Advances in the Management of Chronic Phase CML: ASH 2001

Advances in the Management of Chronic Phase CML: ASH 2001December 7-11, 2001Orlando, FloridaC. D. Buckner M.D.

Interferon

Alpha Interferon remains the primary drug for initial treatment of patients with chronic myeloid leukemia (CML) and will constitute the control for any comparison with Gleevec® or Gleevec® combinations. Investigators continue to evaluate the optimal way to administer alpha interferon and combinations of alpha interferon and other drugs.

Low Dose Interferon Appears to have Equal Efficacy with Fewer side Effects than High Dose Interferon

The MRC Adult Leukemia Working Party and the HOVON 20 CML Group determined the influence of the dose of IFN on the outcome of treatment in CML. Patients were treated with high or low-dose IFN. The high-dose IFN arm was targeted to receive a dose of 5 MU/m 2 daily or the maximal tolerated dose and the low-dose arm was targeted to receive a fixed dose of 3 MU 5 days/week. In addition, hydroxyurea was allowed to control the white blood cell count if necessary.

In total, 197 patients were randomized to high-dose and 197 to low-dose IFN. Complete hematological responses for high and low-dose IFN were 57% and 74% at 3 months, 77% and 80% at 6 months and 76% and 84% at 12 months, respectively. Major cytogenetic responses were seen in 16% of the high-dose arm and 18% of the low-dose arm to date. The mean daily dose of IFN actually received in the high-dose arm at 3, 6 and 12 months was 5.4, 5.4 and 4.7 MU in the HOVON 20 study and 6.1, 5.6 and 4.2 MU in the MRC CML V study. The mean daily dose of IFN in the low-dose arm was 2 MU daily at 3, 6 and 12 months for both studies.

Severe adverse effects of IFN therapy caused it to be abandoned within 12 months in 22% of the high-dose arm and 9% of the low-dose arm (p=0.001). IFN was abandoned by 12 months because of progressive disease in 4% and 7% in the high and low-dose arms, respectively (p=0.1). With a median follow-up of 30 months, overall survival is not significantly different between high and low-dose IFN therapy, with a 5-year survival of 51% and 53%, respectively.

The authors concluded that there are no significant differences in outcome, either major cytogenetic response rate or survival, comparing high and low-dose IFN, but that there are fewer side effects causing IFN therapy to be stopped prematurely in the low-dose arm. These results support earlier CML studies that used low doses of IFN, and is the first (and only) study showing in a randomized setting that low-dose IFN, if combined with hydroxyurea, is likely to be as effective as the more toxic and much more expensive high-dose approach. 1

Low Dose Arabinosyl Cytosine (LDAC) and Interferon Alpha (IFN) Improves Responses But Not Survival When Compared to IFN Alone in Chronic Myeloid Leukemia (CML)

Researchers randomized patients with newly diagnosed CML to receive IFN alone (5MIU/sqm daily) or IFN (same dose) associated with LDAC (40 mg daily s.c. 10 days a month). The study enrolled 528 patients between 1994 and 1997. Results were analyzed according to the intention to treat for response and survival. The complete HR rate at 6 months was 62% in the IFN + LDAC arm vs. 55% in the IFN arm (P=0.11). The major CR rate (Ph neg > 66%) at 24 months was 28% in the IFN + LDAC arm vs. 18% in the IFN arm (P=0.003). However, the 5-year overall survival was unaffected (P=0.77), with a rate of 68% and 65%, respectively. The compliance to the treatment was not different, but the average administered dose of IFN ranged between 0.82 and 0.66 of scheduled in both arms, while the average administered dose of AC decreased from 0.82 to 0.26 of scheduled during the study because in case of hematologic toxicity, AC was discontinued first and a priority was assigned to the continuation of IFN. These results do not suggest that all patients with newly diagnosed CML will benefit from combination chemotherapy with LDAC and IFN. 2

Early Allogeneic Stem Cell Transplant (SCT) May Not Be Best Approach For Low Risk Patients With Chronic Myeloid Leukemia (CML)

The German CML Study Group compared early related allogeneic SCT with the best available drug treatment. The instrument of genetic randomization, e.g. the availability of a related donor in a pre-defined baseline sample has been employed. The study recruited 679 patients, with 54% of patients eligible for SCT. A related donor was found in 38% of 312 evaluable patients, of which 88% were transplanted. Drug treatment of the 195 patients without a related donor was based on interferon (IFN). Intensive chemotherapy with one to several cycles of AraC/Idarubicin was recommended in addition to IFN-therapy in cytogenetic non-responders. Ninety patients received an unrelated SCT in chronic (n=83) or accelerated/blastic phase (n=6) during the course of drug treatment. Chronic phase patients were censored at the time of unrelated transplant. Median time to transplant was 10 months (range 2-43) for related and 16 months (range 5-57) for unrelated transplants. Median observation time after transplant was 24 months (range 0-62) for related transplants and 22 months (range 0-54) for unrelated transplants. Median observation time of the patients who received drug treatment is 33 months (range 3-74).

The 4-year survival of all drug treated patients is projected at 81%. Low-risk patients have a projected 4-year survival of 91%. All patients transplanted with a related donor have a projected 4-year survival of 61% (p<0.0005) and low-risk transplanted patients have a 4-year survival of 66% (p<0.0007) and treatment-related mortality was 29%. At present, survival is superior in IFN treated patients at least up to year 6 after diagnosis. There was no difference regarding survival at any time if related and unrelated SCT in chronic phase were compared.

The results of this first interim analysis of CML study III indicate that, with regard to survival, drug therapy is superior to early related allogeneic SCT during the first 4 years, which is more pronounced in low-risk patients. These authors suggest that low-risk patients and possibly also intermediate-risk patients should be offered a trial of IFN first and a transplant only if the response to IFN is not satisfactory. High-risk patients, they suggest, may benefit from early transplantation. These recommendations will vary depending on the TRM of the individual transplant center and future developments with Gleevec®. 3

Allogeneic Stem Cell Transplantation for CML

Many physicians believe that the optimal treatment for newly diagnosed patients with CML under the age of 55-60 with an HLA-matched donor is an allogeneic transplant in first chronic phase. However, this may change with further experience with Gleevec®. Most of the transplant abstracts at ASH dealt with peripheral blood versus bone marrow as a source of stem cells or comparative results with unrelated donors. The best results continue to be presented by investigators from the Fred Hutchinson Cancer Research Center who reported their most recent data using a targeted busulfan regimen.

Targeted Busulfan and Cytoxan Maybe The Optimal Regimen For Allogeneic Transplants For CML In Chronic Phase

Researchers from the Fred Hutchinson Cancer Research Center reported outcomes of 131 consecutive CML chronic phase patients treated with an allogeneic-related BMT using a targeted BU/CY preparative therapy. The median age of the patients was 43 years (range, 15-67 years). The busulfan dose was targeted to achieve a steady state plasma concentration of at least 900 mg/ml. Cytoxan was given at a dose of 60 mg/kg for each of two consecutive days.

The estimated probability of non-leukemic mortality was 10% and 16% at 1 and 3 years post-transplant, respectively. Relapse was defined as ever demonstrating hematological or cytogenetic recurrence. Estimates of the probabilities of relapse, survival, and relapse-free survival were 2%, 90% and 87% at 1 year post-BMT, and 4%, 86%, and 80% at 3 years post-BMT, respectively. At last contact, 12% of surviving patients were molecularly positive by RT/PCR for Bcr-Abl mRNA at a median of 407 days (range, 75-1731 days) post-transplant. The median level of Bcr-Abl transcripts in these patients was <10 copies/ug RNA (range <10-60 copies/ug RNA). These data suggest that targeted BU/CY is a very effective preparative regimen for CML in chronic phase, associated with a relatively low toxicity, a modest relapse rate and an expected survival of over 85%. 4

Outcome of HLA-Matched Unrelated Donor Bone Marrow Transplantation in Adults: A 10-Year Experience

Researchers at the University of Minnesota reported outcomes of adult URD BMT in 136 patients with myeloid malignancies. Fifty-four percent of patients had a diagnosis of CML and all received transplants from HLA-A,B,DRB1-matched donors. The median age was 36 years. Conditioning was myeloablative, with 99% of patients receiving a cyclophosphamide and TBI based regimen. Patients received graft-versus-host disease (GVHD) prophylaxis with either methotrexate and cyclosporine, or T-cell depletion.

At 2 years, only 14% of patients had relapsed and the overall survival was 41%. Multiple regression analysis showed that the significant factors adversely affecting survival were diagnosis other than CML, age >35 years, delay in time from diagnosis to transplant of > 18 months (chronic phase CML only), and the development of grades III-IV acute GVHD. Patients over 35 years of age with early chronic phase CML had a 2-year survival of 77%, which compared to a survival in similarly aged advanced CML patients of 67%, and for non-CML patients of 37%. Patients older than 35 years had a 2-year survival of 55% for those with early chronic phase CML, 40% for advanced CML and 14% in non-CML patients. The authors concluded that future efforts to improve outcomes of URD BMT should focus on improving the non-relapse mortality for older BMT recipients, especially those with diagnoses other than CML. 5

REFERENCES

  1. Shepherd, P., Kluin-Nelemans, H., Richards, S. et al. A Randomised Comparison of Low or High Dose IFN in Newly Diagnosed CML Patients Shows No Difference in Major Cytogenetic Response Rate or Survival Between the Two Groups Results of MRC CML V & HOVON 20 Trials. American Society of Hematology: 43 rd Annual Meeting Program and Abstracts. Blood. Vol. 98, No. 11, Part 1. 2001. Abstract 3034. p. 727a.
  2. Rosti, G., De Vivo, A., Bonifazi, F., et al. A Randomized Study of Interferon Alfa (IFN) vs. IFN and Low-Dose Arabinosyl Cytosine (LDAC) in Chronic Myeloid Leukemia. American Society of Hematology: 43 rdAnnual Meeting Program and Abstracts. Blood. Vol. 98, No. 11, Part 1. 2001. Abstract 3035. p. 727a.
  3. Hehlmann, R., Berger, U., Hochhaus, A., et al. Randomized Comparison of Early Allogeneic Related Stem Cell Transplantation vs. IFN-Based Therapy in Newly Diagnosed Chronic Myelogenous Leukemia: First Interim Analysis of the German CML Study III. American Society of Hematology: 43 rd Annual Meeting Program and Abstracts. Blood. Vol. 98, No. 11, Part 1. 2001. Abstract 3036. p. 728a.
  4. Radich, J.P., Gooley, T., Clift, R. et al. Allogeneic-Related Transplantation for Chronic Phase Chronic Myeloid Leukemia (CML) Using a Targeted Busulfan and Cytoxan Preparative Regimen. American Society of Hematology: 43 rd Annual Meeting Program and Abstracts. Blood. Vol. 98, No. 11, Part 1. 2001. Abstract 3239. p. 778a.
  5. Barker, J.N., DeFor, R.E., Davies, S.M., et al. Outcome of HLA-Matched Unrelated Donor Bone Marrow Transplantation in Adults: a 10-Year Experience. American Society of Hematology: 43 rd Annual Meeting Program and Abstracts. Blood. Vol. 98, No. 11, Part 1. 2001. Abstract 2823. p. 674a.
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