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JAMA | Brief Report Maternal and Fetal Outcomes After Therapy for Hodgkin or Non-Hodgkin Diagnosed During Pregnancy

Chelsea C. Pinnix, MD, PhD; Eleanor M. Osborne, MD; Dai Chihara, MD; Peter Lai, BS; Shouhao Zhou, PhD; Mildred M. Ramirez, MD; Yasuhiro Oki, MD; Frederick B. Hagemeister, MD; Alma M. Rodriguez, MD; Felipe Samaniego, MD; Nathan Fowler, MD; Jorge E. Romaguera, MD; Francesco Turturro, MD; Luis Fayad, MD; Jason R. Westin, MD; Loretta Nastoupil, MD; Sattva S. Neelapu, MD; Chan Y. Cheah, MD; Bouthaina S. Dabaja, MD; Sarah A. Milgrom, MD; Grace L. Smith, MD, PhD; Patricia Horace, BS; Andrea Milbourne, MD; Christine F. Wogan, BS; Leslie Ballas, MD; Michelle A. Fanale, MD

Supplemental content at IMPORTANCE The management of lymphoma diagnosed during pregnancy is controversial jamaoncology.com and has been guided largely by findings from case reports and small series.

OBJECTIVE To determine maternal and fetal outcomes of women diagnosed with (HL) or non-Hodgkin lymphoma (NHL) during pregnancy.

DESIGN, SETTING, AND PARTICIPANTS This retrospective analysis studied a cohort of 39 pregnant women diagnosed with HL and NHL (31 HL and 8 NHL) at a single specialized institution between January 1991 and December 2014.

MAIN OUTCOMES AND MEASURES We examined data on disease and treatment characteristics, as well as maternal and fetal complications and outcomes. The Kaplan-Meier method was used to compare progression free survival (PFS) and overall survival (OS) according to receipt of antenatal therapy and other clinical factors. Univariate and multivariate analyses were performed by using Cox proportional hazard regression models to identify potential associations between clinical and treatment factors and survival.

RESULTS The median (range) age of the 39 women in the patient cohort was 28 (19-38) years; 32 women (82%) had stage I or II disease at diagnosis, and 13 had bulky disease. Three women electively terminated the pregnancy to allow immediate systemic therapy; of the remaining 36 women, 24 received antenatal therapy ( based combination in 20 of 24 patients), and 12 deferred therapy until after delivery. Four women experienced , all of whom had received antenatal systemic therapy and 2 during the first trimester. Delivery occurred at a median (range) of 37 (32-42) weeks and was no different based on receipt of antenatal (median [range], 37 [33-42] weeks) vs postnatal (median [range], 37 [32-42] weeks) therapy (P = .21). No gross fetal malformations or anomalies were detected. At a median (range) follow-up time of 67.9 (8.8-277.5) months since the diagnosis of lymphoma, 5-year rates of PFS and OS were 74.7% and 82.4%, respectively; these rates did not differ according to timing of therapy. On univariate analysis, bulky disease (>10 cm), extranodal nonbone marrow involvement, and poor performance status (Eastern Cooperative Oncology Group score, Ն2) predicted increased risk of disease progression. On multivariate analysis, extranodal nonbone marrow disease and performance status remained significant for both PFS and OS.

CONCLUSIONS AND RELEVANCE Systemic therapy given for lymphoma after the first trimester of pregnancy is likely safe and results in acceptable maternal and fetal outcomes.

Author Affiliations: Author affiliations are listed at the end of this article. Corresponding author: Michelle A. Fanale, MD, Department of Lymphoma/Myeloma, Unit 429, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, JAMA Oncol. 2016;2(8):1065-1069. doi:10.1001/jamaoncol.2016.1396 Houston, TX 77030 (mfanale Published online May 26, 2016. @mdanderson.org).

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iagnoses of cancer occur in roughly 1 of 1000 pregnancies.1 Emerging reports suggest that stan- Key Points dard chemotherapy administered during the second D Question What are the maternal and fetal outcomes of women and third trimesters results in acceptable maternal and fetal diagnosed with lymphoma during pregnancy? outcomes.2,3 We report maternal and fetal outcomes from a Findings In an analysis of 39 women diagnosed with lymphoma single-institution experience of women diagnosed with lym- during pregnancy, delivery occurred at a median of 37 weeks and phoma during pregnancy. was no different based on administration of antenatal therapy. Five-year progression-free survival and overall survival rates were 74.7% and 82.4% and did not differ according to the timing of Methods therapy. Meaning Systemic therapy after the first trimester is likely safe We identified 47 women diagnosed with HL or NHL while preg- and results in acceptable maternal and fetal outcomes. nant between 1991 and 2014 after institutional review board approval. A waiver of informed consent was granted due to the retrospective nature of the study. Eight women were ex- Table 1. Patient Characteristics cluded for lack of follow-up data or pregnancy during lym- phoma treatment; the final cohort included 31 women with HL Patients, No. (%) All Patients Patients and 8 women with NHL. Patients With HL With NHL All cases were comanaged with a maternal fetal medicine Characteristic (n = 39) (n = 31) (n = 8) P Value (MFM) obstetrician. Staging studies typically included mag- Age, y netic resonance imaging (MRI) and ultrasonography. Com- Median (range) 28 (19-38) 27 (19-35) 30.5 (38) .004 puted tomography (CT) and 18-fluorodeoxyglucose positron Nodular 29 (93.5) NA emission tomography (PET)–CT was generally avoided until the sclerosing HL postpartum period. Response assessment was based on the Lu- Mixed 2 (6.5) NA gano Classification.4 Progression-free survival (PFS) and over- cellularity HL all survival (OS) were defined from the time of lymphoma di- Primary CNS 1 (12.5) NA PMBCL 1 (12.5) NA agnosis and estimated using the Kaplan-Meier method. Clinical DLBCLa 4 (50) NA factors were compared using 2-sample t tests, Fisher exact Follicular 1 (12.5) NA tests, and Cochran-Mantel-Haenszel tests. Multivariate Cox grade IIIB proportional hazard regression and stepwise variable selec- ALK+ ALCL 1 (12.5) NA tion was applied to assess interactions between variables and survival. A significance level of 0.05 was used in statistical tests. Yes 8 (20.5) 6 (19) 2 (25) .66 No 31 (79.5) 25 (81) 6 (75) Stage I 4 (10) 2 (7) 2 (25) Results II 28 (72) 24 (77) 4 (50) .30 Patient Characteristics and Treatment III 1(3) 1(3) 0 Patient and gestational characteristics for the 39 patients are IV 6 (15) 4 (13) 2 (25) ECOG PS in Table 1. Three women underwent elective termination at 0 16 (41.0) 10 (32.3) 6 (75) diagnosis. Of 36 remaining patients, 24 (61%) began antena- 1 15 (38.5) 13 (41.9) 2 (25) .07 tal therapy (AT) and 12 (31%) postponed therapy until deliv- 2 8 (20.5) 8 (25.8) 0 ery (Table 2) (eTable 1 in the Supplement). Four patients Extranodal received supradiaphragmatic (RT), (me- disease,b dian [range] dose, 40.4 [36-50] Gy [to convert milligray to nonbone-marrow Yes 7 (18) 3 (10) 4 (50) rad, multiply by 0.1]). .03 No 32 (82) 28 (90) 4 (50) , Obstetric Characteristics and Complications (HgB <12 g/dL) Delivery did not differ based on receipt of AT (Table 2). Among Yes 26 (67) 20 (64) 6 (75) the 36 women who did not undergo termination at diagnosis, No 9 (23) 7 (23) 2 (25) .92 receipt of AT was not associated with increased rates of pre- Unknown 4 (10) 4 (13) 0

term delivery. Among the 24 women who received treatment (continued) during pregnancy, 7 (29%) experienced preterm delivery compared with 5 of 12 women (42%) who postponed treat- ence miscarriage. The infants of these 31 women showed no ment until after delivery (P = .73). known anomalies at birth. Miscarriage occurred in 4 patients that required immedi- ate therapy during the first (n = 2) and second (n = 2) trimes- Treatment Response and Survival Outcomes ters. Neonatal outcomes were available for 31 of 32 patients who Among the 24 patients who initiated treatment during preg- did not undergo immediate elective termination or experi- nancy, the overall response rate (ORR) was 91.7%, and the

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Table 1. Patient Characteristics (continued) Table 2. Patient Characteristics According to Timing of Therapy

Patients, No. (%) Patients, No. (%) Patients Patients Patients Who Patients Who All Patients With HL With NHL Received Received Characteristic (n = 39) (n = 31) (n=8) P Value Antenatal Postnatal LDH elevated Therapy Therapy Characteristic (n = 24) (n = 12) P Value Yes 5 (13) 4 (13) 1 (12.5) Duration of pregnancy No 27 (69) 20 (64) 7 (87.5) >.99 at diagnosis, wk Unknown 7 (18) 7 (27) 0 Median (range) 18.5 (1-32) 29 (19-36) <.001 Bulky disease Trimester at diagnosis Yes 13 (33) 11 (35) 2 (25) .89 1 4 (17) 0 No 26 (67) 20 (65) 6 (75) 2 17 (71) 4 (33) <.001 Pregnant at diagnosis, wk 3 3 (13) 8 (67) Median (range) 20 (1-36) 21 (2-36) 18.5 (1-31) .36 Antenatal therapy during Trimester at first trimester (n = 2) diagnosis ABVD or ABVD-like 1 NA 1 5 (13) 4 (13) 1 (12.5) CHOP or CHOP-like 1 NA 2 23 (60) 17 (55) 6 (75) .52 Radiation therapy 0 NA 3 11 (28) 10 (32) 1 (12.5) Antenatal therapy during NA Pregnancy duration 2nd trimester (n = 16) at symptom onset, wk ABVD or ABVD-like 8 NA Median (range) 12 (0-30) 11 (0-30) 15 (14-16) .10 CHOP or CHOP-like 5 NA Termination Radiation therapy 3 NA Miscarriage 4 (10) 3 (10) 1 (12.5) Antenatal therapy during Elective 3 (8) 2 (6) 1 (12.5) 3rd trimester (n = 6) termination .81 ABVD or ABVD-like 5 NA at diagnosis CHOP or CHOP-like 0 NA No 32 (82) 26 (84) 6 (7) Trimester at (n=24) (n=19) (n=5) Radiation therapy 1 NA the start Gestational length of therapy at delivery, wk .21 1 2 (8) 1 (5) 1 (20) Median (range) 37 (33-42) 37 (32-42) 2 16 (67) 12 (63) 4 (80) .25 Preterm delivery 3 6 (25) 6 (32) 0 (<37 wk) Weeks at delivery Yes 7 (29) 5 (42) .73 Median (range) 37 (32-42) 37.5 (32-42) 36 (33-37) .02 No 13 (54) 7 (58) Preterm delivery, Miscarriage 4 (17) 0 .30 <37 wk Yes 12 (31) 8 (26) 4 (50) Gestational Diabetes 1 (4) 1 (8) >.99 No 20 (51) 18 (58) 2 (25) .25 PROM 0 1 (8) .35 NA 7 (18) 5 (16) 2 (25) Labor induced 2 (8) 3 (25) .34 NICU admission 2 (8) 1 (8) >.99 Abbreviations: ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; CNS, central nervous system; DLBCL, diffuse large lymphoma; Abbreviations: ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; ECOG PS, Eastern Cooperative Oncology Group performance status; CHOP, , doxorubicin, , ; NA, not HgB, hemoglobin; HL, Hodgkin lymphoma; LDH, ; applicable; NICU, neonatal intensive care unit; PROM, premature rupture of NA, not applicable; NHL, non-Hodgkin lymphoma; PMBCL, primary mediastinal membranes. B cell lymphoma. a Two patients had nongerminal center DLBCL, 1 had ALK DLBCL, and 1 had DLBCL from transformed . and 83.3%, respectively. Among the 36 women who did not b Full positron emission tomography–computed tomography staging was not terminate their pregnancy at diagnosis, no difference was performed; extranodal disease was diagnosed by chest radiography or found in PFS or OS based on receipt of AT (P = .84) (Figure, C magnetic resonance imaging in most cases. and D).

complete response (CR) rate was 75.0%. Of the 12 patients Univariate and Multivariate Analyses who deferred therapy until delivery, both the ORR and the For the 36 patients who did not electively terminate the preg- CR rate were 91.7%. nancy at the time of diagnosis, on univariate analysis bulky At a median (range) follow-up of 67.9 (8.8-277.5) months, disease (PFS hazard ratio [HR], 3.6; 95% [CI], .96-13.54; P = .06), the 5-year PFS and OS rates were 74.7% and 82.4% for the en- extranodal nonbone marrow involvement (HR, 4.2; 95% CI, tire cohort (Figure, A and B). For the 31 women with HL, the 1.04-16.99; P = .04), and poor Eastern Cooperative Oncology 5-year PFS and OS rates were 69.9% and 80%, respectively; for Group performance status (PS) (HR, 3.9; 95% CI, 1.5-10.14); the 8 women with NHL, the 5-year PFS and OS rates were 85.7% P = .005) were associated with increased risk of progression;

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Figure. Progression-Free and Overall Survival

A Progression-free survival B Overall survival

1.0 1.0

0.8 0.8

0.6 0.6

0.4 0.4

All patients All patients Survival ProbabilitySurvival ProbabilitySurvival 0.2 Patients with HL 0.2 Patients with HL Patients with NHL Patients with NHL

0 0 0 50 100 150 200 250 300 0 50 100 150 200 250 300 Time, mo Time, mo No. at risk No. at risk All patients 36 21 9 4 2 1 0 All patients 36 22 10 5 2 1 0 Patients with HL 29 16 9 4 2 1 0 Patients with HL 29 17 10 5 2 1 0 Patients with NHL 7 5 0 0 0 0 0 Patients with NHL 7 5 0 0 0 0 0

C Progression-free survival D Overall survival

1.0 1.0

0.8 0.8

0.6 0.6

0.4 0.4

All patients All patients Survival ProbabilitySurvival ProbabilitySurvival 0.2 Antenatal therapy 0.2 Antenatal therapy No antenatal therapy No antenatal therapy

0 0 0 50 100 150 200 250 300 0 50 100 150 200 250 300 Time, mo Time, mo No. at risk No. at risk All patients 36 21 9 4 2 1 0 All patients 36 22 10 5 2 1 0 Antenatal Antenatal No 12 7 2 1 1 0 0 No 12 8 3 2 1 0 0 Yes 24 14 7 3 1 1 0 Yes 24 14 7 3 1 1 0

A and B, Progression-free survival and overall survival for all 39 patients according to receipt of antenatal therapy. HL indicates Hodgkin lymphoma; according to disease histology. C, Progression-free survival and overall survival NHL, non-Hodgkin lymphoma. for all 36 patients that did not terminate pregnancy at the time of diagnosis

poor PS was associated with OS (HR, 8.88; 95% CI, 2.04-38.7; The miscarriage rate in our series was roughly 10% (n = 4), P = .004). On multivariate analysis, the final Cox propor- higher than previous studies reporting no spontaneous tional hazard model revealed significant associations for abortions.5-7 Multi-agent chemotherapy has been given rarely extranodal nonbone marrow involvement (OS HR, 73.5; during the first trimester because of the vulnerability of the 95% CI, 2.32-2332.86; P = .02; and PFS HR, 8.26; 95% CI, fetus during organogenesis. This concern is justified because 1.67-40.78; P = .01) and PS (OS HR, 26.7; 95% CI, 3.10- both patients who received first-trimester therapy in this study 229.53; P = .003; and PFS HR, 4.89; 95% CI, 1.80-13.23; experienced fetal death. Antenatal therapy is thought to be P = .002). safer for the fetus during the second trimester.2,3,5-7 Two of the 4 occurred in women who received systemic therapy during the second trimester; however, 1 of those pa- Discussion tients was critically ill, so other factors likely contributed to the fetal death. The other patient experienced the loss of 23- The management of lymphoma diagnosed during pregnancy week twin fetuses conceived via in vitro fertilization, after aims to treat the malignancy adequately without harming the ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) fetus. In the current study, 24 women (roughly two-thirds) re- therapy was initiated during gestational week 15. We suspect ceived therapy during pregnancy. Maternal outcomes were not that maternal factors contributed to the adverse fetal out- affected by the delivery of AT, although the 4 women who had comes in at least 1 of these 2 cases. In keeping with previous miscarriages received chemotherapy during pregnancy (4 of reports, our practice is to consider AT during the second and 24 patients who received AT therapy vs 0 of 12 patients who third trimesters if deferring that therapy until after delivery received postnatal therapy; P = 0.30). would be expected to compromise maternal outcome.3,8,9

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Radiation therapy was given during pregnancy to four pa- according to receipt of AT, we contend that disease factors, tients. In contrast to the multicenter study by Evens et al,2 in rather than treatment-related factors, influenced the worse which use of RT during pregnancy was associated with infe- maternal outcomes among patients with HL. rior maternal outcomes, we did not detect any adverse ef- Although the follow-up time is relatively short, no mal- fectsofRTonPFS(P = .23) or OS (P = .24). However, we do not formations have been observed. Rates of preterm labor were advocate the routine use of RT during pregnancy. In cases similar among patients who received AT and those who de- where RT is deemed to be critical, appropriate precautions for ferred treatment. Preterm delivery, and not fetal chemo- the fetus are essential. therapy exposure, has been shown to be the most strongly pre- Maternal outcomes were acceptable, with a PFS rate of 75% dictive of neurocognitive impairment.3,10,11 Thus, an important and an OS rate of 82% at 5 years. Known adverse risk factors goal should be prolonging the pregnancy so as to avoid pre- among nonpregnant patients with lymphoma, such as poor PS term birth. and bulky disease, were also associated with inferior out- comes among the 39 patients in this series. Among patients with HL, the 5-year PFS and OS rates were 70% and 80%, re- Conclusions spectively. This finding contrasts with the 3-year OS rate of 97% for 40 patients with HL in the report from Evens and The diagnosis of lymphoma during pregnancy poses manage- colleagues.2 This difference may reflect the higher propor- ment challenges requiring consideration of the fetus without tion of patients in our series with adverse prognostic factors. compromising potentially curative therapy for the mother. In In the study by Evens et al, only 5% of patients with HL this series, the decision to defer therapy until after delivery did patients had bulky disease compared with 35% in our series. not affect maternal outcomes. Our findings, coupled with those Also, roughly one-fourth of patients in our series had a PS score from previous studies, lead us to recommend delaying therapy of 2, whereas no patients had a score greater than 1 in the mul- to the second trimester if this can be accomplished without ticenter study.2 Because we found no differences in PFS or OS perceived detriment to the patient.

ARTICLE INFORMATION intellectual content: Pinnix, Osborne, Chihara, Lai, Group; Nordic Lymphoma Study Group; Southwest Accepted for Publication: April 1, 2016. Zhou, Ramirez, Oki, Hagemeister, Rodriguez, Oncology Group; United Kingdom National Cancer Samaniego, Fowler, Romaguera, Turturro, Fayad, Research Institute. Recommendations for initial Published Online: May 26, 2016. Westin, Nastoupil, Neelapu, Cheah, Dabaja, evaluation, staging, and response assessment of doi:10.1001/jamaoncol.2016.1396. Milgrom, Smith, Horace, Milbourne, Wogan, Ballas, Hodgkin and non-Hodgkin lymphoma: the Lugano Author Affiliations: Radiation Oncology, The Fanale. classification. J Clin Oncol. 2014;32(27):3059-3068. University of Texas MD Anderson Cancer Center, Statistical analysis: Pinnix, Osborne, Zhou, Cheah. 5. Bachanova V, Connors JM. Hodgkin lymphoma Houston (Pinnix, Osborne, Dabaja, Milgrom, Smith, Administrative, technical, or material support: in pregnancy. Curr Hematol Malig Rep. 2013;8(3): Horace, Wogan); Department of Lymphoma/ Pinnix, Chihara, Oki, Nastoupil, Neelapu, Dabaja, 211-217. Myeloma, The University of Texas MD Anderson Horace, Fanale. Cancer Center, Houston (Chihara, Lai, Oki, Study supervision: Pinnix, Samaniego, Fowler, 6. Avilés A, Neri N, Nambo MJ. Hematological Hagemeister, Rodriguez, Samaniego, Fowler, Fayad, Dabaja, Milbourne, Fanale. malignancies and pregnancy: treat or no treat Romaguera, Turturro, Fayad, Westin, Nastoupil, Providing care and outcome data: Ramirez. during first trimester. Int J Cancer. 2012;131(11): Neelapu, Cheah, Fanale); Department of Other: Wogan. 2678-2683. Biostatistics, The University of Texas MD Anderson Conflict of Interest Disclosures: None reported. 7. Cardonick E, Usmani A, Ghaffar S. Perinatal Cancer Center, Houston (Zhou); Department of outcomes of a pregnancy complicated by cancer, Obstetrics and Gynecology, Baylor College of REFERENCES including neonatal follow-up after in utero Medicine, Houston, Texas (Ramirez); Gynecologic exposure to chemotherapy: results of an Oncology and Reproductive Medicine, The 1. Pavlidis NA. Coexistence of pregnancy and international registry. Am J Clin Oncol. 2010;33(3): University of Texas MD Anderson Cancer Center, malignancy. Oncologist. 2002;7(4):279-287. 221-228. Houston (Milbourne); Department of Radiation 2. Evens AM, Advani R, Press OW, et al. Lymphoma 8. Peccatori FA, Azim HA Jr, Orecchia R, et al; Oncology, University of Southern California, Los occurring during pregnancy: antenatal therapy, ESMO Guidelines Working Group. Cancer, Angeles (Ballas). complications, and maternal survival in a pregnancy and fertility: ESMO Clinical Practice Author Contributions: Dr Pinnix had full access to multicenter analysis. J Clin Oncol. 2013;31(32):4132- Guidelines for diagnosis, treatment and follow-up. all of the data in the study and takes responsibility 4139. Ann Oncol. 2013;24(suppl 6):vi160-vi170. for the integrity of the data and the accuracy of the 3. Vandenbroucke T, Van Calsteren K, Amant F. 9. Eyre TA, Lau IJ, Mackillop L, Collins GP. data analysis. Drs Pinnix and Osborne contributed Pediatric outcome after maternal cancer diagnosed Management and controversies of classical Hodgkin equally to this article. during pregnancy. N Engl J Med. 2016;374(7):693. lymphoma in pregnancy. Br J Haematol. 2015;169 Study concept and design: Pinnix, Osborne, Chihara, 4. Cheson BD, Fisher RI, Barrington SF, et al; (5):613-630. Dabaja, Wogan, Ballas, Fanale. Alliance, Australasian Leukaemia and Lymphoma Acquisition, analysis, or interpretation of data: 10. Loibl S, Han SN, von Minckwitz G, et al. Group; Eastern Cooperative Oncology Group; Treatment of breast cancer during pregnancy: an Pinnix, Osborne, Lai, Zhou, Ramirez, Oki, European Consortium; Hagemeister, Rodriguez, Samaniego, Fowler, observational study. Lancet Oncol. 2012;13(9):887- Italian Lymphoma Foundation; European 896. Romaguera, Turturro, Fayad, Westin, Nastoupil, Organisation for Research; Treatment of Neelapu, Cheah, Dabaja, Milgrom, Smith, Horace, Cancer/Dutch Hemato-Oncology Group; Grupo 11. Amant F, Van Calsteren K, Halaska MJ, et al. Milbourne, Fanale. Español de Médula Ósea; German High-Grade Long-term cognitive and cardiac outcomes after Drafting of the manuscript: Pinnix, Cheah, Dabaja, Lymphoma Study Group; German Hodgkin’s Study prenatal exposure to chemotherapy in children Fanale. Group; Japanese Lymphorra Study Group; aged 18 months or older: an observational study. Critical revision of the manuscript for important Lymphoma Study Association; NCIC Clinical Trials Lancet Oncol. 2012;13(3):256-264.

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