Cessation Of Maintenance Therapy Research Articles

Immune function in children under chemotherapy for standard risk acute lymphoblastic leukaemia – a prospective study of 20 paediatric patients

Multidrug chemotherapy is a highly effective treatment for paediatric acute lymphoblastic leukaemia (ALL), but at the same time compromises immunity of patients. Immune function in a homogenous cohort of 20 children with standard- and intermediate-risk ALL was analysed by immunophenotyping, intracellular cytokine staining, assessment of serum cytokine concentrations, T-cell receptor (TCR) repertoire diversity and thymic function. B-cells were most severely affected by chemotherapy, rapidly declined under induction and did not recover until the cessation of maintenance therapy. This recovery was paralleled by a relative increase in naive IgM(+)IgD(+)CD27(-) B-cells, indicating de novo B-cell generation as the major pathway for B-cell reconstitution. T- and Natural Killer-cells were less severely affected. Although numerically diminished by chemotherapy, they had partially recovered at the end of induction. Interestingly, CD4:CD8 ratio, distribution of naive versus memory T-cells, cytokine production, TCR-repertoire complexity and thymic function were all only marginally affected by chemotherapy. Patients receiving dexamethasone had significantly less IFNgamma(+) T-cells than those receiving prednisone. Our data show that during chemotherapy in standard- and intermediate-risk paediatric ALL patients the T-cell system remains relatively well preserved. Future studies will show if this effect can be exploited for inclusion of immunotherapy in standard ALL treatment protocols.

Minimal Residual Disease in Acute Lymphoblastic Leukaemia—PCR Analysis of Immunoglobulin Gene Rearrangements

Rearrangement of the immunoglobulin heavy chain (IgH) gene can be utilized as a marker of clonality in a number of B-lineage lymphoproliferative disorders including acute lymphoblastic leukaemia (ALL). We have used a PCR technique involving a panel of amplimers for the 6 different Variable (VH) region families and for a consensus sequence of the Joining (JH) segment to detect clonal IgH rearrangements in the peripheral blood (PB) and/or bone marrow (BM) of 28 patients (17 children and 11 adults) with B-lineage ALL at presentation (20 patients) or with overt relapse (8 patients). The age range of the patients was 2-65 years (mean 15.7 years). Follow up remission BM samples were analysed in 22 patients during and after therapy (2-7 samples per patient), 1-50 months after presentation or relapse. In 1 relapsed case, previously stored complete remission (CR) samples were analysed retrospectively. Clonal IgH chain rearrangements were detected by PCR in 90% of patients studied initially. The 2 VH region families most commonly used were the large VH3 family (65%) and the smaller more JH-proximal VH4 family (22%). More than one VH clone was detectable in 25% of the cases. A gene "fingerprinting" modification of a previously described method was applied to the detection of minimal residual disease (MRD) in follow up BM samples with a sensitivity of 10(-3) to 10(-4). In 8 of 14 patients remaining in complete remission (CR) during the time of study, all PCR analyses on BM samples in the first 6 months were negative, in some cases as early as 2 weeks post-induction therapy, and a further patient reverted from being PCR positive in the first month after the commencement of therapy to sustained PCR negativity. One adult remains in CR at 50 months after presentation and has been PCR negative at 2 time points after cessation of maintenance therapy (30 and 50 months). Eight patients relapsed in the study period comprising 6 BM and 2 isolated CNS relapses. In 4 cases of BM relapse occurring within 7 months of the start of therapy, all BM remission samples tested in this period were PCR positive. In 2 other patients BM samples tested 7 and 2 months respectively prior to relapse were PCR negative. In the 2 patients with isolated CNS relapse, PCR of BM samples from 2 and 10 months before the relapse were negative.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of intensified chemotherapy on the pluripotent haematopoietic progenitor cells CFU-GEMM in adult acute lymphoblastic leukaemia.

In order to analyse the short-term and long-term effects of intensified induction chemotherapy, the frequency, cellular composition and proliferative state of the pluripotent haemopoietic progenitor cells CFU-GEMM was investigated in a total of 35 patients with acute lymphoblastic or acute undifferentiated leukaemia at diagnosis, as well as during and after therapy. At diagnosis, the number of CFU-GEMM/ml bone marrow aspirate was significantly reduced to 12.1 (95% confidence interval 2.1-70) as compared to healthy controls (50.4/ml; 95% confidence interval 66-3846/ml). While immediately after the end of induction therapy, the respective values for CFU-GEMM were still decreased (30.4/ml; 95% confidence interval 8.4-108); values not significantly different from normal were reached within the following 4 weeks. During and after cessation of maintenance therapy again no significant deviation from normal values was observed. Immunological analysis of single colonies revealed that during the early phase after remission induction only 60 +/- 7% of mixed colonies contained megakaryocytic cells (normal 86 +/- 3%; P less than 0.01) while normal values were found during and after maintenance therapy. Cell cycle analysis disclosed highly increased proliferative activity of pluripotent progenitor cells during marrow regeneration after induction therapy as well as during maintenance therapy, but a return to the resting state after cessation of maintenance therapy. It is concluded that this intensive chemotherapy regimen does not result in any apparent long-term damage to the pluripotent haemopoietic progenitor cells.

Persistent presence of common ALL-antigen (cALLa)-positive cells in regenerating bone marrow after cessation of maintenance therapy in ALL of childhood

Persistent presence of common ALL-antigen (cALLa)-positive cells in regenerating bone marrow after cessation of maintenance therapy in ALL of childhood

Recovery of immune function after cessation of maintenance therapy in acute lymphoblastic leukemia (ALL) of childhood.

In previously healthy children, serum immunoglobulin levels at diagnosis of acute lymphoblastic leukemia (ALL) were entirely in the normal range. After antileukemic therapy had been given for 26-27 months, serum immunoglobulin levels were low. In 32 children these parameters could be followed for periods up to 3 years after cessation of therapy, the patients remaining in unmaintained remission. At cessation of therapy serum immunoglobulin levels were at the tenth centile of the normal range or slightly below. IgG promptly returned to normal levels and then remained in the normal range. IgA levels were restored much more slowly. Most striking was the slow and incomplete return of serum IgM to normal levels. Even after a follow-up of 3 years the mean was still subnormal. This was not accompanied by clinical signs of disturbed immunity. Our study points out that in assessing the long-term immunosuppressive effects of anticancer therapy the follow-up period must be sufficiently long.