Info

Note.Usually 20-50 metaphases are counted; cytogenetic abnormality is not detected unless it is present in 2-5% of cells.

"Major cytogenetic response = 66-100% Ph-negative cells in bone marrow.

Note.Usually 20-50 metaphases are counted; cytogenetic abnormality is not detected unless it is present in 2-5% of cells.

"Major cytogenetic response = 66-100% Ph-negative cells in bone marrow.

Minimal Residual Disease

Although the response to therapy is measured initially on the basis of hematologic and cytogenetic criteria, it is necessary to perform more sensitive studies when a complete cytogenetic response is attained. The following BCR/ABL studies are used to monitor the presence of minimal residual disease:

Study on bone marrow0 Sensitivity6 Comment

FISH on interphase cells

1 per 1000 cells

False-positive rate 10%

Southern blot

1 per 100 cells

Low sensitivity, so rarely used

Western blot

1-10 per 1000 cells

Low sensitivity, so rarely used

RT-PCRc

1 per 105-106 cells

Most commonly used method

Note.Even when reverse transcriptase polymerase chain reaction (RT-PCR) is negative for the detection of BCR/ABL transcripts, a patient may still have up to a million leukemic cells.

aWhen RT-PCR on bone marrow sample becomes negative, peripheral blood sample can be used in place of bone marrow for the test.

•"Lowest level of detection, i.e., number of leukemic cells per number of normal bone marrow cells. cThree types of RT-PCR: (1) qualitative, (2) quantitative, and (3) real-time (FISH): fluorescence in situ hybridization.

Note.Even when reverse transcriptase polymerase chain reaction (RT-PCR) is negative for the detection of BCR/ABL transcripts, a patient may still have up to a million leukemic cells.

aWhen RT-PCR on bone marrow sample becomes negative, peripheral blood sample can be used in place of bone marrow for the test.

•"Lowest level of detection, i.e., number of leukemic cells per number of normal bone marrow cells. cThree types of RT-PCR: (1) qualitative, (2) quantitative, and (3) real-time (FISH): fluorescence in situ hybridization.

Treatment of Advanced Phases of CML

Most of the information regarding treatment of various phases of CML is mainly derived from experience in adult patients.

Objectives of treatment:

• To attain cytogenetic response

• To achieve a complete hematologic remission

• To achieve a second chronic phase, followed by HSCT, if a suitable donor is available.

Treatment of CML in accelerated phase:

• Imatinib: 600 mg/day in adult patients (dose for children not yet established) OR

• IFN-a as a single agent or in combination with Ara-C (see above for dosages) OR

• Decitabine 15 mg/m2 intravenously daily for 10 days OR

• Investigational drugs; farnesyl transferase inhibitors, retinoids, nucleoside analogs, and imatinib in combination with other drugs.

Treatment of CML in nonlymphoid blastic phase:

• Decitabine: 15 mg/m2 intravenously daily for 10 days OR

• Fludarabine 30 mg/m2 intravenously daily for 5 days and Ara-C 1 g/m2 intravenously daily for 5 days OR

• Idarubicin 12 mg/m2 intravenously daily for 3 days and Ara-C 1.5 g/m2 intravenously daily for 4 days OR

• Fludarabine 30 mg/m2 intravenously daily for 3 days, Ara-C 1 g/m2 intravenously daily for 3 days, and mitoxantrone 10 mg/m2 intravenously daily for 4 days OR

• Vincristine 0.4 mg daily for 4 days by continuous infusion, doxorubicin 12 mg/m2 daily for 4 days by continuous infusion, and dexamethasone 40 mg daily on days 1-4, days 9-12, and days 17-20 OR

• Investigational agents including imatinib in combination with other agents.

Treatment of CML in lymphoid blastic phase:

Treated with the use of pre-B ALL protocol as outlined in chapter on acute leukemias. The remission rates in the blast cell phase of CML are low and duration of remission is usually short.

Allogeneic Stem Cell Transplantation for Chronic Myeloid Leukemia

The graft versus leukemia effect (GVL) results from a genetic disparity between donor and recipient. Therefore, greatest GVL effect occurs when the donor is unrelated to the recipient because of a greater number of incompatible minor histocompatibility antigens and also because of disparities between more major histocompatibility antigens.

Strongest GVL occurs when the transplantation is performed during the chronic phase in the presence of minimal residual disease, detectable by molecular testing. Weakest GVL effect occurs when the transplant is performed in a blastic phase and/or T-cell depletion is used for prevention of GVHD.

Figure 13-5 depicts some of the cellular mechanisms involved in GVL reaction following allogeneic HSCT in CML.

1. CML cells display antigens to antigen presenting cells (APCs).

2. APCs recognize leukemia-related antigens and present them to CD4+ and CD8+ cytotoxic T cells in the context of major histocompatibility (MHC) class

Induction of apoptosis" of CML cell through perforin and granzyme mechanism

BCR/ABL antigen-specific Tcell Proteinase 3-specific Tcells mHA antigen-specific T cells

VARIOUS SUBSETS OF ANTIGEN-SPECIFIC CYTOTOXIC CD8+ TCELLS IMPLICATED IN GRAFT VERSUS LEUKEMIA REACTION IN CML

Fig. 13-5. Some of the cellular mechanisms involved in graft versus leukemia reaction following allogeneic HSCT in CML (see text for explanation). Note: Numbers in parentheses correspond to description in text.

Induction of apoptosis" of CML cell through perforin and granzyme mechanism

CML 34+

Was this article helpful?

0 0

Post a comment