Clinical Challenges and Consequences of Measurable Residual Disease in Non-APL Acute Myeloid Leukemia

The ability to detect residual levels of leukemic blasts (measurable residual disease, MRD) has already been integrated in the daily routine for treatment of patients with chronic myeloid and acute lymphoblastic leukemia. In acute myeloid leukemia (AML), a variety of mostly retrospective studies have shown that individuals in AML remission who tested positive for MRD at specific time-points or had increasing MRD levels are at significantly higher risk of relapse and death compared to MRD-negative patients. However, these studies differ with respect to the “MRD-target”, time-point of MRD determination, material analyzed, and method applied. How this probably very valuable MRD information in individual patients may be adapted in the daily clinical routine, e.g., to separate patients who need more aggressive therapies from those who may be spared additional—potentially toxic—therapies is still a work-in-progress. With the exception of MRD assessment in acute promyelocytic leukemia (APL), the lack of randomized, prospective trials renders MRD-based decisions and clinical implications in AML a difficult task. As of today, we still do not have proof that early intervention in MRD-positive AML patients would improve outcomes, although this is very likely. In this article, we review the current knowledge on non-APL AML MRD assessment and possible clinical consequences

Case Report: Allogeneic Stem Cell Transplantation Following Induction With CPX-351 in Patients With Acute Myeloid Leukemia Is Feasible

Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) and treatment-related acutemyeloid leukemia (tAML) after chemotherapy or radiation therapy for other neoplasms are associated with poor outcomes. CPX-351, a dual-drug liposomal encapsulation of daunorubicin and cytarabine, has been shown to improve outcomes in AML-MRC and tAML compared with standard 7+3 regimens. Here we report the cases of four consecutive patients with AML-MRC or tAML who received CPX-351 as outpatient induction therapy immediately followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). Two patients received allo-HSCT in remission (one in complete remission and one in partial remission) and two patients received allo-HSCT in aplasia (one at 11 days and one at 52 days after the start of induction therapy with CPX-351). With a median follow-up of 188 days after allo-HSCT, all but one patient are alive and two are in remission. Further studies will help define and expand the role of CPX-351 in the treatment of AML-MRC and tAML, especially in patients expected to undergo allo-HSCT

Salvage Therapy With Polatuzumab Vedotin, Bendamustine, and Rituximab Prior to Allogeneic Hematopoietic Transplantation in Patients With Aggressive Lymphomas Relapsing After Therapy With Chimeric Antigen Receptor T-Cells—Report on Two Cases

Up to 60% of patients with aggressive B-cell lymphoma who receive chimeric antigen receptor (CAR) T-cell therapy experience treatment failure and subsequently have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains a potentially curative approach for patients in this situation. Induction of a deep response prior to alloHSCT is crucial for long-term outcomes, but the optimal bridging strategy following relapse after CAR T-cell therapy has not yet been established. Polatuzumab vedotin, an antibody drug conjugate targeting CD79b, is a novel treatment option for use in combination with rituximab and bendamustine (Pola-BR) in relapsed or refractory disease. Patients: We report two heavily pretreated patients with primary refractory diffuse large Bcell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL) respectively who relapsed after therapy with CAR T-cells with both nodal and extranodal manifestations of the disease. After application of three courses of Pola-BR both patients achieved a complete metabolic remission. Both patients underwent alloHSCT from a human leukocyte antigen (HLA)-mismatched donor following conditioning with busulfan and fludarabine and are disease free 362 days and 195 days after alloHSCT respectively. We conclude that Pola-BR can be an effective bridging therapy before alloHSCT of patients relapsing after CAR T-cell therapy. Further studies will be necessary to define the depth and durability of remission of this salvage regimen before alloHSCT

Clinical Challenges and Consequences of Measurable Residual Disease in Non-APL Acute Myeloid Leukemia

The ability to detect residual levels of leukemic blasts (measurable residual disease, MRD) has already been integrated in the daily routine for treatment of patients with chronic myeloid and acute lymphoblastic leukemia. In acute myeloid leukemia (AML), a variety of mostly retrospective studies have shown that individuals in AML remission who tested positive for MRD at specific time-points or had increasing MRD levels are at significantly higher risk of relapse and death compared to MRD-negative patients. However, these studies differ with respect to the “MRD-target”, time-point of MRD determination, material analyzed, and method applied. How this probably very valuable MRD information in individual patients may be adapted in the daily clinical routine, e.g., to separate patients who need more aggressive therapies from those who may be spared additional—potentially toxic—therapies is still a work-in-progress. With the exception of MRD assessment in acute promyelocytic leukemia (APL), the lack of randomized, prospective trials renders MRD-based decisions and clinical implications in AML a difficult task. As of today, we still do not have proof that early intervention in MRD-positive AML patients would improve outcomes, although this is very likely. In this article, we review the current knowledge on non-APL AML MRD assessment and possible clinical consequences

Clinical Challenges and Consequences of Measurable Residual Disease in Non-APL Acute Myeloid Leukemia

The ability to detect residual levels of leukemic blasts (measurable residual disease, MRD) has already been integrated in the daily routine for treatment of patients with chronic myeloid and acute lymphoblastic leukemia. In acute myeloid leukemia (AML), a variety of mostly retrospective studies have shown that individuals in AML remission who tested positive for MRD at specific time-points or had increasing MRD levels are at significantly higher risk of relapse and death compared to MRD-negative patients. However, these studies differ with respect to the “MRD-target”, time-point of MRD determination, material analyzed, and method applied. How this probably very valuable MRD information in individual patients may be adapted in the daily clinical routine, e.g., to separate patients who need more aggressive therapies from those who may be spared additional—potentially toxic—therapies is still a work-in-progress. With the exception of MRD assessment in acute promyelocytic leukemia (APL), the lack of randomized, prospective trials renders MRD-based decisions and clinical implications in AML a difficult task. As of today, we still do not have proof that early intervention in MRD-positive AML patients would improve outcomes, although this is very likely. In this article, we review the current knowledge on non-APL AML MRD assessment and possible clinical consequences

Inverse agonism of cannabinoid CB1 receptor blocks the adhesion of encephalitogenic T cells in inflamed brain venules by a protein kinase A-dependent mechanism

It is well known that the cannabinoid system has a significant role in the regulation of the immune responses. Cannabinoid receptors CB1 and CB2 are expressed on T lymphocytes and mediate the immunomodulatory effects of cannabinoids on T cell functions. Here we show that the treatment of proteolipid protein (PLP)139-151-specific T cells with SR141716A, a CB1 inverse agonist and prototype of the diarylpyrazoles series, induced a strong inhibition of firm adhesion in inflamed brain venules in intravital microscopy experiments. In contrast, SR144528, a potent CB2 inverse agonist, had no significant effect on both rolling and arrest of activated T cells. In addition, two analogs of SR141716A and CB1 inverse agonists, AM251 and AM281 inhibited encephalitogenic T cell adhesion suggesting that selective CB1 inverse agonism interfere with lymphocyte trafficking in the CNS. Flow cytometry experiments showed that CB1 inverse agonists have no effect on adhesion molecule expression suggesting that CB1 blockade interferes with signal transduction pathways controlling T cell adhesion in inflamed brain venules. In addition, integrin clustering was not altered after treatment with CB1 inverse agonists suggesting that adhesion blockade is not due to the modulation of integrin valency. Notably, the inhibitory effect exerted by AM251 and AM281 on the adhesive interactions was completely reverted in the presence of protein kinase A (PKA) inhibitor H89, suggesting that cAMP and PKA activation play a key role in the adhesion blockade mediated by CB1 inverse agonists. To further strengthen these results and unveil a previously unknown inhibitory role of cAMP on activated T cell adhesion in vivo in the context of CNS inflammation, we showed that intracellular increase of cAMP induced by treatment with Bt2cAMP, a permeable analog of cAMP, and phosphodiesterase (PDE) inhibitor theophylline efficiently blocked the arrest of encephalitogenic T cells in inflamed brain venules. Our data show that modulation of CB1 function has anti-inflammatory effects and suggests that inverse agonism of CB1 block signal transduction mechanisms controlling encephalitogenic T cells adhesion in inflamed brain venules by a PKA-dependent mechanism

Staging surgery in early-stage ovarian mucinous tumors according to expansile and infiltrative types

The aim of this study is to determine the value of surgical staging for the two histologic types (expansile or infiltrative) of apparent stage I mucinous ovarian carcinoma. We retrospectively analyzed patients treated from 1976 and 2016 for apparent macroscopic stage I ovarian mucinous carcinoma. Extra-ovarian disease and tumors that metastasized to the ovaries were excluded. Two expert pathologists performed pathologic reviews of tumor data, according to 2014 WHO classification criteria. Tumors were typed as expansile or infiltrative and clinical and histologic characteristics were studied. The value of staging procedures (peritoneal and nodal) was based on the rate of microscopic involvement in macroscopically normal specimens. Of 114 cases reviewed, 46 were excluded (26 with macroscopic stage > I; 20 inaccessible for pathologic review). Of 68 patients included, 29 had expansile and 39 had infiltrative types. 27 patients received one-step surgery and 41 received restaging surgery. 52 patients received “complete” peritoneal surgical staging (including cytology, peritoneal biopsies, and an omentectomy or large omental biopsies). 24 underwent appendectomies and 31 underwent lymphadenectomies (8 expansile and 23 infiltrative). Before histologic analyses of staging specimens, 35 had “initial” stage IA and 33 had IC disease. After histologic analyses of lymph nodes, 4 cases (17%, all infiltrative) had nodal involvement, and 2 showed microscopic peritoneal disease (1 omentum and 1 right diaphragm peritoneum). Three patients were upstaged based on isolated positive peritoneal cytology. To conclude, peritoneal staging procedures are required for both types of mucinous ovarian carcinoma. Lymphadenectomy could be omitted in expansile, but required in infiltrative type

Is uterine preservation combined with bilateral salpingo-oophorectomy to promote subsequent fertility safe in infiltrative mucinous ovarian cancer?

According to the latest World Health Organization classification (2014), mucinous ovarian cancers should be classified histologically as being either expansile or infiltrative. Compared to other epithelial cancers, both of these mucinous patterns are diagnosed, in the main, at an early stage, although they can affect relatively young patients. The infiltrative subtype is characterized by a morphologically and clinically more aggressive disease versus the expansile form. Consequently, even in young patients who would prefer fertility sparing management, the removal of both ovaries (even for a unilateral tumor) remains a common recommendation. However case reports describing the preservation of the uterus for a further potential pregnancy (following oocyte donation) have now been described. In this series, we present six patients treated for stage I mucinous infiltrative cancer using bilateral salpingo-oophorectomy with uterine preservation. All but one patient underwent 1-step (n = 1) or 2-step (n = 4) surgery, including peritoneal and nodal (4 patients) procedures. Disease stages were IA (n = 2), IC1 (n = 1), IC2 (n = 2), or IC3 (n = 1). While two patients subsequently became pregnant, two patients also suffered disease recurrence. For one patient, recurrence was at the pelvic peritoneum. For the second patient, an ultimately lethal disease recurrence involved the uterine serosa with nodal involvement. The results of this short series lead us to question the safety of this uterine-preserving strategy