Nonmyeloablative Allogeneic Stem Cell Transplantation

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Non-myeloablative Allogeneic Stem Cell
Transplantation

• Reduced Intensity Conditioning
• Mini-allogeneic transplants
• Transplant Lite

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The Definition

• Upon engraftment mixed chimerism should be
  present
• If the graft is rejected, prompt autologous
  recovery should occur.

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Reduced Intensity Conditioning
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Reduction of Regimen Related Toxicity ?

• Cytopenias
• -GVHD
• Infectious complications

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Low-dose total body irradiation (TBI) and
fludarabine followed by hematopoieticcell
transplantation (HCT) from HLA-matched or
mismatched unrelated donorsand postgrafting
immunosuppression with cyclosporine and
mycophenolatemofetil (MMF) can induce durable
complete chimerism and sustainedremissions in
patients with hematological diseasesDietger
Niederwieser et al (Blood Feb 2003)

• N52
• Conditioning
• - Flu 30 mg/m2/d from d -4 to d -2
• - 2 Gy TBI on d0
• GVHD prophylaxis MMF CSA
• Complete donor chimerism
• - NK cells d 28
• - Granulocytes d 56
• - CD3 cell d180

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Engraftment
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Decreased transfusion requirements for patients
receiving nonmyeloablativecompared with
conventional peripheral blood stem cell
transplantsfrom HLA-identical siblingsFlorian
Weissinger, Brenda M. Sandmaier, David G.
Maloney, William I. Bensinger, Ted Gooley, and
Rainer Storb(Blood Dec 2001)

• Non-Myeloablative Transplants
• N40 (median age 51 yrs)
• Conditioning 2 Gy TBI
• 2 Gy TBI Flu
• GVHD prophylaxis MMF CSA
• Controls
• N67 (median age 46 yrs)
• Conditioning 12-14.4 Gy TBI Bu
• 12-14.4 Gy TBI Cy
• BuCy
• GVHD prophylaxis CSA Mtx

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Delayed donor red cell chimerism and pure red
cell aplasia following majorABO-incompatible
nonmyeloablative hematopoietic stem cell
transplantationCharles D. Bolan et al (Blood
Sept 2001)

• NMT MT
• N 14 12
• Donor RBC chimerism 114d 40d
• Delayed (gt 100 d) 64 0
• PRCA 29 0

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Rapid and complete donor chimerism in adult
recipients of unrelated donorumbilical cord
blood transplantation after reduced-intensity
conditioningJuliet N. Barker et al (Blood Sept
2003)

• N 43
• Median age 49.5 yrs
• 3.7 x 10e7 TNC (1-2 Ag Mismatched cords)
• Conditioning regimen
• Gp A. Flu 200 mg/m2 Bu 8mg/kg2Gy TBI
• Gp B. Flu 200mg/m2 Cy 50mg/kg 2 Gy TBI
• GVHD Prophylaxis CSA MMF
• Engraftment Gp A 76
• Gp B 94

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Graft-versus-host disease after nonmyeloablative
versus conventionalhematopoietic stem cell
transplantationMarco Mielcarek, Paul J. Martin,
Wendy Leisenring, Mary E. D. Flowers, David G.
Maloney, Brenda M. Sandmaier,Michael B. Maris,
and Rainer Storb(Blood July 2003)

• Non-Myeloablative Transplants
• N44 (median age 56 yrs)
• Conditioning 2 Gy TBI
• 2 Gy TBI Flu
• GVHD prophylaxis MMF CSA
• Controls
• N52 (median age 54 yrs)
• Conditioning gt 10 Gy TBI Cy
• Bu Flu
• Bu Cy
• GVHD prophylaxis CSA Mtx

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Limiting transplantation-related mortality
following unrelated donor stem celltransplantatio
n by using a nonmyeloablative conditioning
regimenRonjon Chakraverty et al (Blood Feb 2002)

• 47 patients with hematologic malignancy. (46 BMT)
• Median age 44 yrs.
• Conditioning
• - CAMPATH-1H 20 mg/d on d -8 to -4
• - Flu 30 mg/m2 on d -7 to -3
• - Mel 140 mg/m2 on d -2
• GVHD prophylaxis
• - CSA alone
• Median F/U 1 yr
• 29/34 full donor chimeras at 28 days.
• Only 3 pts developed gt Gr II acute GVHD and none
  had chronic GVHD.

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High incidence of cytomegalovirus infection after
nonmyeloablativestem cell transplantation
potential role of Campath-1Hin delaying immune
reconstitutionSuparno Chakrabarti, Stephen
Mackinnon et al (Blood June 2002)

• N101 (MUD 34)
• 51 pts had CMV infection
• Median time to inection 27 days
• 3 patients developed CMV disease.

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Risks and outcomes of invasive fungal infections
in recipients of allogeneichematopoietic stem
cell transplants after nonmyeloablative
conditioningTakahiro Fukuda, Michael Boeckh,
Rachel A. Carter, Brenda M. Sandmaier, Michael B.
Maris, David G. Maloney,Paul J. Martin, Rainer
F. Storb, and Kieren A. Marr(Blood Aug 2003)
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Myeloid Neoplasms
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Evidence for a graft-versus-leukemia effect after
allogeneic peripheral blood stem cell
transplantation with reduced-intensity
conditioning in acutemyelogenous leukemia and
myelodysplastic syndromeRodrigo Martino et al
(Blood Sept 2002)

• N37 (AML 17, MDS 20)
• Median age 57yrs
• Conditioning regimen
• Flu 30mg/m2 d -9 to d-5
• Bu 1mg/kg bid d -6 to d -4
• Median F/U 297 days
• Donor chimerism D 28 75
• D 90 85
• Gvhd Gr II-IV 19

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Durable Remissions of Myelodysplastic Syndrome
and AcuteMyeloid Leukemia After
Reduced-Intensity AllograftingBy D.C. Taussig,
et al (JCO Aug 2003)

• N16
• AML CR1 4 CR21
• MDS RA 5 gtRAEB 6
• Conditioning
• Flu 25 mg/m2 x 2 days
• Mel 140 mg/m2 x 1 day
• or
• Cy 1g/m2 x 2 days
• Median F/U 2 yrs
• GVHD Gr I-II 3/16

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Reduced Intensity Conditioning for Unrelated
Donor Hematopoietic Stem Cell Transplantation as
Treatment of Myeloid Malignancies in Patients
Older than 55 Years of Age Raymond Wong et al
(Blood Online July 2003)

• N 29 (AML 13, MDS 7, CML 9)
• Median age 59 yrs
• Conditioning regimen
• Flu Bu
• Flu Mel
• Flu Ara-C Mel
• /- ATG
• Median F/U 27 mths
• GVHD Gr II-IV 41
• Chronic GVHD 63

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Nonmyeloablative allogeneic stem cell
transplantation for the treatmentof chronic
myeloid leukemia in first chronic phaseReuven
Or, (Blood Jan 2003)

• N 24 (5 MUD)
• Conditioning
• Flu 30mg/m2/d on d -10 to -5
• Bu 4mg/kg/d on d -6 and -5
• (ATGAM 10mg/kg/d d -4 to -1 in MUD)
• Median F/U 42 mths
• 6 had mixed chimerism for 4-57 weeks
• GVHD Gr II-IV 13/24

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Lymphoproliferative Disorders
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Evidence of a Graft-Versus-Leukemia Effect in
Chronic Lymphocytic Leukemia After
Reduced-Intensity Conditioning and Allogeneic
Stem-Cell Transplantation The Cooperative German
Transplant Study Group J. Schetelig et al
(JCO July 2003)

• N30 (MUD 15)
• Conditioning
• FluBu ATGAM
• Median F/U 2 yrs
• Median donor chimerism status at 28d 95
• GVHD Gr II-IV 17/30 (56)

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Nonablative allogeneic hematopoietic
transplantation as adoptive immunotherapy for
indolent lymphoma low incidence of toxicity,
acute graft-versus-host disease, and
treatment-related mortality. Issa F Khouri et al
(Blood Dec 2001

• N20
• Conditioning regimen
• Flu 25mg/m2 x 5days
• CY 1g/m2 x 2 days
• /- Rituxan
• Median F/U 21 mths
• Median donor chimerism status at 28d 80
• GVHD Gr II-IV 20

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Chemoresistant or aggressive lymphoma predicts
for a poor outcome following reduced-intensity
allogeneic progenitor cell transplantation an
analysis from the LymphomaWorking Party of the
EuropeanGroup for Blood and Bone Marrow
Transplantation Stephen P. Robinson (Blood Dec
2002)

• N 188(48 had prior auto)
• Median age 40 yrs
• Conditioning regimen
• Flu based 84
• BEAM 10
• Median F/U 283 days
• Full donor chimerism 71
• Ac GVHD Gr II-IV 24
• Chronic GVHD 16

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The Allogeneic Experience in Myeloma

• MYELOABLATIVE
• Series of Pts CR
  100d TRM OS
• Arkansas 97 26 49 18 (3 yr)
• Seattle 106 36 53 23 (4 yr)
• EBMT 266 51 40 30 (4 yr)
• NON-MYELOABLATIVE
• Series of Pts CR
  100d TRM OS
• Arkansas 16 31 0 69 (45-490d)
• EBMT 204 ? 13_at_1yr 49 (2 yr)

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Tandem Auto Nonmyeloablative Allo
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Allografting With Non-Myeloablative Conditioning
Following Cytoreductive Autografts For The
Treatment Of Patients With Multiple Myeloma.
David G. Maloney et al (Blood Prepublished
on-line July, 2003)

• N 54
• Conditioning regimen
• Auto Mel 200/m2
• Allo 2 Gy
• Median F/U 552 days post allograft
• Donor Chimerism d 28
• CD3 90
• Gran 95
• GVHD Gr II-IV 38

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Autografting Followed by Nonmyeloablative
Immunosuppressive Chemotherapy and Allogeneic
Peripheral-Blood Hematopoietic Stem-Cell
Transplantationas Treatment of Resistant
Hodgkins Disease and Non-Hodgkins Lymphoma
Angelo M. Carella et Al JCO Dec 2000)

• N 15 (HD 10, NHL 5)
• Median age 34 yrs
• Conditioning regimen
• Auto BEAM
• Allo Flu/Cy
• Max F/U 700 days post allo
• Complete donor chimerism13/15
• Ac GVHD Gr II-IV 7/15
• Chr GVHD 2/15

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Role of Nonmyeloablative Allogeneic
Stem-CellTransplantation After Failure of
AutologousTransplantation in Patients With
LymphoproliferativeMalignanciesBy Katharine
Branson et al (JCO Oct 2002)

• N 38 (HD 12, MM 12, HGNHL 10, LGNHL 4)
• Conditioning Regimen
• CAMPATH Flu Mel
• DLI in 15
• GVHD Gr I-II 8/38

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Conclusions

• The number of transplants using reduced intensity
  conditioning regimen is growing rapidly.
• Not all reduced intensity conditioning regimens
  are truly non-myeloablative.
• These still carry substantial risk for
  opportunistic infections and GVHD.
• Data regarding efficacy in individual diseases is
  just starting to emerge.