Autologous Stem Cell Transplant for AML

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Autologous Stem Cell Transplant for AML

• David Kuperman, M.D.
• Fellow in Hematology/Oncology
• Washington University in St. Louis
• 10/28/05

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Acute Myelogenous Leukemia

• AML is the most common acute leukemia in adults.
• The incidence is about 2.7 cases per 100,000.
• Standard therapy for AML is based on cytotoxic
  chemotherapy.
• Approximately 60 to 80 of patients will receive
  a complete response with this regimen.

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Standard Therapy for AML

• Patient require multiple rounds of chemotherapy
  to keep them in remission.
• There are several choices available for
  consolidation.

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Choices for Consolidation

• Consolidation chemotherapy
• Allogeneic stem cell transplant
• Autologous stem cell transplant

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Allogeneic Stem Cell Transplant

• An allogeneic stem cell transplant has been shown
  in multiple studies to be the most potent
  antileukemic therapy.
• This is primarily due to the graft versus
  leukemic effect.
• Unfortunately, it is not the best treatment
  option for many patients.
• Not every patient has a matched sibling or is
  able to find a matched unrelated donor.

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Allogeneic Stem Cell Transplant

• Age is a limiting factor for myeloablative
  allogeneic stem cell transplant.
• Significant morbidity and mortality from this
  therapy.

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What about autologous stem cell transplants?

• AML responds to chemotherapy.
• CALGB did a study comparing different doses of
  consolidation cytarabine as reported by Mayer et
  alia.
• Continuous infusions of Ara-C at 100 mg/m2 for 5
  days, 400 mg/m2 for 5 days, and 3 g/m2 Q12 on Day
  1, 3, and 5 x 4 cycles were compared.

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What about autologous stem cell transplants?

• AML can be cured with chemotherapy alone.
• Higher doses of chemotherapy seem to have a
  beneficial effect.
• It seems reasonable that myeloablative doses of
  chemotherapy would be beneficial.

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What about autologous stem cell transplants?

• Autologous stem cell transplants allow us to more
  safely perform myeloablative chemotherapy.

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Purging Grafts

• A concern with ABMT is that leukemia cells will
  be in the graft escaping chemotherapy and
  therefore leading to relapse.
• Brenner et alia infused a neomycin resistance
  gene using a retrovirus into 12 grafts from
  children with AML.
• In the two patients who relapsed, neomycin
  resistance was observed suggesting that the
  recurrence arose from leukemia in the graft

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Purging Grafts

• A number of approaches have been performed to try
  to purge these grafts ex vivo or in vivo.
• The most experience has been with
  4-hydroperoxycyclophosphamide (4HC).
• Miller et alia retrospectively compared 211
  patients receiving 4HC purged marrows to 83 who
  received unpurged.
• The were in CR1(n209) or CR2 (n83).

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Purging Grafts

• The median time to an ANC gt 500 was 40 days in
  the purged marrow vs. 29 days in the unpurged.
• TRM was 12 in the purged vs. 8 in the unpurged
  (p0.31).
• The 3 year DFS was 56 vs. 31 for patients in
  CR1.
• The 3 year DFS was 39 vs. 10 for patients in
  CR2.

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Purging Grafts

• Other methods of ex vivo purging have been used
  to purge grafts including mafofosfamide or
  antibodies.
• In vivo purging consists of giving several
  cycles of chemotherapy prior to collection of the
  graft.
• This seems to give better outcomes.

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Purging Grafts

• Whether this is from killing more residual
  leukemia over all leading to fewer cells to lead
  to a relapse in the patient or the graft or
  selection bias is unclear.

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Prospective Trials

• In the mid to late 1990s, a series of
  prospective clinical trials set out to answer the
  question of what consolidation therapy was the
  best.
• The first trial published was Zittoun et alia in
  1995.

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Zittoun et alia

• Patients in CR received cytarabine (1 g/m2 BID on
  Days 1-6) and amasacrine 120 mg/m2 on days 5, 6,
  and 7.
• The patients with matched siblings received an
  allogeneic transplant and those without were
  randomized to a Cy/TBI ABMT or Ara-C (2 g/m2 BID
  on Days 1-6) and daunorubicin 45 mg/m2 on days 5,
  6, and 7.

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Burnett et alia

• In 1998, Burnett et alia published the results of
  the MRC AML 10 trial.
• In this trial patients underwent 2 cycles of
  induction chemotherapy followed by MACE
  (Amarscine, cytarabine 200 mg/m2 CIVI days1-5,
  and etopside) and then Mitoxantrone HDAC
  (1g/m2 BID on days 1-3.)

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Burnett et alia

• Patients with matched sibs were then taken off
  study.
• The remaining patients were randomized to Cy/TBI
  ABMT or no further chemo.

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Prospective Trials

• Relapse rate was reduced from 49 to 25 (p0.02)
  for patients receiving ABMT in the favorable risk
  group.
• Relapse rate was reduced from 59 to 40 (p0.04)
  in the intermediate risk group.
• Relapse rate was not significantly different for
  poor risk patients.

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Cassileth et alia

• Also in 1998, Cassileth et alia published the
  results of a multicenter U.S. trial.
• Patients underwent standard induction with 73
  and then received a course of 52.
• Patients with a matched sibling were offered an
  allogeneic stem cell transplant.

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Cassileth et alia

• The remaining patients were randomized to HDAC (3
  g/m2 BID on 1, 3, and 5) x 1 or ABMT
• Both allogenic stem cell transplants and ABMT
  were conditioned with Bu/Cy.

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Cassileth et alia

• In a follow up analysis published by Slovak et
  alia, patients with favorable risk cytogenetics
  had improved DFS (71 vs. 35) with allogeneic
  and autologous having similar outcomes.
• In poor risk, allogeneic transplant had a DFS of
  44 vs. 13-15 in either arms.
• Intermediate risk had poorer outcome than
  chemotherapy (36 vs. 55 DFS)

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Difficulties with the Prospective Trials

• High drop out rate.
• Use of bone marrow as a source.
• Cassileth is the only trial without HDAC prior to
  autotransplant.
• Burnett and Cassileth both had one cycle of HDAC
  vs. ABMT which one could argue is not a fair
  comparison.

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Autologous Peripheral Stem Cell Transplant

• Sirohi et alia retrospectively compared ABMT to
  APSCT.
• TRM was 13 vs. 1 (P0.04).
• Time to engraftment was increased to 13.5 days
  vs. 33 days for neutrophils and 18 days versus 36
  for platelets.
• 4 year survival and relapse rates were similar.

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Current Opinions

• Most autologous transplants done today are with
  peripheral blood stem cells.
• Patients with poor risk disease do not benefit
  from autologous transplant in CR1.
• Patients with good risk and intermediate risk
  disease may have some benefit in CR1 but how much
  remains to be seen.

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Current Opinions

• Autotransplant in CR2 is currently reserved for
  APL which has had excellent results.

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References

• ASH-SAP
• Brenner M et alia. Gene-marking to trace origin
  of relapse after autologous bone-marrow
  transplantation . Lancet 341 (1993) pp. 85-86.
• Burnett AK et alia. Randomised Comparison of
  the Addition of Autologous Bone Marrow
  Transplantation to Intensive Chemotherapy for
  acute myeloid Leukaemia in First Remission
  Results of the MRC AML 10 Trial. Lancet 351
  (1998) pp. 700-708.

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References

• Cassileth et alia. Chemotherapy Compared with
  Autologous or Allogeneic Bone Marrow
  Transplantation in the Management of Acute
  Myeloid Leukemia in First Remission. NEJM 339
  (1998) pp. 1649-1656.
• Linker CA. Autologous Stem Cell Transplantation
  for Acute Myeloid Leukemia. Bone Marrow
  Transplantation 31 (2003) pp. 731-738.

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References

• Mayer RJ et alia. Intensive Postremission
  Chemotherapy in Adults with Acute Myeloid
  Leukemia. NEJM 331 (1994) pp. 896-903.
• Miller CB et alia. The Effect of Graft Purging
  with 4-hydroperoxycyclophosphamide in autologous
  bone marrow transplantation for acute Myelogenous
  leukemia. Experimental Hematology 29 (2001) pp.
  1336-1346.

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References

• Sirohi et alia. Reassessing Autotransplantation
  for Acute Myeloid Leukemia in First RemissionA
  Matched Pair Analysis of Autologous Marrow vs.
  Peripheral Blood Stem Cells. Bone Marrow
  Transplantation 33 (2004) pp.1209-1214.

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References

• Slovak ML et alia. Karyotypic Analysis Predicts
  Outcome of Preremission and Postremission Therapy
  in Adult Acute Myeloid Leukemia A Southwest
  Oncology Group/Eastern Cooperative Oncology Group
  Study. Blood 96 (2000) pp. 4075-4083.
• Zittoun et alia. Autologous or Allogeneic Bone
  Marrow Transplantation Compared with Intensive
  Chemotherapy in Acute Myelogenous Leukemia.
  NEJM 332 (1995) pp. 217-223.