Infectious Complications Associated With Immunomodulating Monoclonal Antibodies Used in the Treatment of Hematologic Malignancy

2008 ◽  
Vol 6 (2) ◽  
pp. 202-213 ◽  
Author(s):  
Sophia Koo ◽  
Lindsey R. Baden
Keyword(s):  
Monoclonal Antibodies ◽  
Hematologic Malignancy ◽  
Immunosuppressive Agents ◽  
Cancer Therapeutics ◽  
Hematologic Malignancies ◽  
Gemtuzumab Ozogamicin ◽  
Infectious Complications ◽  
Chemotherapeutic Agents ◽  
Hematopoietic Stem ◽  
Immunomodulating Therapy

Immunomodulating monoclonal antibodies are a relatively new addition to the armamentarium of cancer therapeutics and have been shown to improve clinical outcomes in patients with various hematologic malignancies. Because of their targeted nature, these agents are often believed to be less immunosuppressive than standard cytotoxic chemotherapeutic agents. A clear causal association between an immunomodulating therapy and its infectious sequelae is often difficult to discern because of the burden of comorbid illness, intrinsic immunosuppression from the underlying malignancy, use in the salvage setting, and prior and concomitant use of immunosuppressive agents in this patient population. This article evaluates better-established and anecdotal infectious complications associated with major immunomodulating therapies used in hematologic malignancy and hematopoietic stem cell transplantation, including rituximab, alemtuzumab, gemtuzumab ozogamicin, infliximab, dacluzimab, and basiliximab.

scholarly journals Genome Instability in Multiple Myeloma: Facts and Factors

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5949
Author(s):  
Anna Y. Aksenova ◽  
Anna S. Zhuk ◽  
Artem G. Lada ◽  
Irina V. Zotova ◽  
Elena I. Stepchenkova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Complex Disease ◽  
Plasma Cells ◽  
Genome Instability ◽  
Hematologic Malignancy ◽  
Point Mutations ◽  
Malignant Neoplasm ◽  
Chemotherapeutic Agents ◽  
Hematopoietic Stem ◽  
Social Burden

Multiple myeloma (MM) is a malignant neoplasm of terminally differentiated immunoglobulin-producing B lymphocytes called plasma cells. MM is the second most common hematologic malignancy, and it poses a heavy economic and social burden because it remains incurable and confers a profound disability to patients. Despite current progress in MM treatment, the disease invariably recurs, even after the transplantation of autologous hematopoietic stem cells (ASCT). Biological processes leading to a pathological myeloma clone and the mechanisms of further evolution of the disease are far from complete understanding. Genetically, MM is a complex disease that demonstrates a high level of heterogeneity. Myeloma genomes carry numerous genetic changes, including structural genome variations and chromosomal gains and losses, and these changes occur in combinations with point mutations affecting various cellular pathways, including genome maintenance. MM genome instability in its extreme is manifested in mutation kataegis and complex genomic rearrangements: chromothripsis, templated insertions, and chromoplexy. Chemotherapeutic agents used to treat MM add another level of complexity because many of them exacerbate genome instability. Genome abnormalities are driver events and deciphering their mechanisms will help understand the causes of MM and play a pivotal role in developing new therapies.

HLA mismatch combinations associated with decreased risk of relapse: implications for the molecular mechanism

Blood ◽  
2009 ◽  
Vol 113 (12) ◽  
pp. 2851-2858 ◽  
Author(s):  
Takakazu Kawase ◽  
Keitaro Matsuo ◽  
Koichi Kashiwase ◽  
Hidetoshi Inoko ◽  
Hiroh Saji ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Hematologic Malignancy ◽  
Human Leukocyte ◽  
Hematologic Malignancies ◽  
Hematopoietic Stem ◽  
Clinical Issue ◽  
Leukocyte Antigen ◽  
Unrelated Donors ◽  
Risk Of Relapse ◽  
Made In

Abstract The finding that the risk of relapse in hematologic malignancy decreases after allogeneic hematopoietic stem cell transplantation (HSCT) has lead to the concept of a graft-versus-leukemia (GVL) effect. However, this beneficial effect is considered to be frequently offset by graft-versus-host disease (GVHD). Thus, improving HSCT outcomes by separating GVL from GVHD is a key clinical issue. This cohort study registered 4643 patients with hematologic malignancies who received transplants from unrelated donors. Six major human leukocyte antigen (HLA) loci were retrospectively genotyped. We identified 4 HLA-Cw and 6 HLA-DPB1 mismatch combinations responsible for a decreased risk of relapse; of these, 8 of 10 combinations were different from those responsible for severe acute GVHD, including all 6 of the HLA-DPB1 combinations. Pairs with these combinations of HLA-DPB1 were associated with a significantly better overall survival than were completely matched pairs. Moreover, several amino acid substitutions on specific positions responsible for a decreased risk of relapse were identified in HLA-Cw, but not in HLA-DPB1. These findings might be crucial to elucidating the mechanism of the decreased risk of relapse on the basis of HLA molecule. Donor selection made in consideration of these results might allow the separation of GVL from acute GVHD, especially in HLA-DPB1 mismatch combinations.

Phase I Studies in Hematologic Malignancy: 20-Year Experience from Cancer Therapy Evaluation Program (CTEP) at National Cancer Institute/National Institutes of Health

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-18
Author(s):  
Dai Chihara ◽  
Erich P. Huang ◽  
Shanda R. Finnigan ◽  
Lisa M. Cordes ◽  
Nebojsa Skorupan ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Phase I ◽  
Response Rate ◽  
Hematologic Malignancy ◽  
Phase 1 ◽  
Performance Status ◽  
Hematologic Malignancies ◽  
Phase I Studies ◽  
Grade 5 ◽  
Investigational Agents

Background Phase I study is an essential step of drug development to assess safety, but more recently also to investigate initial insights into potential patient therapeutic response. In the last two decades, treatment of hematologic malignancy has changed dramatically from chemotherapy to targeted agents such as monoclonal antibodies, small molecule inhibitors and immunotherapy. We leveraged a large cohort of phase 1 studies to assess trends in toxicity, response and survival outcomes over time. Methods We reviewed the database of all investigator-initiated phase 1 oncology trials treated patients with hematologic malignancies sponsored by CTEP at the NCI between 2000 and 2019. We report the rates of grade 5 toxicity, response to treatment, and survival outcome following enrollment to the trials. Univariate associations of rates of Grade 5 toxicities possibly, probably, or definitely attributable to treatment and response rate with disease type, year of study activation, or whether each type of treatment was administered were assessed through likelihood ratio tests of a generalized linear mixed model. Results Overall, 3,308 patients were treated in 161 trials. Median age of the patients was 61 (range: 0-96) and 61% were male. Acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) was the most common enrolled malignancy diagnosis (N=1,768) followed by lymphoma (N=921), acute lymphoblastic lymphoma (ALL: N=193) and myeloma (N=153). Forty percent of the trials used an investigational agent as a monotherapy, while 60% of the trials used combination treatment. The most commonly used non-chemotherapy investigational agents were monoclonal antibodies and HDAC inhibitors (28 trials each), followed by DNMT inhibitors (18 trials) and proteasome inhibitors (17 trials). Overall, 468 patients died during trials of which 60 were attributed to the treatment (grade 5 toxicity: 1.81%, 95%CI: 1.36-2.27%). There was a trend of higher grade 5 toxicity in patients with AML/MDS (2.43%) compared to patients with lymphoma (0.98%), ALL (1.55%) or myeloma (0.65%) (p=0.066). Treatment with a PD-1 inhibitor was associated with significantly higher risk of grade 5 toxicities (7.14%, 95%CI: 1.95%-12.3%), compared to patients who did not receive a PD-1 inhibitor (1.65%, 95%CI: 1.21%-2.09%) (odds ratio [OR]: 4.93, 95%CI: 1.54-15.8). The deaths mostly occurred in trials combining a PD-1 inhibitor and a CTLA-4 inhibitor (6 death in 77 pts), although the grade 5 toxicity rate did not significantly differ from PD-1 inhibitor monotherapy (1 death in 21 pts). There was no significant difference in grade 5 toxicity among the time periods when trials were activated (Table. 2000-2005 vs 2006-2012 vs 2013-2019). Baseline characteristics associated with higher risk of grade 5 toxicity were age (OR: 1.02 by 1 year increase in age, 95%CI: 1.01-1.04, p=0.007) and performance status ≥2 at enrollment (OR: 1.56, 95%CI: 1.02-2.39, p=0.039). Response assessment was available in 2,404 patients. Overall response rate (ORR) and CR rate (CRR) from all trials were 25.1% (95%CI: 23.3-26.8%) and 14.7% (95%CI: 13.3-16.2%), respectively. The patients with lymphoma experienced significantly higher ORR (42.8%) compared to patients with AML (18.2%), ALL (13.3%) or myeloma (13.3%). There is a significant increase in both ORR and CRR over time (Table. p<0.001), but the trend of change was different in each disease by investigational agents tested during the period. Monoclonal antibodies, iMIDs, CDK inhibitors and BTK inhibitors were non-chemotherapy agents associated with higher response rate. Overall survival (OS) was available in 2,664 patients. The median OS among all patients after enrollment in phase 1 studies was 277 days (95%CI: 245-305 days). Patients with ALL had significantly shorter median OS (86 days) compared to patients with AML/MDS (255 days), lymphoma (289 days) or myeloma (median not reached). Conclusion There has been a significant improvement of ORR in CTEP sponsored phase I studies in the last 20 years. Grade 5 toxicity rate remained low, but higher age and poor performance status were associated with higher risk. Participation in phase I studies should be encouraged in patients with hematologic malignancies. Table Disclosures No relevant conflicts of interest to declare.

scholarly journals Graft-Versus Host Disease Prophylaxis with Postransplantation Bendamustine in Refractory Leaukemia Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5746-5746
Author(s):  
Ivan S Moiseev ◽  
Sergey N. Bondarenko ◽  
Elena I Darskaya ◽  
Aleksandr Alyanski ◽  
Evgeniya Borzenkova ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Chronic Gvhd ◽  
Immunosuppressive Agents ◽  
Single Agent ◽  
Median Number ◽  
Infectious Complications ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis

Background There was a limited improvement in the results of allogeneic hematopoietic stem cell transplantation (HSCT) in refractory leukemia over the last decades. The major reason of poor results is the relapse of the underlying malignancy. Thus the technologies to augment graft-versus-leukemia (GVL) effect is required for this group of patients. The preclinical study by Stokes et al. (British Journal of Haematology, 2016) indicated prolonged survival in the leukemia mouse model with substitution of posttransplantation cyclophosphamide (PTCy) with bendamustine (PTBenda). Also a small study evaluated the combination of PTCy and PTBenda in young patients and children (Katsanis E et al., 2018). We conducted the prospective study of postransplantation bendamustine as graft-versus-host-disease prophylaxis. Methods Single-center prospective dose-ranging de-escalation study (NCT02799147) evaluated safety and efficacy of PTBenda as GVHD prophylaxis. PTbenda was administered in doses 140, 100 and 70 mg/kg on days +3,+4. Myeloablative conditioning with fludarabine and busulfan was performed. First patients enrolled received single-agent PTbenda and subsequent- combination with other immunosuppressive agents. Inclusion criteria were acute myeloblstic (AML) or lymphoblstic leukemia (ALL) refractory to at least one induction course of chemotherapy or target therapy and more than 5% clonal blasts in the bone marrow. Twenty three patients were enrolled, 7 in the 140 mg/kg cohort, 10 in 100 mg/kg and 6 in 70 mg/kg, including 18 with AML and 5 with ALL. 35% of patients had primary refractory disease, and the rest - second or subsequent relapses, 61% had high-risk cytogenetics, 35% - complex karyotype, 17% - secondary AML, 30% - extramedulary disease. Median number of induction courses was 2 and 39% received target antibodies. Median number of blasts at transplant was 18% (range 6-97%). Two patients had matched related donor (MRD), 15 - unrelated (MUD), 6- haploidentical. Results Median follow-up was 10 months. The 140 mg/kg cohort was closed prematurely due to severe infectious complications. Ninety one percent of patients engrafted. Median time to engraftment was 16 days. Among the engrafted patients CR rate was 95%, and 67% had MRD(-) status. Relapse was documented in 10% of patients with CR. We have observed that PTBena induces a specific cytokine-release syndrome (CRC) with fever, vasculitis-like skin rush, oral mucositis, enteritis, hepatitis and pancreatitis. CNS signs, hypotension and respiratory failure were observed only in a few patients. CRC was observed in 78% of patients, including grade 1-2 in 17%, grade 3 in 26%, grade 4 in 22% and grade 5 in 3 patients. Median level of ferritin during CRC was 15 000 ng/ml and IL-6 levels were also increased (74 vs 8 ng/ml, p=0.036). Tocilizumab was administered to 13 patients and 10 responded. Classical grade II-IV GVHD was observed in 39% of pts and 60% of long-term survivors developed severe chronic GVHD. Non-relapse mortality was 48% with CRC, infectious complications and chronic GVHD as major causes. 1-year overall survival was 35%. Conclusion PTbenda even as a single agent has a significant potential to prevent acute, but not chronic GVHD. Moreover GVHD prophylaxis with PTbenda is a completely novel approach to induction of GVL, but optimal combination of immunosuppressive agents and supportive care should be determined to control the CRC and chronic GVHD. The optimal dosing regimen of PTbenda will be determined after enrollment in the last cohort will be completed. Figure Disclosures Moiseev: Novartis: Consultancy, Honoraria, Other: Travel grants, Speakers Bureau; MSD: Other: Travel grants; Celgene: Consultancy, Other: Travel grants; BMS: Other: Travel grants; Takeda: Other: Travel grants; Pfizer: Other: Travel grants. OffLabel Disclosure: Bendamustine used for graft-versus-host disease prophylaxis.

scholarly journals Alemtuzumab and Natalizumab: The Monoclonal Antibody Story Continues

2006 ◽  
Vol 17 (6) ◽  
pp. 327-329 ◽  
Author(s):  
BL Johnston ◽  
JM Conly
Keyword(s):  
Monoclonal Antibody ◽  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Infectious Complications ◽  
Solid Organ ◽  
Infection Rates ◽  
Hematopoietic Stem ◽  
The Many

In the July/August 2006 issue of this journal, the infectious complications associated with the use of infliximab, etanercept and adalimumab were reviewed (1). These represent only three of the many monoclonal antibodies either licensed or in clinical trials for therapeutic use in cancer and autoimmune disease or to prevent rejection in both solid organ and hematopoietic stem cell transplantation. While most of these agents have not been associated with increased infection rates, alemtuzumab and natalizumab have gained particular attention related to either the frequency or type of infection seen in some individuals who have received them.

scholarly journals 2596. Invasive Fungal Disease in Patients with GATA2 Variant Hematologic Malignancy

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S902-S902
Author(s):  
Tyler D Bold ◽  
Rahul S Vedula ◽  
Matthew P Cheng ◽  
Francisco M Marty ◽  
R Coleman Lindsley
Keyword(s):  
Hematologic Malignancy ◽  
Retrospective Chart Review ◽  
Invasive Fungal Disease ◽  
Hematologic Malignancies ◽  
Fungal Disease ◽  
Infectious Complications ◽  
Genetic Diagnostics ◽  
Cancer Center ◽  
Sequence Variant ◽  
Wide Range

Abstract Background Patients with hematologic malignancies (HM) are at risk of invasive fungal disease (IFD). Identification of those patients at the highest risk for IFD would help optimize prophylactic or preemptive treatment decisions in this population. We previously found that among patients with myeloid malignancies who develop invasive aspergillosis, 15% had a mutation in the gene GATA2. Here, we report the incidence of IFD in a cohort of patients with HM related to a pathogenic sequence variant of GATA2. Methods We identified 6343 patients cared for at Dana-Farber/Brigham and Women’s Cancer Center between January 2014 and August 2018 who underwent a next-generation sequencing assay of 95 genes recurrently mutated in hematologic malignancy. Those found to have a pathogenic GATA2 sequence variant were selected for retrospective chart review with respect to serious infectious complications including IFD. Results We identified 54 patients with a pathogenic GATA2 variant. 5 had a germline mutation related to familial GATA2 deficiency. The other 49 had a HM, mostly (41/49) acute myeloid leukemia or myelodysplastic syndrome. The frequency of the variant GATA2 allele in this group ranged from 2.5 to 92.0% of sequencing reads. 14 patients were excluded due to lack of sufficient follow-up, often related to treatment at another institution. Of the remaining 35 patients, 13 (37%) had proven/probable invasive fungal infection (IFI). Fourteen others had syndromes consistent with possible IFD. In total, 16 of these 35 patients (46%) received antifungal therapy for proven, probable or possible IFD. Four of the patients not treated with antifungals were diagnosed with a serious infection including 2 cases of Staphylococcus aureus bacteremia, and one case of disseminated Mycobacterium avium complex. Conclusion We identified a high incidence of IFD among patients with HM related to a pathogenic sequence variant of GATA2. The wide range of variant allele frequency observed raises the possibility that either inherited or acquired GATA2 dysfunction could incur predisposition to infection. These data suggest that personalized genetic diagnostics of patients with HM may be useful for assessment of infectious risk. Disclosures All authors: No reported disclosures.

Prospective Evaluation of An Agvhd-Specific Proteomic Pattern in More Than 340 Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 347-347
Author(s):  
Eva M. Mischak-Weissinger ◽  
Ernst Holler ◽  
Michael Schleuning ◽  
Gernot Beutel ◽  
Hildegard Greinix ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Early Recognition ◽  
Hematologic Malignancies ◽  
Multicenter Trial ◽  
Infectious Complications ◽  
Hematopoietic Stem ◽  
Peptide Pattern ◽  
Patients At Risk ◽  
Conditioning Regimens ◽  
The University

Abstract Abstract 347 Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for many hematologic malignancies or hematopoietic dysfunction syndromes, but the application is still limited due to major complications, such as severe graft versus host disease (GvHD) and infectious complications. Diagnosis GvHD is based on clinical features and biopsies, a non invasive, unbiased laboratory test does not exist. To date the proteomic pattern specific for aGvHD was evaluated blindly on 961 samples collected from 345 patients undergoing allo-HSCT at MHH and 7 additional clinics, including the University of Michigan. The majority of the patients included were transplanted for hematological malignancies (n=329), 16 for hematopoietic failure syndromes, mainly severe aplastic anemia. Conditioning regimens included dose reduced conditioning regimens (FLAMSA and ClaraC for the majority of the patients of MHH), as well as standard conditioning regimens (TBI+Cy or Busulfan+Cy) for about 35% of the patients. GvHD-prophylaxis was cyclosporine A (CSA) and mycophenolate (MMF) or CSA metothrexate (MTX) as appropriate. In addition, about 80% percent of the patients received ATG (antithymocyte globulin) prior to HSCT. A peptide pattern of 31 peptides - either absent/decreased (15) or present /increased (16) - was previously published (Weissinger et al. 2007). Prospective and blinded evaluation of the patients included in this diagnostic analysis for early recognition of patients at risk for aGvHD development revealed the correct classification of patients developing aGvHD about 7 days prior to the development of clinical symptoms for aGVHD with a sensitivity 76% and specificity of about 85% (fig.1). Additional data obtained from patients transplanted until September 2009 will be reported. Based on these data a pre-emptive therapy multicenter trial, administering steroids upon positivity of the proteomic pattern has been initiated now in 10 German centers, testing the efficacy of the pre-emptive therapy on incidence and severity of aGvHD and a possible benefit on overall survival of the patients. Disclosures: Krons: mosaiques-diagnostics GmbH: Employment. Metzger:mosaiques-diagnostics GmbH: Employment.

scholarly journals Recipient ADAMTS13 Single-Nucleotide Polymorphism Predicts Relapse after Unrelated Bone Marrow Transplantation for Hematologic Malignancy

2019 ◽  
Vol 20 (1) ◽  
pp. 214 ◽  
Author(s):  
Haruka Nomoto ◽  
Akiyoshi Takami ◽  
J. Luis Espinoza ◽  
Makoto Onizuka ◽  
Koichi Kashiwase ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Single Nucleotide Polymorphism ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Hematologic Malignancy ◽  
Disease Free Survival ◽  
Hematologic Malignancies ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Hematopoietic Stem

Relapse remains a major obstacle to the survival of patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation. A disintegrin-like and metalloprotease with a thrombospondin type 1 motif (ADMATS13), which cleaves von Willebrand factor multimers into less active fragments, is encoded by the ADAMTS13 gene and has a functional single-nucleotide polymorphism (SNP) rs2285489 (C > T). We retrospectively examined whether ADAMTS13 rs2285489 affected the transplant outcomes in a cohort of 281 patients who underwent unrelated human leukocyte antigen (HLA)-matched bone marrow transplantation for hematologic malignancies. The recipient ADAMTS13 C/C genotype, which putatively has low inducibility, was associated with an increased relapse rate (hazard ratio [HR], 3.12; 95% confidence interval [CI], 1.25–7.77; P = 0.015), resulting in a lower disease-free survival rate in the patients with a recipient C/C genotype (HR, 1.64; 95% CI, 1.01–2.67; P = 0.045). Therefore, ADAMTS13 rs2285489 genotyping in transplant recipients may be a useful tool for evaluating pretransplantation risks.

Outcomes of renal transplantation in patients with previous hematologic malignancies

2019 ◽  
Vol 3 (3) ◽  
pp. 124-130 ◽  
Author(s):  
Jessica Hedvat ◽  
Vinay Nair ◽  
Leandra Miko ◽  
Madhav C Menon ◽  
Andrew Santeusanio
Keyword(s):  
Renal Transplantation ◽  
De Novo ◽  
Hematologic Malignancy ◽  
Significant Risk ◽  
Hematologic Malignancies ◽  
Cell Transplant ◽  
Allograft Survival ◽  
Hematopoietic Stem ◽  
Serious Infections ◽  
Recurrent Malignancy

Recommendations regarding the appropriateness of renal transplantation in patients with prior hematologic malignancies are limited. Given the lack of available data, studies are needed to assess which of these patients will maximally benefit from renal transplantation. This study was undertaken to describe the incidence of new or recurrent malignancy as well as patient and allograft survival, acute rejection, and serious infections in patients with prior hematologic malignancies receiving renal transplantation. This was a single center retrospective review of all adult patients with a previous hematologic malignancy who received a living or deceased renal transplantation between January 2009 and January 2016. Eight renal transplantation recipients with prior hematologic malignancies were identified and followed for a minimum of 3 years. Six patients received prior chemotherapy and five had a prior hematopoietic stem cell transplant. Median time from remission to transplant was 2.6 years. Three-year patient and allograft survival were 87% and 75%, respectively. Three patients were diagnosed with new cancers within 3 years post-renal transplantation; one of which died from cancer-related complications with a functioning allograft. There was concern for recurrent hematologic malignancies in two patients based on serologic studies, but, both of these patients were alive with functioning allografts at 3-year follow-up. Our experience suggests that renal transplantation can be successfully performed in select patients with prior hematologic malignancy but with a significant risk for de novo malignancy post-transplant, which may be associated with an overall poor prognosis. Decisions regarding renal transplantation candidacy should be made based on risk stratification and multidisciplinary discussions with patients, hematologists, and transplant providers.

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