Dennis A. Carney

Substantial Susceptibility of Chronic Lymphocytic Leukemia to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease

PURPOSE BCL2 overexpression is a hallmark of chronic lymphocytic leukemia (CLL). The novel BH3 mimetic navitoclax (ABT-263) specifically inhibits BCL2 and related proteins BCL-x(l) and BCL-w, potently inducing apoptosis of CLL cells in vitro. A phase I trial in patients with CLL was conducted to evaluate the safety, pharmacokinetics, and biologic activity of oral navitoclax. PATIENTS AND METHODS Twenty-nine patients with relapsed or refractory CLL received daily navitoclax for 14 days (10, 110, 200, or 250 mg/d; n = 15) or 21 days (125, 200, 250, or 300 mg/d; n = 14) of each 21-day cycle. Dose escalation decisions were informed by continual reassessment methodology. RESULTS Lymphocytosis was reduced by more than 50% in 19 of 21 patients with baseline lymphocytosis. Among 26 patients treated with navitoclax ≥ 110 mg/d, nine (35%) achieved a partial response and seven maintained stable disease for more than 6 months. Median treatment duration was 7 months (range, 1 to ≥ 29 months). Median progression-free survival was 25 months. Activity was observed in patients with fludarabine-refractory disease, bulky adenopathy, and del(17p) CLL. Thrombocytopenia due to BCL-x(l) inhibition was the major dose-limiting toxicity and was dose-related. Low MCL1 expression and high BIM:MCL1 or BIM:BCL2 ratios in leukemic cells correlated with response. We determined that the navitoclax dose of 250 mg/d in a continuous dosing schedule was optimal for phase II studies. CONCLUSION BCL2 is a valid therapeutic target in CLL, and its inhibition by navitoclax warrants further evaluation as monotherapy and in combination in this disease.

Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non‐hodgkin lymphoma

The combination of fludarabine, cyclophosphamide, and rituximab (FC‐R) shows significant in vitro synergism and may improve patient outcome with little overlapping toxicity.

Therapy-related myelodysplastic syndrome and acute myeloid leukemia following fludarabine combination chemotherapy

Fludarabine combination chemotherapy achieves high response rates in chronic lymphocytic leukemia (CLL) and indolent lymphoma. The aim of this study was to investigate the incidence and characteristics of treatment-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) after treatment with fludarabine in combination for lymphoproliferative disorders and identify risk factors for its development. In all, 176 patients treated with fludarabine combination were followed for a median of 41 months (range 6–125 months). In all, 19 cases of t-MDS/AML have been identified for an overall rate of 10.8%. Median overall survival post-t-MDS/AML diagnosis was 11 months. Patients developing t-MDS/AML included 11/54 with follicular lymphoma (FL) (crude rate 20.4%), 5/82 with CLL (6.1%) and 3/24 with Waldenstrom macroglobulinemia or marginal zone lymphoma (12.5%). Most patients had other cytotoxic treatments (median 4, range 0–7) but three with FL had fludarabine combination as their only line of treatment. Of the eleven patients (6.3%) who received mitoxantrone with their first fludarabine combination, four (36.4%) developed t-MDS/AML (P=0.007). There was a trend toward prior cytotoxic therapy increasing the risk for t-MDS/AML (P=0.067). Fludarabine combination chemotherapy is associated with a moderate risk of t-MDS/AML particularly when combined with mitoxantrone. This complication should be considered when evaluating the potential benefit of this treatment in lymphoproliferative disorders.

Limited role for surveillance PET–CT scanning in patients with diffuse large B-cell lymphoma in complete metabolic remission following primary therapy

Background:The usefulness of positron emission tomography with computed tomography (PET–CT) in the surveillance of patients with diffuse large B-cell lymphoma (DLBCL) in complete metabolic remission after primary therapy is not well studied.Methods:We performed a retrospective review of our database between 2002 and 2009 for patients with de novo DLBCL who underwent surveillance PET–CT after achieving complete metabolic response (CMR) following primary therapy.Results:Four-hundred and fifty scans were performed in 116 patients, with a median follow-up of 53 (range 8–133) months from completion of therapy. Thirteen patients (11%) relapsed: seven were suspected clinically and six were subclinical (all within first 18 months). The positive predictive value in patients with international prognostic index (IPI) <3 was 56% compared with 80% in patients with IPI⩾3. Including indeterminate scans, PET–CT retained high sensitivity 95% and specificity 97% for relapse.Conclusion:Positron emission tomography with computed tomography is not useful in patients for the majority of patients with diffuse large B-cell lymphoma in CMR after primary therapy, with the possible exception of patients with baseline IPI ⩾3 in the 18 months following completion of primary therapy. This issue could be addressed by a prospective clinical trial.

Phase 1 study of the safety, pharmacokinetics, and antitumour activity of the BCL2 inhibitor navitoclax in combination with rituximab in patients with relapsed or refractory CD20+ lymphoid malignancies.

The oral BCL2 inhibitor navitoclax has moderate single‐agent efficacy in chronic lymphocytic leukaemia (CLL) and minor activity in lymphoma in Phase 1 trials. Navitoclax synergizes with rituximab in preclinical models of B‐cell lymphoid cancers. We report the safety, pharmacokinetics and clinical activity of this combination. Patients received navitoclax (200–325 mg) daily and four standard weekly doses of rituximab. Twenty‐nine patients were enrolled across three dose‐escalation cohorts and a safety expansion cohort (250 mg/d navitoclax). The combination was well tolerated. Common toxicities were mild diarrhoea (79%) and nausea (72%). Grade 4 thrombocytopenia occurred in 17% of patients (dose limiting at 325 mg/d). CD19+ counts were severely reduced, while CD3+ cells (~ 20%) and serum immunoglobulin M levels (~ 33%) were also reduced during the first year. The maximum tolerated dose for navitoclax in combination was 250 mg/d. Pharmacokinetic analyses revealed no apparent interactions between the drugs. The response rate in patients with follicular lymphoma was 9/12, including five complete responses. All five patients with CLL/small lymphocytic leukaemia achieved partial responses. One of nine patients with aggressive lymphoma responded. The addition of rituximab to navitoclax 250 mg/d is safe; the combination demonstrates higher response rates for low‐grade lymphoid cancers than observed for either agent alone in previous Phase 1 trials.

Stem cell transplantation after alemtuzumab in T-cell prolymphocytic leukaemia results in longer survival than after alemtuzumab alone: a multicentre retrospective study.

poietic cell transplantation for chronic lymphocytic leukemia: an evolving concept. Biology of Blood and Marrow Transplant, 13, 373–385. Rawstron, A.C., Green, M.J., Kuzmicki, A., Kennedy, B., Fenton, J.A., Evans, P.A., O’Connor, S.J., Richards, S.J., Morgan, G.J., Jack, A.S. & Hillmen, P. (2002a) Monoclonal B lymphocytes with the characteristics of ‘‘indolent’’ chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts. Blood, 100, 635–639. Rawstron, A.C., Yuille, M.R., Fuller, J., Cullen, M., Kennedy, B., Richards, S.J., Jack, A.S., Matutes, E., Catovsky, D., Hillmen, P. & Houlston, R.S. (2002b) Inherited predisposition to CLL is detectable as subclinical monoclonal B-lymphocyte expansion. Blood, 100, 2289–2290. Rawstron, A.C., Bennett, F.L., O’Connor, S.J., Kwok, M., Fenton, J.A., Plummer, M., de Tute, R., Owen, R.G., Richards, S.J., Jack, A.S. & Hillmen, P. (2008) Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. The New England Journal of Medicine, 359, 575–583. Thiede, C., Bornhauser, M., Oelschlagel, U., Brendel, C., Leo, R., Daxberger, H., Mohr, B., Florek, M., Kroschinsky, F., Geissler, G., Naumann, R., Ritter, M., Prange-Krex, G., Lion, T., Neubauer, A. & Ehninger, G. (2001) Sequential monitoring of chimerism and detection of minimal residual disease after allogeneic blood stem cell transplantation (BSCT) using multiplex PCR amplification of short tandem repeat-markers. Leukemia, 15, 293–302.

Detection of NPM1 exon 12 mutations and FLT3 – internal tandem duplications by high resolution melting analysis in normal karyotype acute myeloid leukemia

BackgroundMolecular characterisation of normal karyotype acute myeloid leukemia (NK-AML) allows prognostic stratification and potentially can alter treatment choices and pathways. Approximately 45–60% of patients with NK-AML carry NPM1 gene mutations and are associated with a favourable clinical outcome when FLT3-internal tandem duplications (ITD) are absent. High resolution melting (HRM) is a novel screening method that enables rapid identification of mutation positive DNA samples.ResultsWe developed HRM assays to detect NPM1 mutations and FLT3-ITD and tested diagnostic samples from 44 NK-AML patients. Eight were NPM1 mutation positive only, 4 were both NPM1 mutation and FLT3-ITD positive and 4 were FLT3-ITD positive only. A novel point mutation Y572C (c.1715A>G) in exon 14 of FLT3 was also detected. In the group with de novo NK-AML, 40% (12/29) were NPM1 mutation positive whereas NPM1 mutations were observed in 20% (3/15) of secondary NK-AML cases. Sequencing was performed and demonstrated 100% concordance with the HRM results.ConclusionHRM is a rapid and efficient method of screening NK-AML samples for both novel and known NPM1 and FLT3 mutations. NPM1 mutations can be observed in both primary and secondary NK-AML cases.

A multicentre retrospective comparison of central nervous system prophylaxis strategies among patients with high-risk diffuse large B-cell lymphoma

Background:Central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is a devastating complication; the optimal prophylactic strategy remains unclear.Methods:We performed a multicentre, retrospective analysis of patients with DLBCL with high risk for CNS relapse as defined by two or more of: multiple extranodal sites, elevated serum LDH and B symptoms or involvement of specific high-risk anatomical sites. We compared three different strategies of CNS-directed therapy: intrathecal (IT) methotrexate (MTX) with (R)-CHOP ‘group 1’; R-CHOP with IT MTX and two cycles of high-dose intravenous (IV) MTX ‘group 2’; dose-intensive systemic antimetabolite-containing chemotherapy (Hyper-CVAD or CODOXM/IVAC) with IT/IV MTX ‘group 3’.Results:Overall, 217 patients were identified (49, 125 and 43 in groups 1–3, respectively). With median follow-up of 3.4 (range 0.2–18.6) years, 23 CNS relapses occurred (12, 10 and 1 in groups 1–3 respectively). The 3-year actuarial rates (95% CI) of CNS relapse were 18.4% (9.5–33.1%), 6.9% (3.5–13.4%) and 2.3% (0.4–15.4%) in groups 1–3, respectively (P=0.009).Conclusions:The addition of high-dose IV MTX and/or cytarabine was associated with lower incidence of CNS relapse compared with IT chemotherapy alone. However, these data are limited by their retrospective nature and warrant confirmation in prospective randomised studies.

Mantle cell lymphoma with central nervous system involvement: frequency and clinical features

Reported rates of central nervous system (CNS) involvement in mantle cell lymphoma (MCL) are highly variable but substantial (4–26%). Data is lacking regarding risk factors for CNS relapse, and for those patients in whom CNS prophylaxis could be beneficial. We present single institution retrospective analysis of data of baseline features, clinical course, rate of CNS disease and putative risk factors in 62 patients with MCL (18 female, 44 male). CNS disease (all cases were symptomatic) occurred in four patients at a median of 12 months (range 1–58) from diagnosis, with a crude incidence of 6·5% and 5‐year actuarial incidence of 5 ± 3%. Two cases had blastic MCL at diagnosis. Survival after CNS relapse ranged from 2–9 months. Patients who developed CNS disease had a significantly shorter survival from diagnosis than those who did not (P = 0·0024). Symptomatic CNS disease in patients with MCL either at presentation or relapse is an uncommon but devastating complication. In younger patients, more aggressive immuno‐chemotherapy regimens containing CNS‐penetrating agents may reduce the incidence of CNS disease. While not routinely justified for all patients, CNS prophylaxis may particularly benefit patients with blastic histology at diagnosis, or those with systemic relapse after first‐line treatment.

The frequency, manifestations, and duration of prolonged cytopenias after first-line fludarabine combination chemotherapy

BACKGROUND Fludarabine-based chemoimmunotherapy has well-recognised efficacy and short-term toxicity in the treatment of lymphoid malignancies. However, the presence and significance of prolonged cytopenias after completion of treatment have not been thoroughly quantified. METHODS Sixty-one patients receiving initial therapy with fludarabine-based regimens were categorised according to the presence of post-treatment cytopenias (haemoglobin <110-130 g/l depending on sex and age, neutrophils <2.0 x 10(9)/l, or platelets <140 x 10(9)/l) lasting >3 months. RESULTS Persistent cytopenias unrelated to persistent disease were found in 43% of patients. Cytopenias were associated with clinically important rates of infection and transfusion requirement (P = 0.03) and predicted for worse overall survival (61% versus 96% at 60 months, P = 0.05). Increasing age predicted for persistent cytopenias (P = 0.02), but the presence of pretreatment cytopenias and delivered dose intensity were not predictive. The median times to resolution of anaemia, neutropenia, and thrombocytopenia were 7, 9, and 10 months, respectively. CONCLUSIONS Cytopenias often persist >3 months after first-line fludarabine combination therapy and can lead to important clinical sequelae. Although cytopenias generally resolve over time, treating physicians should be aware of these factors when considering fludarabine combination chemotherapy and when documenting treatment response status in chronic lymphocytic leukaemia.