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Rituximab plus CHOP for treatment of diffuse large B-cell lymphoma during second trimester of pregnancy
Case Report
Rituximab plus CHOP for treatment of diffuse large B-cell lymphoma during second trimester of pregnancy Michael Decker, Christian Rothermundt, Georg Holländer, André Tichelli, Christoph Rochlitz
A 31 year old woman presented with an enlarged left supraclavicular lymph node and without constitutional symptoms at 15 weeks’ gestation during her first pregnancy. A Tru-cut biopsy showed a diffuse, large, B-cell non-Hodgkin lymphoma. MRI of neck, chest, abdomen, and pelvis showed enlarged lymph nodes in both the mediastinum and the left supraclavicular area and in the fetus (figure 1). Biopsy samples and aspirate of bone marrow did not show infiltration by tumour cells. Haemoglobin was 11·4 g/L, whereas results of all other laboratory tests, including lactate-dehydrogenase concentrations, were within normal ranges. The patient was therefore diagnosed with stage IIA diffuse large Bcell non-Hodgkin’s lymphoma (low risk on the international prognostic index). The patient was given six cycles of R-CHOP on a 14 day schedule: 375 mg/m² rituximab, 750 mg/m² cyclophosphamide, 50 mg/m² doxorubicin, 1·4 mg/m² vincristine, and 100 mg/day prednisone on days 1–5. 300 µg filgrastim was given subcutaneously on days 6–11 after immunochemotherapy. Treatment could be given without any delay. No febrile neutropenia occurred. R-CHOP was very well tolerated, and one dose of metoclopramide was needed for the control of treatment-related side-effects (nausea and vomiting). A complete response confirmed by MRI in accordance with RECIST (response-evaluation criteria in solid tumours) criteria was achieved after the second cycle of treatment. 18 months after treatment, the patient is in complete remission. 2 months after the end of treatment and in the 33rd week of pregnancy, the patient spontaneously delivered a healthy baby girl (weight and size within the 50–90 percentile, APGAR [activity, pulse, grimace, appearance, respiration] score 8/10/10). Because of prematurity, the baby was initially treated in the neonate intensive-care unit for 1 week without specific isolation measures. Use of R-CHOP has been shown to increase survival when compared with CHOP for treatment of diffuse, large B-cell lymphoma in elderly patients aged 60–80 years1 and in patients younger than 60 years with a good outlook.2 The feasibility and efficacy of R-CHOP given in shortened cycles of 14 days have been proven before.3 CHOP is thought to be safe during the second and third trimester of pregnancy;4,5 however, only two case reports have been published for use of R-CHOP during pregnancy, both of which had short clinical and immunological follow-up.6,7 We assessed the patient and the child clinically every 3 months with a follow-up of 16 months so far. Absolute http://oncology.thelancet.com Vol 7 August 2006
numbers and phenotypes of peripheral blood cells, titres of antigen-specific antibodies, and serum rituximab concentrations were monitored in the patient at 8 weeks after start of treatment, and in both patient and child at delivery and 2 months, 3 months, and 8 months thereafter. Neither mother nor child developed any infections during the time of observation. The child is under close assessment every 3 months and has shown no physiological or developmental abnormalities. The treatment resulted in an almost complete loss of peripheral B-cells in the mother, but did not decrease total serum immunoglobulin concentrations. The reconstitution with CD19 and CD20 peripheral B cells began 20 weeks after completion of treatment (ie, 12 weeks after delivery). The emergence of B-cells coincided with a large decrease in serum concentrations of rituximab. The titre of rituximab dropped according to its known half-life of 28 days (figure 2). The child’s B cells were severely diminished (1% of normal) at birth but started to recover 6 weeks later (figure 2) reaching normal range after 12 weeks. At delivery, the serum rituximab concentrations were similar in mother (0·02 g/L) and child (0·03 g/L). Because rituximab is an IgG1 antibody, transplacental transport is efficient. In the child, rituximab concentrations also decreased as expected (figure 2). However, the child’s B cells recovered faster than did those in the mother. Moreover, serum concentrations for antigen-specific antibodies (rubella, measles, mumps, chickenpox, tetanus, and diphtheria) were unchanged in the mother despite treatment. The child showed the physiological decrease typically seen during the first months of life. After vaccination at age 8 weeks and boost at age 16 weeks,
Lancet Oncol 2006; 7: 693–94 Department of Haematology, University Hospital Basel, Switzerland (M Decker MD, Prof A Tichelli MD); Royal Marsden Hospital, London, United Kingdom (Prof C Rothermundt MD); Center for Biomedicine and Paediatric Immunology, University Children’s Hospital of Basel, Switzerland (G Holländer MD); Department of Oncology, University Hospital Basel, Switzerland (Prof C Rochlitz MD) Correspondence to: Dr Michael Decker, University Hospital Basel, Department of Haematology, Petersgraben 4, CH-4031 Basel, Switzerland [email protected]
Figure 1: MRI at diagnosis (A) Mediastinal mass (arrow). (B) Fetus at 15 weeks’ gestation.
693
Case Report
A
B 25 20
%
15 10 5
6 x R-CHOP
6 x R-CHOP
0 –30
–20
–10
0
10
20
30
40
C
–30
–20
–10
0
10
20
30
40
0
10
20
30
40
D
Rituximab serum concentration (ng/mL)
30 000 25 000 20 000 15 000 10 000 5 000
6 x R-CHOP
6 x R-CHOP
0 –30
–20
–10
0
10
20
30
40
–30
Weeks before and after delivery
–20
–10
Weeks before and after delivery
Figure 2: Concentrations of CD19 B cells during and after treatment with R-CHOP B-cell counts in mother (A) and child (B). Rituximab serum concentration in mother (C) and child (D).
the child’s humoral immune response to tetanus, diphtheria, pertussis, and haemophilus was normal, and was confirmed normal at 8 month follow-up. Neither the mother nor the child had hypogammaglobulinaemia; and age-adjusted concentrations of IgG, IgM, IgA, and IgG-subclasses were normal. To our knowledge, this is the first published case of a pregnant patient with diffuse large B-cell lymphoma treated successfully with R-CHOP and with immunological follow-up of 8 months for mother and child after birth and a clinical follow-up of 16 months after diagnosis. Because immunological measurements were normal at that time, we have done no further investigations. Our patient was treated safely and efficiently, even in the second trimester, with this immunochemotherapy. No adverse effects in the fetus or child were seen during the 16 months of follow-up.
References 1 Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B-cell lymphoma. N Engl J Med 2002; 346: 235–42. 2 Pfreundschuh M, Trümper L, Österborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large B-cell lymphoma: a randomized controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006; 7: 379–91. 3 Halaas JL, Moskowitz CH, Horwitz S, et al. R-CHOP 14 in patients with diffuse large B-cell lymphoma: feasibility and preliminary efficacy. Leuk Lymphoma 2005; 46: 541–47 4 Resnik R. Cancer during pregnancy. N Engl J Med 1999; 341: 120–21. 5 Cardonick E, Iacobucci A. Use of chemotherapy during pregnancy. Lancet Oncol 2004; 5: 283–91 6 Herold M, Schnohr S, Bittrich H. Efficacy and safety of combined rituximab chemotherapy during pregnancy. J Clin Oncol 2001; 19: 3439. 7 Kimby E, Sverrisdottir A, Elinder G. Safety of rituximab therapy during the first trimester of pregnancy: a case history. Eur J Haematol 2004; 72: 292–95.
Conflicts of interest We declare no conflicts of interest. Acknowledgments We thank the Laboratoire de Vaccinologie, Hopitaux Universitaires de Genève, Switzerland, for measuring the antibody-titres, and Xendo Laboratories BV, Groningen, Netherlands for measuring rituximab concentrations.
694
http://oncology.thelancet.com Vol 7 August 2006
Rituximab plus CHOP for treatment of diffuse large B-cell lymphoma during second trimester of pregnancy Michael Decker, Christian Rothermundt, Georg Holländer, André Tichelli, Christoph Rochlitz
A 31 year old woman presented with an enlarged left supraclavicular lymph node and without constitutional symptoms at 15 weeks’ gestation during her first pregnancy. A Tru-cut biopsy showed a diffuse, large, B-cell non-Hodgkin lymphoma. MRI of neck, chest, abdomen, and pelvis showed enlarged lymph nodes in both the mediastinum and the left supraclavicular area and in the fetus (figure 1). Biopsy samples and aspirate of bone marrow did not show infiltration by tumour cells. Haemoglobin was 11·4 g/L, whereas results of all other laboratory tests, including lactate-dehydrogenase concentrations, were within normal ranges. The patient was therefore diagnosed with stage IIA diffuse large Bcell non-Hodgkin’s lymphoma (low risk on the international prognostic index). The patient was given six cycles of R-CHOP on a 14 day schedule: 375 mg/m² rituximab, 750 mg/m² cyclophosphamide, 50 mg/m² doxorubicin, 1·4 mg/m² vincristine, and 100 mg/day prednisone on days 1–5. 300 µg filgrastim was given subcutaneously on days 6–11 after immunochemotherapy. Treatment could be given without any delay. No febrile neutropenia occurred. R-CHOP was very well tolerated, and one dose of metoclopramide was needed for the control of treatment-related side-effects (nausea and vomiting). A complete response confirmed by MRI in accordance with RECIST (response-evaluation criteria in solid tumours) criteria was achieved after the second cycle of treatment. 18 months after treatment, the patient is in complete remission. 2 months after the end of treatment and in the 33rd week of pregnancy, the patient spontaneously delivered a healthy baby girl (weight and size within the 50–90 percentile, APGAR [activity, pulse, grimace, appearance, respiration] score 8/10/10). Because of prematurity, the baby was initially treated in the neonate intensive-care unit for 1 week without specific isolation measures. Use of R-CHOP has been shown to increase survival when compared with CHOP for treatment of diffuse, large B-cell lymphoma in elderly patients aged 60–80 years1 and in patients younger than 60 years with a good outlook.2 The feasibility and efficacy of R-CHOP given in shortened cycles of 14 days have been proven before.3 CHOP is thought to be safe during the second and third trimester of pregnancy;4,5 however, only two case reports have been published for use of R-CHOP during pregnancy, both of which had short clinical and immunological follow-up.6,7 We assessed the patient and the child clinically every 3 months with a follow-up of 16 months so far. Absolute http://oncology.thelancet.com Vol 7 August 2006
numbers and phenotypes of peripheral blood cells, titres of antigen-specific antibodies, and serum rituximab concentrations were monitored in the patient at 8 weeks after start of treatment, and in both patient and child at delivery and 2 months, 3 months, and 8 months thereafter. Neither mother nor child developed any infections during the time of observation. The child is under close assessment every 3 months and has shown no physiological or developmental abnormalities. The treatment resulted in an almost complete loss of peripheral B-cells in the mother, but did not decrease total serum immunoglobulin concentrations. The reconstitution with CD19 and CD20 peripheral B cells began 20 weeks after completion of treatment (ie, 12 weeks after delivery). The emergence of B-cells coincided with a large decrease in serum concentrations of rituximab. The titre of rituximab dropped according to its known half-life of 28 days (figure 2). The child’s B cells were severely diminished (1% of normal) at birth but started to recover 6 weeks later (figure 2) reaching normal range after 12 weeks. At delivery, the serum rituximab concentrations were similar in mother (0·02 g/L) and child (0·03 g/L). Because rituximab is an IgG1 antibody, transplacental transport is efficient. In the child, rituximab concentrations also decreased as expected (figure 2). However, the child’s B cells recovered faster than did those in the mother. Moreover, serum concentrations for antigen-specific antibodies (rubella, measles, mumps, chickenpox, tetanus, and diphtheria) were unchanged in the mother despite treatment. The child showed the physiological decrease typically seen during the first months of life. After vaccination at age 8 weeks and boost at age 16 weeks,
Lancet Oncol 2006; 7: 693–94 Department of Haematology, University Hospital Basel, Switzerland (M Decker MD, Prof A Tichelli MD); Royal Marsden Hospital, London, United Kingdom (Prof C Rothermundt MD); Center for Biomedicine and Paediatric Immunology, University Children’s Hospital of Basel, Switzerland (G Holländer MD); Department of Oncology, University Hospital Basel, Switzerland (Prof C Rochlitz MD) Correspondence to: Dr Michael Decker, University Hospital Basel, Department of Haematology, Petersgraben 4, CH-4031 Basel, Switzerland [email protected]
Figure 1: MRI at diagnosis (A) Mediastinal mass (arrow). (B) Fetus at 15 weeks’ gestation.
693
Case Report
A
B 25 20
%
15 10 5
6 x R-CHOP
6 x R-CHOP
0 –30
–20
–10
0
10
20
30
40
C
–30
–20
–10
0
10
20
30
40
0
10
20
30
40
D
Rituximab serum concentration (ng/mL)
30 000 25 000 20 000 15 000 10 000 5 000
6 x R-CHOP
6 x R-CHOP
0 –30
–20
–10
0
10
20
30
40
–30
Weeks before and after delivery
–20
–10
Weeks before and after delivery
Figure 2: Concentrations of CD19 B cells during and after treatment with R-CHOP B-cell counts in mother (A) and child (B). Rituximab serum concentration in mother (C) and child (D).
the child’s humoral immune response to tetanus, diphtheria, pertussis, and haemophilus was normal, and was confirmed normal at 8 month follow-up. Neither the mother nor the child had hypogammaglobulinaemia; and age-adjusted concentrations of IgG, IgM, IgA, and IgG-subclasses were normal. To our knowledge, this is the first published case of a pregnant patient with diffuse large B-cell lymphoma treated successfully with R-CHOP and with immunological follow-up of 8 months for mother and child after birth and a clinical follow-up of 16 months after diagnosis. Because immunological measurements were normal at that time, we have done no further investigations. Our patient was treated safely and efficiently, even in the second trimester, with this immunochemotherapy. No adverse effects in the fetus or child were seen during the 16 months of follow-up.
References 1 Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B-cell lymphoma. N Engl J Med 2002; 346: 235–42. 2 Pfreundschuh M, Trümper L, Österborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large B-cell lymphoma: a randomized controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006; 7: 379–91. 3 Halaas JL, Moskowitz CH, Horwitz S, et al. R-CHOP 14 in patients with diffuse large B-cell lymphoma: feasibility and preliminary efficacy. Leuk Lymphoma 2005; 46: 541–47 4 Resnik R. Cancer during pregnancy. N Engl J Med 1999; 341: 120–21. 5 Cardonick E, Iacobucci A. Use of chemotherapy during pregnancy. Lancet Oncol 2004; 5: 283–91 6 Herold M, Schnohr S, Bittrich H. Efficacy and safety of combined rituximab chemotherapy during pregnancy. J Clin Oncol 2001; 19: 3439. 7 Kimby E, Sverrisdottir A, Elinder G. Safety of rituximab therapy during the first trimester of pregnancy: a case history. Eur J Haematol 2004; 72: 292–95.
Conflicts of interest We declare no conflicts of interest. Acknowledgments We thank the Laboratoire de Vaccinologie, Hopitaux Universitaires de Genève, Switzerland, for measuring the antibody-titres, and Xendo Laboratories BV, Groningen, Netherlands for measuring rituximab concentrations.
694
http://oncology.thelancet.com Vol 7 August 2006