National Cancer Institute-sponsored Working Group Research Articles

Perspectives on the use of new diagnostic tools in the treatment of chronic lymphocytic leukemia

AbstractRecently, considerable progress has been made in the identification of molecular and cellular markers that may predict the tendency for disease progression in patients with chronic lymphocytic leukemia (CLL) or detect minimal residual disease after therapy. These developments have created uncertainty for clinicians who hope to incorporate the use of these markers and new disease-assessment tools into standard clinical practice. However, clinical trials are required to determine whether poor-prognosis leukemia-cell markers, such as expression of unmutated immunoglobulin genes or the zeta-associated protein of 70 kDa (ZAP-70), can be used as the basis for determining the time or type of therapy. Pending the outcome of such trials, treatment decisions outside the context of a clinical trial still should be based on guidelines established by the most recent National Cancer Institute-sponsored Working Group.

Abstract 3453: Medical history, lifestyle, and family history exposures and chronic lymphocytic leukemia outcome

Abstract Background: Associations of medical history, lifestyle, and family history of hematological disorders with risk of chronic lymphocytic leukemia (CLL) have been previously established (1), but these exposures have not been well-studied as contributing factors to CLL prognosis. Here we investigate the association of these exposures with time to first treatment (TTFT) in 730 CLL patients. Methods: Newly diagnosed CLL patients seen at the Mayo Clinic between 2002 and 2012 were enrolled. CLL was defined according to the 1996 NCI-Working Group criteria (2). Risk factor data (including body mass index, smoking, alcohol use, sun exposure, having lived on a farm, any allergy, asthma, eczema, blood transfusion, diabetes, rheumatoid arthritis, and family history of hematological malignancy) were collected from self-administered questionnaires. Clinical and prognostic characteristics for CLL were extracted from medical records. Analyses were performed using Cox regression with first treatment as the event. Hazard ratios (HR) and 95% confidence intervals were estimated. We used Bonferroni correction for multiple testing with statistical significance at 0.004. Results: The median age at CLL diagnosis was 63 years (range 36 - 89); 65% were male, and 95% had a Rai stage< III. The median follow up time was 6.3 years, and 40% received treatment. In unadjusted analyses, patients with any history of allergies had significantly longer TTFT (HR = 0.66, 95% CI: 0.51-0.85, P = 0.001). We also observed borderline significance with history of asthma (HR = 0.53, 95% CI: 0.34-0.85, P = 0.008). These associations held after adjusting for important prognostic factors including age, sex, Rai stage, and IGVH mutational status. The other risk factors had non-significant associations (P>0.1). Conclusions: We observed an improved CLL prognosis in patients with a history of any allergies or asthma. These results were independent of other prognostic markers and suggest that an overactive IgE level from environmental exposures may provide insight into the progression of CLL. Literature Cited 1. Slager SL, Benavente Y, Blair A, Vermeulen R, Cerhan JR, Costantini AS, et al. Medical history, lifestyle, family history, and occupational risk factors for chronic lymphocytic leukemia/small lymphocytic lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr. 2014 Aug;2014(48):41-51. 2. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O’Brien S, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996 Jun 15;87(12):4990-7. Citation Format: Sara Beiggi, James M. Foran, O’Byrne Megan, Celine M. Vachon, Timothy G. Call, Neil E. Kay, Tait D. Shanafelt, James R. Cerhan, Susan L. Slager. Medical history, lifestyle, and family history exposures and chronic lymphocytic leukemia outcome. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3453.

5-Year Follow-up of Patients with Relapsed/Refractory CLL Treated with Standard Chemotherapy with or without Oblimersen in Randomized Phase III Trial: Prognostic Factors and Predictive Factors for Treatment Effect

Background: A randomized Phase 3 trial was performed to compare the efficacy and safety of fludarabine/cyclophosphamide (Flu/Cy) combined with oblimersen (OBL; Genasense®; G3139) or administered alone in patients (pts) with relapsed or refractory CLL. The primary objective was to compare the proportion of pts who achieved complete response (CR, including nodular partial response) between treatment arms.Methods: Pts (N = 241) were stratified according to response to prior fludarabine therapy (relapsed [sensitive] versus [v] refractory); number of prior regimens (1 to 2 v 3 or more), and duration of response to last therapy (> 6 months v ≤ 6 months) and randomly assigned (1:1) to treatment arms. Treatment included up to six 28-day cycles of OBL 3 mg/kg/d as a 7-day continuous IV infusion and Flu 25 mg/m2/d IV over 20 to 30 minutes followed by Cy 250 mg/m2/d IV over 30 to 60 minutes on days 5, 6, and 7, or the Flu/Cy regimen alone on days 1, 2, and 3. Response was determined according to National Cancer Institute-Sponsored Working Group guidelines (Cheson et al, J Clin Oncol, 1996), based on determinations of an independent hematopathologist and expert hematologist who were blinded to treatment. Univariate and multivariate analyses of protocol-specified prognostic factors for overall survival were performed. Five-year survival data were recently collected.Results: The primary endpoint was met; the CR rate was 17% in the OBL + Flu/Cy arm and 7% in the Flu/Cy arm (p = 0.025). Only 7 subjects were lost to 5-year follow-up. Univariate analyses confirmed the prognostic value of the trial stratification factors for survival. In addition, baseline beta-2 microglobulin (< 4 mg/L v ≥ 4 mg/L) and baseline serum LDH (< ULN v ≥ ULN) were highly prognostic (p< 0.0001). Multivariate analyses showed that the number of prior regimens, age (< 65 years v ≥ 65 years), baseline beta-2 microglobulin (< 4 mg/L v ≥ 4 mg/L), and baseline serum LDH (< ULN v ≥ ULN) were prognostic for survival. Among all prognostic factors examined in multivariate analyses, a significant interaction with treatment was detected only for fludarabine sensitivity. Maximum benefit with OBL was observed in fludarabine-sensitive pts (OBL + Flu/Cy arm, 51 pts; Flu/Cy arm, 50 pts), ie, those who had a partial response or better for ≥ 6 months after their last prior fludarabine-containing therapy and then relapsed. The median age of fludarabine-sensitive pts was 64.0 years in both arms; 80% and 70% of these pts were men in the OBL + Flu/Cy arm and the Flu/Cy arm, respectively. Disease-related findings, prognostic factors, and prior treatments among fludarabine-sensitive pts were similar in the 2 treatment arms. The proportion of fludarabine-sensitive pts with CR was significantly greater in the OBL + Flu/Cy arm (25%) than in the Flu/Cy arm (6%; p = 0.016). With 5-year follow-up, there was a statistically significant survival benefit in the OBL + Flu/Cy arm among fludarabine-sensitive pts (hazard ratio = 0.50; p = 0.004; see figure). [Display omitted] Conclusions: In the setting of relapsed/refractory CLL in a randomized Phase III trial, the number of prior regimens, age, beta-2 microglobulin, and serum LDH were prognostic for survival based on multivariate analyses. Fludarabine sensitivity was predictive of the treatment effect of the OBL + Flu/Cy regimen, and a 50% reduction in the risk of death was observed among fludarabine-sensitive pts treated with OBL in addition to a standard Flu/Cy regimen.

Computed Tomography Scans Do Not Improve the Predictive Power of 1996 National Cancer Institute–Sponsored Working Group Chronic Lymphocytic Leukemia Response Criteria

National Cancer Institute-sponsored Working Group (NCI-WG) response criteria for chronic lymphocytic leukemia (CLL) rely on physical examination, blood, and bone marrow evaluations. The widespread use of computed tomography (CT) scans has prompted many to advocate for the incorporation of this test into CLL response criteria. In a retrospective review of 82 CLL patients treated at the Ohio State University (Columbus, OH), we compared CT assessed response using non-Hodgkin's lymphoma (NHL) response definitions with NCI-WG response. Responses by NCI-WG criteria included five complete responses (CRs), 32 partial responses (PRs), 21 patients with stable disease (SD), 17 patients with progressive disease (PD), and seven patients not assessable (NA). Responses by NHL-CT criteria included three CRs, 12 unconfirmed CRs (CRus), 16 PRs, 26 with SD, four with PD, and 21 NA. Using NCI-WG criteria, progression-free survival (PFS) was 27.3 months for CR and 11.4 months for PR. With NHL-CT criteria, PFS was 18.4 months for CR, 11.7 months for CRu, and 14.5 months for PR. In multivariate analysis, both NCI-WG and NHL-CT response correlated with PFS (P = .009 and .001, respectively). Current NCI-WG CLL response criteria are a significant predictor of PFS in previously treated CLL patients, with no additional benefit from the inclusion of CT scans. Although retrospective, these results highlight the importance of prospective validation of CT scans before routine inclusion in CLL response criteria.

Value of Computed Tomography in the Monitoring of Patients With Chronic Lymphocytic Leukemia

conducted retrospective analyses of the medical records of patients with chronic lymphocytic leukemia (CLL) to evaluate the relative value of computed tomography (CT) in assessing the response to therapy. Unlike the guidelines for assessing the response to therapy for most other types of non-Hodgkin’s lymphomas (NHL), the widelyused National Cancer Institute–sponsored Working Group (NCIWG) guidelines for patients with CLL do not incorporate use of CT scans in the response-assessment algorithm. 2 Nevertheless, CT scans increasingly are being used, not only to assess the response to treatment, but also for routine disease monitoring, a practice that has been largely discouraged. 3 In their study, Blum et al found that the use of CT scans, as per NHL response definitions, had little value over the established NCI-WG criteria for assessing the response of CLL patients to therapy or for predicting post-treatment progression-free survival. CLL is a systemic disease. Generally, lymphadenopathy detected at one anatomic site also can be found at other locations, giving rise to the notion that the disease can be followed by physical exam, the CBC, and other blood or marrow tests. However, a recent study published earlier in theJournal challenged this notion. 4 This study found that CT scans could help stratify patients with early, stage 0 disease into two groups that had significantly different risks for disease progression. Thirty-eight of 140 patients who were not found to have enlarged lymph nodes by physical exam (hence the stage 0 classification) were found to have enlarged lymph nodes by CT scan, albeit of less than 2 cm in diameter except in five patients. Surprisingly, 13 patients (9% of the total) also were found to have splenic enlargement on CT scan that was not appreciated by physical exam. 4 Patients who had evidence for lymph node enlargement in this study had a shorter time to initial treatment and poorer survival than did patients without detectable abnormalities on the CT scan. As such, this study challenged the notion that the physical exam for lymphadenopathy or splenomegaly can suffice for accurately staging patients with CLL. However, an important question that needs to be addressed is whether CT scans can improve on our ability to predict outcome when other diagnostic and laboratory studies are available. In the former study by Muntanola et al, 4 a significantly higher proportion of patients who had enlarged lymph nodes detectable only by CT scan also were found to have other known adverse prognostic indicators, such as leukemia cell expression of ZAP-70 or short lymphocyte-doubling times, than did patients without lymphadenopathy on CT evaluation. These other risk parameters also could delineate a subgroup of patients who had a relatively short median time from diagnosis to initial therapy independent of the results obtained by CT scans. In the retrospective study presented in this issue, Blum et al noted that achievement of either a complete response or partial response by NCI-WG criteria had a significant bearing on the ability to predict overall survival regardless of the results obtained via CT. Moreover, the NHL-CT assessment of response did not perform better than standard NCI-WG criteria in predicting the length of progression-free survival. More studies are needed to evaluate the relative value of CT scans in monitoring patients with CLL. The need for this is particularly apparent with the advent of therapy with alemtuzumab, an anti-CD52 monoclonal antibody with therapeutic efficacy in inducing complete responses in CLL that appears inversely proportional to the extent of lymphadenopathy, which more often is being assessed with CT scans before therapy. 5 Because of the need for further study, the upcoming revision in the guidelines for treatment-response assessment will suggest that CT scans be performed before and after treatment in clinical trials involving patients with CLL. The prospective analyses of the value of CT scans relative to that of other CLL-associated risk indicators in predicting outcome will be necessary before making recommendations to use, or not to use, CT scans in the routine clinical evaluation and monitoring of patients with this disease. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.

Addition of fresh frozen plasma as a source of complement to rituximab in advanced chronic lymphocytic leukaemia

A 59-year-old woman with a 12-year history of chronic lymphocytic leukaemia was sequentially treated with chlorambucil pulses, followed by ten cycles of fludarabine and cyclophosphamide for 5 years. Initially, protracted responses of up to 18 months were obtained of which the best was partial response according to the working group criteria of the National Cancer Institute. 1 Cheson BD Bennett JM Grever M et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996; 87: 4990-4997 PubMed Google Scholar However, during the final year of treatment the disease progressed, with severe malaise and marked B symptoms (eg, night sweats and weight loss) associated with massive lymphadenopathy and splenomegaly. Concentration of peripheral blood lymphocytes increased to 450×109/L and serum lactate dehydrogenase reached 2400 IU/L. This time the disease was resistant to regimens that contained fludarabine. Alemtuzumab was not yet approved for use in Israel at that time. The disease was also resistant to treatment with six cycles of rituximab combined with dose-modified cyclophosphamide, doxorubicin, vincristine, and prednisone-like chemotherapy (CHOP-R). Modest response was noted with the first four CHOP-R cycles, whereas two additional cycles yielded no lasting response. After the last cycle, complete blood count showed haemoglobin (Hb) concentration as 110 g/L, white blood cells (WBC) 180×109/L (92% lymphocytes), and platelets 200×109/L. However, within 8 weeks the patient deteriorated and showed no response to single agent rituximab. Her last blood count was Hb 90 g/L, WBC 458×109/L (450×109/L lymphocytes), and platelets 40×109/L. The patient was, therefore, assessed as having advanced and progressive disease, supported by the presence of massive peripheral lymph-node enlargement and hepatosplenomegaly (20 cm spleen confirmed by ultrasound). Peripheral blood smears, repeated immunophenotyping, and lymph node biopsy ruled out transformation into aggressive lymphoma (figure). Peripheral blood lymphocytes were positive for CD5, CD19, and CD23, and 40% were positive for CD38. They were negative for FMC7. The patient became catabolic and bed-ridden. She developed chronic culture-negative diarrhoea, which was diagnosed after colonoscopy and biopsy as specific involvement of the colon by chronic lymphocytic leukaemia. Allogeneic stem-cell transplantation was not feasible because no potential donor was available. (A) Bone marrow biopsy showing interstitial and nodular patterns of infiltration with small lymphocytes (arrow), characteristic of chronic lymphocytic leukaemia. (B) Lymph node biopsy showing diffuse nodal effacement and perinodal adipose tissue infiltration. Scattered small pale areas, representing proliferation centres, can also be seen (arrow), characteristic of lymph-node involvement by chronic lymphocytic leukaemia (haemotoxylin and eosin stain; ×40 magnification).

Eradication of Minimal Residual Disease in B-Cell Chronic Lymphocytic Leukemia After Alemtuzumab Therapy Is Associated With Prolonged Survival

To test whether eradication of minimal residual disease (MRD) in B-cell chronic lymphocytic leukemia (CLL) by alemtuzumab is associated with a prolongation of treatment-free and overall survival. Ninety-one previously treated patients with CLL (74 men and 17 women; median age, 58 years [range, 32 to 75 years]; 44 were refractory to purine analogs) received a median of 9 weeks of alemtuzumab treatment between 1996 and 2003. Regular bone marrow assessments by MRD flow cytometry were performed with the aim of eradicating detectable MRD (< 1 CLL cell in 10(5) normal cells). Responses according to National Cancer Institute-sponsored working group response criteria were complete remission (CR) in 32 patients (36%), partial remission (PR) in 17 patients (19%), and no response (NR) in 42 patients (46%). Twenty-two (50%) of 44 purine analog-refractory patients responded to alemtuzumab. Detectable CLL was eradicated from the blood and marrow in 18 patients (20%). Median survival was significantly longer in MRD-negative patients compared with those achieving an MRD-positive CR, PR, or NR. Patients achieving an MRD-negative CR had a longer treatment-free survival than patients with MRD-positive CRs, PR, or NR: MRD-negative CRs, not reached; MRD-positive CRs, 20 months; PRs, 13 months; NR, 6 months (P < .0001). Overall survival for the 18 patients with MRD-negative remissions was 84% at 60 months. Eight (47%) of the MRD-negative patients converted to MRD positivity at a median of 28 months. MRD-negative remission in CLL is achievable with alemtuzumab, leading to an improved overall and treatment-free survival.

National Cancer Institute-Sponsored Working Group Guidelines for Chronic Lymphocytic Leukemia: Revised Guidelines for Diagnosis and Treatment

N 1988, THE National Cancer Institute-sponsored Working Group (NCI-WC) on chronic lymphocytic leukemia (CLL) published guidelines for the design and conduct of clinical trials in CLL with two major objectives: first, to facilitate comparisons of results of clinical trials in CLL by providing standardized eligibility, response, and toxicity criteria; and, second, to encourage a framework on which to evaluate new scientific studies related to our increasing understanding of the biology and immunology of this disease.' These guidelines were rapidly adopted by the majority of the clinical trials community, and were also used by the Food and Drug Administration during its evaluation process for the approval of fludarabine. The differences between these guidelines and those subsequently published by the International Working Group on CLL (IWCLL), which were general-practice recommendations' are listed in Table 1. For diagnosis, the NCI-WC requires a lymphocyte count of 5 X loy& which is lower than the 10 X 109/L required by the IWCLL, unless the lymphocytes are B cells and the bone marrow is involved. To be considered a complete remission (CR), the NCI-WC criteria specify that less than 30% lymphocytes must be present in the bone marrow, with a recommendation that the clinical significance of lymphoid nodules be assessed prospectively (Table 1); the IWCLL allows focal infiltrates or nodules in the bone marrow aspirate and biopsy for CR. The IWCLL uses a shift in clinical stage as the sole index of partial remission (PR), whereas the NCI-WC provides more specific criteria and recommends validation of the relevance of stage shift. The major differences were the well-defined criteria in the NCI guidelines regarding when to initiate therapy, hematologic toxicity, and other important components for clinical trials design. The purpose of this report is to present those revisions as considered necessary in view of advances in the past 8 years. Many of these revisions evolved as the guidelines were used in a systematic fashion in large clinical trials and, also, with the experience following the use of newer, more effective agents, such as fludarabine.' Although this report will focus on those changes recommended by the NCI-sponsored CLL Working Group, it will include sufficient details from the original guidelines so that the reader would find it a complete document by itself without having to refer to the older version.