Chapter 104. Acute and Chronic Myeloid Leukemia (Part 15) ppt

Donor leukocyte infusions without any preparative chemotherapy or GVHD prophylaxis can induce hematologic and cytogenetic remissions in patients with CML who have relapsed after allogene

Chapter 104 Acute and Chronic

Myeloid Leukemia

(Part 15)

Posttransplantation Treatment

BCR/ABL transcript levels have served as early predictors for hematologic

relapse following transplantation These should facilitate risk-adapted approaches with immunosuppression or TK inhibitor(s), or a combination of the two Donor leukocyte infusions (without any preparative chemotherapy or GVHD prophylaxis) can induce hematologic and cytogenetic remissions in patients with CML who have relapsed after allogeneic SCT

Imatinib can control CML that has recurred after allogeneic SCT but is sometimes associated with myelosuppression and recurrence of severe GVHD Imatinib after allogeneic SCT is being studied for prevention of relapse in patients

with advanced disease at the time of transplantation (i.e., patients at high risk for relapse), patients undergoing reduced-intensity transplants, or patients with slow

reduction of BCR/ABL message following transplantation Imatinib has also been

combined with donor lymphocytes to induce rapid molecular remissions in CML patients with disease relapse after allogeneic SCT Of interest are studies with newer TK inhibitors following transplantation for imatinib-resistant CML

Imatinib Mesylate

Imatinib mesylate (Gleevec) functions through competitive inhibition at the ATP binding site of the Abl kinase in the inactive conformation, which leads to inhibition of tyrosine phosphorylation of proteins involved in Bcr/Abl signal transduction It shows specificity for Bcr/Abl, the receptor for platelet-derived growth factor, and Kit tyrosine kinases Imatinib induces apoptosis in cells expressing Bcr/Abl

In newly diagnosed CML, imatinib (400 mg/d) is more effective than

IFN-α and cytarabine The complete hematologic remission rate, at 18 months, of patients treated with imatinib was 97% compared to 69% in patients treated with IFN-α and cytarabine Similarly, the complete cytogenetic remission rate was 76% with imatinib compared to 14% with IFN-α and cytarabine

All imatinib-treated patients who achieved major molecular remission

(26%), defined as ≥3 log reduction in BCR/ABL transcript level at 18 months

compared to pretreatment level, were free at 5 years The progression-free survival (PFS) at 5 years for patients achieving complete cytogenetic remission but less pronounced molecular remission is 98% The 5-year PFS for patients not achieving complete cytogenetic remission at 18 months was 87% These results have led to a consensus that molecular responses can be used as a treatment goal in CML Specific milestones have been developed for chronic-phase CML patients (Table 104-4) For example, chronic-chronic-phase CML patients who

do not achieve any cytogenetic remission following six months of imatinib are unlikely to achieve major molecular remission and should be offered other treatment approaches

Progression to accelerated/blastic phases of the disease was noted in 3% of patients treated with imatinib as compared to 8.5% of patients treated with IFN-α and cytarabine during the first year Over time, the annual incidence of disease progression on imatinib decreased gradually to <1% during the fourth and fifth years, and no patient who achieved complete cytogenetic remission during the first year of imatinib treatment progressed to the accelerated/blastic phases of the disease

Imatinib is administered orally The main side effects are fluid retention, nausea, muscle cramps, diarrhea, and skin rashes The management of these side effects is usually supportive Myelosuppression is the most common hematologic side effect Myelosuppression, while rare, may require holding drug and/or growth

factor support Doses <300 mg/d seem ineffective and may lead to development of resistance

Four mechanisms of resistance to imatinib have been described to date These are (1) gene amplification, (2) mutations at the kinase site, (3) enhanced expression of multidrug exporter proteins, and (4) alternative signaling pathways functionally compensating for the imatinib-sensitive mechanisms All four mechanisms are being targeted in clinical trials

BCR/ABL gene amplification and decreased intracellular imatinib

concentrations are addressed by intensifying the therapy with higher (up to 800 mg/d) imatinib doses Response in some patients has led to early intensification of imatinib dosage in newly diagnosed CML patients, resulting in improved major molecular remissions when retrospectively compared to controls treated with 400 mg/d Randomized studies comparing 400 mg/d doses to 800 mg/d in newly diagnosed CML patients are ongoing

Mutations at the kinase domain are being targeted by novel TK inhibitors that have a different conformation than imatinib, demonstrating activity against most imatinib-resistant mutations Nilotinib (Tasigma), like imatinib, binds to the kinase domain in the inactive conformation Dasatinib (Sprycel) binds to the kinase domain in the open conformation and also inhibits the SRC (sarcoma)

family of kinases, addressing the last mechanism of resistance CML with the T315I mutation is resistant to imatinib, nilotinib, and dasatinib

Dasatinib is approved by the FDA for the treatment of all stages of CML with resistance or intolerance to prior therapy, including imatinib Nilotinib will likely follow suit Both are oral agents given twice daily, with toxicity profiles similar to imatinib with small but significant differences Dasatinib was shown to cause pleural effusion in 22% of patients with 7% developing grade 3-4 toxicity Nilotinib was associated with sudden death in six of approximately 550 CML patients A suspected relationship to nilotinib was reported in two of these cases

These new agents have changed the treatment algorithm of CML For example, patients who do not achieve any cytogenetic remission at six months on imatinib will now be offered either dasatinib or SCT IFN-α, though FDA-approved for CML, will only be offered if all other options have failed

The encouraging results with imatinib have led clinicians to offer it as first-line therapy for newly diagnosed CML patients, including those who otherwise would have benefited from transplant (e.g., young patients with a matched sibling donor) Prior exposure to imatinib does not affect transplant outcome However, delaying BMT for high-risk patients (Sokal/Hasford criteria) may result in disease progression SCT after disease progression is associated with poorer outcome

Therefore, we recommend close monitoring of imatinib response, especially in these patients (Table 104-4)