Pharmacologic Therapies to Prevent Relapse of Acute Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation

Relapse is the main cause of mortality in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Adverse cytogenetic or molecular risk factors, as well as refractory disease or persistent measurable residual disease (MRD) at the time of transplantation are associated with an increased risk of recurrence. Salvage therapy for AML relapse after allo-HSCT is often limited to chemotherapy, donor lymphocyte infusions and/or second transplants and is rarely successful. Effective post-transplant preventive intervention in high risk AML may be crucial. The most frequent and promising approach is the use of post-transplant maintenance with hypomethylating agents or with FLT3 tyrosine kinase inhibitors when the target is present. Moreover, IDH1/IDH2 inhibitors and BCL-2 inhibitors in combination with other strategies are promising approaches in the maintenance setting. Here we summarize the current knowledge about the preemptive and prophylactic use of pharmacologic agents after allo-HSCT to prevent relapse of AML

Novel strategies to prevent and overcome relapse after allogeneic hematopoietic cell transplantation in acute lymphoblastic leukemia

The outcome of B-cell acute lymphoblastic leukemia (B-ALL) has improved over time with the incorporation of multi-agent chemotherapy in the treatment landscape as well as the recent approval of immunotherapeutic agents allowing a larger proportion of patients to undergo allogeneic hematopoietic cell transplantation (allo-HCT) which is still considered a potential curative approach. However, relapse post-transplant is still occurring and constitutes a common cause of treatment failure in B-ALL. The present review aims to discuss the novel strategies and therapies used to prevent and overcome relapse post allo-HCT in patients with ALL, focusing on the role of tyrosine kinase inhibitors in Philadelphia chromosome positive B-ALL, the role of innovative agents such as blinatumomab and inotuzumab ozogamicin, and finally the role of cellular therapy

Impact of luteinizing hormone suppression on hematopoietic recovery after intensive chemotherapy in patients with leukemia

Treatment of acute leukemia with intensive chemotherapy leads to an increased risk of myelosuppression. Luteinizing hormone (LH) blockade improves hematopoietic recovery in mice after radiation or chemotherapy, through protection of the hematopoietic stem cells which express the LH receptor. We hypothesized that LH blockade improves hematopoietic recovery following intensive chemotherapy in patients with leukemia. We conducted a retrospective analysis on pre-menopausal women with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) who received intensive chemotherapy and leuprolide given for abnormal uterine bleeding prevention or treatment. Given that leuprolide was more commonly administered in younger patients, we performed propensity score matching between the leuprolide (AML N=64; ALL N=49) and control groups (AML N=128; ALL N=98 patients). Patients with AML who received leuprolide had an additional increase of 13.8 x 109/L/year in their platelet count, and a 0.19 x 109/L/year increase in their lymphocyte count after chemotherapy compared to control (P=0.02; P=0.03 respectively). Those with ALL who received leuprolide had an additional increase of 0.37 x 109/L/year in their absolute neutrophil count (P=0.02). In AML, leuprolide was associated with higher long-term hemoglobin levels (P<0.001) and less blood transfusions (mean: 23.9 vs 34.7 units; P=0.002) compared to control. In a multivariate analysis, leuprolide was identified as an independent factor predicting improved hemoglobin levels, lymphocyte and platelet counts in AML. In conclusion, leuprolide use in leukemia patients receiving intensive chemotherapy was associated with improved long-term blood count recovery and was associated with decreased transfusion requirements in AML

Clinical practice recommendation on hematopoietic stem cell transplantation for acute myeloid leukemia patients with FLT3 internal tandem duplication: a position statement from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in 25-30% of patients with acute myeloid leukemia . Because of the poor prognosis associated with FMS-like tyrosine kinase 3 internal tandem duplication mutated Acute myeloid leukemia, allogeneic-hematopoietic stem-cell transplantation was commonly performed in first complete remission. Remarkable progress has been made in frontline treatments with the incorporation of FLT3 inhibitors and the development of highly sensitive minimal/measurable residual disease assays. Similarly, recent progress in allogeneic-hematopoietic stem-cell transplantation includes improvement of transplant techniques, the use of haplo-identical donors in patients lacking an HLA matched donor, and the introduction of FLT3 inhibitors as posttransplant maintenance therapy. Nevertheless, current transplant strategies vary between centers and differ in terms of transplant indications based on the internal tandem duplication allelic ratio and concomitant nucleophosmin-1 mutation, as well as in terms of post-transplant maintenance/consolidation. This review generated by international leukemia or transplant experts, mostly from the European Society for Blood and Marrow Transplantation, attempts to develop a position statement on best approaches for allogeneic-hematopoietic stem-cell transplantation for acute myeloid leukemia with FMS-like tyrosine kinase internal tandem duplication including indications and modalities of allogeneic-hematopoietic stem-cell transplantation and on potential optimization of post-transplant maintenance with FMS-like tyrosine kinase inhibitors

Pharmacologic Strategies for Post-Transplant Maintenance in Acute Myeloid Leukemia: It Is Time to Consider!

Patients with high-risk acute myeloid leukemia are offered allogeneic hematopoietic cell transplantation (allo-HCT) in first remission to reduce risk of relapse. However, disease recurrence remains the major reason of allo-HCT failure, occurring in around 35&ndash;45% of patients, and leading to dismal outcomes. Strategies to reduce the risk of relapse are greatly needed, especially in the early post-transplant phase where the graft-versus-leukemia (GVL) effect is not yet activated. Some practices include the use of myeloablative conditioning regimens, close monitoring of measurable residual disease and donor chimerism, rapid tapering of immunosuppression, and implementation of pre-emptive strategies as the use of donor lymphocyte infusion. However, it&rsquo;s time to consider prophylactic pharmacologic interventions post allo-HCT that aim at maintaining leukemic clones under control by both direct cytotoxic activity and by enhancing the GVL effect. In this current review, available data on drugs targeting epigenetic pathways like azacitidine, or actionable mutations like FLT3 and IDH1/2 inhibitors used as maintenance post allo-HCT, will be discussed

Primary small cell carcinoma of the breast: a case report

Abstract Background Neuroendocrine breast cancer is a rare entity that was defined in 2003 by the World Health Organization as a separate breast cancer subtype. The diagnosis of neuroendocrine breast cancer requires the presence of neuroendocrine features in at least 50% of malignant cells, the exclusion of non-mammary primary tumors, as well as the presence of an in situ component in breast histology. The treatment and prognosis of neuroendocrine breast cancer are still not well established. Small cell carcinoma of the breast is a subtype of neuroendocrine cancer, resembling small cell carcinoma of the lung. It has a very poor prognosis and warrants treatment with platinum-based chemotherapy. Case presentation We herein report the case of a 47-year-old white woman with a left breast mass that was found to be an early-stage, high-grade small cell carcinoma of the breast. Positron emission tomography-computed tomography imaging excluded any other primary disease. Our patient underwent a left total mastectomy with sentinel lymph node biopsy and received cisplatin-based adjuvant chemotherapy. Our patient remains free of disease to date. Conclusions This case report sheds light on a rarely described disease and provides a comprehensive approach to diagnosis and management. Neuroendocrine carcinoma of the breast is a well-defined histologic subtype of breast cancer. Small cell carcinoma of the breast is a rare subtype of neuroendocrine breast cancer. Due to the rarity of this entity, prognosis has still not been well established, and treatment has not been standardized, cisplatin-based treatment has been used in this case similar to small cell carcinoma of the lung

Safety and Efficacy of Elective Switch from Nilotinib to Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia

Abstract The treatment of newly diagnosed chronic phase chronic myeloid leukemia (CML) with nilotinib has resulted in a higher rate of major molecular (MMR) and complete cytogenetic response (CCyR) at 12 months compared to imatinib but at a higher cumulative cost and increased risk of serious adverse events. To maintain long-term efficacy and minimize both toxicity and costs, we aimed at evaluating in a prospective single-center trial the efficacy and safety of a response-directed switch from nilotinib to imatinib after 12 months in patients newly diagnosed with chronic phase CML. Thirteen adult patients were enrolled. Twelve patients started on nilotinib 300 mg twice daily. Eleven patients completed one year of nilotinib and were switched to imatinib 400 mg daily as per protocol. At 3 months, all patients achieved a complete hematologic response, with 7 (58%) patients had early molecular response. At 12 months, all patients achieved CCyR, of whom 5 (42%) and 4 (33%) patients achieved MMR and MR4.5, respectively. Three (27%) patients switched back to nilotinib after 18, 24, and 51 months respectively: 1 patient because of loss of CCyR after 18 months, and 2 patients because of imatinib intolerance. At last follow-up, all patients (n = 12) were alive and in MMR, 6 (50%) of them in continuous MR4.5. These findings suggest that response directed switch from nilotinib to imatinib at 12 months is capable of maintaining long-term response, with manageable side effects. This approach warrants further exploration with larger prospective trials. Clinical trial registration: Clinicaltrials.gov identifier: NCT01316250, https://clinicaltrials.gov/ct2/results?cond=&term=NCT01316250&cntry=&state=&city=&dist= .

Efficacy and safety of generic imatinib after switching from original imatinib in patients treated for chronic myeloid leukemia in the United States

Abstract Introduction Imatinib is standard therapy for patients with chronic myeloid leukemia (CML). In February 2016, a generic formulation entered the US market. Physicians and patients are frequently concerned about whether switching from original to generic drugs may affect the efficacy and/or safety. Materials and methods This is an observational retrospective study using medical charts of patients diagnosed with CML in the chronic phase who were treated with original imatinib from the year 2000 to 2017 and who were subsequently switched to generic imatinib. Results In this study, 38 patients have switched to generic imatinib. Before the switch, responses were assessed on all patients, all of them were in CCyR and 36 (95%) were in MMR, including 28 (74%) with MR4.5. Patients have received generic imatinib for a median of 19.4 (range, 3.4‐46.3) months. Molecular responses after switching were stable in 89%, improved in 8%, and worsened in 3% of patients. After switching, 15 (39%) patients reported new or worsening adverse events, including 5 (13%) patients with edema, 8 (21%) muscle cramps, 7 (18%) nausea, 6 (16%) diarrhea, and 5 (13%) fatigue. Discussion Bioequivalence studies demonstrated the same rate and extent of absorption of generic imatinib compared to the original form, which led to the FDA approval. In our observational series, most of the patients maintained their responses and none lost MMR. Adverse events noted were mild and well tolerated. Conclusion A change from original to generic imatinib appears to maintain efficacy and be generally safe. More patients and longer follow‐up are required to confirm these observations