Lenalidomide combined with mismatched microtransplantation for acute myeloid leukemia
Authors: Amir T. Fathi, Gabriela Hobbs, Bimalangshu R. Dey, Yi‐Bin Chen
Journal: American Journal of Hematology (2018)

Although allogeneic hematopoietic cell transplantation (HCT) offers potent disease control for patients with acute myeloid leukemia (AML), significant toxicities such as graft-versus-host disease (GVHD) limit its success. A 2012 phase II study of 101 Chinese patients assessed "microtransplantation" with nonengrafting related HLA-mismatched GPBSCs given concurrently with consolidation chemotherapy for patients with AML.1 Although no patients had measurable donor chimerism by standard methods, 20 of 23 assayed patients had detectable levels of "microchimerism" as tested by PCR (polymerase chain reaction) of the SRY (sex-determing region Y) region of the Y chromosome, and overall outcomes were promising.2 A subsequent multicenter study focusing on elderly patients has also shown preliminarily compelling results.3 The immunomodulatory agent lenalidomide, at higher doses (eg, 50 mg daily), has been shown to be relatively safe and effective in some patients with advanced AML,4 and it has also been linked to instigating or enhancing the graft versus malignancy effect following HCT.5 We hypothesized that lenalidomide may enhance the antileukemia effect in HLA-mismatched donor microtransplantation. Herein, we report the clinical trajectory of 3 patients treated at our site with lenalidomide combined with a mismatched microtransplantation protocol as consolidation therapy. Three cycles of consolidation were planned, and for each, consolidation cytarabine was to be given at a dose of 2 g/m2, administered once daily by intravenous infusion on days 1 through 5. This cytarabine dose was selected as an "intermediate-dose", as opposed to cycles of high-dose cytarabine (eg, 3 g twice daily on days 1, 3, and 5), given that many patients on this protocol would be aged over 60, a group in whom intermediate dose cytarabine is preferred by consensus guidelines. On day 6 of each cycle of consolidation, donor haploidentical GPBSCs, at a target dose of 1.0 × 108 CD3+ cells/kg of recipient weight, were infused, and lenalidomide was initiated at 10 mg daily by mouth for 21 days. Maintenance treatment with lenalidomide at a dose of 10 mg daily, given for 21 days of a 28 day cycles, followed the cycles of consolidation, for up to 12 months. Our first patient was a 79-year old female with NPM1-mutated, karyotypically normal AML who had achieved CR1 after "7 + 3" cytarabine- and anthracycline-based induction chemotherapy. During her first cycle on trial, she experienced a potentially delayed infusion reaction of rash and some fevers following administration of a haploidentical cells from her son, although fevers occurred during neutropenia and the rash could have been from a drug reaction. Her second cycle of treatment was complicated by febrile neutropenia, labial infection, and prolonged cytopenias, prompting early discontinuation of lenalidomide on day 22 of the cycle. Her third and final cycle of post-remission therapy was only complicated by febrile neutropenia, which resolved on intravenous antibiotics. On count recovery, she went on to start lenalidomide maintenance at 10 mg daily given for 21 days of 28-day cycles. Due to rash and cytopenias during the first cycle, the start of her second cycle of maintenance was delayed. Upon improvement, she received 5 additional cycles of maintenance therapy at a reduced dose 5 mg daily, which she tolerated well with no recurrence of severe cytopenias or rash. She remains alive and well, nearly 30 months following the start of post-remission therapy. Our second patient was a 77-year old female with NPM1-mutated, karyotypically normal AML. She had achieved CR1 with "7 + 3" cytarabine- and anthracycline-based induction chemotherapy. With the first cycle of post-remission therapy, she experienced a likely cytokine-mediated reaction hours after microtransplantation, manifesting with fevers, chills and mild hypotension, responsive to intravenous fluids and supportive care. Her course was subsequently complicated by enterococcal sepsis, severe desquamation, not thought to be GVHD as the rash started with cytarabine initation and invasive mucormycosis. Given multi-organ failure and overwhelming inoperable infection, the patient and family opted for comfort measures, and the patient expired 32 days after starting postremission therapy. Our third patient was a 66-year old male with karyotypically normal, NPM1-mutated AM, who had achieved a remission at an outside hospital following induction with mitoxantrone and cytarabine. His first cycle of therapy on trial was complicated by fever and rash prior to infusion of cells, thought to be related to cytarabine. This recurred during the second cycle of treatment, but was similarly transient and prior to cell infusion. His third cycle of post remission therapy was complicated by polymicrobial sepsis and Clostridium difficile colitis. After recovery, he was initiated on lenalidomide maintenance and has since remained in remission for more than 2 years. Correlative analysis from the 2 surviving patients did not reveal any potential mechanisms of action (data not shown), although lack of numbers and a control group hamper any conclusions. Serial chimerism studies measured through short tandem repeat analysis never showed any measurable donor cell chimerism in the total leukocyte fraction, the CD33+ lineage, nor the CD3+ lineage. Nonengrafting cellular therapy approaches are increasing in use, both commercially and experimentally, as they potentially hold the promise of cultivating immunological anti-cancer activity without GVHD. The lack of a specific target remains a significant obstacle for myeloid diseases such as AML. HLA-mismatched microtransplantation is a cellular therapy without the requirement for a specific target and a proposed mechanism of action involving both graft-versus-host and host-versus-graft allogeneic responses.5 The observation that antitumor responses occur in association with rejection of mismatched related donor hematopoietic cells has been reported by our group in the past.6 Several ongoing studies are attempting to define the role of microtransplantation for patients with AML. These include a phase I study for patients not suitable for conventional HCT (NCT02189824), a phase II study for intermediate risk AML (NCT02587871), a donor versus microtransplantation study (NCT02461121), combination microtransplantation with induction chemotherapy (NCT01484171), and a phase 3 randomized trial comparing microtransplantation with chemotherapy to chemotherapy alone for elderly patients with AML led by the International Microtransplantation Cooperative Group (NCT02171117). Unfortunately, our study was closed prematurely due to lack of accrual, as the majority of our eligible elderly patients currently proceed to conventional allogeneic HCT even with mismatched unrelated or related haploidentical donors. Allogeneic HCT in first remission for elderly patients with AML is rapidly becoming the standard of care. It therefore remains to be seen if such ongoing microtransplantation trials will be able to sufficiently enroll patients to truly investigate its activity. In summary, we report on 3 cases of elderly AML who were treated with a microtransplantation protocol incorporating lenalidomide at our institution. Although the 2 patients that survived the initial courses of therapy remain alive and in remission, any conclusion is limited by the small number of evaluated patients. Additional studies are necessary to further assess the promise and understand the mechanism of this unique approach to cellular immunological therapy. Based on the limited numbers in our cohort, it is also difficult to determine whether the addition of lenalidomide or any immunomodulatory agent impacts the efficacy or safety of microtransplantation. Indeed, with the increasing success of reduced intensity allogeneic transplantation for elderly AML, these studies will likely be conducted in patients who are not optimal candidates for conventional allogeneic hematopoietic cell transplantation. This study was funded by Celgene Pharmaceuticals. ATF: Consulting and Clinical Trial Support from Celgene. The authors declare that they have no conflict of interest with the contents of this article.