Remission Induction Therapy

Prednisone, vincristine, and L-asparaginase, based on pediatric regimens, formed the backbone of early trials in adult ALL. CR rates were 40-65%, with remission duration of only 3-7 months. However, the addition of an anthracycline (daunorubicin or doxorubicin) increased the CR rate to between 72 and 92%, and increased the median remission duration to approximately 18 months.631-34 CR rates were similar when different anthracyclines (daunorubicin and mitox-antrone) were compared during induction therapy in a CALGB trial.35 Intensification of the daunorubicin dose during induction has been reported to improve CR rates and DFS,36 37 and was the focus of a recently completed trial in the CALGB.38

From several pediatric ALL clinical trials, it appears that dexamethasone provides better antileukemic activity than prednisone; in part, this may be because of its ability to achieve higher drug levels in the CNS.39-41 The MD Anderson adult ALL trials have used dexametha-sone during induction and postremission therapy as part of their "hyper-CVAD" regimen.42 The CALGB is exploring the substitution of dexamethasone for pred-nisone during induction and postremission therapy.

L-Asparaginase has resulted in significant toxicities, including hepatotoxicity, neurotoxicity, pancreatitis, and coagulopathy in older adults with ALL, and its importance in adult ALL regimens remains somewhat controversial. A retrospective analysis performed by the CALGB demonstrated a marginal benefit in DFS for adults who received all prescribed doses of L-asparagi-nase in comparison to those who failed to receive all recommended doses.43 Currently, the optimization of L-asparaginase pharmacokinetics utilizing the polyethylene glycol conjugate of this agent is being studied in both pediatric and adult regimens.

The usual four-drug induction regimen (anthracy-cline, glucocorticoid, vincristine, and L-asparaginase) yields CR rates of up to 75-95% (see Table 13.2), and it has been difficult to demonstrate further improvement with additional drugs. The German Multicenter ALL

Cooperative Group (GMALL) has also used a 5-7-day "prophase" with prednisone and cyclophosphamide given prior to standard induction therapy for cytore-duction in an effort to minimize the risk of tumor lysis and its complications.50 Randomized studies have not demonstrated a benefit to the addition of agents such as cyclophosphamide or cytarabine,4951 although the addition of these agents to specific subsets of ALL may improve outcome.

To avoid exposure to the toxicities of L-asparaginase, steroids, and vincristine, investigators at Memorial Sloan Kettering Cancer Center have studied an alternative induction regimen for adults with ALL. This effective approach employs high-dose cytarabine and mitoxantrone and has resulted in a CR rate of 84%.52 L-Asparaginase has been omitted from the hyper-CVAD regimen at MD Anderson.42 The key components of hyper-CVAD consist of alternating cycles of fractionated doses of cyclophosphamide, high-dose methotrexate (MTX), and cytarabine with intensive CNS prophylaxis, followed by 2 years of maintenance with 6-mercaptopurine (6-MP), MTX, vincristine, and prednisone (POMP). In a long-term follow-up of results for this hyper-CVAD regimen in ALL, the overall CR rate was 92%. With a median follow-up of 63 months, the 5-year survival and CR duration rates were 38%.53

CONSOLIDATION/INTENSIFICATION

Although induction CR rates are 90% in many series of adult ALL, the long-term DFS over the last decade remains 25-50%, despite attempts to modify and improve postremission therapy through schedules with a variety of drugs that are active in ALL. These agents include oral and higher doses of intravenous MTX, antimetabolites such as 6-MP and 6-thioguanine, low-and high-dose cytarabine, and etoposide. In addition, many of the drugs that are used during induction therapy (anthracyclines, glucocorticoids, vincristine, and L-asparaginase) have also been reintroduced during postremission therapy. The value of postremission dose intensity has been addressed in several large prospective clinical trials with promising results. In a large phase II study from the CALGB, patients received both early and late intensification courses of treatment with eight drugs followed by maintenance chemotherapy for 2 years after diagnosis.44 Compared to previous CALGB trials where less intensive postremission therapy was administered, the median remission duration and survival improved to 29 and 36 months, respectively. Investigators at MD Anderson center have also explored dose intensification in their hyper-CVAD regimen. As mentioned above, the median survival for 288 patients treated between 1992 and 2000 was 32 months, with a 5-year survival of 38%.53

Successive German multicenter trials have evaluated the impact of subset-specific dose intensification during postremission therapy.54 Recently, patients

Results of recent chemotherapy studies in adult ALL

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