Acute Leukemias - Republican Scientific Medical Library

a Acknowledgments 143
ment in DFS as reported by others. However, very few
relapses after 2 years have been noted. CNS prophylaxis
without cranial RT has been well tolerated and has not
resulted in an increase in CNS relapses. Longer followup
is needed to determine the potential benefit of intensified
Dnr on late relapses. Nevertheless, further Dnr
dose escalation seems unlikely to result in significant
improvements in outcome. Novel agents that eradicate
minimal residual disease should be introduced into clinical
trials of adult ALL.
10.8 CALGB Study 19801: T-cell ALL in Relapse
There have been almost no new drugs introduced into
the treatment of ALL in recent years. Nelarabine (Compound
506U78; GlaxoSmithKline) is a pro-drug of 9-Darabinofuranosylguanine
(ara-G), a deoxyguanosine
analog. Previous studies have demonstrated that immature
T-lymphocytes are extremely sensitive to the cytotoxic
effects of deoxyguanosine [20]. The toxicity of
deoxyguanosine to T-cells is related to the accumulation
of deoxyguanosine triphosphate (dGTP) with subsequent
inhibition of ribonucleotide reductase, inhibition
of DNA synthesis, and resultant cell death. Recent information
indicates that the rate of ara-GTP catabolism is
similar in T-cells and B-cells, but that initial ara-G concentrations
are higher in T-cells than B-cells for a given
dose. Thus, T-cells have a greater intracellular exposure
to ara-GTP than do B-cells.
Prior phase I studies determined a maximum tolerated
dose of 40 mg/kg/day for 5 days in adult patients.
The dose limiting toxicity was neurologic, consisting
of seizures, obtundation and ascending paralysis. As
predicted by preclinical in vitro studies, the highest response
rates were observed in patients with relapsed Tcell
ALL and lymphoblastic lymphoma (LBL). In order
to decrease the risk of neurologic toxicities, we tested a
dosing regimen of 1.5 g/m 2 given IV once per day on an
alternate day schedule (days 1, 3, 5) in an intergroup
study carried out by the CALGB and the Southwest Oncology
Group (SWOG).
Between 1998 and 2001, a total of 40 patients were
enrolled, 22 with T-ALL and 18 with LBL [21]. Patients
with greater than 25% lymphoblasts within the bone
marrow were considered to have ALL. The lymphoblasts
had to express at least two T-cell antigens. All patients
were refractory to at least one induction regimen or
were in first or greater relapse after achieving a CR. Pa-
tients could not have evidence of CNS disease and had
to have a calculated creatinine clearance of greater than
50 ml/min. A maximum of two induction courses was
administered. Each cycle was repeated every 21 days.
Those patients achieving a CR were allowed to receive
an additional two courses as consolidation therapy.
The median age was 34 years (range 16 to 66). There
were 33 males and seven females. Of the 21 evaluable patients
with ALL, there were six CRs and two partial remissions
(PR) for a total response rate of 38% (95% CI,
18–62%). For the 17 evaluable patients with LBL, there
were four CRs and no PRs for a total response rate of
24% (95% CI, 7–50%). The overall response rate
(CR+PR) for the 38 evaluable patients was 32% (95%
CI, 18–49%). One patient had a seizure and subsequent
confusion, which resolved. One patient developed hallucinations
but was also receiving narcotics. He was retreated
without the recurrence of additional neurologic
symptoms. The principal toxicity was marrow suppression.
Grade 3 or 4 neutropenia and thrombocytopenia
occurred in 43% and 33% of patients, respectively.
The median OS for the 40 patients was 4.6 months
(95% CI, 3–10 months). The median DFS for the 10 patients
achieving CR was 9.8 months (95% CI, 3–15
months). The 1-year OS is 32% (95% CI, 16–47%) and
the 1-year DFS is 40% (95% CI, 10–70%). These results
suggest that nelarabine is well tolerated, and has significant
antitumor activity in patients with relapsed or refractory
T-cell lymphoblastic leukemia/lymphoma.
Studies using nelarabine in patients with newly diagnosed
T-cell malignancies are warranted.
Acknowledgments
We thank the many physicians, nurses, and data managers
at each of the CALGB institutions and their affiliated
hospitals for their assistance with the conduct
of these clinical trials. Drs. Ted P. Szatrowski, Stanley
R. Frankel, Edward J. Lee, David A. Rizzieri, Daniel J.
DeAngelo, and Wendy Stock have chaired the clinical
studies described above. Dr. Clara D. Bloomfield chaired
the central cytogenetic review study. This research was
supported in part by grants from the National Cancer
Institute to the Cancer and Leukemia Group B
(CA31946 and CA41287), to the CALGB Statistical Center
(CA33601), and to CALGB member institutions.