Ponatinib Induces a Persistent Molecular Response and Graft-versus-Host Disease/Graft-versus-Leukemia Effect in a Patient with Philadelphia-Positive Acute Lymphoblastic Leukemia with a T315I Mutation following Early Relapse after Allogeneic Transplant

Abstract

We describe the case of a patient with a Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) treated with dasatinib plus steroids as the first-line therapy who achieved a molecular complete remission and then underwent a matched, unrelated donor allogeneic transplant. Five months after the transplant, he experienced a disease relapse with an T315I mutation, which was resistant to salvage Key WordsAcute lymphoblastic leukemia · Philadelphia chromosome · Allogeneic transplant · Ponatinib · T315I mutation · Graft-versus-host disease · Graft-versus-leukemia effect · Thyroid dysfunction Established Facts• Ponatinib is a highly effective treatment for Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) with T315I mutation, and is well tolerated. Novel Insights• Ponatinib as a single-agent treatment is able to determine the molecular complete response in Ph+ ALL with T315I mutation after early relapse following allogeneic stem cell transplantation, and can induce a graft-versus-host disease/graft-versus-leukemia effect. chemotherapy. Once the details of the T315I mutation were acquired, we initiated ponatinib treatment at a standard dosage and observed a rapid decrease of minimal residual disease (MRD) at molecular assessment. The bone marrow evaluation after 2, 3, 6, 10 and 13 months was negative for MRD. After starting ponatinib, the patient experienced a skin graft-versus-host disease (GVHD), whereas no occurrence of GVHD was observed after transplant, suggesting that the efficacy of ponatinib could be related not only to the direct antileukemic effect, but also to its ability to promote an indirect graft-versus-leukemia effect. Ponatinib was well tolerated but a thyroid dysfunction mimicking a cardiovascular toxicity was observed and solved with hormonal substitutive treatment.

Ponatinib-Induced Graft-versus-Host Disease/Graft-versus-Leukemia Effect in a Patient with Philadelphia-Positive Acute Lymphoblastic Leukemia without the T315I Mutation Relapsing after Allogeneic Transplant

“…Three clinical trials have confirmed the efficacy of ponatinib in the relapsed and front-line setting in Ph+ ALL patients, even in the presence of the T315I mutation. These data support the characterization of ponatinib as a pan-BCR/ABL inhibitor and therefore supports its use in Ph+ ALL patients resistant or intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate, or in patients harboring the T315I mutation [8,9,10]. …”

“…Recently, a similar case report described a patient with Ph+ ALL with the acquisition of T315I mutation who was treated with ponatinib at relapse after an allogeneic transplant. This patient also experienced a skin GVHD, suggesting that the efficacy of ponatinib could be related to its ability to promote an indirect GVL effect [10]. This finding reinforces the use of immunotherapy in the treatment of onco-hematological diseases [13].…”

Spotlight on ponatinib in the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia: patient selection and perspectives

“…Although both patients achieved deep molecular responses, they also developed cutaneous GVHD which required medication discontinuation in the patient with CML 47. Skin GVHD following initiation of ponatinib for posttransplant relapses has also been described in other case reports, suggesting a potential role of ponatinib to enhance the graft-versus-leukemia effect 48,49. Overall, 43 patients have received ponatinib for posttransplant relapses in the early phase clinical trials; however, their clinical outcomes and side-effect profile have not been reported separately 15,16…”

Long-Term Molecular Remission Achieved by Antibody Anti-CD22 and Ponatinib in a Patient Affected by Ph’+ Acute Lymphoblastic Leukemia Relapsed after Second Allogeneic Hematopoietic Stem Cell Transplantation: A Case Report

“…New drugs, such as monoclonal antibodies or third generation TKIs, offer new possibilities for treatment of these patients. Few clinical experiences published so far evaluate the use of these drugs in the “posttransplant” setting [19, 20]. We described the case of a patient affected by Ph’+ ALL following early relapse after a second HSCT, who was treated with a combination of IO, DLI, and ponatinib.…”