Type-1 Interferon to Prevent Leukemia Relapse after Allogeneic Transplantation

A potent graft-versus-leukemia (GVL) response is crucial in preventing relapse, the major impediment to successful allogeneic hematopoietic cell transplantation (HCT). In preclinical studies, Type-1 interferon (IFNα) enhanced cross-presentation of leukemia specific antigens by CD8α dendritic cells (DCs) and amplified GVL. This observation was translated into a proof-of-concept phase I/II clinical trial with long-acting IFNα (pegIFNα) in patients undergoing HCT for high-risk acute myeloid leukemia (AML). Patients with treatment resistant AML not in remission or poor risk leukemia were administered four dosages of pegIFNα every 14 days beginning at day -1 before HCT. Dose selection was established by adaptive design that continuously assessed the probability of dose limiting toxicities throughout the trial. Efficacy was evaluated by determining the six-month incidence of relapse at the maximum tolerated dose (MTD). Thirty-six patients (median age of 60 years) received pegIFNα treatment. Grade 3 or greater SAEs occurred in 25% of patients establishing 180mcg as the MTD. In phase II, the incidence of relapse was 39% at six-months, which was sustained through one-year post HCT. The incidence of transplant-related mortality was 13% and severe grade III-IV acute GVHD occurred in 11%. Paired blood samples from donors and recipients after HCT indicated elevated levels of Type-1 IFN with cellular response, persistence of cross-presenting DCs and circulating leukemia antigen specific T cells. These data suggest that prophylactic administration of pegIFNα is feasible in the peri-HCT period. In high-risk AML, increased toxicity was not observed with preliminary evidence for reduction in leukemia relapse after HCT.

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Apoptosis and proliferation ofperipheral blood T-cells as alternative processes in pathogenesis of diabetes mellitus type 1

Medical alphabet ◽

10.33667/2078-5631-2019-1-4(379)-16-20 ◽

2019 ◽

Vol 1 (4) ◽

pp. 16-20 ◽

Cited By ~ 1

Author(s):

A. V. Lugovaya ◽

N. M. Kalinina ◽

V. Ph. Mitreikin ◽

Yu. P. Kovaltchuk ◽

A. V. Artyomova ◽

...

Keyword(s):

Diabetes Mellitus ◽

T Cells ◽

High Risk ◽

Peripheral Blood ◽

Cellular Response ◽

Proliferative Potential ◽

Autoreactive T Cells ◽

Alternative Processes

Apoptosis, along with proliferation, is a form of lymphocyte response to activating stimuli. In the early stages of cell differentiation, the apoptotic response prevails and it results to the formation of tolerance to inductor antigen. Mature lymphocytes proliferate in response to stimulation and it means the initial stage in the development of the immune response. Since in this case apoptosis and proliferation acts as alternative processes, their ratio can serve as a measure of the effectiveness of the cellular response to activating signals. The resistance of autoreactive T-cells to apoptosis is the main key point in the development of type 1 diabetes mellitus (T1DM). Autoreactive T-cells migrates from the bloodstream to the islet tissue of the pancreas and take an active part in b cells destruction. The resistance of autoreactive effector T-cells to apoptosis may suggest their high proliferative potential. Therefore, the comparative evaluation of apoptosis and proliferation of peripheral blood lymphocytes can give a more complete picture of their functional state and thus will help to reveal the causes of ineffective peripheral blood T-ceiis apoptosis in patients with T1DM and will help to understand more deeply the pathogenesis of the disease. in this article, the features of proliferative response of peripheral blood T-cells in patients with T1DM and in individuals with high risk of developing T1DM have been studied. Apoptosis of T-cell subpopulations has been investigated. The correlation between the apoptotic markers and the intensity of spontaneous and activation- induced in vitro T-cells proliferation of was revealed. it was determined, that autoreactive peripheral blood T-cells were resistant to apoptosis and demonstrated the increased proliferative potential in patients with T1DM and in individuals with high risk of developing T1DM.

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The Hematopoietic Cell Transplantation-Specific Comorbidity Index Fails to Predict Outcomes in High-Risk AML Patients Undergoing Allogeneic Transplantation—Investigation of Potential Limitations of the Index

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2011.06.009 ◽

2011 ◽

Vol 17 (12) ◽

pp. 1822-1832 ◽

Cited By ~ 21

Author(s):

Nicole Birninger ◽

Martin Bornhäuser ◽

Markus Schaich ◽

Gerhard Ehninger ◽

Johannes Schetelig

Keyword(s):

High Risk ◽

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

Allogeneic Transplantation ◽

Hematopoietic Cell ◽

Comorbidity Index

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A Phase I/II Clinical Trial of Type 1 Interferon for Reduction of Relapse after HCT in High Risk AML

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2018.12.078 ◽

2019 ◽

Vol 25 (3) ◽

pp. S12-S13

Author(s):

John M Magenau ◽

Attaphol Pawarode ◽

Mary M Riwes ◽

Brian Parkin ◽

Sarah Anand ◽

...

Keyword(s):

Clinical Trial ◽

High Risk ◽

Phase I ◽

Type 1 Interferon

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Role of MRD Monitoring in Childhood Acute Lymphoblastic Leukemia after Allogeneic Transplantation.

Blood ◽

10.1182/blood.v104.11.983.983 ◽

2004 ◽

Vol 104 (11) ◽

pp. 983-983 ◽

Cited By ~ 1

Author(s):

Adriana Balduzzi ◽

Sonia Bonanomi ◽

Monica Manenti Tech ◽

Maria Dassi ◽

Giovanni Cazzaniga ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Hematopoietic Cell Transplantation ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Conditioning Regimen ◽

Allogeneic Transplantation ◽

Childhood All ◽

Log Reduction ◽

Long Time

Abstract Relapse of acute lymphoblastic leukemia (ALL) after allogeneic transplant has very poor prognosis; whether early prediction of relapse by means of minimal residual disease (MRD) analysis could allow effective treatment is still to be assessed. Eighteen patients at high risk of relapse were prospectively monitored in a single transplant center. MRD analysis and clinical follow up were completed for the first series of 11 patients. This includes 9 males and 2 females (median age 11ys, range 2–16) who received allogeneic hematopoietic cell transplantation (HCT) from compatible (5), one locus mismatched (1) or haploidentical (1) related or unrelated (4) donor for ALL in 1st (5), 2nd (4), or 3rd (2) complete remission (CR), after conditioning regimen containing total body irradiation (TBI) and etoposide (9) or others, and GVHD prophylaxis consisting of cyclosporine, associated with ATG in transplant from other than compatible related donor. Grafts consisted of unmanipulated bone marrow (9), containing a median of 6.6x106CD34+/Kg (range 1.7–8.6) and 57.2x106CD3+/Kg (range 24.4–96.2), or peripheral (1), containing 11x106CD34+/Kg and 174x106CD3+/Kg, or positively selected peripheral (1) containing 12x106CD34+/Kg and 0.04x106CD3+/Kg. Five patients developed grade II–IV acute GVHD, requiring ATG in 4 cases. Five of 11 patients are alive in CR at a median of 15 months (range 11–21), 1 died in CR at 7 months, 5 relapsed at a median of 8 months (range 3–23), and 3 of them died. Patients were monitored by clone-specific RQ-PCR of one (4) or two (7) Ig/TcR markers, with a sensitivity of at least 10−4. At the time of transplant 7 patients were positive at the analysis of the MRD, while 4 were negative; patients were monitored at 1, 3, 6, 9 and 12 months after transplantation, or according to clinical requirements. Among the 4 MRD negative patients, 1 remained negative and is in CR at 19 months, 1 became positive 6 months after unrelated transplant and relapsed 2 months later, 1 relapsed 30 months after haploidentical transplant, a long time after MRD monitoring had stopped, while 1 died in CR. Among the 7 MRD positive patients, 2 remained always MRD positive and relapsed 3 and 7 months after transplant, and 5 experienced MRD negativity at a certain time after transplant; 1 of 5 became MRD positive at the 6th month after transient negativity and relapsed 3 months later, 3 of 5 became negative since the 1st or 3rd month, remained negative, and are alive in CR at 9, 12, and 13 months after transplant, while the remaining 1 alternated negative and positive MRD results and is in CR at 6 months. In 5 patients quantitative MRD data allowed early immunosuppression tapering or discontinuation, yielding severe GVHD in 1, and DLI treatment was planned in 2, but refused in 1; 2 of these 5 are in CR, while 3 relapsed, despite 1 experienced transient MRD 1-log reduction and 1 negativization. In conclusion, MRD monitoring after BMT might direct either early immunosuppression tapering or DLI for prevention of relapse in high risk childhood ALL transplanted patients.

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A multicenter phase 1 study of nivolumab for relapsed hematologic malignancies after allogeneic transplantation

Blood ◽

10.1182/blood.2019004710 ◽

2020 ◽

Vol 135 (24) ◽

pp. 2182-2191 ◽

Cited By ~ 2

Author(s):

Matthew S. Davids ◽

Haesook T. Kim ◽

Caitlin Costello ◽

Alex F. Herrera ◽

Frederick L. Locke ◽

...

Keyword(s):

Clinical Trial ◽

Hematopoietic Cell Transplantation ◽

Phase 1 ◽

Progression Free Survival ◽

Allogeneic Transplantation ◽

Hematologic Malignancies ◽

Maximum Tolerated Dose ◽

Primary Objective ◽

Mitigation Strategies ◽

Prospective Clinical Trial

Abstract Programmed cell death-1 (PD-1)/programmed death ligand-1 blockade may potentially augment graft-vs-tumor effects following allogeneic hematopoietic cell transplantation (alloHCT), but retrospective studies of anti–PD-1 therapy reported substantial toxicity from graft-versus-host-disease (GVHD). Here, we report the results of a prospective clinical trial of PD-1 blockade for relapsed hematologic malignancies (HMs) after alloHCT (NCT01822509). The primary objective in this phase 1 multicenter, investigator-initiated study was to determine maximum tolerated dose and safety. Secondary objectives were to assess efficacy and immunologic activity. Patients with relapsed HMs following alloHCT were eligible. Nivolumab was administered every 2 weeks until progression or unacceptable toxicity, starting with a 1-mg/kg cohort, with planned deescalation based on toxicity to a 0.5-mg/kg cohort. Twenty-eight patients were treated (n = 19 myeloid, n = 9 lymphoid). Median age was 57 years (range 27-76), and median time from alloHCT to enrollment was 21 months (range 5.6-108.5). Two of 6 patients treated at 1 mg/kg experienced dose-limiting toxicity (DLT) from immune-related adverse events (irAEs). Twenty-two patients were treated at 0.5 mg/kg, and 4 DLTs occurred, including 2 irAEs and 2 with fatal GVHD. The overall response rate in efficacy-evaluable patients was 32% (8/25). With a median follow-up of 11 months, the 1-year progression-free survival and overall survival were 23% and 56%, respectively. In this first prospective clinical trial of an anti–PD-1 antibody for post–alloHCT relapse, GVHD and irAEs occurred, requiring dose deescalation, with only modest antitumor activity. Further studies of anti–PD-1 therapy post–alloHCT may require specific toxicity mitigation strategies. This trial was registered at www.clinicaltrials.gov as #NCT 01822509.

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Spontaneous Remission of Acute Myeloid Leukemia Relapse after Hematopoietic Cell Transplantation in a High-Risk Patient with 11q23/MLL Abnormality

Acta Haematologica ◽

10.1159/000121827 ◽

2008 ◽

Vol 119 (2) ◽

pp. 111-114 ◽

Cited By ~ 1

Author(s):

Michael Hudecek ◽

Kristina Bartsch ◽

Nadja Jäkel ◽

Simone Heyn ◽

Roald Pfannes ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Cell Transplantation ◽

Myeloid Leukemia ◽

Hematopoietic Cell Transplantation ◽

High Risk Patient ◽

Spontaneous Remission ◽

Hematopoietic Cell ◽

Leukemia Relapse ◽

Acute Myeloid

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Who is fit for allogeneic transplantation?

Blood ◽

10.1182/blood-2010-07-259358 ◽

2010 ◽

Vol 116 (23) ◽

pp. 4762-4770 ◽

Cited By ~ 56

Author(s):

H. Joachim Deeg ◽

Brenda M. Sandmaier

Keyword(s):

High Risk ◽

Hematopoietic Cell Transplantation ◽

Advanced Disease ◽

Allogeneic Transplantation ◽

High Dose ◽

Comorbid Conditions ◽

Delayed Effects ◽

Graft Versus Host ◽

Social Support System ◽

Unrelated Donors

AbstractThe use of allogeneic hematopoietic cell transplantation (HCT) has expanded progressively, facilitated by the increasing availability of unrelated donors and cord blood, and the inclusion of older patients as transplantation candidates. Indications remain diagnosis-dependent. As novel nontransplantation modalities have been developed concurrently, many patients come to HCT only when no longer responding to such therapy. However, patients with refractory or advanced disease frequently relapse after HCT, even with high-dose conditioning, and more so with reduced-intensity regimens as used for patients of older age or with comorbid conditions. Thus, patients with high-risk malignancies who have substantial comorbidities or are of advanced age are at high risk of both relapse and nonrelapse mortality and should probably not be transplanted. Being in remission or at least having shown responsiveness to pre-HCT therapy is generally associated with increased transplantation success. In addition, to handle the stress associated with HCT, patients need a good social support system and a secure financial net. They must be well informed, not only about the transplantation process, but also about expected or potential post-HCT events, including graft-versus-host disease and delayed effects that may become manifest only years after HCT.

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