New Research on Combination Chemotherapy, Prognostic Biomarkers, and PET-guided Radiation Therapy in B-cell Malignancies 


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The 12th International Conference on Malignant Lymphoma was held June 19-22, 2013, in Lugano, Switzerland. Over 3,000 hematologists, clinical oncologists, pathologists, and leading researchers attended the meeting, which featured new research on B-cell malignancies, follicular lymphoma, as well as updated data on ibrutinib in chronic lymphocytic leukemia. The ASCO Post has selected several key abstracts for summary in the following roundup.

Biomarkers in Diffuse Large B-cell Lymphoma

In studies to identify prognostic factors in diffuse large B-cell lymphomas, Thierry J. Molina, MD, PhD, of Paris Descartes University, and colleagues assessed expression of MYC, BCL2, MYC/BCL2, IgM, and germinal center B-cell–like and non–germinal center B-cell–like subtypes in a large series of patients with de novo disease treated with rituximab (Rituxan) and anthracycline-based chemotherapy. Multivariate analysis showed that BCL2 overexpression and the non–germinal center B-cell–like subtype were significantly associated with poorer progression-free survival and overall survival.1

The study involved 670 patients with de novo CD20-positive diffuse large B-cell lymphoma enrolled in six GELA (Groupe d’Etudes des Lymphomes de l’Adulte) LNH-03 trials and stratified according to age and age-adjusted international prognostic index (IPI). Of these, 237 had received intensive R-ACVBP (dose-intensive rituximab plus doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) and 433 had received R-CHOP/R-mini-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). Tumor samples were analyzed by immunohistochemistry using CD10, BCL6, MUM1, MYC (40% threshold), BCL2 (70% threshold), and IgM antibodies on tissue microarrays.

Overall, 304 patients (45.4%) were classified as germinal center B-cell–like subtype and 366 (54.6%) as non–germinal center B-cell–like subtype according to the Hans algorithm. Tumors were positive for IgM in 52.4% of cases, 29.5% of cases were MYC-positive, 55.3% were BCL2-positive, and 21% were positive for BCL2/MYC coexpression.

Progression-free survival and overall survival were significantly worse among patients with high IPI score (P < .0001 for both progression-free and overall survival), non–germinal center B-cell–like subtype (P < .0001 for both), and IgM-positive (P < .0001 for progression-free survival, P = .02 for overall survival), MYC-positive (P < .001, P < .01), BCL2-positive (P < .001 for both), and MYC/BCL2-positive (P = .003, P = .005) tumors.

On multivariate analysis, in addition to IPI score, only BCL2 overexpression and non–germinal center B-cell–like subtype predicted significantly worse progression-free survival (P = .0002 and P = .002, respectively) and significantly worse overall survival (P = .03 and P = .002, respectively). The prognostic values of BCL2 (P = .002 for progression-free survival and P = .02 for overall survival) and non–germinal B-cell–like subtype (P = .002 for both progression-free survival and overall survival) were confirmed when analysis was limited to patients treated with R-CHOP.

The investigators concluded, “Our study confirmed the relevance of immunohistochemistry to identify significant prognostic biomarkers for clinical use. Above all, we fully validated the strong and independent prognostic value of the Hans algorithm, daily used by the pathologists to subtype diffuse large B-cell lymphoma, as well as BCL2 overexpression.”

Vitamin D Deficiency in B-cell Lymphoma

Vitamin D deficiency recently was shown to be associated with worse outcome in patients with non-Hodgkin lymphoma. To determine whether such an association exists in patients with aggressive B-cell lymphoma, Jörg T. ­Bittenbring, MD, of Saarland University Medical School, Germany, and colleagues in the German High-Grade Non-Hodgkin Lymphoma Study Group analyzed the relationship between serum vitamin D levels and outcome in elderly patients with diffuse large B-cell lymphoma receiving CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CHOP.2 The results were also reported earlier at the 2013 ASCO Annual Meeting in Chicago.3 Vitamin D deficiency was associated with significantly reduced event-free survival and overall survival in patients receiving R-CHOP and significantly reduced overall survival in those receiving CHOP.

In the study, 25-OH vitamin D serum levels were measured by chemoluminescence immunoassay in elderly patients receiving six or eight cycles of CHOP with or without rituximab. Of 359 patients, 193 (54%) had vitamin D deficiency (< 10 ng/mL) and 165 (46%) had vitamin D insufficiency (10–30 ng/mL).

Among patients receiving R-CHOP, those with vitamin D deficiency had 3-year event-free survival of 59% and 3-year overall survival of 70% compared with 79% and 82%, respectively, in patients without
vitamin D deficiency. In a multivariate analysis adjusting for IPI risk factors, these differences were significant for both event-free survival (hazard ratio [HR] = 2.1, P = .008) and overall survival (HR = 1.9, P = .040).

In multivariate analysis among patients receiving CHOP without rituximab, those with vitamin D
deficiency had a significantly poorer overall survival (HR = 1.8, P = .025) but not event-free survival (HR = 1.2, P = .388) compared with those with higher vitamin D levels. The results were confirmed in an independent validation set of 63 patients in the prospective RICOVER-no-Rx study.

As stated by the investigators, “Vitamin D deficiency is associated with a significantly worse outcome of patients with diffuse large B-cell lymphoma treated with R-CHOP. The stronger adverse effect of vitamin D deficiency in patients receiving rituximab suggests that vitamin D deficiency interferes with the mechanisms of action of this antibody. A prospective study evaluating the effects of vitamin D [supplementation] on outcome of patients receiving R-CHOP is warranted.”

Chlorambucil plus Rituximab in Extranodal Marginal Zone B-cell Lymphoma

The International Extranodal Lymphoma Study Group (IELSG)-19 trial is the largest randomized trial in extranodal marginal zone B-cell lymphoma conducted to date. As reported by Emanuele Zucca, MD, of the Oncology Institute of Southern Switzerland, and colleagues, preliminary final results of the trial indicate that the combination of chlorambucil (Leukeran) and rituximab resulted in improved event-free and progression-free survival compared with either agent alone although no differences in overall survival were observed.4

In the trial, patients with disseminated lymphoma or localized disease not suitable for local therapy were randomized to receive daily chlorambucil 6 mg/m2 for 6 weeks, with patients with response or stable disease receiving 6 mg/m2 daily for 14 consecutive days every 28 days for four cycles; intravenous rituximab 375 mg/m2 on days 1, 8, 15, 22, 56, 84, 112, and 140; or both.

The preliminary analysis included 393 patients with complete data, consisting of 130 patients in the chlorambucil group, 132 in the rituximab group, and 131 in the combination group. The primary site of lymphoma was the stomach in 43% of patients, lymph nodes were involved in 34%, 81% had low or low-intermediate International Prognostic Index scores, and 8% of patients had received prior local therapy.

With a median follow-up of 67 months, 5-year event-free survival, the primary endpoint of the trial, was 70% in the combination group compared with 52% in the chlorambucil group (P = .0005) and 51% in the rituximab group (P = .0015). Progression-free survival was also significantly longer in the combination group compared with the chlorambucil group (P = .0128) and the rituximab group (P = .0058). Overall survival was 90% at 5 years in the total population, with no significant differences between treatment arms. No unexpected severe side effects were reported. Hematologic toxicity was more pronounced in the combination group.

The investigators concluded, “This is the largest randomized study ever conducted in extranodal marginal zone B-cell lymphoma and is the first trial to compare chemotherapy vs rituximab and vs the combination of both. Longer event-free survival and progression-free survival were attained in the combination arm but this did not translate into improved overall survival.”

PET-guided Radiation in Patients with Advanced B-cell Lymphoma

Residual masses are often detected on post-therapy computed tomography (CT) scans in patients with diffuse large B-cell lymphoma, and the potential role of consolidative radiation therapy in such cases remains undefined. An analysis of the use of PET-guided radiation therapy presented by Laurie H. Sehn, MD, and colleagues from the British Columbia Cancer Agency indicated favorable outcomes with PET-guided radiation therapy in select patients.5

A policy has been in place in British Columbia (BC) since 2005 that recommends post-therapy PET evaluation for patients with advanced-stage diffuse large B-cell lymphoma who have residual masses > 2 cm on CT, with radiation therapy being administered to PET-positive sites when feasible. Patients with a negative PET scan are observed irrespective of initial or residual bulk, and patients who are PET-positive but not suitable for radiation therapy are treated according to physician discretion.

The BC Cancer Agency Lymphoid Cancer Database was used to identify all newly diagnosed patients with advanced-stage diffuse large B-cell lymphoma between January 2005 and February 2012 treated with curative-intent R-CHOP who underwent a post-therapy PET scan. Patients in complete remission on CT, HIV-infected patients, and patients with primary progressive disease, primary mediastinal large B-cell lymphoma, or transformed lymphoma were not included in the analysis.

A total of 262 patients were included in the analysis. Patients had a median age of 65 years, 60% were male, 69% had stage III/IV disease, 42% had a bulky site > 10 cm, and 48% had International Prognostic Index scores of 3 to 5. Of these patients, 167 (64%) were PET-negative, 82 (31%) were PET-positive, and 13 (5%) had indeterminate PET findings. Of the PET-positive patients, 60 (73%) received radiation therapy (30-45 Gy, 56 in single and four in multiple fields); of the 21 not receiving radiation therapy, 13 were not amenable to treatment, physicians decided against treatment in 7, and 2 had negative biopsy. One PET-negative patient received radiation therapy.

The median follow-up for living patients was 45 months. Relapse occurred in 10 of 60 PET-positive patients receiving radiation therapy, with in-field relapse occurring in 6. Four-year rates of freedom from progression and overall survival in PET-positive patients receiving radiation therapy (81% and 85%) were similar to those in PET-negative patients not  receiving radiation therapy (74% and 83%) and better than those in PET-positive patients not receiving radiation therapy (33% and 30%).

The investigators concluded, “Patients with advanced-stage diffuse large B-cell lymphoma with residual CT abnormalities after R-CHOP who receive consolidative radiation therapy to sites of PET positivity have an unexpectedly favorable outcome, strongly supporting the rationale for the use of PET-guided radiation therapy. Patients with PET-negative residual CT abnormalities also have a favorable outcome and should be spared unnecessary toxicity.”

Ibrutinib in CLL with 17p Deletion

The 17p deletion in chronic lymphocytic leukemia (CLL) is associated with worse outcome in patients receiving standard chemotherapy. The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has shown durable antitumor activity in high-risk CLL. In a phase II study of ibrutinib in patients who had CLL with 17p deletion, Adrian Wiestner, MD, PhD, of the National Institutes of Health, and colleagues found that that ibrutinib achieves rapid and durable control over disease and is associated with an acceptable safety profile.6

Findings were available for the first 29 patients in the trial, with a median follow-up of 9 months. In the trial, treatment-naive patients (n = 15, age range 33–82 years) and patients with relapsed/refractory CLL (n = 14, age range 56–79 years) received oral ibrutinib 420 mg daily until disease progression. High-risk disease (Rai stage III/IV) was present in 66% of patients.

At 6 months, 88% of 25 evaluable patients had a nodal response (70% median reduction in lymph node size), 48% had a partial response by International Workshop on CLL (IWCLL) criteria, and 40% had a partial response with lymphocytosis. One patient had progressive disease (presumed transformation). Nodal response was observed in 93% of the patients with relapsed/refractory disease and in 82% of treatment-naive patients.

The estimated event-free survival at 12 months was 90%. All patients exhibited a reduction in splenomegaly, with a median reduction in spleen volume of 446 mL (46%) from baseline. Bone marrow biopsy at 6 months in 23 patients showed a median 76% reduction from baseline in tumor burden as assessed by immunohistochemistry for CD79a. Fluorescence in situ hybridization measurement of percent of tumor cells with the 17p deletion at 6 months in 18 patients showed a reduction from baseline in 15 patients (median reduction, 55%), no change in 1, and an increase in 3
patients.

Treatment was well tolerated, with nonhematologic toxicities of grade 3 or higher observed in 14% of patients. Two deaths occurred during the study and were not considered treatment-related.

The investigators concluded, “Ibrutinib as a single agent is effective in both treatment-naïve and relapsed/refractory patients with 17p deletion CLL, achieving rapid control over disease in blood, nodes, spleen, and marrow that is durable with an acceptable safety profile. Ibrutinib will be further investigated as a strategy for these high-risk patients.” ■

Disclosure: Drs. Molina, Bittenbring, Zucca, Sehn, and Wiestner reported no potential conflicts of interest.

References

1. Molina TJ, Briere J, Copie-Bergman C, et al: Overexpression of MYC, BCL2, MYC/BCL2, IgM, and nongerminal centre B cell-like immunophenotype predicts a worse progression-free survival and overall survival in a series of 670 de novo diffuse large B-cell lymphomas: S LYSA study. 12th International Conference on Malignant Lymphoma. Abstract 178. Presented June 19, 2013.

2. Bittenbring JT, Achenbach M, Altmann B, et al: Inferior Outcome of elderly DLBCL patients with 25-OH vitamin D deficiency treated with CHOP plus rituximab: Results of the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). 12th International Conference on Malignant Lymphoma. Abstract 103. Presented June 20, 2013.

3. Bittenbring JT, Achenbach M, Altmann B, et al: Association of 25-OH vitamin D deficiency with worse outcome for elderly patients with aggressive B-cell lymphomas treated with CHOP plus rituximab (R): An analysis of the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). 2013 ASCO Annual Meeting. Abstract 8569. Presented June 2, 2013.

4. Zucca E, Concini A, Martinelli G, et al: Chlorambucil plus rituximab produces better event-free and progression-free survival in comparison with chlorambucil or rituximab alone in extranodal marginal zone B-cell lymphoma (MALT lymphoma): Final results of the IELSG-19 study. 12th International Conference on Malignant Lymphoma. Abstract 007. Presented June 19, 2013.

5. Sehn LH, Klasa R, Shenkier T, et al: Long-term experience with PET-guided consolidative radiation therapy in patients with advanced-stage diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP. 12th International Conference on Malignant Lymphoma. Abstract 123. Presented June 21, 2013.

6. Wiestner A, Farooqui M, Valdez J, et al: Single agent ibrutinib (PCI-32765) is highly effective in chronic lymphocytic leukaemia patients with 17p deletion. 12th International Conference on Malignant Lymphoma. Abstract 008. Presented June 19, 2013.



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