Clonal Hematopoiesis is a Risk Factor for Chemotherapy-Related Complications

Study Overview
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Brief Summary
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'CHIP' stands for Clonal Hematopoiesis of Indeterminate Significance, which are mutations in bone marrow stem cells that give that population of cells a survival or 'clonal' advantage for growth. This study investigates whether CHIP in lymphoma patients aged 60 years and older is a risk factor for chemotherapy-related complications like low blood counts, infections, cardiac events, hospitalizations, dose delays and dose reductions, and failure to recover normal blood counts after chemotherapy finishes.

Detailed Description
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'CHIP' stands for Clonal Hematopoiesis of Indeterminate Significance (1-4). Up to 20% of individuals in the general population acquire mutations in their bone marrow stem cells as they age that give that population of cells a survival or 'clonal' advantage for growth. The frequency of CHIP may be higher in patients with other cancers. CHIP increases with age, and has been shown to be a risk factor associated with cardiovascular disease and a tendency to the development of bone marrow cancers at a rate of 1% per year (1,2,5). CHIP is also associated with the development of bone marrow cancers that occur after chemotherapy. The investigators want to investigate whether CHIP is also a risk factor for chemotherapy-related complications like low blood counts, infections, cardiac events, hospitalizations, dose delays and dose reductions. They are also interested in determining if CHIP may explain why some patients do not recover normal blood counts after chemotherapy finishes. The results from this study may help physicians better understand why some people have difficulty with chemotherapy (in the short and long-term) while others do not. Screening for CHIP in older patients may become a recommended standard that allows physicians to tailor anti-cancer treatment to the patient.

Official Title
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A Single Centre Cohort Study to Determine if Clonal Hematopoieses of Indeterminate Potential (CHIP) is a Risk Factor for Chemotherapy-Related Complications in Lymphoma Patients >= 60 Receiving Cytotoxic Chemotherapy

Conditions
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Lymphoma, Chemotherapeutic Toxicity

Intervention / Treatment
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* Other: Blood test for determination of CHIP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of a lymphoma (ex: diffuse large B cell lymphoma (DLBCL), follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia, Hodgkin's lymphoma, peripheral T cell lymphoma, anaplastic large cell lymphoma, angioimmunoblastic lymphoma, hairy cell leukemia, Waldenstrom's macroglobulinemia, anaplastic large cell lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia, and mantle cell lymphoma). Commencing first or second-line cytotoxic chemotherapy for lymphoma with or without rituximab [ex: cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), cyclophosphamide, vincristine and prednisone (CVP), Fludarabine, fludarabine cyclophosphamide (FC), Bendamustine, cisplatin, cytarabine, dexamethasone (DHAP), etoposide, cytarabine, cisplatin, prednisone (ESHAP), gemcitabine, cisplatin and dexamethasone (GDP), Cladribine, Cyclophosphamide, Epirubicin, Vincristine, Prednisone (CEOP), dose-adjusted Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (DA-EPOCH)] Exclusion Criteria: Pre-existing diagnosis of myeloid neoplasm Circulating lymphocyte count > 10 x 109/L Significant uncontrolled renal or hepatic impairment [>1.5 x upper limit of normal (ULN) bilirubin, >1.5 x ULN Alanine aminotransferase (ALT), >1.5 x ULN creatinine] HIV Active infection

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Lymphoma patients >=60 receiving cytotoxic chemotherapy<br>Lymphoma patients >=60 receiving cytotoxic chemotherapy who have consented to DNA extraction and analysis for CHIP. | Other: Blood test for determination of CHIP<br>* Patients will have one additional blood draw to be sent for DNA extraction and sequencing for CHIP.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine if CHIP is an independent risk factor for chemotherapy-induced complications. | Complications during chemotherapy defined as any or all of the following: febrile neutropenia, new grades 3-4 anemia, thrombocytopenia and neutropenia immediately (day -1 or 0) preceding next cycle of chemotherapy, secondary dose reductions or dose delays due to myelosuppression or toxicity, cardiovascular toxicity (arrhythmias, congestive heart failure, symptomatic coronary disease), secondary granulocyte colony-stimulating factor (GCSF) use due to neutropenia, inability to complete all scheduled cycles due to chemotherapy related complications, dose delays that exceed 7 days. | Up to 24 weeks | 
| Emerging dysmyelopoiesis after chemotherapy | The number of patients with and without CHIP who, following at 6 and 12 months post chemotherapy have: Hemoglobin, white blood cell (WBC) or platelet (PLT) count that does not recover to normal pre-chemotherapy levels Persistant macrocytosis defined as mean cell volume (MCV) > 96 fl Persistant anisocytosis defined as red cell distribution width (RDW) > 14.5% | Up to 12 months after completion of chemotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Expansion of clonal hematopoietic stem cells | Expansion of clonal hematopoietic stem cells over time measured using next generation sequencing of 40 myeloid genes in patients with CHIP at baseline defined by variant allele frequency (VAF) that increases by 10% of more or the emergence of new clones | Up to 5 years after completion of chemotherapy | 
| Development of therapy-related myeloid neoplasm | Therapy-related myeloid neoplasm defined as any of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), myeloproliferative neoplasm (MPN), MDS/MPN diagnosed by bone marrow exam | Up to 5 years after completion of chemotherapy | 
| Overall survival | Overall survival | Up to 5 years after completion of chemotherapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clonal Hematopoiesis of Indeterminate Significance, Chemotherapy, Lymphoma, Chemotherapy complications