Bone marrow transplantation versus prolonged intensive chemotherapy for children with acute lymphoblastic leukemia and an initial bone marrow relapse within 12 months of the completion of primary therapy: Children's Oncology Group study CCG-1941.

PURPOSE: To compare conventional sibling bone marrow transplantation (CBMT), BMT with alternative donor (ABMT), and chemotherapy (CT) for children with acute lymphoblastic leukemia (ALL) and an early first marrow relapse. PATIENTS AND METHODS: After informed consent, 214 patients with ALL and early marrow relapse began multiagent induction therapy. One hundred sixty-three patients with fewer than 25% marrow blasts and count recovery at the end of induction (second remission [CR2]) were allocated by donor availability. Fifty patients with sibling donors were allocated to CBMT. Seventy-two patients were randomly allocated between ABMT and CT while 41 patients refused allocation. RESULTS: Overall, 3-year event free survival from entry is 19% +/- 3%. Thirty-two of 50 CBMT patients (64%) and 19 of 37 ABMT patients (51%) underwent transplantation in CR2 with 3-year disease-free survival of 42% +/- 7% and 29% +/- 7%. The 3-year DFS is 29% +/- 7%, 21% +/- 7%, and 27% +/- 8% for patients allocated to CBMT, ABMT, and CT, respectively. Contrary to protocol, 12 of 35 patients allocated to CT underwent BMT in CR2. Of these, five patients died after BMT and 5 patients relapsed. CONCLUSION: More than one half of patients died, failed reinduction, or relapsed again before 3 months after CR2 (median time to BMT). Intent-to-treat pair-wise comparison of ABMT with CT, CT with CBMT, and CBMT with ABMT yields hazards of 1.2, 1.1, 0.8 with P values of .56, .80, and .36, respectively. Outcomes remain similar and poor for children with ALL and early marrow relapse. BMT is not a complete answer to the challenge of ALL and early marrow relapse.

Asparagine depletion after pegylated E. coli asparaginase treatment and induction outcome in children with acute lymphoblastic leukemia in first bone marrow relapse: a Children's Oncology Group study (CCG-1941).

PURPOSE: Re-induction outcomes vary for children with acute lymphoblastic leukemia (ALL) and marrow relapse. We explored possible relationships among asparaginase (ASNase) activity levels, asparagine (ASN) depletion, anti-ASNase antibody titers, and response to re-induction therapy in children and adolescents with ALL and an 'early' first marrow relapse. PATIENTS AND METHODS: After appropriate informed consent, we enrolled children and adolescents 1-21 years old with ALL and first marrow relapse within 12 months of completion of primary therapy. Induction therapy included intramuscular pegylated ASNase on Days 2 and 16. We assessed ASNase activity, anti-ASNase antibody titers against native and pegylated (E. coli) ASNase, and amino acid levels of asparagine (ASN) and glutamine (GLN) on Days 0, 14, and 35 of re-induction. RESULTS: Ninety-three patients were at least partially assessable. Among 21 patients with M1 marrow status at Day 35, the median Day 14 ASN level was <1 microM. This is significantly lower than the median Day 14 ASN level of 4 microM in the group of patients with M3 marrow at Day 35. Neither Day 0 nor Day 35 antibody titers predicted ASNase enzymatic activity level on Day 14. Surprisingly, Day 14 ASNase activity did not predict serum ASN level on Day 14. However, Day 0 and Day 35 anti-native ASNase antibody titers, and Day 0 anti-PEG ASNase antibody titers correlated positively with Day 14 serum ASN levels as one might expect from neutralizing antibody. Day 35 anti-PEG ASNase antibody titers did not. CONCLUSIONS: Patients with greater ASN depletion were more likely to achieve second remission in the context of six-drug therapy.

Risk classification at the time of diagnosis differentially affects the level of residual disease in children with B-precursor acute lymphoblastic leukemia after completion of therapy.

We have previously reported that children with B-precursor acute lymphoblastic leukemia (ALL) who remained in remission after successfully completing therapy had leukemia cells detectable by polymerase chain reaction (PCR) (N Engl J Med 1997;336(5):317-23). These patients were treated by an institutional protocol (P89-04) that lacked the post-remission intensification features of the contemporary Berlin-Frankfurt-Münster (BFM) based ALL protocols. In this report, we compared residual leukemia levels for patients on the P89-04 (n=15) and BFM-based Children's Cancer Group (CCG) studies (n=23) and for patients stratified according to risk group. Our goal was to establish which risk factors correlated with level of residual disease. Patients enrolled on the CCG protocols had lower levels of residual disease after completion of therapy than the P89-04 patients (P<0.019). Patients with high-risk disease also had lower levels of residual disease than patients with low risk disease (P<0.0001). Three-way analysis including time off treatment, risk group determined by features at presentation, and treatment protocol showed that risk group was the only significant independent variable (P<0.001).

Molecular monitoring of cerebrospinal fluid can predict clinical relapse in acute lymphoblastic leukemia with eosinophilia.

In a patient with precursor B-cell acute lymphoblastic leukemia (ALL) associated with eosinophilia that completely responded to induction chemotherapy, we assayed serial remission cerebrospinal fluid and bone marrow specimens for minimal residual disease using a quantitative polymerase chain reaction assay to assess for clone-specific immunoglobulin heavy-chain gene cluster (IGH) gene rearrangement. Cerebrospinal fluid eosinophilia and minimal residual disease were detected on day 406, preceding the morphologic diagnosis of central nervous system relapse on day 578. By day 841, the bone marrow had 35% blasts. Despite aggressive therapy, including unrelated umbilical cord blood transplantation, the patient developed testicular and bone marrow relapses and died of disease. We conclude that increasing levels of minimal residual disease in cerebrospinal fluid can predict recurrence of ALL prior to clinical and morphologic relapse. Furthermore, we demonstrate a novel translocation in this tumor, the t(5;9)(q31;p24), that possibly led to fusion of the interleukin-3 (IL3) (5q31) and JAK2 (9p24) genes and may explain the concomitant appearance of eosinophilia and ALL.

Residual leukaemia after bone marrow transplant in children with acute lymphoblastic leukaemia after first haematological relapse or with poor initial presenting features.

Relapse is the major obstacle to cure for children with acute lymphoblastic leukaemia (ALL) after allogeneic bone marrow transplant (BMT). Development of salvage therapy for post-transplant relapse could be expedited by understanding the post-transplant behaviour of microscopically undetectable leukaemia and the ability to predict impending relapse. We have used a quantitative polymerase chain reaction method (sensitivity of 5.0 x 10-6) to measure residual leukaemia before the conditioning regimen, and at five time-points after transplantation. In total, 18 patients with ALL transplanted in first or second remission were studied for 1 year: For the first year post BMT, 12 remained in remission, four had haematological relapses, one had a cutaneous relapse, and one died of severe graft-versus-host disease. The post-engraftment levels of the leukaemia-specific immunoglobulin heavy (IgH) chain gene rearrangement for patients with haematological relapses were significantly different from those who remained in remission. The levels for the patients who remained in remission decreased with time, although there were occasional increases consistent with the known standard deviation of the measurement assay. In contrast, all clinical relapses were preceded by a rapid increase in levels. Both the rate of this increase and its timing were variable. These results suggest that residual leukaemia measurements can be used to direct post-transplant interventions and measure their effects.

Minocycline-ethylenediaminetetraacetate lock solution for the prevention of implantable port infections in children with cancer.

In this prospective cohort study, minocycline-ethylenediaminetetraacetate (M-EDTA) was used as a lock solution in indwelling ports inserted in 14 children with cancer. No port infections, thrombotic events, or other adverse events were observed, compared with 10 port infections that occurred in 48 control patients whose ports were flushed with heparin. M-EDTA is a promising lock solution in long-term catheters.