GALLIUM trial: the tortoise (rituximab) and the hare (obinutuzumab) race

Ricardo Garcı́a-Muñoz*,1, Judit Anton-Remirez2, Marı́a Josefa Nájera1, Elena Gutierrez-Gamarra3, Raisa Peralta1 & Jesús Feliu1 1Department of Hematology, Hospital San Pedro, Logroño, La Rioja, Spain 2Department of Physical Medicine & Rehabilitation, Complejo Hospitalario de Navarra, Pamplona, Spain 3Department of Hematology, Hospital Poniente, Almerı́a, El Ejido, Andalucı́a, Spain *Author for correspondence: rgmunoz@riojasalud.es


If we assume that bendamustine and CHOP are similar in CR rate, the question that arises is why can obinutuzumab not increase the CR rate in clinical trials if in vitro it is superior when compared with rituximab?
The first clue is that obinutuzumab needs a fit immune system to cause an effect; it especially depends on NK cells to induce an ADCC effect, but we and others have demonstrated that obinutuzumab itself induces depletion of NK cells after the first-dose infusion [7,8]. This fact evidently benefits the rituximab arm, because rituximab uses complement to act and has only a modest ADCC effect. This also may be the explanation for the results in the Phase II GAUSS study [3].
The second clue is that, surprisingly, several patients show low NK cell counts in peripheral blood and this 'immunologic pretreatment signature' is associated with inferior overall survival in patients with follicular lymphoma [11]. Again, this patient characteristic may hinder the action of obinutuzumab and benefit the rituximab arm, because complement-dependent cytotoxicity is not largely impaired in follicular lymphoma patients. Unfortunately, no information about NK cells or complement during the GALLIUM trial has been given [5].
The third clue is that chemotherapy, especially bendamustine, induces an important reduction of NK cells, again favoring the rituximab arm [12]. Despite this initial destruction of NK cells in the first cycle of obinutuzumabbendamustine, the combination may be of benefit to the patient by the initial first cycle NK-ADCC effect. Unfortunately, bendamustine also may be associated with increased risk of infections and severe adverse events [5,6]. We speculate that this NK cell destruction may be another explanation for the similar results in the CR rate of rituximab-bendamustine and obinutuzumab-bendamustine, because without this first obinutuzumab-NK-ADCC cycle, obinutuzumab plus bendamustine may be similar to a cycle of bendamustine alone when NK cells are too low to be efficient. Importantly, the benefit of bendamustine is a double-edged sword. Bendamustine may destroy CD4 + helper T cells that may support follicular lymphoma; however, it may diminish CD4 + T cells that may protect against infections and second neoplasms [5,6,12].
The fourth clue is that similar results in the CHOP arms indicate that after a first obinutuzumab-NK-ADCC effect, the next cycles lost the power of the obinutuzumab-induced ADCC effect [5,6]. However, the less potent action of rituximab is permanent in all the cycles, as we observe a similar balance after the end of induction treatment [5,6].
In summary, the low pretreatment NK cells seen in some patients with high-risk follicular lymphoma [2,11], the mechanism of action of obinutuzumab itself [1,2,7,8] and the influence of chemotherapy partners [5,6,8,12] benefit rituximab outcomes to the detriment of obinutuzumab.
At this point, induction immune-chemotherapy would be expected to obtain similar results with either obinutuzumab or rituximab combined with chemotherapy because rituximab arms are privileged. However, the conclusion of the GALLIUM study is that improved progression-free survival was observed for obinutuzumab plus chemotherapy [4][5][6]. Importantly, the most compelling rationale to recommend obinutuzumab over rituximab would be a 34% reduced risk of a progression event at 2 years [4][5][6]. We speculate that during maintenance treatment, some patients may recover their NK cells [8,12] and maintain better immune surveillance to destroy the residual tumoral cells that cannot be killed by immunochemotherapy induction more efficiently than rituximab [2]. Alas, this variable was not controlled during the GALLIUM study [5] and, in general, the perception is that the advantage of obinutuzumab over rituximab is small [6]. However, patient-derived expanded NK cells armed with obinutuzumab may be a reasonable therapeutic strategy and should be explored in a similar way to other clinical trials with lymphokine-activated cells (LAK cells) and rituximab (clinicaltrials.gov identifier NCT01329354) [13].
In conclusion, combination of obinutuzumab with NK cells may help optimize the potential of this novel anti-CD20 monoclonal antibody.
Author contributions R García-Muñoz, R Peralta and J Feliu were responsible for conception and design. Manuscript writing was undertaken by R García-Muñoz and J Feliu. All authors analyzed and interpreted the data of bibliography and approved the final version of the manuscript.

Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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