What is the Cooperative Group protocol for the treatment of pediatric small noncleaved cell lymphoma?

Updated: Jun 14, 2018
  • Author: J Martin Johnston, MD; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
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Answer

Three cooperative groups conducted an international trial for patients with small noncleaved cell lymphoma (SNCCL); specifically, the French Society of Pediatric Oncology (SFOP), in France, Belgium, and the Netherlands; the Children's Cancer Group, in the United States, Canada, and Australia; and the United Kingdom Children's Cancer Study Group (UKCCSG), in the United Kingdom and Ireland.

Chemotherapy was based on the SFOP LMB-89 study, in which event-free survival rates ranged from 100% in group A to 87.5% in group C. Patients with B-cell acute lymphoblastic leukemia (ALL) were included in this protocol. Subjects were staged (as described above) and then were assigned to clinical risk groups. (See Tables 3, 4, 5, and 6, below.)

Table 3. Clinical Risk Groups in the International Trial for Patients With SNCCL (Children's Cancer Group study 5961) (Open Table in a new window)

Clinical Group

Subjects,

Estimated %

Definition

A

10

All resected stage I or abdominal stage II tumors

B

65

Unresected stage I or II tumor, stage III, tumor, or stage IV tumor with no CNS involvement and < 25% marrow blasts

C

25

CNS involvement or >25% marrow blasts

Table 4. Standard Therapy in the International Trial for Patients With SNCCL, Group A* (Open Table in a new window)

Drug

Route

Prednisone

PO

Vincristine, cyclophosphamide, doxorubicin

IV

Filgrastim (G-CSF), to enhance neutrophil recovery

SC or IV

G-CSF = granulocyte colony-stimulating factor; IV = intravenous; PO = oral; SC = subcutaneous

* See Table 3 for the definition of group A. All subjects received 2 cycles.

With median follow-up of more than 4 years, the 4-year event-free survival rate for group A patients was 98.3%, and the overall survival rate was 99.2%. [66]

In this trial, patients with advanced disease (groups B and C) received an initial moderately intensive "reduction" phase of chemotherapy. This was intended to reduce the tumor burden with minimal risk of inducing or exacerbating tumor lysis syndrome. Patients in group B were randomized to 1 of 4 treatment arms: the 3 experimental treatment arms involved incremental decreases in the intensity and/or duration of chemotherapy.

For patients in group B with an "early response" to therapy (at least 20% tumor decrease after 7 days of treatment), outcomes with standard therapy were not superior to outcomes with any of the experimental (reduced therapy) arms. (See Table 5, below.)

The results indicated, therefore, that pediatric patients with intermediate-risk B non-Hodgkin lymphoma who have an early response and achieve a complete remission after the first consolidation course can be effectively treated using a 4-course regimen with a total dose of only 3.3 g/m2 cyclophosphamide and 120 mg/m2 doxorubicin. [67]

Table 5. Standard Therapy in the International Trial for Patients With SNCCL, Group B* (Open Table in a new window)

Phase

Drug

Route

Reduction

Prednisone

PO

 

Vincristine, cyclophosphamide

IV

 

Methotrexate/hydrocortisone

IT

Phase

Cycles

Drug

Route

Induction

2, starting 7 days after reduction

Prednisone

PO

Vincristine, methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin

IV

Methotrexate/hydrocortisone

IT

Filgrastim (G-CSF)

SC or IV

Consolidation

2

Methotrexate with leucovorin rescue, Ara-C

 

Methotrexate/hydrocortisone, Ara-C/hydrocortisone

 

Filgrastim (G-CSF)

 

Maintenance**

1

Prednisone

PO

Vincristine, methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin

IV

Methotrexate/hydrocortisone

IT

Ara-C = cytarabine; G-CSF = granulocyte colony-stimulating factor; IT = intrathecal; IV = intravenous; PO = oral, SC = subcutaneous

* See Table 3 for the definition of group B.

** Based on published results from this trial, equivalent outcomes are expected with a reduced (50%) dose of cyclophosphamide in induction phase 2 and/or elimination of maintenance phase 1.

Group C patients in remission after 3 cycles were randomized to standard versus reduced-intensity therapy (omitting the last 3 cycles of maintenance). The 4-year event-free survival rate after randomization was 90% ± 3.1% versus 80% ± 4.2%, respectively, whereas the overall survival rate was 93% ± 2.7% versus 83% ± 4%, respectively. Patients with either combined marrow and CNS disease at diagnosis or a poor response to reduction therapy had significantly inferior event-free survival and overall survival. [68]

Therefore, decreasing therapy in this subgroup of patients appears unwise; standard-intensity therapy is recommended for children with high-risk B non-Hodgkin lymphoma. (See Table 6, below.)

Table 6. Standard Therapy in the International Trial for Patients With SNCCL, Group C* (Open Table in a new window)

Phase

Drug

Route

Reduction

Prednisone

PO

Vincristine, cyclophosphamide

IV

Methotrexate/Ara-C/hydrocortisone

IT

Induction, cycle 1 starting 7 days after reduction

Prednisone

PO

Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin

IV

Methotrexate/Ara-C/hydrocortisone

IT

Filgrastim (G-CSF)

SC or IV

Induction, cycle 2

Prednisone

PO

Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin

IV

Methotrexate/Ara-C/hydrocortisone

IT

Filgrastim (G-CSF)

SC or IV

Consolidation, 2 cycles

High-dose Ara-C, etoposide (VP-16)

IV

Filgrastim (G-CSF), days 7-21

SC or IV

High-dose methotrexate with leucovorin rescue

IV

Methotrexate/Ara-C/hydrocortisone

IT

Maintenance 1

Prednisone

PO

Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin

IV

Methotrexate/Ara-C/hydrocortisone

IT

Maintenance 2

Ara-C, etoposide (VP-16)

IT

Maintenance 3

Prednisone

PO

Vincristine, cyclophosphamide, doxorubicin

IV

Maintenance 4

Ara-C, etoposide (VP-16)

IV

Ara-C = cytarabine; G-CSF = granulocyte colony-stimulating factor; IT = intrathecal; IV = intravenous; PO = oral, SC = subcutaneous

* See Table 3 for the definition of group C.

For patients with CNS involvement, during consolidation cycle 1 only.

An alternative treatment approach has been developed over a series of randomized trials by the German Berlin, Frankfurt, Muenster (BFM) group. [69] In particular, the role of intermediate-dose or high-dose methotrexate has been investigated among the different clinical risk groups.

Pilot protocols for patients with B-cell non-Hodgkin lymphoma include monoclonal antibodies (eg, anti-CD20 rituximab) for children with high-risk disease (ie, patients with CNS disease at diagnosis or those with advanced-stage disease and elevated levels of lactate dehydrogenase).


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