Carolyn Owen

Obinutuzumab plus Chlorambucil in Patients with CLL and Coexisting Conditions

BACKGROUND The monoclonal anti-CD20 antibody rituximab, combined with chemotherapeutic agents, has been shown to prolong overall survival in physically fit patients with previously untreated chronic lymphocytic leukemia (CLL) but not in those with coexisting conditions. We investigated the benefit of the type 2, glycoengineered antibody obinutuzumab (also known as GA101) as compared with that of rituximab, each combined with chlorambucil, in patients with previously untreated CLL and coexisting conditions. METHODS We randomly assigned 781 patients with previously untreated CLL and a score higher than 6 on the Cumulative Illness Rating Scale (CIRS) (range, 0 to 56, with higher scores indicating worse health status) or an estimated creatinine clearance of 30 to 69 ml per minute to receive chlorambucil, obinutuzumab plus chlorambucil, or rituximab plus chlorambucil. The primary end point was investigator-assessed progression-free survival. RESULTS The patients had a median age of 73 years, creatinine clearance of 62 ml per minute, and CIRS score of 8 at baseline. Treatment with obinutuzumab-chlorambucil or rituximab-chlorambucil, as compared with chlorambucil monotherapy, increased response rates and prolonged progression-free survival (median progression-free survival, 26.7 months with obinutuzumab-chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio for progression or death, 0.18; 95% confidence interval [CI], 0.13 to 0.24; P<0.001; and 16.3 months with rituximab-chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio, 0.44; 95% CI, 0.34 to 0.57; P<0.001). Treatment with obinutuzumab-chlorambucil, as compared with chlorambucil alone, prolonged overall survival (hazard ratio for death, 0.41; 95% CI, 0.23 to 0.74; P=0.002). Treatment with obinutuzumab-chlorambucil, as compared with rituximab-chlorambucil, resulted in prolongation of progression-free survival (hazard ratio, 0.39; 95% CI, 0.31 to 0.49; P<0.001) and higher rates of complete response (20.7% vs. 7.0%) and molecular response. Infusion-related reactions and neutropenia were more common with obinutuzumab-chlorambucil than with rituximab-chlorambucil, but the risk of infection was not increased. CONCLUSIONS Combining an anti-CD20 antibody with chemotherapy improved outcomes in patients with CLL and coexisting conditions. In this patient population, obinutuzumab was superior to rituximab when each was combined with chlorambucil. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT01010061.).

Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia

BACKGROUND Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma. METHODS We randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee. RESULTS The median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib. CONCLUSIONS Ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.).

Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy

Familial platelet disorder with propensity to myeloid malignancy (FPD/AML) is an autosomal dominant syndrome characterized by platelet abnormalities and a predisposition to myelodysplasia (MDS) and/or acute myeloid leukemia (AML). The disorder, caused by inherited mutations in RUNX1, is uncommon with only 14 pedigrees reported. We screened 10 families with a history of more than one first degree relative with MDS/AML for inherited mutations in RUNX1. Germ- line RUNX1 mutations were identified in 5 pedigrees with a 3:2 predominance of N-terminal mutations. Several affected members had normal platelet counts or platelet function, features not previously reported in FPD/AML. The median incidence of MDS/AML among carriers of RUNX1 mutation was 35%. Individual treatments varied but included hematopoietic stem cell transplantation from siblings before recognition of the inherited leukemogenic mutation. Transplantation was associated with a high incidence of complications including early relapse, failure of engraftment, and posttransplantation lymphoproliferative disorder. Given the small size of modern families and the clinical heterogeneity of this syndrome, the diagnosis of FPD/AML could be easily overlooked and may be more prevalent than previously recognized. Therefore, it would appear prudent to screen young patients with MDS/AML for RUNX1 mutation, before consideration of sibling hematopoietic stem cell transplantation.

Familial myelodysplasia and acute myeloid leukaemia--a review.

Familial occurrence of myelodysplasia (MDS) and/or acute myeloid leukaemia (AML) is rare but can provide a useful resource for the investigation of predisposing mutations in these myeloid malignancies. To date, examination of families with MDS/AML has lead to the detection of two culprit genes, RUNX1 and CEBPA. Germline mutations in RUNX1 result in familial platelet disorder with propensity to myeloid malignancy and inherited mutations of CEBPA predispose to AML. Unfortunately, the genetic cause remains obscure in most other reported pedigrees. Further insight into the molecular mechanisms of familial MDS/AML will require awareness by clinicians of new patients with relevant family histories.

Familial myelodysplastic syndromes - a review of the literature

Familial cases of myelodysplastic syndromes are rare, but are immensely valuable for the investigation of the molecular pathogenesis of myelodysplasia in general. The best-characterized familial myelodysplastic syndrome is that of familial platelet disorder with propensity to myeloid malignancy, caused by heterozygous germline RUNX1 mutations. Recently, there has been an increase in the number of reported cases, allowing for better understanding of the incidence, clinical features, and pathogenesis of this disorder. These recent cases have highlighted the clinical variability of the disorder and confirmed that many patients lack a bleeding and/or thrombocytopenia history. Additionally, several cases of T-acute lymphoblastic leukemia have now been reported, confirming a risk of lymphoid leukemia in patients with inherited RUNX1 mutations. Furthermore, an increased awareness of clinicians has helped detect a number of additional families affected by inherited myelodysplastic syndromes, resulting in the identification of novel causative mechanisms of disease, such as RUNX1 deficiency resulting from constitutional microdeletions of 21q22 and myelodysplasia-associated with telomerase deficiency. Awareness of predisposition to myelodysplastic syndromes and acute myeloid leukemia in families may be of critical importance in the management of younger patients with myelodysplasia in whom allogeneic hematopoietic stem cell transplantation is considered. Such families should be investigated for inherited deficiencies of RUNX1 and/or telomerase to prevent the use of an affected sibling as a donor for transplantation. Here we provide an update on familial platelet disorder in addition to a review of other known familial myelodysplastic syndromes.

Germ-line GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival

While most myelodysplastic syndrome/acute myeloid leukemia cases are sporadic, rare familial cases occur and provide some insight into leukemogenesis. The most clearly defined familial cases result from inherited mutations in RUNX1 or CEBPA. Recently, novel germline mutations in GATA2 have been reported. We, therefore, investigated individuals from families with one or more first-degree relatives with myelodysplastic syndrome/acute myeloid leukemia with wild-type RUNX1 and CEBPA, for GATA2 mutations. Screening for other recurrent mutations was also performed. A GATA2 p.Thr354Met mutation was observed in a pedigree in which 2 first-degree cousins developed high-risk myelodys-plastic syndrome with monosomy 7. They were also observed to have acquired identical somatic ASXL1 mutations and both died despite stem cell transplantation. These findings confirm that germline GATA2 mutations predispose to familial myelodysplastic syndrome/acute myeloid leukemia, and that monosomy 7 and ASXL1 mutations may be recurrent secondary genetic abnormalities triggering overt malignancy in these families.

Obinutuzumab for the First-Line Treatment of Follicular Lymphoma

BACKGROUND Rituximab‐based immunochemotherapy has improved outcomes in patients with follicular lymphoma. Obinutuzumab is a glycoengineered type II anti‐CD20 monoclonal antibody. We compared rituximab‐based chemotherapy with obinutuzumab‐based chemotherapy in patients with previously untreated advanced‐stage follicular lymphoma. METHODS We randomly assigned patients to undergo induction treatment with obinutuzumab‐based chemotherapy or rituximab‐based chemotherapy. Patients with a response received maintenance treatment for up to 2 years with the same antibody that they had received in induction. The primary end point was investigator‐assessed progression‐free survival. RESULTS A total of 1202 patients with follicular lymphoma underwent randomization (601 patients in each group). After a median follow‐up of 34.5 months (range, 0 to 54.5), a planned interim analysis showed that obinutuzumab‐based chemotherapy resulted in a significantly lower risk of progression, relapse, or death than rituximab‐based chemotherapy (estimated 3‐year rate of progression‐free survival, 80.0% vs. 73.3%; hazard ratio for progression, relapse, or death, 0.66; 95% confidence interval [CI], 0.51 to 0.85; P=0.001). Similar results were seen with regard to independently reviewed progression‐free survival and other time‐to‐event end points. Response rates were similar in the two groups (88.5% in the obinutuzumab group and 86.9% in the rituximab group). Adverse events of grade 3 to 5 were more frequent in the obinutuzumab group than in the rituximab group (74.6% vs. 67.8%), as were serious adverse events (46.1% vs. 39.9%). The rates of adverse events resulting in death were similar in the two groups (4.0% in the obinutuzumab group and 3.4% in the rituximab group). The most common adverse events were infusion‐related events that were considered by the investigators to be largely due to obinutuzumab in 353 of 595 patients (59.3%; 95% CI, 55.3 to 63.2) and to rituximab in 292 of 597 patients (48.9%; 95% CI, 44.9 to 52.9; P<0.001). Nausea and neutropenia were common. A total of 35 patients (5.8%) in the obinutuzumab group and 46 (7.7%) in the rituximab group died. CONCLUSIONS Obinutuzumab‐based immunochemotherapy and maintenance therapy resulted in longer progression‐free survival than rituximab‐based therapy. High‐grade adverse events were more common with obinutuzumab‐based chemotherapy. (Funded by F. Hoffmann–La Roche; GALLIUM ClinicalTrials.gov number, NCT01332968.)

Proposal for the clinical detection and management of patients and their family members with familial myelodysplastic syndrome/acute leukemia predisposition syndromes

As with most genetic cancer predisposition syndromes, inherited susceptibility to myelodysplastic syndrome (MDS) and acute leukemia (AL) is likely to be more common than previously appreciated. As next-generation sequencing technologies become integrated into clinical practice, we anticipate that the number of cases of familial MDS/AL identified will increase. Although the existence of syndromes predisposing to MDS/AL has been known for some time, clinical guidelines for the screening and management of suspected or confirmed cases do not exist. Based on our collective experience caring for families with these syndromes, we propose recommendations for genetic counseling, testing, and clinical management. We welcome discussion about these proposals and hope that they will catalyze an ongoing dialog leading to optimal medical and psychosocial care for these patients.

The clinical relevance of Wilms Tumour 1 (WT1) gene mutations in acute leukaemia

Recurrent genetic aberrations are important predictors of outcome in acute myeloid leukaemia (AML). Numerous novel molecular abnormalities have been identified and investigated in recent years adding to the risk stratification and prognostication of conventional karyotyping. Mutations in the Wilms Tumour 1 (WT1) gene were first described more than a decade ago but their clinical significance has only recently been evaluated. WT1 mutations occur in approximately 10% of adult AML patients at diagnosis and are most frequent in the cytogenetically normal (CN) AML subgroup. These mutations appear to confer a negative prognostic outcome by increasing the risk of relapse and death. Mutation frequency is higher in pediatric patients and also appears to confer a negative impact on relapse and survival. Herein, we discuss the importance of WT1 mutations in AML. Copyright

SAGE analysis demonstrates increased expression of TOSO contributing to Fas-mediated resistance in CLL

To identify novel genes involved in the molecular pathogenesis of chronic lymphocytic leukemia (CLL) we performed a serial analysis of gene expression (SAGE) in CLL cells, and compared this with healthy B cells (nCD19(+)). We found a high level of similarity among CLL subtypes, but a comparison of CLL versus nCD19(+) libraries revealed 55 genes that were over-represented and 49 genes that were down-regulated in CLL. A gene ontology analysis revealed that TOSO, which plays a functional role upstream of Fas extrinsic apoptosis pathway, was over-expressed in CLL cells. This finding was confirmed by real-time reverse transcription-polymerase chain reaction in 78 CLL and 12 nCD19(+) cases (P < .001). We validated expression using flow cytometry and tissue microarray and demonstrated a 5.6-fold increase of TOSO protein in circulating CLL cells (P = .013) and lymph nodes (P = .006). Our SAGE results have demonstrated that TOSO is a novel over-expressed antiapoptotic gene in CLL.