Abstract
In the recent years T-ALL/LBL has turned to a favourable subtype of adult ALL due to intensive chemotherapy and/or SCT in first CR. At relapse, however, the disease is highly refractory and rapidly progressive. In the GMALL study 05/93 in ‘early’ relapse during therapy the CR rate with HD regimens was 29% and the survival 8%. The major problem was achievement of CR in order to proceed to SCT. Therefore the T-cell specific purine analogue compound GW506U78 (NSC 686673, Nelarabine) was evaluated. The compound was provided by the National Cancer Institute and administered as single drug (1.5 g/m2 day 1,3,5) in 53 adult pts. The median age was 31 (19–81) yrs. 47 (89%) had T-ALL and 6 T-LBL. 44 presented BM and 9 only extramedullary involvement. All pts had heavily pretreated, refractory disease. 36 (68%) were included in 1st ‘early’, 7 (13%) in 2nd relapse, 7 (13%) in relapse after SCT. 3 (6%) had never obtained CR. 32/36 pts in 1st relapse were refractory to >= one HD salvage therapy (FLAG-IDA 5, Cladribine/VP16/HDAC 18, other HDAC/HDMTX based 9).
25/53 evaluable pts (47%) achieved CR, 7 PR (13%) and 21 (40%) were refractory. The highest CR rate was achieved in pts with thymic T-ALL (76%). 19/25 CR pts (76%) were rapidly transferred to SCT (4 sibling, 14 MUD, 1 auto). Median time to SCT was 41 (20–83) d. 7/25 CR pts are in continuous CR at median 13 (1–36) mo. 4 pts died in CR (1 sepsis/liver failure, 3 transplant related). 14 pts relapsed, 10 after SCT. Time to relapse was median 5 (1–8) mo. 2 pts developed AML in relapse after SCT. 10 pts were included in the programme a second time, 8 in relapse after SCT. 4 CRs, 1 subjective improvement and 5 failures were observed. The probability of survival in the whole cohort is 16%, but significantly higher in pts who achieved CR (27%). Moderate bone marrow suppression and elevated liver enzymes were the most frequent toxicities. Neurotoxicity was encountered in only two pts (reversible psychosyndrome with agitation and somnolence).
We conclude that the compound has a impressive single drug activity in highly resistant relapsed T-ALL and is well tolerated even in heavily pretreated pts. Exploration in earlier stages e.g. molecular relapse, in front-line therapy and in combination is warranted. Since a durable remission cannot be expected with chemotherapy a high proportion of CR pts was transferred to SCT. Importantly no unexpected mortality or morbidity was observed after SCT. Long-term relapse free survival was achieved in some pts. The major problem were relapses. Therefore a better remission quality and lower tumor load before SCT should be obtained e.g. by consolidation cycles with the compound. After SCT close monitoring should aim for early detection of beginning relapse by MRD analysis in order to decide on interventions e.g. reduction of GvHD prophylaxis, donor lymphocyte infusions or additional cycles with the compound.Partly supported by Deutsche Krebshilfe (M84/92Ho1), NCI/CTEP and GlaxoSmithKline
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