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Daratumumab at the frontiers of post-transplant refractory T-acute lymphoblastic leukemia—a worthwhile strategy?

Bone Marrow Transplantation volume 53, pages 1487–1489 (2018)Cite this article

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Adult ALL is a heterogeneous disease both clinically and genetically. The management of ALL in adults remains a daunting task. The therapeutic options in relapsed / refractory setting post allogeneic hematopoietic stem cell transplantation are limited. The emergence of targeted immunotherapeutic strategies in cancers paved way for the detection of suitable targets and drugs with cytotoxic abilities. However no safe and effective immunotherapies have been developed for T ALL. CD 38, also referred to as T10, was identified in 1980 in a project investigating cell surface molecules of human WBC using thymocyte-specific murine monoclonal antibodies [1]. It is recognized as a marker of both differentiation and activation of lymphocytes. It is expressed at high levels on the cell surface of activated T cells and terminally differentiated B cells, but at relatively low levels on normal lymphoid and myeloid cells [2]. Most notably, CD 38 is expressed in a large number of hematological malignancies [3,4,5,6,7,8,9,10,11,12]. Daratumumab is a human IgG1κ monoclonal antibody that binds to a unique CD 38 epitope and recently FDA approved for the treatment of refractory multiple myeloma. Preclinical studies have shown that CD 38 is a relevant target in T ALL and its surface expression does not change with chemotherapy [13]. Hence daratumumab with its broad antitumor spectrum may be used in T ALL. We report a patient with early precursor T cell acute lymphoblastic leukemia who relapsed post allogeneic hematopoietic stem cell transplantation and was salvaged with daratumumab.

A 32-year-old lady presented to our center in June 2013, with generalized lymphadenopathy. On evaluation she was diagnosed to have an acute leukemia of ambiguous lineage (CD 13, CD 33, CD 38, CD 45 and CD 7 positive). She received induction chemotherapy with 3 + 7 (cytarabine and daunorubicin) followed by three cycles of high dose cytarabine consolidation. She was in morphological complete remission. After a treatment-free interval of 2 months, she relapsed with an early precursor T cell phenotype (CD 1a negative, TdT, CD 10, CD 34, CD 38 positive). She was then given ALL like induction therapy and achieved a complete remission without measurable residual disease (MRD negative). She underwent allogeneic stem cell transplantation from a matched sibling donor with myeloablative conditioning (cyclophosphamide with total body irradiation) in January 2014. She relapsed after 21 months. The marrow revealed 76% lymphoid blasts expressing CD 34, CD 7, CD 10, CD 38 and negative for CD 1a, CD 4, and CD8. She received salvage induction with vincristine, etoposide, bortezomib, dexamethasone, adriamycin and L asparaginase. With this, she did not achieve remission. This was followed by one cycle of FLAG IDA with which she achieved complete remission morphologically (but with MRD of 0.17% by flow cytometry). As she had another fully HLA matched sibling donor, she underwent second allogeneic stem cell transplant with reduced intensity conditioning (fludarabine + treosulfan) in February 2016. In view of a high risk of relapse, she received prophylactic donor lymphocyte infusion (DLI) on day +94 along with lenalidomide 10 mg per day subsequently. She developed skin and liver GVHD which was managed with systemic steroids and topical tacrolimus. Bone marrow studies done at day 90 and 1 year after 2nd allogeneic transplant showed MRD negativity. She developed a relapse after 18 months with marrow showing 86% lymphoid blasts with CD 7 bright, CD 1a negative, CD 20 negative, CD 34 bright, and CD 38 bright while CD 4 and CD 8 were negative. In view of her young age and good performance status, she received salvage chemotherapy with pegylated L asparaginase, dexamethasone, bortezomib and vincristine. During this chemotherapy she developed sub-acute bilateral lower limb flaccid weakness suggestive of acute demyelinating polyneuropathy for which she received intravenous immunoglobulin. A repeat marrow study done at 32 days after salvage chemotherapy showed 4% blasts but with 15.6% MRD by flow cytometry. As she still had measurable disease with bright CD 38 expression on the blast population she was given daratumumab at 16 mg/kg dose every week (along with weekly intrathecal methotrexate) on compassionate basis. Post three doses of daratumumab she achieved MRD negativity in marrow. Her course was complicated by repeated urinary tract infections (UTI) with Pseudomonas. Presently she is doing well and is on maintenance therapy with daratumumab 2 weekly with 6 mercaptopurine and methotrexate. So far, she has received a cumulative of 12 doses of daratumumab (4 weekly and 8 two-weekly doses). A repeat marrow after the 8th dose confirmed maintenance of MRD negativity. She continues to be in remission at the time of this writing (about 5 months from the first documentation of MRD negative status).

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  1. Stem cell transplant unit, Department of Medical Oncology, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai, India

    Avinash Bonda, Sachin Punatar, Anant Gokarn, Aniket Mohite, Kartthik Shanmugam, Lingaraj Nayak, Mounika Bopanna, Badira Cheriyalinkal Parambil & Navin Khattry

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Correspondence to Navin Khattry.

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Bonda, A., Punatar, S., Gokarn, A. et al. Daratumumab at the frontiers of post-transplant refractory T-acute lymphoblastic leukemia—a worthwhile strategy?. Bone Marrow Transplant 53, 1487–1489 (2018). https://doi.org/10.1038/s41409-018-0222-5

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