone
Prospective cohort/case studies without historical controlsNR 
HD11 M53
Michallet[20]
2001
ALL25NRNRYesFlu/Bu/ATG
Ida/Flu/AraC OAT/LG
Retrospective case series analysisAll HLA-identical sibling; 1 HLA-identical unrelated donor but not reported according to disease categoryConditioning regimens and HLA types not reported separately by disease; 3 patients with solid tumors excluded from abstracting and analysis; data extracted on evaluable patients
MDS9
NHL13
MM11
HD3
CLL3
CML12
Mohty[31]
2001
NHL31 F, 2 M42 (26-47)YesBu/FluProspective cohort/case studies without historical controlHLA-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
HD11 M40
CLL11 M49
MM63 F, 3 M54 (47-62)
Chakraverty[33]
2002
MM125 F, 7 M47 (34-52)YesCAMPATH1H/Flu/MelProspective cohort study without historical controlsNot specified according to disease; all patients had MUD transplantLow-and high-grade lymphoma grouped as NHL
NHL155 F, 10 M39 (18-56)
CML52 F, 3 M48 (36-53)
AML64 F, 2 M49 (30-55)
ALL21 F, 1 M22 (18-27)
HD53 F, 2 M31 (22-38)
CLL (T-PLL)11 F50
CMML11 M62
Corradini[19]
2002
AML517 F, 28 MNEYesThiotepa/Cy/FluProspective cohort study without historical controlsNot specified by disease; HLA-identical (n=42) or single HLA locus mismatched (n=3) siblingIndolent and high-grade lymphoma grouped as NHL
MDS6
ALL1
NHL24
HD4
MM5
Schlenk[34]
2002
AML93 F, 6 M61 (30-64)YesFlu/Cy/Ida/etoposideProspective cohort study without historical controlAll HLA-identical sibling (n=11) 
ALL11 M57
CML11 M62
Nagler[21]
2001
CML71 F, 6 M17 (12-48)YesFlu/Bu/ATGProspective cohort study without historical controlsMUD (n=16) 
AML42 F, 2 M21 (18-27)
ALL44 M10 (8-17)
NHL11 M13
Pawson[18]
2001
AML75 F, 2 M32 (24-48)YesFLAG (n=2)
FLAG-Ida (n=4)
FLAG-X (n=1)
Prospective cohort/case series with no historical controlFull HLA-matched (n=13), 1-antigen-mismatched (n=1) 
ALL55 M18 (9-31)FLAG-Ida (n=4)
FLAG-X (n=1)
MDS/(RAEB-t)22 F40 (38-42)FLAG-Ida
Badros[10]
2002
MM3113 F, 18 M56 (38-69)YesMel/TBI/FluProspective cohort/case studies with historical controlsHLA-matched sibling (n=25); MUD (n=6)Conditioning regimen for HLA-matched transplant differed from MUD transplant
Baron[32]
2002
ALL11 M25NoFlu/TBIProspective cohort/case studies with no historical controlMUD, identicalPatients 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
AML11 F57 TBIHLA-matched sibling
CLL11 F61TBIHLA-matched sibling
CML21 F, 1 M60 (58-62)TBI (n=1) Flu/TBI (n=1)HLA-matched sibling
HD11 M22TBIHLA-matched sibling

Table Abbreviations
ALL=acute lymphocytic leukemia
AML=acute myelocytic leukemia
AraC=cytarabine
ATG=antithymocyte globulin
Bu=busulfan
BW=body weight
CDA=chloroadenosine
CLL=chronic lymphocytic leukemia
CML=chronic myelogenous leukemia
CMML=chronic myelomonocytic leukemia
CMV=cytomegalovirus
CR=complete remission
Cy=cyclophosphamide
d=days
DBM=dibromomannitol
DFS=disease-free survival
EMP=extramedullary plasmacytoma
FLAG=Flu/AraC/G-CSF
FLAG-Ida=FLAG with Ida
FLAG-X=FLAG with daunorubicin
Flu=fludarabine
GVHD=graft-vs-host disease
HD=Hodgkin's disease
Ida=idarubicin
LCL=large-cell lymphoma
MDS=myelodysplastic syndrome
Mel=melphalan
MM=multiple myeloma
MUD=matched unrelated donor
NE=not extractable
NHL=non-Hodgkin's lymphoma
NR=not reported
NS=not stated
OAT/LG=other regimens with ATG or ALG
PFS=progression-free survival
PR=partial remission
PS=performance status
RAEB=refractory anemia with excess blasts
RAEB-t=RAEB in transformation
RCC=renal cell carcinoma
TBI=total body irradiation
TI=thymic irradiation
T-PLL=T-cell prolymphocytic leukemia
TRM=treatment-related mortality
WM=Waldenström macroglobulinemia
yr=year

Appendix 1B: NM-Allo-SCT in Hematologic Malignancies: Benefits


ReferenceDiseaseOverall Survival at 1-5 YrsDisease-Free Survival at 1-5 YrsMedian or Survival RangeComplete ResponsePartial ResponseMixed ChimerismFull ChimerismComments
Giralt[17]
1997
(updated
2001[15])
AML30% at 400 d32% at 400 dNENENRYesYes2-yr survival for all patients was 28% (95% CI, 20-39); 2-yr disease-free survival for all patients was 23% (95% CI, 15-34)
MDS30% at 400 d32% at 400 dNE
CML40% at 400 d40% at 400 d70% (19/27)
HD20% at 400 d20% at 400 d25% (1/4)
NHL20% at 400 d20% at 400 d22% (2/9)
ALL20% at 400 d20% at 400 d33% (1/3)
Carella[24]
1998
CMLNENE4 mos (2-10)50% (1/2)0% (0/2)YesYesNo patients required sterile room or red cell/platelet transfusion
HDNE50% (2/4)25% (1/4)
NHL4 mos (2-10)50% (1/2)50% (1/2)
MDS4 mos (2-10)100% (1/1)0% (0/1)
Kelemen[11]
1998
CML89% at 4 yrs (17/19)82% at 4 yrs (14/17)NENRNRYesYesChimerism investigated at 6 mos in 16 patients
Khouri[16]
1998
CLLNENENE38% (3/8)25% (2/8)YesYes50% probability of survival at 1 yr for the whole group based on median follow-up of 180 days (range 90 to 767 days)
NHL/LCL71% (5/7)14% (1/7)
Slavin[8]
1998
ALLNENENENRNRYesYesNo procedure-related deaths reported; survival for whole group at >1 yr was 85% (22/26); 21% disease free, included patients with nonmalignant hematologicdisease
AML
CML
NHL
MDS
MM
Childs[22]
1999
CMLNENE206 d (106-379)75% (3/4)NEYesYes 
NHL220 d100% (1/1)
MDS226 d (205-248)0% (0/2)
MM121 d0% (0/1)
Garban[26]
1999
(updated
2001[13])
MMNENE>6 - >15 mos33% (4/12)58% (7/12)YesYes 
Giralt[14]
1999
MM33% at 1 yr30% at 1 yr194 d (0-582)47% (8/18)NEYesYes 
Sykes[12]
1999
NHL0% at 1 yr (1/5)NE20% (1/5)20% (1/5)20% (1/5)YesYes 
Bornhauser[29]
2000
ALLNENENE100% (1/1)0% (0/1)YesYes100-day survival was 95% for the whole group
AML80% (8/10)NE
CLL67% (2/3)33% (1/3)
CML100% (4/4)0% (0/4)
HDNE50% (1/2)
NHLNENE
Gomez-
Almaguer[25]
(updated
Ruiz-
Arguelles,
2001[37])
AMLNENE60-360 d (4/6 alive)60% (4/6)NRYesYesMedian survival for all patients was 249 days; 1 graft failure reported
MDS90 d (1 died)NR
CML60-360 d (4/8 alive)50% (4/8)
ALL30-300 d (5/10 alive)50% (5/10)
McSweeney[7]
1999
(updated
2001[5])
AMLNENE2- > 15 mos64% (7/11)0% (0/11)YesYesMedian follow-up for whole group was 417 days (320-769 days); overall survival for all patients was 67% (30/45); 20% (9/44) rejected graft between 2 and 4 mos; no fatal rejections; overall TRM was 7% (3/45); relapse-related mortality was 27%; full chimerism in 21 patients by day 56
CML6- > 12 mos56% (5/9)0% (0/9)
CLL4- > 12 mos38% (3/8)38% (3/8)
NHL2 mos (died)100% (1/1)NA
HD4- > 10 mos50% (2/4)0% (0/4)
ALL11 mos100% (1/1)NA
MM2- > 24 mos50% (4/8)38% (3/8)
MDS6 mos (died)0% (0/1)0% (0/1)
WM11- > 12 mos0% (0/2)0% (0/2)
Nagler[28]
2000
NHLNENENENENEYesYes 
HD
Spitzer[27]
2000
ALLNENENE0% (0/1)0% (0/1)YesYes 
AML33% (1/3)33% (1/3)
HD50% (2/4)25% (1/4)
NHL36% (4/11)27% (3/11)
CLL50% (1/2)50% (1/2)
Elmaagacli[9]
2001
ALLNENENENENEYesYesSurvival/DFS/CR/PR not reported by disease: Survival at 1 and 2 yrs in the group receiving reduced conditioning regimen compared to conventional BMT was 77% and 74%, respectively
AML
CML
Lee[30]
2001
NHLNRNRNR33% (2/6)0% (0/6)YesNoSurvival not reported according to disease group
HD0% (0/1)100% (1/1)
Michallet[20]
2001
ALLNENRNE36% (9/25)16% (4/25)YesYesSurvival not reported by disease; overall survival was 38% at 1 yr and 31% at 2 yrs
MDS22% (2/9)11% (1/9)
NHL8% (1/13)85% (11/13)
MM0% (0/11)54% (6/11)
HD42% (5/12)0% (0/12)
CLL0% (0/3)33% (1/3)
CML0% (0/3)67% (2/3)
Mohty[31]
2001
NHLNRNRNR33% (1/3)33% (1/3)YesYes 
HD100% (1/1)0% (0 /1)
CLL0% (0/1)0% (0/1)
MM33% (2/6)0% (0/6)
Chakraverty[33]
2002
MMNENENE0% (0/12)45% (5/12)YesYesSurvival or DFS not reported by disease; at 1 yr, overall was 76% and PFS was 62%
NHL47% (7/15)7% (1/15)
CML100% (5/5)0% (0/5)
AML67% (4/6)0% (0/6)
ALL50% (1/2)0% (0/2)
HD40% (2/5)0% (0/5)
CLL (T-PLL)0% (0/1)0% (0/1)
CMML100% (1/1)0% (0/1)
Corradini[19]
2002
AMLNENENE60% (3/5)0% (0/5)YesYesSurvival not reported by disease; overall survival at 2 yrs was 53%; progression-free survival at 20 mos was 57%
MDS83% (5/6)0% (0/6)
ALL100% (1/1)0% (0/1)
NHL67% (16/24)25% (6/24)
HD25% (1/4)0% (0/4)
MM20% (1/5)60% (3/5)
Schlenk[34]
2002
AMLNRNRNR67% (6/9)0% (0/9)YesNoSurvival not reported by disease; overall survival at 22 mos was 44%
ALL100% (1/1)0% (0/1)
CML0% (0/1)0% (0/1)
Nagler[21]
2001
CMLNENENE0% (0/7)14% (1/7)YesYesSurvival/DFS not reported by disease; actuarial survival and DFS at 36 mos were 75% and 60%, respectively; alive and continuously disease-free were considered CR in this analysis; alive and well were considered PR
AML25% (1/4)50% (2/4)
ALL25% (1/4)50% (2/4)
NHL0% (0/1)100% (1/1)
AML25% (1/4)50% (2/4)
Pawson[18]
2001
AMLNENENE86% (6/7)14% (1/7)YesYesSurvival and DFS not reported by disease; overall survival was 75% at 1 yr and 62% at 2, 3, 4, and 5 yrs; DFS was 63% at 1 yr, 38% at 2 yrs, and 26% at 3, 4, and 5 yrs
ALL100% (5/5)0% (0/5)
MDS (RAEB-t)100% (2/2)0% (0/2)
Badros[10]
2002
MM1 yr: 68%
2 yrs: 30%
NRNE61% (19/31)10% (3/31)YesYesMedian survival was 15 mos; projected actuarial survival at 1 yr was 71% and 31% at 2 yrs; survival at 1 yr posttransplant was 71% for mini allograft compared to 45% for historical controls with conventional allo-SCT
Baron[32]
2002
NHLNENENE100% (5/5)0% (0/5)YesYesSurvival not reported by disease; overall survival at 1 yr was 69%
CML50% (1/2)0% (0/2)
CLL0% (0/1)100% (1/1)
AML100% (1/1)0% (0/1)
ALL100% (1/1)0% (0/1)

Appendix 1C: NM-Allo-SCT in Hematologic Malignancies: Harms


ReferenceDiseaseTransplant-Related MortalityAcute GVHDChronic GVHDVeno-Occlusive DiseaseRelapseOther Toxicity (Grade III-IV) and Comments
Giralt[17]
1997
(updated
2001[15])
AML43% (16/43)49% (95% CI 38-60)68% ± 9% (21/46)NR27% (23/86)Nonrelapse mortality at 2 yrs was ~45%
MDS60% (34/76)NENE
CML25% (7/27)NE
HD75% (3/4)
NHL78% (7/9)
ALL67% (2/3)
Carella[24]
1998
CML0% (0/2)50% (1/2)NRNRNRNo severe procedure-related toxicity
HD25% (1/4)50% (2/4)
NHL0% (0/2)0% (0/2)
MDS (RAEB)0% (0/1)0% (0/1)
Kelemen[11]
1998
CML11% (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
CLL38% (3/8)NE13% (1/8)NRNEToxicity NE; acute GVHD occurred after initial transplantation in 5 patients; not specified according to disease
NHL43% (3/7)14% (1/7)
Slavin[8]
1998
ALL0% (0/2)NE50% (1/2)NE50% (1/2)Differences noted in reporting on GVHD between text and Table 3; data extracted from Table 3
AML25% (2/8)38% (3/8)13% (1/8)13% (1/8)
CML25% (2/8)50% (4/8)13% (1/8)0% (0/8)
NHL0% (0/2)NE50% (1/2)0% (0/2)
MDS0% (0/1)NENS0% (0/1)
MM0% (0/1)NENS0% (0/1)
Childs[22]
1999
CMLNE50% (2/4)25% (1/4)0% (0/4)0% (0/4)2 patients died of transplant-related causes (1 had melanoma)
NHL100% (1/1)0% (0/1)0% (0/1)0% (0/1)
MDS50% (1/2)0% (1/2)50% (1/2)0% (0/2)
MM0% (0/1)0% (0/1)0% (0/1)100% (1/1)
Garban[26]
1999
(updated
2001[13])
MM17% (2/12)50% (6/12)58% (7/12) (2 extensive)NR8% (1/12)5 of 11 patients developed CMV infection (1 died of CMV encephalitis)
Giralt[14]
1999
MM47% (8/17)52% (9/17)18% (3/17)NRNR 
Sykes[12]
1999
NHL40% (2/5)100% (5/5)0% (1/5)NR20% (1/5) 
Bornhauser[29]
2000
ALLNE100% (1/1)0% (0/1)NENE100% (1/1)
AML10% (1/10)40% (4/10)50% (5/10)30% (3/10)10% (1/10)
CLLNE67% (2/3)33% (1/3)0% (0/3)33% (1/3)
CML75% (3/4)25% (1/4)50% (2/4)0% (0/4)
HD50% (1/2)0% (0/2)100% (2/2)50% (1/2)
NHL100% (1/1)0% (0/1)NE0% (0/1)
Gomez-
Almaguer[25]
2000
(updated
Ruiz-
Arguelles,
2001[37])
ALLNE30% (3/10)29% (2/7)NE60% (3/5)TRM was 12% (3/25) for all patients; each died of acute GVHD
AML0% (0/6)0% (0/5)50% (2/4)
CML62% (5/8)63% (5/8)75% (3/4)
MDS100% (1/1)100% (1/1)0% (0/1)
McSweeney[7]
2000
(updated
2001[5])
AML0% (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
CML0% (0/9)67% (6/9)44% (4/9)0% (0/9)
CLL13% (1/8)63% (5/8)75% (6/8)0% (0/8)
NHL100% (1/1)100% (1/1)NR0% (0/1)
ALL0% (0/1)100% (1/1)0% (0/1)0% (0/1)
MM13% (1/8)50% (4/8)17% (1/6)13% (1/8)
HD0% (0/4)75% (3/4)50% (2/4)0% (0/4)
MDS0% (0/1)0% (0/1)NR0% (0/1)
WM0% (0/2)50% (1/2)100% (2/2) 1 extensive0% (0/2) stable disease
Nagler[28]
2000
NHLNENENE0% (0/19)NE7 patients died (4 of grade III-IV GVHD and severe infections, 2 of bacterial sepsis, 1 of pulmonary failure)
HD0% (0/4)
Spitzer[27]
2000
ALL0% (0/1)0% (0/1)NENENENE
AML33% (1/3)67% (2/3)
CLL0% (0/2)100% (2/2)
HD0% (0/4)100% (4/4)
NHL9% (1/11)36% (4/11)9% (1/11)
Elmaagacli[9]
2001
ALLNENENENENENE
AML
CML
Lee[30]
2001
NHL100% (6/6)50% (3/6)17% (1/6)NRNENR
HD100% (1/1)100% (1/1)100% (1/1)
Michallet[20]
2001
ALL96% (24/25)24% (6/25)24% (6/25)NR16% (4/25)NE
MDS44% (4/9)44% (4/9)22% (2/9)11% (1/9)
NHL54% (7/13)62% (8/13)8% (1/13)0% (0/13)
MM55% (6/11)72% (8/11)27% (3/11)37% (4/11)
HD17% (2/12)42% (5/12)42% (5/12)0% (0/12)
CLL67% (2/3)67% (2/3)0% (0/3)0% (0/3)
CML0% (0/3)33% (1/3)33% (1/3)0% (0/3)
Mohty[31]
2001
NHL67% (2/3)0% (0/3)NR0% (0/3)NRAll patients survived beyond day 30 and maintained good oral intake throughout the procedure
HD100% (1/1)100% (1/1)0% (0/1)
CLL100% (1/1)100% (1/1)0% (0/1)
MM33% (2/6)100% (6/6)0% (0/6)
Chakraverty[33]
2002
MM17% (2/12)50% (6/12)0% (0/12)0% (0/12)8% (1/12)NR
NHL47% (6/15)27% (4/15)0% (0/15)0% (0/15)0% (0/15)
CML0% (0/5)60% (3/5)20% (1/5)0% (0/5)0% (0/5)
AML17% (1/6)33% (2/6)17% (1/6)0% (0/6)17% (1/6)
ALL50% (1/2)0% (0/2)0% (0/2)0% (0/2)0% (0/2)
HD20% (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)
CMML0% (0/1)0% (0/1)0% (0/1)0% (0/1)0% (0/1)
Corradini[19]
2002
AMLNE40% (2/5)40% (2/5)NRNENR
MDS83% (5/6)17% (1/6)
ALL100% (1/1)0% (0/1)
NHL75% (18/24)42% (10/24)
HD50% (2/4)75% (3/4)
MM80% (4/5)40% (2/5)
Schlenk[34]
2002
AML4% (4/9)22% (2/9)0% (0/9)NR44% (4/9)11% (1/9)
ALL0% (0/1)0% (0/1)0% (0/1)100% (1/1)0% (0/1)
CML100% (1/1)100% (1/1)100% (1/1)100% (1/1)0% (0/1)
Nagler[21]
2001
CML67% (2/7)86% (6/7)0% (0/7)NR0% (0/7)14% (1/7)
AML25% (1/4)100% (4/4)0% (0/4)25% (1/4)25% (1/4)
ALL25% (1/4)100% (4/4)0% (0/4)50% (2/4)0% (0/4)
NHL0% (0/1)100% (1/1)0% (0/1)0% (0/1)0% (0/1)
Pawson[18]
2001
AMLNE29% (2/7)0% (0/7)NRNERelapse not reported by disease but 10 of 14 patients relapsed
ALL60% (3/5)60% (3/5)
MDS (RAEB-t)50% (1/2)50% (1/2)
Badros[10]
2002
MM10% (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
NHL20% (1/5)60% (3/5)80% (4/5)NRNRNR
CML50% (1/2)0% (0/2)0% (0/2)
CLL100% (1/1)100% (1/1)0% (0/1)
AML0% (0/1)0% (0/1)00% (1/1)
ALL100% (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


AuthorComorbid ConditionReasons for Consideration of NM-allo-SCT vs StandardHLAMUDGraft FailureComments
Giralt[17]
1997
(update
2001[15])
Concurrent medical conditions were also eligiblePatients considered poor candidates for conventional allotransplant because of age (> 50 yrs) or concurrent medical conditionsHLA-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=0n=0Evidence of 100% donor cell engraftment in 6 patients
Kelemen[11]
1998
NSNSHLA-identical siblings (n=19)n=0n=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 comorbiditiesHLA-identical siblings (n=15)n=0n=0 
Slavin[8]
1998
NS26 patients with standard indications for allogeneic BMT; NSHLA-matched related donors (n=22)n=0n=0 
Childs[22]
1999
NSEligibility criteria for hematologic malignancies included disease with a probability of slow progression or in remission in patients >55 yrsHLA-identical siblings (n=8)n=0n=0One patient rejected transplant with subsequent recovery of autologous hematopoiesis
Garban[26]
1999
(update
2001[13])
NSPoor candidates to conventional allogeneic transplantation with high-risk or relapsing myeloma patientsHLA-identical siblings (n=12)n=0n=0 
Giralt[14]
1999
NSPatients having failed prior auto SCT (n=7)HLA-identical siblings (n=13)n=5n=08 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 functionChemotherapy-refractory NHL performance status 2 or less, age 65 yrs or less, and adequate organ functionHaploidentical-related donor sharing at least 1 HLA A, B, or D allele on the mismatch haplotypen=0n=0 
Bornhauser[29]
2000
NS according to patients and diseasePatients with reduced performance status or major infectious complications not eligible for standard transplant procedureHLA-matched siblings (n=21)n=0n=0 
Gomez-
Almaguer[25]
2000
(update
Ruiz-
Arguelles
2001[37])
NSNSHLA-identical siblings in all instances 6/6 (n=25)n=0n=1Full 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 specifiedPatients 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=0n=953% 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
NSAll 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 treatmentHLA-matched siblings (n=22)n=1n=0 
Spitzer[27]
2000
NSChemotherapy-refractory hematologic malignanciesHLA genotypic ally (n=20) or phenotypic ally (n=1) matched-donor transplantn=0n=0 
Elmaagacli[9]
2001
NSTo assess the efficacy of NM-allo-SCT vs BMTHLA sibling (n=7); HLA partially matched family (n=2)n=0n=0 
Lee[30]
2001
NS according to patients and diseaseTo investigate the effectiveness of nonmyeloablative stem-cell transplantation for patients with heavily pretreated refractory lymphomaNRNRNEHLA type not reported in this study
Michallet[20]
2001
NS according to treatment and diseaseTo assess the impact of pre-and post-transplantation factors on the outcome after nonmyeloablative preparative regimensHLA-identical sibling (n=78)n=0NR 
Mohty[31]
2001
NSNSHLA-identical sibling (n=11)n=0n=0 
Chakraverty[33]
2002
NSTo investigate the effectiveness of reduced-intensity conditioning regimen in patients undergoing transplant from matched unrelated donorn=0n=47NE 
Corradini[19]
2002
NS according to diseaseTo investigate the effectiveness of reduced-intensity conditioning regimen in patients considered as poor candidates for conventional myeloablative regimensHLA-identical (n=42) or single HLA locus-mismatched (n=3) siblingsn=0NE 
Schlenk[34]
2002
NS according to patients and diseaseAssess toxicity and feasibility of achieving engraftment of allogenic blood progenitor cells following nonmyeloablative conditioningHLA-identical sibling (n=11)n=0NR 
Nagler[21]
2001
NSTo investigate the feasibility of low intensity conditioning for BMT from matched unrelated donorsn=0n=16n=0 
Pawson[18]
2001
NSTo test the use of reduced intensity conditioning regimens to lessen transplant-related morbidity and mortalityFull HLA match (n=13); one-antigen-mismatch (n=1)n=0n=0 
Badros[10]
2002
NSTo investigate the feasibility of low-intensity melphalan-based conditioning regimenHLA-identical siblings (n=25)n=6n=0 
Baron[32]
2002
NSPatients were not eligible for standard SCTHLA siblings (n=7); HLA sibling one-mismatch (n=2)n=2NR 

Appendix 3: Conditioning Regimens Used in Studies of Nonmyeloablative Allo-SCT


StudyConditioning Regimen DosesComments
FluBuCYATGTBITIMelOther
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
30 mg/m2 x 4 days IVAra-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 daysRemarkable 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 days1000 mg/m2 IV x 2 days4 patients
30 mg/m2 IV x 2 daysCisplatin 25 mg/m2 IV x 2 days, cytarabine 500 mg/m2 x 2 days4 patients with Richter's syndrome
Slavin[8]
1998
30 mg/m2 IV x 6 daysOral 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 days2 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/kg30 mg/kg 7 Gy on day-1   
Bornhauser[29]
2000
30 mg/m2 IV x 5 days3.3 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 daysOral 4 mg/kg x 2 days350 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-330 mg/kg x 2 days 7 Gy on day-1   
Elmaagacli[9]
2001
30 mg/m2 IV x 4 days1 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-24 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 days2 to 4 mg/kg/d for 2 days 2.5 mg/kg/d for 3, 4 or 5 daysALG 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 days3 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 days2 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-2CAMPATH-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-31/11 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 54 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 1-3Dose 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