Gleevec usage prior to transplant -link not working

[Guest guest]

Sorry, all. The link wouldn't work so I copied and pasted the whole

thing.

Barb

Conference Coverage

Stem Cell Transplants for Chronic Myeloid Leukemia (CML) EBMT 2004

Date: March 28-31, 2004

Location: Barcelona, Spain

Author: C. D. Buckner, MD

Introduction

The European Group for Bone Marrow Transplantation (EBMT) held the 30th

annual meeting in Barcelona from March 28-31 2004. At this meeting

there were several presentations about the outcomes of patients

receiving allogeneic stem cell transplants for CML. All the transplant

centers have observed a 50% or greater reduction in the number of

patients transplanted for CML in the chronic phase since the

introduction of Gleevec® in 2000. Dr. Goldman of Hammersmith

Hospital, who is considered to be the world’s experts on CML, delivered

an opening address outlining the status of allogeneic stem cell

transplantation in the Gleevec® era.

Summary of Opening Lecture: “Allogeneic Stem Cell Transplantation for

CML in the Imatinib Era” by Goldman

Dr. Goldman stated that Gleevec® has become the initial treatment of

choice for newly diagnosed patients with CML since the publication of

the IRIS study comparing Gleevec® to interferon and cytarabine.1-3

Current data suggests that 97% of newly diagnosed patients with CML

will achieve a complete hematological remission, 87% will have a major

cytogenetic reduction and 76% will have a complete cytogenetic

remission following Gleevec® treatment. Seventy-nine percent of the 553

patients entered on this trial are still receiving first-line therapy

with Gleevec®. Dr. Goldman stated that progression-free survival

following Gleevec® treatment depends on the log reduction of BCR-ABL.

Those with a 3 log reduction have a 100% PFS at 30 months compared to

93% for a 2 log reduction and 81% for a 1 log reduction. Despite these

results, Dr. Goldman stated that it is still too early to determine if

single agent Gleevec® will prolong overall survival compared with the

best available non-transplant therapy. He also stated that it is

unlikely that patients will be cured with Gleevec® since only 5% have

become PCR negative.

At the present time, most transplant centers have seen a 50-75%

reduction in the number of transplants for chronic phase CML over the

past 4 years because patients have opted for Gleevec® rather than a

transplant. The issue of timing of transplantation for patients with a

stem cell donor were discussed. There were 2 options presented with the

first being related to response to Gleevec®. In this option, patients

with a suitable donor are transplanted if they do not achieve a

complete hematologic response with 3 months of Gleevec® if they are

predominantly PH positive at 6 months or still have >35% PH positive

metaphases at 12 months. In option one, patients would also be

transplanted if they had loss of a previous hematologic or cytogenetic

response or had a 1 log increase in BCR-ABL transcripts in a patients

who had achieved a complete cytogenetic response. The second option is

to transplant patients in chronic phase up to age 45 years who have a

sibling donor or up to the age of 35 years in those with a molecularly

matched unrelated donor as initial treatment. Dr. Goldman would also

use predictive models for success of Gleevec® versus success of

transplant. He presented data showing that the Sokal score, developed

in the busulfan era, also predicted for response to Gleevec®. Patients

at low risk on the Sokal score had a 94% PFS at 30 months, intermediate

risk and 88% PFS while high risk patients had an 80% PFS. There are

also predictive factors for success or failure of allogeneic

transplants. In registry data (EBMT and IBMTR), transplant related

mortality for patients 45 years of age or under is 15% but can be

higher with the presence of one or more adverse risk factors, such as

increasing time from diagnosis to transplant, a female donor,

increasing age and CMV positivity. Patients without any of these risk

factors would have a decreased treatment related mortality.

Effects of Gleevec® on Transplant Related Mortality

There is emerging evidence that Gleevec® can affect transplant related

mortality (TRM) and Dr. Goldman recommended at least 30 days between

discontinuing Gleevec® and transplant, citing deaths from

hepatotoxicity and a possible interaction with Tylenol and Gleevec®. In

a separate presentation from Hamburg, Dr. Zander reported that

treatment related mortality was 74% among 21 patients who had received

Gleevec® before transplant with an even higher rate for those receiving

Gleevec® within 15 days of transplant.4 In this study TRM in 21

patients who had received Gleevec® was compared to 23 control patients

who had not received Gleevec®. Treatment related mortality was 74% in

the Gleevec® compared to 40% in the control group while overall

survival was 16% in the Gleevec® group and 48% in the control group.

The major causes of increased TRM were severe GVHD and liver problems.

Treatment related mortality for those receiving Gleevec® within 15 days

was 80%.

Risk Factors and Outcomes of Allogeneic Stem Cell Transplants for CML 

Researchers from Spain reported outcomes of over 1000 allogeneic

transplants for CML.5 The EBMT score is based on the cumulative number

of previously reported major pretransplant risk factors:

histocompatibility, stage of disease at time of transplantation, age

and sex of donor and recipient, and time from diagnosis to

transplantation.6 One of the major findings of this study was an

overall improvement for transplants performed after 1995. They observed

that patients in chronic phase less than two years from diagnosis and

less than 40 years old who were transplanted from an HLA matched donor

had a DFS of almost 80%.

Survival After Relapse of CML

There are a variety of treatments available for patients with CML who

relapse after an allogeneic transplant, including Gleevec®, interferon,

donor lymphocyte infusions and even a second transplant. Researchers

from Spain reported a 63% survival at 5 years for 106 patients

relapsing after an allogeneic stem cell transplant for CML in chronic

phase.7 They also reported a 20% 5 year survival of 20% in patients

transplanted for more advanced disease. The average time to relapse was

15 months and almost half the patients had only a molecular or

cytogenetic relapse. The most frequent treatments were interferon and

donor lymphocyte infusions. Factors that were associated with improved

survival were increased time from transplant to relapse and a

cytogenetic relapse.

In Summary

Patients with newly diagnosed CML will probably be treated initially

with Gleevec® and allogeneic stem cell transplantation reserved for

failures. At the present time virtually all patients will have a donor

when one includes siblings, unrelated donors and umbilical cord blood.

For younger patients a conventional stem cell transplant with

myeloablative conditioning is probably the treatment of choice but the

impact of Gleevec® on outcome is yet to be determined. Researchers are

currently trying to extend the age at which successful transplants can

be carried out by using non-marrow ablative regimens. Whether or not

this approach will be successful remains to be determined.

References

1. TP, Kaeda J, Branford S, et al. Frequency of Major Molecular

Responses to Imatinib or Interferon Alfa plus Cytarabine in Newly

Diagnosed Chronic Myeloid Leukemia. New England Journal of Medicine.

2003;349:1423-1432.

2. O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with

interferon and low-dose cytarabine for newly diagnosed chronic-phase

chronic myeloid leukemia. New England Journal of Medicine.

2003;348:994-1004.

3. Lowenberg Bob, Perspective: Minimal Residual Disease in Chronic

Myeloid Leukemia. New England Journal of Medicine. 2003;349:1399-1401.

4. Zander A, Zabelina T, Renges H, et al. Pre-Treatment with Glivec

Increases Transplant-Related Mortality after Transplantation. Bone

Marrow Transplant. 2004;33, supplement 1:S60, abstract O352.

5. A Risk Factor Approach for Selecting Patients with Chronic Myeloid

Leukemia for Allogeneic SCT: A Model Based on the EBMT Score Applied to

the Spanish Registry. Bone Marrow Transplant. 2004;33, supplement

1:S60, abstract O354.

6. Gratwohl A, Hermans J, Goldman JM, et al. Risk assessment for

patients with chronic myeloid leukaemia before allogeneic blood or

marrow transplantation. Chronic Leukemia Working Party of the European

Group for Blood and Marrow Transplantation. Lancet. 1998;352:1087-92.

7. ez C, Gomez- de Soria V, Tomas JF, et al. Relapse Of

Chronic Myeloid Leukemia after Allogeneic Stem Cell Transplantation:

Outcome and Prognostic Factors. Bone Marrow Transplant. 2004;33,

supplement 1:S60, abstract O354.

http://www.caringbridge.org/wi/tomneddo