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ORIGINAL REPORTS
Hematologic Malignancy
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Lymphoma Occurring During Pregnancy: Antenatal Therapy, Complications, and Maternal Survival in a Multicenter Analysis
Abstract
Lymphoma is the fourth most frequent cancer in pregnancy; however, current clinical practice is based largely on small series and case reports.
In a multicenter retrospective analysis, we examined treatment, complications, and outcomes for Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) occurring during pregnancy.
Among 90 patients (NHL, n = 50; HL, n = 40), median age was 30 years (range, 18 to 44 years) and median diagnosis occurred at 24 weeks gestation. Of patients with NHL, 52% had advanced-stage versus 25% of patients with HL (P = .01). Pregnancy was terminated in six patients. Among the other 84 patients, 28 (33%) had therapy deferred to postpartum; these patients were diagnosed at a median 30 weeks gestation. This compared with 56 patients (67%) who received antenatal therapy with median lymphoma diagnosis at 21 weeks (P < .001); 89% of these patients received combination chemotherapy. The most common preterm complication was induction of labor (33%). Gestation went to full term in 56% of patients with delivery occurring at a median of 37 weeks. There were no differences in maternal complications, perinatal events, or median infant birth weight based on deferred versus antenatal therapy. At 41 months, 3-year progression-free survival (PFS) and overall survival (OS) for NHL were 53% and 82%, respectively, and 85% and 97%, respectively, for HL. On univariate analysis for NHL, radiotherapy predicted inferior PFS, and increased lactate dehydrogenase and poor Eastern Cooperative Oncology Group performance status (ECOG PS) portended worse OS. For HL patients, nulliparous status and “B” symptoms predicted inferior PFS.
Approximately 3,500 to 4,000 cases of cancer are diagnosed during pregnancy each year in the United States, which translates to approximately one in every 1,000 gestations.1–5 Lymphoma is the fourth most frequent cancer that occurs during pregnancy, with Hodgkin lymphoma (HL) being more commonly seen compared with non-Hodgkin lymphoma (NHL).1 Due in part to pathologic and clinical heterogeneity, however, current clinical practice of treating lymphoma during pregnancy is based largely on case reports and small case series. There remains a deficiency in the literature of lymphoma-specific data to guide clinicians and patients regarding disease presentation, optimal timing of therapy, maternal complications, perinatal events, and fetal and maternal outcomes.
Furthermore, there is a paucity of data describing the complications and outcomes associated with chemotherapy for lymphoma given during gestation. Lishner et al6 reported outcomes on 48 patients with HL during 50 pregnancies; however, only 10 patients were diagnosed during gestation with six who received antenatal chemotherapy. Most NHL data consist of case reports or small case series. Ward and Weiss7 compiled data on 42 patients with NHL during pregnancy from the literature and reported a composite overall survival (OS) rate of 31%; most patients had been managed with steroids, radiotherapy, or single-agent chemotherapy. In addition, none of these reports analyzed prognostic factors that may predict maternal survival.
Here, we report a multicenter collaboration that examined a cohort of 90 patients with an established diagnosis of lymphoma during pregnancy. Approximately two thirds of patients received antenatal therapy which, in most cases, was combination chemotherapy. The aims of this analysis were to examine detailed maternal and fetal characteristics with attention to therapy received in the antenatal period, preterm and perinatal complications, and potential disease and treatment-related prognostic factors that predicted maternal survival.
We conducted a multicenter, retrospective analysis at 11 academic centers of patients who had a diagnosis of NHL or HL during pregnancy over a 13-year period (1999-2011). Investigators collected data for all associated consecutive patients treated at their local institutions. There were 102 patients identified; eight were excluded from the analysis because of diagnosis of lymphoma after pregnancy and four were excluded because of incomplete records (ie, no survival data). The final analysis was performed on 90 patients (NHL, n = 50; HL, n = 40). The study was approved by the institutional review board at each participating institution. Diagnosis was established by biopsy and reviewed by a hematopathologist at each institution. Staging and therapy were performed at the discretion of the treating physician; the majority of staging was completed by magnetic resonance imaging and ultrasonography. Functional imaging (eg, [18F]fluorodeoxyglucose-positron emission tomography) was not performed in any patient antepartum. It is also important to highlight that all patients were comanaged with high-risk maternal-fetal medicine consultation.
Data on disease characteristics, treatment, obstetric complications, and fetal outcomes were examined, including detailed perinatal events such as endometritis, postpartum hemorrhage (ie, > 500 mL for vaginal delivery, > 1,000 mL for cesarean section), transfusion of blood products, chorioamnionitis, route of delivery (ie, cesarean v vaginal), gestational diabetes, and pre-eclampsia. Data were collected regarding preterm delivery (ie, < 37 weeks) and spontaneous preterm delivery (ie, premature rupture of membranes [PROM] or preterm labor). For patients who received therapy during pregnancy, data were collected regarding treatment received (nonsteroid) and use of growth factors and complications of therapy.
Progression-free survival (PFS) was calculated from the time of lymphoma diagnosis to the time of disease relapse/progression or death. OS was measured from the date of lymphoma diagnosis to the date of death. Complete response (CR) was defined as complete resolution of the disease or absence of any disease-specific findings. PFS and OS were calculated by using the Kaplan-Meier method, and survival differences between the treatment groups were assessed by using the log-rank test. Hazard ratios (HRs) and their 95% CIs were reported. Univariable analyses were performed by using Cox proportional hazards models. Factors included in the univariable model are listed in Appendix Table A1 (online only). SAS version 9.2 (SAS Institute, Cary, NC) was used for all statistical analyses.
Baseline characteristics for the 90 patients with NHL (n = 50) and HL (n = 40) during pregnancy are depicted in Tables 1 and 2. Median age at diagnosis for all patients with HL was 29 years (range, 18 to 40 years) versus 32 years (range, 19 to 44 years) for patients with NHL (P = .13). Median age for B-cell NHL was 29.5 years (range, 20 to 44 years) versus 34 years (range, 19 to 37 years) for T-cell lymphoma (TCL; P = .09). The most common NHL diagnosis was diffuse large B-cell lymphoma (DLBCL), which constituted 56% of all NHLs and 73% of B-cell NHLs. TCL subtypes included anaplastic large-cell lymphoma (n = 7; four anaplastic lymphoma kinase (ALK) –positive and three ALK-negative), natural killer TCL (n = 2), and peripheral TCL not otherwise specified (n = 1).
|
| Characteristic | No. | % |
|---|---|---|
| Disease histology | ||
| DLBCL* | 28 | 56 |
| T-cell lymphoma | 10 | 20 |
| Follicular lymphoma | 5 | 10 |
| Burkitt's lymphoma | 4 | 5 |
| MALT | 1 | 2 |
| Composite (DLBCL and FL) | 1 | 2 |
| Prior pregnancies | ||
| Nulliparous | 20 | 40 |
| 1 | 13 | 26 |
| > 1 | 11 | 22 |
| N/A | 2 | 4 |
| “B” symptoms | ||
| Yes | 19 | 38 |
| No | 30 | 60 |
| N/A | 1 | 2 |
| ECOG PS | ||
| 0 | 29 | 38 |
| 1 | 10 | 20 |
| 2 | 6 | 12 |
| 3 | 3 | 6 |
| N/A | 2 | 4 |
| Anemia | ||
| Yes | 25 | 50 |
| No | 22 | 44 |
| N/A | 3 | 6 |
| Lactate dehydrogenase | ||
| Increased | 21 | 42 |
| Normal | 25 | 50 |
| N/A | 4 | 8 |
| Albumin | ||
| Decreased | 28 | 56 |
| Normal | 17 | 34 |
| N/A | 5 | 10 |
| Bone marrow involvement | ||
| Yes | 4 | 8 |
| No | 37 | 74 |
| Not performed | 9 | 18 |
| Extranodal disease (nonmarrow) | ||
| Yes† | 28* | 56 |
| No | 21 | 42 |
| N/A | 1 | 2 |
| Bulky disease | ||
| Yes | 3 | 6 |
| No | 45 | 90 |
| N/A | 2 | 4 |
| Stage‡ | ||
| I | 11 | 22 |
| II | 13 | 26 |
| III | 5 | 10 |
| IV | 15 | 30 |
| N/A | 1 | 2 |
Abbreviations: DLBCL, diffuse large B-cell lymphoma; ECOG PS, Eastern Cooperative Oncology Group performance status; FL, follicular lymphoma; MALT, mucosa-associated lymphoid tissue; N/A, not available.
*Included two patients with primary CNS lymphoma.
†Thirteen patients had more than one extranodal site: liver, n = 5; breast, n = 4; lung, n = 3; bone, n = 3; vagina, n = 3; soft tissue, n = 3; kidney, n = 3; psoas, n = 2; brain, n = 2; skin, n = 2; ovary, n = 2; epidural, n = 2; nasopharyngeal, n = 2; gastrointestinal, n = 2; thyroid, n = 1; intraocular, n = 1; parotid, n = 1; and cardiac, n =1.
‡One patient had relapsed disease.
|
| Characteristic | No. | % |
|---|---|---|
| Disease histology | ||
| Nodular sclerosis | 35 | 88 |
| Not otherwise specified | 3 | 7 |
| Mixed cellularity | 2 | 5 |
| Prior pregnancies | ||
| Nulliparous | 7 | 18 |
| 1 | 18 | 45 |
| > 1 | 10 | 25 |
| N/A | 5 | 12 |
| “B” symptoms | ||
| Yes | 9 | 23 |
| No | 27 | 67 |
| N/A | 4 | 10 |
| ECOG PS | ||
| 0 | 28 | 70 |
| 1 | 7 | 18 |
| 2-4 | 0 | 0 |
| N/A | 5 | 12 |
| Anemia | ||
| Yes | 26 | 65 |
| No | 10 | 25 |
| N/A | 4 | 10 |
| Albumin | ||
| Decreased | 24 | 60 |
| Normal | 11 | 28 |
| N/A | 5 | 12 |
| Bone marrow involvement | ||
| Yes | 1 | 3 |
| No | 32 | 80 |
| Not performed | 5 | 12 |
| N/A | 2 | 5 |
| Extranodal disease (nonmarrow) | ||
| Yes* | 2* | 5 |
| No | 37 | 92 |
| N/A | 1 | 3 |
| Bulky disease | ||
| Yes | 2 | 5 |
| No | 38 | 95 |
| Stage† | ||
| I | 2 | 5 |
| II | 28 | 70 |
| III | 8 | 20 |
| IV | 2 | 5 |
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; N/A, not available.
*One patient with lung involvement and one patient with lung and liver involvement.
†One patient had relapsed disease.
Hemoglobin was decreased in approximately half the patients with NHL or HL at diagnosis (median 9.8 g/dL [range, 8.2 to 11.6 g/dL] and 10.8 g/dL [range, 9.4 to 11.8 g/dL], respectively). Patients with NHL more commonly had stage III to IV disease compared with patients with HL (54% v 25%; P = .01). Of patients with stage I to II disease, 17% of patients with NHL and 30% of patients with HL had “B” symptoms and/or bulky disease. Approximately 85% of patients had bone marrow evaluation; only 8% of patients with NHL and 3% of patients with HL had involvement. Extranodal disease was frequently identified in patients with NHL, with 26% of patients having more than one extranodal site with several atypical sites seen (Table 1). Of the 26 patients with DLBCL (non-CNS), the median International Prognostic Index (IPI) score was 1 (range, 0 to 4); 13 of these patients had stage III to IV disease with a median IPI score of 3 (range, 1 to 4).
For the entire cohort, the diagnosis of lymphoma occurred at a median of 24 weeks gestation (range, 10 to 38 weeks). There were no differences based on NHL versus HL (25 and 23 weeks; P = .49) or by NHL subtype (data not shown). Two patients had a pre-existing diagnosis of follicular lymphoma that was also present during gestation. Among all other patients, 11 (12%) of 88 were diagnosed in the first trimester, 44 (50%) of 88 in the second trimester, and 33 (38%) of 88 in the third trimester, with no differences based on lymphoma type. All but one patient with NHL and one patient with HL had newly diagnosed disease. The patient with HL was a 31-year-old female who presented with relapsed disease during pregnancy following an 8-year remission, and the patient with NHL was a 36-year-old female who relapsed during pregnancy 21 years after treatment for anaplastic large-cell lymphoma (ALK-positive).
Pregnancy was terminated in six patients (three with NHL and three with HL) to enable immediate chemotherapy (five in first trimester [at 5, 8, 10, 10, and 12 weeks] and one patient early in second trimester who warranted high-dose methotrexate). Among the other 84 patients, 28 (33%) had therapy deferred until postpartum (15 [32%] of 47 with NHL and 13 [35%] of 37 with HL). Those 28 patients were diagnosed with lymphoma at a median of 30 weeks gestation (range, 12 to 38 weeks) compared with 56 (67%) patients who received antenatal therapy were diagnosed with lymphoma at a median gestation of 22 weeks (range, 6 to 32 weeks; P < .001; NHL: 22 weeks [range, 10 to 32 weeks]; HL: 20 weeks [range, 6 to 30 weeks]; P = .35). Specific histologic subtypes for patients with NHL who received antenatal therapy are described in the footnote of Table 3.
|
| Week Therapy Started | NHL (n = 32)* | HL (n = 24) | ||
|---|---|---|---|---|
| Therapy | No. of Patients | Therapy | No. of Patients | |
| Second trimester | ||||
| 13-17 | R-CHOP | 3 | ABVD | 4 |
| CHOP | 1 | RT | 2 | |
| Modified hyper-CVAD† | 1 | AVD | 1 | |
| 18-22 | R-CHOP | 4 | ABVD | 4 |
| CHOP | 1 | RT | 1 | |
| EPOCH | 1 | |||
| 23-27 | R-CHOP | 3 | ABVD | 4 |
| CHOP | 2 | |||
| CHOP + RT | 2 | |||
| CHOP/etoposide + RT | 1 | |||
| Modified CODOX-M/IVAC+ | 1 | |||
| RT | 1 | |||
| Third trimester | ||||
| 28-30 | CHOP | 3 | ABVD | 2 |
| R-CHOP | 2 | AVD | 2 | |
| R-CHOP + RT with modified CODOX-M/IVAC+ | 1 | RT | 1 | |
| 31-33 | R-CHOP | 2 | ABVD | 3 |
| Modified ESHAP | 1 | |||
| 34-38 | Rituximab and steroids | 1 | — | |
Abbreviations: ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; AVD, doxorubicin, vinblastine, dacarbazine; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CODOX-M/IVAC, cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, high-dose cytarabine; EPOCH, etoposide, vincristine, doxorubicin, cyclophosphamide, prednisone; ESHAP, etoposide, methylprednisolone, cisplatin, cytarabine; HL, Hodgkin lymphoma; hyper-CVAD, cyclophosphamide, vincristine, doxorubicine, dexamethasone, followed by methotrexate and cytarabine; NHL, non-Hodgkin lymphoma; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; RT, radiotherapy.
*Histologies for patients who received antenatal therapy were diffuse large B-cell lymphoma (n = 21), T-cell lymphoma (n = 7), Burkitt's lymphoma (n = 3), and follicular lymphoma (n = 1); histologies for patients who had therapy deferred to postpartum were diffuse large B-cell lymphoma (n = 5), follicular lymphoma (n = 4), T-cell lymphoma (n = 3), Burkitt's lymphoma (n = 2), and marginal zone lymphoma (n = 1).
†Modified hyper-CVAD regimen.8
+Without high-dose methotrexate.
Antenatal treatment was initiated in 56 patients at a median of 25 weeks gestation (range, 13 to 37 weeks) with no difference based on lymphoma subtype (data not shown). Further, therapy was initiated in the second trimester for 37 (66%) of 56 of patients. Treatment by lymphoma subtype and gestational period is delineated in Table 3. The only patient with follicular lymphoma who received antenatal therapy was a 28-year-old diagnosed at 19 weeks gestation with stage IVXE disease with leukemic phase and a 14- × 11-cm pelvic mass causing epidural compression. Four of the five patients with NHL and all of the four patients with HL who received antenatal radiotherapy (range, 25.2 to 30.0 Gy) had supradiaphragmatic stage I to II disease. For supportive therapy, 14 patients with NHL and seven with HL received antenatal myeloid growth factor, and three patients with NHL and one with HL received erythropoietin. Restaging was done postpartum after completion of all intended first-line therapy in all cases, this included functional imaging. The overall response rate (ORR) for the 56 patients who received antenatal therapy was 82% (CR rate, 64%); ORR for patients with NHL was 71% (CR, 50%) versus 96% (CR, 83%) for patients with HL (ORR, P = .03; CR, P = .013).
Obstetrical information was available for 72 of 84 patients in whom pregnancy had not been terminated. Among these, preterm complications included induction of labor in 33% of patients (Table 4). Perinatal events included PROM in 13% and pre-eclampsia in 7%. There were no episodes of chorioamnionitis or endometritis. Furthermore, there were no differences in complications detected among patients who received antenatal treatment (radiotherapy and/or chemotherapy) versus deferred therapy. There were trends identified for an increased incidence of PROM (P = .07) and pre-eclampsia (P = .06) in patients with NHL versus HL. The route of delivery was cesarean section in 33% of patients; more patients with NHL versus HL had cesarean section (44% v 19%, respectively; P = .007). Timing of delivery was available in 83 of 84 patients; 44% had preterm deliveries with no difference based on NHL versus HL (51% v 36%; P = .19).
|
| Complication | NHL (n = 41) | HL (n = 31) | ||||||
|---|---|---|---|---|---|---|---|---|
| Antenatal Therapy (n = 28) | No Therapy (n = 13) | Antenatal Therapy (n = 20) | No Therapy (n = 11) | |||||
| No. | % | No. | % | No. | % | No. | % | |
| Gestational DM | 2 | 7 | 0 | 0 | 1 | 9 | ||
| Pre-eclampsia | 3 | 11 | 2 | 15 | 0 | 0 | ||
| IOL | 8 | 29 | 4 | 31 | 7 | 35 | 5 | 45 |
| PROM | 5 | 18 | 3 | 23 | 0 | 1 | 9 | |
| Preterm delivery* | 17 | 32 | 6 | 40 | 9 | 39 | 5 | 38 |
| Cesarean section | 11 | 39 | 7 | 54 | 4 | 20 | 2 | 18 |
| Postpartum hemorrhage† | 1 | 4 | 1 | 7‡ | 2 | 10 | 0 | |
| NICU admission | 5 | 18 | 3 | 23 | 0 | 0 | ||
| Fetal demise (miscarriage) | 1 | 4 | 0 | 0 | 0 | |||
| Malformations | 1 | 4 | 0 | 0 | 0 | |||
| Low gestational age§ | 9 | 41 | 1 | 9 | 2 | 10 | 2 | 29 |
Abbreviations: DM, diabetes mellitus; HL, Hodgkin lymphoma; IOL, induction of labor; NHL, non-Hodgkin lymphoma; NICU, neonatal intensive care unit; PROM, premature rupture of membranes.
*For this single category, the denominators for patients with NHL who received therapy v no therapy were n = 32 and n = 15, respectively; the denominators for patients with HL who received therapy v no therapy were n = 24 and n = 13, respectively. In addition, the incidence of spontaneous preterm birth (defined as delivery occurring at < 37 weeks, patients whose membranes ruptured, and/or patients who had spontaneous onset of preterm labor) was six of 23 for patients with NHL v six of 14 for patients with HL.
†Between 500 and 1,000 mL (associated with delivery).
‡Not including one patient with HELLP syndrome [hemolysis, elevated liver enzymes, and low platelet count] associated with < 500 mL of blood loss.
§Defined as below the 10th percentile by gestational age and sex. Data known for children of 33 patients with NHL (22 were treated during gestation and 11 deferred therapy) and 27 patients with HL (20 were treated during gestation and seven deferred therapy).
The median gestation at delivery was 37 weeks (range, 31 to 40 weeks). Notably, gestation went to full term in 47 (56%) of 84 patients with no differences between lymphoma types or whether antenatal therapy was given (Table 4). There was one instance of fetal demise (miscarriage) that occurred at 19 weeks gestation in a 34-year-old patient with double-hit NHL (ie, concurrent c-MYC and BCL-2 rearrangements) following one cycle of R-CHOP (rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone). The median birth weight of infants was 2,668 g (range, 1,005 to 3,628 g) with no difference based on receipt of antenatal chemotherapy versus deferred therapy (2,670 v 2,665 g, respectively; P = .74); however, there was a trend for infants to be small for gestational age if their mothers received antenatal versus deferred therapy (41% v 9%, respectively; P = .09). Of gestations for which information was available, eight (11%) of 72 infants required admission to the neonatal intensive care unit (median stay, 12 days; range, 3 to 40 days) with no differences based on antenatal therapy versus deferred therapy (Table 4). All infants who were admitted to the neonatal intensive care unit were born to patients with NHL. Microcephaly was reported in one infant following four antenatal cycles of CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone] for the mother's DLBCL (treatment started at 28 weeks gestation; delivery was at 38 weeks). Grade 1 pelviectasis was seen in one infant whose mother was treated with four antenatal cycles of R-CHOP for DLBCL at 21 weeks gestation and delivered at 34 weeks due to pre-eclampsia. There were no other malformations detected.
At a median follow-up of 41 months (range, 6 to 147 months), the 3-year PFS and OS for all patients with NHL and HL were 53% and 82%, and 85% and 97%, respectively (Fig 1). Three-year PFS and OS for all patients with DLBCL were 55% and 79%, respectively, compared with 37% and 90%, respectively, for patients with T-cell NHL (P = .43 and P = .60, respectively). There were eight deaths related to NHL, including five DLBCL, one peripheral TCL not otherwise specified, one Burkitt's lymphoma, and one double-hit NHL. Three of these eight patients had received antenatal chemotherapy, and the other four patients had therapy deferred to postpartum.
Fig 1. Survival. The 3-year (A) progression-free survival (PFS) and (B) overall survival (OS) in the 50 patients with a diagnosis of non-Hodgkin lymphoma during pregnancy were 53% and 82%, respectively. Kaplan-Meier curves comparing (C) PFS and (D) OS for patients with diffuse large B-cell lymphoma; 3-year PFS and OS were 55% and 79%, respectively. Kaplan-Meier curves of (E) PFS and (F) OS for 40 patients with a diagnosis of Hodgkin lymphoma during pregnancy; 3-year PFS and OS were 85% and 97%, respectively.
Multiple variables were analyzed (Appendix Table A1) in univariable analysis to predict outcomes. The only variable that predicted for increased risk of disease progression in the NHL cohort was the receipt of radiotherapy (HR, 5.19; 95% CI, 1.76 to 15.34; P = .003). All patients with NHL received radiotherapy during pregnancy. Poor Eastern Cooperative Oncology Group performance status (ECOG PS, 2 to 4: HR, 5.51; 95% CI, 1.36 to 22.39; P = .001) and increased lactate dehydrogenase (HR, 9.93; 95% CI, 1.22 to 80.87; P = .03) predicted for inferior OS. For patients with DLBCL, radiotherapy predicted inferior PFS (HR, 7.72; 95% CI, 1.72 to 34.55; P = .008) and poor ECOG PS predicted worse OS (HR, 2.33; 95% CI, 1.40 to 5.10; P = .04). For patients with HL, multiparous status predicted improved PFS (HR, 0.07; 95% CI, 0.01 to 0.66; P = .01), although the presence of B symptoms at diagnosis predicted inferior PFS (HR, 10.78; 95% CI, 1.12 to 103.75; P = .04); there were no variables in HL that were predictive of OS. Table 5 depicts the corresponding 3-year Kaplan and Meier survival rates for prognostic factors identified on univariate analysis.
|
| Variable | No. of Patients | 3-Year PFS | 3-Year OS | ||||
|---|---|---|---|---|---|---|---|
| % | 95% CI | P | % | 95% CI | P | ||
| Non-Hodgkin lymphoma | |||||||
| Received RT as part of therapy | .001 | .88 | |||||
| Yes* | 5 | 0 | 0 to 0 | 80 | 20 to 97 | ||
| No | 43 | 65 | 46 to 79 | 81 | 64 to 91 | ||
| ECOG PS | .33 | .007 | |||||
| 0-1 | 39 | 54 | 34 to 71 | 88 | 70 to 95 | ||
| 2-3 | 9 | 53 | 18 to 80 | 56 | 20 to 80 | ||
| LDH | .29 | .008 | |||||
| Normal | 21 | 59 | 32 to 78 | 95 | 72 to 99 | ||
| Increased | 25 | 48 | 22 to 70 | 62 | 35 to 80 | ||
| Hodgkin lymphoma | |||||||
| No. of prior pregnancies | .002 | .04 | |||||
| Nulliparous | 7 | 57 | 17 to 84 | 80 | 20 to 97 | ||
| > 1 | 28 | 96 | 76 to 99 | 100 | 100 to 100 | ||
| Presence of “B” symptoms | .009 | .08 | |||||
| No | 27 | 96 | 75 to 99 | 100 | 100 to 100 | ||
| Yes | 9 | 63 | 23 to 86 | 83 | 27 to 97 | ||
NOTE. Three-year progression-free survival (PFS) and overall survival (OS) by Kaplan-Meier analysis are reported; variables with P < .10 in at least one category (ie, PFS or OS) are included.
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; RT, radiotherapy.
*All patients (n = 5) received antenatal RT; two non-Hodgkin lymphoma patients had unknown RT status.
Lymphoma diagnosis during pregnancy has an approximate prevalence of 1 in every 5,000 to 6,000 gestations, with HL occurring more frequently than NHL.1–4,9 This likely reflects the younger typical age of onset of HL compared with NHL. Here, we report data on 90 patients with lymphoma from 11 academic centers who were diagnosed/managed during pregnancy. Approximately two thirds of patients received antenatal therapy, most commonly combination chemotherapy. To the best of our knowledge, this is the largest series of HL or NHL during pregnancy in which the majority of patients received standard combination chemotherapy.
Only one quarter of patients with HL and just over half the patients with NHL in our series had advanced-stage disease. A likely contributing factor to these low rates of advanced-stage disease was the absence of functional imaging as well as less frequent use of other commonly used staging modalities (eg, bone marrow biopsy). Despite the nonstandard and suboptimal staging performed, we identified a high rate of extranodal involvement in patients with NHL for whom several atypical sites were noted (eg, vaginal and ovary). This has been reported in prior series10–12 and may relate to increased blood flow to reproductive organs during gestation or possibly due to expression of gestational hormone receptors.
The decision to use chemotherapy during gestation is individualized, with the risk of antenatal chemotherapy weighed against the potential adverse effect of delaying curative therapy. As expected, the treatment approaches here were heterogeneous, although a consistent finding for all patients was the use of antenatal therapy for patients diagnosed earlier in gestation. The median gestational age at diagnosis of lymphoma for patients who received antenatal therapy was 22 weeks. Furthermore, 89% of these patients received combination chemotherapy, with the most common regimens being standard for the particular lymphoma subtype. A concern regarding use of antenatal chemotherapy is the risk of perinatal complications for the fetus and the mother.
The most commonly identified perinatal events were induction of labor, PROM, and cesarean delivery. Interestingly, there were no differences in events among patients who received antenatal versus deferred therapy; this is consistent with recent data in pregnant patients with breast cancer.5 The rate of miscarriage identified in the current data set was 1.1%, consistent with other cancer-related pregnancy data.4,5 Van Calsteren et al4 showed that preterm labor occurred in 54% of pregnancies, with the risk being increased in patients who received antenatal cytotoxic therapy. The rate of preterm labor appeared slightly lower in our study. In addition, we did not identify an overall difference in median birth weight among patients with NHL or HL who received antenatal therapy compared with those who had therapy deferred to postpartum. This is in contrast to other series,4,5 although in the Loibl5 series, the difference was not significant.
A critical aspect in the management of cancer during pregnancy is timing of delivery. The general goal in all cancer-associated gestations should be to continue the pregnancy to full term. This point was emphasized by Amant et al,13 who reported recent data on 236 cycles of chemotherapy administered in 68 pregnancies. When compared with chemotherapy for the general population, antenatal chemotherapy was not associated with increased neurologic, cardiac, auditory, general health, or development impairments. The most significant factor that predicted for an impairment in cognitive development was preterm delivery. Moreover, for each additional month of gestation, the average intelligence quotient was increased by 11.6 points.
Our data also support prior findings that antenatal chemotherapy with standard regimens (non–antimetabolite) during the second or third trimester does not appear to increase morbidity or mortality for the fetus.5,14 This includes in utero anthracyline exposure, which has been shown to not adversely affect maternal or fetal cardiac function.13,15–18 We did not identify an increased rate of congenital malformations, consistent with prior data.4,5 It is important to note that none of the patients in our series received antenatal therapy during the first trimester. Avilés et al19 reported that administration of antenatal therapy during the first trimester may be tenable in select patients, although most guidelines do not advocate this practice.20,21 Limitations of this study are the unintended selection and referral biases as well as the lack of long-term outcomes due to its retrospective nature and nonsystematic treatment or assessments. It is also important to acknowledge that subtle changes in neurocognitive or other developmental abnormalities of children exposed to antenatal chemotherapy cannot be excluded in our cohort. Avilés and Neri22 followed 62 children who had been exposed to antenatal chemotherapy. They reported that all children developed normally physically and neurologically when matching school performance and intelligence quotient testing with controls. Nonetheless, more research is needed regarding appropriate chemotherapy dosing and calculation in pregnancy, safety of supportive care therapy, and long-term study of child cognition and development.
There is a paucity of available data assessing potential prognostic factors for survival of patients diagnosed with lymphoma during pregnancy. The survival rates in our study were consistent with the expected lymphoma-related outcomes. In univariate analyses of prognostic factors for survival, nulliparous status and the presence of B symptoms predicted for inferior PFS. The finding of prior pregnancy status affecting PFS is interesting and may be related to hormonal alterations.23,24 In NHL, poor ECOG PS and increased lactate dehydrogenase at diagnosis were associated with inferior OS, and receipt of radiotherapy had an adverse impact on PFS. The latter is an interesting finding and is likely a reflection of the systemic nature of NHL. Although the adverse impact of radiotherapy on PFS did not translate to an OS disadvantage, if treatment is considered in NHL, chemotherapy should likely be the first choice. In contrast, for HL, there are data showing that in select patients (ie, those with supradiaphragmatic disease), radiotherapy may be successfully used during pregnancy with careful shielding of the fetus. Woo et al25 reported on 16 patients with HL diagnosed during pregnancy over a 35-year period who received antenatal radiotherapy for supradiaphragmatic disease without adverse impact on fetal or maternal outcome.
In summary, we found that standard chemotherapy regimens for NHL and HL (without antimetabolites) administered during the second and third trimester, including as early as 13 weeks gestation in some cases, was associated with minimal maternal complications or fetal detriment. In addition, patients with low-risk clinical scenarios (eg, indolent NHL, low tumor burden, and/or late gestational diagnosis) had therapy safely deferred to postpartum. It should be underscored that all patients were managed concurrently with high-risk maternal-fetal medical consultation. In our experience, this approach was associated with maternal and fetal complications that appeared consistent with a healthy population and expected lymphoma-related outcomes.
Presented at the 11th International Conference on Malignant Lymphoma, Lugano, Switzerland, June 15-18, 2011, and the 53rd American Society of Hematology Annual Meeting and Exposition, San Francisco, CA, December 11-13, 2011.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
The author(s) indicated no potential conflicts of interest.
Conception and design: Andrew M. Evens, Ranjana Advani, Oliver W. Press, Izidore S. Lossos, Barrett K. Robinson, Aimee Kroll-Desrosiers, Leo I. Gordon, Thomas M. Habermann, Nancy L. Bartlett
Financial support: Andrew M. Evens
Administrative support: Andrew M. Evens, Linda M. Parker
Provision of study materials or patients: Andrew M. Evens, Ranjana Advani, Julie M. Vose, Christopher R. Flowers
Collection and assembly of data: Andrew M. Evens, Ranjana Advani, Oliver W. Press, Izidore S. Lossos, Julie M. Vose, Francisco J. Hernandez-Ilizaliturri, Stavroula Otis, Liat Nadav Dagan, Ramsey Abdallah, Jessica L. Yarber, Jose Sandoval, Kelley Foyil, Linda M. Parker, Kristie A. Blum, Christopher R. Flowers, John P. Leonard, Thomas M. Habermann, Nancy L. Bartlett
Data analysis and interpretation: Andrew M. Evens, Ranjana Advani, Oliver W. Press, Izidore S. Lossos, Julie M. Vose, Francisco J. Hernandez-Ilizaliturri, Barrett K. Robinson, Stavroula Otis, Liat Nadav Dagan, Ramsey Abdallah, Aimee Kroll-Desrosiers, Jessica L. Yarber, Kelley Foyil, Kristie A. Blum, Christopher R. Flowers, John P. Leonard, Thomas M. Habermann, Nancy L. Bartlett
Manuscript writing: All authors
Final approval of manuscript: All authors
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| Non-Hodgkin lymphoma (n = 50) |
| Age: as continuous variable and also above and below median (ie, 29 years) |
| No. of prior pregnancies: 0 v > 1 |
| No. of prior deliveries: 0 v > 1 |
| Type and No. of prior abortions: 0 v > 1 |
| Presence of “B” symptoms (yes v no) |
| Body mass index: ≤ 25 v > 25 |
| ECOG PS at diagnosis: continuous variable and 0-1 v 2-4 |
| Hemoglobin at diagnosis (decreased v normal) |
| LDH at diagnosis (increased v normal) |
| Albumin at diagnosis (low v normal) |
| Stage at diagnosis: continuous variable and I-II v III-IV |
| Bone marrow involved (yes v no) |
| Other extranodal sites (yes v no) |
| More than one extranodal site (yes v no) |
| Prognostic score: as continuous variable and 0-2 v 3-5 |
| Diagnosis date: as continuous variable and in groups of 0-12 v 13-27 v 28-40 weeks |
| Date started treatment: as continuous variable and in groups of 13-27 v 28-40 weeks |
| Treatment during pregnancy (yes v no) |
| Rituximab treatment during pregnancy (yes v no) |
| Radiotherapy was part of the treatment plan during pregnancy (yes v no) |
| Response to first treatment: as continuous (ie, CR, PR, SD, PD) and also CR/PR v SD/PD |
| Use of myeloid growth factor (yes v no) |
| Use of epoetin growth factor (yes v no) |
| Preterm delivery at < 37 weeks (yes, n = 1; no, n = 2) |
| Perinatal outcomes: route of delivery (cesarean, n = 1; vaginal, n = 2) |
| Hodgkin lymphoma (n = 40) |
| Age: as continuous variable and above and below median (ie, 30 years) |
| No. of prior pregnancies: 0 v > 1 |
| No. of prior deliveries: 0 v > 1 |
| Type and No. of prior abortions: 0 v > 1 |
| Presence of B symptoms (yes v no) |
| Body mass index: ≤ 25 v > 25 |
| ECOG PS at diagnosis: continuous variable and 0-1 v 2-4 |
| Hemoglobin at diagnosis (decreased v normal) |
| LDH at diagnosis (increased v normal) |
| Albumin at diagnosis (low v normal) |
| Stage at diagnosis: continuous variable and I-II v III-IV |
| Bone marrow involved (yes v no) |
| Other extranodal sites (yes v no) |
| More than one extranodal site (yes v no) |
| Prognostic score: as continuous variable and 0-2 v 3-7 |
| Diagnosis date: as continuous variable and in groups of 0-12 v 13-27 v 28-40 weeks |
| Date started treatment: as continuous variable and in groups of 13-27 v 28-40 weeks |
| Treatment during pregnancy (yes v no) |
| Radiotherapy was part of the treatment plan during pregnancy (yes v no) |
| Response to first treatment: as continuous (ie, CR, PR, SD, PD) and CR/PR v SD/PD |
| Use of myeloid growth factor (yes v no) |
| Use of epoetin growth factor (yes v no) |
| Preterm delivery (< 37 weeks) (yes, n = 1; no, n = 2) |
| Perinatal outcomes: route of delivery (cesarean, n = 1; vaginal, n = 2) |
Abbreviations: CR, complete response; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; PD, progressive disease; PR, partial response; SD, stable disease.
