The Prognostic Value of IgH Clonality in Bone Marrow with Negative Pathology in B Cell Lymphoma
Authors: Toyama Kazuhiro , Tsukamoto Ayato , Yamazaki Sho , Nakamura Fumihiko , Kurokawa Mineo 
Published: October 2019

Abstract
Background
Bone marrow infiltration is widely accepted as an important prognostic factor in malignant lymphomas. Although multiplex polymerase chain reaction for the detection of clonal immunoglobulin heavy chain (IgH) gene rearrangements is a helpful tool for the confirmation of minimal infiltration in B cell lymphomas, it has not been elucidated that IgH clonality of the bone marrow at the initial evaluation is a valuable prognostic factor and a predicting marker for the initial therapy in the patients with B cell lymphomas who had a bone marrow biopsy with negative pathology.
Methods
All patients with DLBCL (n=61) and indolent B cell non-Hodgkin's lymphomas (iB-NHL) including FL, MCL and MALT lymphoma (n=51) who had a bone marrow biopsy and a bone marrow IgH clonality obtained at diagnosis in our institute it the period between March 2002 and 2016 were included in this study. The clinical information including the overall survival (OS), progression free survival (PFS), laboratory findings, backgrounds, and the response to the first line therapy were collected from the clinical charts.
Result
Bone marrow infiltration by pathological examination was reported in 20% (12/61) of DLBCL patients and in 24% (12/51) of iB-NHL patients (Path-pos group). In the patients with negative pathological report, 21% of the DLBCL patients (13/61) and 33% of the iB-NHL patients (17/51) were positive bone marrow involvement by PCR (Path-neg/PCR-pos group). The other 59% of the DLBCL patients (36/61) and 43% of the iB-NHL patients (22/51) were negative bone marrow involvement by both pathological examination and PCR (Path-neg/PCR-neg group).
In DLBCL cohort, the 5-year OS rates in Path-pos, Path-neg/ PCR-pos, and Path-neg/ PCR-neg groups were 46.9% (95% CI, 13.2% to 75.3%), 92.3% (95% CI, 56.6% to 98.9%), and 85.5% (95% CI, 68.7% to 93.7%), respectively (p=0.0735). The 5-year PFS rates in Path-pos, Path-neg/PCR-pos, and Path-neg/PCR-neg group were 33.3% (95% CI, 10.3% to 58.8%), 76.9% (95% CI, 44.2% to 91.9%), and 71.1% (95% CI, 52.9% to 83.3%), respectively (p=0.0331). There were no significant difference between Path-neg/ PCR-pos group and Path-neg/ PCR-neg group in the 5-year OS and PFS rates (p=0.698). In DLBCL patients, the positivity of pathological examination of bone marrow was identified as a valuable prognostic factor, but the positivity of PCR was not a prognostic factor.
In iB-NHL cohort, the 5-year OS rates in Path-pos, Path-neg/PCR-pos, and Path-neg/PCR-neg groups were 77.5% (95% CI, 44.8% to 92.3%), 100% (95% CI, 100% to 100%), and 94.4% (95% CI, 66.6% to 99.2%), respectively (p=0.114). The 5-year PFS rates in Path-pos, Path-neg/PCR-pos, and Path-neg/PCR-neg group were 45.7% (95% CI, 17.3% to 70.5%), 46.8% (95% CI, 19.6% to 70.2%), and 87.1% (95% CI, 57.3% to 96.6%), respectively (p=0.152). There were almost no difference between Path-pos, Path-neg/PCR-pos, and Path-neg/PCR-neg group in the 5-year OS rate, but the 5-year PFS rate in Path-pos and Path-neg/PCR-pos group tend to be lower than in Path-neg/PCR-neg group (p=0.0641 and p=0.0891, respectively). In iB-NHL cohort, in addition to the positivity of pathological examination, the positivity of PCR is possible to be a prognostic factor.
Univariate analysis of PFS in pathology negative patients in iB-NHL revealed that performance status was a significant prognostic factor, and IgH clonality also seemed to be a prognostic factor. Multivariate analysis of PFS in pathology negative patients in iB-NHL showed that there was no significant independent risk factor.
In the response to the first line therapy in DLBCL cohort, the rate of complete response in Path-pos, Path-neg/PCR-pos, and Path-neg/PCR-neg groups were 83.3%, 90.9%, and 80.0%, respectively (p=0.8871). In iB-NHL cohort, the rate of complete response were 60.0%, 71.4%, and 82.4%, respectively (p=0.4623). In each cohort, there were no difference between each groups in overall response rate and complete response rate.
Conclusion
Positive IgH clonality with negative pathology in bone marrow is a valuable prognostic factor for PFS at diagnosis in the patients with iB-NHL.

Disclosures
Kurokawa: Eizai: Research Funding; MSD: Honoraria, Research Funding; Chugai Pharmaceutical: Research Funding; Teijin Pharma: Research Funding; Takeda Pharmaceutical: Research Funding; Pfizer: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Research Funding; Sumitomo Dainippon Pharma: Research Funding; Nippon Sinyaku: Honoraria, Research Funding; Otsuka Pharmaceutical: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding.