ASH Clinical News November 2016 | Page 37

CLINICAL NEWS

Patients with chronic lymphocytic leukemia ( CLL ) who achieved a complete remission after treatment with chemoimmunotherapy may still have residual disease that could lead to disease relapse . Post-treatment minimal residual disease ( MRD ) negativity has been demonstrated to have prognostic significance in these patients , but the long-term benefit of MRD-negative status and its relevance in the relapsed / refractory setting is unclear .

In a retrospective study published in Blood , Marwan Kwok , MD , of the Hematological Malignancy Diagnostic Service in the Department of Haematology at St . James ’ University Hospital in Leeds , United Kingdom , and authors assessed the long-term prognostic value of MRD status across different therapeutic settings in 133 patients with CLL . According to the results , MRD negativity was associated with both prolonged progression-free survival ( PFS ) and overall survival ( OS ).

“ Our results demonstrate the longterm benefit of achieving MRD negativity , regardless of the therapeutic setting and treatment modality , and support its use as a prognostic marker for long-term PFS and as a potential therapeutic goal in CLL ,” the authors wrote .

Dr . Kwok and colleagues enrolled patients who completed treatment for CLL between 1996 and 2007 at St . James ’ University Hospital , achieved at least a partial response ( PR ), and received a bone marrow MRD assessment within six months of treatment completion . Patients were excluded from the analysis if they failed to respond or died before treatment completion or received an allogeneic hematopoietic cell transplant ( as graft-versus-leukemia effect can lead to continued elimination of residual disease ). MRD was assessed via multiparameter flow cytometry .

Of the 133 patients included in the analysis , 67 received combination chemotherapy or chemoimmunotherapy , 31 received single-agent chemotherapy , seven underwent autologous hematopoietic cell transplantation , and 28 received chemotherapy-free regimens , mostly with monoclonal antibody therapy . Fifty-seven patients had not previously received treatment for CLL , while the remaining 76 patients had received a range of one to seven prior therapies .

Forty-one percent of patients ( n = 55 ) were MRD-negative post-treatment ( defined as < 1 CLL cell detectable per 10 4 leukocytes , or < 0.01 %), including 46 with complete remission with incomplete blood count recovery ( CRi ) and nine with PR / nodular PR . After a median follow-up of 10.1 years ( range = 7.8-18.6 years ), the median PFS was ( p < 0.001 ):

• 7.6 years for MRD-negative patients

• 3.3 years for patients with 0.01-1 % MRD positivity

• 2 years for patients with > 1 % MRD positivity

The median OS was also higher in patients who achieved MRD-negative status ( p < 0.001 ):

• 10.6 years for MRD-negative patients

• 5.3 years for patients with 0.01-1 % MRD positivity

• 3.6 years for patients with > 1 % MRD positivity

When MRD response was considered together with established prognostic factors including age , Binet stage , cytopenias , prior treatment , adverse cytogenetics evaluated at the time of treatment , treatment modality , and International Workshop on CLL response , MRD negativity was the only factor to predict both longer PFS ( hazard ratio [ HR ] = 2.07 ; 95 % CI 1.59-2.69 ; p < 0.001 ) and OS ( HR = 1.39 ; 95 % CI 1.13-1.70 ; p = 0.002 ).

For patients who achieved MRD-negativity , adverse cytogenetics was predictive of longer PFS ( HR = 2.00 ; 95 % CI 1.16-3.45 ; p = 0.013 ); age ( HR = 2.41 ; 95 % CI 1.45- 4.00 ; p = 0.001 ); disease stage ( A or B vs . C ; HR = 2.23 ; 95 % CI 1.14-4.33 ; p = 0.018 ); and prior treatment ( yes or no ; HR = 2.61 ; 95 % CI 1.61-4 / 23 ; p < 0.001 ) were predictive of OS .”

Overall , Dr . Kwok and co-authors found that patients receiving both frontline and subsequent treatments derived a significant survival benefit from achieving MRD-negative status . However , they added that greater long-term benefit was observed when MRD negativity was achieved upfront . For patients who achieved MRD-negative status with the first agent they received , 10-year PFS was 65 percent , versus 10 percent for those who were still MRD-positive ( p < 0.001 ), and 10-year OS was 70 percent versus 30 percent ( p < 0.001 ), respectively . In the relapsed / refractory setting , 10-year PFS was 30 percent versus 0 percent , respectively , and 10-year OS was 74 percent versus 11 percent , respectively ( p values not provided ).

For the 23 patients who achieved upfront MRD negativity , the PFS curve appeared to plateau at 7.7 years , and no clinical relapse was observed among the 52 percent ( n = 12 ) who remained in remission . The authors also found that patients with del ( 17p ) and del ( 11q ) mutations who achieved MRD negativity appeared to partially overcome the poor prognosis of these mutations , “ suggesting that targeting MRD may potentially be of value in this patient group ,” they wrote .

“ At present , MRD negativity is achieved predominantly through chemotherapycontaining regimens with considerable toxicity , thus precluding its use in frailer CLL patients ,” Dr . Kwok and colleagues concluded . “ Newer agents such as venetoclax can also produce MRD negativity in substantial proportions of CLL patients , including in individuals with del ( 17p ).”

The study is limited by its retrospective design , and the need to validate prospectively the prognostic significance of MRD with novel treatments . In addition , MRD assessment would need to be standardized . “ In the future , chemotherapy-free combinations may potentially allow MRD eradication with minimal toxicity , making MRD negativity a feasible therapeutic goal ,” the authors concluded .

REFERENCE

Kwok M , Rawstron AC , Varaghese A , et al . Minimal residual disease is an independent predictor for 10-year progression-free and overall survival in CLL . Blood . 2016 October 3 . [ Epub ahead of print ]

As is the case with Epstein-Barr virus , hepatitis C virus ( HCV ) infection has been linked to the development of B-cell lymphoproliferative disorders , and the prevalence of HCV is higher in patients with B-cell non-Hodgkin lymphoma ( NHL ) than in the general population , leading researchers to question whether treatments for HCV could induce a hematologic response in patients with B-cell lymphoproliferative disorders .

In a retrospective study published in Blood , Luca Arcaini , MD , of the Department of Molecular Medicine at the University of Pavia Medical School in Italy , and authors examined whether direct-acting antiviral ( DAA ) therapies for HCV ( which have been shown to induce viral eradication in more than 90 % of HCV patients and to be safer and more tolerable than interferon-based antiviral therapies ) led to a hematologic overall response rate ( ORR ; based on response criteria from the Lugano Classification and the International Workshop on CLL ) of 67 percent of patients co-infected with HCV and indolent lymphoproliferative disorders .

“[ Based on these results ], indolent lymphomas associated with

TABLE 2 . Hematologic Response Rates

Complete response

All patients ( n = 46 ) 12 ( 26 %)

Partial response

19 ( 41 %)

Stable disease

11 ( 24 %)

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