Successful Pregnancies during Crizotinib Therapy for ALK+ Lymphoma

Anaplastic large cell lymphoma (ALK⁺ALCL) is most frequently observed in young adults and it usually defined by the t(2; 5)(p23;q35) chromosome translocation. The advent of crizotinib has represented a turning point in relapsed-refractory disease, allowing responses in > 2/3 of cases. However, clinical unmet needs remain, such as managing therapy in patients desiring parenthood. Here we provide the first description of four cases of successful pregnancies during crizotinib treatment for ALK+ lymphomas.

Patient 1, diagnosed with ALK+ALCL at 30, achieved complete response (CR) with VACOP-B. At 38, she relapsed with nodal and hepatic involvement, confirmed by positive t(2;5)/NPM1-ALK signal via RT-PCR on peripheral blood (PB). She attained a second CR with Brentuximab vedotin, followed by autologous stem cell transplant (ASCT). However, B symptoms and adenopathies reappeared at day +47 post ASCT. Crizotinib was initiated, resulting in metabolic and molecular CR after two months. After two years of treatment, at 41, the patient experienced iatrogenic menopause post-ASCT and desired motherhood through assisted reproductive technology. Prior ovarian stimulation and oocyte cryopreservation were done. In vitro fertilization (IVF) was performed, and crizotinib was stopped two weeks before embryo transfer (ET). A first-trimester scan confirmed a single gestational sac. Screening for Down syndrome (combined test and NIPT) was negative, but preeclampsia screening indicated heightened risk, leading to low-dose aspirin administration. Ultrasounds showed regular fetal growth. The pregnancy was uneventful except for a mild SARS-CoV-2 infection. Monthly NPM1-ALK RT-PCR remained negative. At 39 weeks, after spontaneous membrane rupture, labor was induced, resulting in the vaginal delivery of a healthy male newborn (3300 grams, 44th percentile on the INeS chart, Apgar scores 9 and 9 at 1 and 5 minutes). Postpartum was uncomplicated, and the patient chose not to breastfeed. Crizotinib was resumed two weeks later. The child, now 2, is healthy with normal development. After 20 months of stable molecular response, the patient, at 43, sought a second pregnancy with two cryopreserved blastocysts. Crizotinib was interrupted again. The first ET failed, but the second, attempted four weeks later, succeeded. Cardiac activity was detected in a single gestational sac at five weeks. The pregnancy, now at 16 weeks, is proceeding normally with minimal decidual detachment, and low-dose aspirin was started as in the previous pregnancy.

Patient 2, a 25-year-old male with ALK+ALCL, was treated with CHOEP, achieving metabolic CR but remaining t(2;5) positive on PB. Crizotinib was started, gaining molecular response within a month without any adverse events. Despite our recommendation to use barrier contraception, he conceived a child after four years of continuous therapy and stable remission, with no crizotinib interruption. At 34, he fathered a second child. Both daughters, born at 3430 and 3500 grams, had normal, complication-free pregnancies. They are now 7 and 2 years old and in good health.

Crizotinib is a specific, non-mutagenic drug, though ALK is selectively expressed in the central nervous system, and the MET gene, another target of crizotinib, can cause Non-Syndromic Autosomal Recessive Deafness if mutated. Therefore, we advised the first patient to stop crizotinib during pregnancy, whereas the second patient continued it while conceiving two daughters. Literature includes reports of women on crizotinib for ALK+ lung adenocarcinoma during pregnancy, but treatments often started either during or after pregnancy. There are no reports of men conceiving while on crizotinib. Notably, patient 1, who stopped crizotinib after 40 months, showed no lymphoma regrowth during a 10-month treatment break. A new crizotinib discontinuation is underway. Patient 2's case suggests crizotinib may not affect spermiogenesis. These cases do not pretend to provide definitive answers regarding the discontinuation of crizotinib or the safety of pregnancy during treatment; prospective studies and pharmacodynamic investigations will be required to fully address these questions. Our aim is to signal the feasibility of conceiving during crizotinib treatment considering not only the control of the underlying disease, but also the importance of quality of life and the patient's needs, including the desire for parenthood.

No relevant conflicts of interest to declare.